Unexplained Fever

A guide to the diagnosis and management

of febrile states in medicine, surgery,
pediatrics, and subspecialties

Editor-in-Chief
Benedict Isaac
lchilov Hospital
Tel Aviv Medical Center
Tel Aviv, Israel

Associate Editors
Serge Kernbaum
Consultant in Internal Medicine and Infectious Diseases
American Hospital of Paris
Paris, France

Michael Burke
Lecturer in Medicine
Sackler School of Medicine
Senior Consultant in Internal Medicine and Immunology
Tel Aviv Medical Center
Tel Aviv, Israel

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ISBN-13: 978-0-8493-4556-2 (hbk)

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Library of Congress Card Number 90-2484

Library of Congress Cataloging-in-Publication Data

Unexplained fever: a guide to the diagnosis and management of febrile

states in medicine, surgery, pediatrics, and subspecialties/
Benedict Isaac editor-in-chief; Serge Kernbaum, associate editor,
Michael Burke, associate editor.
p. cm.
Includes bibliographical references
Includes index.
ISBN 0-8493-4556-1
I. Fever. I. Isaac, Benedict. II. Kembaum, S. III. Burke,
Michael, 1942-
[DNLM: I. Fever of Unknown Origin. WB 152 U56]
RBl29.U54 1991
616' .047--dc20
DNLM/DLC
for Library of Congress 90-2484
CIP
 PREFACE

Persistent, undiagnosed fever is currently one of the most frequently encountered reasons
for patient consultation. Assessment of the actual characteristics of fever and its accompa-
nying symptoms, together with accurate interpretation of clinical data and selection of
appropriate investigations, require a particularly astute sense of clinical awareness.
This special quality, refined with a varied and long-standing experience, is all the more
critical for a publication dedicated to the febrile condition. These strengths are drawn together
by the authors of this book, Benedict Isaac, Serge Kembaum, and Michael Burke. All three
are internists and are leading figures in the field of infectious diseases. Furthermore, they
have already researched a number of aspects concerning undiagnosed fevers.
Benedict Isaac is Honorary Clinical Investigator at the Tel Aviv Medical Center, Serge
Kembaum, M.D. is a Consultant in the field of Internal and Infectious Diseases at the
American Hospital in Paris, and Michael Burke, M.D., B.S. is Senior Consultant in the
Department of Medicine and Immunology at the Tel Aviv Medical Center.
The book is divided into six sections. The first section highlights a range of routine
problems and particularly the semiologic analysis of fever and its pathophysiology. A sub-
chapter focuses on the examination procedures tailored to the febrile patient.
The following section seeks to provide precise explanations to all the possible disorders
linked to undiagnosed fever with special reference to the cardiovascular, respiratory, gas-
trointestinal, hepatobiliary, and pancreatic systems.
The third section of the book may appear less homogeneous to the reader, but by the
very nature of the subject, it is impossible to neatly assign identified and emerging conditions
to distinct, clear-cut categories. In this section, the authors describe iatrogenic fevers, fevers
observed in autoimmune disease, and fevers of bacterial, viral, or fungal origin. The subject
of fever in immunosuppressive states and in patients returning from tropical regions are also
discussed in detail.
The fourth section presents the problems of fever in urologic, gynecologic, obstetric,
and general surgery.
In the fifth section the reader is given answers to problems concerning fever in the
pediatric and geriatric patient.
The book continues with an inventory of biological examinations and technical methods,
and advice on optimum choices for in-depth investigation.
The last chapter concentrates on the therapeutics of the febrile condition.
It is rare and indeed a pleasure to find a book of this volume and pedagogical value
dedicated to a subject so frequently encountered and one currently breaking exciting new
ground. I am sure it will provide physicians with a wealth of information and the long-
awaited key to the mysteries of the febrile condition.

Professor R. F. Bastin
Académie Nationale de Médecine
Paris
February 1990
 THE EDITORS
Benedict Isaac, M.D., obtained his training at the University of Bucharest, Romania.
After completing residency at the Colentina Hospital, Bucharest, under the supervision of
Prof. Lupu, he received his specialty degree in Internal Medicine. He served as Assistant
Professor at the Infectious Disease Clinic at this Hospital. Subsequently, he served as
“ Physician in Chief’’ at the “ Victor Babes’’ Hospital of Infectious Disease. After moving
to Israel, he became Consultant Specialist in Internal Medicine at the Federation of Workers’
Health Fund. He has been a Visiting Associate at the Infectious Diseases Clinic at the Claude
Bernard Hospital, Paris. Recently he has served as Honorary Clinical Investigator at the
Department of Medicine, Tel Aviv Medical Center.
Dr. Isaac has written extensively on infectious diseases as well as other fields in Internal
Medicine. His paper on “ Prolonged Unexplained Fevers’’ in La Nouvelle Presse Medicale
has been widely read and has been translated into Spanish. Dr. Isaac has written a book on
Human Brucellosis. He is a recipient of an Award by the Council for Research and Devel-
opment of Israel for research into the problem of Fever of Unknown Origin. He is a member
of the Israel Society of Internal Medicine and the New York Academy of Sciences.

Serge Kernbaum, M.D., is a Consultant in Internal Medicine and Infectious Diseases

in the American Hospital of Paris, Attaché des Hôpitaux de Paris and has a private practice
in Internal Medicine.
Dr. Kernbaum was Interne des Hôpitaux de Paris in 1965. He was a specialist in
Immunology in 1968, he graduated in Paris (Faculté Bichat-Beaujon) in 1971 and was Chef
de Clinique — Assistant des Hôpitaux de Paris from 1971 to 1978. Dr. Kernbaum is
Corresponding Fellow of the Infectious Diseases Society of America, is membre de la Société
de Pathologie Infectieuse de Langue Française and is member of the American Society of
Microbiology. Dr. Kernbaum has presented over 30 invited lectures at International Meetings
and over 20 invited lectures at National Meetings. He has published more than 150 research
papers, as well as one book devoted to Infectious Diseases (in French) and one medical
dictionary (in French). His current major research interest includes clinical research in Internal
Medicine and Opportunistic Infections.

Michael Burke, M. B. B. S., obtained his training at the University of Melbourne,

Victoria, Australia. After moving to Israel, he completed a residency at the Tel Aviv Medical
Center and he received his specialty degree in Internal Medicine. He has served as Senior
Physician and subsequently as Associate Director of the Department of Medicine at this
Hospital. He currently serves as Senior Consultant in Immunology at this Institution.
Dr. Burke served as a Fellow in Immunology at the Children’s Hospital Medical Center,
Harvard Medical School, Boston, Massachusetts during the years 1976— 1978. He is a
Lecturer in Internal Medicine at the Tel Aviv University Sackler Medical School and a
member of the Examinations Committee in Internal Medicine at the faculty. He has been
actively involved in clinical teaching of students at this University for many years. In 1986,
he underwent a sabbatical as Associate in the Department of Immunology and Allergy at
the Albert Einstein College of Medicine, New York.
His particular interests include Fever of Unknown Origin, Immune Deficiency, and
Autoimmune Diseases. He is a member of the Israel Society of Internal Medicine and the
Israel Society of Immunology and Allergy.
 ACKNOWLEDGMENT

The editors gratefully acknowledge the assistance of their colleagues all over the world.
A particular mention is forthcoming to the following physicians: Prof. Dan Michaeli, Di-
rector-General of the Tel Aviv Souraski Medical Center, Israel for his encouragement and
advice, Prof. R. F. Bastin of the French National Academy of Medicine for his magnanimous
gesture to undertake the writing of a preface for this work, Prof. Louis Weinstein of Harvard
University, Boston, Massachusetts and Prof. Sheldon Wolff of Tufts University, Boston,
Massachusetts for their support and helpful criticism, Prof. G. Winckelmann of the Deutsche
Klinik fur Diagnostik, Wiesbaden, Germany and Dr. J. M. Gonzalez Lahoz of Hospital
Nacional de Enfermedades Infecciosa, Madrid, Spain for supplying valuable data and ap-
propriate reference materials.
 DEDICATION

To my three grandsons
Vivian, Michael, and Yair Stemmer
with the wish that they should continue
the tradition of our family:
the love of learning and teaching

Benedict Isaac, M.D.

To my wife

Serge Kembaum, M.D.

To my dear wife, parents, and children,

for their inspiration and encouragement

Michael Burke, M.B.B.S.

 CONTRIBUTORS

Isac Alteras Michael Burke

Associate Professor of Dermatology Lecturer in Medicine
Tel Aviv University Tel Aviv University
Director, Department of Dermatology Sackler School of Medicine
Beilinson Medical Center Senior Consultant in Medicine and
Petach Tikva, Israel Immunology
Tel Aviv Medical Center
Tel Aviv, Israel
Ami Ballin
Lecturer, Pediatrics and Hematology Guy Charmot
Tel Aviv University Emeritus Professor of Medicine
Sackler School of Medicine Health Services of the French Army
Senior Staff Physician Hospital Claude Bernard
Department of Hematology Paris, France
Edith Wolfson Hospital
Holon, Israel Jacob R. Cohen
Registrar
Eliezer Bar-Natan Department of Obstetrics and
Gynecology
Director
Tel Aviv Medical Center
Department of Psychiatry
Tel Aviv, Israel
Tel Aviv Medical Center
Tel Aviv, Israel
Menahem Fainaru
Professor of Medicine
Jack M. Baron Tel Aviv University
Director Sackler School of Medicine
Department of Nuclear Medicine Director, Department of Medicine A
Tel Aviv Medical Center Beilinson Hospital
Tel Aviv, Israel Petach Tikva, Israel

Natan Gadoth
Amos Ber Professor of Neurology
Senior Registrar Tel Aviv University
Department of Obstetrics and Sackler School of Medicine
Gynecology B Deputy Director
Tel Aviv Medical Center Department of Neurology
Tel Aviv, Israel Beilinson Medical Center
Petach Tikva, Israel

Stephen A. Berger Ygal Gilboa

Associate Professor of Medicine Associate Professor of Medicine
Tel Aviv University Tel Aviv University
Sackler School om Medicine Sackler School of Medicine
Director Director, Department of Medicine B and
Department of Microbiology Endocrinologic Clinic
Tel Aviv Medical Center Asaf Harofe Hospital
Tel Aviv, Israel Zerifin, Israel
A. Golan Shaul Z. Margaliot
Senior Registrar Senior Physician
Department of Obstetrics and Department of Medicine E
Gynecology Chaim Shiba Medical Center
Asaf Harofe Hospital Tel Hashomer, Israel
Zerifin, Israel
Charlotte Merdler
David Goldray
Instructor in Medicine
Instructor in Medicine
Tel Aviv University
Tel Aviv University
Sackler School of Medicine
Sackler School of Medicine
Deputy Director, Department of
Director, Department of Geriatrics B
Geriatrics B
Tel Aviv Medical Center
Tel Aviv Medical Center
Tel Aviv, Israel
Tel Aviv, Israel
Anna Hazani
Senior Physician Ephraim Merimsky
Hematology Unit Senior Lecturer in Urology
Rambam Medical Center Tel Aviv University
Haifa, Israel Sackler School of Medicine
Senior Physician
Elisabeth Horer Department of Urology
Clinical Instructor in Endocrinology Tel Aviv Medical Center
Tel Aviv University Tel Aviv, Israel
Sackler School of Medicine
Senior Physician Dina Meytes
Department of Endocrinology Associate Professor of Medicine and
Tel Aviv Medical Center Hematology
Tel Aviv, Israel Tel Aviv University
Sackler School of Medicine
Theodore C. Iancu Director, Department of Hematology
Associate Professor of Pediatrics Edith Wolfson Hospital
Technion Israel Institute of Technology Holon, Israel
Faculty of Medicine
Director of Department of Pediatrics and
Pediatric Research Jacob Schächter
Carmel Hospital Instructor in Medicine
Haifa, Israel Tel Aviv University
Sackler School of Medicine
Benedict Isaac Senior Physician
Honorary Clinical Investigator Department of Oncology
Ichilov Hospital Beilinson Hospital
Tel Aviv Medical Center Petach Tikva, Israel
Tel Aviv, Israel
David Schlossberg
Serge Kernbaum Director of Medicine
Consultant in Internal Medicine and Episcopal Hospital
Infectious Diseases Professor of Medicine
American Hospital of Paris The Medical College of Pennsylvania
Paris, France Philadelphia, Pennsylvania
Yardena Siegmann-Igra Jona Stadler
Lecturer in Medicine Senior Lecturer in Surgery
Tel Aviv University Tel Aviv University
Sackler School of Medicine Sackler School of Medicine
Director, Infectious Diseases Unit Deputy Director
Tel Aviv Medical Center Department of Surgery
Tel Aviv, Israel Tel Aviv Medical Center
Tel Aviv, Israel
Albert Solomon
Professor of Radiology and Organ Hartley Stern
Imaging Assistant Professor of Surgery
Tel Aviv University University of Toronto
Director, Department of Radiology and Consultant Surgeon
Organ Imaging Mt. Sinai Hospital
Tel Aviv Medical Center Toronto, Ontario, Canada
Tel Aviv, Israel
 TABLE OF CONTENTS
Part I
GENERAL ASPECTS OF FEVER

Chapter 1
Introduction — Definition of Unexplained Fever, History of Fever,
Statistical Data, Classification.............................................................................................. 1
B. Isaac, S. Kernbaum, and M. Burke

Chapter 2
The Anatomy and Physiology of Normal Thermoregulation.............................................. 15
N. Gadoth

Chapter 3
Pathophysiology of F ever.................................................................................................... 23
C. Merdler and M. Burke

Chapter 4
Thermometry......................................................................................................................... 33
M. Burke and C. Merdler

Chapter 5
Approach to the Febrile Patient...........................................................................................39
B. Isaac

Part II
UNEXPLAINED FEVER ASSOCIATED WITH DISEASES OF ORGAN SYSTEMS

Chapter 6
Fever in Diseases of the Cardiovascular System................................................................63
M. Burke and B. Isaac

Chapter 7
Fever in Respiratory Diseases........................................................................................... 85
S. Z. Margaliot

Chapter 8
Unexplained Fever Associated with Diseases of the Gastrointestinal Tract................... 101
B. Isaac and M. Burke

Chapter 9
Diseases of the Hepatobiliary Tree and Pancreas Associated with Fever...................... 125
B. Isaac and M. Burke

Chapter 10
Unexplained Fever in Neurological Disorders..................................................................157
N. Gadoth

Chapter 11
Unexplained Fever Associated with Musculoskeletal Disorders...................................... 173
S. Kernbaum
Chapter 12
Unexplained Fever in Hematologic Disorders: Section 1 — Benign
Hematologic Disorders...................................................................................................... 189
A. Hazani and B. Isaac

Chapter 13
Unexplained Fever in Hematologic Disorders: Section 2 — Malignant
Hematologic Disorders.......................................................................................................209
D. Meytes and A. Ballin

Chapter 14
Fever in Endocrinologie Disorders....................................................................................225
Y. Gilboa, E. Horer, and B. Isaac

Chapter 15
Fever in Inherited and Metabolic Disorders..................................................................... 235
M. Fainaru

Chapter 16
Unexplained Fever Associated with Cutaneous Manifestations....................................... 243
I. Altéras

Part III
ENVIRONMENTAL AND BIOLOGIC CAUSES OF UNEXPLAINED FEVER

Chapter 17
Iatrogenic and Occupational Fever....................................................................................261
D. Schlossberg

Chapter 18
Unexplained Fever Associated with Hypersensitivity and Auto-immune Diseases........275
S. Kernbaum

Chapter 19
Unexplained Fever in Infectious Diseases: Section 1 — Viruses, Chlamydia,
Mycoplasma, Rickettsiae, Higher Bacteria, Cell-Wall Deficient Bacteria,
and Fungi............................................................................................................................299
S. Kernbaum

Chapter 20
Unexplained Fever in Infectious Diseases: Section 2 — Commonly Encountered
Aerobic, Facultative Anaerobic, and Strict Anaerobic Bacteria, Spirochetes,
and Parasites.......................................................................................................................327
B. Isaac

Chapter 21
Unexplained Fever in the Immunocompromised Patient 355
S. Kernbaum
Chapter 22
Unexplained Fever in Patients Returning from the Tropics Including U.F.
Associated with Hypereosinophilia.................................................................................... 365
G. Charmot and S. Kernbaum

Chapter 23
Fever in Oncology............................................................................................................... 381
J. Schacter

Chapter 24
Fever of Unexplained Origin — Psychiatric Aspects....................................................... 385
E. Bar-Natan

Chapter 25
Miscellaneous Causes of Unexplained Fever.................................................................... 393
S. Kernbaum

Part IV
UNEXPLAINED FEVER IN SURGERY

Chapter 26
Surgical Aspects of Fever.................................................................................................. 407
J. Stadler, H. Stern, and J. Bohnen

Chapter 27
Unexplained Fever in Urology....................................................................................415
E. Merimsky

Chapter 28
Unexplained Fever in Gynecology...............................................................................435
J. R. Cohen, M. Burke, and A. Ber

Chapter 29
Unexplained Fever in Obstetrics..................................................................................445
A. Ber, A. Golan, and J. R. Cohen

Part V
UNEXPLAINED FEVER AT DIFFERENT AGES

Chapter 30
Unexplained Fever in the Pediatric Age Group................................................................457
T. C. Iancu

Chapter 31
Unexplained Fever in Geriatrics........................................................................................473
M. Burke, C. Merdler, and D. Goldrey

Part VI
DIAGNOSTIC PROCEDURES AND MANAGEMENT OF UNEXPLAINED FEVER

Chapter 32
Laboratory Diagnostic Tests in the Evaluation of Fever................................................. 481
S. A. Berger
Chapter 33
System Imaging in Unexplained Fever............................................................................ 495
A. Solomon and J. Baron

Chapter 34
Treatment............................................................................................................................505
Y. Siegmann-Igra

INDEX.................................................................................................................................517
Part I
General Aspects of Fever
 1

Chapter 1

INTRODUCTION — DEFINITION OF UNEXPLAINED FEVER,

HISTORY OF FEVER, STATISTICAL DATA, CLASSIFICATION

B. Isaac, S. Kernbaum, and M. Burke

INTRODUCTION

Fever is only a symptom or sign of disease, although it is important enough to direct

the clinician to find its cause in order to diagnose and treat the condition without delay. In
some disorders fever is such a prominent manifestation that the condition is named in relation
to certain characteristics of the fever. These may be infections, such as relapsing fever,
undulant fever, and spotted fevers, or noninfectious diseases, including drug fever, and
familial Mediterranean fever. The onset of fever is variable. It may occur de novo in a
previously healthy individual, as a complication of a nonfebrile disorder, or be superimposed
upon the compromised host. Fever may occur at all ages from the preterm neonate to the
very old. Until a diagnosis is made, the physician does not know whether the cause is serious
or trivial. Certain fever patterns have been described, yet none of these is entirely specific
for any particular clinical entity. Although some form of standardization of approach is
necessary, it must be appreciated that each febrile patient has his own particular facets which
must be considered in the clinical work-up.
When evaluated initially, fever may appear to be due to a clinically obvious, known,
certain, determined, or explained source, or conversely, the cause may be obscure,
unknown, uncertain, undetermined, or unexplained. The latter group includes FUO14
(fever of unexplained, unknown, or undetermined origin), in which the fever generally lasts
at least 2 or 3 weeks.2 In a subgroup called prolonged FUO, the duration of fever is usually
6 months or more.5 However, there remains quite a considerable group of patients with
potentially lethal conditions that have been largely ignored by authors because the duration
of unexplained fever is less than 2 to 3 weeks. Inadvertently the impression has been created
that these patients usually have “ short-lived” or “ self-limited” conditions and will recover
without the need for carrying out an extensive work-up in order to reach a precise diagnosis.
This view may lead to unfortunate consequences, which may be fatal in cases such as spotted
fever without spots,6,7 and systemic herpes simplex infection,8,9 or may result in increased
morbidity because of a delay in diagnosis and appropriate therapy. We feel that these patients
cannot be bypassed with a “ wait and see” attitude, i.e., either the patient will recover or
the fever will persist so that he becomes a “ true” case of FUO. We therefore have proposed
to include all patients whose cause of fever is not obvious within a few days into a larger
group of unexplained fever.

DEFINITION OF UNEXPLAINED FEVER

The definition of unexplained fever is a febrile state with or without localizing symptoms
and signs in which a definite diagnosis cannot be made following a clinical work-up that
comprises a thorough history and physical examination together with initial laboratory in-
vestigations. The latter should include a complete blood count with smear, ESR, routine
urine analysis, and conventional microbiologic tests (e.g., blood and urine culture), and a
chest X-ray. Clearly this definition puts no time limit on the duration of the fever, but
usually involves several days and up to 2 weeks. (If the fever lasts longer than this period,
the patient is regarded as having FUO.)
2 Unexplained Fever

HISTORY OF FEVER
Fever as a cardinal manifestation of disease has been known since antiquity. It is
described in Sumerian cuneiform writings, Egyptian hieroglyphic inscriptions, and in the
Bible. The greatest physician of the ancient world, Hippocrates (460—377 B.C.), considered
fever to be a major feature of acute diseases. His elegant descriptions of certain febrile
diseases, such as malaria, pneumonia, and enteric fever, are remarkable. He also described
the supervention of tumors and articular pain in long-lasting fevers.
Before the thermometer was invented, physicians used three main procedures for de-
termining temperature: the patient’s perception of his own body warmth, his appearance,
and the use of the “ educated hand’’ on various parts of the body. Hand thermometry as a
clinical method was taught to physicians as an art.
Galen (131—201) designated neutral heat as being neither hot nor cold and achieved it
by mixing equal quantities of ice and boiling water. A person with hot hands would regard
this mixture as chilly and one with cold hands would perceive it as warm. However, it was
not for nearly another millennium and a half that measurement of temperature came into
effect.
The forerunner of the thermometer was first constructed by Galileo in about 1593. This
device was actually an air-thermoscope, which consisted of a glass bulb attached to a long,
narrow, open-mouthed neck. When the neck was inverted and dipped in water and the bulb
was heated, air was expelled from the neck into the water. On cooling, water again rose in
the neck. On re warming, the air in the bulb expanded and the water level in the neck
dropped. Sanctorius, a colleague of Galileo, was the first physician to employ instruments
of precision in the practice of medicine. In 1625, he converted this elementary, uncalibrated
air-thermoscope into a true thermometer by adding a scale, which was determined by the
application of snow or a candle flame for the low and high points, respectively, and sub-
dividing the intervening distance into 110 equal parts. The bulb of the thermometer was
either grasped by the patients in their hands or inserted into the mouth.
Rey, a French physician, devised the first liquid-in-glass thermometer in 1632. This
device consisted of a flask with a long, narrow neck down which water was poured. When
the flask was heated the water would ascend in the neck.
Florentine thermometers were introduced around the year 1641 and became very popular
all over Europe. Wine spirits were placed in the bulb and the stem was closed. The spirit,
when heated, would rise in the stem, and on cooling, fell back into the bulb. Glass beads
fused onto the stem marked high and low values. However, standardization was not yet
perfected.
In 1694, Renaldini, a member of the Academia del Cimento, proposed using the freezing
and boiling points of water as a temperature range. The following year, his colleague,
Bouilliau, suggested the substitution of mercury for alcohol in the bulb.
In 1701, Newton proposed a scale in which the freezing point of salted ice was set at
zero and the temperature of the human body was set at 12°. Fahrenheit, in 1717, multiplied
this scale by 8, using a value of zero for the lowest temperature that could be attained by
freezing salt water and 96° for body temperature. He noted a value of 100° for the temperature
of a febrile patient. His thermometer employed mercury, possibly due to the suggestion of
the physician Boerhaave, and the bulb was modified into an oval shape.
Boerhaave (1668— 1738), who was Professor of Medicine, Botany, and Chemistry at
Leyden, was one of the greatest consultants of the time. Together with his pupils, van
Swieten and de Haen, he noted the potential utility of the Fahrenheit thermometer in medicine.
The instrument was first used on a healthy man and calibrated accordingly. The thermometer
was then used to measure the temperature of a febrile patient by placing it in the hand or
mouth, on the bare chest, or in the axilla.
 3

Reaumur, in 1730, established a thermometer calling the freezing point of water 0, and
boiling point 80 units. Celsius, in 1742, employed a scale using 100 units with ice at 100°
and boiling water at 0°. The next year Christin reversed these points to establish the centigrade
scale which has been in use since.
The first systematic record of temperature was carried out in 1852 by Traube, who
probably influenced Wunderlich to make a systematic study of the subject. At about this
time the German surgeon Billroth produced fever in cats by injecting filtrates of pus, although
it would take another century until the mechanism was elucidated.
Thermometry was introduced into clinical practice by Wunderlich in 1868, when he
published his classic treatise “ Das Verhalten der Eigenwarme in Krankheiten” ;10 3 years
later an English version was released.11 He originally applied a 30-cm long weather ther-
mometer to the axilla for 20 min. He considered the mouth and the closed fist to be unreliable,
and the rectum and vagina indecent for measurement. Together with his colleagues and
students, he made observations on temperature changes in 25,000 patients, and he wrote
his classic treatise on fever patterns. The instrument was later modified to resemble the
modem clinical thermometer which required placement for only 6 to 10 min. The universal
employment of thermometry in clinical practice soon became established.
von Liebermeister postulated in 1875 that fever results from a disorder which resets the
body temperature at a higher level.12 In the following year Claude Bernard proposed the
basic principles of thermoregulation within the framework of general body homeostasis, and
he analyzed the mechanisms responsible for the constancy of the temperature of the milieu
intérieur in hot-blooded animals.13 Welch in 1888 described the location of the thermore-
gulatory center in the subcortical areas of the brain and suggested that bacterial pyrogens
act indirectly via a release of a leukocyte “ ferment” to produce fever.14
The first treatise on differential diagnosis which included a discussion about prolonged
fevers was made by Cabot in 1922.15 The classic work on the mechanisms of heat regulation
was provided by Dubois in 1937.16
Menkin, in 1943, isolated from inflammatory exudates a substance called “ pyrexin” ,
which caused fever when injected into rabbits.17 However, the pyrogenic effect was later
shown to be due to a contaminating endotoxin. Beeson, in 1948, demonstrated the existence
of endogenous pyrogen (EP), derived from rabbit polymorphonuclear leukocytes and distinct
from endotoxin. He postulated that EP mediated most cases of clinical fever.18 In 1950—1953,
together with Bennett, he established the properties and biological effects of the EP.1921 EP
has subsequently been found to be identical with a lymphocyte-activating factor, and the
substance is currently referred to as interleukin-1 (IL-1). More recently, other leukocyte
products such as tumor necrosis factor (cathectin) and interferon have also been found to
produce fever in man and animals.22
In 1961 Petersdorf and Beeson published their classic prospective study of fever of
unexplained origin (FUO). They precisely defined the entity and presented a classification
of the diagnostic categories which is still in use today.1

FREQUENCY OF VARIOUS CAUSES AND THE CHANGING

SPECTRUM OF FEBRILE DISEASES

Cabot, already mentioned above, in 1907, was the first to propose a classification of
prolonged fevers in his manuscript on “ The Three Long Continued Fevers of New Eng-
land” .23 He analyzed 784 cases of fever lasting at least 2 weeks. The three principal causes
were typhoid fever, sepsis, and tuberculosis and accounted for 90% of the cases. He included
in the term “ sepsis” bacteremic or localized pyogenic infections (deep abscesses, empyema,
tonsillitis, dental abscesses). Rarely, other diseases such as leukemia, cancer, cirrhosis,
trichinosis, and syphilis were found to be responsible for persistent fever. Only 11 cases
remained undiagnosed — an exceedingly low proportion (1.4%).
4 Unexplained Fever

During the 1930s many retrospective and prospective studies on prolonged fever were
carried out. However, these are difficult to compare since different criteria were employed.
The work of Oppel and Bernstein24 deserves special mention. They surveyed 110 patients
admitted to a New York hospital over a period of 2 years, and used strict criteria for case
selection. A team of three to seven physicians participated in overall care of the patients
during and occasionally following hospitalization. The final diagnosis was established by a
medical team which comprised hospital staff and attending physicians.
The various series listed in Table 1 cover a period of almost 80 years and comprise
more than 3500 patients. These tables present a global view of the respective importance
of the various causes of unexplained fever. However, one must keep in mind that the relative
frequency of a certain etiology depends upon many factors, which, on one hand, include
geographic, heredofamilial, ethnic, socioeconomic, epidemiologic, and other aspects in a
particular population, and on the other hand, are related to the nature of the medical facility
where the study was performed (e.g., regional or community hospital, central or teaching
institution, speciality bias, etc.). Most studies have been conducted in the more developed
countries and it is unfortunate that series from the developing countries are rare. Patients
presenting to a major university-affiliated teaching hospital are more likely to be suffering
from a rare condition than those admitted to a community hospital. In the latter, Gleckman
et al.25 found a much higher incidence of alcoholic hepatitis and of pulmonary embolism
than is reported in other series.
Table 1 represents, to our knowledge, the largest compilation of series dealing with
prolonged and unexplained fevers. This overview highlights the major causes of unexplained
fever which fall into the four primary groups, namely, infections, neoplasms, immunologic,
and miscellaneous disorders. In all series there is a certain percentage of undiagnosed cases,
which appears to be decreasing in incidence, presumably as a result of an improved under-
standing of the problem and of technical advances.

THE AUTHORS’ CLASSIFICATION

Although many previously published series have been excellent, we nevertheless feel
that there is a place for a newer and broader account of the various causes of unexplained
fever. It is not our aim to cite an exhaustive list of diseases, but rather to present logical
guidelines to help the physician in the approach to the febrile patient. As has already been
pointed out by Weinstein and Fields,61 “ there are more than 100 causes of fever of unknown
origin and all cannot be studied simultaneously” . Our classification, presented here in Table
2, was initially proposed by two of us in 1981,62 based on the literature as well as the
authors’ own experience, and has been updated. The purpose of this classification is to
permit the clinician to consult a previously prepared table and at the same time to follow a
reasonable and conventional work-up. It should serve to remind the clinician of the wide
variety of conditions which potentially are accompanied by unexplained fever. For more
details on each condition the reader is referred to the respective chapter.

UNEXPLAINED FEVER IN THE EIGHTIES AND NINETIES

In recent years many clinical and technical advances have brought about changes in the
approach to unexplained fever. On the clinical side, “ new” or previously unrecognized
disorders have emerged: for example, Legionnaire’s disease, angioimmunoblastic lymph-
adenopathy, granulomatous hepatitis, Lyme arthritis, and acquired immune deficiency syn-
drome (AIDS). In addition, there has been a “ shift” in certain diseases, formerly rare in
adults, but currently occurring with increased frequency in immunocompromised patients,
e.g., herpesvirus, Pneumocystis carinii, and various fungi. Further, there is a greater aware-
 TABLE 1
Fever of Unknown Origin Over the Years

Ietiology (percent of total cases)

Collagen
No. of vascular
Authors Years of study cases Infection Neoplasia disease Miscellaneous Undiagnosed Ref.

Alt & Barker 1913— 1930 101 10 6 6 1 77 26

Kintner & Rowntree 1919— 1930 100 2 2 0 0 96 27
Hamman & Wainwright 1929— 1935 90 39 15.5 0 5.5 40 28,29
Keefer 1930— 1939 80 60 20 4 16 0 30
Wolf & Jacobs 1940— 1944 36 5 3 0 3 89 31
Bottiger 1940— 1949 158 10 7 2.5 2.5 78 32
Oppel & Bernstein 1951— 1952 110 64 1 3 19 20 24
Reid 1953— 1955 113 35 8 2 19 36 33
Geraci, Weed, Nichols 1959 70 21 30 4 19 26 34
Petersdorf & Beeson 1952— 1957 100 36 19 13 25 7 1
Sheon & Van Ommen 1959— 1960 60 21 6 13 20 40 35
Petterssen 1950— 1959 83 18 5 6 4 67 36
Effersoe 1960— 1963 77 66 5 9 12 8 37
Jambon-Bertand-Cortet 1951— 1965 528 49 27 4 9 11 38
Fray ha & Uwaydah 1967— 1970 49 43 27 14 6 5 39
Deal 1970 34 35 20.5 15 9 20.5 40
Jacoby & Swartz 1957— 1971 128 40 20 15 17 8 3
Arriaga et al. 1972 65 54 20 9 1.5 15.5 41
Soto & Vega 1972 100 51 7 11 15 16 42
Rault 1973 240 36 18 14 25.5 6.5 43
Rachmilevitz & Alkan 1974 80 32.5 16 15 29 7.5 44
Hassan & Farid 1974 129 60 14 10 4 12 45
Moya Mir et al. 1964— 1975 58 41 19 9 17 14 46
Palacio Perez-Medel 1976 31 74 10 0 6 6 47
Gleckman et al. 1977 34 18 9 9 30 35 25
Barbado et al. 1968— 1984 133 31 18 13 17 21 48
Howard et al. 1969— 1976 100 37 31 19 8 5 49
Lafaix et al. 1971— 1978 72 60 5 14 11 10 50
5

Esposito & Gleckman 1978 111 37 23.5 25 9 5.5 51

 6

TABLE 1 (continued)
Fever of Unknown Origin Over the Years

______________________ Etiology (percent of total cases)

Collagen
No. of vascular
Authors Years of study cases Infection Neoplasia disease Miscellaneous Undiagnosed Ref.

Rodriguez et al. 1972— 1975 32 47 22 19 3 9 52

Wanvarie et al. 1974— 1979 25 40 20 12 16 12 53
Unexplained Fever

Sanz Ortiz et al. 1975— 1981 96 59 10 8 6 15 54

Larson et al. 1970— 1980 105 30.5 32.5 8.5 16 12.5 55
Cuesta Munoz et al. 1975— 1980 45 40 22 11 22 5 56
Hidalgo et al. 1976— 1979 64 64 11 5 11 9 57
Smith et al. 1979— 1985 80 50 15 5 22 8 58
Gonzalez Lahoz 1978— 1984 23 70 22 0 4 4 59
Burke et al. 1982— 1984 100 41 10 7 24 20 60

Total 3540
 TABLE 2
Classification of Febrile States

A. Nonpathologic hyperthermia
1. “ Physiologic” fevers: premenstrual, postexertional, postprandial
2. Fever related to habits: heavy smokers, chewing gum consumers
3. Habitual hyperthermia
4. Exaggerated circadian temperature rhythm

B. Psychic hyperthermia
1. Factitious and self-induced fevers
2. Psychogenic fever

C. Fever due to thermoregulatory disorders

1. “ Central” fever (due to hypothalamic lesion)
2. “ Peripheral” fever: dehydration fever, secondary to diffuse skin disease — ichthyosis, scleroderma,
congenital ectodermal dysplasia

D. Iatrogenic fever
1. Drug fever
a. Drug contamination by pyrogen (bacterial, others)
b. Fever related to irritant effects of parenteral drugs
c. Fever due to pharmacologic effect of drug
i. Interaction with organism — Jarish-Herxheimer phenomenon
ii. Reaction related to host factor — hemolysis induced by sulfas in a patient with G-6PD
(glucose-6-phosphate dehydrogenase) deficiency
d. Hypersensitivity: antihistamines, barbiturates, betalactams and other antibiotics, diphenylhydan-
toin, hydralazine, iodides, isoniazid, mercaptopurine, methyldopa, nitrofurantoin, procainamide,
quinidine, salicylates, thiouracil
2. Fever due to investigations
a. Iodine allergy
b. Endoscopy and biopsy (fever due to hemorrhage and/or infection)
c. Postoperative fever — hemorrhage, infection, foreign body reactions, halothane anesthesia, post
pericardiotomy syndrome, fever following ablation of some neural tumors

E. Occupational fevers
7

1. Infections — brucellosis in veterinarians and meat-handlers, leptospirosis in sanitary workers

 8

TABLE 2 (continued)
Classification of Febrile States

2. Antigen inhalation
a. Vegetable origin — farmer’s lung disease, bagassiosis, coffee, tea, tobacco, melt, mushroom
b. Animal origin — pigeons, ducks, turkeys
c. Mineral origin — zinc welders’ fever
d. Humidifier fever — actinomycosis, aspergillosis, Legionnaires’ disease

F. Infectious diseases
Unexplained Fever

1. Generalized
a. Specific or single agent
i. Viral — AIDS (HIV), infectious mononucleosis (EBV), cytomegalovirus, viral hepatitis
ii. Infections due to Rickettsia, Mycoplasma, and Chlamydia
iii. Bacterial (confirmed by smear, culture or serologic tests)
• Acid fast — tuberculosis, especially miliary
• Gram positive — Staphylococcus, Streptococcus, Pneumococcus, Listeria mono-
cytogenes, Erysipelothrix rhusopathiae
• Gram negative — Meningococcus, Gonococcus, Enterobacteriaciae, especially Sal-
monella, Escherichia coli, and Proteus, Hemophilus, Campylobacter, Yersinia,
Tularemia, Brucellosis, Legionella, rat-bite fever, cat scratch fever
iv. Spirochetal — Syphilis, leptospirosis, relapsing fever, Lyme disease
v. Mycoses — Candida, Aspergillus, Cryptococcus, Histoplasma
vi. Parasitic diseases — Malaria, Toxoplasmosis, visceral Leishmaniasis, Trichinosis, Try-
panosomiasis
b. Syndrome produced by various or multiple agents
i. Infective endocarditis
ii. Septicemia (may be mono- or polymicrobial)
iii. Anaerobic infections
2. Localized
a. Extraabdominal infections
i. Subcutaneous — pyogenic,anaerobic,cellulitis
ii. Central nervous system — abscess, subdural empyema, encephalitis, meningitis, septic
venous thrombosis
iii. ENT — sinusitis, otitis, mastoiditis, tonsillitis, retropharyngeal abscess
iv. Oropharyngeal — dental,parotid, deep sublingual infections
v. Thoracic — pneumonia, lung abscess, pleurisy, empyema, pericarditis, mediastinitis
 vi. Musculoskeletal — osteomyelitis, myositis, deep intramuscular abscess, septic arthritis
vii. Vascular — deep thrombophlebitis, infective arteritis
b. Intraabdominal infections
i. Intraperitoneal — tuberculous peritonitis, abscess secondary to perforation of hollow
viscus
ii. Retroperitoneal — lymphadenitis, pancreatic abscess, psoas abscess, infected aortic aneu-
rysm
iii. Hepatobiliary infections — liver abscess (pyogenic, amebic), subphrenic and subhepatic
abscesses, perihepatitis (Neisseria gonorrheae, Chlamydia), granulomata (tuberculosis,
schistosomiasis, brucellosis, leprosy), parasitic diseases (hydatid cyst, fascioliasis), cho-
lecystitis and cholangitis
iv. Digestive tract — appendicitis,diverticulitis, pericolonic and rectal abscesses
v. Urogenital — renal and perinephric abscess, papillary necrosis,pylelonephritis, prosta-
titis, pelvic inflammatory disease, ovarian abscess
vi. Splenic abscess
vii. Suppurative pylephlebitis
3. Fever of infectious origin in a patient returning from a tropical region. In addition to the above-
mentioned generalized and localized infections, the following conditions should be considered: schis-
tosomiasis, amebiasis, filariasis, visceral larva migrans, melioidosis, various helminthic infestations

G. Neoplasia and related disorders

1. Malignant solid neoplasms — all tumors, especially kidney, liver, lung, pancreas, colon, neuroblastoma
2. Métastasés to all viscera, especially liver, arising principally from the digestive tract, lung, carcinoid,
kidney, bone, melanoma, thyroid
3. Hematologic disorders — lymphoma, angioimmunoblastic lymphadenopathy, leukemias, myeloma,
macroglobulinemia
4. Reticuloses — histiocytosis X, pseudolymphoma, giant hyperplasia of lymph nodes, infantile cortical
hyperostosis
5. Benign tumors — atrial myxoma, leiomyoma, renal angiomyolipoma

H. Immune diseases
Collagen diseases and hypersensitivity disorders: systemic lupus erythematosus, mixed connective dis-
ease, scleroderma, dermatomyositis, vasculitides (including polyarteritis nodosa), serum sickness, giant cell
arteritis, Takayasu’s disease, Wegener’s granulomatosis and Kawasaki’s disease, rheumatoid arthritis, ju-
venile and adult Still’s disease, rheumatic fever, pericarditis (some cases)
Granulomatous, noninfectious disorders: sarcoidosis, granulomatous hepatitis, Crohn’s disease
Various disorders with systemic manifestations — ulcerative colitis, Behcet’s disease, relapsing po-
lychondritis, Weber Christian disease
9

Cyclic neutropenia
 10

TABLE 2 (continued)
Classification of Febrile States

I. Vascular disturbances, hemorrhages and tissue damage

1. Vascular thrombosis: peripheral or deep — including pelvic and cerebral thrombophlebitis, pulmonary
thromboembolism, thromboangiitis obliterans (Buerger’s disease)
2. Hematoma — especially cryptic (within enclosed space)
3. Tissue necrosis — following trauma, bums, radiation, ischemia, chronic hepatitis, and cirrhosis
4. Hemolytic disorders
5. Deep, “ silent” hemorrhages: intraluminal (abdominal hollow viscus), cerebral ventricle, within tissues
Unexplained Fever

J. Endocrine, metabolic and related disorders

1. Subacute thyroiditis, hyperthyroidism, hyperparathyroidism, adrenal insufficiency, pheochromocy-
toma, diabetes insipidus
2. Gout, FMF, Fabry’s disease
3. Deficiency of essential nutrients: iron (febrile hypochromic anemia), vitamin B12 and folic acid (meg-
aloblastic anemia), scurvy (in infants)

Adapted from Isaac and Kembaum, 1981.

 11

ness of atypical features of well-known conditions, such as infectious endocarditis, especially

right-sided, spotted fever without spots, etc. Without a doubt, the introduction of comput-
erized modem laboratory and imaging techniques have made an impact on the diagnostic
evaluation of febrile conditions at an earlier stage, before a full-blown or “ classic” clinical
picture emerges; these techniques include nuclear medicine, ultrasonography, computerized
tomography, subtraction angiography, magnetic resonance imaging, radioimmunassy, and
monoclonal antibodies. Recently, CT has been shown to reduce the number of negative
biopsies in patients with FUO.63
This book discusses the problem-orientated approach to the diagnosis of the patient with
unexplained or perplexing fever. It is not intended to be a comprehensive survey of all
febrile infectious and noninfectious conditions. Rather, it is meant to serve as a guide to
the clinician in his efforts to diagnose the patient with fever. The book underscores ways
to reach the correct diagnosis at an earlier stage and is constructed on an organ-system basis.
The clinical features have been emphasized, and tables have been provided throughout the
book to demonstrate the association of fever with various symptoms and signs. The editors
have endeavored to highlight the value of modem diagnostic techniques and to survey the
problematic febrile patient within a universal framework. In attempting such a task, the
editors have made an effort to visit many medical centers in various countries around the
world, especially France, West Germany, Spain, and Sweden. In a multidisciplinary ap-
proach to a complex topic of unexplained fever, some degree of overlap in the various
chapters is inevitable. With respect to such a vast subject it would not be surprising if certain
aspects of various conditions would not receive the consideration that is expected. We humbly
request the readers to inform us of any omissions that they suggest should be corrected in
a future edition.

REFERENCES
1. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin; report of 100 cases, Medicine, 40, 1,
1961.
2. Dinarello, C. A. and Wolff, S. M., Fever of unknown origin, in Principles and Practice of Infectious
Diseases, 2nd ed., Mandell, G. L., Douglas, R. G., Jr., and Bennett, J. E., Eds., John Wiley & Sons,
New York, 1985, 339.
3. Jacoby, G. A. and Swartz, M. N., Fever of undetermined origin, N. Engl. J. Med., 289, 1407, 1973.
4. Brusch, J. L. and Weinstein, L., Fever of unknown origin, Med. Clin. North Am., 72, 1247, 1988.
5. Aduan, R. P., Fauci, A. S., Dale, D. C., and Wolff, S. M., Prolonged fever of unknown origin, Clin.
Res., 26, 558A, 1978.
6. Manoux, A., Ferchal, F., Bars, L., Beaugrand, M., Loirat, P., Chapman, A., Barbagelatta, Callard,
P., and Perol, Y., Hepatite herpetite mortelle chez un adulte apparemment sain, Gastroenterol. Clin. Biol.,
7, 340, 1983.
7. Rubin, M. H., Ward, D. M., and Painter, J., Fulminant hepatic failure caused by genital herpes in a
healthy person, JAMA, 253, 1299, 1985.
8. Westerman, E. L., Rocky Mountain spotless fever — a dilemma for the clinician, Arch. Intern. Med.,
142, 1106, 1982.
9. Turner, R. C., Chaplinski, T. J., and Adams, H. G., Rocky Mountain spotted fever presenting as
thrombotic thrombocytopenic purpura, Am. J. Med., 81, 153, 1986.
10. Wunderlich, C. A., Das Verhalten der Eigenwaerme in Krankheiten, O. Wigand, Leipzig, 1868.
11. Wunderlich, C. A., On the Temperature in Diseases: A Manual of Medical Thermometry, New Sydenham
Society, London, 1871.
12. von Liebermeister, C., Handbuch der Pathologies und Therapie des Fiebers, Vogel, Leipzig, 1875.
13. Bernard, C., Lecons sur la chaleur animale, Baillere, Paris, 1876.
14. Welch, W. H., The Cartwright lectures on the general pathology of fever, Med. News (Philadelphia), 52,
365, 393, 539, 565, 1888.
15. Cabot, R., Differential Diagnosis, W. B. Saunders, Philadelphia, 1922.
12 Unexplained Fever

16. DuBois, E. F., Mechanism of heat loss and temperature regulation, Lane Medical Lectures, Stanford Univ.
Publ. — Univ. Series 3, 386, 1937.
17. Menkin, V., Chemical basis of injury in inflammation, Arch. Pathol., 36, 268, 1943.
18. Beeson, P. B., Temperature-elevating effect of a substance obtained from polymorphonuclear leukocytes,
J. Clin. Invest., 27, 524, 1948.
19. Bennett, J. L., Jr. and Beeson, P. B., The properties and biologic effects of bacterial pyrogens, Medicine,
29, 365, 1950.
20. Bennett, J. L., Jr. and Beeson, P. B., Studies on the pathogenesis of fever. I, J. Exp. Med., 98, 477,
1953.
21. Bennett, J. L., Jr. and Beeson, P. B., Studies on the pathogenesis of fever. II, J. Exp. Med., 98, 493,
1953.
22. Dinarello, C. A., Cannon, J. G., and Wolff, S. M., New concepts on the pathogenesis of fever, Rev.
Infect. Dis., 10, 168, 1988.
23. Cabot, R. C., The three long continued fevers of New England, Boston Med. Surg. J., 282, 356, 1907.
24. Oppel, T. W. and Bernstein, C. A., Jr., The differential diagnosis of fevers; the present status of the
problem of fever of unknown origin, Med. Clin. North Am., 38, 891, 1954.
25. Gleckman, R., Crowley, M., and Esposito, A., Fever of unknown origin; a view from the community
hospital, Am. J. Med. Sci., 274, 21, 1977.
26. Alt, H. L. and Barker, M. H., Fever of unknown origin, JAMA, 94, 1457, 1930.
27. Kintner, A. R. and Rowntree, L. G., Long, continued, low grade idiopathic fever; analysis of one hundred
cases, JAMA, 102, 889, 1934.
28. Hamman, L. and Wainwright, C. W., The diagnosis of obscure fever. I. The diagnosis of unexplained,
long-continued, low-grade fever, Bull. Johns Hopkins Hosp., 58, 109, 1936.
29. Hamman, L. and Wainwright, C. W., The diagnosis of obscure fever. II. The diagnosis of unexplained
high fever, Bull. Johns Hopkins Hosp., 58, 307, 1936.
30. Keefer, C. S., The diagnosis of the causes of obscure fever, Texas State J. Med., 35, 203, 1939.
31. Wolf, H. L. and Jacobs, S., Fever of undetermined origin, New Orleans Med. Surg. J., 99, 441, 1947.
32. Bottiger, L. E., Fever of unknown origin; with some remarks on the normal temperature in man, Acta
Med. Scand., 147, 133, 1953.
33. Reid, I. U. O., Pyrexia of unknown.origin; study of a series of cases, Br. Med. J., 2, 23, 1956.
34. Geraci, J. E., Weed, L. A., and Nichols, D. R., Fever of obscure origin; the value of abdominal exploration
in diagnosis, JAMA, 169, 1306, 1959.
35. Sheon, R. P. and Van Ommen, R. A., Fever of obscure origin; diagnosis and treatment based on a series
of sixty cases, Am. J. Med., 34, 486, 1963.
36. Petterssen, T., Fever of obscure origin; a follow-up investigation of 88 cases, Acta Med. Scand., 171,
575, 1962.
37. Effersoe, P., Fever of unknown origin; a follow-up study of 34 patients discharged without diagnosis,
Dan. Med. B ull, 15, 240, 1968.
38. Godlewski, G. and Godlewski, J., Synthèse des Assises departmentales sur les fièvres prolongées, Les
Assises de Medecine, 20, 129, 1965.
39. Frayha, R. and Uwaydah, M., Fever of unknown origin, Leb. Med. J., 26, 49, 1973.
40. Deal, W. B., Fever of unknown origin; analysis of 34 cases, Postgrad. Med., 50, 182, 1971.
41. Arriaga, L., Fiebre en estudio; revision de 65 casos, Rev. Invest. Clin. (Mexico), 24, 7, 1972.
42. Soto, S. and Vega, E., Sindrome febril prolongado; analsis de 100 cases, Rev. Med. Chile, 100, 37, 1972.
43. Rault, P., Les fiebres prolongées de diagnostic difficile, These Med. Paris Bichat 1973, No. 90
44. Rachmilevitz, D. and Alcan, M., Fever of unknown origin: analysis of 80 cases, Harefuah, 86, 57, 1974.
45. Hassan, A. and Farid, Z., Fever of undetermined origin in Cairo, N. Engl. J. Med., 290, 807, 1974.
46. Moya Mir, M. S., Barbadillo, R., Mosquera, J. M., and Gonzalez Serrano, M. -L., Fiebre de origen
desconocido; analisis de 58 casos, Rev. Clin. Esp., 141, 119, 1976.
47. Palacio Perez-Medel, A., Moya Geromini, I., Pozuelo Gonzalez, A., and Schuller Perez, A., Fiebre
de origen desconocido; experiencia personal de 31 casos, Med. Clin. (Barcelona), 67, 387, 1976.
48. Barbado, J. F., Vazquez, J. J., Pena, J. M., et al., Fever of unknown origin; a survey on 133 patients,
J. Med., 15, 185, 1984.
49. Howard, P., Jr., Hahn, H. H., Palmer, R. L., and Hardin, W. J., Fever of unknown origin; a prospective
study of 100 patients, Texas Med., 73, 56, 1977.
50. Lafaix, C., Cadoz, M., Lamotte, J., and Canuel, C., Approche diagnostique des fièvres au long cours
(a propos de 72 cas), Ann. Med. Intern. (Paris), 128, 99, 1977.
51. Esposito, A. and Gleckman, R., Fever of unknown origin in the elderly, J. Am. Geriat. Soc., 26, 498,
1978.
52. Mercado Rodriguez, U., Whiza Lugo, V., and Rozen Fuller, E., Fiebre de origen desconocido; diag-
nostic y traitamiento basados en 32 casos, Rev. Clin. Esp., 148, 463, 1978.
 13

53. Wanvarie, S., Tanphaichitra, D., and Limsuwan, A., Fever of unknown origin; a review of 25 cases
in Ramathibodi Hospital, J. Med. Assoc. Thailand, 64, 155, 1981.
54. Sanz Ortis, J., Farinas Alvarez, M. C., Mendez Batan, M. A., and Gomerez Serrano, F. M., Porcentaje
de Fiebre de origen desconocido en 1584 historias revisadas: análisis de 96 casos, Med. Clin. (Barcelona),
80, 826, 1983.
55. Larson, E. B., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin; diagnosis and
follow-up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
56. Cuesto Munoz, J., Faure Nogueras, E., Hortells Aznar, J. L., Martinez Taberno, R., Roche Asensio,
M.-J., and Guillen Martinez, G., Fiebre de origen desconocido; nuestra casuística de 5 anos, Rev. Clin.
Esp., 162, 33, 1981.
57. Maradona Hidalgo, J. A., Alvarez Alvarez C., Fernandez Rippe, M. L., Suarez Garcia, E., Rodriguez
Fidalgo, A., and Estrad Rato, F., Estudio critico de la fiebre de origen desconocido; aportación de nuestra
casuística, Med. Clin. (Barcelona), 78, 9, 1982.
58. Smith, J. W., Southwestern Internal Medicine conference: Fever of undetermined origin; not what it used
to be, Am. J. Med. Sci., 292, 56, 1986.
59. Gonzalez Lahoz, J. M., personal communication.
60. Burke, M., personal communication.
61. Weinstein, L. and Fields, B., Fever of obscure origin, Semin. Infect. Dis., 1,1, 1978.
62. Isaac, B. and Kernbaum, S., Fièvres prolongées inexpliquées, Presse Med., 10, 3311, 1981.
63. Rowland, M. D. and Del Bene, V. E., Use of computerized tomography to evaluate fever of unknown
origin, J. Infect. Dis., 156, 408, 1987.
 15

Chapter 2

THE ANATOMY AND PHYSIOLOGY OF NORMAL

THERMOREGULATION

N. Gadoth

INTRODUCTION

Thermoregulation or keeping the human temperature in a narrow normal range utilizes

mechanisms which actively control heat production and heat loss. It is evident at present
that the central nervous system determines peripheral heat production and loss, in a mech-
anism by which hypothalamic cellular membrane properties are changed in response to a
universal pyrogen.
In the following chapter, clinical and experimental evidence for central thermoregulation
and its neurochemical properties will be discussed.

NORMAL BODY TEMPERATURE

The normal range of temperature recorded orally from humans is 35.8 to 37.8°C. Rectal
recordings will give values higher in one degree. In any one individual variations throughout
the day may occur. The maximum reading is usually obtained in the late afternoon — early
evening, and the minimum, sometimes reaching a difference of 1 to 2°C, is usually recorded
at 5 A.M. The stability of body temperature (BT) varies with the size of the body. In infants
with intense metabolic rate and a relatively large surface area, rectal temperature might vary
at a range twice that of adults. BT regulation becomes inactive when the internal temperature
reaches 23°C, because the neural mechanism regulating BT is inactivated below this critical
temperature.
It is generally agreed that the lowest lethal temperature for humans is about 26°C, and
death is due to cardiac failure. The average upper lethal is about 43°C rectal temperature.
Heat regulation is achieved by a dynamic balance between heat production and heat
loss. There are several mechanisms of heat loss:

1. Radiation and conduction from skin

2. Adjusting temperature and humidity of inspired air
3. Sweating
4. By urine and feces

Out of these mechanisms only skin heat transfer and sweating are under physiological
control.

RADIATION
Several physiological mechanisms play a role in adjustment of skin radiation:

(a) The quantity of blood circulating through skin can increase dramatically upon exposure
to heat. It was shown that the amount of blood circulating through the skin may reach
12% of the cardiac output at ambient temperature of 34°C. The fingers seem to serve
as major radiators of heat. The finger blood flow was shown to increase from 1 ml/
min/100 g of tissue, to 80 to 90 ml/min upon heat exposure.
(b) Upon exposure to heat sufficient to cause diffuse cutaneous vasodilatation, the total
16 Unexplained Fever

circulating blood volume dramatically increases due to dilution by fluid drawn from
skin, muscles and liver; hematocrit drops and the concentration of plasma proteins
decreases. On the other hand, a sudden exposure to cold causes a rapid decrease of
blood volume followed by marked diuresis.
(c) Upon exposure to heat, cardiac output increases, causing rapid blood flow through
the dilated cutaneous vessels.

Thus, the skin may be regarded as a very efficient radiator and, in the standing position,
85% of its surface can be involved in heat radiation.

SWEATING
The 2.5*106 sweat glands in the human skin are cholinergic organs. Sweating is controlled
by neural mechanisms present in almost all levels of the central nervous system. Initially,
muscular activity-induced sweating is initiated by impulses from the motor cortex; this occurs
early before there is a significant increase in heat load. Later on, the rising temperature of
blood causes an increase in hypothalamic temperature (see below).
The fact that quadriplegics may sweat below the level of spinal transection points to the
presence of independent spinal centers for segmental sweating.

HEAT PRODUCTION
Muscles are efficient heat producers, responding promptly to fall in BT due to cool
external environment. The sensitivity of muscles to rising BT is expressed by the fact that
muscular tension rises even before initiation of shivering. In nude males the temperature
23°C is considered to be the shivering or “ critical temperature” . During maximal shivering,
heat production may reach values three times that of basal rate. The control of muscular
heat production is maintained by the somatic efferent innervation.

CENTRAL REGULATION OF HEAT PRODUCTION AND HEAT LOSS

There is convincing evidence to support the claim commonly held that central ther-
moregulation is located in the hypothalamus. Cooper et al.1 have shown by selective intra-
arterial infusions of warm saline that warmth receptors evoking peripheral vasodilation in
man are located in the distribution of the internal carotid artery reaching the hypothalamus
or anterior segments of the cerebral hemispheres.1 With the aid of brain sectioning and
extirpation experiments it was shown that the hypothalamus is an essential region for ther-
moregulation in animals,2 in particular the posterior hypothalamus is concerned with re-
sponses to cold3 and the anterior hypothalamus with responses to heat.4
Bilateral lesions placed in the caudal hypothalamus caused impaired thermoregulation
both in cold and hot environments, while lesions near the septum and in the anterior hy-
pothalamus caused severe hypothermia.5
Electrical stimulation of the anterior hypothalamus resulted in skin vasconstriction6 while
stimulation of the preoptic area resulted in marked shivering.7
Single neuron recordings from the anterior hypothalamus in cats disclosed that 20% of
neurons out of 100 recorded, increased their rate of firing when local temperature was raised
from 31 to 41°C. The remaining neurons did not change their rate of firing and no neurons
were found to respond to cooling.8 It seems that hypothalamic thermoregulation is mediated
by hypothalamic blood flow and its temperature is normally cooled by the blood flowing
through the region. Consequently, changes in the thermoregulatory response are initiated
with alterations of local blood flow or its temperature.9
An additional mechanism such as increased permeability of the hypothalamic blood brain
barrier (BBB) to pyrogen could also play a role in hypothalamic thermoregulation. Indeed,
there is a rich vascular network close to the preoptic anterior hypothalamic neurons known
 17

as the Organ Vasculosum Laminae Terminalis (OVLT) which manifests little if any BBB
properties. The role of OVLT in thermoregulation is clearly demonstrated by its surgical
ablation. Following this procedure peripheral administration of pyrogen fails to raise body
temperature while this is achieved after intracerebral injection of the same pyrogen.10
Out of the data mentioned above and the bulk of experimental data not brought in this
short review, it seems that the hypothalamus governs heat production and heat loss in
laboratory animals.
The rostral hypothalamus suppresses heat production and facilitates heat loss. It appears
that the hypothalamus serves as a thermostat for the rest of the body, detecting blood
temperature, and originating a negative feedback, thus utilizing the rest of the body to
stabilize its own temperature.11
It is now well established that there exists a “ set-point” in the hypothalamus determining
the constant (normal) body temperature by inducing heat loss or heat production. Any
deviation of this set-point will lead to a change in body temperature. Deviation from the
normal set-point can be caused by local anatomical changes, exercise, sleep, and febrile
illness.
The mechanism for establishing a certain hypothalamic set-point is unknown. However,
it is most probable that in primates, an inborn mechanism of keeping a constant ratio between
sodium and calcium in the posterior hypothalamus is responsible for establishing the set-
point for body temperature at 37°C.12

PATHOPHYSIOLOGY OF FEVER
Fever is a term applied to elevated body temperature caused by an elevation of the
hypothalamic set-point. The programming of the set-point to a higher than normal value
leads to perception of the current core temperature as being too low, even though it is normal
in reality. The hypothalamus will regulate the body temperature by activating heat gain and
suppressing heat loss mechanisms.
In all other conditions of body temperature elevation caused by strenuous exercise or
exposure to high ambient temperature, the set-point in the anterior hypothalamus is not
altered and body temperature elevation thus represents the failure of thermoregulation.
However, in heat stroke or in anesthetic-induced malignant hyperthermia, central controlling
mechanisms are lost and temperature may reach lethal levels.13
Numerous substances are known to induce fever and are considered “ pyrogens” . Among
these are viruses, Gram-positive bacteria and their exotoxins, Gram-negative fungi, antigens
producing delayed hypersensitivity reactions, and a number of nonorganic substances. In
response to one of these “ exogeneous pyrogens” a common mediator called the “ endogenous
pyrogen” is produced and affects the hypothalamus causing a shift of its normal thermo-
regulatory “ set-point” to produce fever. There are also a number of endogenous products
which can induce the production of endogenous pyrogen. These include antigen-antibody
complexes in the presence of complement, certain androgenic steroid metabolites, inflam-
matory bile acids, complement components, and some lymphocytic products.

ENDOGENOUS PYROGENS
Fever induction by endogenous leukocytic products was postulated in the 19th century
but the demonstration of a pyrogenic leukocytic material was made possible only some 30
years ago. This material was originally called granulocytic, leukocytic, or endogenous
pyrogen. Consequently, it was shown that these pyrogenic substrates are synthesized fol-
lowing the appropriate activation of macrophages or monocytes.
At present it is customary to use the term “ interleukins” for a number of molecules
isolated from the classical “ endogenous pyrogen” and its major constituent is termed in-
terleukin-1 or IL-1. Although at least three separate molecules have been isolated from IL-
18 Unexplained Fever

1, only two are considered as endogenous pyrogens and are termed IL-1 (3 and IL-la. The
first is a 17.3 kDa molecule, with an isoelectric point (pi) of 5 and N-terminus at the 115
(serine) position. The second, (IL-1) is a 17.7 kDa peptide with a pi of 7 and N-terminus
at the 117 (alanine) position. Both peptides circulate, cross the blood brain barrier to enter
the cerebrospinal fluid and finally reach the preoptic neurons to reset body temperature
homeostasis.14 Although the precise mechanism of IL-1 production by macrophages is not
yet defined, preliminary data suggest that a soluble factor produced by T-lymphocytes may
activate the macrophages to synthesize IL-1.15
As interleukin-1 is a name used for several pyrogenic proteins we will use the term
endogenous pyrogens (EP) throughout this chapter.

INDUCTION OF EP
Viruses
Viruses may induce EP. This ability is closely related to the presence of an essential
lipid-carbohydrate moiety of the viral hemagglutinin.16

Gram-Positive Organisms
Intravenous injection of a number of living Gram-positive organisms or dead bacteria
produces fever in rabbits while circulating EP can be demonstrated in the febrile plasma. It
is thought that the pyrogenic response is induced by a repeating sequence of V-acetylglu-
cosamine linked to V-acetylmuramic acid in a peptidoglycan structure, an important con-
stituent of all bacterial cell walls.17

Gram-Negative Bacteria
Although peptidoglycan is present in bacterial cell wall of Gram-negative bacteria, the
pyrogenicity of these organisms is caused by a lipopolysaccharide (endotoxin).

Fungi
Nonpathogenic and pathogenic fungi may induce fever. This can be shown when live
or killed yeast cells are injected intravenously into rabbits.18It is suggested that the mechanism
for inducing EP production in vitro is related to phagocytosis of the yeast cell.19

Mycobacteria
Fever can be produced in rabbits and guinea pigs by injecting BCG and later by intra-
venous administration of PPD (purified protein derivative), or old tuberculin, with circulation
EP present in the febrile plasma.20 It is suggested that stimulation of EP production from
unsensitized cells can be induced by tuberculin which causes formation of immune complexes
or precipitates the attachment of cytophilic antibodies.

Spirochetes
Although several strains of Borrelia may induce relapsing fever it does not contain
endotoxin. Its pyrogenic activity is achieved by induction of EP.

Immune Mechanisms and Fever

Two types of fever are known to be associated with immune-related nonbacterial anti-
gens. In immune fever the pyrogenicity of the antigen is expressed only by a specific
circulating antibody, while some immune related fevers are induced by certain sensitized
cells. Induction of EP by immune complexes was achieved experimentally after challenge
with human serum albumin. This resulted in the appearance of circulating EP, 5 min following
albumin injection.21
 19

Another mechanism involved in sensitized cells pyrogenicity was demonstrated in an-

imals and humans. In humans sensitized to type D erythrocytes and circulating leukoagglu-
tinins, fever was induced by challenging with the specific antigen.22

Steroids
The most studied pyrogenic metabolite of the adrenal and testicular hormones is ethio-
cholanolone. As in other pyrogenic steroids, the beta position of the hydrogen on the 5-
carbon imparts pyrogenicity. Although ethiocholanolone is not pyrogenic in dogs, cats,
guinea pigs, rats, mice, and rabbits, the incubation of ethiocholanolone with human peripheral
leukocytes results in release of EP.23

Cellular Sources of Pyrogen

Only bone marrow-derived mononuclear phagocytes appear to produce EP. Tissue fixed
macrophages such as rabbit splenic macrophages, or human and rabbit lung alveolar mac-
rophages serve also as an EP source.24

Tumor and Transformed Cells

Several tumor cells were shown to synthesize EP. These include lymph nodes and
splenocytes from patients with Hodgkin’s disease and renal cell carcinoma.26 27 Although
no EP is produced by human blood leukocytes taken during febrile episodes from patients
with malignant disease or sarcoidosis, stimulated monocytes from patients with sarcoidosis
produce more EP than monocytes from normal donors.28 This indicates that certain trans-
formed cells may indeed produce EP.

The Mechanism of Pyrogenic Activity of Endogenous Pyrogens

Human EP is quite resistant to oxidation. Its lipid or carbohydrate moieties are not
essential for its biological activity. These small soluble protein molecules enter the draining
lymph nodes and the circulation. When injected intravenously, it produces fever after some
15 min only.29 The pattern of fever due to EP is monophasic.
EP is degradated by the liver and kidney and excreted by the kidneys.30 It can be assumed
from these data that EP gains entry into the circulation from its site of production, produces
its primary effect in the CNS, and is rapidly metabolized and excreted by the kidney, thus
only a small portion of the original EP reaches the CNS. The amount of EP in the circulation
which is necessary to produce fever is still unknown. It was clearly shown that the preoptic
anterior hypothalamus is extremely sensitive to microinjections of EP in several species,
causing a rapid increase in rectal temperature associated with vasoconstriction and decreasing
peripheral blood flow. The observations suggesting extreme susceptibility of the pre-optic
area to EP are supported by reports that identical injections in other sites of the CNS such
as lateral and posterior hypothalamus, midbrain, pons, cerebellum, or cerebral cortex failed
to cause fever.31'34 Further proof comes from intraneuronal recording from the anterior
hypothalamus, showing increased neuronal firing rate in response to proximate injections
of EP.35 The posterior hypothalamus which plays a major role in maintaining homothermy
does not respond to injections of EP.
Several sites in the medulla oblongata and midbrain also respond to EP but they are
considered to play a secondary role in the control of body temperature. These secondary
thermoregulatory sites are less differentiated than those in the anterior hypothalamus, but
they are able to respond to EP when the “ primary” hypothalamic centers are destroyed by
disease or experimentally in laboratory animals.36 37
20 Unexplained Fever

BIOCHEMICAL MECHANISMS RESPONSIBLE FOR EP EFFECT

ON THE HYPOTHALAMUS
MONOAMINES
Although various monoamines are believed to have major thermoregulatory effects,
injection of EP into rabbits has no effect on hypothalamic levels of norepinephrine or 5-
hydroxytryptamine.38 However, depletion of brain monoamines prevents EP-induced fever.39
It is generally believed that monoamines mediate EP, and the integrity of the monoaminergic
neurons is vital for hypothalamic thermoregulatory functions.40 41

PROSTAGLANDINS
There is increasing evidence that prostaglandins play an important role in thermoregu-
lation. During experimental fever, prostaglandin E levels are elevated and CSF from patients
with a variety of febrile diseases contains elevated levels of prostaglandin E.42,43
There is considerable evidence that prostaglandin E2 (PGE2) is the major arachidonic
acid metabolite associated with increase of the hypothalamic “ set-point” to febrile levels.
Even arachidonic acid alone, injected into the hypothalamus can cause fever. PGE2 produces
fever minutes following intrahypothalamic injection. The central effects of prostaglandins
were demonstrated by inducing fever after intraventricular injection of prostaglandins.44
More convincing is the fact that prostaglandin E2, when injected into the CNS of rats, cats,
or rabbits, will produce fever only when injected into the pre-optic anterior hypothalamus.45
The fever mediating role of prostaglandins appears more rapidly than after similar injection
of EP. The link between EP and prostaglandins is demonstrated by the fact that highly
purified human EP increased prostaglandins E2 release from brain slices.46 It is suggested
that EP is capable of inducing hypothalamic prostaglandin synthesis which in turn initiates
fever.
An important observation in support of the prostaglandin theory is the ability of aspirin
and other antipyretics to reduce fever by blocking brain cyclooxygenase activity and thus
blocking prostaglandin synthesis.47 The fact that humans with elevated body temperature
due to prostaglandin E methyl esterase do not respond to aspirin48 suggests that the critical
step of the antipyretic property of salicylates is the prevention of prostaglandin synthesis.
This is also supported by the observation that in fever induced by EP or by endotoxins, the
CSF levels of prostaglandin E2 increases with rising body temperature and falls during
aspirin-induced antipyresis.49,50
The current theory is that (1) EP causes release of arachidonic acid with subsequent
synthesis of prostaglandins and prostaglandin like substances; (2) these products modulate
the hypothalamic thermoregulatory centers by increasing the set-point from normothermic
to fever levels; (3) antipyretics with prostaglandin synthetase inhibiting properties reduce
fever by preventing synthesis of prostaglandins from arachidonic acid.
The pathogenesis of fever can now be summarized as follows:51 endogenous pyrogens
are produced and released into the circulation, reaching the anterior hypothalamus via its
arterial tree and penetrating the specialized local arrangement of the BBB in the region of
the OVLT. This results in local arachidonic acid release which is then rapidly metabolized
into PGE2. PGE2 elevates the hypothalamic thermoregulatory “ set-point” . This change is
mediated by nerve efferents, especially sympathetic pathways to induce peripheral vaso-
constriction leading to heat conservation. This process continues until the now “ warmer
blood” reaching the hypothalamus matches the “ new” set-point. When the concentration
of EP falls and/or EP induced prostaglandin synthesis is blocked by antipyretics capable of
inhibiting brain cyclooxygenase, the hypothalamus can now reset and body temperature can
return to normal.
 21

REFERENCES
1. Cooper, K. E., Cranston, W. I., and Snell, E. S., Temperature regulation during fever in man, Clin.
Sci., 27, 345, 1964.
2. Keller, A. D., Role of circulation in physiology of heat regulation, Phys. Ther. Rev., 30, 511, 1950.
3. Murgatroyd, D., Keller, A. D., and Hardy, J. D., Warmth discrimination in the dog after hypothalamic
ablation, Am. J. Physiol., 195, 276, 1958.
4. Cooper, K. E., Temperature regulation and the hypothalamus, Br. Med. Bull., 22, 238, 1966.
5. Bond, D. D., Randt, C. T., Bidder, T. G., and Rowland, V., Posterior septal fomical, and anterior
thalamic lesions in the cat: vegetative and behavioral changes with anatomical and physiological correlations,
AMA Arch. Neurol. Psychiatry, 78, 143, 1957.
6. Strom, G., Vasomotor responses to thermal and electrical stimulation of frontal lobe and hypothalamus,
Acta Physiol. Scand., (Suppl. 70), 20, 83, 1950.
7. Hemingway, A., Forgrave, P., and Birzis, L., Shivering suppression by hypothalamic stimulation, J.
Neurophysiol., 17, 375, 1954.
8. Hardy, J. D., Hellon, R. F., and Sutherland, K., Temperature-sensitive neurons in the dog’s hypo-
thalamus, J. Physiol. (London), 175, 242, 1964.
9. McCook, R. D., Peiss, C. N., and Randall, W. C., Hypothalamic temperatures and blood flow, Proc.
Soc. Exp. Biol. Med., 109, 518, 1962.
10. Stitt, J. T., Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile
response of rabbits and rats, J. Physiol., 368, 501, 1985.
11. Benzinger, T. H., Clinical temperature. New physiological basic, JAMA, 209, 1200, 1969.
12. Myers, R. D. and Yaksh, T. L., Thermoregulation around a new “ set-point” established in the monkey
by altering the ratio of sodium to calcium ions within the hypothalamus, J. Physiol. (London), 218, 609,
1971.
13. Bernheim, H. A., Block, L. H., and Atkins, E., Fever: pathogenesis, pathophysiology, and purpose,
Ann. Intern. Med., 91, 261, 1979.
14. Fever of unknown origin in a 71-year-old woman, Clinicopathologic Conference, Am. J. Med., 79, 373,
1985.
15. Amento, E. P., Kurnick, J. T., and Krane, S. M., Interleukin-1 production by human monocyte cell
line U937 requires a lymphokine induction signal distinct from interleukin-2 or interferons, J. Immunol.,
134, 350, 1985.
16. Dinarello, C. A. and Wolff, S. M., Molecular basis of fever in humans, Am. J. Med., 72, 799, 1982.
17. Rotta, J., Endotoxin-like properties of the peptidoglycan, Z. Immunitaetsforch., 149, 230, 1975.
18. Briggs, R. S. and Atkins, E., Studies in cryptococcal fever. I. Responses to intact organisms and to a
soluble agent derived from crytpococci, Yale J. Biol. Med., 38, 431, 1966.
19. Gordon, A. H. and Parker, I. D., A pyrogen derived from human white cells which is active in mice,
Br. J. Exp. Pathol., 61, 534, 1980.
20. Allen, I. V., The pathogenesis of fever in delayed hypersensitivity, Irish J. Med. Sci., 6, 247, 1965.
21. Root, R. K. and Wolff, S. M., Pathogenetic mechanisms in experimental immune fever, J. Exp. Med.,
128, 309, 1968.
22. Brittingham, T. E. and Chaplin, H., Jr., Febrile transfusion reactions caused by sensitivity of donor
leukocytes and platelets, JAMA, 165, 819, 1957.
23. Beloeil, J. C., Esnault, C., Fetizon, M., and Henry, R., Synthesis and pyrogenic effect of 3 alpha, 7
alpha-dihydroxy-5-beta-androstan-17-one and 3 alpha-hydroxy-5-beta-androstane-7, 17-dione, Steroids, 35,
281, 1980.
24. Cunningham, C. M., Barsumian, E. L., and Watson, D. W., Further purification of group A streptococcal
pyrogenic exotoxin and characterization of purified toxin, Infect. Immunol., 14, 767, 1977.
25. Chao, P., Francis, L., and Atkins, E., The release of an endogenous pyrogen from guinea pig leukocytes
in vitro, J. Exp. Med., 145, 1288, 1977.
26. Bodel, P. T., Pyrogen release in vitro by lymphoid tissue from patients with Hodgkin’s disease, Yale J.
Biol. Med., 47, 101, 1974.
27. Rawlins, M. D., Luff, R. H., and Cranston, W. I., Pyrexia in renal carcinoma, Lancet, 1, 1371, 1970.
28. Bodel, P. T., Major, P. T., and Gee, J. B., Increased production of endogenous pyrogen and lysosome
by blood monocytes in sarcoidosis, Yale J. Biol. Med., 52, 247, 1979.
29. Allen, I. V., The cerebral effect of endogenous serum and granulocytic pyrogen, Br. J. Exp. Pathol., 46,
25, 1965.
30. Dinarello, C. A., Weiner, P., and Wolff, S. M., Radiolabelling and disposition in rabbits of purified
human leukocytic pyrogen, Clin. Res., 26, 522A, 1978.
31. Cooper, K. E., Cranston, W. I., and Honour, A. J., Observations on the site and mode of action of
pyrogens in the rabbit brain, J. Physiol. (London), 191, 325, 1967.
22 Unexplained Fever

32. Jackson, D. L., A hypothalamic region responsive to localized injection of pyrogens, J. Neurophysiol.,
30, 586, 1967.
33. Rosendorff, C. and Mooney, J. J., Central nervous system sites of action of purified leucocyte pyrogen,
Am. J. Physiol., 220, 597, 1971.
34. Lipton, J. M., Dinarello, C. A., and Kennedy, J. I., Fever produced in the squirrel monkey by human
leucocytic pyrogen, Proc. Soc. Exp. Biol. Med., 160, 426, 1979.
35. Schoener, E. P. and Wang, S. C., Leukocytic pyrogen and sodium acetylsalicylate on hypothalamic
neurons in the cat, Am. J. Physiol., 229, 185, 1975.
36. Sakata, Y., Effects of pyrogen on the medullary temperature-responsive neurons of rabbits, Jpn. J. Physiol.,
29, 585, 1979.
37. Lipton, J. M. and Trzcinka, G. P., Persistence of febrile response to pyrogens after PO/AH lesions in
squirrel monkeys, Am. J. Physiol., 231, 1638, 1976.
38. Metcalf, G. and Thompson, J. W., The effect of various amine-depleting drugs on the fever response
exhibited by rabbits to bacterial or leukocyte pyrogen, Br. J. Pharmacol., 53, 21, 1975.
39. Teddy, P. J., Mechanism of action of pyrogen, in Pyrogen and Fever, Wolstenholm, G. E. and Birch,
J., Eds., Churchill Livingstone, Edinburgh, 1971, 124.
40. Rosendorff, C., The pathogenesis of fever: neurochemical aspects, Isr. J. Med. Sci., 12, 960, 1976.
41. Hellon, R. F., Monoamines, pyrogens and cations: their actions on central control of body temperature,
Pharmacol. Rev,, 26, 289, 1974.
42. Feldberg, W., Gupta, K. P., Milton, A. S., and Wendlandt, S., Effect of pyrogen and antipyretics on
prostaglandin activity in cisternal CSF of unanesthetized cats, J. Physiol. (London), 234, 279, 1973.
43. Saxena, P. N., Beg, M. M., Singhal, K. C., and Ahmad, M., Prostaglandin-like activity in cerebrospinal
fluid of febrile patients, Indian J. Med. Res., 70, 495, 1979.
44. Milton, A. S. and Wendlandt, S., Effects on body temperature of prostaglandins of the A, E and F series
on injection into the third ventricle of unanesthetized cats and rabbits, J. Physiol. (London), 218, 325,
1971.
45. Veale, W. L. and Cooper, K. E,, Comparison of sites of action of prostaglandin E and leucocyte pyrogen
in brain, in Temperature Regulation and Drug Action, Symposium, 1974, Paris, S. Karger, Basel, 1975,
218.
46. Dinarello, C. A. and Bernheim, H. A., Ability of human leukocytic pyrogen to stimulate brain prosta-
glandin synthesis in vitro, J. Neurochem., 37, 702, 1981.
47. Vane, J. R., Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs, Nature,
231, 232, 1971.
48. Brenner, W. E., Dingfelder, J. R., and Staurovsky, L. G., The efficacy and safety of intramuscularly
administered 15 (s) 15-methylprostaglandin E2 methyl ester for induction of artificial abortion, Am. J.
Obstet. Gynecol., 123, 19, 1975.
49. Harvey, C. A., Milton, A. S., and Straughtan, D. W., Proceedings: Prostaglandin E levels in cerebrospinal
fluid of rabbits and the effects of bacterial pyrogen and antipyretic drugs, J. Physiol. (London), 248, 26P,
1975.
50. Dey, P. K., Feldberg, W., Gupta, K. P., Milton, A. S., and Wendlandt, S., Further studies on the
role of prostaglandin in fever, J. Physiol. (London), 241, 629, 1974.
51. Dinarello, C. A., Cannon, J. G., and Wolff, S. M., New concepts on the pathogenesis of fever, Rev.
Infect. Dis., 10, 168, 1988.
 23

Chapter 3

PATHOPHYSIOLOGY OF FEVER
C. Merdier and M. Burke

INTRODUCTION
Our knowledge of fever dates from the beginnings of written records, with descriptions
on the Akadian cuneiform inscriptions (6th century B.C.) of fever and local warmth of
inflammatory process as flaming blaziers.1 Later descriptions in Pericle’s period (450 B.C.)
contain physical signs associated with fever in typhoid fever and other infections. It is
fascinating to discover that centuries before the invention of the thermometer, physicians
could accurately describe various febrile diseases. In the writings of Hippocrates one can
recognize entities such as malaria, pneumonia, and enteric fever according to the charac-
teristic fever charts.

FEVER: BENEFICIAL OR HARMFUL

The cornerstone of the new era was the introduction of the clinical thermometer, which
permitted the measurement of patient’s body temperature to become routine.2 However, this
major development failed to bring with it the solution to the question of whether fever is
advantageous or disadvantageous to the host. Fever represents a regulated increase in body
temperature, usually not exceeding 41.1°C in humans. In contrast, the temperature in ma-
lignant hyperthermia or heat stroke may rise to higher, lethal levels.3 Early studies did not
demonstrate a positive role for fever.4 In fact, even normal body temperature has a circadian
rhythm, with a maximum level in the late afternoon and a gradual fall to the minimum in
the morning. Various factors such as environmental temperature changes, exercise, or men-
strual cycle can influence normal temperature.5
The development of fever is a metabolically costly process and independent of the cause,
most of the physiological processes follow the same pattern. Fever may be observed in
numerous diseases, such as infections, vascular injury (pulmonary embolism, myocardial
infarction), malignancy (e.g., acute leukemia, lymphoma, hypernephroma, hepatoma) drug
intoxication, (atropine) dehydration (especially in children), endocrinopathy (such as thy-
rotoxicosis and pheochromocytoma), hypersensitivity (serum sickness, transfusion reactions)
and collagen vascular diseases (e.g., SLE, juvenile rheumatoid arthritis, acute rheumatic
fever).
The presence of fever in such widely different entities highlights the problem of its
ultimate benefit. Despite extensive studies into its pathophysiology, it is not clear whether
one is dealing with a defense mechanism, which is enhancing survival, or, a harmful response
which accompanies injury or stress. These doubts were best expressed by Dubois,6 who
stated: “ Fever is only a symptom, and we are not sure that it is an enemy. Perhaps it is a
friend’’.
The regional fever differences which normally occur between the core and the extremities
or scrotum can be significant in modulation of the infective processes. The effect of fever
on infectious agents is widespread, involving many factors, such as growth rate, metabolism,
virulence, and production of toxins.
Host defenses are also temperature dependent.710 By modulating the ambient temperature
(cooling and heating), the effects of the external environment can be evaluated. A number
of different species have been shown to be highly susceptible to infection in a cold envi-
24 Unexplained Fever

ronment, whereas warmth had a protective effect.7,9,11 Changing the ambient temperature
of the food pads of the guinea pig can prevent infection by Leishmania or cure the lesion.13
Improvement of psoriatic lesions in man can be observed in the summer and on exposure
to the sun.14In the pre-antibiotic era, heat was used to treat syphilis and gonococcal infection.3
Heat therapy has also had a limited success in healing malignant processes,15,16 especially
skin tumors.
Kluger et al.17 have demonstrated that fever enhances survival in lizards inoculated with
live Aeromonas hydrophilia. When fever was prevented, the mortality increased significantly,
whereas recurrent heating promoted recovery. The same effects have been observed in fish.18
Similarly, the newborn of various species exhibit an incomplete heat regulatory system
and they also demonstrate a dependence on environmental heating in order to survive in-
fection.
The beneficial effect of fever on survival in mammals is far from clear. The results of
experiments on amphibians and lower fever cannot necessarily be applied. Excessive fever
can be harmful not only to the pathogen but also to the host. It appears that mammals seldom
have an increase in temperature of more than 2.5°C. Beyond this value survival seems to
decrease.17,19
Although fever may have a beneficial effect (in fact some children appear quite well
despite temperatures of 40°C), most febrile patients develop unpleasant symptoms such as
malaise, headache, lassitude, and even delirium and heat convulsions. Taking into account
the favorable effects of fever and its diagnostic value as well as the potential side effects of
antipyretic agents,20,21 it may not always be desirable to reduce the temperature. Careful
medical management is achieved by making the patient comfortable and providing symp-
tomatic relief while not causing harm.
Nevertheless, fever has undesirable effects on all body systems. An elevation of body
temperature by 1°C raises the basal metabolic rate by 10 to 12%, with corresponding increases
in oxygen consumption and C 02 production, as well as caloric and fluid requirements.
Increased metabolic demands may place an additional burden on the cardiovascular system,
especially in the elderly, and precipitate acute cardiac ischemia and/or cardiac failure. Febrile
injury to the nervous system, especially in children, causes delirium, hallucinations, and
convulsions. Perinatal fever may be related to certain neurologic abnormalities. A dual effect
of fever may be observed in immunologic reactions. Although elevated temperatures may
enhance some immune responses, prolonged or high fever may diminish certain defense
mechanisms such as cell viability and lymphocyte function.22
At the present time, on the basis of available data, we can state that fever is advantageous
to several species during various infections. However, it is difficult to assess the overall
beneficial effect of fever in all infectious diseases. The advantage of fever in noninfectious
diseases such as hypersensitivity reactions or malignancy still remains an enigma.

EFFECT OF ELEVATED TEMPERATURE ON BODY SYSTEMS

The effect of fever can be observed in all body systems and can lead to anatomo-
pathologic and functional changes.
Endogenous pyrogen was considered as causing fever and the various systemic changes.
However, extensive investigations lead to discovery of interleukin-1 and also tumor necrosis
factor and interferon, which can produce fever, so that our concepts about the pathophys-
iology of fever have to be reevaluated.23
In spite of its beneficial role in some cases, temperature elevation can also have lethal
effects. The thermosensitivity of living cells varies according to their species, the most
sensitive being those cells originating from animals with low body temperatures. Heating
has different effects on the dividing cells, those in S-phase24 being the most sensitive to
inhibition by high temperatures.
 25

Results of experiments concerning cellular activity during heating emphasize the dif-
ferences at various degrees of temperature elevations, a fact best illustrated by lymphocytes.
Whereas moderate temperature stimulate cellular activity, intense heating caused delayed
activity or even cellular death. Continuous or intermittent heating can also promote the
development of thermotolerance, although the mechanism is still obscure.

BLOOD AND BLOOD FORMING ORGANS

Elevated temperature may produce various changes in the hemopoietic system. The most
common effect of experimental or therapeutic heating on the blood cells is leukocytosis.
However, endotoxin injection or hyperthermia may first cause leukopenia.25 26 which is then
followed by leukocytosis,27 often with a left shift, which is more pronounced in women
than men. The primary leukocytosis with neutrophilia and a relative lymphopenia is due to
enhanced migration from bone marrow.
Thermosensitive lymphocytes are destroyed by elevated temperatures, resulting in an
absolute lymphopenia.9 Depending on the degree of heat, transient lymphocytosis may be
noted.
There is general agreement that heating reduces the number of circulatory eosinophils,
but there is a controversy concerning the monocytes, some reporting monocytosis, others
describing monocytopenia. There is general agreement that in the initial stages a decreased
monocyte count is seen.
After a brief exposure to heat, the number of platelets in peripheral blood rises, but 7
days after hyperthermia, a decrease may be seen. During heat stroke, thrombocytopenia and
bleeding have been demonstrated, and megakaryocytes may even disappear from the bone
marrow.11
The changes in red blood cells with temperature elevation are usually less striking.
Erythrocytosis occurs in the first stage as a result of hemoconcentration, whereas severe
hyperthermia causes hemolysis and a consequent reduction in the erythrocyte count.

CARDIOVASCULAR SYSTEM
The effect of fever on the heart rate is known for many years, as was revealed also by
Langendorff’s review from 1903. During the last century, many advances have been made
by precise laboratory experiments.
On the cellular level, there are differences in the thermosensitivity of various myocardial
cells: sinus node and atrium cells are the most resistant, whereas left ventricular muscle
cells are the most sensitive to hyperthermia.
Anatomopathologie examinations have demonstrated cellular damage in the form of
subendocardial and intramyocardial hemorrhages, fatty degeneration of myofibrils, and oc-
casionally, necrosis and patchy calcification.
The pathophysiologic causes for the clinical changes during temperature elevation, namely,
tachycardia, arrhythmias, and conduction disturbances, and myocardial ischemia, have been
attributed to the elevated catecholamine level30 and a shift of intracellular potassium to
extracellular space.31

LIVER
The liver is a “ thermosensitive” organ as can be seen from clinical and experimental
studies. Much information on the effect of fever on the liver has been obtained from studies
performed on biopsy and necropsy material from patients with heat stroke. Similar changes
have been observed during experimental and clinical hyperthermia, namely, sinusoidal wid-
ening with blood stasis,32 fatty degeneration,33 round cell infiltration, vacuolization of hé-
patocytes, centrilobular necrosis,34 and occasionally, cholestasis and loss of glycogen. At
the electron microscopic level, shortening of microvilli, nuclear changes — increased number
of vacuoles, dilatation of Golgi elements, and endoplasmic reticulum — have been described.
26 U nex p la in ed F e ve r

The damage is proportional to the temperature elevation and also to its duration with
heat stroke causing more damage that repeated short periods of heat.

KIDNEYS
The kidney may also be the target of heat damage. Moderate elevations of temperature
have no influence on filtration rate.35 However, in patients with left heart failure, there may
be a reduction in renal blood flow, osmotic clearance, and electrolyte excretion.
The anatomopathologic changes after temperature elevation are numerous: renal enlarge-
ment with blood stasis, vacuolar degeneration, and necrosis of the tubules, infarction,
hyperplasia of the juxtaglomerular apparatus, interstitial inflammation with infiltrates, pig-
ment deposits in the tubular lumen36 and lower nephron nephrosis.
Recent studies on experimental animals and men showed that elevated temperature cause
a rise in the plasma renin activity. It seems that the mechanisms underlying this phenomenon
is not simply sympathetic stimulation, but that other factors such as reduced glomerular
filtration, a low concentration of Na+ in macula densa play a role.37

ENDOCRINE SYSTEM
The endocrine system plays an important role in heat regulation and acclimatization,
the regulatory mechanisms are only partially known. Various studies have shown that the
endocrine glands react in different ways to heating, depending upon duration and degree of
temperature elevation.
The most important features of heat effects on the specific glands will be summarized.

Hypophysis
Histologic studies of this gland have been carried and on tissue exposed to prolonged
hyperthermia, several changes were observed in rats including reduced cell size, increased
number of chromophobe cells, and a decreased quantity of acidophilic cells,38 with variable
nuclear size.
Hypophyseal function is also altered by heating, with hypersecretion of ADH, ACTH,
GH, prolactin in man, and gonadotropins in rats.

Adrenals
Prolonged elevated temperature causes histologic changes of the adrenals, with atrophy
of zona glomerulosa and fasciculata and an increased mass of the zona reticulosa. The
secretion of glucocorticoids is unchanged or even reduced during prolonged hyperthermia,
whereas a short period of heating causes an increased level.39 Aldosterone concentration is
increased by both brief and prolonged heating, although its concentration is determined also
by the amount of sodium loss. Catecholamine levels were observed in a man resting in a
sauna and adrenalin concentration was found to be increased. In rats, heating causes a
decrease of adrenalin concentration and an increase of noradrenalin.

Thyroid
In mammals, the hypophyseal-thyroid axis is stimulated by heating, although sustained
heating causes a decrease of its activity.39 Hypofunction may be accompanied by low acinary
epithelium and large acini, full of colloid. The laboratory findings are variable, depending
on experimental conditions, for example, in guinea pigs, physical heating reduced T4 con-
centration.40 Injection of endotoxin reduces T3 while T4 is only slightly reduced and returns
rapidly to baseline levels.
Parathyroid
The parathyroid gland has not been extensively investigated. It is known that guinea
pigs exhibit enhanced resistance to hyperthermic challenge, being without parathyroid glands.
Long-standing heating causes no histologic changes in laboratory animals.38
 27

Pancreas
Repeated heating of ambient temperature to 42°C for 3 h in dogs caused an increase in
insulin and glucagon concentrations. It is interesting to note that the peak rise of glucagon
coincides with that of cortisol.
Sauna in man produces a rapid release of subcutaneous depot insulin that may result in
hypoglycemia in the diabetic patient.41

CENTRAL NERVOUS SYSTEM

The various neurologic symptoms which accompany heat stroke have histologic cor-
relations in the central nervous system.
Necropsy studies of human brains from patients who died after heat stroke revealed
extensive hemorrhages in the brain and leptomeninges,42 edema of the brain nuclei, degen-
eration of ganglion cells, and sometimes intravascular thrombi. The glutamate concentration
in brain decreases during overheating whereas the catecholamine level remains unchanged.
Hyperthermia causes a decrease in cerebral blood flow in immobilized rats,43 but blood
flow increases gradually as the temperature rises above 40°C. These changes are less prom-
inent in the hypothalamic region. The same authors show that overheating causes at first an
increasing neuronal activity, as long as the temperature is maintained under 43°C.
Laboratory studies revealed that the brain is more sensitive than the liver to overheating,
although the mitochondria of brain cells are more resistant.44
The electrical activity of the brain, as recorded by EEG, changes on hyperthermia43 with
an increase of evoked potentials.
Even higher brain functions are altered during high temperatures with a decrease of
counting ability, while the sensorium is extremely sensitive.45

GASTROINTESTINAL TRACT
Misiewicz et al. showed that overheating causes stomach hypomotility (without a change
in the intestinal motility) together with hypo- or even an-acidity.46
The histologic picture of the gastric mucosa shows edema and hyperemia, flattening of
the epithelial cells and, in fatal heat stroke, disseminated subserosal hemorrhages.
The gastrointestinal tract reacts to hyperthermia with reduced blood perfusion and re-
duced absorption of amino acids in jejunum and ileum.

LUNGS
The histologic picture of lungs exposed to hyperthermia is variable and nonspecific. In
experimental animals, changes such as hyperemia, atelectasis, pneumonia, dilatation of
capillary vessels, and desquamation of alveolar epithelium have been seen. Heat stroke can
cause the following injuries: hemorrhage, hemorrhagic pneumonia, acute emphysema, and
increased permeability of pulmonary vessels (lung edema).47
In man, the pulmonary function alters on overheating, with a reduced diffusion capacity
and a decrease of capillary blood volume.

SKIN
Local overheating of the skin causes vasodilation, but hyperthermia and radiotherapy
of superficial skin tumors affect the subcutaneous layers, causing edema, hemorrhage,
thrombosis, PMN infiltration and later, fibrosis, diffuse mononuclear infiltration, giant cells,
necrosis, and abscesses.

MUSCLES
Even the muscular tissue is affected by raised temperature, immediate and chronic
changes being distinguished. Immediate changes in muscular tissue of anesthetized pigs
28 Unexplained Fever

include edema, hemorrhages, and necrosis of myocytes. Late changes comprise fibrosis,
histiocytic and lymphocytic infiltration, lipid vacuoles, and giant cells. The loss of muscular
tissue can be prominent with weight loss of a kilogram per day.

JOINTS
The effect of high temperature on joints is interesting in view of the clinical implication
on various rheumatic diseases. Experimental studies have demonstrated that prolonged heat-
ing slows the synthesis and also hastens destruction of the matrix. The observations suggest
that overheating in rheumatoid arthritis can bring about further joint damage.

METABOLIC CHANGES
In the accompanying table (Table 1), various metabolic effects of fever and hyperthermia
are listed.
 29

TABLE 1
Effect of Elevated Temperature on Biochemical Parameters

Parameter Changes Ref.

Acid base balance Alkalosis usually, metabolic aci- 48, 49

dosis in sauna overwhelmed after- 50
wards by respiratory alkalosis
Serum electrolytes and minerals Na — no change
K — hyperkalemia was observed 51
Ca — hyper, — , hypo — , or nor-
mocalemia
P — hypophosphatemia
Mg — hypomagnesemia 52
Iron and ferritin — decreased con- 53
centration
Zn Cu — decreased serum level 54
Liver function tests SGPT, SGOT — elevated 55-57
Bilirubin—increased 56
LDH — increased 58
Hydroxybutyrate dehydrogenase 59
Alkaline phosphatase — no change 60, 61
Aldoase — increased 59, 62
Phosphohexoseisomerase — in- 63
creased
Acid phosphatase — increased
Lipase — increased
Omithine-carbamyl-transferase —
increased
Serum glucose Hyperglycemia 64
Hypoglycemia in dogs in over- 65
heated surrounding
Proteins No significant change 66
Sometimes a decrease in albumin 67
concentration
Prolonged hyperthermia can cause 68, 69
elevation of a and (3 globulin and
decrease of y globulin concentra-
tion
Lipid profile Hyper or hypocholesterolemia 71
Decreased lipid fommation in over- 72
heating
Triglycerides and free fatty acids 73
are unchanged
Hematologic findings Hypoprothrombinemia 74
Thrombocytopenia 75
Hypofibrinogenemia
Decrease of factor V, VI, VIII, 74, 76
concentrations
Increased capillary permeability 75, 77
Increased spontaneous fibrinolytic 75
activity
Consumption coagulopathy, DIC 78
30 Unexplained Fever

REFERENCES
1. Magno, G., The Healing Hand: Man and Wound in the Ancient World, Harvard University Press, Cambridge
1975, 56.
2. Wunderlich, C. A., On the Temperature in Diseases: A Manual of Clinical Thermometry, The New
Sydenham Society, London, 1871.
3. Stitt, Y. T., Fever versus hyperthermia, Fed. Proc., 38, 39, 1978.
4. Bennett, I. L. Jr. and Nicastri, A., Fever as a mechanism of resistance, Bacteriol. Rev., 24, 16, 1969.
5. Wolff, S. M., Fever, in Medical Microbiology and Infectious Diseases, Braude, A. I., Ed., W. B. Saunders,
Philadelphia, 1981, 794.
6. Dubois, E. F., Fever and the Regulation o f Body Temperature, Charles C Thomas, Springfield, IL, 1984,
57.
7. Lwoff, A., Factors influencing the evolution of viral diseases at the cellular level and in the organism,
Bacteriol. Rev., 23, 109, 1957.
8. Weinberg, E. D., Iron and susceptibility to infectious disease, Science, 184, 952, 1974.
9. Bernheim, H. A., Block, L., and Atkins, E., Fever: Pathogenesis, Pathophysiology and Purpose, Ann.
Intern. Med., 91, 261, 1979.
10. Roberts, N. J., Jr., Temperature and host defense, Microbiol. Rev., 43, 241, 1979.
11. Rodbard, D., Wochslicht, Rodbard, H., and Rodbard, S., Temperature: a critical factor determining
localization and natural history of infectious, metabolic and immunological diseases, Perspect. Biol. Med.,
23, 439, 1980.
12. Mackinnon, J. E., The effect of temperature on the deep mycoses, in Systemic Mycoses, Wolstenholme,
G. E. W. and Porter, R., Eds., Little, Brown, Boston, 1968, 164.
13. Zeledon, R., Blanco, E., and de Monge, E., Comparative experimental infections with Costa Rican
strains of Leishmania braziliensis Vianna 1911, Acta Trop. (Basel), 26, 136, 1969.
14. Orenberg, E. K., Deneau, D. G., and Farber, E. M., Response of chronic psoriatic plaques to localized
heating induced by ultrasound, Arch. Dermatol., 116, 893, 1980.
15. Demey, W. C. and Freeman, M. L., Rationale for use of hyperthermia in cancer therapy, Ann. N.Y.
Acad. Sci., 335, 372, 1980.
16. Hahn, G. M., Potential for therapy of drugs and hyperthermia, Cancer Res., 39, 2264, 1979.
17. Kluger, M. J., Ringler, D. H., and Anver, M. R., Fever and survival, Science, 198, 166, 1975.
18. Covert, J. B. and Reynolds, W. W., Survival value of fever in fish, Nature, 267, 43, 1977.
19. Kluger, M. J., Temperature regulation, fever and disease, in International Review of Physiology; Envi-
ronmental Physiology 111, Robertshara, D., Ed., Vol. 20, Perle Press, Baltimore, 209.
20. Pottathil, R., Chandrabose, K. A., Cuatrescasas, P., and Lang, D. J., Establishment of the interferon,
mediated antiviral states: role of fatty acid cyclooxygenase, Proc. Natl. Acad. Sci. U.S.A., 77, 5437, 1980.
21. Stanley, E. D., Jackson, G. G., Panusarn, C., Rubenis, M., and Dirda, V., Increased virus shedding
with aspirin treatment of rhinovirus infection, JAMA, 231, 1248, 1975.
22. Roberts, N. J. and Steigbigel, R. T., Hyperthermia and human leucocyte function: effects on response
of lymphocytes to mitogens and antigens and bactericidal capacity of monocytes and neutrophils, Infect.
Immun., 18, 673, 1977.
23. Dinarello, C. A., Cannon, J. G., and Wolff, S. M., New concepts on the pathogenesis of fever, Rev.
Infect. Dis., 10, 168, 1988.
24. Gerreok, L. E. and Dewey, W. C., Variation in response to heat during the mammalian cell cycle, in
Proc. Int. Symp. on Cancer Therapy by Hyperthermia and Radiation, Washington, 1975, 16.
25. Herion, J. C., Walker, R. I., and Palmer, J. G., Relation of leucocytes and fever response to bacterial
endotoxin, Am. J. Physiol., 199, 809, 1960.
26. Wolff, Sh. M., Rubenstein, M., Mullholland, J. M., and Ailing, D. W., Comparison of hematologic
and febrile response to endotoxin in man, Blood, 26, 190, 1965.
27. Hubler, W. L., Higgins, G. N., and Herrick, J. F., Certain endocrine influences governing the leucocytic
response to fever, Blood, 7, 326, 1952.
28. Latter, J. S. and Nelson, W. M., The effect of experimental hyperpyrexia and restraint on the blood and
hemopoietic organs of the albino rats, Am. J. Anat., 82, 321, 1948.
29. Knochek, J. P., Beisel, W. R., Herndon, E. G., Jr., Gerard, E. S., and Barry, K. G., The renal,
cardiovascular, hematologic and serum electrolyte abnormalites of heat stroke, Am. J. Med., 30, 299, 1961.
30. Taggart, P., Parkinson, P., and Carruthers, M., Cardiac response to thermal physical and emotional
stress, Br. Med. J., 3, 71, 1972.
31. Spurr, G. B., Barlow, G., and Lambert, H., Influence of prolonged hypothermia and hyperthermia on
cardiac response to injected potassium, Am. J. Physiol., 196, 696, 1959.
32. Reed, W. A., Manning, R. T., and Hopkins, L. T., Jr., Effects of hypoxia and hyperthermia on hepatic
tissue of the dog, Am. J. Physiol., 206, 1304, 1964.
 31

33. Wendt, F. and Budde, C., Das Verhalten der alkalischen Leukozytenphosphatase während der Initialphase
der Feiber: Reaktion nach Injektion von bakteriellem Endotoxin und endogoner Pyrogen beim Menschen,
Folio Haematol., 6, 149, 1961.
34. Schrier, R. W., Henderson, H. S., Tisher, C. C., and Tannen, R. L., Nephropathy associated with
heat stress and exercise, Ann. Intern Med., 67, 356, 1967.
35. Abramson, N., Piemme, Th.E., and Kaufman, W. C., Effect of heat stress upon human renal function,
Aerospace Med., 38, 234, 1967.
36. Kew, M. C., Abrahams, C., and Seftel, K. C., Chronic interstitial nephritis as a consequence of heat
stroke, Q. J. Med. N.S. 38, 189, 1970.
37. Gross, F., Ardeleanu, S., and Lazar, I., Plasma renin activity in hyperthermic rats, Rev. Roum. Morphol.
Embryol. Physiol., 18, 83, 1981.
38. Hale, H. B., Mefferd, R. B., Jr., Vawter, G., Foester, G., and Criscuolo, D., Influence of long term
exposure to adverse environments on organ weight and histology, Am. J. Physiol., 196, 520, 1959.
39. Collins, K. J. and Weiner, J. S., Endocrinological aspects of exposure to high environmental temperatures,
Physiol. Rev., 48, 785, 1968.
40. Shafer, R. B., Oken, M. M., and Elson, M. K., Effects of fever and hyperthermia on thyroid function,
J. Nucl. Med., 21, 1158, 1980.
41. Koivisto, V. A., Sauna-induced acceleration in insulin absorption from subcutaneous injection site, Br.
Med. J., 280, 1411, 1980.
42. Bernheim, J. and Cox, J. N., Coup de chaleur et intoxication amphetaminique chez un sportif, Schweiz.
Med. Wschr., 90, 323, 1960.
43. Yamada, N., Tanaka, R., Kanayama, T., Takeda, N., Suzuki, Y., Sekiguchi, K., and Saito, Y., The
influence of hyperthermia on brain functions — blood flow, metabolism and electroencephalography, in
Hyperthermic Oncology, Matsuda, T. and Kikuchi, M., Eds., Tokyo, 1984, 65.
44. Cristiansen, E. N. and Kvamme, E., Effects of thermal treatment on mitochondria of brain, liver and
ascites cells, Acta Physiol. Scand., 76, 472, 1969.
45. Wilkinson, R. T., Fox, R. H., Goldsmith, R., Hampton, I. F. G., and Lewis, H. E., Psychological
and physiological responses to raised body temperature, J. Appl. Physiol., 19, 287, 1964.
46. Misiewicz, J. J., Waller, Sh.L., Fox, R. H., Goldsmith, R., and Hunt, T. J., The effect of elevated
body temperature and of stress on the motility of stomach and colon in man, Clin. Sei., 34, 149, 1968.
47. Yoshikoa, M., Inoue, M., Yonezawa, T., Matsuzaki, Y., Chiyotanda, S., Sakoda, K., Onitsuka, T.,
Shibata, K., and Koga, Y., Response of extravascular lung water during systemic hyperthermia in dogs,
in Hyperthermic Oncology, Matsuda, T. and Kikuchi, M., Tokyo, 1984, 45.
48. Pomp, H., Ipach, R., and Young, Veränderung des Säure-Basen-Haushalts unter der Hyperthermie, Klin.
Wschr., 50, 383, 1972.
49. Senay, L. C., Jr. and Cristensen, M. J., Variations of certain blood constituents during acute heat
exposure, J. Appl. Physiol., 24, 302, 1968.
50. Franz-Mikoleit, R. and Schlegel, M., Die arteriellen Blutgas-spannungen in der Sauna, Arch. Phys. Ther.,
22, 13, 1970.
51. Goldberg, L. J., Ezell, H. K., and Walton, R.P., Electrocardiographic and serum potassium changes in
fatal hyperthermia, Am. Heart J., 44, 754, 1952.
52. Beisei, W. R., Goldman, R. F., and Joy, R. J. T., Metabolic balance studies during induced hyperthermia
in man, J. Appl. Physiol., 24, 1, 1968.
53. Uhari, M., Pakarinen, A., Hietala, J., Nurmi, T., and Kouvalinen, K., Serom iron, copper, zinc,
ferritin and ceruloplasmin after heat exposure, Eur. J. Appl. Physiol., 51, 331, 1973.
54. Bianchi, L., Schwerer Leberschaden nach Hitzschlag und seine Rückbildung, Scliweiz. Med. Wschr., 51,
493, 1967.
55. Shibolet, S., Coll, R., Gilat, T., and Sohar, E., Heatstroke: its clinical picture and mechanism in 36
cases, Q. J. Med., 36, 525, 1967.
56. Schrier, R. W., Henderson, H. S., Tisher, C. C., and Tannen, R. L., Nephropathy associated with
heat stress and exercise, Ann. Intern. Med., 67, 356, 1967.
57. Vascia, F. G. and Peck, O. G., Liver disease from heat stroke, Gastroenterology, 43, 340, 1962.
58. Kerkhoven, B., Müller, W. A., and Truninger, B., Laboratoriumsbefunde bein Hitzschlage, Dtsch.
Med. Wschr., 94, 1293, 1969.
59. Mendez, J., Scrimshaw, N. S., Salvado, C., and Lopez Selva, M., Effects of artificially induced fever
on serum proteins, vitamin levels and hematological values in human subjects, J. Appl. Physiol., 14, 768,
1959.
60. Mackenzie, A., McLeod, K., Cassels-Smith, A. J., and Dickson, J. A., Total body hyperthermia:
techniques and patient management, in Proc. Int. Symp. on Cancer Therapy by Hyperthermia and Radiation,
Washington, 1975, 272.
61. Scholer, H., E’Lo, Z., and Baranovic, D., Myokardalteration und Hepatopathie nach Wärmestauung und
Leistungüberforderung. Modell eine Herzschädigung als Folge ein Dekompensation der Anpassung an
peristatische Verhältnisse., Dtsch. Med. Wsch., 93, 210, 1968.
32 Unexplained Fever

62. Bedrak, E., Blood serum enzyme activity of dogs exposed to heat and muscular exercise, J. Appl. Physiol.,
20, 587, 1965.
63. Kew, M. C., Tucker, R. B. K., Bersohn, I., and Seftel, H. C., The heart in heatstroke, Am. Heart J.,
77, 324, 1969.
64. Schnetx, H., Die vegetativ nervöse Beeinflusung der Pankreassekretion, Wiener Klin. Wsch., 5, 180, 1951.
65. Kanter, G. G. and Lubinski, R. H., Cause of hypoglycemia in dogs exposed to heat, Am. J. Physiol.,
196, 629, 1959.
66. Senay, L. C., Jr. and Christensen, M. L., Variations of certain blood constituents during acute heat
exposure, J. Appl. Physiol., 24, 302, 1968.
67. Lozsa, A., Kereszti, Z., and Berencsi, G., Effect of heat and cold exposure on serum proteins, glycoprotein
and lipoproteins in the rabbit, Acta Physiol. Sei. Hung., 35, 63, 1969.
68. Malmejac, J., Cruck, S., and Neverre, G., Reactions cutanées a l’hyperthermie. Oedeme par la chaleur
et perméabilité capillare aux protides, C. R. Soc. Biol. (Paris), 145, 1516, 1961.
69. Schleich, G., Ueber das Verhalten der Hamstoffproduktion bei künstlicher Steigerung der Körpertemperatur,
Arch. Exp. Pathol. Pharmakol., 4, 82, 1975.
70. Gettler, D. T., Colip, F. M., and Schloreb, P. R., The effect of kidney hyperthermia on renal tolerance
to total ischemia, Surg. Gynecol. Obstet., 112, 559, 1961.
71. Bobek, P. and Ginter, E., Metabolism of lipids in rats exposed to heat under conditions of abnormal and
a high fat-high cholesterol diet, J. Nutr., 89, 373, 1966.
72. Taggart, P., Parkinson, P., and Carruthers, M., Cardiac responses to thermal, physical and emotional
stress, Br. Med. J., 3, 71, 1972.
73. Kerkhoven, B., Müller, W. A., and Truninger, B., Laboratori umsberunde bei Hitzschlag, Dtsch. Med.
Wschr., 94, 1293, 1969.
74. Shibolet, S., Fisher, S., Gilat, T., Bank, H., and Heller, H., Fibrinolysis and hemorrhages in fatal
heatstroke, N. Engl. J. Med., 266, 169, 1962.
75. Kessinger, A. and Rigby, P. G., Hemorrhage and heat stroke, Geriatrics, 25, 113, 1970.
76. Soahl, R. S., Shin Chien Sun, Colccolough, H. L., and Burch, G. E., Heat stroke. An electron
microscopic study of endothelial cell damage and disseminated intravascular coagulation, Arch. Intern.
Med., 122, 43, 1968.
77. Weber, M. B. and Blakely, M. B., The haemorrhagic diathesis of heatstroke. A consumpation coagulopathy
successfully treated with heparin, Lancet, 1, 1192, 1969.
78. Pettigrew, R. T. et al., Clinical effect of whole-body hyperthermia in advanced malignancy. Br. Med. J.,
4, 679, 1974.
 33

Chapter 4

THERMOMETRY
M. Burke and C. Merdier

TEMPERATURE SCALES
The most widely used temperature scale, Celsius or Centigrade, is based on a 100°
interval scale, with the fixed values of the freezing and boiling points of water at 0° and
100°, respectively. The alternative Fahrenheit system, still widely used in North America,
has the freezing point of water standardized at 32° and its boiling point at 212°, the two
values being separated by 180°. Conversion of one to the other is obtained simply by the
formulae: (See also Figure 1.)

NORMAL BODY TEMPERATURE

The normal body temperature is not constant and depends upon cyclic, environmental,
and physiologic factors. There are three cycles, namely, diurnal (circadian), monthly (men-
strual), and annual (seasonal). The circadian rhythm is characterized by diurnal temperature
changes showing a peak value in the late afternoon or early evening and a trough in the
early morning. During the menstrual cycle the average diurnal temperature is lower during
the 2 weeks prior to ovulation, when a 1°C rise occurs. The higher temperature persists until
the subsequent menses. A recent study on a general population sample has shown a seasonal
variation in body temperature with a peak in winter and a trough in summer.1 In addition,
the body temperature is affected by age, physical activity, emotion, eating, pregnancy, and
state of hydration, as well as the external temperature.
A normal person may have an evening temperature of 38°C or more, and unless the
physician makes multiple readings and performs a careful clinical evaluation, including a
history and physical examination, the condition may be incorrectly labeled a fever.21

TYPES OF CLINICAL THERMOMETERS

The mercury-in-glass thermometer—This is a modified version of the instrument used
in the days of Boerhaave and Wunderlich and is still most frequently employed for measuring
the temperature. Its major drawbacks are its relative inaccuracy,34 observer error in reading
the temperature off the scale, and the prolonged duration of placement. In order to reach
the maximal value the glass thermometer requires at least 2 to 3 min when placed rectally,5
7 to 9 min for the oral site,5a and 5 min,6 in the axilla. Furthermore, it carries the risk of
glass breakage with subsequent local tissue injury and possible mercury poisoning.
The electronic thermometer—This can reach a steady state within 30 sec. Not only
is its use time-saving, but this thermometer is also more accurate than the glass instrument4,7
and its digital recording allows a correct reading of the temperature. However, this type of
thermometer does ultimately require servicing and recharging or replacement of batteries.
34 Unexplained Fever

FIGURE 1. Conversion between Centrigade and Fahr-

enheit scales.

On the one hand, it can break just like the glass instrument, and, on the other hand, it is
more expensive. At least one report suggests it has no advantage over the glass thermometer.8
Liquid crystal temperature strips—These are devices for measuring skin temperature,
usually on the forehead. They consist of plastic-encased thermophototropic substances that
change color over a specific short range of temperature. They have been shown to be less
reliable than either mercury or electronic thermometers in detecting fever,910 or even than
mothers’ subjective assessment of fever in their children.11 However, in one study it was
found that the forehead temperature by this method was more closely correlated to the oral
temperature than was the axillary temperature.12
Thermistors—These may be placed within certain cavities, such as the esophagus,
tympanic cavity, rectum, or urinary bladder, for continuous monitoring of the temperature
in surgical or critically ill patients. They may be also placed on the skin surface.
Infrared thermometry13—This has certain potential advantages over conventional meth-
ods. Contact with the patient is not necessary. This would allow ready measurement in
children as well as patients who are asleep or comatose. In addition, the risk of cross-
infection in immunosuppressed or burned patients could be minimized. As yet, the correlation
of this method with standard thermometry is suboptimal, and the equipment is expensive.
However, infrared thermometry in the future may have a definite role in selected patients.

SITES FOR CLINICAL MEASUREMENT

There is some contention as to the ideal site for estimation of body temperature. Certain
sites are more convenient for the patient or physician, but the measurement will not always
be the most reliable. There are two main types of measurement depending on the depth of
the tissue examined: superficial (skin) or deep (“ core” ). Ideally, the physician would like
 35

to have an estimate of the core temperature. The usual sites of measurement are the mouth,
axilla, and rectum. However, on occasions, forehead and truncal skin, the groin, esophagus,
tympanic membrane, urine, and urinary bladder have been employed.
The oral temperature is convenient in most adults, although it does have several
drawbacks. Oral readings tend to be from 0.3 to 0.65° lower than values obtained rectally,
and therefore do not represent true core temperature. It is essential that the thermometer is
placed under the tongue and the patient keeps the mouth closed so that the external air does
not affect the reading.
Oral readings may be spuriously low under certain conditions, such as if the subject has
just had a cold drink, which cools the oral mucosa, in the presence of nasal obstruction
which prevents closure of the mouth, and during tachypnea, where fever may go undetected,
possibly because of subclinical mouth-breathing leading to increased evaporative cooling of
the oral cavity.14 A further drawback of the oral temperature recording is its limitation in
the intensive care unit and recovery room after surgery. The “ short’’ time required to interrupt
the oxygen mask in order to obtain an oral reading may produce severed hypoxemia.15 The
oral temperature record may be deceptively high after a hot drink which warms the oral
mucosa, but not the blood.
The uncooperative patient or young child may bite the thermometer causing self-injury
from the glass as well as possibly developing mercury poisoning. Although the thermometer
is cleaned between patients, there is a small but definite risk of cross-infection.16
The axillary temperature is the most convenient and safest site in children, and may
also be used in adults. The patient must maintain the thermometer deep in the closed axilla
in order to prevent cooling by the surrounding air. Nevertheless, it is the skin temperature
which is being measured and lack of accuracy is the major drawback of this method.
Temperature recordings at the axilla may differ widely from the core temperature. Kresch
found that temperature measurement at this site in children gave variable results with de-
creased sensitivity as well as a low positive predictive value,17 although Mayfield et al.
found that the axillary temperature was as reliable as the rectal temperature.6
The rectal temperature is considered to be the best approximation of core temperature.
Its major disadvantages are patient discomfort and the quite definite risk of complications,
especially in very young and uncooperative patients. In the infant, a rectal thermometer may
cause hemorrhage or even perforation of the rectum or colon;18 peritonitis and pneumoper-
itoneum have also been reported.19,20 Another complication is the spread of infection from
one patient to another by successive use of the same thermometer.21,22 A further potential
risk is that rectal stimulation may trigger arrhythmias in cardiac patients. Although considered
to be the most accurate estimation of core temperature, rectal temperature may be affected
by the blood flow to the lower limbs. During muscular exercise, the rectal temperature rises,
whereas the skin temperature falls as a result of sweating.
The esophageal temperature is measured after the patient swallows a temperature probe.
In the lower esophagus the temperature approximates cardiac temperature and is 0.2°C below
the rectal value. This method is clearly limited in general clinical practice. However, it is
of value when one wishes to monitor temperature during surgery. The probe may be in-
correctly placed in or be dislodged to the upper esophagus where the temperature is affected
by respiration and is markedly lower than core temperature.
The tympanic temperature is measured by inserting a thermistor probe through the
external auditory canal and allowing its tip to rest on the tympanic membrane. This reading
is usually 0.05 to 0.25°C below the rectal temperature. This technique is useful for monitoring
the temperature during the course of an operation and in the intensive care or resuscitation
unit.23 An unusual complication of the method is perforation of the tympanic membrane.24
To measure the urinary temperature, a freshly passed specimen is examined imme-
diately. The urinary temperature readings have been shown to be consistent with simulta-
36 U nex p la in ed F e ve r

neously recorded oral and rectal values.25 This examination is particularly useful for detecting
factitious fever resulting from manipulation of oral or rectal thermometers.25 26 While this
method has no complications, it does, however, require a cooperative and continent patient.
Urinary bladder temperature monitoring has been recently proposed for intraoperative
and postoperative adult patients with urethral catheters.27 This method appears to be reliable,
safe, and convenient, and gives a good assessment of core temperature.
Skin temperature is best estimated using thermistors placed on the body surface, but
may also be assessed by using liquid crystal temperature strips or by conventional ther-
mometry. The major drawback is the lack of accuracy when compared to the core temper-
ature.

THE THERMOMETER AS A CAUSE OF UNEXPLAINED

FEVER

Occasionally the patient presenting with “ unexplained fever” does not, in fact, have
fever! However, the physician has failed to recognize that either a normal individual may
occasionally have a temperature reaching 38°C in the evening or the reading on the recording
instrument, namely, the thermometer, is incorrect. The latter situation occurs mainly under
two circumstances: (1) intentionally on the part of the patient, as in factitious fever (see
Chapter 24, or (2) rarely as a result of a faulty thermometer.28 Much time can be saved if
the clinician carries out a few simple rules:

1. Use a different thermometer.

2. Note diurnal rhythm; most organic fevers follow a physiological pattern.
3. Observe patient throughout duration of temperature measurement.
4. When indicated, measure temperature at a different site, such as the urine.
5. Avoid estimating oral temperature after hot drinks.
6. Consider physiological factors: avoid measurement immediately after exercise.
7. Look for the presence or absence of accompanying clinical features, such as headache,
myalgia, arthralgia, nausea, vomiting, flushing, tachycardia, tachypnea.
8. Note subsequent defervescence unaccompanied by diaphoresis.

REFERENCES
1. Eriksson, H., Svardsudd, K., Larsson, B., Welin, L., Ohlson, L.-O., and Wilhelmsen, L., Body
temperature in general population samples: the study of men bom in 1913 and 1923, Acta Med. Scand.,
217, 347, 1985.
2. Wolff, S. M., Fever, in Medical Microbiology and Infectious Disease, Braude, A. I., Ed., W. B. Saunders,
Philadelphia, 1981, 794.
3. Dimond, E. G. and Andrews, M. H., Clinical thermometers and urinometers: determination of their
accuracy, JAMA, 156, 125, 1954.
4. Knapp, H. A., Accuracy of glass clinical thermometers compared to electronic thermometers, Am. J.
Surg., 112, 139, 1966.
5. Nichols, G. A. and Kucha, D. H., Taking adult temperatures: oral measurements, Am. J. Nurs., 72,
1091, 1972.
5a. Nichols, G. A., Taking adult temperatures: rectal measurements, Am. J. Nurs., 72, 1092, 1972.
6. Mayfield, S. R., Bahtia, J., Nakamura, K. T., Rios, G. R., and Bell, E. F., Temperature measurement
in term and preterm neonates, J. Pediatr., 104, 271, 1984.
7. Ferguson, G. T., Gohrke, C., and Mansfield, L., The advantages of the electronic thermometer, Hos-
pitals, 45(15), 62, 1971.
8. Shanks, N. J., Lambourne, A., Morton, C., and Sanford, J. R. A., Comparison of accuracy of digital
and standard mercury thermometers. Br. Med. J., 287, 1263, 1983.
 37

9. Reisinger, K. S., Kao, J., and Grant, D. M., Inaccuracy of the Clintemp skin thermometer, Pediatrics,
64, 4, 1979.
10. Scholefleld, J. H., Gerber, M. A., and Dwyer, P., Liquid crystal forehead temperature strips: a clinical
appraisal, Am. J. Dis. Child., 136, 198, 1982.
11. Banco, L. and Veltri, D., Ability of mothers to subjectively assess the presence of fever in their children,
Am. J. Dis. Child., 138, 976, 1984.
12. Masters, J. E., Comparison of axillary, oral and forehead temperature, Arch. Dis. Child., 55, 896, 1980.
13. Hughes, W. T., Patterson, G. G., Thornton, D., Williams, B. J., Lott, L., and Dodge, R., Detection
of fever with infrared thermometry: a feasability study, J. Infect. Dis., 152, 301, 1985.
14. Tandberg, D. and Sklar, D., Effect of tachypnea in the estimation of body temperature by an oral
thermometer, N. Engl. J. Med., 308, 945, 1983.
15. Felton, C. L., Hypoxemia and oral temperatures, Am. J. Nurs., 78, 56, 1978.
16. Saxena, S. K., Chaudhary, S. K., and Saxena, G. R., Risk of transmission of HB-Ag throughoraluse
of thermometer (letter), J. Assoc. Physician India, 30, 339, 1982.
17. Kresch, M. J., Axillary temperature as a screening test for fever in children, J.Pediatr., 104, 596, 1984.
18. Leading article, Hazards of temperature taking, Br. Med. J., 1,4, 1970.
19. Greenbaum, E. I., Carson, M., Kincancammon, W. N., and O’Loughlin, B. J., Rectal thermometer-
induced pneumoperitoneum in the newborn, J. Pediatr., 44, 539, 1969.
20. Horwitz, M. A. and Bennett, J. V., Nursery outbreak of peritonitis with pneumoperitoneum, probably
caused by thermometer-induced rectal perforation, Am. J. Epidemiol., 104, 632, 1976.
21. Im, S. W. K., Chow, K., and Chau, P. Y., Rectal thermometer mediated cross-infection with Salmonella
wandsworth in a paediatric ward, J. Hosp. Infect., 2, 171, 1984.
22. McAllister, T. A., Roud, J. A., Marshall, A., Holland, B. M., and Turner, T. L., Outbreak of
Salmonella eimsbuettel in newborn infants spread by rectal thermometers, Lancet, 1, 1262, 1986.
23. Murray, H. W., Tuazon, C. U., Guerrero, I. C., Claudio, M. S., Ailing, D. W., and Sheagren, J.
N., Urinary temperature: a clue to early diagnosis of factitious fever, N. Engl. J. Med., 296, 23, 1977.
24. Ellenbogen, C. and Nord, B. M., Freshly voided urine temperature: a test for factitial fever, JAMA, 219,
912, 1972.
25. Benzinger, M., Typanic thermometry in surgery and anesthesia, JAMA, 209, 1207, 1969.
26. Tabor, M. W., Blaho, D. M., and Schriver, W. R., Tympanic membrane perforation: complication of
tympanic thermometry during general anesthesia, Oral Surg., 51, 581, 1982.
27. Lilly, J. K., Boland, J. P., and Zekan, S., Urinary bladder temperature monitoring: a new index of body
core temperature, Crit. Care Med., 8, 742, 1980.
28. Martin, E. A., The thermometer as a cause of F.U.O. A report of two cases, J. Irish Med. Assoc., 61,
163, 1966.
 39

Chapter 5

APPROACH TO THE FEBRILE PATIENT

Benedict Isaac

INTRODUCTION
A large number of patients with febrile diseases come daily to the attention of physicians;
they involve consideration of a great number and variety of etiologic factors. Most of these
patients will be assessed initially by the general practitioner or the pediatrician. A great part
of their diseases, mostly viral in origin, and self-limited — will resolve within a short time,
even at the time of presentation. But, when the cause is not obvious, fever becomes a
worrisome problem for the patient and the physician alike. Every author writing about the
approach to the febrile patient underscores that it is a difficult challenge to the physician.
The necessary work-up is demanding, difficult, sometimes frustrating, but also very inter-
esting and often rewarding. It is one of the most difficult and fascinating problems of clinical
medicine. It requires various qualities: the physician must have an open mind and a good
knowledge of the multiple causes of febrile conditions, must be guided by reason and good
clinical judgement, must be meticulous and at the same time must never forget to give to
the unhappy patient understanding and compassion.
Unfortunately, there is not a unique diagnostic strategy to follow in every patient; there
are a lot of causes of febrile states and many febrile diseases have similar nonspecific
associated signs and symptoms, such as headache, myalgias and/or arthralgias, asthenia,
anorexia, hepato- and/or splenomegaly. A systematic approach to the problem is required.
A basic principle is that fevers of unknown origin are more often due to atypical presentations
of common diseases than to common presentations of atypical diseases.30 We shall endeavor
to describe clinical guidelines, conceived, if possible, as a “ systematic comprehensive
protocol” in order to reach the correct diagnosis.
The purpose of the approach is to gather all kinds of information which may be able to
aid in the decision-making process for establishing the diagnosis. The diagnostic evaluation
involves the composition of a complete data base consisting of medical history, physical
examination, and initial laboratory and imaging tests. This data base may provide pertinent
information or leads for further tests and procedures. If at the initial assessment, a patient
does not appear seriously ill, and improves within a few days, a more extensive investigation
is unwarranted. However, if the fever persists, the patient must be instructed to rest and to
record his temperature four times daily, at fixed hours (7 — 12— 17:30 — 21); one must
initiate also basic investigations.
The sequence in which we shall discuss the main aspects of the approach is as follows:

1. Clinical features of fever

2. The medical history
3. The physical examination
4. Establishing the diagnosis
5. The problem list

CLINICAL FEATURES OF FEVER

Fever is defined as any temperature greater than normal for a particular individual. For
most authors, oral temperature above 37.0°C (98.6°F) in persons confined to bed, and above
37.2°C (99.0°F) in persons who are moderately active, may be generally considered as fever.
40 U nex p la in ed F e ve r

TABLE 1
Diseases Manifested by Chills

Diseases Manifested by Single Chill

Infectious
Viral: Influenza
Rickettsial: Typhus (epidemic)
Bacterial: Lobar pneumonia, erysipelas
Tularemia: Leptospirosis, osteomyelitis, sepsis (puerperal or following instrumentation, particularly in the
urological setting)
Noninfectious
Acute hemolytic crises

Diseases Manifested by Recurrent Chills

Infectious
Bacterial: Septicemia, infective endocarditis, cholangitis, abscess formation, brucellosis, rat-bite fever,
thrombophlebitis (pelvic, lateral sinus, pyelephlebitis)
Protozoal: Malaria
Noninfectious
Neoplasms: Lymphoma, leukemia, hypernephroma. Repeated use of antipyretics in a patient with sustained
fever

Rectal temperatures are usually 0.3° to 0.6°C (0.5° to 1°F) higher. According to Reese,1
any oral temperature above 37.8°C (100°F) is ordinarily considered fever, and diurnal var-
iation may normally be as much as 1°C (1.8°F) or more, in any given individual.
There are some accompaniments of the febrile episode varying from one case to another:
chills, sweating, convulsions, delirium, and herpetic lesions. One may add albuminuria as
a frequent laboratory accompaniment. All these clinical features may sometimes provide
clues for diagnosis.
The tolerance of fever is variable and depends on the underlying disease and the reactivity
of the patient: in tuberculosis and brucellosis some patients may be unaware of fever as high
as 39.5°C (103°F).2 A good tolerance of fever may also be sometimes found in infective
endocarditis, in Hodgkin’s disease, and in localized infections. One may appreciate the
tolerance of fever by very simple means: to check simultaneously the respiratory rate, the
pulse, and the blood pressure. Upon such simple clinical tests, it is possible to detect the
first signs of disturbances in acid-balance; tachypnea is one of the first symptoms of a poor
tolerance of fever.
Chills — A chilly sensation occurs in almost all fevers, especially in viral and bacterial
infections. A true chill is accompanied by chattering of the teeth and shivering. The skin
becomes pale, cyanotic, and covered with “ goose flesh’’. This state may continue for 10
to 40 min, then the skin becomes pink and warm and there may be sweating. Antipyretic
drugs (especially aspirin), may precipitate or perpetuate chills. Chills may occur singly and
are often prominent at the onset of the febrile disease or may be multiple4 (see Table 1).
Sweating — This is seen in the phase of defervescence of the febrile episode. During
this phase, heat loss is intense. Sweating can lead to a great loss of water (at a maximal
rate 8 to 10 liters per day). Profuse sweating suggests brucellosis, rheumatic fever, tuber-
culosis, acute osteomyelitis, pyelonephritis, postpartum infection, or hyperthyroidism.
Convulsions — Associated with fever, these occur particularly in infants and children
less than 5 years old, especially at the onset of infectious diseases and usually at temperatures
higher than 41.1°C (106°F). The most frequent cases, in children, are associated with otitis,
meningitis, or meningoencephalitis. Occasionally, convulsions may occur also in adults in
association with the following febrile (or potentially febrile) diseases: bacterial meningitis,
viral, treponemal or parasitic encephalitis, brain tumor or abscess, Gram-negative sepsis
 41

with shock, delirium tremens, barbiturate withdrawal syndrome, acute nephropathy, renal
failure of SLE, neoplasms in the terminal phase, intractable congestive heart failure, old
cerebral infarcts, thyrotoxic storm, porphyria, heat stroke, dehydration, abrupt cessation of
steroid therapy, and Reye’s syndrome. Fever may precipitate seizures in epileptic patients.
The differential diagnosis of seizures associated with fever includes the ingestion of
convulsant drugs such as isoniazide, imipramine, theophylline (or other xanthique bases),
nalidixic acid (Neggram), and nitrofurantoin (Macrodantin).
Confusion and delirium — These are sometimes associated with high fever, especially
in the elderly and the alcoholic. Usually, the delirium of febrile diseases is mild and consists
of incoherence of verbal expression interrupted by periods of lucidity (quiet delirium).
Confusion and delirium depend not only on the degree of the fever, but also on the nature
of the underlying disease and the psychological state of the patient. In a case of fever
associated with confusion and/or delirium, without any obvious cause, one must search for
(a) infection (sepsis, pneumonia, typhoid fever, rheumatic fever, meningitis, especially
tuberculous, encephalitis); (b) a neurological disease (vascular, neoplastic, subarachnoid
hemorrhage, subdural hematoma); (c) a metabolic disorder (thyrotoxicosis, porphyria); (d)
a drug intoxication.
Fever blisters — Herpetic lesions occur frequently about the mouth and the lips, in
certain febrile diseases. These are single or multiple clusters of small vesicles filled with
clear fluid, on slightly raised inflammatory bases. Primary herpes infection in childhood is
frequent; in 70% of healthy adults one may disclose antibodies to herpes virus.3 Herpes
simplex virus resides in a quiescent state within nerve tissue. Some febrile illnesses may
reactivate the latent herpetic infection. The painful vesicles may persist for a few days, then
begin to dry, forming a thin yellowish crust. Fever blisters appear especially in pneumococcal
pneumonia, meningococcal meningitis, streptococcal infections, malaria, and rickettsioses.
Proteinuria — A transient proteinuria is often observed in many febrile diseases. Readily
available dipsticks permit simple, daily, rapid testing; they may detect as little as 50 mg
protein per liter. Normal adults may excrete up to 150 mg protein daily. More than this
amount is termed pathological proteinuria. If the 24 h excretion rate of protein is more than
1 g in a febrile patient, he must be investigated for a collagen vascular disease, multiple
myeloma, acute pyelonephritis, or renal tuberculosis.

CHARACTERISTICS OF THE FEBRILE EPISODE — FEVER

PATTERNS
The classical features of the fever patterns have, to a great extent, lost their value.5
Antipyretics, antibiotics, steroids, and other medications alter the course of the underlying
disease and the fever curve. Sometimes the data furnished by the fever pattern may be useful
in providing a clue for a diagnosis.
The mode of onset and the way of development of the febrile episode have three main
types:

1. Acute — The sudden frank increase of temperature, often accompanied by chills,

which may be caused, in most cases, by a viral, bacterial or parasitic infection. But
there are also cases with acute onset, of noninfectious cause (e.g., acute hemolytic
crises, acute leukemia, SLE, allergic or drug reactions, sickle cell crisis).
2. Progressive — The elevation of temperature is slight and high fever is attained after
many days. It suggests typhoid fever, tuberculosis, Hodgkin’s disease.
3. Insidious — The precise day of the beginning of the fever is ignored. It suggests
infective endocarditis, collagen vascular disease, tuberculosis, neoplasia.
42 U nex p la in ed F e ve r

The febrile episode is frequently divided into three phases: (1) chill, (2) plateau, and (3)
defervescence. Modem treatment has also altered these features. Body temperature has
normally a diurnal variation, as much as 1.1° to 1.7°C (2° to 3°F), with a peak at about 5
to 6 P.M. and the nadir at approximately 4 to 5 A.M. The fever pattern in most infected
patients follows such a diurnal variation.5 This variation may be reversed in some cases of
disseminated tuberculosis, typhoid fever, and polyarteritis nodosa.6
The various fever patterns are

1. Sustained — A persistent elevated temperature with a small diurnal variation, 0.3°C

(0.5°F) or less. Examples include bacterial diseases (pneumococcal pneumonia, typhoid
fever, brucellosis, tularemia), rickettsiosis (Rocky Mountain spotted fever), chlamydia
(psittacosis), central nervous system infections, drug fever (in most cases).
2. Remittent — The temperature is elevated and it falls each day, but not to normal.
This is the most common type of pattern. Examples include acute respiratory viral
infections, tuberculosis, mycoplasma pneumonia, P la sm o d iu m fa lc ip a ru m malaria,
infections with L eg io n e lla .
3. Intermittent — The temperature is elevated, but falls to normal (or below) each day.
A spiking, hectic or septic fever is said to occur when there is a large difference
between the peak and the nadir. This pattern is observed especially in biliary and
urinary tract infections, acute infective endocarditis, lymphomas, malaria, miliary
tuberculosis, visceral leishmaniasis and frequent use of antipyretics. When a paroxysm
of intermittent fever occurs daily, the type is q u o tid ia n ; when on alternate days, tertian
(P lasm o d iu m viva x ); when 2 days intervene between consecutive attacks qu artan (P la s-
m odiu m m a la ria e). Alternate-day fever may be observed sometimes in alternate-day
dosage schedules of steroids. A daily double fever spike may be observed in gonococcal
endocarditis, adult Still’s disease, miliary tuberculosis, Legionnaires’ disease, and
Kala-azar, but it may be necessary to check the temperature every 2 h to state precisely
this pattern.
4. Relapsing or recurrent — The febrile episodes are separated by periods of normal
temperature. Examples include borreliosis, rat-bite fever, dengue, biliary obstruction,
diverticulitis, inflammatory bowel disease (Crohn’s disease, ulcerative colitis) and
some types of granulomatous diseases. This pattern in brucellosis is called also undulant
fever and in Hodgkin’s disease, Pel-Ebstein fever. Cyclic neutropenia is an unusual
hematologic disorder characterized by episodes of neutropenia and fever at 21-day
intervals.
5. Low grade fever — Usually below 38°C (100.4°F) with small diurnal oscillations
6. Bi-phasic (or camel-back) pattern — In some infectious diseases there may be a
prodromal febrile phase, followed by a variable period of apyrexia and then, by a
second febrile phase. Examples include poliomyelitis, dengue, leptospirosis (pomona
and mitis) and Colorado tick fever
7. Irregular pattern — Not characterized by any fixed rule, continuity or rate, seen
especially in factitious fever

In fact, all authors agree that a fever pattern cannot be considered pathognomonic for any
particular disease. However, when the temperature is recorded for a longer period of time,
the character of the fever curve, may, at times, yield clues for diagnosis. According to
Dinarello and Wolff7 there are some notable exceptions in which the fever curve is most
suggestive of a specific diagnosis, e.g., (1) malaria (tertian and quartian); (2) cyclic neu-
tropenia, and, to a lesser extent, (3) the Pel-Ebstein curve (Hodgkin’s disease).
Fever may be absent or diminished in the newborn, the elderly, the severely ill, in
uremia, and in patients receiving corticosteroids or an excessive dose of antipyretics. The
 43

circadian rhythm is absent in neonates and infants; it is well established after 2 years. Young
children may have exaggerated febrile reactions, even in mild infections. The diurnal tem-
perature difference tends to be greater for children than for adults and greater in young
women than in young men.8 A relative bradycardia (temperature-pulse disproportion) may
be observed in typhoid fever, Legionnaires’ disease, brucellosis, psittacosis, leptospirosis,
and factitious and drug fever. An increase in the pulse rate relative to the temperature may
be observed in multiple small pulmonary emboli, diphtheria, and clostridial infection.

EXTREME PYREXIA
Temperatures in excess of 41.2°C (106°F) is rarely caused by an infection: bacterial
meningitis, pneumonia, miliary tuberculosis, AIDS, malaria, and bacterermia (especially
due to Gram-negative organisms). According to Simon,910 extreme elevations of body
temperature are often caused by defective thermoregulation, represented by (1) increased
heat production: malignant hyperthermia, thyrotoxicosis, pheochromocytoma and exercise
hyperthermia; (2) decreased heat dissipation (heatstroke, dehydration, autonomic disfunction,
occlusive dressings and atropine); (3) hypothalamic disorders (encephalitis, granulomas,
tumors, trauma, vascular insults, and antipsychotic drugs). In many cases, combined dis-
orders (infection associated with thermoregulatory failure) are responsible for the extreme
pyrexia.
High degrees of fever may cause complications, sometimes severe: dehydration, febrile
seizures, delirium, unconsciousness and even permanent brain damage. In elderly patients,
especially those with cardiovascular or chronic lung diseases, hyperthermia may precipitate
severe coronary complications, arrythmias or congestive heart failure.
A high fever, out of proportion with the clinical well-being of the patient suggests either
factitious or drug fever.

LOW GRADE FEVER

In recent years, little attention has been paid in the Anglo-Saxon medical literature to
this aspect of prolonged fever. In the 1930s and 1940s a great number of studies on this
subject were published in the U.S. and Europe including a monograph from Italy based on
the study of 615 cases.11 Keefer and Leard’s book12 contains a vast bibliography and a
number of illustrative cases.
Even today many patients seek medical advice for low grade fever; the problem continues
to be of considerable importance. The following possibilities must be considered in a case
of prolonged low grade fever:

1. Psychogenic fever. The body temperature is labile in some persons and may be elevated
by emotional stimuli. This aspect is discussed in Chapter 24.
2. Habitual hyperthermia, i.e., an oral temperature of 99° to 100.5°F (37.2°C) persisting
for weeks or months. Most of these patients are young women. Extensive clinical and
laboratory investigation disclose no abnormalities. Weinstein13 notes that “ Simulta-
neous determination of the oral and rectal temperatures fails to demonstrate the usual
difference of about 1°F (0.6°C).’’ Petersdorf and Root14 mention that “ Possibly, there
are some persons whose normal temperature is in this range; however there is no
certain way of identifying such individuals.’’ Winckelmann et al.15 in West Germany
carried out a study on 100 patients (85 women and 15 men), presenting with low grade
fever for at least 4 months. The age of the patients was between 16 and 61 years.
Organic diseases were excluded after extensive evaluation. We quote a part of the
conclusions of the authors: “ Compared with 100 healthy control subjects, these patients
had inadequate movement-dependent temperature elevations with a usually pronounced
discrepancy between the rectal temperature, predominantly more than 38°C and a
44 U nex p la in ed F e ve r

normal or only slightly raised axillary temperature, recorded after bodily movement.
Other characteristics were that the elevated temperature was uninfluenced by antipyretic
drugs. Harmless faulty regulation of body temperature, special constitutional reactivity,
psychological factors and possibly previous febrile infections are likely to be involved
as precipitating causes.
3. Indication of organic disease. The approach to prolonged low-grade fever should be
the same as for fevers higher than 100.4°F (38°C). Organic diseases which may
frequently evolve with low grade fever include focal infections, mild forms of some
infectious diseases (especially typhoid fever in vaccinated persons), brucellosis, in-
fectious mononucleosis, leptospirosis, the convalescence of influenza, thyrotoxicosis,
anemia, tumors (uterine myomas), hematomas, and metal intoxications. In infective
endocarditis and chronic malaria one may observe long periods of low grade fever
interchanging with episodes of high fever.

THE MEDICAL HISTORY

The first step in a systematic approach to the patient with unexplained fever is a complete
and high detailed history. The ability to secure a good history is a skill which requires
training, perseverance, a good knowledge of febrile conditions and clinical judgment. A
routine mechanical recording of data cannot realize a good medical history. Printed forms
with a systematic number of questions may only serve as reminders. The particular clinical
setting of the actual patient and his own complaints must guide the discussion and the
investigations.16 18 A plan of execution comprises the following aspects:

1. The present illness. The description of complaints, which should be recounted by the
patient himself. The physician must appreciate the patient’s personality (lucid, appre-
hensive, calm). Not always may he or she present an objective account of the illness.
Chief complaints, as noticed by the patient, may differ from the signs and symptoms
as recorded by the physician. Frequently, important information may be obtained from
the spouse or another member of the family, from a friend or a neighbor. Sometimes
it may be necessary to communicate with physicians or hospitals that have treated the
patient in the past. One may combine interrogation and listening. Important questions
are the mode of onset of the febrile episode, its duration, the clinical accompaniments,
and the main complaints. In general, the admission history should not be definitive.
New insights may emerge from repeated questioning on a daily basis. Continuation
notes should record the disappearance of some symptoms and the appearance of new
ones.
2. The past history must include any events in the patient’s life which may have been
of pertinence: childhood diseases, allergies or idiosyncrasies, previous medical or
surgical illnesses, exposure to infectious agents, toxins, humidifiers, and animals. One
should note also dental treatment, trauma, travel, prolonged recumbency, diagnostic
procedures (especially invasive). In the female one must record menstrual disorders
or other abnormal bleeding, evolution and complications of pregnancies, the use of
oral contraceptives and menopausal troubles. A daunting challenge for the clinician
is the immunocompromised patient. Facing a case with a protracted unexplained fever,
the attending physician should consider a breakdown in the patient’s defense mech-
anisms which may favor a superinfection. For further details the reader is referred to
Chapter 21.
3. The family history may also provide diagnostic clues. Some disorders may have a
genetic pattern. The following ethnic origins may suggest certain diseases: African
blacks, hemoglobinopathies, especially alpha and beta thalassemias; Armenians and
 45

Sephardic Jews, familial Mediterranean fever; Ashkenazi Jews, familial dysautonomia

(Riley-Day syndrome), Gaucher’s disease; Chinese, alpha thalassemia, G6PD; Med-
iterranean peoples (Greeks, Italians), beta-thalassemia, F.M.F.: Northern Europeans,
cystic fibrosis; South African whites, porphyria variegata. In addition, certain poten-
tially febrile disorders may have a familial or hereditary basis: tuberculosis, neoplasia,
collagen vascular diseases (SLE, rheumatoid arthritis), diabetes mellitus, diabetes
insipidus, acute intermittent porphyria, sickle-cell anemia, Wilson’s disease, Fabry’s
disease, chronic granulomatous disease, bronchiectasis, chorea, megaloblastic anemia,
pancreatitis, familial colonic polyposis, hereditary spherocytosis, retinoblastoma, scurvy,
congenital agammaglobulinemia, and pheochromocytoma. One should note the im-
portant illnesses and the cause of death of immediate relatives.
4. Social and occupational history. One should record the patient’s age, weight, profes-
sion, economic status, residence, work and social life, sexual life, excessive use of
tobacco or alcohol, poor food habits, malnutrition, emotional factors, and psychiatric
problems (obsessions, anxiety, depression). Evaluation of all the drugs and other
various treatments received by the patient is mandatory. There are medications (e.g.,
corticosteroids) which may alter the response to the illness, the physical changes, the
mental state and even the laboratory data. Concerning the occupational history, one
must record consecutively the dates and times of the patient’s jobs and especially those
with exposure to noxious substances or infections. There may be a long latent period
between exposure to the chemical carcinogen and the development of a neoplasm.
Other environmental hazards which must be considered are (a) travel history which
should include all the patient’s journeys, — recent or old, — during his life, and the
countries where he lived in the past; (b) animal contact: pets, hunting, fishing, camping
and eating of raw or game meat which may favor various infectious diseases or food-
poisoning.
5. Epidemiologic data. It is of great importance to know: Any endemic or epidemic
disease in or around the place where the patient is living or where he spends his
weekend or holidays; the health of the patient’s close contacts (family, friends, neigh-
bors, comrades at work). Concerning the food habits of some persons, one must
mention that: raw meat can transmit salmonellosis, toxoplasmosis, trichinosis, taenia;
seafood can transmit salmonellosis; raw milk and some varieties of cheese can transmit
brucellosis, salmonellosis, mycobacteria; watercress can transmit liver fluke infection
{Fasciola hepatica). Concerning febrile diseases associated with animal or insect ex-
posures, we refer the reader to Table 2. One should note all the vaccinations performed
and the results of tuberculin tests (if they were performed).

Some symptoms42,43 resulting from the febrile state may be habitual accompaniments:
headache, asthenia, lack of appetite, arthralgia, myalgia, lumbar pain. Esposito and Gleckman19
have emphasized the importance of paying attention to poorly characterized, vague and
ostensibly trivial complaints. Thus, very often, patients with unexplained fever have atypical
manifestations of their disease, slight or transient, and many symptoms are not readily
recalled during routine questioning. Some of the above-mentioned accompaniments may be
more pronounced and deserve additional comments.
A persistent and severe headache may suggest temporal arteritis, an intracranial ex-
panding lesion, the onset of a meningitis (even without signs of meningeal irritation), typhoid
fever or brucellosis. Headache associated with facial pain suggest sinusitis. Severe myalgia
may occur in (1) viral diseases (Bornholm disease, dengue, Colorado tick fever and in herpes
zoster, (in the prodromal phase, preceding the eruption by 4— 5 days); (2) bacterial (bru-
cellosis, tularemia, glanders); (3) spirochetal (leptospirosis, relapsing fever); (4) parasitic
(trichinosis, toxoplasmosis, malaria); (5) collagen vascular diseases (polyarteritis nodosa,
rheumatic fever).
46 U n ex p la in ed F ever

TABLE 2
Febrile Diseases Associated with Animal or Insect Exposure (Contact, Ingestion,
Inhalation, or Bites)

Animals

Dogs
Infection with Pasteurella multocida, Leptospira, Brucella canis, Toxocara canis, Campylobacter, Listeria
monocytogenes, Bacillus anthracis, Leishmania donovani, Pneumocystis carimi, Echinococcus, and Giardia
Cats
Infection with Toxoplasma, Pasteurella multocida, Tularemia, Campylobacter, Yersinia, Leishmania, plague
and cat-scratch disease
Cattle
Infection with Brucella, M . tuberculosis, Salmonella, Leptospira, Listeria, Campylobacter, Bacillus anthracis,
Rickettsia burnetii (Q fever), Echinococcus, and foot and mouth disease
Swine
Infection with Salmonella (cholerae suis), Brucella (suis), Trichinella, Erysipelothrix, Campylobacter, Echino-
coccus, Leptospira, and Listeria
Rodents
Infection with Leptospira, plague, Leishmania, Trypanosoma, Salmonella, Schistosoma, Rocky Mountain spotted
fever, lymphocytic choriomeningitis, Boutonneuse fever, rat-bite fever, and relapsing fever

Other Animals

Sheep, Goats
Brucella, Campylobacter, Rickettsia burnetii (Q fever), Echinococcus, Leptospira, Tularemia, M. tuberculosis
Horses
Melioidosis, glanders
Rabbits
Tularemia and Pasteurella multocida
Birds
Psittacosis (parakeets), Cryptococcosis (pigeons), Salmonellosis, Histoplasmosis (chickens)
Turtles
Salmonella

Insects

Lice:
Epidemic typhus, relapsing fever
Mosquitoes
Malaria, dengue, yellow fever, arborvirus infections
Ticks
Colorado tick fever, Tularemia, Rocky Mountain spotted fever, tickbome relapsing fever, babesiosis and Lyme
disease
Fleas
Murine typhus, plague
Deer flies
Tularemia

Severe asthenia, fatigue and/or anorexia associated with fever may occur in the prodromal
phase of viral hepatitis, in tuberculosis, typhoid fever, collagen-vascular diseases (especially
P.A.N.), neoplasia, adrenal insufficiency, pernicious anemia and sarcoidosis. Asthenia and
anorexia are dependent also on the psychic condition of the patient and on the treatments
received (antipyretics and sulfonamides may diminish appetite).
Fever per se predisposes to sleep disturbance; there may be severe insomnia in typhoid
fever and in cases of jaundice evolving with fever (especially acute cholangitis).
Chronic nonproductive cough may suggest pulmonary tuberculosis, an infectious focus
ENT, bronchial carcinoma, pleural diseases (inclusive primary mesothelioma) and Q fever.
 47

Hiccup may suggest (1) an intrathoracic disorder such as pneumonia in the lower lobes,
mediastinitis or a mediastinal tumor, pericarditis, pleurisy (especially diaphragmatic), an
aortic aneurysm and, occasionally, a recent myocardial infarction; (2) an intra-abdominal
disorder such as subphrenic abscess, pancreatitis, hepatitis, hepatic metastases, and peritoneal
infection (where it may be an initial manifestation); (3) a neurologic disorder, such as
meningitis or meningoencephalitis, an intracranial neoplasm (posterior fossa tumor, cere-
bellar tumor); (4) in typhoid fever, hiccup is one of the first signs of an intestinal perforation.
Dysphagia may suggest a pharyngeal or parapharyngeal process (latero-, peri-, or re-
tropharyngeal abscess); epiglottitis; Ludwig’s angina; Zencker’s diverticulum; esophageal
tumor; aortic aneurysm; pericarditis; a mediastinal process (adenopathy, tumor, pleurisy);
tracheobronchial carcinoma and a retrosternal goiter. Dysphagia of C.N.S. or origin may
occur in some infectious or neurologic diseases with potentially febrile evolution (tetanus,
encephalitis, brain tumor).
Pain may be associated with fever in various organ system disease. Headache and
myalgias were already discussed above. Fever and abdominal pain are discussed in Chapter
7.
Several important characteristics of pain must be analyzed in a systematic order. One
must question the patient about the site, mode of onset, and duration of the pain; whether
it is localized or diffuse, constant or intermittent, radiation, intensity, aggravating or alle-
viating factors, relation to meals, occurring during the day or the night. One must distinguish
between true pain, tenderness, and a sense of discomfort. Thus, sternal and bone tenderness
may suggest marrow invasion or metastatic tumor; true pains in the region of the sternum
and/or the ribs may suggest Hodgkin’s disease, multiple myeloma, or eosinophilic granu-
loma.
Back pain associated with fever may be observed in various conditions: pyelonephritis,
perinephric abscess, renal infarction or tumor, pelvic infections, acute prostatitis, vertebral
metastases, paravertebral tumoral masses, epidural abscess, subdural empyema, subphrenic
abscess, pancreatitis or pancreatic abscess, splenic infarct or abscess, retroperitoneal hem-
orrhage, aortic dissection, diverticulitis, infective endocarditis, and multiple myeloma.

THE PHYSICAL EXAMINATION

Physical Signs as Diagnostic Clues
The physical examination must be meticulously accomplished; it must be complete and
repeated on a daily basis, since some physical signs may appear late in the course of the
disease. The physician must follow a planned program of examination, having in view the
detection of clues pointing to a particular organ or tissue.
In this chapter we cannot detail all the essential physical signs which may provide
diagnostic clues. The plan of this book — according to organ systems — allows the reader
to isolate readily specific areas of interest. We shall give in this chapter some guidelines
for a review of systems and we shall emphasize some pertinent findings. The physical
examination should include the following:

1. General appearance: — behavior, intelligence, emotional state, disturbance of con-

sciousness (confusion, depression), state of nutrition (emaciation, edema, obesity),
deformities, swelling, gait. To assess the patient’s build, one must always inquire
about loss of weight. According to Gleckman et al.20 conspicuous weight loss (greater
than 2 lb/week), in the hospital, was always associated with a serious underlying
disease. The prominence of the frontalis fossae may be indicative of significant weight
loss. The patient’s facies may provide diagnostic clues: conjunctivitis with excessive
lacrimation — and edema of the eyelids in the initial period of measles; stiffness of
the jaw (risus sardonicus) — in tetanus; sunken eyes (Hippocratic facies) in acute
48 Unexplained Fever

peritonitis; exophthalmos, (frightened face) in Graves’ disease; the pinched and blue
facies and the malar flush in advanced mitral stenosis; the anxious edematous and
cyanotic face of severe congestive heart failure; the frontal bossing, saddle nose, and
poorly developed maxilla of late congenital syphilis; the hairy gro'v h, most apparent
on the face and ears of hypertrichosis lanugosa, which may be associated with neoplasia
(carcinoma of the breast, lung, gallbladder, urinary bladder, colon, and rectum).
Acute edema of the face associated with fever may suggest trichinosis or African
trypanosomiasis. Unilateral parotitis may suggest sepsis. The facial area may harbor
occult infectious (dental, sinusitis, otitis), lacking local signs and symptoms.21 Pressure
applied over the sinuses is mandatory; pain over the orbit or forehead suggests frontal
sinusitis; pain in the temporal area, retro-orbital area, upper-nose and mastoid area
suggests ethmoidal sinusitis; facial pain localized to the cheek or maxillary teeth
suggests maxillary sinusitis. Any particular position of the patient, when he lies in
bed, may provide a diagnostic clue such as orthopnea, to alleviate the dyspnea in
severe heart failure or respiratory insufficiency; the opisthotonos of tetanus; the lateral
decubitus on the affected side in a large pleural effusion, a large pneumothorax or a
pulmonary tumor; the ventral decubitus in abdominal colics; the stiff neck of acute
meningitis; the patient with retroperitoneal masses who prefers to jackknife his legs
onto his abdomen; the patient with acute pericarditis who cannot lie flat for his pains
are relieved by sitting up and leaning forward.
2. Skin and lymph nodes — Before performing the examination of the various organ
systems, it is mandatory to strip the patient and to carry out, by daylight, a meticulous
observation of the skin (including axillae, breasts, folds, genitalia, peri-anal region,
the soles, and the palms). The skin can harbor manifestations of various diseases, both
infectious and noninfectious, some of them life-threatening. One must note pallor,
cyanosis, jaundice, eruption, hemorrhage, and pigmentation. The skin can be the portal
of entry of a pyogenic infection; a meticulous search of pyoderma, wound, decubitus
ulcer, and trace of previous furuncle must be done. Cutaneous diagnostic clues may
suggest collagen-vascular disease; the characteristic malar “ butterfly erythema’’, the
discoid lesions, and the erythematous, firm, maculopapular lesions of the face, neck,
upper chest, and back of SLE; the urticaria, purpura, papules, nodules, vesicles, and
necrotic ulcerations of vasculitis; the shiny and atrophic skin over the fingers and the
palmar erythema of rheumatoid arthritis; and the maculopapular erythema of adult
Still’s disease. A cutaneous punch-biopsy may frequently identify the vascular lesions
which sometimes may require immediate therapy. The focal nodular lesions of the
skin and/or subcutaneous tissue may also provide diagnostic clues; they may suggest
sarcoidosis, P.A.N., and especially subcutaneous metastases. Biopsy of these nodules
may reveal a hitherto unsuspected primary tumor (carcinoma of the lung, pancreas,
breast, gastrointestinal tract, hypernephroma, thyroid, ovary, and uterus), sometimes
at a treatable stage.
The lymph nodes must be checked in the area of the neck, axilla, supraclavicular,
epitrochlear, and groin. One must note if they are localized or generalized, distinct or
fused together, adherent to adjacent structures, tender, firm or fluctuant. For further
information we refer the reader to Chapters 12 and 13.
3. Head and neck — The head is examined for shape, deformities, and the hair distri-
bution. The neck is examined for mobility, tenderness, adenopathy or other palpable
masses, carotid pulsations or bruits, vein distension, hepatojugular reflex, tracheal
deviation, and thyroid enlargement.
4. Mouth and throat — One must note the condition of the teeth, the oral mucosa, the
gums, the tongue, the palate and, the uvula. An infected oral cavity provides a potential
source of severe infections such as infective endocarditis and pulmonary suppuration.
 49

Bleeding from the gums and/or oral mucosa, associated with fever, may be observed
in Waldenstrom’s macroglobulinemia, in Vincent’s infection (Fusospirochetosis); in
acute herpetic gingivostomatitis, acute leukemia, infectious mononucleosis, and scurvy.
Vesicular, bullous, or ulcerative lesions of the oral mucosa, pharynx, or tongue,
associated with fever, may be seen in herpangina (Coxsackie virus A), acute herpetic
gingivostomatitis; chickenpox; infectious mononucleosis; hand-foot-and-mouth dis-
ease; erythema multiforme, histoplasmosis, acute leukemia, secondary syphilis, re-
current aphtous stomatitis (fever in severe attacks), and Behcet’s syndrome. Some
characteristic aspects of the tongue in potentially febrile diseases are strawberry in
scarlet fever, bald (atrophy of papillae) in syphilis, and pernicious anemia and fuli-
ginous in severe infections. The tonsils are examined for inflammation, exudates,
discharge, and hypertrophy. In retropharyngeal abscess the posterior wall of the phar-
ynx bulges inwards.
5. Thorax — The chest is examined by all four classical methods: inspection, palpation,
percussion, and auscultation. One must note the shape and the symmetry: some pul-
monary diseases (tuberculosis, severe obstructive airways diseases) may produce sig-
nificant deformities of the chest. Dyspnea is a frequent symptom: one must establish
whether it is produced by heart or lung disease, pulmonary emboli, exertion, anemia,
acidosis, excitement, or abnormalities of the chest wall. One should note whether
breathing is thoracic or abdominal. Any abnormal sounds such as rales, wheezes,
rubs, rhonchi, or crepitations should be noted. Concerning the cardiovascular system,
one should note also murmurs, thrills, the position of the apex beat, the carotid
pulsations, the neck veins, pulsation in unusual sites (aneurysm of the aorta), the veins
of the chest wall (collateral channels in intrathoracic growths, aneurysms). The radial
pulse (rate, rhythm, volume) and the blood pressure should be noted.
An examination of the breasts should be done for masses or growths. The nipples
should be examined for induration, discharge, or retraction. Tumulty6 recommends
the palpation of the upper borders of both trapezius muscles sustaining that “ any
condition producing inflammation of the upper or lower surfaces of the diaphragm can
result in reflex tenderness of the trapezius muscle on the affected side. ’’ Such tenderness
may suggest a pleural or pulmonary process or a liver or subdiaphragmatic abscess.
6. The abdomen — This is best examined with the patient fully recumbent. On inspection
one must notice the shape (normal; protuberant or sunken); any asymmetry or local
bulging (tumor, cyst, hernia, hepato- or splenomegaly); the presence of ascites, he-
matoma, scars, distended veins; any abnormal pulsation (aneurysm of the abdominal
aorta); the movements of abdominal wall (in paralysis of the diaphragm the normal
type is reversed; bulginess during the expiration and fall in during the inspiration); in
peritonitis there is absence of movement of the abdominal wall. One should check
tenderness (both direct and rebound); costovertebral angle tenderness; guarding, rig-
idity; masses or organ enlargement (liver, spleen, kidneys, and others); shifting dullness
and fluid thrill. Observation and palpation of the umbilicus (depression, bulginess,
nodule in the lip) may provide diagnostic clues. Intra-abdominal neoplasms, especially
carcinoma of pancreas and ovary, may metastasize early to the navel and they may
be easily biopsied.
By auscultation of the abdomen one may establish the presence of normal bowel
sounds or abnormal bruits in areas of pain or tenderness. Thus, friction rub in the area
of the liver may suggest perihepatitis or abscess; systolic bruits may be heard, over
aneurysms or, in the left upper quadrant, over partially obstructed arteries (mesenteric,
renal, splenic) in a carcinoma of the tail of the pancreas. A localized bruit heard over
the lumbar spine may represent a choriocarcinoma. In generalized peritonitis or in
ileus, bowel sounds may be reduced or absent.
50 Unexplained Fever

Rectal examination is mandatory in all cases of unexplained fever. Hemorrhoids,

fistulae, ulcerations, masses, and secondary malignant deposits may provide diagnostic
clues. In the immunosuppressed patient a perirectal abscess if often overlooked. Sig-
moidoscopy is frequently essential to exclude significant bowel disorders. A rectal
swab for bacteriological examination should be taken and biopsy performed of any
ulceration. Examination of the sacral and coccygeal areas may reveal fistula openings
or pilonidal cysts.
7. Genitourinary/pelvic — The male genitalia must be examined for rashes, swellings,
lesions, or masses. The size and consistency of each testis and epididymis should be
noted. In renal carcinoma, often evolving with fever, a varicocele may result from
obstruction of either the spermatic or left renal vein within the abdomen. A testicular
nodule may occasionally be a metastasis from a pancreatic carcinoma. In elderly men
with recurrent urinary infection, the epididymis becomes irregular, craggy, and en-
larged. Also, tender nodules in the epididymis may be observed in disseminated
granulomatous infections such as tuberculosis. In polyarteritis nodosa one may observe
tenderness, swelling, or atrophy of one or both testes. The external female genitalia
should be examined for swelling, deformities, cysts, and discharge. A gynecological
examination must be considered an essential part of a general examination in all non-
virgin women presenting with unexplained fever.
8. The extremities — These should be examined for any deformities, characteristic move-
ments or attitudes, trophic changes, clubbing, cyanosis, or edema. Clubbing of the
distal phalanges of the fingers and toes associated with potentially febrile diseases
may be observed in:
a. Pleuro-pulmonary-diseases: Chronic infections (bronchiectasis, abscess, em-
pyema); pleural neoplasms; bronchogenic carcinoma (rare with metastatic tumor);
pulmonary tuberculosis
b. Cardiac disorders: Infective endocarditis; cyanotic congenital heart diseases; car-
diac tumors
c. Alimentary system: Crohn’s disease; ulcerative colitis; neoplasms; intestinal tuber-
culosis; chronic bacillary and amebic dysentery; cirrhosis
d. Miscellanea: Hyperthyroidism; chronic osteomyelitis (especially with amyloidosis).
The bones and joints must be examined for any abnormality (tenderness, swelling,
crepitus, limitation of motion). The peripheral pulses (dorsalis pedis and posterior
tibial) must be checked. In peripheral vascular diseases the skin is shiny and hair does
not grow on ischemic regions.
9. Neurological examination — The following points should be looked for carefully:
a. Signs of meningeal irritation
b. Inspection for dermal sinuses and skin laceration in the neck, face and scalp area
c. Evaluation of the state of consciousness, pattern of breathing, gait, posture, speech,
motor function (active and passive movements), sensory function (pain, thermal),
cranial nerves (pupil size, reaction to light and distance, corneal reflex, nystagmus,
visual acuity and fields, facial asymmetry; coordination (finger to nose test), hear-
ing, taste, smell, sphincter troubles, trophic changes.
If a lumbar puncture is indicated, one should inspect attentively the back area for
presence of skin infection or previous back operation as there may cause entry of
bacteria into sterile C.S.F. or difficulties in performing the puncture.
10. Consultation with specialists — This may sometimes be mandatory. Of the greatest
importance, according to the particular case, are the ophthalmologist, otorhinolaryn-
gologist, gynecologist, surgeon, hematologist, neurologist, specialist in infectious dis-
eases, and occasionally the psychiatrist.
The ophthalmological examination is often necessary because the eyes are often
 51

involved in infectious, systemic, and neoplastic diseases. The following are some
ophthalmologic complications in diseases with potentially febrile evolution:
a. Orbital involvement with proptosis in lymphoma of the orbit, metastatic carcinoma,
retrorbital granulomatosis (Wegener), neurofibromas, orbital cellulitis
b. Band keratopathy in juvenile rheumatoid arthritis and sarcoidosis
c. Conjunctivitis in tuberculosis, syphilis, tularemia, histoplasmosis, cat-scratch dis-
ease, erythema multiforme, erythema nodosum, conjunctival lesions in viral and
chlamydial infections
d. Dry-eyes (xerophthalmia) in collagen-vascular diseases (especially SLE)
e. Marginal ulceration of the cornea in vasculitis
f. Uveitis in SLE, vasculitis, toxoplasmosis, tuberculosis, sarcoidosis, syphilis, Still’s
disease, serum sickness
g. Choroid inflammation (often in association with iridocyclitis) in toxoplasmosis,
histoplasmosis, and sarcoidosis; choroidal tubercles in tuberculous meningitis
h. Papilledema (choked disk) in intracranial pressure (tumor, abscess, hemorrhage)
i. Hemorrhage in the ocular fundi in infective endocarditis (Roth’s spots, petechial
hemorrhages in conjunctival and retinal vessels).
Examination of the eyes, and especially ophthalmascopy, is indicated in every patient
with unexplained fever, even in the absence of ophthalmologic symptoms.
11. Finally, the physician must examine, by naked eye, the urine, sputum, stools, and
vomit.

ESTABLISHING THE DIAGNOSIS

The Problem List
The diagnostic work-up in unexplained fever may be applied to a patient at various
phases in the evolution of the illness: at the beginning, after a period of investigations,
without diagnosis being reached, or the fever may occur during the course of a nonfebrile
illness or following surgery. An initial step should be a careful re-examination of the records
and results of previous tests which may have been overlooked or misinterpreted. If this
review fails to yield pertinent information, the work-up should be resumed in an orderly
manner. At the onset of the febrile episode and subsequently, the presence of fever must
be ascertained objectively. The initial laboratory work-up should consist of the following:

1. Complete blood count with differential

2. Erythrocyte sedimentation rate
3. Urine analysis and culture (including direct examination, with and without gram stain)
4. Blood cultures (aerobic, anaerobic, and on media for fungi: usually three bottles in
24 h are adequate (some authors recommend six bottles over 48 h)
5. Smears and cultures of material from the site of an infection (body fluids, discharge,
cutaneous lesions)
6. Stool examination for occult blood, for parasites and ova
7. Tuberculin skin test
8. Chest radiographs (postero-anterior and lateral)
9. To store 10 ml of serum in the freezer for acute phase titers (if serologic studies will
be necessary additional sera will be secured after 10 to 14 days, for convalescent phase
titers).

These screening tests may constitute a common starting point, but, depending on clues
elicited from the history and physical examination, additional tests may be necessary, even
on the first days. During the first week of the febrile episode, one must confirm or exclude
a number of short term, febrile diseases, both infectious and noninfectious. In the group of
52 Unexplained Fever

infectious diseases there are — in the first row — self-limited viral illnesses and, subse-
quently, bacterial infections of the throat, ear, paranasal sinuses, bronchi or urinary tract.
Short-term bacterial infections may require X-rays (sinus radiographs and other imaging
techniques) and often the aid of specialists (ENT, stomatologist). The noninfectious group
of short-lived fevers includes hemolytic crises, allergic fevers, drug fever, an acute attack
of gouty arthritis, an episode of thromboembolism. Most of these may be confirmed by
means of clinical examination, the initial laboratory work-up and some additional tests and
procedures (laboratory evaluation for hemolysis, dosage of serum uric acid, radiologic
examination of the peripheral joints, lung scan).
Rarely, fulminant herpes virus infection may occur — especially in immunocompromised
host, but also in a healthy person. Disseminated viral infection, fulminant hepatitis, hepatic
failure, pancreatitis, and other complications may lead to death within 24 to 48 h. Modem
methods of rapid diagnosis of such severe infections and therapy with new antiviral drugs
may be lifesaving.22 23 For details we refer the reader to Chapters 9 and 21.
At the beginning of the work-up for a case of unexplained fever, one must also rule out
the possibility of physiologic or functional causes, termed by Weinstein213 “ clinically benign
fevers” . The pattern of these fevers is usually low grade. Ingestion of a large meal, heavy
smoking, excessive gum chewing, strenuous physical exertion, sojourn in a hot and humid
climate, or taking a hot bath may increase the temperature from 1 to 2°F (0.6 to 1.2°C) and
sometimes more. Thus, a runner, after a race of 1 h, may develop a rectal temperature of
103.1°F (39.5°C).
During the menstrual cycle, there is a temperature rise of 1°F (0.6°C) for the 2 weeks
prior to menstruation; after the beginning of the hemorrhage the temperature returns to
normal. Reimann24 mentions rare cases of premenstrual fever till 104°F (40°C) preceded by
or associated with edema, purpura, and neutropenia. Habitual or oral essential hyperthermia
is discussed above. Emotion, excitement, or fear may also raise the temperature.
There are a lot of causes of fever, and not all can be considered simultaneously in every
patient; a systematic approach to the problem is required and a hierarchy of tests must be
established. A scale of evaluation, divided into three levels, is considered by most authors.
As a rule, level one is represented by the initial laboratory work-up, level two by a com-
prehensive row of tests and procedures, according to the pertinent clues provided by the
data base, level three by rare and complex laboratory tests and procedures (most of them
invasive), by surgical exploration or therapeutic trial. The selection of tests and their inclusion
in each of the three levels vary sometimes from one author to another. Thus, Marrie25 states
that “ sigmoidoscopy should be included for all patients” . In France, Lebas et al.26 assert
that abdominal CT succeeded, in their study on 36 patients with unexplained fever, to
establish the diagnosis in 25% of cases in less than 3 days. Some authors27 28 also include
in the first-level evaluation the following laboratory tests and procedures:

1. Liver function tests (serum transaminases, alkaline phosphatase, bilirubin)

2. Serology (anti-nuclear antibodies, rheumatoid factor, V.D.R.L.)
3. Serum chemistries and electrolytes such as glucose, urea, uric acid, creatinine, calcium,
and phosphor
4. Heterophil agglutinin test (monospot screen)
5. Antistreptolysin titer
6. Protein electrophoresis
7. Tests to rule out anergy (Candida, tricophyton, and streptokinase-streptodomase skin
tests)
8. An electrocardiogram
9. Film of clinically suspicious area
10. Diagnostic ultrasound of the heart and abdomen
11. A lumbar puncture if there are even slight clinical clues of C.N.S. involvement.
 53

This extended first-level evaluation is useful and may be accomplished during the first 10
days of investigation. It allows to obtain more clues for certain diagnostic considerations.
An important and useful technique is diagnostic ultrasonography. It is inexpensive,
noninvasive, and may lead to early diagnosis of intra-abdominal or cardiac conditions. Liver
function tests may be particularly useful for screening infiltrative and other lesions of the
liver, since this organ is frequently involved in systemic diseases.
During the course of the febrile illness and occasionally at the onset, the physician must
determine whether the case is urgent or critical, requiring immediate treatment, including
hospitalization. The following is a nonexhaustive list of such conditions:

1. Suspected severe infections, e.g., septicemia, meningitis, suspicion of infective en-

docarditis or deep abscesses in various organ systems, pneumonia with severe hypoxia,
blackwater fever (Plasmodium falciparum, the most important emergency in a patient
returning from regions with endemic malaria)
2. Suspected surgical infections, especially acute abdomen
3. Fever in a cardiovascular patient, liable to decompensation or other complications;
suspicion of shock of various causes, pericarditis
4. Fever and confusion, lethargy, convulsions, or focal neurological deficit
5. Suspicion of a thyroid or adrenal crisis
6. Fever and severe dehydration (e.g., abundant diarrhea)
7. Extreme pyrexia (suspected heat stroke or malignant hyperthermia)
8. Fever and j aundice.

In addition, the following conditions require a careful evaluation:

1. Fever associate • with hematological disorders (hemorrhage, thrombocytopenia, ane-

mia, severe leukopenia)
2. Fever associated with hepato- and/or splenomegaly or conspicuous lymphadenopathy
3. Fever associated with peripheral neuropathy

Within 7 to 10 days after the onset of the febrile episode, most of the short-term self-limited
diseases and the prodromal periods of some acute infections diseases will be over. If the
patient remains pyrexial and the data base (history, physical examination, and initial screening
tests) are inconclusive, further investigations should be carried out. The steps that will most
likely lead to a specific diagnosis must be individualized and based on the patient’s clinical
picture. A thorough reappraisal of the situation is required. The performance of a complete
history and physical examination by another physician, who is unbiased by the previous
findings, may discover new diagnostic clues. Initial laboratory tests and chest radiographs
should also be repeated. Additional tests of level two may be suggested by the nature of
the patient’s complaints. It is unusual for fever above 100.4°F (38°C) to persist for 2 weeks
without leaving some clinical and laboratory clues as to its nature. Particular attention should
be paid to (a) the patient with severe constitutional symptoms and clinical deterioration; (b)
diseases amenable to cure; (c) laboratory tests and procedures which have the greatest yield
in establishing the diagnosis; (d) noninvasive investigations which should be contemplated
before an invasive procedure is undertaken; and (e) diseases that most commonly produce
prolonged fever.
Statistical reports on prolonged fevers mention that, among these patients for which a
diagnosis has been established, approximately 80% have either infection, neoplasm, or
collagen-vascular disease; 10% are due to miscellaneous causes. A methodical manner to
organize, at level two, the battery of available tests, is to try to include the actual patient
in any of the above-mentioned diagnostic categories. Clinical features that suggest an in-
54 Unexplained Fever

fectious cause are abrupt onset; high fever with or without chills; local organ-system or
tissue manifestations (especially respiratory, gastrointestinal or urological); acute enlarge-
ment of lymph nodes or spleen; sore throat; skin eruption, meningeal signs; leukocytosis,
or leukopenia. However, such signs and symptoms may also occur in noninfectious diseases.
The sequence of investigations is dictated by the clinical and epidemiological setting. One
should determine whether the pertinent data accumulated point to a systemic specific infection
or to a localized one. In the former, one must place emphasis on the isolation of a specific
agent and to the corresponding serological tests. In the latter, the evaluation indicates a
disease in a specific area. In search for an infectious cause, of primary importance are the
standard microbiologic and immunological techniques; blood cultures for viral, bacterial,
and fungal infections; cultures of sputum, urine, spinal fluid, various other body fluids, or
secretions (nasopharynx, pleural effusion, ascites), cultures of any suspicious skin, mucous
membrane or soft tissue lesion, lymph nodes, or other surgical excisions and tissue biopsy
specimens and stains for identifying bacteria, mycobacteria, chlamydia, fungi, protozoa,
and helminths.
Serological studies include acute and convalescent complement-fixing antibody titers;
detection of streptococcal antibodies (ASO titers); febrile agglutinins (which are designed
to detect antibodies to Salmonella, Brucella, Pasteurella tularensis, and certain Rickettsiae).
Febrile agglutinins are not useful as a screening test, but, as stated by Reese and Douglas;1
“ One should order individual tests with a particular disease entity in mind, based on the
clinical picture” . Blood should be sampled several times for serological studies, as the
antibody titer may rise during the course of the illness. A case of prolonged, unexplained
fever, without any localization, due to Mycoplasma pneumoniae, was confirmed only through
serology. The complement fixation test, which was initially 1/8 rose after 2 months to 1/
256.41
Currently there are methods of rapid diagnosis of infections which permit the physician
to establish a diagnosis definitively or presumptively, in sufficiently short a period to influ-
ence patient management.23 24 Among these tests, the most useful, widespread and least
expensive is ELISA (enzyme linked immunosorbent assay) which may detect a wide variety
of infectious agents. Other tests for a rapid diagnosis are counterimmunoelectrophoresis
(C.I.E.); latex agglutination, immunofluorescence; radioimmunoassay and electron micros-
copy. All these above-mentioned tests should be used in conjunction with standard micro-
biologic techniques.
If the results of the tests suggest a specific diagnosis, the direction of further investigations
is obvious, e.g., if tuberculosis or infective endocarditis is suggested one should perform
appropriate laboratory tests and procedures as indicated in the respective chapters. When
the characteristic manifestations of a specific or localized infection have reached their full
development, the diagnosis is obvious. But, in the early stages of such infections, when
there are nonspecific signs and symptoms common to many diseases, the occurrence of even
minimal signs of inflammation should raise suspicion of an infectious process. The clinical
pattern of localized infections may manifest as an occult focus of infection, usually in a
deep organ site, often overlooked, or a localized infection, with or without abscess formation.
The occurrence of a small degree of warmth, redness, or induration or any tiny amount of
purulence should raise the suspicion of a local infectious process. The most frequent local-
izations of a focal infection should be looked for in the following regions: ENT, respiratory
and hepatobiliary system, gastrointestinal and genitourinary tract. But a systemic review of
all organ systems may discover a localized infection in many other areas of the body.
While searching for an infectious cause, and especially after these were ruled out, one
should also consider other causes. If, according to the history, there are genetic, occupational
and/or environmental factors which may suggest a neoplasm, especially in elderly people,
the evaluation points towards this etiology. The clinical features may be loss of weight,
 55

unusual bleeding or discharge, change in bowel or bladder habits, indigestion or difficulty

in swallowing, nagging cough or hoarseness, persistent anemia and other signs and symptoms
in accordance with the localization of the tumor.
In collagen-vascular diseases the presenting feature may be persistent headache, lassi-
tude, changes in visual acuity, loss of sensation, muscular pain, arthralgias, morning stiff-
ness, splenomegaly, pleuritis, pericarditis, skin lesions (especially maculopapular),
lymphadenopathy, abdominal complaints (all these symptoms especially in women). Thus,
we have discussed succinctly the signs and symptoms of the main diagnostic categories (the
big three), which account for 80% of prolonged fevers. The remaining 10% is represented
by miscellaneous causes, with a great variation of clinical patterns.
During the first 10 days, the physician attempts to rule out self-limited and short-lived
febrile disorders and to place the actual case in one of the main categories. If a diagnosis
is not established and the fever persists, one must go to a second level of investigations.
The range of diagnostic tests and procedures is very large, but the studies must be performed
as indicated by the pertinent data already obtained and not merely in a routine fashion. In
fact, there is no fine dividing line between level 1 and 2; some of the tests indicated further
below may be performed in the first 10 days in case of need. If there are clues pointing to
a particular organ or tissue, the investigations are aimed toward this area. The investigations
for a localized infection may also be helpful for identifying a tumor. In the first place, these
would be imaging procedures and various laboratory tests. For a detailed discussion on the
various techniques for the diagnosis and evaluation of tumors, the reader is referred to
Chapters 23 and 33.
Biopsy with histologic examination is of great value; many authors include biopsy
routinely at the third level of investigation because it is an invasive procedure. However,
there are situations when early biopsy is required, e.g., in a suspicion of temporal arteritis
in an elderly febrile patient or in order to prevent a serious complication such as blindness.
According to the clinical setting, one may perform biopsy of liver, bone marrow, lymph
node, rectum, pleura, muscle, intestine, skin, artery, nerve, or any tissue or organ that may
be involved in the pathologic process. Computed tomographic or sonographic directed biopsy
may be even more productive. A suspicion of neoplasm may also require endoscopy of the
respiratory, digestive, or urinary tract and various laboratory tests. Thus, as crude screen
tests, in serum, are determination of calcium, uric acid, iron, alkaline phosphatase, L.D.H.,
protein, and immunoelectrophoresis.
If there are guidelines for some distinct localization, one should perform blood tests for
prostatic acid phosphatase; alpha-fetoprotein (liver), carcinoembryonic antigen (CEA-breast-
colon); gastrin (stomach); calcitonin (thyroid, lung, breast, islet cell, ovary, and carcinoid
syndrome); prolactin (sarcoidosis, craniopharyngioma). If there are leads for a collagen
vascular disease, one should perform in addition to previous screening tests, immunoglob-
ulins, LE cells, antinuclear tests, rheumatoid factor, serum complement levels, Coombs’
test, Australia antigen, haptoglobin, CPK. Angiography may also be helpful.
A number of diseases which cannot be included with certainty in any of the three above
mentioned diagnostic categories (the big three) are considered miscellaneous. According to
many statistical reports,7,30 32 this category includes hematological diseases (preleukemia,
hemolytic syndromes, cyclic neutropenia); cardiovascular (thromboses, nonspecific peri-
carditis, pulmonary embolism), metabolic and gastrointestinal disorders (FMF; cirrhosis,
alcoholic hepatitis, granulomatous hepatitis, inflammatory bowel diseases, Whipple’s dis-
ease, porphyria, sarcoidosis); endocrine and various other disorders which are discussed in
this book on an organ system basis. In such a variety of clinical pictures and etiologies, an
organized and orderly approach is not possible. The diagnostic studies should be performed
in each individual case as indicated by the particular signs and symptoms and the results of
the preliminary tests. Thus, level three includes the above-mentioned miscellaneous diseases,
56 Unexplained Fever

those which require multiple or difficult invasive procedures and the decision-making process
for establishing a diagnosis (provisional or definite). The investigation of miscellaneous
diseases and those difficult to diagnose presents an increased challenge to the physician; to
pay attention to the smallest details, to pursue the pertinent leads, to avoid the indiscriminate
ordering of a large number of tests, to ensure that specimens were obtained properly. New
information, derived from a more extensive work-up, may become available.37
Depending on the results obtained, one would next go to establishing the problem list
and subsequently a tentative diagnosis. The problem list is a piece of writing annexed to
the patient’s record that contains the pertinent clinical and laboratory information, updated
daily. Beneath each of these diagnostic clues one must note, as the case stands, the working
hypothesis, the provisional diagnosis. The hypotheses must be formulated by induction from
available data and integration of findings already discovered. It is unusual for there to be
no clues, but this may happen. The decision-making process puts to the test the physician’s
clinical acumen, his experience and his judgment. He must carry out a thorough appraisal
of the situation, to appreciate the value of more specific additional tests, to select the expertise
of specialists, to establish the problem list, and to elaborate a provisional diagnosis and
treatment.
In severe or complicated cases, the establishment of the problem list may be hard,
painstaking work. In an illustrative case, published by Musher33 concerning fever in a
quadriplegic patient, clinical and ancillary data suggested the following hypotheses: intra-
abdominal abscess, pneumonia, empyema, osteomyelitis, urinary tract infection, thrombo-
phlebitis, transfusion-related infection, and pulmonary emboli. In the frame of the evaluation,
antibiotics (ampicillin) were discontinued and the patient promptly defervesced. As he was
rechallenged with ampicillin, fever promptly recurred. The diagnosis of drug fever was
established. This illustrative case is very instructive through its lively discussion and the
conclusion that suppressing for a short time all medication, and especially antibiotics, may
be a part of the work-up to reach the diagnosis. Another illustrative case published by Piette
et al.34 concerns a prolonged fever in a patient who underwent a left pneumonectomy many
years previously for severe hemoptysis due to bronchiectasis. The actual febrile episode,
which lasted 10 months until the diagnosis was established, was characterized by intermittent
periods of fever, thoracic pains, anemia, loss of weight, bone pains, purulent expectoration,
dysuria, elevated ESR. According to the clinical data and the ancillary tests and procedures,
the problem list included post-pneumonectomy empyema, pericarditis, chronic pyelone-
phritis, occult dental infection. The most likely diagnosis was considered to be one of the
late onset post pneumonectomy complications, especially empyema. An exploratory tho-
racotomy was planned but on repeated physical examination, a small degree of ascites was
detected and confirmed by CT scanning. Instead of a thoracotomy, the surgeon performed
an exploratory laparatomy, which detected a mesothelioma. This instructive case report
shows the value of repeated physical examinations and the fact that, sometimes, the pro-
gression of the disease reveals new signs and symptoms which may lead to the diagnosis.
In fact, the reappraisal of the situation may result in one of the following possibilities:
(a) a reasonably certain diagnosis may be reached on the basis of the medical history, clinical
findings and patient’s course. In the series published by Larson et al.31 and by Marrie25 12%
of patients were found in this category; (b) clinical and laboratory clues are suggestive of
a specific diagnosis: the need of further investigations is obvious; (c) equivocal clues,
abnormal laboratory results, without diagnostic significance, persistent fever, continuous or
relapsing: these are difficult or complicated cases, which need a careful follow-up, evaluation
of many tissue or organ-systems, consultation with specialists and, sometimes, review of
published lists of causes of prolonged fevers. For those physicians with computer facilities,
the assistance of a medical data base searcher may be very helpful. A literature search for
an obscure symptom or complication may rapidly point out their value and the tests to be
 57

performed for further investigation; (d) occasionally, there are no clinical clues and laboratory
tests are normal. Such a situation suggests factitious fever or a very rare case of drug fever
without associated physical findings.
In some obscure cases one should await the progression of the disease before drawing
conclusions, which depend on the possible clinical deterioration of the patient. The younger
patient, without severe constitutional symptoms, may be discharged and observed on an
outpatient basis. He may be readmitted after sometime, for a réévaluation. The older patient,
with clinical deterioration and significant weight loss, requires an urgent decision: a ther-
apeutic trial, even empiric treatment, or a surgical intervention, or to refer the patient to a
university medical center, for special procedures such as open lung biopsy, renal biopsy or
others.

FEVER IN HOSPITALIZED PATIENTS

When fever occurs in a patient already hospitalized, one must consider certain infectious
and noninfectious entities.

Infections
Infections acquired as a result of a procedure, environmental hazards or opportunistic
suprainfection as follows: (a) intravascular catheters (phlebitis, especially around intravenous
sites); (b) urinary tract infection; (c) respiratory complications (especially pneumonia) as-
sociated with respiratory therapy or aspiration pneumonia; (d) inadequate drainage of fluid
(e.g., pleural fluid); (e) any infections caused by medical or hospital devices (endoscopes,
pressure monitors, suctioning equipment, humidifiers); (f) post-perfusion syndrome (cyto-
megalovirus and Epstein-Barr virus); (g) surgical wound infection; and (h) infections with
opportunistic pathogens in immunosuppressed patients.

Non-infectious Causes
(a) “ admission fever” (of psychogenic cause) in patients following admission to the hospital
for diseases not usually accompanied by fever; (b) anesthesia induced fever (including
malignant hyperthermia); (c) drug fever; (d) transfusion reaction; (e) postcardiotomy syn-
drome; (f) pulmonary emboli; (g) atelectasis following surgery; (h) deep vein thrombosis.
Diagnostic difficulties may arise from several sources:
(a) Nonspecific constitutional symptoms
(b) Atypical presentations of some diseases (brucellosis, histoplasmosis, leptospirosis,
hypernephroma, polyarteritis nodosa)
(c) Diseases whose classical clinical picture has been altered by administration of anti-
biotics, steroids, or vaccines
(d) Diseases which should be diagnosed according to criteria established by commissions
of experts (AIDS, SLE, rheumatic fever, sarcoidosis)
(e) Diseases diagnosed only by exclusion and/or follow-up (adult Still’s disease, nonspe-
cific pericarditis, granulomatous hepatitis). Physicians are slow to consider those di-
agnoses.31
(f) Diseases of medical progress, caused by instrumentation (intravascular devices) or
foreign material in tissues
(g) Diseases which require surgical assistance for elucidation (anatomical abnormalities,
cryptic hematomas in enclosed space, associated nidus of infection)
(h) Difficulties in obtaining a good history or performing a meticulous physical exami-
nation
(i) Ignoring important clinical complaints or obvious clues
(j) Difficulties (or mistakes) in interpreting laboratory data or histology

The list is not exhaustive.

58 Unexplained Fever

Concerning the key diagnostic tests and methods of final diagnosis it is a notable
difference between the series published in the 1960s30*35 and those in the 1980s.25,31 Thus,
we shall quote the lattermost as representing the actual advances in diagnostic capabilities.
In Larson’s series31 in 105 patients, the final diagnosis was reached through the following
methods: biopsy, 33 cases; laparatomy and biopsy, 19 cases; culture, 5 cases; serology, 5
cases; X-rays or scan, 10 cases; 13 cases remained undiagnosed. In a series quoted by
Marrie,25 on an unspecified number of cases, the key diagnostic tests were as follows:
roentgenographic examinations 27%, biopsy 25%, laparatomy 23%, cultures 19%, clinical
course 12%, enzyme determination 9%, serologic tests 6%, liver scan 5%, bone marrow
examination 5%, proctoscopy 2%, C.S.F. examination 1% and postmortem 1%. Despite an
extensive evaluation, a variable percentage of patients, ranging from 7 to 38%, remain
undiagnosed. However, in most reports, this percentage approaches 10%.
The outcome of patients in whom fever persisted for longer than 6 months was extensively
investigated in two large medical institutions. In the U.S. 347 patients were studied from
1961 to 1977 at the National Institutes of Health.36 Fever was present for more than 1 year
in 70% of the cases. In the conclusion of this study36 one may observe a greater incidence
of granulomatous diseases and the adult manifestations of Still’s disease. Infections were
only 6%, neoplasms 7%, and collagen-vascular diseases 4%.
In West Germany, at the Deutsche Klinik fur Diagnostik from Wiesbaden, Winckelmann
and colleagues studies 85 patients having recurrent fever above 38.3°C (101.3°F) for more
than 6 months.38 The patients ages ranged from 16 to 77 years; the fever lasted from 6
months to 30 years, not in a continuous form but in relapses of variable duration, separated
by periods of weeks or months of normal temperature. The diagnostic categories in this
study were infections, 10 cases (12%); malignancy, 12 cases (14%); collagen-vascular
diseases, 15 cases (18%); familial Mediterranean fever (F.M.F.), 5 cases (6%); miscellaneous
(sarcoidosis, pulmonary emboli, cirrhosis, and others) 9 cases, (10%); periodic fever, 18
cases (21%); undiagnosed, 16 cases (19%). The diagnostic category entitled “ periodic fever’’
represents a clinical entity distinct from F.M.F. by the absence of arthritis and serositis,
according to the authors’ personal conception.
The outcome of patients in whom a definitive diagnosis cannot be established after an
extensive work-up is variable:

1. In approximately 20% of cases a spontaneous remission may be attained in self-limited,

idiopathic fevers, most of them probably prolonged viral infections. The remission
may appear even after several months of persistent fever.31
2. In a group of cryptic bacterial infections, a complete remission may be attained after
medical and/or surgical treatment.
3. Another group has a steroid responsive fever which suggests vasculitis or another
immunologically mediated disease, which cannot be included in any known syn-
drome.31
4. The underlying nonidentified disease, (most probable neoplasms, collagen-vascular
disease, adult Still’s disease,) may persist as continuous or recurrent bouts of fever.

The prognosis and mortality depend on the underlying disease. In Barbaro-Hemandez’s study
on 123 cases of prolonged fevers with extensive evaluation, the mortality rate was 22%.39
Most authors conclude that the eventual outcome of prolonged fevers is generally good and
without deleterious sequelae.2,31,39,40
 59

REFERENCES
1. Reese, R. E. and Douglas, R. G., A Practical Approach to Infectious Diseases, Little, Brown, Boston,
1986.
2. Weinstein, L. and Fields, B. N., Fever of obscure origin, in Seminars in Infectious Diseases, Vol. 1,
Stratton Intercontinental, 1978.
3. Fattorusso, V. and Ritter, O., Vademécum Clinique. Du symptôme à l’ordonnance, 10th ed., Masson
(Paris) 1985, 349.
4. Fever of obscure origin, in Differential Diagnosis, Harvey, Boardley, and Barondess, W. B. Saunders,
Philadelphia, 1979.
5. Musher, D. U. et al., Fever patterns. Their lack of clinical significance, Arch. Intern. Med., 139, 1225,
1979.
6. Tumulty, P. H., in Fever of Undetermined Origin, Murray, H. W., Ed., Futura, 1983.
7. Dinarello, C. A. and Wolff, S. W., Fever of unknown origin, in Principles and Practice of Infectious
Diseases Mandell, Douglas, and Bennett, Eds., John Wiley & Sons, New York, 1979.
8. Martin, L., The Febrile Child, John Wiley & Sons, New York, 1982.
9. Harvey, S., Extreme Pyrexia in Fever, Lipton, J., Ed., Raven Press, New York, 1980.
10. Harvey, S., Extreme pyrexia, Hosp. Prac., May 30, 123, 1986.
11. Marconi, F., Le Febricole, Vallecchi Editore, Firenze, 1950.
12. Keefer, C. and Leard, S., Prolonged and Perplexing Fevers, Little, Brown, Boston, 1955.
13. Weinstein, L., Clinically benign fever of unknown origin: a personal retrospective, Rev. Infect. Dis., 7(5),
692, 1985.
14. Petersdorf, R. G. and Root, R. K., in Harrison s Principles of Internal Medicine, 11th ed., International
Edition, McGraw-Hill, 1987, 55.
15. Winckelmann, G. et al., Vegetative Hyperthermie: Thermoregulationsstorung oder Variante der Norm?,
Dtsch. Med. Wschr., I l l , 1590, 1986.
16. Musher, D., Fever of unknown origin: diagnostic principles, Hosp. Pract., June 89, 1982.
17. Louria, D., Fever of unknown origin, Del. Med., 5(43), 343, 1971.
18. Howard, P., Jr. et al., Diagnostic evaluation of patients with fever of unknown origin, South. Med. J.,
69, 933, 1976.
19. Esposito, A. L. and Gleckman, R. A., A diagnostic approach to the adult with F.U.O., Arch. Intern.
Med., 139, 575, 1979.
20. Gleckman, R. A. et al., Fever of unknown origin: a view from the Community Hospital, Am. J. Med.
Sci., 274, 21, 1977.
21. Naschitz, J. E. and Yeshurun, D., Occult infection in the facial area presenting as fever of unknown
origin, Isr. J. Med. Sci., 21, 995, 1985.
22. Luechtrath, H. et al., A case of fulminant Herpes Simplex hepatitis in an adult, Path. Res. Pract., 179,
235, 1984.
23. Broughton, R. A., Rapid diagnosis of infections, Postgrad. Med., 77(3), 201, 1985.
24. Reimann, H. A., Periodic Diseases, F. A. Davis, Philadelphia, 1963.
25. Marrie, T. J., Fever of uncertain origin, in Essentials of Infectious Diseases, Mandell, L. and Ralph, E.,
Eds., Blackwell Scientific, London, 1985.
26. Lebas, J. et al., Fièvres prolongées et syndromes inflammatoires inexpliqués. Intérêt diagnostique de la
tomodensitométrie abdominale, Presse Med. (Paris), 14(10), 577, 1985.
27. Gantz, N. M. and Gleckman, R. A., Manual of Clinical Problems in Infectious Diseases, Little, Brown,
Boston, 1979.
28. Deetz, Th. R. and DuPont, H. L., Fevers of unknown origin, in Infectious Diseases of Children and
Adults, Pickering, L. K. and DuPont, H. L., Eds., Addison-Wesley, 1986.
29. Hammerberg, O. and Chernesky, M. A., Methods of rapid diagnosis of infectious diseases, in Essentials
of Infectious Diseases, Mandell, L. and Ralph, E., Eds., Blackwell Scientific, London, 1985.
30. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report of 100 cases, Medicine, 40, 1,
1961.
31. Larson, E. B. et al., Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970— 1980,
Medicine, 61(5), 269, 1982.
32. Kaufmann, W. and Peters, G., Differential diagnostische Strategie bei unklarem Fieber, Therapiewoche,
32, 1453, 1982.
33. Hurley, D. L., Fever in adults. What to do when the cause is not obvious, Postgrad. Med., 74(5), 232,
1983.
34. Piette, J. C. et al., Confrontation anatoma-clinique. Hôpital de la Pitié-Salpêtrière Fièvre prolongée chez
un pneumonectomisé, Ann. Med. Intern. (Paris), 137(1), 65, 1986.
35. Sheon, R. P. and Van Omnen, R. A., Fever of obscure origin, Am. J. Med., 34, 486, 1963.
60 Unexplained Fever

36. Aduan, R. P., Fauci, A. S., Dale, D. C., and Wolff, S. M., Prolonged fever of unknown origin (FUO):
a prospective study of 347 patients, Clin. Res., 26, 588A, 1979.
37. Wolff, S. M., Fauci, A. S., and Dale, D. C., Unusual etiologies of fever and their evaluation Annu. Rev.
Med., 26, 177, 1975.
38. Winckelmann, G. et al., Ueber 6 Monate bestehendes rezidivierendes Fieber ungeklaerter Ursache, Dtsch.
Med. Wschr., 107, 1003, 1982.
39. Barbado-Hernandez, F. J. et al., La mortalidad en la fiebre de origen desconocido, Med. Clin., 79(7),
3!8, 1982.
40. Isaac, B. and Kernbaum, S., Fièvres prolongées inexpliquées, Presse Méd. (Paris), 40, 3311, 1981.
41. Chagnon, A. and Auzanneau, G., et al., Responsabilité de mycoplasma pneumoniae dans une fièvre
prolongée sans penumopathie, Presse Med. (Paris), 40, 2021, 1986.
42. Lode, H., Fieber unbekannter Ursache, Diagnostik (Muenchen), 18(12), 26, 1985.
43. Gries, E., Hoensch, H., and Ohnhaus, E. E., Differentialdiagnose beis bisher ungeklaertem Fieber:
Bedeutung klinischer Begleitsymptome, Klin. Wochenschr., 64, 307, 1986.
Part II
Unexplained Fever Associated with Diseases
of Organ Systems
 63

Chapter 6

FEVER IN DISEASES OF THE CARDIOVASCULAR SYSTEM

Michael Burke and Benedict Isaac

INTRODUCTION
Diseases of the cardiovascular system are extremely common, and even laymen are
familiar with their main symptoms, such as chest pain, dyspnea, palpitations, and fainting.
Fever frequently accompanies other manifestations and, although it is not usually the major
complaint, on occasion it constitutes a source of difficulty in diagnosis and management.
Most classical texts in the field of cardiology make only a cursory mention of the subject.
A notable exception is the work of Silber and Katz,1 who wrote a chapter entitled “ Fever
in Patients with Heart Disease” . These authors emphasize the “ striking metabolic and
circulatory alterations” that are induced by fever, and go on to state that “ many of the
causes of fever that are without far-reaching consequences in otherwise healthy individuals
may be serious, even life-threatening in predisposed cardiac patients” .
While the cardiac patient may develop fever from various unrelated causes, including
infection, tumors, and others, in many cases fever may be closely related to underlying
cardiovascular disease. The clinical course of cardiovascular disorders has been influenced
by modem technology and therapy. Procedures such as arterial catheterization, angioplasty,
pacemaker insertion, valve replacement, and heart-lung bypass surgery may be complicated
by febrile events, including infection, post-transfusion fever, and the postcardiotomy syn-
drome. Improved survival in coronary artery disease and cardiac failure renders these patients
more liable to long-term febrile complications.
The elucidation of the cause of fever in patients with cardiovascular disease may be
enigmatic. The diagnostician needs to be equipped with an understanding of the patho-
physiology of circulatory disorders and their complications, side effects of cardiovascular
drugs and surgery, as well as an awareness of the ancillary investigations pertinent to the
disorder suspected of causing fever.

APPROACH TO THE FEBRILE PATIENT WITH

CARDIOVASCULAR DISEASE
The principles outlined in the general approach to the febrile patient (Chapter 5) are
applicable to patients who have, in addition, evidence of cardiovascular disease. However,
certain aspects require emphasis when one is dealing with the circulatory system.
Attention should be paid to the history in a recent infection (viral or bacterial, especially
streptococcal pharyngitis or tonsillitis), dental extraction, surgery, prolonged recumbency,
catheterization (venous, arterial, urinary), and to symptoms such as night sweats, anorexia,
and weight loss. A family history and past history of cardiovascular disease, rheumatic
fever, arthritis, and thyroid disease should be sought.
The clinical setting in which the fever develops is important (see Table 1). Certain types
of diseases of the heart and blood vessels occur more frequently in specific age groups,
e.g., congenital and rheumatic heart disease in the young and giant cell arteritis and ath-
erosclerotic heart disease in older patients. Accompanying clinical clues such as murmurs,
dyspnea, hemoptysis, pericardial and pleural friction rubs, embolic phenomena, petechiae,
and splenomegaly may suggest the correct diagnosis. Patients with certain types of cardio-
vascular disease are more prone to particular febrile complications. For example, congenital
64 U n ex p la in ed F e ve r

TABLE 1
Clinical Clues in the Differential Diagnosis of Fever in Cardiovascular
Disease

History

Recent viral infection Viral peri- and myocarditis, myositis of chest wall
Recent pharyngitis, scarlet fever or ton- Rheumatic fever
sillitis
Previous rheumatic fever Recurrent rheumatic fever, infective endocarditis
Dental extraction, urinary manipulation Infective endocarditis
Night sweats, anorexia, weight loss Infective endocarditis, tuberculous pericarditis,
malignant pericardial involvement
Surgery, recumbency Pulmonary embolism
Hemoptysis and dyspnea Pulmonary infarction, pneumonia

Physical Findings

Murmurs See Table 2

Pericardial friction rub See Table 6
Pleural friction rub Pulmonary embolism and infarction, Dressier’s syn-
drome, systemic lupus erythematosus, familial
Mediterranean fever, infection
Embolic phenomena Infective endocarditis, nonbacterial thrombotic en-
docarditis, myxoma and intracardiac tumors, cer-
tain cardiomyopathies
Clubbing Infective endocarditis, cyanotic heart disease
Tachypnea Pulmonary embolism

Age

Young Rheumatic fever, Takayasu’s arteritis

Elderly Giant cell arteritis, congestive heart failure

cyanotic heart disease may predispose to cerebral abscess, mitral stenosis to pulmonary
disease, venous stasis and atrial fibrillation to embolism, and congestive heart failure to
respiratory infection.1
Cardiac murmurs may be difficult to assess in the febrile patient. They may be overlooked
in the elderly patient, many of whom exhibit basal, atherosclerotic murmurs, or they may
remain undetected in a small number of cases of verified valvulitis.2 Frequently, tachycardia
and fever from any cause may increase blood flow, creating turbulence and functional
murmurs, which must be differentiated from organic murmurs. The conditions to be con-
sidered in the differential diagnosis of murmurs in the febrile patient are listed in Table 2.
In some cardiovascular conditions remote symptoms and signs may present a confusing
clinical picture. Motor paresis, ocular findings, cutaneous lesions, arthralgia, abdominal
pain, and ascites are merely but a few examples.
In the past, three of the most common disorders causing unexplained fever in the cardiac
patient were infective endocarditis, pulmonary thromboembolism, and rheumatic fever.
Nowadays, a vast number of other conditions involving the circulatory system may be
associated with obscure fever. Traditionally, this review will begin with the three “ classical”
diseases.

INFECTIVE ENDOCARDITIS

PROBLEMS IN DIAGNOSIS
Over the past two decades there has been a marked shift in the clinical pattern and
etiology of infective endocarditis.3,4 There has been a noticeable rise in the average age of
 65

TABLE 2
Conditions Characterized by Fever and a Murmur

• Rheumatic fever
• Infective endocarditis
• Nonbacterial thrombotic endocarditis
• Myxoma and other intracardiac tumors
• Collagen-vascular disease — systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis,
relapsing polychondritis
• Reiter’s Syndrome
• Becker’s Disease (African cardiomyopathy)
• Loffler’s endocarditis
• Functional or flow murmurs related to fever
• Hyperthyroidism
• Valvular disease or congenital heart disease, associated with extracardiac infection

patients and a decline in the number of cases with underlying rheumatic valvular disease
with an increase in those occurring in atherosclerotic heart disease and mitral valve prolapse.
Classic microembolic phenomena are decreasing in incidence and “ atypical” presentations
are occurring more commonly. Further, there has been a change in the types of microor-
ganisms involved: Gram-negative bacteria, fungi, and rickettsiae are being discovered more
frequently.
The introduction of newer antibiotics, the decline in the incidence of rheumatic fever
and rheumatic heart disease in developed countries, advances in cardiac surgery, prevalence
of nocosomial infections secondary to procedures such as catheterization, dialysis, prosthetic
valve replacement, and the abuse of narcotic drugs all play a role in the changing picture
of infective endocarditis.

CLINICAL MANIFESTATIONS
Traditionally, infective endocarditis has been subdivided into acute and subacute forms.
Acute infective endocarditis is said to occur in patients without previous heart disease and
has an abrupt onset, whereas subacute infective endocarditis is described as appearing
insidiously in a patient with known heart disease. It is now known that virtually any organism
may produce either form of endocarditis, and although there may be considerable overlap
between them, clinical differentiation between the two forms is not clear-cut.
The classical clinical features of infective endocarditis are fever, cardiac murmur, con-
stitutional symptoms (such as malaise, night sweats, anorexia, and weight loss), headache,
myalgia, arthralgia, clubbing, splenomegaly, Roth’s spots in the optic fundi, and cutaneous
lesions. A typical clinical picture can be diagnosed promptly and managed without difficulty.
Infective endocarditis should be suspected in the febrile patient who is known to suffer from
valvular or heart disease (rheumatic, congenital, or atherosclerotic), has a prosthetic heart
valve, or is an intravenous drug addict, especially when the above-mentioned so-called
classical features are present. However, typical manifestations are frequently absent, while
unusual or misleading presentations are being encountered more and more.
Unexplained fever is a common form of presentation. Sometimes the diagnosis is ob-
scured because the fever appears to be explained, albeit incorrectly, by another infection,
such as pneumonia or urinary infection, especially in the elderly. The “ explained” fever
may persist or remit initially following a short course of antibiotic therapy, only to recur
later. A small proportion of patients may be afebrile,2,5'8 owing to prior antibiotic admin-
istration,4,6,9 renal failure,2,10 intracerebral or subarachnoid hemorrhage,7,9,11 congestive heart
failure,2 and advanced age.2,10,11 Rigors, once a common feature, are observed much less
frequently today.12
Although heart murmurs occur in most cases, they may be absent in right-sided or mural
66 U nex p la in ed F e ve r

endocarditis13,14 or in acute valvular lesions.15 Sometimes a murmur appears during treatment

and occasionally only after cessation of therapy. Change in the character of a murmur is an
oft-quoted, yet uncommon finding.
Microembolic manifestations which were once frequent are not seen regularly in most
cases today. Splinter hemorrhages are not confined to patients with valvular infection, and
are often seen in others, such as the elderly or in individuals with occupation-related trauma.16,17
Osier nodes are found in some cases, but may be seen in other diseases, including marantic
endocarditis, systemic lupus erythematosus, hemolysis, and gonococcal infections. Janeway
lesions are more specific and they are more common in staphylococcal endocarditis. Petechiae
are not rare, yet less common than previously. However, they may occur in association with
a prolonged prothrombin time secondary to heart failure with hepatic congestion or during
coumadin administration or salicylate ingestion.1 Conjunctival petechiae, in the absence of
infection, are frequently observed in patients who have recently undergone cardiac surgery
with heart-lung bypass, and are probably the result of fat microembolism.18 Roth spots occur
much less often than previously,2 and they may be found in sepsis of any origin, AIDS,
leukemia, severe anemia, and systemic lupus erythematosus.6,19 They have been reported
in a 27-year-old female with fatal rheumatic endocarditis.20
Together with other peripheral manifestations, the incidence of splenomegaly and club-
bing has declined in recent years. Further, splenic enlargement may occur in noninfective
cardiac diseases, including mitral stenosis associated with congestive heart failure or splenic
infarction, and occasionally, rheumatic heart disease and rheumatic fever.20'22
Atypical presentations of infective endocarditis may divert the clinician’s attention away
from the heart or promote suspicion of a disorder of another organ system. The nervous
system is frequently involved23 and neuropsychiatric manifestations may be the initial clinical
features. The mechanisms of neurologic compromise following septic embolism are related
to arterial occlusion, mycotic aneurysms and their complications, and infection.23 Toxic
confusional states, psychosis, stroke, seizures, headache, meningoencephalitis, dyskinesia,
and cranial and peripheral nerve lesions have been described.23 26
A common source of diagnostic confusion is the presence of local or regional infection,
frequently resulting from infected emboli, e.g., pneumonia (right-sided lesions), mycotic
aneurysm, suppurative arthritis,9,27 osteomyelitis,28,29 and suppurative phlebitis.
A variety of musculoskeletal manifestations30,31 in infective endocarditis may be present
and initially suggest a rheumatic or other disorder. In addition to the features related to
infection of bones and joints just mentioned, backache,31'33 lower limb or diffuse myalgia,30,34
arthritis and arthralgia,35,36 clubbing,2,8 31 hypertrophic osteoarthropathy,37,38 and Achilles
tendinitis may occur. Occlusion of a large vessel may produce cerebral infarction or a painful,
ischemic limb. In addition to the skin lesions mentioned above, cafe-au-lait pigmentation,
purpura, and ecchymosis, and a peculiar necrotic lesion of the digital tips may occur.39
Febrile local cardiac complications may themselves mask the underlying condition. The
physician may diagnose myocardial infarction (as a result of coronary artery embolism),
congestive heart failure, myocarditis or myocardial abscess without recognizing the presence
of the basic disease.

SPECIAL FORMS OF INFECTIVE ENDOCARDITIS

A frequently misdiagnosed entity is right-sided endocarditis.13,40,41 The incidence, cur-
rently about 5 to 10% of cases, has risen in recent years, primarily due to intravenous drug
abuse. Frequently, no history of underlying heart disease can be found. There is a predilection
for triscupid valve involvement, and a murmur may be soft and atypical or even inaudible.
The major site of embolism is the lung, and the major form of presentation is with fever
and pulmonary symptoms, suggesting recurrent pulmonary infarction or infection. Peripheral
stigmata are uncommon; vague symptoms such as malaise and weight loss sometimes occur.
 67

TABLE 3
Causes of Culture-Negative Endocarditis

Factors Related to Host

Prior antibiotic administration

Right-sided endocarditis, especially subacute
Uremia44
Incorrect diagnosis, including atrial myxoma, marantic or noninfective endocarditis, rheumatic fever, endocar-
dial fibroelastosis

Factors Related to Infectious Agent

Fastidious bacteria
Nutritionally variant streptococci
Cell-wall deficient organisms
Slow-growing organisms — anaerobes, Brucella, Neisseria
Acid fast bacteria — Mycobacteria, Nocardia
Nonbacterial organism
Fungus — Aspergillus, Candida, Histoplasma
Rickettsia — Q fever
Chlamydia — C. psittaci, C. trachomatis

Other features are hepatosplenomegaly, mild jaundice, visceral abscesses, and renal insuf-
ficiency.
Culture-negative endocarditis42 45 as a cause of unexplained fever is frequently difficult
to diagnose. It presents with essentially the same clinical manifestations as the culture-
positive form, although major embolic occlusions (cerebral, visceral, limb), congestive heart
failure, splenomegaly, hematuria, and Osier’s nodes feature more prominently.
Fungal endocarditis46 47 is becoming an increasing problem in the modem era. The disease
occurs primarily in drug addicts, following cardiac surgery, in systemic fungal infections
and during corticosteroid or prolonged antibiotic administration. Many cases have occurred
as suprainfections during therapy for bacterial endocarditis! The clinical manifestations are
essentially those of any form of infective endocarditis. The condition should be suspected
in the appropriate clinical setting, especially when patients fail to respond to antibiotics for
suspected bacterial infection. The presence of endophthalmitis may be a clue to Candida
infection.48

LABORATORY TESTS
Culture — The most definitive test for the diagnosis of infective endocarditis is the
isolation of the causal agent on blood culture, which will be positive in 37 to 97% of cases.11
The principal causes of negative cultures are stated in Table 3. Ideally, five or six separate
cultures should be performed before the onset of therapy; even more specimens may be
required if antibiotic treatment has been instituted previously. The cultures should be in-
cubated with appropriate media for anaerobes and fungi. Four to six weeks should be provided
to allow slow-growing forms to emerge. At least two cultures should yield the same organism.
In most cases peripheral venous blood is suitable, although occasionally arterial blood,49 50
bone marrow,50 Osier node aspirates,5152 urine,53 54 and resected emboli54 have been em-
ployed to isolate the pathogen.
Hematological findings — The blood picture is relatively nonspecific. An elevated
ESR is the most common feature and anemia is frequent. The leukocyte count is typically
not very high in subacute infective endocarditis, although a left shift is usual. Very occa-
sionally phagocytic cells are present in peripheral blood.55 56 Thrombocytopenia may occur
as a result of disseminated intravascular coagulation.
68 Unexplained Fever

Serologic and immunologic findings — Antibodies to certain microorganisms may be

required for diagnosis of infective endocarditis, especially due to Coxsackie burnetii, Chla-
mydia, Brucella, Staphylococcus (techoic acid antibodies, counterimmunoelectropho-
resis),57,58 Candida, and Cryptococcus. Hyperglobulinemia59 and plasmocytosis of the bone
marrow are common in subacute infective endocarditis. Anti-heart antibodies and cryoglob-
ulins have been observed.60,61 Rheumatoid factor is present in 50% of cases62 and circulating
immune complexes may also be found.63 In many cases these findings revert to normal
following successful therapy. A low serum complement may occur in patients with immune
complex nephritis.62,64

DIAGNOSTIC PROCEDURES
Echocardiography65 — Two-dimensional echocardiography is a noninvasive, useful
technique for detecting vegetations, greater than 2 mm in size, especially those caused by
fungi and Staphylococcus aureus. It is particularly useful in culture-negative endocarditis,66
such as that caused by Chlamydia.61
Gallium scanning — May be of some use when blood cultures are persistently nega-
tive,68 although there is at least a 40% false-negative rate.
Cardiac catheterization — This is an invasive technique which has been successfully
used on occasions to detect right-sided69 and left-sided70 endocarditis or serious complications
such as mycotic aneurysm and ventricular septal defect.

PERSISTENT FEVER IN INFECTIVE ENDOCARDITIS

Persistence or recurrence of fever during antibiotic administration in infective endocarditis71
raises certain possibilities which have to be considered:

1. Insufficient or unsuitable antibiotic therapy

2. Microbial resistance despite appropriate antibiotic therapy
3. Suppurative complications, usually due to staphylococcus

(a) Local (cardiac) — myocardial abscess, purulent pericarditis

(b) Systemic — septic arthritis, osteomyelitis, visceral abscess, mycotic aneurysm

4. Recurrent pulmonary or visceral emboli, arising in the endocardium or from deep vein
thrombosis
5. Complications of drug administration

(a) Drug fever

(b) Local reactions at injection site, including phlebitis and hematoma

6. Infection at a different site

(a) Intercurrent infection, especially of the respiratory or urinary tracts

(b) Infective nidus, such as the tonsil, teeth, maxillary or frontal sinuses

7. Superinfection, which may be either fungal or bacterial

8. Reactivation of underlying disease, such as rheumatic fever or systemic lupus erythe-
matosus
9. Incorrect diagnosis

DIFFERENTIAL DIAGNOSIS
The differential diagnosis of infective endocarditis is extensive. Any of the numerous
clinical manifestations may lead the physician to suspect a remote condition or different
 69

cardiac disorder. The following is a partial list of diseases which may be confused with
infective endocarditis.

Noncardiac

1. Infections
(a) Systemic
(i) Bacterial — Septicemia (especially when accompanied by DIC)
(ii) Malaria
(iii) Viral — Influenza, CMV (especially following surgical valve replacement
and multiple blood transfusions)
(b) Regional — Pneumonia, suppurative arthritis, osteomyelitis, cerebral abscess
2. Neoplasia — Lymphoma, hepatoma, renal carcinoma, disseminated carcinoma
3. Miscellaneous
(a) Collagen-vascular disease — systemic lupus erythematosus, polyarteritis nodosa
(b) Sarcoidosis

2. Cardiac

1. Rheumatic fever
2. Nonbacterial thrombotic (marantic) endocarditis
3. Atrial myxoma and other primary heart cardiac tumors
4. Secondary tumors to the heart
5. Atrial thrombus
6. Pericarditis

RHEUMATIC FEVER AND CARDITIS

Despite a decline in the incidence of rheumatic fever in developed countries,72 the
condition remains an important clinical problem in developing countries, where crowding,
dampness, and economic factors play a role. Rheumatic fever is an acute febrile illness
characterized by inflammation, principally of the joints, heart, skin, and nervous system.
The disease primarily affects children aged 5 to 15, but may occur or recur at any age, and
onset in adults has been well documented.73'75
The clinical picture includes fever, arthralgia, or polyarthritis, tachycardia, dispropor-
tionate to the degree of fever and persisting during sleep, murmurs, conduction disturbances
and cardiac failure. Additional “ major” manifestations, viz., chorea, erythema marginatum,
and subcutaneous nodules, are exceedingly rare. Some patients will present as a FUO,76,77
although most cases will have migratory polyarthritis as well. Any joint may be involved,
the larger lower limbs joints being affected most frequently. Arthritis tends to be of longer
duration and more severe in the adult.76 Carditis usually occurs within the first 3 weeks of
the attack and is virtually always manifested by a regurgitant murmur (mitral and/or aortic)
and frequently by an apical middiastolic (Carey—Coombs) murmur. Pericardial friction rub
and signs of cardiac failure may also be present. Carditis is most frequent in the younger
age group and is less common in adults.
There is no pathognomonic test for rheumatic fever, and the diagnosis depends upon
modified Jones’ criteria (see Table 4) which may serve as a guide but must be subject to
critical review by the physician in any particular instance. The presence of a high titer of
streptococcal antibodies — antistreptolysin O (ASLO) as well as antistreptococcal hyalu-
ronidase and deoxyribonuclease B — or a positive antistreptozyme test provide supportive
evidence of recent streptococcal infection. Throat cultures for group A streptococcus are,
70 U n ex p la in ed F e ve r

TABLE 4
Revised Jones’ Criteria

Minor
Major

Carditis Clinical Laboratory

Pericarditis Fever Elevated ESR
Myocarditis
Endocarditis Arthralgia Leukocytosis
Polyarthritis Abdominal pain Elevated CRP
Chorea Previous rheumatic fever or rheu- Prolonged P-R interval
Subcutaneous nodules matic heart disease
Erythema marginatum

Supportive evidence of streptococcal infection

Elevated titer of streptococcal antibodies

ASLO >330 U(children) or >250 U (adults)
Antistreptococcal hyaluronidase
Antistreptococcal DNAase B
Antistreptozyme 200 U/ml
Positive throat culture for Group A Streptococcus
Recent scarlet fever

TABLE 5
Differential Diagnosis of Fever and Heart Failure

Cardiac
Heart failure per se
Endocarditis
Myocarditis and pericarditis
Dressier’s syndrome
Superimposed Infection
Respiratory
Other
Thromboembolism
Venous thrombosis
Pulmonary embolism
Miscellaneous
Drug fever
Dehydration fever
Thyrotoxicosis

on the other hand, quite unreliable. A therapeutic response to high-dose salicylates contributes
to but does not confirm the diagnosis.
In contrast to polyarthritis, carditis may be asymptomatic, and the diagnosis is more
likely to be overlooked when joint pain is absent. Therefore, clinical examination, electro-
cardiography, and the chest radiograph are important in the evaluation of any patient with
unexplained fever. In addition to clinically manifested features of carditis — pericardial
friction rub, valvular murmurs and heart failure — disturbances of conduction and rhythm
are frequently noted. These include heart block, especially first degree (prolonged P-R
interval), as well as junctional rhythms, premature ventricular beats, and tachycardias.
Many conditions must be considered in the differential diagnosis. They may be subdi-
vided into two main categories, depending upon their association with known rheumatic
heart disease (see Table 5).
 71

PULMONARY THROMBOEMBOLISM
PATHOGENESIS
Unexplained fever may be caused by recurrent pulmonary embolism in patients with
underlying cardiac or venous disease as well as those without antecedent cardiovascular
disorders. The mechanism of fever in pulmonary embolism and thrombosis is unclear.
Potential pyrogenic sources include tissue injury following infarction,78 hemorrhage leading
to extravascular sequestration of blood,79 local vascular irritation or inflammation, atelectasis,
and occult infection.80 Emboli may migrate from detached portions of thrombi originating
in the veins of the legs or the pelvis, or occasionally, in the right side of the heart. Cardiac
conditions which may predispose to pulmonary thromboembolism include congestive heart
failure, myocardial infarction (especially when extensive), rheumatic heart disease, atrial
fibrillation, and right-sided endocarditis. Other conditions which may contribute to the
development of pulmonary embolism are prolonged recumbency, including immobilization
following surgery, childbirth, obesity, advanced age, diabetes, chronic lung disease, infec-
tion, malignancy, thrombocytosis, and fractures, especially of the lower half of the body.

CLINICAL MANIFESTATIONS
There is no typical clinical picture in pulmonary embolism, which may simulate a vast
number of conditions. Important clinical features include chest pain (often pleuritic in nature),
dyspnea, tachypnea, and tachycardia. Fever occurs in over 2/5 of cases.81 Occasionally a
hectic or septic picture can be seen.80*82 Hemoptysis occurs in only a minority of patients,
and clinical evidence of phlebitis is noted in only one third of cases.81 In establishing the
diagnosis, the physician must take into account the clinical setting in which pulmonary
thromboembolism may develop. Unexplained fever may be the presenting feature of multiple
pulmonary emboli, occurring in congestive heart failure,83 and bed confinement,83’84 or
complicating pelvic thrombophlebitis,85 surgery, and trauma.86 Since pulmonary embolism
may precipitate heart failure, the diagnosis should be considered in any patient with heart
failure and fever who fails to respond to adequate therapy with digitalis, diuretics, together
with antibiotics.
Septic pulmonary embolism is invariably accompanied by fever and often by chills as
well. The condition is often difficult to diagnose. Its most common presentations are unex-
plained fever or “ nonresponding pneumonia” . It is more likely to occur in the following
situations: right-sided infective endocarditis, intravenous drug abuse, infected intravenous
catheters or arteriovenous shunts, and septic thrombophlebitis, especially of the pelvic veins.85

INVESTIGATIONS
X-ray abnormalities are frequently found, but are nonspecific. Consolidation and ele-
vation of the hemidiaphragm are commonly observed. Pleural effusion, pulmonary artery
prominence, and atelectasis may also be recognized in some cases. Serum LDH and bilirubin
elevations are of little assistance in diagnosis. Arterial hypoxia is very common, but a normal
p 0 2 does not exclude pulmonary embolism. In septic embolism blood cultures may be
positive.
A useful noninvasive technique utilizes ventilation scintography with radiolabeled xenon
or 81krypton together with pulmonary perfusion scanning. An abnormal ventilation-perfusion
scan with multiple sequential mismatched defects is highly suggestive of pulmonary em-
bolism, although false-positive and -negative results have been observed.87 The most defin-
itive method of diagnosis is pulmonary angiography, which is indicated when the diagnosis
is in doubt or the patient requires high-risk therapy, such as thrombolysis, or surgery (inferior
vein interruption or pulmonary embolectomy). This invasive technique is extremely accurate,
but is time-consuming, expensive, not readily available in all institutions, and does carry
72 Unexplained Fever

an inherent risk to the patient. Employing noninvasive impedance plethysmography to detect

proximal deep vein thrombosis may somewhat curb the use of pulmonary angiography.88

FEVER IN MYOCARDIAL INFARCTION

Fever is an accompaniment of most cases of myocardial infarction and occurs as a
response to tissue necrosis with subsequent release of leukocytic pyrogen. The temperature
tends to rise within 4 to 8 h of the onset of infarction and may reach 38° to 39°C, usually
by day 2 to 5, and generally subsides by the eighth day. However, occasionally the fever
persists or recurs and the clinician is faced with a diagnostic problem: is this a case of
infarction fever or is some complication present? Lofnark et al.89 found an incidence of
4.2% of fever lasting 18 days or more in 168 patients with uncomplicated myocardial
infarction. They suggest that a cause other than acute infarction should be considered when
the temperature is greater than 38.2°C on the first hospital morning, if it reaches a maximum
before day 2 or after day 5, or the maximum is above 39°C, or if the temperature increases
by more than 0.6°C after day 5. Although pain is the most outstanding feature of myocardial
infarction, this symptom may be minimal or absent. Silent myocardial infarction is more
likely to occur following abdominal surgery as well as in the alcoholic, uremic, or diabetic
patient. The differential diagnosis of persistent or recurrent fever in myocardial infarction
includes the following conditions:

1. Infarction fever (extension of necrosis) or recurrent infarction.

2. Infection
(a) Incidental — Pneumonia, urinary tract, infected intravenous line, cholecystitis,
decubitus ulcer
(b) Myocardial abscess (rare)90,91
3. Postmyocardial infarction syndrome (Dressler’s syndrome)
4. Thromboembolism — Pulmonary embolism, mural thrombosis with systemic embo-
lism, deep thrombophlebitis
5. Vasculitis of the coronary arteries — polyarteritis nodosa, systemic lupus erythema-
tosus
6. Coronary embolism in infective endocarditis or atrial myxoma
7. Pericarditis
8. Febrile heart failure
9. Meliodosis92
10. Drug fever, e.g., procainamide,93 quinidine

FEVER IN CIRCULATORY COMPROMISE

Certain patients may present as acute medical emergencies characterized by a compro-
mised circulation together with fever. In many cases, but not all, the principal cause is
infection. Circulatory compromise may be central — cardiac failure — or peripheral —
hypotension or shock.

FEVER IN CARDIAC FAILURE

A frequent clinical problem is the febrile patient with heart failure. Occasionally, the
decompensated patient exhibits a mild elevation in temperature.1This febrile reaction is due
to a combination of enhanced heat production, associated with increased oxygen consumption
and muscular activity of dyspnea, and impaired heat dissipation resulting from a low cardiac
output, decreased sweating from cutaneous vasoconstriction and an insulating effect of edema
on the core temperature. Notwithstanding that fever may be due to cardiac failure per se, a
 73

thorough search should be made before reaching this conclusion. The most important con-
ditions to be considered are infection, pulmonary thromboembolism, and unsuspected car-
ditis. A checklist of disorders which have been associated with fever and heart failure appears
below.

HYPOTENSION ASSOCIATED WITH FEVER

A variety of conditions may be considered under these circumstances:

• Systemic
Septic shock (with or without disseminated intravascularcoagulation)
Toxic shock syndrome
Acute hemolysis
Anaphylactic shock
Severe dehydration associated with infection
• Cardiovascular
Cardiac — Pericarditis with cardiac tamponade (e.g., purulent pericarditis), myo-
cardial infarction, intracardiac ball-valve mass — myxoma, thrombus
Vascular aortic dissection, aneurysm of large artery, pulmonary embolism (severe)
• Extracardiac thoracic — Mediastinitis, severe pneumonia with hypoxia.
• Abdominal — Peritonitis, severe diarrhea,gastrointestinal hemorrhage, especially
when associated with infection, pancreatitis, and acute adrenal insufficiency.

FEVER ASSOCIATED WITH MYOCARDITIS AND

PERICARDITIS

Fever is a frequent manifestation of myocardial and pericardial involvement in infections,

systemic disorders, and primary cardiac disease. The diagnosis of myocarditis and pericarditis
may be difficult.

MYOCARDITIS
The clinical manifestations of myocarditis may vary from an asymptomatic condition
(detected only by electrocardiography) to a full-blown picture characterized by chest pain,
dyspnea, palpitations, malaise, headache, arthralgia, myalgia, and fever. The chest pain
may be precordial in nature, pericardial (suggesting the coexistence of pericarditis) or non-
specific. Fever is usually short-lived but occasionally is persistent. Physical examination
may reveal tachycardia disproportional to the temperature elevation, equalization of the first
and second heart sounds, gallop rhythm with a third heart sound, systolic murmurs, and
signs of cardiac failure. Conduction disturbances, arrhythmias and S-T segment and T-wave
changes may be noted on the ECG. The serum creatine kinase, and its MB isoenzyme are
frequently elevated. Recently, newer spatial imaging techniques have been employed in the
diagnosis of myocarditis: echocardiography may demonstrate left ventricular asynergy94 and
nuclear magnetic resonance (NMR) imaging may reveal focal areas of edema.95
The ECG should be performed in all patients with unexplained fever because of the
possible seriousness of a seemingly innocuous condition. Myocarditis may be complicated
by syncope, circulatory collapse, systemic, or pulmonary embolism,96 and sudden death.
The cause of myocarditis may be infectious or noninfectious. The infectious agent may
be viral (Coxsackie, ECHO, arbor, poliomyelitis, mumps, Epstein-Barr (EBV) and cyto-
megalic (CMV), rickettsial, mycoplasma, psittacosis, bacterial (typhoid fever, diphtheria,
tuberculosis, leptospirosis, bacterial endocarditis), fungal, protozoal (Chaga’s disease) or
metazoal. The noninfectious diseases include collagen-vascular diseases and pheochromo-
cytoma.
74 U n ex p la in ed F e ve r

Isolated myocarditis (Fielder’s myocarditis) is a very rare condition occurring in young

adults, usually male, and commonly follows a respiratory infection. Pathologically, the
inflammatory lesion is limited to the myocardium. The clinical picture includes dyspnea,
weakness, and chest pain. Initially, the patient is afebrile or has mild temperature elevation;
however, fever tends to be more marked during the course of the illness. In rare instances
there is a septic course which may resemble infective endocarditis. Cerebral or pulmonary
emboli may supervene and further complicate the clinical picture.5,97
Coxsackie B viral myocarditis in the adult is usually preceded or accompanied by
systemic manifestations of viral disease.98 Fever, upper respiratory and abdominal symptoms,
and muscle and joint pains are frequent. Chest pain may be pleuropericardial, pleurodynia-
like, or anginal in nature. A friction rub is audible in one third of cases. Rash, pneumonitis,
meningoencephalitis, hepatitis, pancreatitis, orchitis, or oophoritis may be present.
In bacterial endocarditis, myocarditis,99 myocardial abscesses, false aneurysms, mycotic
aneurysms, septal defects, and conduction disturbances, ventricular premature beats may
occur.
Tuberculosis of the myocardium is very rare and its diagnosis is extremely difficult.100
Cardiac manifestations are sparse and the presentation is nonspecific. The patient may appear
to be febrile and extremely ill without obvious cause; only later, active pulmonary or miliary
tuberculosis is discovered.
Myocardial abscess is a rare cause of prolonged obscure fever. The condition is usually
a complication of infective endocarditis or overwhelming sepsis,91 but is occasionally as-
sociated with myocardial infarction.90 Predisposing conditions include alcoholic hepatitis,
systemic lupus erythematosus, renal failure, surgery, and malignancy.91,101 The diagnosis is
extremely difficult: a high degree of suspicion in a febrile patient whose cardiac condition
is worsening despite antibiotic therapy is the main clue. Two-dimensional echocardiography
and isotopic scanning may be useful in localizing abscesses.

PERICARDITIS
Pericarditis may present as chest pain and dyspnea, associated with a pericardial friction
rub or as a systemic illness with fever and toxemia.102 Occasionally, the condition is com-
plicated by pericardial tamponade with its attendant manifestations. Pericardial pain is ag-
gravated by deep respiration or rotating the thorax, and alleviated by sitting up and leaning
forward. Although the pain is often striking in acute viral or nonspecific pericarditis, it may
be absent, transient, or very mild.
The pericardial friction rub, which is a valuable clue in the diagnosis, may be transient,
intermittent, or persistent. A large number of conditions may be manifest by fever and
pericardial friction rub, and are listed in Table 6.
Systemic manifestations of fever, such as chills, diaphoresis, weakness, and weight
loss, are often present and may dominate the clinical picture. Unexplained fever has been
described in cases of specific and nonspecific pericarditis.77,103 Tuberculous pericarditis may
be extremely difficult to diagnose.77,104 Other conditions frequently characterized by febrile
pericarditis include the postcardiotomy syndrome,105 Dressler’s syndrome (postmyocardial
infarction syndrome),106 uremia,107 and collagen-vascular diseases, such as rheumatoid
arthritis108 and systemic lupus erythematosus.
At times, pericarditis is recognized by typical ECG changes of generalized concave
upward S-T segment elevations. Low voltage QRS complexes suggest the presence of a
pericardial effusion, which may be confirmed on chest X-ray when a rapidly progressive
cardioperieardial shadow develops in the presence of clear lung fields, or by echocardio-
graphy. Isotopic scanning has been employed to detect pericarditis.108,109 Pericardiocentesis
is indicated for suspected neoplastic or bacterial involvement, or if the patient has cardiac
tamponade. Pericardial biopsy is occasionally necessary to reach a diagnosis, especially in
cases of tuberculosis.
 75

TABLE 6
Conditions Characterized by Fever and a Pericardial Friction Rub

Cardiac
Rheumatic fever and carditis
Infective endocarditis
Postcardiac injury (immunopathic) syndromes
Dressier’s syndrome
Postcardiotomy syndrome
Infective Pericarditis
Viral
Rickettsial
Chlamydial
Bacterial
Tuberculous
Fungal
Parasitic
Hypersensitivity and Collagen-Vascular Diseases
Serum sickness
Smallpox vaccination
Drugs — penicillin, procainamide, hydralazine
Systemic lupus erythematosus
Rheumatoid arthritis
Scleroderma
Polyarteritis nodosa
Neoplastic Involvement of Pericardium
Lung cancer
Breast cancer
Malignant melanoma
Lymphoma
Leukemia
Miscellaneous
Sarcoidosis
Inflammatory bowel disease
Whipple’s disease
Familial Mediterranean fever
Gout
Uremia

FEVER ASSOCIATED WITH CARDIAC TUMORS

Unexplained fever may be caused by primary or secondary neoplasms involving the

pericardium, myocardium or endocardium. Metastatic tumors are more common than pri-
mary cardiac tumors and the most common sources are carcinoma of the lung, carcinoma
of the breast, malignant melanoma, leukemia, and lymphoma. Clinical manifestations are
variable; cardiac symptoms occur in less than 10% of cases. Nevertheless, cardiac metastasis
should be suspected in any patient who develops cardiac dysfunction without apparent cause.
Constitutional features such as fever, malaise, anorexia, and weight loss may accompany
cardiac symptoms such as dyspnea110or chest discomfort. Pericardial metastases may produce
a clinical picture of febrile pericarditis, although this condition may also be radiation-induced
or idiopathic in origin.111 A pericardial friction rub112,113 or evidence of a pericardial effusion114
may be found. Fever of unknown origin and a cardiac murmur were presenting features in
a patient with metastatic squamous cell carcinoma to the heart 6 months after removal of
oral cancer.115 Metastases to mural or valvular endocardium may result in systemic or
pulmonary embolism and mimic infective endocarditis.116 An unusual nonmetastatic cardiac
complication of remote malignancy is nonbacterial thrombotic (marantic) endocarditis, which
may occasionally present seizures and fever.117
76 Unexplained Fever

Of the primary cardiac tumors, the most important is atrial myxoma, commonly left-
sided, which produces three principal clinical manifestations:118119

1. Obstructive — murmurs of valvular stenosis, murmurs changing with position, re-

gurgitant murmurs, fatigue, syncope, dyspnea, and precordial pressure
2. Embolism — systemic or pulmonary
3. Constitutional — fever, arthralgia, weight loss, anemia, thrombocytopenia, clubbing,
raised ESR, and hypergammaglobulinemia; polycythemia occasionally occurs in right
atrial myxoma.

The initial features of atrial myxoma may resemble those of infective endocarditis. The
blood cultures are persistently negative, and this is a major cause of “ culture negative
endocarditis” . Exceptionally, secondary infection can occur presenting a diagnostically
confusing “ culture positive” noninfective endocarditis.120 In contrast to infective endocar-
ditis, splenomegaly is invariably absent.
Other primary cardiac tumors may simulate primary atrial myxoma both anatomically
and clinically. Sarcomas may present with febrile manifestations and may initially be misdi-
agnosed as rheumatic fever,121 myocarditis,122 collagen-vascular disease123 or a flu-like syn-
drome.124 A 47-year-old female presented with fever, backache, weakness of the arm with
palmar numbness, a murmur, progressive cardiac failure and clubbing, was found to have
a left atrial fibrosarcoma with vertebral metastases.125
The diagnosis of cardiac tumors relies upon two-dimensional echocardiography and
computerized tomography to demonstrate an intracardiac mass. Other techniques that have
been employed include angiocardiography, radioisotopic scanning and magnetic resonance
imaging. Occasionally the diagnosis of myxoma is established by the discovery of myxo-
matous tissue at embolectomy. A right atrial mass can be biopsied during transvenous
catheterization. Pericardial masses may be examined histologically following pericardi-
otomy. Other tumors can be identified only after thoracotomy.

FEVER ASSOCIATED WITH VASCULAR DISEASES

Fever is a common accompaniment of disorders of the vascular system, both arterial

and venous. Some of these conditions are listed in Table 7. In most cases the cause of the
fever will be obvious, but occasionally these conditions may present with unexplained fever
and without localizing features.

ARTERIAL DISEASES
Aortic Dissection (Dissecting Aneurysm)
Aortic dissection may present with protean manifestations including fever, although this
symptom has not been appreciated sufficiently. Unexplained fever was a prominent feature
of aortic dissection in several recently reported cases.79 126 127 In some patients a murmur
was heard and infective endocarditis was suspected initially. A history of chest and back
pain, hypertension, and a tendency to large rather than small vessel occlusion, together with
negative blood cultures should suggest the condition. Intensive review of the chest X-ray
showing widening of the aortic shadow, and subsequent confirmation by echocardiography,
computered tomography, and aortography will clarify the diagnosis. The mechanism of fever
production in aortic dissection is unclear. Tissue destruction, phagocytosis with subsequent
pyrogen release, inflammation secondary to extravascular sequestration of blood, infarction
of vital organs, and hemorrhagic pericarditis have been implicated.78,126
 77

TABLE 7
Fever Associated with Vascular Diseases

Arterial Diseases

Aortic dissection
Takayasu’s arteritis
Giant cell arteritis
Polyarteritis nodosa
Arthritis-associated arteritis
Rheumatic fever
Ankylosing spondylitis
Psoriasis
Regional enteritis
Ulcerative colitis
Relapsing polychondritis
Reiter’s syndrome
Mycotic aneurysm
False aneurysm
Tumors

Venous Diseases

Phlebitis
Peripheral
Superficial
Deep
Visceral
Tumors

Arteritis
Arteritis encompasses a large group of diseases of various etiologies which involve
arteries of different sizes in an inflammatory process. These conditions may manifest them-
selves as fever, malaise, and local pain or loss of function due to peripheral or visceral
arterial involvement. On occasions, the major manifestation is unexplained fever. The major
conditions characterized by arteritis are polyarteritis nodosa, giant cell arteritis (temporal
arteritis), and Takayasu’s arteritis. The first two diseases are described in Chapter 18; the
latter disorder and another arterial disease, Kawasaki's disease, will be discussed here.
Takayasu’s arteritis (aortic arch arteritis, pulseless disease)128'130 is a nonspecific ar-
teritis with a worldwide distribution, occurring principally in young females. In its early
stage the condition may present with protean manifestations, including unexplained fever,
malaise, weight loss, night sweats, arthralgia, and myalgia. Occasionally, pleuritis, peri-
carditis, and Raynaud’s phenomenon are present. Nonspecific laboratory findings include
anemia, leukocytosis, elevated serum gamma- and alpha-2 globulins and ESR. At a later
stage features of arterial obstruction appear: loss of pulse of one or more vessels, bruit,
hypertension (renal arterial involvement), syncope, impaired vision, paresthesiae, headache,
limb pain, and hemiplegia. The diagnosis should be considered in young females with
appropriate symptomatology and may be confirmed by arteriography. Timely use of im-
munosuppressive therapy may help to arrest the disease progress.
Kawasaki’s disease131132 is an acute febrile exanthematous disease of very young chil-
dren, associated with edematous, reddened palms and soles, cervical lymphadenopathy,
cardiac murmurs, and ECG changes. Coronary arteries are mainly involved and exhibit
aneurysms and tortuosity, although other vessels may also be affected. The disease first
described in Japan is now attaining worldwide recognition.
78 Unexplained Fever

Noninfected Arteriosclerotic Aneurysm

Very occasionally, a leaking or ruptured (noninfected) aortic aneurysm with retroperi-
toneal hematoma may be manifested by a febrile or septic state.133'135 The diagnosis may
be suspected by the presence of back or abdominal pain, rapidly progressive anemia, and
fever. A supportive laboratory finding is leukocytosis with negative blood cultures.

Arterial Infection
Arterial infections have been recently classified into four types:136

1. Mycotic aneurysms are usually secondary to infective endocarditis and is accompanied

by typical manifestations of the latter, such as fever, cardiac murmur, splenomegaly,
and signs of peripheral embolism. The condition may involve virtually all arteries.
2. Infected atherosclerotic aneurysms typically occur in the distal aorta. The diagnosis
of this potentially lethal condition is very difficult. Many patients do not present with
the clinical triad of fever, back or abdominal pain, and a pulsatile abdominal mass,
combined with positive blood cultures. Protean features of infection, such as malaise,
weakness, myalgia, and weight loss or fever of obscure origin137' 139 may continue for
weeks or months prior to diagnosis. Evidence of vascular impairment in the presence
of fever is suggestive. Persistent bacteremia is a major cornerstone of diagnosis. The
infective organisms are usually Staphylococcus, Escherichia coli, Salmonella,137140
and more recently, Campylobacter fetus,141143 The plain abdominal radiography may
reveal vascular calcification, suggesting aneurysm formation, and occasionally, os-
teomyelitis of the lumbar spine. CT and isotopic scanning may be useful noninvasive
examinations, but the definitive method of diagnosis lies with aortography.
3. Microbial arteritis occurs in patients without infective endocarditis through the invasion
by bacteria of underlying arterial lesions, occurring in congenital, atherosclerotic or
hypertensive vascular disease, or vascular trauma, including arterial catheterization
and surgery. The main vessels involved are the aorta, iliac and superficial femoral
arteries. The organism is commonly Salmonella or some other Gram-negative rod.
The diagnosis is complicated by the lack of specific clinical features. The main aspects
are the patient’s history of systemic symptoms following spontaneous or traumatic
arterial injury, together with positive blood cultures.
4. A false aneurysm, unlike a true aneurysm whose wall consists of intimal, medial, and
adventitial layers, has its wall composed of compressed periarterial tissue and clot.
Their rising incidence is a result of an increase in traumatic injuries and the wider use
of vascular operations and invasive diagnostic techniques. Prolonged unexplained fever
and anemia were observed in a case of a false aneurysm in a transplant patient, although
the mechanism of fever was not clear.144

Arterial Tumor
Sarcoma arising in the walls of a large artery is a very rare condition which is extremely
difficult to diagnose. A young female with fever, cough, weight loss, elevated ESR, and a
nodular opacity in the lung was found to have a leiomyosarcoma of the pulmonary artery
at autopsy.145 Another patient with respiratory and cerebral symptoms in addition to low-
grade fever, malaise, myalgia, and chills was observed at postmortem examination to have
suffered from an undifferentiated sarcoma of the extra- and intrapulmonary arteries.146

VENOUS DISEASES
Thrombophlebitis
Thrombophlebitis is a very common condition which may involve superficial or deep
veins of the extremities, or visceral vessels. It is a condition which presents little difficulty
for diagnosis when classic clinical features are to be found. However, occasionally, as a
 79

result of an incomplete physical examination or because of actual limitations of access to

certain body regions, especially the abdomen and pelvis, the patient may present with
unexplained fever. Systemic features of fever, tachycardia, and restlessness may be the only
manifestations of deep thrombophlebitis.147 Clinical examination of the legs may fail to
disclose a venous thrombosis.148 The absence of classical signs of inflammation may make
difficult the diagnosis of thrombophlebitis in certain regions, for example, following place-
ment of a plastic catheter in the antecubital, subclavian, jugular, or saphenous vein. Septic
thrombophlebitis in pelvic, cerebral, and portal veins may also present with obscure fever
and are discussed elsewhere in the book. Pelvic thrombophlebitis following gynecologic
surgery or parturition is notorious for its ability to produce “ enigmatic fever“ .85
Certain bacteria have a propensity for venous involvement. They include Staphylococcus
aureus, anaerobic Gram-positive peptostreptococci, and peptococci, as well as Campylo-
bacter fetus. A case of bilateral deep brachial vein thrombophlebitis associated with the
latter has been described.149
Thrombophlebitis migrans may be associated with a low-grade fever and segmental
venous involvement especially of the lower extremities. It may be an antecedent manifestation
of Buerger’s disease (thromboangitis obliterans) or a feature of occult malignancy in the
pancreas, lung, ovary, or gastrointestinal tract.
Visceral thrombophlebitis migrans is a rare condition involving peripheral and visceral
veins. It is characterized by fever together with protean manifestations, depending upon the
affected venous segment, e.g., mesenteric, portal, or splenic thrombosis, pulmonary in-
farction, and cerebral symptoms. Laboratory examination may demonstrate leukocytosis,
elevated ESR, eosinophilia, and thrombocytopenia.
Since the bedside diagnosis of deep vein thrombosis is often inaccurate, 125I-labeled
fibrinogen, Doppler ultrasonography, or plethysmography should be employed, and where
necessary, radionuclide or contrast venography may be performed. For suspected intra-
abdominal or pelvic thrombophlebitis, venography and laparoscopy may be indicated.

Tumor
An unusual case of a venous tumor — leiomyosarcoma of the inferior vena cava pre-
senting with unexplained fever, has recently been described.150

REFERENCES
1. Silber, E. N. and Katz, L. N., Fever in patients with heart disease, Med. Clin. N. Am., 50, 211, 1966.
2. Lerner, P. I. and Weinstein, L., Infective endocarditis in the antibiotic era, N. Engl. J. Med., 274, 199,
259, 323, 387, 1966.
3. Weinstein, L. and Rubin, R. H., Infective endocarditis— 1973, Prog. Cardiovasc. Dis., 16, 239, 1973.
4. Petersdorf, R. G. and Goldman, P. L., Changes in the natural history of bacterial endocarditis, J. Chron.
Dis., 32, 287, 1979.
5. Friedberg, C. K., Disease of the Heart, 3rd ed., W. B. Saunders, Philadelphia, 1966.
6. Scheid, W. M. and Sande, M. A., Endocarditis and intravascular infections, in Principles and Practice
of Infectious Diseases, 2nd ed., Mandell, G. L., Douglas, R. G., Jr., and Bennett, J. E., Eds., John Wiley
& Sons, New York 1985, 504.
7. Newman, W., Torres, J. M., and Guck, J. K., Bacterial endocarditis: an analysis of fifty-two cases,
Am. J. Med., 16, 535, 1954.
8. Vogler, W. R., Dorney, F. R., and Bridges, H. A., Bacterial endocarditis: a review of 148 cases, Am.
J. Med., 32, 910, 1962.
9. Tomsett, R., Bacterial endocarditis: changes in the clinical spectrum, Arch. Intern. Med., 119, 329, 1967.
10. Case records of the Massachusetts General Hospital (Case 56-1964), N. Engl. J . Med., 271, 1109, 1964.
11. Weinstein, L., Infective endocarditis, in Heart Disease: A Textbook of Cardiovascular Medicine, Braun-
wald, E., Ed., W. B. Saunders, Philadelphia, 1980, 1166.
80 Unexplained Fever

12. Weinstein, L., “ Modem” infective endocarditis, JAMA, 233, 260, 1975.
13. Bain, R. C., Edwards, J. E., Scheifley, C. H., and Geraci, J. E., Right-sided bacterial endocarditis
and endarteritis: a clinical and pathologic study, Am. J. Med., 24, 98, 1958.
14. Persaud, V., Two unusual cases of mural endocarditis, with a review of the literature, Am. J. Clin. Pathol.,
563, 832, 1970.
15. Pankey, G. A., Subacute bacterial endocarditis at University of Minnesota Hospitals, 1939— 1959, Ann.
Intern. Med., 55, 550, 1961.
16. Gross, N. J. and Tall, R., Clinical significance of splinter hemorrhages, Br. Med. J., 2, 1496, 1963.
17. Kilpatrick, Z. M., Greenberg, P. A., and Sanford, J. P., Splinter hemorrhages — their clinical sig-
nificance, Arch. Intern. Med. 115, 730, 1965.
18. Willerson, J. T., Moellering, R. C., Jr., and Buckley, M. J., Conjunctival petechiae after open-heart
surgery, N. Engl. J. Med., 284, 539, 1971.
19. Walshe, F. B. and Hoyt, W. F., Clinical Neuro-ophthalmology, 3rd ed., Williams & Wilkins, Baltimore,
1969, 1863.
20. Ross, R. S., McKusick, V. A., and Harvey, J. C., The problem of fever in patients with valvular heart
disease, JAMA , 165, 1, 1957.
21. Bennett, W. L. and Durant, T. M., Splenomegaly associated with rheumatic heart disease: its diagnostic
significance, Am. Heart J., 42, 137, 1951.
22. Amir, J., Djaldetti, M., and DeVries, A., Prolonged fever and hepatosplenomegaly, Harefuah (Heb.),
72, 307, 1967.
23. Lerner, P. I., Neurological complications of infective endocarditis, Med. Clin. North Am., 69, 385, 1985.
24. Ziment, I., Nervous system complications in bacterial endocarditis, Am. J. Med., 47, 593, 1969.
25. Jones, H. R., Siekert, R. G., and Geraci, J. E., Neurological manifestations of bacterial endocarditis,
Ann. Intern. Med., 71, 21, 1969.
26. Pruitt, A. A., Rubin, R. H., Karchmer, A. W., and Duncan, G. W., Neurological complications of
bacterial endocarditis, Medicine, 57, 329, 1978.
27. Good, A. E., Hague, J. M., and Kauffman, C. A., Streptococcal endocarditis initially seen as septic
arthritis, Arch. Intern. Med., 138, 805, 1978.
28. Case records of the Massachusetts General Hospital (Case 31-1968), N. Engl. J. Med., 279, 260, 1968.
29. Unterecker, W. J. and Hanna, B. A., Endocarditis and osteomyelitis caused by Aerococcus viridans,
Mt. Sinai. J. Med., 43, 248, 1976.
30. Churchill, M. A., Jr., Geraci, J. E., and Hunder, G. G., Musculoskeletal manifestations of bacterial
endocarditis, Ann. Intern. Med., 87, 754, 1977.
31. Wedgwood, J., Early diagnosis of subacute bacterial endocarditis, Lancet, 2, 1058, 1955.
32. Holler, J. V. and Pecora, J. S., Backache in bacterial endocarditis, N.Y. State J. Med., 70, 1903, 1970.
33. Harkonen, M., Olin, P.-E., and Wennstrom, J., Severe backache as a presenting sign of bacterial
endocarditis, Acta Med. Scand., 210, 329, 1981.
34. Irvin, R. G. and Sade, R. M., Endocarditis and musculoskeletal manifestations, Ann. Intern. Med., 88,
578, 1978.
35. Doyle, E. F., Spagnuolo, M., Taranta, A., Kuttner, A. G., and Markowitz, M., The risk of bacterial
endocarditis during antirheumatic prophylaxis, JAMA, 201, 129, 1967.
36. Myers, A. R. and Schumacher, R., Jr., Arthritis of subacute bacterial endocarditis (SBE) (abstract),
Arthritis Rheum., 19, 813, 1976.
37. McCord, M. C. and Moberly, J., Acute hypertrophic osteoarthropathy associated with subacute bacterial
endocarditis, Ann. Intern. Med., 39, 640, 1953.
38. Walker, I., Hypertrophic osteoarthropathy: report of a rare association with endocarditis, Med. J. Aust.,
2, 537, 1970.
39. Proudflt, W. L., Skin signs in infective endocarditis, Am. Heart J., 106, 1451, 1983.
40. Bashour, F. A. and Winchell, C. P., Right-sided bacterial endocarditis, Am. J. Med. Sci., 240, 411,
1960.
41. Panidis, I. P., Kottler, M. N., Mintz, G. S., Ross, J. J., and Weber, J., Clinical and echocardiographic
correlations in right heart endocarditis, Int. J. Cardiol., 6, 17, 1984.
42a. Pazin, G. J., Saul, S., and Thompson, M. E., Blood culture positivity: suppression of outpatient antibiotic
therapy in patients with bacterial endocarditis, Arch. Intern. Med., 142, 263, 1982.
42. Canady, P. B., Jr. and Sanford, J. P., Negative blood cultures in infective endocarditis: a review, South.
Med. J., 69, 1420, 1976.
43. Pesanti, E. L. and Smith, I. M., Infective endocarditis with negative blood cultures: an analysis of 52
cases, Am. J. Med., 66, 43, 1979.
44. Van Scoy, R. E., Culture-negative endocarditis, Mayo Clin. Proc., 57, 149, 1982.
45. Villareal, H. and Sokoloff, L., The occurrence of renal insufficiency in subacute bacterial endocarditis,
Am. J. Med. Sci., 220, 655, 1950.
 81

46. Rubinstein, E., Noriega, E. R., Simberkoff, M. S., Holzman, R., and Rabat, J. J., Jr., Fungal
endocarditis: analysis of 24 cases and review of the literature, Medicine, 54, 331, 1975.
47. Seelig, M. S., Speth, C. P., Kozinn, P. J., Taschdjian, C. L., Toni, E. F., and Goldberg, P., Patterns
of candida endocarditis following cardiac surgery: importance of early diagnosis and therapy (an analysis
of 91 cases), Prog. Cardiovasc. Dis., 17, 125, 1974.
48. Louria, D. B. and Dineen, P., Amphotericin B in treatment of disseminated moniliasis, JAMA, 174, 273,
1960.
49. Beeson, P. B., Brannon, E. S., and Warren, J. V., Observations on the sites of removal of bacteria
from the blood in patients with bacterial endocarditis, J. Exp. Med., 81, 9, 1945.
50. Mallen, M. S., Hube, E. L., and Brenes, M., Comparative study of blood cultures made from artery,
vein and bone marrow in patients with subacute bacterial endocarditis, Am. Heart. J., 33, 692, 1947.
51. Puklin, J. E., Balis, G. A., and Bentley, D. W., Culture of an Osier’s node; a diagnostic tool, Arch.
Intern. Med., 127, 296, 1971.
52. Alpert, J. S., Krous, H. F., Dalen, J. E., O’Rourke, R. A., and Bioor, C. M., Pathogenesis of Osier’s
nodes, Ann. Intern. Med., 85, 471, 1976.
53. Mandell, G. L., Kaye, D., and Levison, M. E., Enterococcal endocarditis: an analysis of 38 patients
observed at the New York Hospital-Comell University Medical Center, Arch. Intern. Med., 125, 258,
1970.
54. Merchant, R. K., Louria, D. B., Geisler, P. H., Edgcomb, J. H., and Utz, J. P., Fungal endocarditis:
review of the literature and report of three cases, Ann. Intern. Med., 48, 242, 1958.
55. Hill, R. W. and Bayrd, E. D., Phagocytic reticuloendothelial cells in subacute bacterial endocarditis with
negative cultures, Ann. Intern. Med., 52, 310, 1960.
56. Engle, R. L., Jr. and Koprowska, I., The appearance of histiocytes in the blood in subacute bacterial
endocarditis, Am. J. Med., 26, 965, 1959.
57. Crowder, J. G. and White, A., Teichoic acid antibodies in staphylococcal and nonstaphylococcal en-
docarditis, Ann. Intern. Med., 77, 87, 1972.
58. Nagel, J. G., Tuazon, C. U., Cardella, T. A., and Sheagren, J. N., Teichoic acid serologic diagnosis
of staphylococcal endocarditis, Ann. Intern. Med., 82, 13, 1975.
59. Cordeiro, A., Costa, H., and Laginha, F., Editorial: Immunologic phase of subacute bacterial endocarditis:
a new concept and general considerations, Am. J. Cardiol., 16, 477, 1965.
60. Das, S. K. and Cassidy, J. T., Importance of heart antibody in infective endocarditis, Arch. Intern. Med.,
137, 591, 1977.
61. Hurwitz, D., Quismoro, F. P., and Triou, G. J., Cryoglobulins in patients with infectious endocarditis,
Clin. Exp. Immunol., 19, 887, 1976.
62. Williams, R. G. and Kunkel, H. G., Rheumatoid factor, complement and conglutin aberrations in patients
with subacute bacterial endocarditis, J. Clin. Invest., 41, 666, 1962.
63. Bayer, A. S., Theofilopoulos, A. N., Eisenberg, R., Dixon, F. J., and Guze, L. B., Circulating immune
complexes in infective endocarditis, N. Engl. J. Med., 295, 1500, 1976.
64. Mandell, G. L., The laboratory in diagnosis and management, in Infective Endocarditis, Kaye, D., Ed.,
University Park Press, Baltimore, 1976, 155.
65. Stewart, J. A., Silimperi, D., Harris, P., Wise, N. K., Fraker, T. D., Jr., and Kisslo, J. A.,
Echocardiographic documentation of vegetative lesions in infective endocarditis: clinical implications, Cir-
culation, 61, 374, 1980.
66. Rubenson, D. S., Tucker, C. R., and Stinson, E. B., The use of echocardiography in diagnosing culture-
negative endocarditis, Circulation, 64, 641, 1981.
67. Dimmitt, S. B., Pearman, J. W., and Woollard, K. V., Chlamydial endocarditis, Ausi. N. Z. J. Med.,
15, 340, 1985.
68. Wiseman, J., Rouleau, J., Rigo, P., Strauss, H. W., and Pitt, B., Gallium-67 myocardial imaging for
the detection of bacterial endocarditis, Radiology, 120, 135, 1976.
69. Pazin, G. J., Peterson, K. L., Griff, F. W., Shaver, J. A., and Ho, M., Determination of site of
infection in endocarditis, Ann. Intern. Med., 82, 746, 1975.
70. Mills, J., Abbott, J., Utley, J. R., et al., Role of cardiac catheterization in infective endocarditis, Chest,
1A, 576, 1977.
71. Douglas, A., Moore-Gillon, J., and Eykyn, S., Fever during treatment of infective endocarditis, Lancet,
1, 1341, 1986.
72. McCarty, M., The streptococcus and human disease, Am. J. Med., 65, 717, 1978.
73. Barnert, A. L., Terry, E. E., and Persellin, R. H., Acute rheumatic fever in adults, JAMA, 232, 925,
1975.
74. McDonald, E. C. and Weisman, M. H., Articular manifestations of rheumatic fever in adults, Ann.
Intern. Med., 89, 917, 1978.
75. Ben Dov, I., Acute rheumatic fever in adults over the age of 45 years: an analysis of 23 patients together
with a review of the literature, Semin. Arthritis Rheum., 10, 100, 1980.
82 Unexplained Fever

76. Persellin, R. H., Acute rheumatic fever: changing manifestations, Ann. Intern. Med., 89, 1002, 1978.
77. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report on 100 cases, Medicine, 40,
1, 1961.
78. Atkins, E. and Stitt, J. T., Fever, in MacBryde's Signs and Symptoms: Applied Pathologic Physiology
and Clinical Interpretation, 6th ed., Blacklow, R. S., Ed., Lippincott, Philadelphia, 1983, 441.
79. Murray, H. W., Mann, J. J., Genecin, A., and McKusick, V. A., Fever with dissecting aneurysm of
the aorta, Am. J. Med., 61, 140, 1976.
80. Murray, H. W., Ellis, G. C., Blumenthal, D. S., and Sos, T. A., Fever and pulmonary thromboembolism,
Am. J. Med., 67, 232, 1979.
81. Bell, W. R., Simon, T. L., and DeMets, D. L., The clinical features of submassive and massive pulmonary
emboli, Am. J. Med., 62, 355, 1977.
82. Grivaux, M. and Bagnet, J. C., Signes, evolution et diagnostic des embolies et infarctus pulmonaires,
Rev. Pract., 17, 4934, 1967.
83. Gleckman, R., Crowley, M., and Esposito, A., Fever of unknown origin: a view from the community
hospital, Am. J. Med. Sei., 274, 21, 1977.
84. Watanakunakorn, C. and Hayek, F., High fever (greater than 39°C) as a clinical manifestation of
pulmonary embolism, Postgrad. Med. J. 63, 951, 1987.
85. Dunn, L. J. and Vanvoorhis, L. W., Enigmatic fever and pelvic thrombophlebitis: response to antico-
agulants, N. Engl. J. Med., 276, 265, 1967.
86. Wilson, K. H. and Tuazon, C. U., Pulmonary emboli 5 days postinjury presenting as fever of unknown
origin, J. Trauma, 20, 259, 1980.
87. Marsh, J. D., Glynn, M., and Torman, H. A., Pulmonary angiography: application in a new spectrum
of patients, Am. J. Med., 75, 763, 1985.
88. Hull, R. D., Hirsh, J., Carter, C. J., et al., Diagnostic value of ventilation-perfusion lung scanning in
patients with suspected pulmonary embolism, Chest, 88, 819, 1985.
89. Lofmark, R., Nordländer, R., and Orinus, E., The temperature course in acute myocardial infarction,
Am. Heart J., 96, 153, 1978.
90. Finley, R. W. and Marr, J. J., Anaerobic myocardial abscess following myocardial infarction, Am. J.
Med., 78, 513, 1985.
91. Kim, H. S., Weilbacher, D. G., Lie, J. T., and Titus, J. L., Myocardial abscesses, Am. J. Clin. Pathol.,
70, 18, 1978.
92. Baumann, B. B. and Morata, E. T., Systemic melioidosis presenting as myocardial infarction, Ann.
Intern. Med., 67, 836, 1967.
93. El Shahawy, M. and Flowers, N. C., Unexplained fever and chills associated with myocardial infarction,
Chest, 62, 263, 1972.
94. Chandaratna, P. A. N., Nimalasuriya, A., Reid, C. L., Cohn, S., and Rahimtoola, S. H., Left
ventricular asynergy in acute myocarditis, JAMA, 250, 1428, 1983.
95. Chandaratna, P. A. N., Bradley, W. G., Kortman, K. E., Minagoe, S., Delvicario, M., and Rahim-
toola, S. H., Detection of acute myocarditis using nuclear magnetic resonance imaging, Am. J. Med., 83,
1144, 1987.
96. Editorial, Nonrheumatic myopericarditis, Br. Med. J., 2, 544, 1971.
97. Oram, S., Clinical Heart Disease, Heinemann, London, 1971, 746.
98. Smith, W. G., Coxsackie B myopericarditis in adults, Am. Heart J., 80, 34, 1970.
99. Perry, E. L., Fleming, R. G., and Edwards, J. F., Myocardial lesions in subacute bacterial endocarditis,
Ann. Intern. Med., 36, 126, 1952.
100. Jason, M. K., Zoneraich, S., and Silverman, G., Tuberculosis of the myocardium. N.Y. State J. Med.,
81, 368, 1981.
101. Abela, G. S., Majmudar, B., and Feiner, J. M., Myocardial abscesses unassociated with infective
endocarditis, South. Med. J., 74, 432, 1981.
102. Fowler, N. O. and Manitsas, G. T., Infectious pericarditis, Prog. Cardiovasc. Dis., 16, 323, 1973.
103. Larson, E., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow-up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
104. Weinstein, L. and Fields, B. N., Fever of obscure origin, Semin. Infect. Dis., 1, 1, 1978.
105. Engle, M. A., Gay, W. A., Jr., Zabriskie, J. B., and Senterflt, L. B., The postpericardiotomy syndrome:
25 years’ experience, J. Cardiovasc. Med., 9, 321, 1984.
106. Dressier, W., A post-myocardial-infarction syndrome: preliminary report of a complication resembling
idiopathic, recurrent, benign pericarditis, JAMA, 160, 1379, 1956.
107. Luft, F. C., Filman, J. K., and Weymann, A. E., Pericarditis in the patient with uremia: clinical and
electrocardiographic evaluation, Nephron, 25, 160, 1980.
108. Oster-Jorgensen, E., Freeriksen, P. B., and Rasmusssen, J. W ., 57Co-Bleomycin: a diagnostic aid in
fever of obscure origin, Dan. Med. Bull., 30, 198, 1983.
 83

109. Fleg, J. L., Siegel, B. A., and Roberts, R., Detection of pericarditis with "technetium pyrophosphate
images (abstr.), Am. J. Cardiol., 39, 273, 1977.
110. Kutalek, S. P., Panidis, I. P., Kotler, M. N., Mintz, G. S., Carver, J., and Ross, J. J., Metastatic
tumors of the heart detected by two-dimensional echocardiography, Am. Heart J., 109, 343, 1985.
111. Posner, M. R., Cohen, G. I., and Skarin, A. T., Pericardial disease in patients with cancer: the differ-
entiation of malignant from idiopathic and radiation-induced pericarditis, Am. J. Med., 71, 407, 1981.
112. Howe, C. W. S. and Rosenthal, D. S., Malignancy and the heart, J. Cardiovasc. Med., 9, 155, 1984.
113. Brandenburg, R. O. and Edwards, J. E., Cardiac sarcoma: report of case and comparison with a case
of metastatic carcinoma of the pericardium, Proc. Mayo Clin., 29, 437, 1954.
114. Vesterinen, E., Kivinen, S., and Nieminen, U., Cervical carcinoma complicated by malignant pericarditis,
Acta Obstet. Gynecol. Scand., 66, 569, 1987.
115. Hood, R. P., Geraci, J. E., Broadbent, J. C., and Titus, J. L., Metastatic squamous cell carcinoma
of the heart presenting as fever of unknown origin, Mayo Clin. Proc., 42, 556, 1967.
116. Yater, W. M., Tumors of the heart and pericardium: pathology, symptomology and report of nine cases,
Arch. Intern. Med., 48, 627, 1931.
117. Biller, J., Challa, V. R., Toole, J. F., et al., Nonbacterial thrombotic endocarditis: a neurologic perspective
of clinicopathologic correlations of 99 patients, Arch. Neurol., 39, 95, 1982.
118. Goodwin, J. F., Diagnosis of left atrial myxoma, Lancet, 1, 464, 1963.
119. D’Angelo, G. J., Kish, G. F., Sardesi, P. G., and Tan, W. S., Cardiac tumors in 19 years of private
practice, Am. Surg., 53, 105, 1987.
120. Rajpal, R. S., Leibson, J. A., Liekweg, W. G., et al., Infected left atrial myxoma with bacteremia
simulating infective endocarditis, Arch. Intern. Med., 139, 1176, 1979.
121. Pascuzzi, C. A., Parkin, T. W., Bruwer, A. J., and Edwards, J. E., Hypertrophic osteoarthropathy
associated with primary rhabdomyosarcoma of the heart, Proc. Mayo Clin., 32, 30, 1957.
122. Williams, A. and Slowman, J. G., Myosarcoma of the heart in an infant, J. Pathol. Bacteriol., 72, 421,
1956.
123. Fitzpatrick, A. P., Langham, J. G., and Doyle, D. V., Cardiac tumours simulating collagen vascular
disease, Br. Heart J., 55, 592, 1986.
124. Harvey, W. P., Clinical aspects of cardiac tumors, Am. J. Cardiol., 21, 328, 1968.
125. Woll, E. and Vickery, A. L., Primary fibrosarcoma of the heart with a vertebral metastasis, Arch. Pathol.,
43, 244, 1947.
126. Mackowiak, P. A., Lipscomb, K. M., Mills, L. J., and Smith, J. W., Dissecting aortic aneurysm
manifested as fever of unknown origin, JAMA , 236, 1725, 1976.
127. Ruderman, A., Mackowiak, P. A., and Smith, J. W., Fever as a manifestation of dissecting aneurysm
of the aorta, Am. J. Cardiol., 44, 581, 1979.
128. Roberts, W. C., MacGregor, R. R., Deblanc, H. J., Jr., Beiser, G. D., and Wolff, S. M., The
prepulseless phase of pulseless disease or pulseless disease with pulses: a newly recognized cause of cardiac
disease, monoclonal gammopathy and “ fever of unknwon origin’’, Am. J. Med., 46, 313, 1969.
129. Hall, S., Barr, W., Lie, J. T., Stan son, A. W., Kazmier, F. J., and Hunder, G. G., Takayasu arteritis,
a study of 32 North American patients, Medicine, 64, 89, 1985.
130. Lupi-Herrera, E., Sanchez-Torres, G., Macushamer, J., et al., Takayasu’s arteritis: clinical study of
107 cases, Am. Heart J., 93, 94, 1977.
131. Melish, M., Kawasaki syndrome, Annu. Rev. Med., 33, 569, 1982.
132. Chung, K., Brandt, L., Fulton, D., et al., Cardiac and coronary involvement in children from New
England with mucocutaneous lymph node syndrome, Am. J. Cardiol., 50, 136, 1982.
133. Morgan, W. L., Important diagnostic signs of a leaking abdominal aortic aneurysm, Arch. Intern. Med.,
99, 134, 1957.
134. Szilagyi, D. E., Elliott, J. P., Jr., and Smith, R. F., Ruptured abdominal aneurysm, Arch. Surg., 91,
263, 1965.
135. Bennett, D. E. and Cherry, J. K., Bacterial infection of aortic aneurysm: a clinicopathologic study, Am.
J. Surg., 113, 321, 1967.
136. Wilson, S. E., Wagenen, P. V., and Passao, E., Jr., Arterial infection, Curr. Prob. Surg., 15(9), 1,
1978.
137. Davies, O. G., Thorburn, J. D., and Powell, P., Cryptic mycotic abdominal aorta aneurysms, Am. J.
Surg., 136, 96, 1978.
138. Jarrett, F., Darling, R. C., Mundth, E. D., and Austem, G., Experience with infected aneurysms of
the abdominal aorta, Arch. Surg., 110, 1281, 1979.
139. Bronsther, O. and Schanzer, H., Infected abdominal aorta aneurysm. Mt. Sinai J. Med., 48, 440, 1981.
140. Mendelowitz, D. S., Ramstedt, R., Yao, J. S. T., and Bergan, J. J., Abdominal aortic salmonellosis,
Surgery, 85, 514, 1979.
141. Anolik, J. R., Mildvan, D., Winter, J. W., Puttlitz, D., Rubenstein, S., and Cozman, H., Mycotic
aortic aneurysm: a complication of Campylobacter fetus septicemia, Arch. Intern. Med., 143, 609, 1983.
84 Unexplained Fever

142. File, T. M., Jr., Barnistran, J., and Fass, R. J., Campylobacterfetus sepsis with mycotic aortic aneurysm,
Arch. Pathol. Lab. Med., 103, 143, 1979.
143. Marty, A. T., Welb, T. A., Stubbs, G., and Penkava, R. R., Inflammatory abdominal aorta aneurysm
infected by Campylobacter fetus, JAMA, 249, 1190, 1983.
144. Levi, J., Zevin, D., Barak, I., and Admon, M., Prolonged fever and anemia as the sole presentation of
a false aneurysm in a transplant patient, Isr. J. Med. Sci., 15, 910, 1979.
145. Ali, M. Y. and Lee, G. S., Sarcoma of the pulmonary artery, Cancer, 17, 1220, 1964.
146. Shmookler, B. M., Marsh, H. B., and Roberts, W. C., Primary sarcoma of the pulmonary trunk, and/
or right or left main pulmonary artery — a rare cause of obstruction to right ventricular outflow: report of
two patients and analysis of 35 previously reported patients, Am. J. Med., 63, 263, 1977.
147. Shafer, N. and Duboff, S., Physical signs in the early diagnosis of thrombophlebitis, Angiology, 22, 18,
1971.
148. Haeger, K., Problems of acute deep venous thrombosis. I. The interpretation of signs and symptoms,
Angiology, 20, 219, 1969.
149. Vesely, D., MacIntyre, S., and Ratzan, K. R., Bilateral deep brachial vein thrombophlebitis due to vibrio
fetus, Arch. Intern. Med., 135, 994, 1975.
150. Flore Torre, M., Merino Angulo, J., Villanueva Marcos, R., and Aguirre Errasti, C., Leiomyosarcome
de la veine cave inferieure révélé par un syndrome febrile d’etiologie obscure, Nouv. Presse Med., 10,
3493, 1981.
 85

Chapter 7

FEVER IN RESPIRATORY DISEASES

Shaul Z. Margaliot

INTRODUCTION
Years ago fever was believed to be a diagnostic sign of pulmonary disease of infectious
etiology. The level and pattern of the fever were of utmost importance in establishing the
diagnosis. Low-grade fever with night sweats was essentially sine qua non tuberculosis while
persistent high fever was believed to be pneumonia until proven otherwise. Obviously, this
is not the case. Most of the respiratory diseases presenting with fever, especially those which
are more difficult to diagnose, are not of infectious origin. In the era of abundant use of
antibiotics, even the classic febrile diseases such as tuberculosis changed their presentation
altogether. Nowadays, neither the level nor the pattern of the temperature is considered
diagnostic.
Fever is merely an indicator of a disease process. This is why the advanced and so-
phisticated tools such as computed tomography or bronchoalveolar lavage with electron
microscopy of the cells become so important in evaluating the patients with fever of res-
piratory origin.
Many pulmonary diseases of various etiologies present with fever, occasionally pro-
longed, with or without other systemic symptoms. Not infrequently, respiratory symptoms
are absent or minimal. The approach to the febrile patient and the pathogenesis of fever are
discussed elsewhere in this book.
Some of the lung and pleural diseases have pathognomonic features but in many others
the signs, symptoms, and laboratory tests are nonspecific and diagnosis may be very difficult
to establish.
Physiologically, the lung has limited ways to respond, so that lung function tests are
not sufficient for definitive diagnosis in most cases.

DIAGNOSTIC TECHNIQUES IN EVALUATING THE FEBRILE

PATIENT WITH PULMONARY DISEASE
CHEST RADIOLOGY
The chest radiograph is the most common diagnostic tool in pulmonary medicine. Most
pulmonary diseases have a characteristic appearance on the chest X-ray. Certain appearances
on the chest roentgenogram direct the viewer to a relatively short list of differential diagnoses
(Table 1), but quite often the radiographic appearance is atypical and other methods are
necessary for diagnosis. Diffuse granulomatous and fibrotic diseases of the lung may be
present with a normal chest roentgenogram.
Computed tomography (CT) has become well established in examining the chest. CT
is the most sensitive noninvasive method for the detection of pulmonary nodules. CT is
valuable in providing consistently satisfactory cross-sectional information in the medias-
tinum, where there are many superimposed structures. CT can be useful in demonstrating
primary pleural disease or direct extension to the pleura from lung parenchymal and extra-
pleural pathologic processes. As the pleura becomes involved in a pathologic process, it
becomes visible on CT, manifesting abnormal attenuation, contour and thickness.1
86 U nex p la in ed F e ve r

TABLE 1
Differential Diagnosis of Fever Related to the Radiological Pattern

Radiological pattern Corresponding clinical diagnosis Comments

Opacities Localized to one lobe or segment

(with predominantly aci- Lobar or segmental pneumonia, pul-
nar pattern) monary infarction, lobar or segmen-
tal atelectasis
Bronchogenic carcinoma, bronchiec-
tasis, mucus plug, primary T.B.
(lymph node or bronchostenosis) post-
operative, foreign body
Localized to several lobes or segments
Pneumonia, pulmonary edema, lym- Hodgkin’s or non-Hodgkin’s, bron-
phoma, bronchogenic carcinoma, chiolo-alveolar carcinoma
chronic eosinophilic pneumonia, ir-
radiation pneumonitis, inhalational
pneumonitis
Nodular Solitary
pattem Infectious
Lung abscess, Tuberculoma, Histo-
plasmoma, Cryptococcus, Nocar-
dia, Aspergilloma,
Coccidioidomycosis, Blastomy-
cosis, hydatid cyst
Tumors — benign
Bronchial adenoma, hamartoma,
lipoma, chondroma
Tumors — malignant
Primary, secondary
Immunological
Rheumatoid arthritis, (necrobiotic More often multiple
nodule) Wegener’s granulomatosis
Inhalation pneumonia
Lipoid pneumonia
Developmental
Sequestration, bronchogenic cyst,
arteriovenous malformation
Multiple — micronodular (less than
5 mm in diameter)
Miliary tuberculosis, sarcoidosis,
pneumoconiosis
Multiple — macronodular (more than
5 mm in diameter)
Infectious
Bacterial, pyemic abscesses Commonly caused by Staph, aureus
which commonly cavitates
Fungal
Histoplasma caps., Coccidioides
immitis Particularly upper lobes
Parasitic Parasitic
Paragonimus westermani May see thin-walled cysts
Tumors
Primary bronchogenic, secondary
metastatic, non-Hodgkin’s
lymphoma
Sarcoidosis, Pneumoconioses
Immunological causes
 87

TABLE 1 (continued)
Differential Diagnosis of Fever Related to the Radiological Pattern

Radiological pattern Corresponding clinical diagnosis Comments

Rheumatoid arthritis (necrobiotic Often peripheral

nodules)
Wegener’s granulomatosis
Reticular pattern Infectious
Interstitial pneumonias, — including
viral and mycoplasma
Interstitial pulmonary edema
Hypersensitivity pneumonitis
Acinar opacities are common in the
acute phase
Immunological causes
Rheumatoid arthritis, systemic lupus er-
ythematosus, systemic sclerosis (sclero-
derma), sjogren’s syndrome,
dermatomyositis and polymyositis,
Nitrofurantoin — induced
Waldenstrom’s macroglobulinemia Usually associated with peripheral
blood eosinophilia
Idiopathic pulmonary fibrosis
Sarcoidosis Stage 3
Pneumoconioses
Histiocytosis-X (eosinophilic granuloma)
Lymphangitic carcinomatosis Particularly metastatic spread from
breast, stomach, thyroid, pancreas
Cavities and cysts Localized
Tuberculous cavity
Pulmonary abscess
Hydatid cyst
Infected bronchogenic cyst
Post pulmonary infarction
Cystic bronchiectasis
Bronchogenic carcinoma with
cavitation
Pneumatocoele (Staph, pneumonia)
Emphysematous bulla
Regional Volume loss Obstructing endobronchial lesion (be-
nign or malignant)
Extrinsic pressure on bronchi due to
lymph node enlargement:
Primary mycobacterial infections
Lymphoma (Hodgkin’s or non-Hodg-
kin’s)
Sarcoidosis
Intrabronchial foreign body
Pulmonary thromboembolism Due to obstruction of a major pulmo-
nary artery

FIBEROPTIC BRONCHOSCOPY (FOB)

FOB is one of the most common diagnostic procedures in pulmonary medicine. It serves
in the diagnosis of carcinoma of the lung, hemoptysis, pulmonary infections, and interstitial
lung disease.2
88 Unexplained Fever

Lung Cancer
Endobronchial masses are readily seen. The reported yield on direct forceps biopsy
ranges from 70 to 100%. Washings and brushings have about 80% yield in endobronchial
lesions. In a friable lesion, bronchoscopie needle aspiration can be used instead of biopsy
(yield 65 to 80%).
Submucosal or peribronchial spread of cancer can be sampled by bronchoscopie needle
aspiration. The combined yield of forceps biopsy, needle aspiration, washings and brushings
in these tumors reaches 97%.
Sixty to seventy percent of occult carcinoma (cases with positive cytology and negative
chest radiograph) can be detected on the first bronchoscopy.
Peripheral masses (visible on chest radiograph, but not through the bronchoscope), can
be sampled by transbronchial biopsy and brushings. The reported yield ranges from 30 to
90%, depending on the size of the lesion.

Pulmonary Infections
The main problem using FOB for diagnosis of bacterial infections is the contamination
of the bronchoscope by upper airway flora. The protected bacteriological brush can overcome
this problem.3 FOB is very useful in diagnosing tuberculosis and fungal infections. Bron-
choscopy increases significantly the immediate diagnosis by staining the specimens and the
positive cultures in cases in whom expectorated sputum smears are negative. Bronchoalveolar
lavage is helpful in diagnosing fungal infections.
Bronchoscopy is particularly useful in the detection of opportunistic infections in the
immunocompromised host. By combining bronchoalveolar lavage and transbronchial biopsy
the yield is close to 100%.

Interstitial Lung Disease

The usefulness of bronchoscopy in the diagnosis of diffuse interstitial lung disease is
doubtful. There are only a few interstitial diseases where FOB is very helpful in diagnosis.
Transbronchial biopsy is very effective in diagnosing sarcoidosis; the granulomas are diffuse
and the yield is as high as 90%.4 Histiocytosis can also be diagnosed by histology on
transbronchial biopsy and by characteristic EM findings on cells from lavage.5

BRONCHOALVEOLAR LAVAGE (BAL)

The procedure is performed through a fiberoptic bronchoscope. The tip of the broncho-
scope is wedged in a subsegmental bronchus. Small amounts (20 to 60 ml) of normal saline
are injected and gently aspirated. The maneuver is repeated several times. The procedure
is easy and safe and carries a high diagnostic yield.
The clinical value of BAL includes analysis of the total and differential counts of
inflammatory cells, identification of abnormal cells, analysis of material in supernatants and
staining and culture of bacteria, viruses, fungi and protozoa.
BAL is useful in diagnosing various interstitial diseases, e.g., eosinophilic granuloma
where the appearance of cytoplasmic tubular structures on electron microscopy and antibody
staining of Langerhans cells by immunofluorescence are pathognomonic.56 The technique
is of considerable value in the diagnosis of infections, e.g., Pneumocystis carinii pneumonia,
where the cysts can be seen on silver stain and the trophozoites on May Grunwald Giemsa
stain or the identification of intracellular inclusions of cytomegalovirus.

TRANSTHORACIC NEEDLE ASPIRATION

The yield in the use of the procedure for cytologic evaluation in suspected pulmonary
neoplasm is as high as 96%. The diagnostic yield in using the technique to evaluate suspected
infections ranged from 36 to 82%.
 89

THORACOSCOPY-GUIDED BIOPSY
A flexible endoscope (thoracoscope) is inserted between the parietal and visceral pleura
and biopsy specimens of lung parenchyma are obtained under direct inspection of the worst
appearing affected lung. Like fine needle aspiration, this technique too suffers from the same
limitations: sampling only the periphery of the lung and complications of pneumothorax and
hemorrhage.

OPEN LUNG BIOPSY

The aforementioned methods for obtaining biopsy specimens suffer from limitations in
approaching peripheral or localized infiltrates. When it comes to interstitial lung disease,
the size of the forceps’ biopsy is usually too small to demonstrate all of the extent of the
pathologic changes (except for sarcoidosis). Open lung biopsy can overcome these limita-
tions. In the immunocompromised patient with pulmonary infiltrates, a specific etiologic
diagnosis is necessary so that the appropriate therapy can be initiated. In several reported
series, open lung biopsy was thought to be superior for establishing a specific etiologic
diagnosis in the immunocompromised patient and was associated with fewer complications
than some of the less invasive techniques.7
Limited thoracotomy is performed with the patient under general anesthesia, and one
or several wedge-shaped specimens is obtained from the affected lung tissue. The size of
the specimen enables complete pathologic evaluation and microbiologic work-up of the
tissue.
The complications rate is relatively low. The major complications are pneumothorax
and hemorrhage.

METHODS FOR DIAGNOSING PULMONARY INFECTIONS

STAINING AND CULTURE OF COLLECTED SPUTUM
Expectorated sputum, in contrast to saliva, should contain less than ten squamous ep-
ithelial cells per low power field. The presence of many polymorphonuclear cells (>25 per
low power field) increases the likelihood of the specimen to be true sputum.
Positive Gram stain is only suggestive of bacterial pneumonia, but nevertheless it has
value in directing therapy.8
Flatauer et al. suggested that the Gram’s stain of bronchoscopically obtained pulmonary
secretions gives better clinical correlation than does culture of the same specimen.9
Wet mount potassium hydroxide preparation can demonstrate fungal infection.
Pneumocystis carinii can be stained by methenamine silver nitrate.
Direct fluorescent antibody should be supplied for the identification of Legionella pneu-
mophila.
Sputum cultures may eventually yield organisms, but it should be noted that some of
the pathogens will grow in culture only after a long time. For example, Legionella takes 3
to 10 days to grow, various fungi will take up to 6 weeks and Mycobacterium tuberculosis
2 to 8 weeks.

TRANSTRACHEAL ASPIRATION
Overall the procedure does not have a higher yield compared to collected sputum while
it may be associated with some complications. Its advantage is only when anaerobic bacterial
infection is highly suspected.

PERCUTANEOUS FINE NEEDLE ASPIRATION

The procedure is performed with a thin walled long needle (18 to 20 gauge) or with the
“ skinny needle” (25 gauge). It yields uncontaminated material from the lung parenchyma.
The reported yield of specific diagnosis in immunocompromised patients is 55 to 76%.10
90 Unexplained Fever

The procedure is limited for sampling only peripheral lung tissue. Other disadvantages of
this procedure are the frequent complications: pneumothorax in up to 26% of cases and
hemorrhage in up to 18%.

PULMONARY INFECTIONS
PNEUMONIA
Pneumonia, microbial infection of the lower respiratory tract, remains the most common
cause of infectious disease death in the U.S. Therefore, early diagnosis is very important.
Pneumonia can be caused by many diverse pathogens. The frequency of differing causes of
pneumonia is determined by host age, underlying disease, and whether infection is com-
munity or hospital acquired. Most cases will present with fever. The radiologic pattern of
the infiltrate can provide a clue to the diagnosis, but a microbiologic or serologic diagnosis
is important for the correct treatment.
Table 2 lists the microorganisms capable of producing pneumonia in the immune-
competent patient.
FUO of infectious origin is discussed in detail in Chapters 19 and 20. Only some of the
more specific pulmonary infections will be discussed here.

LEGIONELLOSIS (LEGIONNAIRE’S DISEASE)

The causative agent is Legionella pneumophila, a pleomorphic, waterborne, Gram-
negative bacillus, which is not seen on routine Gram stains and requires special culture
mediums to grow. The disease can present in the following patterns:

A. Sporadic cases, in the community

B. Epidemic outbreaks (short outbreaks in hotels)
C. Nosocomial outbreaks
D. Pontiac fever, a nonpneumonic febrile syndrome

According to Woo et al., most, if not all, outbreaks originate from portable water
distribution contamination. The primary hospital reservoir is the hot water tank. The organism
has a predilection for lodging within the sediment of water fixtures.11
The disease is more frequent in cigarette smokers and patients with chronic obstructive
lung disease. The clinical presentation is that of pneumonia. Fifty percent of the patients
present with high fever of 40°C or greater.
There are many extrapulmonic nonspecific manifestations including anemia, hematuria,
granular and hyaline casts in the urinary sediment, absolute hypophosphatemia, hyponatre-
mia, and abnormal liver function tests.
Isolation of the organism is absolutely specific. The sensitivity of sputum culture is
70%, that of transtracheal aspirate is 90%, and of blood culture 40%. The sensitivity of
direct immunofluorescent antibody stain of respiratory secretions is 30 to 50% with specificity
of 95% and the sensitivity of indirect immunofluorescent antibody serology for acute and
convalescent (which takes 8 weeks for results) is 70 to 90% specificity.

TUBERCULOSIS
Tuberculosis is a systemic disease, caused by Mycobacterium tuberculosis, with protean
manifestations. It may mimic many diseases in many parts of the body. About 15% of cases
involve extrapulmonary sites.
Tuberculosis is unevenly distributed throughout the world. Even in the U.S. it is not
distributed uniformly in the population. Case rates vary markedly by age, sex, race, and
geographic location.12 Socioeconomic factors are also important determinants of the prev-
alence of tuberculosis.13
 91

Although tuberculosis is less prevalent than it was in former years, it does still occur
and may advance consistently while more fashionable diagnoses are being pursued.
With the decline in sources of new infections among young persons today, tuberculosis
is rapidly becoming a disease of the elderly in the U.S. Healed infection is still fairly
prevalent among the elderly due to the great prevalence of the infection early in this century.
Reactivation of the infection as well as new infection is a threat, especially in immu-
nosuppressed patients (AIDS, malignancy, immunosuppressive and corticosteroid therapy,
and chronic hemodialysis) and in patients with diabetes, silicosis, or postgastrectomy.
The clinical and radiologic presentation of tuberculosis among the elderly may be quite
atypical.
The tuberculin skin test (preferably using PPD) has been the traditional method of
diagnosing tuberculous infection. It should be noted that the test is not specific and positive
reaction may be due to nontuberculous mycobacteria and in any case it does not necessarily
indicate active disease. On the other hand, negative test (anergy) does not exclude active
tuberculosis.
Definitive diagnosis requires the demonstration of M . tu b ercu lo sis in the patients’s tissues
or secretions by microscopy and cultures.
Tuberculosis should be suspected when a pneumonia fails to resolve or there is a
persisting cough or a persisting fever.

MILIARY TUBERCULOSIS
Miliary tuberculosis is a disease produced by acute diffuse dissemination of tubercle
bacilli via the blood stream. In the lung the process is manifested by the appearance of tiny
discrete foci uniformly distributed. By definition, miliary tuberculosis must have a diffuse
infiltrate visible by chest roentgenogram or a miliary pattern of tubercles visualized in multiple
organs, at pathologic examination.15
The clinical presentation of miliary tuberculosis is nonspecific. The onset of symptoms
is usually insidious and the duration of symptoms is several weeks to 4 months. Common
presenting symptoms include malaise, anorexia, weight loss, f e v e r , and cough. The fever
may be continuously low grade or spiking. Fever is the most common presenting physical
sign.16
Miliary tuberculosis tends to occur in late adulthood and in a “ cryptic” pattern, which
lacks the clinical and radiographic features of classic miliary tuberculosis. It presents as an
occult illness with a gradual decrement in general health often without significant fever and
with a negative tuberculin skin test and a normal chest roentgenogram.
Microbiolgic and histologic tests are essential for the diagnosis.

ATYPICAL MYCOBACTERIA
Lung disease caused by nontuberculous M y c o b a c te ria 11 18 is essentially similar to tu-
berculosis and it is only the laboratory results which make the difference. The most common
pulmonary pathogens in this group are M . ka n sa sii and M . a v iu m -in tra c e llu la re , but there
are reports of disease caused by M . fo rtu itu m and M. scrofu laceu m as well. Typically, the
disease would show in a middle-aged male with some sort of chronic lung disease who
presents with a 3 month history of increasingly productive cough, night sweats, a lo w g ra d e
f e v e r , and moderate weight loss. The chest roentgenogram and positive smear for AFB
provide the diagnosis.
The classic predisposing conditions include pneumoconiosis, previous tuberculosis, chronic
bronchitis, bronchiectasis, and chronic aspiration from esophageal disease. Another major
factor predisposing for nontuberculosis mycobacterial infection is deficiency of cellular
immunity and in recent years most reported cases are among AIDS and cancer patients.
Whenever a patient with one of the predisposing conditions with some of the afore-
92 Unexplained Fever

mentioned clinical symptoms presents with one or more of the following roentgenographic
features, mycobacterial disease should be suspected:

A. Increased relative extent of cavitation for total lung involvement

B. Thin-walled cavities with less dense surrounding infiltration
C. Less bronchogenic but more contiguous spread
D. More involvement of the apical and anterior segments of the upper lobes
E. Marked pleural thickening over the involved areas of lung, but less basal pleural
reaction
F. Clustered opacities around irregular translucent areas with line shadows radiating from
each lesion

The definitive diagnosis is provided by positive cultures. Because of the possibility of

environmental contamination, there should be several positive cultures. Isolations of non-
tuberculous mycobacteria can be intermittent or persistent.
Atypical mycobacteria can affect organ systems other than the lung and present as
lymphadenitis, soft tissue infection, bone and joint disease, genitourinary disease, meningitis,
or disseminated disease.

ANAEROBIC INFECTIONS
Fever is the second most common symptom in patients with anaerobic pleuropulmonary
infection. Usually the patient presents with radiologic findings (pneumonitis, necrotizing
pneumonia, abscess, or empyema). The average duration of symptoms before presentation
is 7 weeks.
The most frequent isolates from pleuropulmonary anaerobic infections are Bacteroides
melanogenicus (41%), Fusobacterium nucleatum (40%), and Peptostreptococcus (36%).19
Anaerobic lung infection should be suspected in febrile patients with predisposition to
aspiration either from impaired consciousness (alcoholism, drug addiction, diabetic coma,
seizures, general anesthesia, stroke, dental procedures) or esophageal (swallowing) dys-
function (achalasia, scleroderma, neurologic deficits, and strictures).

FUNGAL INFECTIONS
The three major systemic fungal infections occurring in immunologically normal indi-
viduals involving the lung are histoplasmosis, coccidioidomycosis, and blastomycosis (Table
2). All of them are very similar to tuberculosis in their pathogenesis, clinical features, and
course of disease.
The clinical course and the extent of dissemination of these mycoses depend on host
factors such as age, immunologic competence and structural integrity of the lung. The
intensity of the disease depends also on the amount of inhalation exposure.
Fever is a major presenting symptom in all three infections in the acute primary disease
as well as pulmonary symptoms. Pleuritic chest pain may occur in each of these infections.
The three mycoses differ in their distribution. Histoplasmosis, though a worldwide
infection, is especially prevalent in the Mississippi and Ohio River valleys of the U.S.
Coccidioidomycosis is confined to the Western Hemisphere. Endemic areas in the U.S.
include the San Jaoquin Valley in California and parts of Arizona, Texas, Utah, New Mexico,
and Nevada. Blastomycosis occurs predominantly in North America and is endemic in the
southeastern U.S.
As in tuberculosis, the primary disease is confined to the lungs, but in a later stage,
lymphohematogeneous dissemination may occur.
Fungal infection should be suspected in any febrile patient with pulmonary and systemic
 93

TABLE 2
Microorganisms Causing Pneumonia

Bacteria Viruses Fungi

Streptococcus pneumoniae Respiratory syncytial virus, Histoplasma capsulatum,

ß-hemolytic streptococci parainfluenza virus, influ- Coccidioides immitis,
Staphylococcus aureus enza virus, adenovirus, Blastomyces dermatitidis
Hemophilus influenzae measles, varicella
Gram-negative bacilli
(Klebsiella pneumoniae,
Pseudomonas aeruginosa,
Actineobacter species)
Legionella pneumophila
Mycoplasma pneumoniae
Chlamydia psittaci
(Psittacosis)
Coxiella burnetii
(Q-fever)
M. tuberculosis
Nontuberculous mycobacteria
Rare pathogens: anthrax,
plague, tularemia, and
brucellosis

symptoms, with no other obvious cause, who lived or traveled in the aforementioned regions.
The radiographic findings are rarely pathognomonic.
The methods for diagnosing each of these mycoses are listed in Table 3.

PULMONARY INFECTIONS IN THE IMMUNOCOMPROMISED HOST

Virtually any microorganism can cause pneumonitis in the immunocompromised patient;
all of them may present with f e v e r , usually with pulmonary infiltrates.
The prevalence of the various pathogens depends on the type of immunologic defect or
related factors.20
Bacterial infections include L iste ria m o n o c y to g e n e s, N o c a r d ia , S alm o n ella (non-typhi),
M y c o b a c te ria , L e g io n e lla , S. p n e u m o n ia e , H . in flu en zae, P seu d o m o n a s a e ru g in o sa , E. c o li,
K le b s ie lla , S e rra tia , and N e isse ria m en in g itid is.
Fungi causing pneumonitis include C ryp to c o cc u s n eo fo rm a n s, H isto p la sm a c a p su la tu m ,
C o c cid io id es im m itis , B la sto m y ce s d e r m a titid is , T rich o sp o ro n , A s p e rg illu s , and Z y g o m y -
ce te s. Viruses affecting the lung in the immunocompromised include cytomegalovirus, var-
icella-zoster, and herpes simplex. Parasites capable of infecting those patients are Pneum ocystis
carin ii, T oxoplasm a g o n d ii, and S tro n g y lo id e s ste rc o ra lis.
The availability of effective therapy, in particular antibiotics, makes the correct diagnosis
of such conditions of utmost importance. Quite often, invasive diagnostic procedures are
necessary for definitive diagnosis.
AIDS patients often present with FUO and the common pulmonary diseases diagnosed
in those patients include P n e u m o cystis ca rin ii pneumonia, Kaposi’s sarcoma, cytomegalo-
virus, M yco b a c teriu m a viu m -in tra ce llu la re , M . tu b ercu lo sis, C ry p to c o c c u s n eoform an s, A s -
p erg illu s, N o c a rd ia , and C ry p to sp o rid iu m .21

P N E U M O C Y ST IC C A R IN II PNEUM ONIA
P n eu m o cy stis ca rin ii pneumonia (PCP) is an increasingly common infection in the
immunocompromised patient. It represents the most common severe pulmonary infection in
patients with AIDS; 60% of new cases have PCP at the time of initial diagnosis.
94 U nex p la in ed F e ve r

TABLE 3
Diseases with Granuloma Formation and Methods to Establish the Diagnosis

Disorder Definitive diagnosis

Infection

Mycobacteria Demonstration of pathogen in secretions or tissue either by Ziehl-

M. tuberculosis Neelsen staining or by culture
M. kensasii
M. avium
M. marinum
M. balnei
Leprosy Identification of bacilli in granuloma
Bacteria
Brucella Positive blood cultures; specific antibodies and specific agglutinins;
Francicella tularensis culture by transmission to animals; culture from excised tissue
Yersinia
Spirochetes
Treponema
Protozoa
Leishmania Demonstration of parasite in macrophages of organ aspirate; serum
antibodies; skin test
Toxoplasma gondii Titer of Sabin Feldman test, toxoplasma immunofluorescence
reaction
Helminths
Schistosoma Evidence of ova; intradermal test; CFT blood and skin tests with
Toxocara eosinophilia and IgE in blood
Viral
Cat scratch disease Cat scratch skin test; CFT for psittacosis
Chlamydia
Lymphogranuloma CFT
Fungi
Blastomyces dermatitides CFT, culture of clinical specimens
Coccidioides immitis Demonstration of fungus in tissue; CFT; coccidiodin skin test
culture
Histoplasma capsulatum CFT, immunodiffusion, positive histoplasmin skin test
Sporothrix schenkii Culture of nodule tissue; latex agglutination; immunodiffusion
Aspergillus Serology; detection of fungal antigenin BAL/IgE; positive skin test
Cryptococcus neformons Demonstration of budding encapsulated yeast in spinal fluid and
sputum; latex agglutination

Chemicals

Beryllium Positive beryllium skin test, positive beryllium lymphocyte transfer

test
Mineral oils Demonstration of oil bearing macrophages in the alveoli at lung
biopsy
Silica Demonstration of refractile particles within alveolar macrophages
in BAL
Starch
Talc Biréfringent talc crystals or feruginous bodies in BAL fluid; dem-
onstration of double refractile particles engulfed in macrophages
within foreign body granuloma
Chromolyn sodium
Methotrexate Reversible lesion after discontinuing of the drug

Idiopathic

Sarcoidosis Positive Kveim-Siltzbach test, SACE, demonstration of granuloma

with no other etiology
 95

TABLE 3 (continued)
Diseases with Granuloma Formation and Methods to Establish the Diagnosis

Disorder Definitive diagnosis

Regional enteritis
Primary biliary cirrhosis
Giant cell arteritis
Hypogammaglobulinemia See appropriate chapter
Systemic lupus erythematosus
Granulomatous hepatitis
Periarteritis nodosa
Wegener’s granulomatosis Open lung biopsy: vasculitis and prominent necrosis resembling
infarcts
Churg-Strauss allergic granulomatosis On lung biopsy: vasculitis involving small arteries and occasionally
veins.
Necrotic granulomata with intense eosinophilia
Lymphomatoid granulomatosis
Necrotizing sarcoidal granulomatosis Prominent necrosis and vasculitis in biopsy
Bronchocentric granulomatosis Granulomata centered around bronchi and bronchioles with necrosis
Histiocytosis X Appearance of cytoplasmic tubular structures on electron micros-
copy and antibody staining of Langerhans cells by immunodif-
fusion, in BAL or biopsy specimen
Neoplasia
Lymphoma
Carcinoma
Dysgerminoma
Seminoma
Extrinsic allergic alveolitis Circulating precipitins

Note: CFT — complement-fixation test; BAL — bronchoalveolar lavage; SACE — serum angiotensin converting
enzyme.

The onset of disease in the adult may be insidious with fever, coryza, and a dry non-
productive cough. The most commonly reported symptoms were dyspnea (91%), fever
(66%), cough (47%) and cyanosis (39%). Hypoxemia is very common.
The typical roentgenographic appearance of PCP is that of a diffuse bilateral interstitial-
alveolar pattern which is more prominent in the perihilar regions. This pattern is not specific
for PCP.
Fiberoptic bronchoscopy and bronchoalveolar lavage proved to be useful, high yield and
safe procedures for the rapid diagnosis of PCP.
The cysts of Pneumocystis carinii can be readily demonstrated with methenamine silver
or toluidine blue O stains. The intracystic sporozoite and the trophozoite require staining
with Giemsa or Wright’s stain.

GRANULOMA-FORMING DISEASES

Granulomas are chronic inflammatory follicles in which persistent or poorly degradable

antigens or other irritants are enmeshed in a web of mononuclear cells and the lymphokines
produced by the lymphocyte population.
The ongoing immunologic process may cause pyrexia, so that many of the granuloma-
forming diseases may manifest with fever or present as FUO.
Table 3 lists the disorders in which noncaseating granuloma may be found, with the
methods to obtain definitive diagnosis.
Some of these diseases will be discussed in more detail, while others are discussed
elsewhere in this book.
96 Unexplained Fever

SARCOIDOSIS
Sarcoidosis is a multisystem disease of unknown etiology characterized by the formation
of noncaseating granulomas in the affected organs.
The lung is affected in 94% of cases, lymph nodes in 73%, skin in 32%, liver in 21%,
eye in 21%, spleen in 18%, bone in 14%, upper airways in 11%, and in decreasing order:
salivary glands, joints, heart, nervous system, kidneys, lacrimal glands, skeletal muscle,
breast, gastrointestinal tract, and uterus.22
The incidence and prevalence of sarcoidosis vary widely from country to country and
among ethnic groups within a single country.23
Fever is a presenting symptom of sarcoidosis in up to 22% of cases. Fever is generally
mild, but temperature elevations to 39 to 40°C are not uncommon. The other systemic
symptoms are fatigue (27%), weakness (7.4%), malaise (15%), and weight loss (17%).
Noncaseating granuloma is the hallmark of sarcoidosis, but it is not pathognomonic.
Radiologically sarcoidosis is classified into four types, according to the chest roentgenogram:
type O — normal, type I — hilar lymphadenopathy, type II — lymphadenopathy and
infiltrates, type III — infiltrates with or without fibrosis.

DIAGNOSIS AND ACTIVITY MARKERS

In addition to transbronchial biopsy which shows noncaseating granulomas, SACE level
and 67Ga lung scan are helpful in diagnosing and assessing disease activity. There are some
markers in bronchoalveolar lavage, but they are not as yet of proved clinical value. The
Kveim test delays the diagnosis and there is a problem in obtaining validated antigen.24 25

Serum Angiotensin Converting Enzyme (SACE)

SACE is increased in about 60% of sarcoidosis patients. SACE levels may be elevated
in other conditions such as silicosis, asbestosis, granulomatous hepatitis, liver cirrhosis,
lymphoma, miliary tuberculosis, diabetes mellitus, and inflammatory bowel disease.

Gallium-67 Lung Scanning

The isotope accumulates in the acute and chronic inflammatory and immune effector
cells. Abnormal 67Ga uptake is not specific for sarcoidosis and can be found in various
interstitial lung diseases, carcinoma, infections, hypersensitivity pneumonitis, pneumocon-
iosis, and lymphoma. The gallium index expresses semiquantitatively the uptake of 67Ga by
the lung. It is increased in 65% of patients with sarcoidosis. The scan is a simple, noninvasive
procedure, well tolerated and with low radiation exposure to the patient.

WEGENER GRANULOMATOSIS
Wegener granulomatosis is characterized by necrotizing granulomatous vasculitis of the
upper and lower respiratory tracts, glomerulonephritis and small vessel vasculitis. A limited
form of Wegener’s granulomatosis, without renal involvement was also described.26 The
cause of the disease is not known. It can occur in any age group, although the mean age
of presentation is 40 years.27
Fever is a presenting symptom in 34% of cases. The other common symptoms are
sinusitis - 67%, arthralgia or arthritis — 44%, otitis — 25%, cough — 34%, rhinitis or
nasal symptoms — 22%, hemoptysis — 18%, ocular inflammation — 16%, and weight
loss — 16%.
The lung is the most common organ system involved (94% of cases) to be followed by
the paranasal sinuses — 91%, kidney — 85%, joints — 67%, nose or nasopharynx — 69%,
ear — 61%, eye — 58%, skin — 45%, nervous system — 22%, and heart — 12%.
In 71% of patients there were pulmonary infiltrates on the chest roentgenogram.
The definitive diagnosis is obtained by open lung biopsy (Table 3).
 97

EOSINOPHILIC GRANULOMA OF THE LUNG (PRIMARY PULMONARY

HISTIOCYTOSIS-X)
Eosinophilic granuloma is a subacute or chronic proliferative disorder of unknown
etiology characterized by infiltration by atypical histiocytes.
Eosinophilic granuloma of the lung is considered a localized variant of the nonmalignant
histiocytoses, blending without sharp distinction into the multisystem syndrome of Hand-
Schuller-Christian disease.28
Fever as part of constitutional symptoms can be a presenting symptom for eosinophilic
granuloma of the lung. Specific pulmonary signs and symptoms are dyspnea, cough, pneu-
mothorax, chest pain, and hemoptysis. Physical signs, except in patients with pneumothorax,
are insignificant.29
The chest roentgenogram can reveal micronodular and reticular opacities, or larger
nodules or cysts. Changes are bilateral and widespread but not always symmetrical.
Pulmonary function tests often demonstrate restrictive defects and low diffusion capacity,
but there may be an obstructive pattern (correlating with radiologic cyst formation).
The characteristic histological findings are atypical histiocytes which establish the di-
agnosis and interstitial accumulation of eosinophils. Infiltration of the walls of blood vessels
with a granulomatous reaction is a feature of the pathology of eosinophilic granuloma.
As noted in Table 3, open lung biopsy is no longer needed in many cases and the
diagnosis can be obtained by fiberoptic bronchoscopy, FOB.

PULMONARY INFILTRATES WITH PERIPHERAL

EOSINOPHILIA
Fever can be a presenting symptom for all types of pulmonary infiltrates with eosinophilia
(PIE).
Crofton’s classification of PIE30 includes three groups: (1) Illnesses in which PIE is a
major component; (2) illnesses in which PIE occurs infrequently and is a minor component;
(3) PIE without features of the above groups.
In the first group there are six types: allergic bronchopulmonary aspergillosis, chronic
eosinophilic pneumonia, drug reaction, hypereosinophilic syndrome, parasitic infestation,
and polyarteritis nodosa.

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)

ABPA is a reaction to inhaled spores of the ubiquitous fungus Aspergillus fumigatus.
It occurs in asthmatic patients. The bronchi are colonized and the antigens released by the
fungus cause allergic reaction.
The asthmatic patient develops fever, cough, purulent sputum, and brown sputum plugs.
Typically the chest radiograph shows migratory, especially upper lobe, infiltrates or atelec-
tasis. Microscopic examination of the sputum reveals eosinophils and hyphae. Sputum
cultures grow Aspergillus. There is peripheral eosinophilia and markedly increased IgE
levels. The skin test to Aspergillus is positive and serology is positive for precipitating
antibody against the fungus.
Unfortunately most of these findings may be absent. Another diagnostic obstacle is the
lack of specificity of most of these findings.

CHRONIC EOSINOPHILIC PNEUMONIA

The disease is most common in women in their third decade. It presents with cough,
dyspnea, malaise, weight loss, night sweats, and high fever. There may be asthma and
hemoptysis. The characteristic chest X-ray reveals “ photographic negative of pulmonary
edema’’.31 The erythrocyte sedimentation rate is markedly elevated. There may be anemia
98 Unexplained Fever

and peripheral eosinophilia. There is restrictive impairment on pulmonary function tests and
decreased diffusion capacity.
The findings on lung biopsy include interstitial and intraalveolar infiltrates with eosi-
nophils and macrophages (which contain eosinophilic granules and Charcot-Leyden crystals),
as well as some lymphocytes and plasma cells.

DRUG REACTIONS
Many drugs have been reported to produce PIE (see Chapter 17).

HYPEREOSINOPHILIC SYNDROME
The lung is involved in approximately 40% of patients (see Chapter 18).

PARASITIC INFESTATION
Many parasites are associated with PIE. Tropical eosinophilia should be suspected in
patients from endemic regions for filaria (see Chapter 20).

CHURG-STRAUSS SYNDROME
Allergic angiitis and granulomatosis is a variant of polyarteritis nodosa. It has prominent
lung involvement, asthma and eosinophilia and pathologically it differs from classic PAN
by the presence of vascular and extravascular granulomas.
The patients present with respiratory symptoms, most commonly asthma, which precede
any evidence of systemic involvement by a month to several years. There may be episodes
of pneumonia. Fever is a common constitutional manifestation.
The diagnosis should be suspected in febrile asthmatic patients presenting with recurrent
pneumonia, marked eosinophilia and systemic symptoms.
Definitive diagnosis requires tissue diagnosis.
The diseases in which PIE occurs infrequently and is a minor component include infection
(discussed in this chapter), neoplasm, and immunologic disorders, discussed elsewhere in
this book.

BRONCHIOLITIS OBLITERANS ORGANIZING PNEUMONIA

In distinction from bronchiolitis obliterans secondary to other diseases (e.g., toxic fume
inhalation or connective tissue disease), there are cases with no apparent cause or associated
disease.
One third of the patients present with a flu-like illness with fever, sore throat, and malaise
lasting typically 2 to 10 weeks, but in some patients for more than 3 months. One quarter
of patients have no abnormal physical findings. Chest roentgenograms showed an unusual
pattern of patchy densities with a “ ground glass” appearance in 81% and in less than 10%
there were seen diffuse, small, linear or nodular opacities. Physiologically 72% demonstrate
restriction and 86% have impaired diffusing capacity.32
Histology of specimens obtained by open lung biopsy shows polypoid masses of gran-
ulation tissue in lumens of small airways, alveolar ducts and some alveoli. The fibrosis is
uniform in age. The distribution is patchy, with preservation of background architecture.
The distinction of idiopathic bronchiolitis obliterans with organizing pneumonia is im-
portant in view of its benign course and therapeutic response to corticosteroids.

PULMONARY EMBOLISM

Fever frequently accompanies pulmonary thromboemoblism.33 In a large series of an-

giographically established pulmonary emboli (PE), 44% had fever, which was present 5
days or more prior to the establishment of the diagnosis.34
 99

It has long been known that recurrent PE may present as fever of unknown origin
(FUO).35 Petersdorf and Beeson described three patients with pulmonary emboli who pre-
sented with prolonged fever in their classic paper in 1961.36
Cases of pulmonary emboli presenting as FUO are usually patients with severe systemic
illness: bedridden patients, often elderly with congestive heart failure or chronic obstructive
lung disease. However, it may appear without any of the classic features or predisposing
factors.37 The clinician should inquire and look for any tachypnea and tachycardia and lung
scan may be sufficient to prove the diagnosis. There should be a high index of suspicion
for PE in any case of FUO in a patient who sustained trauma.

NEOPLASTIC DISEASES
Tumors as causes for fever are discussed in more detail in Chapter 23.
The thoracic cavity can host a large variety of benign and malignant neoplasms.
Benign lung tumors comprise only a small percentage of thoracic tumors. They include
bronchial adenoma, hamartoma, papilloma, leiomyoma, teratoma, and neurogenic tumors.
Endobronchial as well as parenchymal tumors may present as fever due to pneumonitis
secondary to bronchial obstruction.
Many primary tumors can develop in the respiratory system: epidermoid carcinomas,
small cell carcinomas, adenocarcinomas, large cell carcinomas, carcinoid tumors, mixed
tumors, and carcinosarcoma, sarcomas, mesotheliomas, melanoma, unclassified lymphomas,
and multiple myeloma (plasmacytoma).
A whole variety of metastatic neoplasm can spread in the lung parenchyma as well as
in the thoracic lymph nodes.
In addition to the regular mechanism of pyrexia caused by malignant tumors, fever can
be a presenting symptom of lung tumor causing post-obstruction pneumonia.
Usually radiologic techniques are useful in localizing tumors in the chest and assessing
their size and spread, but for definitive diagnosis some tissue or cytology specimens are
necessary.

REFERENCES
1. Williford, M. E. et al., Computed tomography of pleural disease, Am. J. Roentgenol., 140, 909, 1983.
2. Shure, D., Fiberoptic bronchoscopy — diagnostic applications, Clin. Chest Med., 8, 1, 1987.
3. Wimberley, N. et al., A fiberoptic bronchoscopic technique to obtain uncontaminated airway secretions
for bacterial culture, Am. Rev. Respir. Dis., 119, 337, 1979.
4. Thrasher, D. R. and Briggs, D. D., Pulmonary sarcoidosis, Clin. Chest Med., 3, 537, 1982.
5. Basset, F. et al., Ultrastructural examination of bronchoalveolar lavage for the diagnosis of pulmonary
histiocytosis-X: preliminary report on 4 cases, Thorax, 32, 303, 1977.
6. Chollet, S. et al., Diagnosis of pulmonary histiocytosis-X by immunodetection of Langerhans cells in
bronchoalveolar lavage fluid, Am. J. Pathol., 115, 225, 1984.
7. Leight, G. S., Jr. and Michaelis, L. L., Open lung biopsy for the diagnosis of acute, diffuse pulmonary
infiltrates in the immunosuppressed patient, Chest, 73, 477, 1978.
8. Boerner, D. F. and Zawdyk, P., The value of the sputum Gram’s stain in community acquired pneumonia,
JAMA, 247, 642, 1982.
9. Flatauer, F. E. et al., Fiberoptic bronchoscopy in bacteriologic assessment of lower respiratory tract
secretions: importance of microscopic examination, JAMA, 244 , 2427, 1980.
10. Wilson, W. R. et al., Pulmonary disease in the immunocompromised host, Mayo Clin. Proc., 60, 610,
1985.
11. Woo, A. H. et al., Potential in-hospital modes of transmission of Legionella pneumophila: demonstration
experiments for dissemination by showers, humidifiers and rinsing of ventilation bag apparatus, Am. J.
Med., 80, 567, 1986.
100 Unexplained Fever

12. Center for Disease Control, Tuberculosis in the United States, 1977, Atlanta: Center for Disease Control,
1979 (DHEW publication no. (CDC) 779-8322).
13. Ashley, M. J. et al., The influence of immigration on tuberculosis in Ontario, Am. Rev. Respir. Dis.,
110, 137, 1974.
14. Khan, A. A. et al., Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult, Am.
J. Med., 62, 31, 1977.
15. Sahn, S. A. and Neff, T. A., Miliary tuberculosis, Am. J. Med., 56, 495, 1974.
16. Munt, P. W., Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults,
Medicine, 51, 139, 1971.
17. Chapman, J. S., The atypical mycobacteria, Part 2, Am. Rev. Respir. Dis., 125, 119, 1982.
18. Wolinsky, E., Nontuberculous mycobacteria and associated diseases, Am. Rev. Respir. Dis., 119, 107,
1969.
19. Bartlett, J. G. et al., Anaerobic infections of the lung and pleural space, Am. Rev. Respir. Dis., 110, 56,
1974.
20. Wilson, W. R. et al., Pulmonary disease in the immunocompromised host, Mayo Clin. Proc., 60, 610,
1985.
21. Gottlieb, M. S., Pulmonary disease in the Acquired Immune Deficiency Syndrome, Chest, 86, 29S, 1984.
22. Maycock, R. L. et al., Manifestations of sarcoidosis, Am. J. Med., 35, 67, 1963.
23. Bascom, B. and JoNus, C. J., The natural history and management of sarcoidosis, Adv. Intern. Med.,
31, 213, 1986.
24. Sharma, O. P., Diagnosis of sarcoidosis, Arch. Intern. Med., 143, 1418, 1983.
25. Rizzato, G., Markers of activity, Semin. Respir. Med., 8, 30, 1986.
26. Carrington, C. B. and Liebow, A. A., Limited forms of angiitis and granulomatosis of Wegener’s type,
Am. J. Med., 41, 497, 1966.
27. Fauci, A. S. et al., Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85
patients for 21 years, Ann. Intern. Med., 98, 76, 1983.
28. Basset, F. et al., Pulmonary Histiocytosis-X, Am. Rev. Respir. Dis., 118, 811, 198.
29. Friedman, P. J. et al., Eosinophilic granuloma of lung. Clinical aspects of primary pulmonary histiocytosis
in the adult, Medicine, 60, 385, 1981.
30. Crofton, J. W. et al., Pulmonary eosinophilia, Thorax, 7, 1, 1952.
31. Gaensler, E. A. and Carrington, C. B., Peripheral opacities in chronic eosinophilic pneumonia: the
photographic negative of pulmonary edema, Am. J. Roentgenol., 128, 1, 1977.
32. Fpler, G. R. et al., Bronchiolitis obliterans organizing pneumonia, N. Engl. J. Med., 312, 152, 1985.
33. Murray, H. E. et al., Fever and pulmonary thromboembolism, Am. J. Med., 67, 232, 1979.
34. Bell, W. R. et al., The clinical features of submassive and massive pulmonary emboli, Am. J. Med., 62,
355, 1977.
35. Sagall, E. L. et al., Clinical syndrome in patients with pulmonary embolism, Arch. Intern. Med., 76,
234, 1945.
36. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report of 100 cases, Medicine, 40, 1,
1961.
37. Wilson, K. H. and Tuazon, L. V., Pulmonary emboli 5 days postinjury presenting as fever of unknown
origin, J. Trauma, 20, 259, 1980.
 101

Chapter 8

UNEXPLAINED FEVER ASSOCIATED WITH DISEASES OF THE

GASTROINTESTINAL TRACT

Benedict Isaac and Michael Burke

INTRODUCTION
Disorders of the gastrointestinal tract are a frequent cause of fever1 although the claim
that this symptom is often neglected by the clinician2 appears to be justified by its superficial
treatment in standard textbooks. Fever is a nonspecific manifestation unlike the major gas-
trointestinal symptoms, such as abdominal pain and swelling, heartburn, dysphagia, nausea,
vomiting, constipation, diarrhea, hematemesis, melena, and jaundice. Nevertheless, fever
is sometimes the predominant or only feature of disease of the alimentary system.3 In other
cases, fever may accompany one or more of the typical gastrointestinal symptoms.
The alimentary tract is often involved in systemic febrile disorders, such as vasculitis,
septicemia, leukemia, lymphoma, and secondary malignancy (especially in the liver). Con-
versely, primary disease of the alimentary system may present initially with remote or
systemic manifestations, such as arthralgia, pericarditis, pleuritis, and anemia, which may
be associated with fever. The physician may find himself in a quandary when consulted for
fever in the presence of gastrointestinal disorders such as peptic ulcer or cholelithiasis. The
fever may be incidental to a frequent disease or may represent a complication of the primary
alimentary disorder. Short-lived fever is a frequent accompaniment of gastrointestinal bleed-
ing, which may go unnoticed by the patient, especially the elderly.
Fever may be associated with pathology of almost any part of the alimentary system.
Infection, inflammation, hemorrhage, ischemia, hollow viscus obstruction, neoplasia, and
hereditary diseases may be manifested by a nonspecific febrile illness which may antedate
more localizing features. A discerning use of ancillary tests and modem imaging techniques
may permit the physician to reach a diagnosis at an earlier stage than if he were to wait for
more specific symptoms and signs. Naturally the clinician must be guided by a thorough
medical history and clinical examination before embarking on laboratory, roentgenographic,
and endoscopic studies. Epidemiologic investigations and drug history are very important.
Drugs may produce conditions that simulate inflammatory bowel disease and various types
of hepatitis.
Medical imaging of the alimentary system is of major importance although such inves-
tigations will be useful only if ordered in the correct sequence, and the patient has been
prepared adequately. In addition, attention should be paid to contraindications to various
procedures, e.g., introduction of barium may convert a partial bowel obstruction into a
complete bowel obstruction. Neither should superfluous examinations be ordered nor in-
sufficient investigations carried out. In one series,2 more than half of a sample of unselected
patients hospitalized for fever of unknown origin and subsequently discharged with this
diagnosis had either undergone incomplete roentgenographic examination of the digestive
tract or no gastrointestinal studies at all. Consultation between the clinician and medical
imagist will often be fruitful in cases of unexplained fever.
One should remember that investigations of the gastrointestinal tract themselves may be
associated with febrile complications. The following serve as examples: liver abscess or
septicemia after a barium enema,4,5 or rarely, liver biopsy,6,7 acute gouty arthritis resulting
from oral cholecystographic media,8 pneumonia subsequent to aspiration of barium in de-
bilitated patients, sepsis following endoscopic retrograde cholangiopancreatography (ERCP).9
102 U n ex p la in ed F e ve r

The digestive system may be involved in diseases of diverse etiology, such as infection,
inflammation, hypersensitivity, and neoplasia, and fever may be a prominent or minor feature
of these disorders. In some cases, e.g., salmonellosis or systemic lupus erythematosus, fever
is a classic feature, but many conditions are only occasionally accompanied by fever,
especially when a complication supervenes. The latter diseases often present difficulties in
diagnosis and will be given consideration in the following pages.

APPROACH TO THE PATIENT WITH FEVER AND ABDOMINAL

PAIN
Abdominal pain is one of the commonest complaints in medicine. Many texts of medicine
and gastrointestinal diseases include chapters on the differential diagnosis of abdominal pain,
with considerations of mechanisms, location, mode of onset and other aspects, but none
make mention of the diagnostic evaluation of fever and abdominal pain. These two complaints
may occur within the symptom complex of many diseases, and a delay in diagnosis may
have fatal consequences. The subject is of importance to both the physician and the surgeon,
and in many cases, consultation between them is essential.
The basic causes of abdominal pain are inflammation, obstruction, hemorrhage, is-
chemia, perforation, functional disorders, and referred pain. On an anatomical basis one
may subdivide abdominal pain into three main groups: (1) visceral, (2) somatic (parietal),
and (3) referred pain. Visceral pain arises from an abdominal organ, somatic pain from the
parietal peritoneum or structures in the abdominal wall, and referred pain from remote areas
where the diseased organ shares a neural segment with a certain region of the abdomen.
In addition to the general approach to the febrile patient (see Chapter 5), special details
must be obtained in the case of a patient with fever and abdominal pain. In the history,
particular attention should be paid to the mode of onset of pain (sudden or gradual), its
intensity (constant, intermittent, sharp, or dull), location, radiation, relation to meals, bowel
motion, and body movement, as well as alleviating or aggravating factors. The physician
should ascertain if the fever and pain have appeared within the framework of an acute or a
chronic illness, what the psychological state of the patient is, and whether he or she has
been taking analgesic drugs. Associated classic alimentary symptoms (mentioned above)
and other complaints, including dyspnea, chest pain, hiccup, weight loss, and confusion
should be noted.
Physical examination should be directed to looking for surgical scars, fistulae, collateral
venous circulation, visible peristalsis, abdominal distension or rigidity, quality of bowel
sounds, jaundice, loss of hepatic dullness, palpable organs, such as liver, gallbladder, kidney,
and spleen, and other abdominal masses, and hernias. Rectal and pelvic examinations are
mandatory. During the examination the clinician must carefully determine whether the case
is one of an “ acute abdomen” , which requires immediate hospitalization.
Elucidation of the cause of fever and abdominal pain may be extremely difficult for a
number of reasons. First, there are no reliable parameters for quantifying pain. Second,
superinfection or strangulation leading to ischemia and necrosis may result in fever com-
plicating a condition which is usually afebrile. Further, a wide spectrum of diseases may
present in a similar fashion. Another important aspect is that the intensity of the pain does
not parallel the severity of the disease. Levy suggests that most cases of abdominal pain are
due to functional disorders rather than organic lesions.10 Approximately half the cases of
acute abdominal pain seen in the emergency room were subsequently found to have non-
specific pain related to gastroenteritis, menstrual disturbances, or other disorders.11 Of
patients sick enough for admission to the hospital only half had the same diagnosis on
discharge as initially.12In a study on 1000 consecutive cases of abdominal pain in a university
hospital emergency room,13 the most common diagnoses were as follows: unknown 41%,
 103

TABLE 1
Causes of Abdominal Pain and Fever

Intra-abdominal

Parietal
Myalgia and myositis of the abdominal wall (usually within the framework of infection) — Bornholm’s disease
(epidemic myalgia), infectious mononucleosis, rheumatic fever, typhoid fever, progressive disseminated his-
toplasmosis, malaria, amebiasis, trichinosis, ascariasis
Hematoma of rectus sheath (usually associated with anticoagulant therapy)
Acute relapsing panniculitis
Visceral
Peritonitis — (a) primary bacterial — pneumococcus, (b) sterile — following accidental introduction of starch,
or leakage of gastric or pancreatic juice, bile, urine (with ensuing secondary infection), (c) secondary to
perforation of a hollow viscus, (d) localized peritonitis (which may subsequently become generalized).
Inflammation or infection of viscus or mesentery — gastroenteritis, appendicitis, cholecystitis, cholangitis,
pancreatitis, hepatitis, rupture or infection of hydatid cyst, pyelephlebitis, mesenteric lymphadenitis, intra-
abdominal abscess, inflammatory bowel disease, ileocecal tuberculosis, diverticulitis, pelvic inflammatory
disease, familial Mediterranean fever
Mechanical — (a) obstruction — bowel obstruction with strangulation, biliary obstruction (calculus, tumor), (b)
torsion of ovarian cyst or fibroid, (c) capsule distension — liver disease, congestive heart failure, (d) intus-
susception
Vascular — (a) ischemia — intestinal ischemia or infarction, hepatic and splenic infarction, vasculitis, recurrent
vasoocclusive phenomena in sickle cell anemia, tumor necrosis, (b) intraperitoneal bleeding — leaking aneurysm
(aorta, hepatic, splenic, other arteries), rupture of organ (liver, spleen, mesentery)
Neoplastic — solid abdominal tumors, leukemia, lymphoma
Urinary tract — renal or perinephric abscess, pyelonephritis, infection associated with nephrolithiasis or hydro-
nephrosis, renal infarction
Extra-abdominal

Referred Pain
Thoracic — pneumonia, empyema, pulmonary tuberculosis, pleurisy (especially diaphragmatic), tumors of lung
or pleura, myocardial infarction, pericarditis, esophageal perforation with mediastinitis, rib metastases
Spinal — epidural abscess, spondylitis and discitis, psoas abscess, multiple myeloma
Neurogenic — herpes zoster
Metabolic
Exogenous — black widow spider bite, snake bite
Endogenous — acute porphyria, acute hemolysis, acute adrenal insufficiency, carcinoid syndrome
Immunologic — systemic lupus erythematosus, polyarteritis nodosa, Henoch-Schonlein purpura

gastroenteritis 7%, pelvic inflammatory disease 7%, urinary infection 5%, ureteral stone
4%, appendicitis 4%, acute cholecystitis 2.5%, intestinal obstruction 2.5, constipation 2%,
and duodenal ulcer 2%. Fever was present in 42% of cases of appendicitis, 30% of acute
cholecystitis, 20% of gastroenteritis, and 13% of cases of abdominal pain of unknown cause,
and 11% of cases with intestinal obstruction. As expected, fever occurred commonly in
acute surgical illness, but also was quite frequent in patients with nonsurgical “ medical”
abdominal pain. A complete analysis of the acute abdomen is beyond the scope of this
chapter, and the interested reader is referred to the excellent review by De Dombal.14 For
the convenience of the reader, Table 1, although not exhaustive, may serve as a guide to
the diagnosis of the febrile patient with abdominal pain.
Occasionally the clinician is faced with a patient complaining of acute epigastric pain
and fever. The differential diagnosis should include the following conditions: esophageal
rupture, CMV-associated gastroduodenal ulceration,143acute cholecystitis, acute pancreatitis,
mesenteric vein thrombosis, acute pyelonephritis, aortic dissection, acute myocardial in-
farction, and pulmonary embolism.
104 U nex p la in ed F e ve r

ESOPHAGEAL DISORDERS

Diseases of the esophagus are not usually febrile, although occasionally, infection,
perforation, diverticula, and neoplasms have been associated with unexplained fever.

ESOPHAGITIS
Bacterial infection of the esophagus is extremely uncommon nowadays due to a decrease
in the frequency of most causative factors. Suppurative esophagitis is still described in the
French literature, especially as a complication of trauma to the mucous membrane; the
condition manifests as a localized abscess, esophageal phlegmon, or diffuse phlegmonous
esophagitis.15 In recent years monilial esophagitis16 has been observed more frequently in
immunocompromised patients, especially in the acquired immune deficiency syndrome (AIDS).
This disorder is characterized by pain and dysphagia, but sometimes is accompanied by
fever. Ulcerations may be visualized on X-ray examination, or, preferably, on endoscopy,
which permits a biopsy (for histology and culture) to be performed. Viruses rarely may
cause esophagitis: herpes simplex can produce both esophagitis and tracheobronchitis in the
immunocompromised host. CMV-induced acute erosive esophagitis manifested by chest pain
and fever has been described in a young adult following splenectomy for trauma.17
Very rarely, patients who have ingested corrosives (either accidentally or in a suicide
attempt) may develop esophageal damage in the absence of pharyngeal or mouth bums18
and may present with fever, painful swallowing, marked salivation, and hematemesis.

PERFORATION
Perforation or rupture of the esophagus leading to an esophagomediastinal sinus or an
esophagorespiratory fistula may be associated with fever. The fistula is suspected when the
patient coughs or chokes on swallowing liquids. Perforation may complicate both (a) diseases
of the esophagus such as esophagitis, peptic ulceration, or neoplasm, and (b) injuries from
trauma or instrumentation. Rarely, the cause of the perforation is not apparent, and this may
create difficulty in diagnosis, especially in the elderly. The condition may mimic myocardial
infarction, acute pancreatitis, or perforation of an abdominal viscus. Esophagomediastinal
fistula with fever may be caused by the rupture of a caseating, necrotic mediastinal, lymph
node into both the esophagus and the tracheobronchial tree, or by an ulcerative lesion of
the esophagus involving the mediastinum. Pulmonary rather than esophageal features may
dominate the clinical picture: recurrent attacks of pneumonia, lung abscess or bronchiectasis
may occur. Rarely, tuberculosis, syphilis, actinomycosis, histoplasmosis, moniliasis, herpes
viruses, and CMV may give rise to esophagorespiratory fistula.
The Boerhaave syndrome,183 which may evolve with fever, occurs principally in middle-
aged men and is frequently associated with alcoholism. It involves an esophageal perforation
typically through the left posterolateral wall of its distal portion. The clinical presentation
in addition to fever, which may be septic in nature, includes nausea, vomiting, thoracic
pain, dyspnea, air hunger, painful dysphagia, and thirst. Physical examination may reveal
tachycardia, hypotension, signs of pneumomediastinum — crepitus in the neck, Hamman’s
crunch sign (a crunching sound synchronous with the heartbeat heard over the precordium)
and hyperresonance in the anterior chest — as well as basilar rales and dullness, the latter
usually on the left side. A common complication is pneumothorax. The chest X-ray may
show abnormal thoracic gas collections. The diagnosis may be confirmed by contrast swallow
studies, initially using a water-soluble agent such as gastrographin, and if necessary, a
follow-up barium swallow examination.

DIVERTICULA
The common posterior hypopharyngeal esophageal diverticulum of Zenker, as well as
an epiphrenic diverticulum may result in regurgitation and nocturnal aspiration of undigested
 105

food and the development of acute or chronic pulmonary infection. Occasionally, the mid-
esophageal (traction) diverticulum may become obstructed and infected, leading to abscess
formation and subsequent rupture into the mediastinum. Surgical resection is necessary to
control symptoms. In achalasia (cardiospasm), regurgitation of food may be followed by
recurrent bouts of aspiration pneumonia with fever. Regurgitation and vomiting may be
subtle in hiatus hernia and result in aspiration pneumonia.3
Rakatansky and Kirsner2 report the case of a male with fever of 3 months duration who
failed to respond to antibiotic therapy. Physical examination was normal. However, ra-
diological examination disclosed a large epiphrenic esophageal diverticulum. Retrospective
questioning revealed that he had experienced recurrent bouts of regurgitation of food as-
sociated with coughing and choking, when he was lying down. Subsequent surgical removal
of the diverticulum resulted in the disappearance of the fever.

CARCINOMA
Carcinoma of the esophagus may rarely present with unexplained fever together with19
or without20 dysphagia. Fever was the first symptom in 1% of cases in a large series of
esophageal carcinoma.21 Aspiration, a common complication of esophageal obstruction, may
lead to pulmonary infection with dyspnea, pleuritic pain, and fever.22

DISEASES OF THE STOMACH AND DUODENUM

PHLEGMONOUS GASTRITIS
Acute gastric infections are very rare because of acid and antibacterial factors which
impede their development. Chronic infections such as tuberculosis and syphilis rarely involve
the stomach today. Occasionally, fungal disorders such as histoplasmosis and candidiasis
may be found. A severe febrile condition of the stomach which may sometimes be encoun-
tered is phlegmonous gastritis.23 Predisposing factors to this condition include chronic gas-
tritis, alcoholism, and trauma. Bacteria may penetrate the gastric wall in several ways: (a)
via an ulcerative lesion, (b) after instrumental or surgical manipulation, (c) by hematogenous
spread from a septic focus in the ear, nose, or throat, and (d) secondary' to infective en-
docarditis.24 The clinical picture consists of severe upper abdominal pain, fever, and vom-
iting. The barium meal X-ray may reveal a dilated stomach with edematous folds and rigidity
of the antrum. Definitive diagnosis is made by gastroscopy. Bactériologie examination of
the gastric juice may identify the causative agent. Early diagnosis, appropriate antibiotic
therapy, and subsequent surgical resection and drainage may be lifesaving. The previously
high mortality has been reduced to 25% by conservative treatment.25

COMPLICATED PEPTIC ULCER

In the past, fever was a presenting symptom in a number of cases of peptic ulcer,26 27
although the incidence was usually higher in the presence of acute blood loss. However, it
now appears that the earlier series included febrile reactions to blood transfusions, which
are less commonly encountered nowadays and are not specific. As stated by Rakatansky
and Kirsner,2 “ benign peptic ulcer, in the absence of complications such as penetration with
abscess formation, as a cause of fever, is exceptional” . Fever is not so uncommon in the
presence of a perforation with an inflammatory mass involving the omentum, gallbladder,
or other tissues.28 A gastric ulcer may gradually erode into the body of the pancreas and a
posterior duodenal ulcer may penetrate into the tissue above the head of the pancreas in the
choledochal and perirenal regions. Recently, an immunocompetent patient with prolonged
fever, epigastric pain, vomiting, and atypical lymphocytosis was found to have gastro-
duodenal ulceration associated with CMV infection.133
106 U n ex p la in ed F e ve r

GASTRIC TUMORS
Gastric neoplasms may occasionally present with unexplained fever.29 In 1955, Keefer
and Leard30 observed fever as a presenting sign in 25 out of 74 cases (34%) of uncomplicated
gastric cancer. In recent years the incidence of fever in gastric carcinoma appears to have
decreased, except in the presence of hepatic metastases. In Olearchyc’s series31 of 243 cases
of carcinoma of the stomach, there were only four cases (1.6%) which were associated with
fever. A single case of FUO due to carcinoma of the stomach is reported by Petersdorf and
Beeson.18 The mechanism of fever production may be through ulceration and necrosis in
the center of the tumor.24 Other gastric tumors which may sometimes cause fever include
lymphoma, leiomyoma,32 and leiomyosarcoma.2

GASTRIC INFARCTION
Gastric infarction secondary to staphylococcal endocarditis was associated with unex-
plained fever in a diabetic patient described by Patel et al.33 Following a course of antibiotics,
the fever subsided only to recur several days later. Subsequently the patient developed
disseminated intravascular coagulation and died. At autopsy, occluding terminal vessels
supplying the stomach and extensive gastric infarction were found.

INFECTED DUODENAL DIVERTICULUM

Duodenal diverticula may occasionally become inflamed and produce fever. Acute di-
verticulitis presents with abdominal pain, fever, gastrointestinal bleeding or, rarely, perfo-
ration. Infection may also involve the biliary and pancreatic ducts.

TUBERCULOSIS OF THE DUODENUM

Rarely, tuberculosis of the duodenum may present as unexplained fever. Gleason et al.34
describe a 27-year-old male who developed daily elevations of temperature to 40°C, accom-
panied by diaphoresis, and subsequently by hematemesis and melena. Endoscopy, revealed
an irregular ulcer, 2 cm in size, with a necrotic base, situated in the third part of the
duodenum. An upper GI series, ultrasonogram, and CT scan were not contributory. After
1 month’s febrile course the patient underwent an exploratory laparotomy which disclosed
an inflammatory mass composed of mesocolon, greater omentum, and matted para-aortic
lymph nodes, walling off a perforation of the third portion of the duodenum. Biopsy revealed
a granulomatous inflammation with caseous necrosis. On staining, acid fast bacilli were
demonstrated. In the approximately 50 reported cases of duodenal tuberculosis, only 10
were associated with pulmonary or generalized involvement. Thus, the duodenal form may
present in the absence of pulmonary tuberculosis.

DUODENAL ULCER
A postbulbar duodenal ulcer associated with fever suggests Crohn’s disease.

DISEASES OF THE SMALL AND LARGE INTESTINE

The small and large intestine are a frequent source of febrile disorders. The principal
symptoms of disease of the intestines are diarrhea and abdominal pain. As the latter has
already been discussed, we shall begin this section with the approach to the febrile patient
with diarrhea.

APPROACH TO THE PATIENT WITH FEVER AND DIARRHEA

General Aspects
Diarrhea is a very common symptom encountered in clinical practice. Currently, diarrhea
is defined as a change in bowel habit with an increase in stool fluidity and/or volume, often
accompanied by increased stool frequency.35 Febrile diarrhea may be a perplexing diagnostic
 107

and therapeutic problem. Many cases remain undiagnosed because various causative agents
are not considered. Modem laboratory techniques permit the isolation of newly recognized
pathogens, such as enterotoxigenic E sch erich ia co li, Y ersin ia , C a m p y lo b a c te r , and Norwalk
virus. Today it is possible to define the precise agent causing febrile diarrhea in the majority
of cases. Severe diarrhea can be a debilitating or even life-threatening disease.
The medical history should include the following questions: (1) Is the diarrhea acute,
chronic, or relapsing? (2) What is the nature and consistency of the stool? (watery, loose,
mucoid, bloody, purulent, greasy) (3) Does the patient suffer from any underlying disease
of the digestive tract? (4) Does the patient have any nondigestive disorder? (Diarrhea is
sometimes a nonspecific manifestation of gram negative bacteremia, pyelonephritis, pelvic
inflammatory disease and some systemic disorders) (5) Which drugs was the patient taking
prior to the onset of diarrhea? (6) What are the sexual habits of the patient? (7) Is there a
history of recurrent infections? (immune deficiency). In addition, it is important to obtain
epidemiologic information such as animal contact, recent travel, and public health reports
on current diarrhea-causing pathogens.
On physical examination, the following features should be noted: general, mental, and
nutritional condition and especially, state of hydration. In a severely dehydrated patient,
restoration of fluid and electrolyte balance is a medical emergency and takes precedence
over making a diagnosis. Abdominal findings may include tenderness, a mass, fullness due
to matted loops of bowel (as occurs in Crohn’s disease), hepatosplenomegaly, and ascites.
Rectal examination may reveal a mass or fecal impaction. General examination may disclose
flushing (suggestive of carcinoid syndrome), goiter, and lymphadenopathy (lymphoma,
Whipple’s disease), signs of advanced atherosclerosis (possibly accompanying mesenteric
ischemia), evidence of collagen-vascular disease (mesenteric arteritis), fistulae (Crohn’s
disease), jaundice, clubbing of the fingers, and skin rashes.
The differential diagnosis of febrile diarrhea is extensive; the etiologic factors include
microorganisms, toxins, and drugs, and inflammatory bowel disease as well as various
disorders of the alimentary tract and other organ systems.35 38

Classification
It would be impossible to classify all the febrile diarrheas within a single table. Several
criteria may be employed: mode of onset and duration, etiology, and nature of the stool,
but no classification is entirely satisfactory.

1. Etiologic classification (see Table 2). The various causes may be subdivided into the
following main groups:
(a) Infectious
(b) Inflammatory
(c) Malabsorption
(d) Systemic
(e) Postoperative
(f) Drug-induced
2. Mode of onset and duration. Febrile diarrhea may be classified as either
(a) Acute, characterized by a sudden onset and lasting usually less than 2 weeks, and
not more than 3, or
(b) Chronic, which has an insidious onset and a prolonged duration (over 3 weeks);
chronic diarrheas are listed in Table 3.
3. Nature of the stool
(a) Watery diarrhea may occur in infections, especially viral, E sch erich ia c o li, S a l-
m on ella, Yersinia (which may sometimes cause dysentery) and G ia rd ia lam blia.
(b) Bloody stools can occur in both infectious and noninfectious disorders. Infective
agents include bacteria, such as S h igella, E sch erich ia co li, and C a m p y lo b a c te r
108 U n ex p la in ed F e ve r

TABLE 2
Etiologie Agents of Febrile Diarrhea

Infections
Viral
Rotavirus
Enteric adenovirus
Bacterial
Invasive — Salmonella, including Salm, typhi, Shigella, invasive Escherichia coli, Yersinia enterocolitica,
Vibrio parahemolyticus, Campylobacter fetus ss jejuni, Staphylococcus aureus, Neisseria gonorrhoeae,
Mycobacterium tuberculosis
Enterotoxigenic — enterotoxigenic Escherichia coli, Clostridium perfringens, Clostridium difficile, entero-
toxigenic Staphylococcus aureus
Fungal — Candida, Mucor sp., Histoplasma
Protozoa — Entamoeba histolytica, Giardia lamblia, Balantidium coli, Coccidia isospora, Leishmania donovani
Helminths — Schistosoma mansoni and japonic urn, Fasciola hepatica, Faciolepsis buski, Trichuris, Tricinella
spiralis, Strongyloides stercoralis
Traveler’s Diarrhea (see text)
Systemic, remote, or adjacent infection — intra-abdominal abscess, acute appendicitis (especially retrocecal),
pelvic inflammatory disease, otitis media, meningitis, pneumonia and other infections in children, Gram-negative
bacteremia, malaria, peritonitis
Inflammatory — Crohn’s disease, ulcerative colitis, diverticulitis
Malabsorption — tropical sprue, Whipple’s disease
Systemic — Collagen-vascular disease, lymphoma, adenocarcinoma of pancreas (body and tail), carcinoma of
colon
Postoperative — systemic candidiasis, cytomegalovirus infection
Drug-Induced — antibiotics (penicillins, cephalosporins, clindamycin, lincomycin, erythromycin, tetracyclines,
chloramphenicol), cotrimethoxazole, procainamide, quinidine, iodides, bismuth, thiocyanates

TABLE 3
Chronic and Relapsing Diarrhea

Infections
Bacterial — ileocecal tuberculosis, Yersinia, Campylobacter, Actinomycosis
Chlamydial — C. trachomatosis, C. psittaci
Fungal — Candidiasis, Phycomycosis, Histoplasmosis
Parasitic — Schistosomiasis (japonicum, mansoni), Chaga’s disease, amebiasis, isosporiasis, cryptosporidiasis
Inflammatory — Crohn’s disease, ulcerative colitis, diverticulitis
Immunologic — systemic lupus erythematosus, polyarteritis nodosa
Neoplasia — Colonic tumors, intestinal lymphoma

and parasites, especially E n ta m o eb a h isto ly tic a . Ulcerative colitis, divertic-

fe tu s,
ulitis, and colorectal carcinoma may also be manifest by bloody stools.
(c) Steatorrhea, characterized by bulky, light-colored, fatty, malodorous stools, may
be seen in febrile malabsorption syndromes, such as Whipple’s disease, tropical
sprue, giardiasis, and some forms of intestinal lymphoma.

Clinical Features of Febrile Diarrheas

Most febrile diarrheas are of an infectious origin. Many factors are involved, including
host factors (immune response, gastric acidity, small-bowel motility, resident intestinal
flora39) and those related to the etiologic e.gent (number of organisms ingested, pathogenicity,
invasiveness, and toxin production).
The invasive bacteria, which destroy the gut mucosal cells, include S a lm o n ella , S h igella,
Y ersinia en te ro co litic a , C a m p y lo b a c te r fe tu s, V ibrio p a ra h em o lyticu s, and invasive forms
of E sch erich ia co li. Infection caused by these organisms is usually associated with fever,
headache, and myalgia.
 109

Noninvasive bacterial pathogens include enterotoxigenic E sch erich ia c o li and S ta p h y-

lo co ccu s a u re u s ,
and C lo strid iu m p erfrin g en s. Low-grade fever may accompany infection
by these organisms, especially E. coli. Occasionally, noninvasive strains of K le b sie lla and
E n te ro b a cte r may cause acute diarrheal disease.
Febrile diarrheas caused by viruses, such as rotavirus and the Norwalk-like agent, usually
affect children, are mild, self-limited, and of short duration. However, in the immunosup-
pressed individual the course may be more severe. These viruses may be identified in feces
by a radioimmunoassay technique and serum antibody to viruses may be measured as well.
An important, yet simple, test will differentiate diarrhea caused by invasive forms from
that due to enterotoxigenic bacteria and viruses. A fecal smear stained with methylene blue
or Wright’s stain is examined under the high power light microscope for white blood cells.
Fecal leukocytes are present in infectious diarrhea due to invasive bacteria, as well as Crohn’s
disease, ulcerative colitis, acute amebic colitis (in small numbers) and drug-induced entero-
colitis (pseudomembranous colitis). Fecal leukocytes are not observed in viral gastroenteritis,
and in diarrhea produced by enterotoxigenic bacteria and most parasites.
Traveler’s Diarrhea (Turista), occurring in foreign travelers and tourists, is characterized
by watery diarrhea, nausea, mild abdominal pain, and fever. The illness may last up to 10
days. The principal etiologic agents are enterotoxigenic E sch erich ia co li and G ia rd ia lam b lia.
Food and water-borne poisoning are occasionally associated with fever. The main symp-
toms are abdominal cramps, vomiting, and diarrhea. The majority of cases are of short
duration and are due to S h ig e lla , S a lm o n e lla , S ta p h y lo c o c c u s , and invasive E sch erich ia coli.
In the water-borne form, when bacteriologic confirmation is lacking, it is important to search
for G ia rd ia la m b lia in the stool since this organism may produce persistent infection.
Pseudomembranous colitis (PMC), or antibiotic-related colitis40,41 is characterized by
the sudden onset of fever, abdominal pain, and diarrhea, which is usually of a watery or
mucoid nature, but occasionally may be bloody. This may be a life-threatening condition.
Typically, it begins on the 4th to 9th day after administration of an antibiotic, especially
clindamycin. However, several cases occurring 2 to 6 weeks after cessation of antibiotic
therapy have been reported. Very rarely, patients present with FUO or unexplained fever
without diarrhea. PMC is more common following oral therapy and in older patients. When
a patient on antibiotic therapy develops severe diarrhea, fever, or unexplained deterioration,
the clinician should consider PMC and perform rectosigmoidoscopy, looking for typical
pseudomembranes. Usually C lo strid iu m difficile and occasionally, S ta p h y lo co c cu s or other
bacteria are involved.42 It is mandatory to stop antibiotic administration. Very rarely PMC
is not associated with antibiotic therapy.43 Prophylaxis and treatment are discussed by George
et al.44
Recently recognized pathogens Y ersinia and C a m p y lo b a c te r may cause febrile diarrhea
or may simulate inflammatory bowel disease or even acute appendicitis. In Yersinia enteritis45,46
the most important symptoms are fever, abdominal pain, and diarrhea. Fever occurs in
approximately 50% of cases and may vary from high temperatures of brief duration to low-
grade fever lasting for weeks. C a m p y lo b a c te r enteritis47,48 is characterized by a prodromal
stage of fever, malaise, abdominal pain, nausea, and myalgia, followed by diarrhea, which
may be bloody. The condition usually subsides in 3 to 4 days, but in debilitated or im-
munosuppressed patients, it can become severe and prolonged or relapsing. Other manifes-
tations and methods of diagnosis of these infections are discussed elsewhere (see Chapter
20).
Febrile diarrhea in homosexuals may occur in association with the acquired immune
deficiency syndrome (AIDS), shigellosis, rectal syphilis and gonorrhea, amebiasis, giardi-
asis, and cryptococcosis, or infection by herpes simplex, CMV, C h la m yd ia tra c h o m a tis ,
and M yco b a c teriu m a viu m -in tra cellu la re. Prolonged fever and diarrhea in a young male is
very suggestive of AIDS, and the diarrhea may be a particularly distressing problem in such
patients.49
110 U nex p la in ed F ever

Chronic inflammatory enteritis may be caused by local or disseminated C a n d id a infec-

tion. The main symptoms are nonbloody diarrhea and abdominal cramps; fever is variably
present.50 In the compromised host, C a n d id a may localize on lesions such as peptic ulcer,
ulcerative colitis or tumors. Definitive diagnosis of invasive candidiasis can only be made
by identification of filamentous forms of the fungus in the tissues.51 According to Eras,52
when C a n d id a organisms are simultaneously cultured from the throat and the feces, the
likelihood of gastrointestinal candidiasis reaches 90%.
Two protozoa of the Coccidia subclass, C ryp to sp o rid iu m and Iso sp o ra b e lli , may cause
a protracted enteritis, manifested by diarrhea, fever, abdominal pain, weight loss, and
malabsorption. Cryptosporidium may produce copious amounts of watery diarrhea. These
organisms have become increasingly important in recent years because of their propensity
to infect the immunocompromised host, especially those suffering from AIDS, although
immunocompetent individuals may also become infected. The diagnosis is established by
identifying oocysts in the stool using a special acid-fast stain.
Fever, diarrhea, and weight loss may occur in inflammatory bowel disease, Whipple’s
disease, lymphoma, leukemia, colonic carcinoma, carcinoid syndrome, systemic lupus er-
ythematosus, scleroderma, polyarteritis nodosa, hyperthyroidism, Addison’s disease, AIDS,
and ARC (AIDS-related complex).

D iagn ostic A pproach to F ebrile D iarrhea

Initial investigation — In most cases acute diarrhea does not require an involved
diagnostic work-up. The following checklist applies to diarrhea of 5 days duration or less:

1. Blood — Complete blood count, including eosinophil count, ESR, culture, electrolytes,
glucose, urea, creatinine, amylase, serology (such as antibodies to ameba, others
according to epidemiologic setting)
2. Stool — Consistency, frequency (per 24 h), volume (per 24 h), occult blood, mi-
croscopy, including staining for leukocytes by Wright’s stain or methylene blue, and
identification of culture for enteric pathogen
3. Urine — Microscopy, chemical analysis, culture (when necessary)
4. Culture of f o o d sa m p le (when applicable)

Later investigations — After 5 days, if there is no improvement, despite symptomatic

or antimicrobial therapy and, especially when the patient’s condition is deteriorating or the
stool becomes bloody, then additional tests are indicated. For convenience, these may be
divided into two phases:
Phase 1
Blood — Microbiologic and serologic tests
Stool
(a) Gram stain and microscopy in search for S ta p h y lo co c cu s and C a n d id a a lb ic a n s
(overgrowth)
(b) Repeat culture and search for ova or parasites
(c) Sudan stain for excess fat
(d) Toxin identification, especially C lo strid iu m difficile and enterotoxigenic E. co li
(when required and available)
Phase 2. When diarrhea is prolonged, then according to the clinical setting, certain of the
following tests will be performed:
Medical imaging
(a) Conventional radiology, mainly barium enema, upper GI series, including small
bowel follow-through
(b) Ultrasonography
(c) Computerized tomography
 I ll

Small and large bowel studies

(a) Duodenal samples — aspirate, touch biopsy
(b) Small bowel aspirate — colony count, culture
(c) Small bowel biopsy may be of assistance in the diagnosis of Whipple’s disease,
lymphoma, amyloidosis, giardiasis, coccidioidomycosis, strongyloidosis, crypto-
sporidiosis
(d) Endoscopy — upper gastrointestinal tract, colonoscopy, proctoscopy (with mucosal
biopsy or smear for identification of pus)
Room search for drugs

INFLAMMATORY BOWEL DISEASE

Inflammatory bowel disease comprises regional enteritis (Crohn’s disease) and ulcerative
colitis. Fever may be a major symptom of these bowel diseases, either as a result of the
basic disease or due to a complication.

Crohn’s Disease
Crohn’s disease is a granulomatous inflammation of unknown etiology affecting any
part of the gastrointestinal tract, frequently in discontinuity. The main clinical features are
abdominal pain, diarrhea, fever, anemia, and weight loss. The anatomical location of the
lesions influences the pattern of the clinical symptomatology and of the complications. The
most frequent location is in the distal ileum and proximal colon (50% of cases); the small
intestine alone is involved in 20 to 30%, and the colon alone in 15 to 30% of cases.53
Fever may be the sole feature, preceding gastrointestinal symptoms by several months
to more than 1 year. Bockus54 describes the case of a 12-year-old boy who had recurrent
bouts of fever lasting 2 to 3 months, without other symptomatology for a period of 1V2
years. During the last febrile episode he developed acute right lower quadrant pain and
appendicitis was suspected. He underwent surgery, where granulomatous Crohn’s disease
involving the terminal ileum and proximal colon was observed and resected.
The most difficult cases to diagnose are those presenting with fever, anemia, and weight
loss, without abdominal pain and diarrhea. Lee and Davies55 reported two such cases. One
patient presented with fever, joint pains, mild anemia, and an elevated ESR. Rheumatic
fever was suspected and the patient was treated accordingly. After 3 months in which the
patient failed to respond to therapy, he developed severe, colicky, lower abdominal pain.
The patient underwent operation; histologic examination of the resected gut revealed Crohn’s
disease. A second patient presented with fever, a systolic murmur, and splenomegaly. The
presumptive diagnosis was bacterial endocarditis. Again there was no response to treatment.
Subsequently a tender, mobile, sausage-shaped mass was palpated in the right iliac fossa.
The diagnosis of regional enteritis was confirmed by histologic examination of resected
intestine. Wolff et al.56 report several patients with recurrent, spiking fevers, sometimes
without gastrointestinal symptoms, who were shown to have regional enteritis.
Fever occurs in one third to one half of cases of Crohn’s disease. In uncomplicated
cases, the fever does not usually exceed 39°C. In view of the protean clinical manifestations
of Crohn’s disease, the work-up of fever and weight loss in the adult should include barium
enema and small bowel examinations. If either of these is suggestive of inflammatory bowel
disease, then endoscopy and biopsy should be performed. The standard laboratory tests are
of little value: increased ESR, positive C-reactive protein, anemia (microcytic or less com-
monly, macrocytic) and a positive guaiac stool may be present. Bactériologie examination
of the blood and feces, as well as serologic tests, should be carried out to exclude pathogens
such as Yersinia and Campylobacter.

Ulcerative Colitis
In ulcerative colitis the large bowel mucosa either partially or completely becomes
112 U n ex p la in ed F e ve r

inflamed and may undergo ulceration. The disease may be confined to the rectum, or may
involve the rectosigmoid and descending colon. Occasionally the transverse colon is affected
and rarely the entire colon is diseased. The principal symptom is that of bloody diarrhea,
but there may be associated constitutional and extracolonic manifestations.
The severity of the disease correlates well with certain clinical and laboratory parameters:
fever, amount of blood in stools, weight loss, persistence of abdominal pain, tachycardia,
elevated ESR, anemia, and hypoalbuminemia. Ulcerative colitis is classified into three
categories, according to severity:57

1. Mild (60% of cases) — characterized by fewer than four bowel movements a day and
without fever, weight loss, anemia, or hypoalbuminemia, although extracolonic and
anorectal manifestations may be present.
2. Moderate (25% of cases) — characterized by low-grade fever (up to 37.7°C), frequent
loose, bloody stools (about 4 to 5/day) and abdominal cramps; occasionally this form
undergoes rapid deterioration and converts into the severe variety.
3. Severe (15% of cases) — characterized by high fever (38.3 to 39.5°C), profuse diarrhea
and rectal bleeding, rapid loss of weight, marked weakness, tachycardia, anemia,
leukocytosis, hypoalbuminemia, and severe electrolyte disturbances.

An occasional patient will present with fever with minimal or absent gastrointestinal
features.5859
Many local and systemic complications are associated with fever.60

1. Local — perianal and perirectal fistula with abscess formation, perforation, toxic
dilatation of the colon, carcinoma of the bowel. Toxic megacolon61 is a very serious
complication of ulcerative colitis. The patient appears toxic, dehydrated, febrile, with
a distended abdomen, sometimes with visible outlining of the dilated bowel. A decrease
in the number of bowel motions is an ominous sign. A plain X-ray of the abdomen
is very useful to confirm the diagnosis: it shows dilatation of the colon, usually
transverse, with intramural gas. The patient should be kept under close scrutiny by
medical and surgical teams ready for emergency treatment.
2. Systemic — hepatobiliary disorders (sclerosing cholangitis, pericholangitis, etc., see
Chapter 9), acute arthritis, vascular (venous thrombosis, thromboembolism), urinary
tract infection (secondary to nephrolithiasis), erythema nodosum.

The differential diagnosis of inflammatory bowel disease62 may be very difficult, because
these conditions may be simulated by several diseases, not only clinically but also on
endoscopic and radiographic examinations. The diagnosis generally depends upon the clinical
stage of the disease. Initially there may be no localizing features and the problem is one of
unexplained fever. Later there may be localization in either the small or large intestine alone,
or both. Involvement of the small bowel is usually accompanied by steatorrhea or malab-
sorption, whereas colo-rectal lesions are generally associated with rectal bleeding. Some
principal conditions to be considered in the differential diagnosis are listed in Table 4. In
cases of a postbulbar duodenal ulcer associated with fever, Crohn’s disease should be
considered. In 25 to 35% of cases of involvement of colon and rectum a definitive diagnosis
of inflammatory bowel disease cannot be made. These “ indeterminate” cases present a
number of difficulties therapeutically and prognostically. The presence of weight loss, ar-
thritis, anemia, or liver disease favors the diagnosis of ulcerative colitis.

INTESTINAL TUBERCULOSIS
With the decline of pulmonary tuberculosis in Western countries there has been a
corresponding decrease in the incidence of the intestinal form of the disease, yet it still
 113

TABLE 4
Diseases Whose Radiologic or Endoscopic Features Simulate Inflammatory Bowel
Disease

Shigellosis
Salmonellosis
Campylobacter fetus infection
Yersinia enterocolitica infection
Amebiasis
Intestinal tuberculosis
Histoplasmosis
Colitis in systemic lupus erythematosus
Enterocolitis in Behcet’s syndrome
Lymphoma

TABLE 5
Differential Diagnosis of Fever and Ileocecal Mass

Crohn’s disease
Intestinal tuberculosis
Periappendicular or pericecal mass (abscess)
Mesenteric adenitis (especially due to Yersinia)
Abdominal actinomycosis
Ameboma
Small intestinal lymphoma
Carcinoma of right colon and cecum (especially following perforation)
Carcinoid tumor
Foreign body reaction (Fish bone or chicken bone)

remains an important problem in Asia. In the past, intestinal tuberculosis was usually a
complication of pulmonary tuberculosis; however, it not infrequently occurs in the absence
of the latter. The principal localization of the intestinal form is in the ileocecal region.
The clinical manifestations are not specific: fever, night sweats, abdominal pain, an-
orexia, vomiting and weight loss; diarrhea occurs in one third of cases. Physical examination
frequently discloses a mass in the right lower quadrant. The tuberculin test is positive in
most cases. In the absence of obvious pulmonary involvement, the diagnosis requires a fairly
rigorous evaluation, including barium studies of the colon and small intestine, colonoscopy,
laparoscopy, identification of acid fast bacilli in sputum, gastric aspirate, bone marrow, and
liver. A search for acid-fast bacilli in the stools is usually unrewarding. Not infrequently,
definitive diagnosis is made only after surgical resection, from where mycobacteria are
cultured from or demonstrated in mesenteric lymph nodes or other tissue. The differential
diagnosis of fever associated with a mass in the ileocecal region is quite extensive. Several
diagnostic possibilities are listed in Table 5.

DIVERTICULAR DISEASE
Diverticulitis of the small intestine is diagnosed infrequently. It may be manifested by
acute attacks of mid-abdominal or lower quadrant pain. Fingerhut et al.63 describe a patient
who presented with fever, right lower quadrant pain, and partial intestinal obstruction of 15
days duration. At surgery, a small infected diverticulum was found 7 cm proximal to the
ileocecal valve. Inflammation of a Meckel’s diverticulum may produce an acute or subacute
abdominal syndrome, mimicking acute appendicitis. The diagnosis is usually made when
the surgeon finds a normal appendix at laparotomy and then explores the small bowel.
A more important clinical problem is diverticulitis of the colon, which is primarily a
disease of Western populations. The clinical manifestations include fever, vomiting, left
114 U n ex p la in ed F e ve r

lower quadrant pain with tenderness and guarding, and leukocytosis (mirror-image or left-
sided appendicitis). Occasionally, rectal bleeding or a left iliac mass is present. The disease
may be characterized by a recurrence of such episodes until a complication, usually febrile,
supervenes. The complications include pericolic or pelvic abscess, localized or generalized
peritonitis, pylephlebitis with portal pyemia and liver abscess, fistulae, and intestinal ob-
struction. Bowel symptoms and pain may be minimal, and fever may be the only presenting
symptom.64 Sometimes, a pericolic abscess may communicate with a small tributary of the
inferior mesenteric vein, permitting “ drainage” of purulent material into the portal system,
leading to metastatic suppuration and portal pyemia, and producing a clinical picture of
unexplained fever. Diagnosis may be very difficult since blood cultuers are frequently sterile,
the liver acting as a block to bacterial access into the systemic circulation. Nemeth et al.65
describe a case of suppurative pylephlebitis and hepatic abscess complicating diverticulitis
of the colon.

INTESTINAL TUMORS
Tumors of the Small Intestine
Carcinoma, lymphoma, and rarely, carcinoid — are rare sources of fever. Among the
mechanisms of fever production, erosion or ulceration of the tumor, secondary bacterial or
fungal infection, as well as sepsis associated with gastrointestinal bleeding may play a role.
Adenocarcinoma occurs mainly in the duodenum and may produce bleeding, obstruction,
weight loss, and occasionally, fever.
Lymphoma tends to involve the jejunum and ileum either as a primary or more com-
monly, secondary disorder. The clinical features include signs of intestinal obstruction,66
anorexia, weight loss, nausea, vomiting and, at times, fever. An abdominal mass may be
felt, and hepatosplenomegaly may be present when generalized lymphoma is associated with
intestinal involvement. The rare Mediterranean abdominal lymphoma, or immunoprolifer-
ative small intestinal disease (IPSID),67 affects people in the second and third decades of
life in underdeveloped parts of the world, including Southeast Asia, South and Central
America, and Africa, as well as the Middle East. The condition may be manifest by mal-
absorption, weight loss, abdominal pain, and mass, clubbing, and occasionally, fever.
Very occasionally, the carcinoid syndrome is accompanied by fever, usually in asso-
ciation with necrosis of hepatic metastases.
Because of the protean symptomatology, the diagnosis of small bowel tumors is ex-
ceedingly difficult. The epidemiologic setting and a high index of suspicion may aid in cases
of IPSID-associated lymphoma, where the demonstration alpha chains on protein electro-
phoresis is a valuable laboratory marker, especially in the early stages. The investigation of
small bowel tumors includes barium follow-through X-ray, endoscopy, selective arteriog-
raphy, biopsy, and laparotomy with surgical resection and histologic examination. The
diagnostic effort is worthwhile, since many tumors are resectable and the prognosis vastly
improved.

Tumors of the Colon

Although fever is not generally considered to be a characteristic manifestation of car-
cinoma of the colon, certain authors68,69 claim that fever may be one of the earliest symptoms
of colorectal cancer. Fever of unknown origin has been described in this condition by other
authors.58,70 Initially, when tumor size is small, the symptomatology is variable and non-
specific. Later the complaints become more typical according to the side of the colon affected.
Right-sided features include diarrhea alternating with constipation, vomiting, abdominal
pain, anemia, rectal bleeding (late), a palpable mass, and fever. On the left side, the
manifestations are mainly abdominal distension, constipation, rarely diarrhea, obstructive
features, rectal bleeding (in 70% of cases), and a palpable mass.
 115

Several mechanisms are operative in producing fever in the patient with colonic cancer:70

1. Extension of the tumor through the serosa with secondary infection producing a peri-
colic abscess.
2. Penetration of the tumor into adjacent organs, such as uterus, urinary bladder, blood
vessels, with occasional fistula formation
3. Ulceration, necrosis or abscess within the tumor
4. Hepatic metastases
5. Septicemia due to colonic inhabitants, such as Bacteroides, Clostridium, Streptococcus
fecalis, Strep, bovis, or rarely, more than one of them (polymicrobial); the presence
of Strep, bovis bacteremia itself should alert the physician to its very frequent asso-
ciation with adenoma or carcinoma of the colon.71

Appendicular Tumor
A 47-year-old female presented with a 5-week history of lower abdominal pain, nausea,
vomiting, and fever with leukocytosis. A tender mass was palpated in the right lower quadrant
on abdominal and pelvic examinations. A sonogram revealed an abscess. At laparotomy, a
periappendicular abscess was found to be associated with an adenocarcinoma of the appendix
with metastases to the adjacent adnexa.72

INTRA-ABDOMINAL INFECTIONS AND ABSCESSES

Intra-abdominal infection presents a diagnostic and therapeutic challenge to the clinician.
The frequently hidden location of an abscess or other infection and the insidious and non-
specific clinical manifestations can easily mislead the physician. Unfortunately, delay in
recognition and appropriate treatment produces an overall morbidity and mortality that are
still quite high despite modem antimicrobial drugs.

PERITONITIS
Intra-abdominal infection may be primary or secondary, diffuse or localized; abscess
formation may or may not be present. In primary peritonitis the route of infection is unknown
but presumed to be hematogenous, lymph-bome, or via transmural migration through the
gut or Fallopian tube. The condition occurs principally under two circumstances: (a) children
with nephrotic syndrome and (b) cirrhosis. The main etiologic agents are Streptococcus
pneumoniae, group A Streptococcus, Gram-negative enteric bacilli (especially Escherichia
coli), anaerobes, Neisseria gonorrheae, and Mycobacterium tuberculosis. Spontaneous or
primary peritonitis manifests itself generally as an acute febrile illness, which may be
confused with appendicitis. However, in adults the onset is sometimes insidious. Other
aspects of this condition are dealt with elsewhere (tuberculosis peritonitis, see Chapter 20,
“ Tuberculosis” , perihepatitis, see Chapter 9, “ Perihepatitis” , peritonitis in cirrhosis, see
Chapter 9, “ Inflammation Involving the Liver” .
Secondary intraperitoneal infection is usually a complication of intra-abdominal disease
or surgery. The infective agents gain entry into the peritoneal cavity via perforation of a
hollow viscus or passage through the walls of a diseased organ. Infection is usually poly-
microbial: anaerobes, such as Bacteroides fragilis, Clostridium, anaerobic streptococci) and
facultative aerobic organisms, such as Escherichia coli, Proteus, Klebsiella, Pseudomonas,
group D Streptococcus. Various intra-abdominal conditions may lead to secondary peritonitis
and include (1) perforation, either traumatic, or spontaneous, in diseases such as peptic
ulcer, typhoid fever, tuberculosis, amebiasis, inflammatory bowel disease, appendicitis, and
diverticulitis, (2) necrosis of bowel due to obstruction, infarction or neoplasm, and (3) intra-
abdominal suppuration, foreign body, and chemical inflammation.
116 Unexplained Fever

The clinical features of acute peritonitis may be divided into two main groups: (1) reflex
— abdominal pain (localized or generalized), vomiting, muscular rigidity, and (2) toxic —
distension, intestinal paresis, toxemia, and fever. There is no characteristic temperature
curve in acute peritonitis, which may rarely present as unexplained fever. The differential
diagnosis of peritonitis with regard to acute abdominal febrile syndromes, includes inflam-
matory bowel disease, acute hemorrhagic pancreatitis, empyema of the gallbladder, rupture
of a dissecting aneurysm, retroperitoneal hemorrhage, acute porphyria, and familial Medi-
terranean fever (see Table 1 — Causes of Fever and Abdominal Pain).

APPENDICITIS
Appendicitis with perforation and abscess formation may cause unexplained fever, es-
pecially in the elderly. The differential diagnosis of acute or subacute appendicitis is extensive
and beyond the scope of this chapter; only a few conditions will be mentioned here: mesenteric
adenitis, Meckel’s diverticulitis, diverticulitis of the colon, acute cholecystitis, acute pan-
creatitis, pelvic inflammatory disease, and acute porphyria. Approximately 20% of cases
presenting with a clinical picture resembling appendicitis are incorrectly diagnosed, but in
women aged 20 to 40 years, the negative appendectomy rate exceeds 40%.74 Occasionally,
unexplained fever and diarrhea may be due to an inflamed retrocecal appendix.75

SUBPHRENIC AND OTHER INTRA-ABDOMINAL ABSCESSES

Intra-abdominal abscesses are probably the most perplexing diagnostic and therapeutic
problems of all intra-abdominal infections. They represented approximately 10% of cases
of fever of unknown origin in a French series.76 The usual causes are infection or perforation
of an abdominal organ. Altmeier77 found the principal causes were in descending order of
frequency as follows: appendicitis 19%, genitourinary disease 18%, pancreatic disorders
12%, biliary tract disease 8%, diverticulitis 7%, actinomycosis 4%, perforating tumors 3%,
trauma 3%, peptic ulcer 2%, leaking anastomotic suture line 2%. The most frequently isolated
organisms are Escherichia coli, Staphylococcus aureus, anaerobic streptococci, Bacteroides,
Klebsiella, and Enterobacter, although the flora is polymicrobial in many cases.
A variety of clinical features may be observed. Fever occurs in over 90% of cases and
may be accompanied by localizing symptoms and signs. Pain or tenderness over a developing
abscess is characteristic. A focus adjacent to the urinary tract may cause hematuria or pyuria.
Pleuritic pain may occur in the case of a hepatic or splenic abscess. Patients who do not
have localizing features present with unexplained fever. Nonspecific fever, rigors, night
sweats and progressive weight loss may persist for weeks or months, and severe cachexia
or death may supervene if the diagnosis is not made.77 Early recognition and treatment may
be life-saving. The diagnosis should always be entertained in a patient with postoperative
fever.
There is usually a peripheral leukocytosis, which may reach 20,000 per mm3 in deep-
seated infections, and is accompanied by a left shift. The ESR is elevated in the majority
of cases. Diagnostic techniques for localizing deep-seated abscesses include conventional
radiography, radioisotopic scanning, ultrasonography, angiography, computerized tomog-
raphy, and recently, nuclear magnetic resonance imaging. Skillful use of modem imaging
techniques permits accurate diagnosis and localization, and avoids the necessity of explorative
laparotomy. For example, in a prospective study on 36 patients presenting with FUO in
Salpetriere Hospital of Paris, early abdominal CT was found to reduce the time for diag-
nosis.78
Subphrenic abscess frequently arises as a complication of abdominal surgery, most
commonly on the stomach, colon, and biliary tract.79 In other cases the abscess originates
from metastatic suppuration or by extension from a diseased neighboring organ into the
subdiaphragmatic space. A right-sided subphrenic abscess may be a complication of per-
 117

forated peptic ulcer, cholecystitis, hepatic abscess, or generalized peritonitis; a left-sided

abscess may result from an infected splenic infarct, or pancreatitis; both abscesses may arise
from perirenal suppuration. Right-sided subphrenic abscesses are more common.
The presenting manifestations are fever, shoulder pain, dyspnea, local tenderness, an
elevated diaphragm, a pleural effusion, and a pulmonary infiltrate, although many of these
features may be absent. The clinical picture may be one of long-standing or overwhelming
sepsis, or an insidious illness with low-grade fever and progressive weight loss. Leukocytosis
and an elevated ESR are usual. A high index of suspicion is very important in making the
diagnosis.
Other deep-seated infections are discussed elsewhere (retroperitoneal abscesses, see next
section, hepatic abscess, Chapter 9, pancreatic abscess, Chapter 9, renal and perinephric
abscess, Chapter 27).

FEVER ASSOCIATED WITH MESENTERIC AND

RETROPERITONEAL DISORDERS

MESENTERIC ADENITIS
Mesenteric adenitis occurs mainly in children and young adults and may produce a
febrile syndrome resembling acute appendicitis. The cause is believed to be viral, although
Gram-negative bacilli, especially from the genus Yersinia — enterocolitica and pseudotu-
berculosis — have been isolated from patients undergoing surgery for a provisional diagnosis
of “ appendicitis” .80,81 At operation, the appendix is usually normal or slightly inflamed,
the mesenteric lymph nodes are inflamed and may contain small abscesses.
Mesenteric adenitis is usually a self-limited illness and is characterized by fever, right
lower quadrant pain and tenderness, vomiting, and diarrhea. Leukocytosis is usual and
polymorphonuclear leukocytes may be found in the stool. Culture of lymph nodes and blood
serologic tests may confirm the diagnosis. The differential diagnosis includes acute appen-
dicitis and conditions which simulate it.

RETROPERITONEAL ABSCESS
Retroperitoneal abscess refers to infection in the lumbar and iliac regions. Lumbar abscess
may present as fever, low back pain, tenderness, and lumbar muscle spasm. It results from
infection in the spine or retroperitoneal structures, such as kidney, pancreas lymph nodes,
and aortic aneurysm, or from a posterior perforation of the bowel or appendix. Pyogenic
psoas abscess is difficult to diagnose because of its concealed location and nonspecific
manifestations.82 A major cause in the past was tuberculosis, usually as a complication of
Pott’s disease of the spine. Nowadays, pyogenic bacteria, Escherichia coli, Proteus, entero-
cocci, and anaerobes are the etiologic agents. Most cases are secondary to periappendicular
abscess, diverticulitis, inflammatory bowel disease, spinal osteomyelitis, perinephric ab-
scess, and abdominal trauma. The main clinical features are fever, lower abdominal pain,
and inguinal mass. Hip spasm (psoas sign) and an abnormal straight leg raising test are
frequently present. Bacteremia is occasionally detected, especially in cases of Staphylococcus
aureus infection. Conventional radiology such as plain abdomen film, barium enema, and
intravenous pyelography may contribute to the diagnosis; however, ultrasonography, gallium
scanning, and especially computerized tomography83 are more useful. Treatment involves
surgical drainage as well as antibiotics.
Perirectal and pericolic abscesses may cause unexplained fever,30 especially in immu-
nosuppressed patients. Supra-elevator abscesses, situated above the pelvic diaphragm, may
present with fever, vague abdominal pain, brief bouts of diarrhea, and sometimes urinary
symptoms, which may confuse the picture.
Periproctitis, which may follow hemorrhoidal injection or surgery, may also present
118 Unexplained Fever

with unexplained fever, without localizing signs until low-grade perineal and scrotal cellulitis
supervenes.30 Because rectal diseases may be responsible for otherwise unexplained fever,
digital and endoscopic examination of the rectum are mandatory.

RETROPERITONEAL FIBROSIS
Retroperitoneal fibrosis is a recent addition to the long list of causes of fever of unknown
origin. Fever associated with obstructive uropathy due to idiopathic retroperitoneal fibrosis
is discussed in Chapter 27 The etiology is unknown; it may represent a hypersensitivity
response to a variety of antigens, including bacteria, fungi, tumor-associated antigens and
drug-hapten combinations. Retroperitoneal fibrosis has been described in association with
methysergide administration, as well as certain constitutional and connective tissue dis-
eases.84,85
The clinical features include abdominal or back pain, fever, headache, anorexia, weight
loss, splenomegaly, pleurisy with effusion, pericarditis, intermittent claudication and hy-
pertension. The ESR is elevated and hyperglobulinemia is present. Diagnosis may be aided
by intravenous pyelography, CT, or arteriography.
Byrd et al. described the case of a 21-year-old male,84 hospitalized for 4 months because
of prolonged fever, drenching night sweats, headache, weight loss, arthralgia and hepato-
splenomegaly. After extensive laboratory, radiologic, and isotopic investigations failed to
reveal the diagnosis, the patient underwent laparotomy, where a large mass was observed
in the rectosigmoid region, at the brim of the sacrum. The histology of the mass was consistent
with retroperitoneal fibrosis. A diverting colostomy was performed and prednisone therapy
was initiated. Within 48 h the fever subsided. Steroids were gradually tapered and stopped
after 372 months. Another illustrative case is that of a 10-year-old girl with recurrent episodes
of upper respiratory tract infection followed by abdominal pain, fever, weight loss, anorexia,
insomnia, irritability, and cervical lymphadenopathy.86 During the symptom-free period, the
girl was in excellent health. Laparotomy disclosed a mass at the base of the mesentery and
in the left retroperitoneum. Histopathologic examination revealed fibrosis of both of these
tissues with retractile mesenteritis. The condition was successfully treated with intermittent
corticosteroid administration.
The differential diagnosis is quite extensive and includes tuberculosis, sarcoidosis, sys-
temic lupus erythematosus, polyarteritis nodosa, giant cell arteritis, adult Still’s disease,
Weber-Christian disease, infective endocarditis, and thyrotoxicosis, as well as other con-
ditions causing prolonged fever.

CELLULAR INFLAMMATORY PSEUDOTUMOR

Cellular inflammatory pseudotumor is a variant of retractile mesenteritis. It is a rare,
solitary, expansile, well-circumscribed inflammatory mass situated in various anatomical
regions, usually the ileal mesentery, to which it is attached by a short, broad pedicle. An
interesting case is described of a 31-year-old male, who suffered for 3 months from an
illness characterized by fever, Campylobacter enteritis, weight loss, abdominal mass, ane-
mia, and liver dysfunction. After a thorough investigation the final diagnosis was found to
be cellular inflammatory pseudotumor.87

MALABSORPTIVE DISORDERS
The malabsorption syndrome is defined as an impairment of the small bowel to absorb
normal dietary constituents such as fat, protein, carbohydrates, essential minerals, and
vitamins. The principal clinical features are diarrhea, steatorrhea, weight loss, weakness,
edema, tetany, muscle cramps, osteoporosis, bleeding diathesis, and anemia. The diagnosis
depends upon the demonstration of abnormal fecal fat loss, decreased xylose or vitamin B12
absorption, small bowel X-ray, and peroral jejunal biopsy.
 119

Although fever is not a prominent symptom in most cases of the malabsorption syndrome,
it may occur in certain conditions, such as tropical sprue, Whipple’s disease, intestinal
lymphoma, and Giardia lamblia infestation.

TROPICAL SPRUE
Tropical sprue is a malabsorptive disorder of unknown etiology which affects the in-
digenous population as well as travelers to the tropics. The diagnosis is established by
evidence of malabsorption in the appropriate epidemiologic setting. The clinical features
include diarrhea, which is occasionally bloody, steatorrhea, abdominal pain, weight loss,
fever, glossitis, and anemia. The condition should be suspected when a patient with diarrhea
and malabsorption resides in or has recently returned from an endemic tropical area. The
duration in the tropics may be brief and may precede the onset of symptoms by months or
even years. The disease may be simulated by intestinal infections, especially giardiasis, but
also amebiasis and shigellosis. Nontropical sprue is not usually accompanied by fever, and
its presence during the course of this disorder suggests a complication such as intestinal
lymphoma.

WHIPPLE’S DISEASE
Whipple’s disease88 is a rare malabsorptive disorder which is nevertheless accompanied
by fever in over 50% of cases. The disease occurs principally in males aged 40 or over.
The clinical manifestations are varied and include diarrhea, steatorrhea, lymphadenopathy,
fever, arthropathy, cardiac murmurs, neurologic abnormalities, pigmentation of the skin,
anemia (iron and folate deficiency), hypotension, and cachexia. Fever and arthralgia may
precede the intestinal manifestations by months or years and the condition must be considered
in the differential diagnosis of unexplained fever, especially when features of malabsorption
are present. The diagnosis is made by the identification of periodic acid-Schiff (PAS) positive
macrophages in peroral small intestine or lymph node biopsy specimens. Although the
etiology of the disorder is unclear, treatment with antibiotics may induce dramatic improve-
ment.

FEVER ASSOCIATED WITH VASCULAR AND BLEEDING

DISORDERS OF THE GASTROINTESTINAL TRACT

VASCULAR DISORDERS
Vascular and collagen diseases may cause ischemic lesions in the stomach as well as
the small and large intestine. Ischemic disease of the gut may produce variable events from
mild, transient tissue damage to necrosis and perforation. Although fever is not prominent
in the early stages, it may occur in the presence of infarction.89 The etiology of the ischemic
process includes atheromatous occlusion, thrombosis, systemic embolism, and external
compression of the arterial tree, occlusion of large veins, and occlusive vasculitis. Underlying
disorders such as atherosclerosis, mitral valve disease, atrial fibrillation, or collagen disease
may be present. Rheumatoid arthritis may produce a febrile colitic syndrome.90 Oral con-
traceptives have also been implicated.
The superior mesenteric artery is affected in the majority of cases. The clinical features
comprise colicky abdominal pain, distension, occasional bloody diarrhea, leukocytosis, and
later in the course, fever, tachycardia, and hypotension.
Localized ischemia of the small intestine and ischemic colitis may occur. The latter is
frequently confused with dysentery, inflammatory bowel disease, or diverticulitis. Radiologic
investigation, especially selective angiography, may be useful in diagnosis. Acute intestinal
ischemia is a life-threatening condition, the mortality in established necrosis being very
high, and requires emergency surgery.
120 U nex p la in ed F e ve r

A large number of disorders may be associated with venous thrombosis: (A) Abdomi-
nopelvic (1) inflammatory bowel disease, (2) infectious — peritonitis, diverticulitis, (3)
trauma — surgery, injury, (B) mechanical — portal hypertension, congestive heart failure,
(C) hypercoaguability — polycythemia vera, antithrombin III deficiency, oral contraceptives,
certain neoplasms (such as pancreatic and colonic adenocarcinoma). Approximately 15 to
45% of mesenteric venous occlusions are idiopathic. Most cases of venous thrombosis may
present abruptly as an acute bowel infarction but, in some cases, there may be an insidious
development of abdominal pain over a period of up to 2 or 3 weeks. In acute mesenteric
venous thrombosis, pain is out of proportion to tenderness elicited on physical examination.
Gastrointestinal bleeding and serosanguinous ascites may also be present.
The diagnosis of mesenteric ischemia or infarction is often very difficult91 and requires
a high index of suspicion. While not a prominent symptom, fever may have prognostic
value: in advanced ischemia of the gut, severe abdominal distension and fever are ominous
signs. Early diagnosis before the development of irreversible lesions may be life-saving.
Interdepartmental consultation among the internist, surgeon, and radiologist should help
discover the nature of the condition before it becomes fulminant.

GASTROINTESTINAL BLEEDING
Fever occurs in the majority of patients with significant gastrointestinal bleeding, re-
gardless of the source. The temperature usually rises within the first 24 h, until reaching
39.4°C and may last for a week. Chapman and Mohamed92 observed fever lasting from 1
to 10 days and elevated ESR in one third of 155 patients with acute gastrointestinal hem-
orrhage.

REFERENCES
1. Turnen, H. J., Fever as symptom of gastrointestinal disease, Am. J. Dig. Dis., 9, 314, 1964.
2. Rakatansky, H. and Kirsner, J. B., The gastrointestinal tract: an often forgotten source of prolonged
fever, Arch. Intern. Med., 119, 321, 1967.
3. Symptoms, in Pediatric Clinical Gastroenterology, 3rd ed., Silverman, A. and Roy, C. C., Eds., C. V.
Mosby, St. Louis, 1983, 3.
4. Isaacs, I., Nissen, R., and Epstein, B. S., Liver abscess resulting from barium enema in a case of chronic
ulcerative colitis, N.Y. State J. Med., 50, 332, 1950.
5. Richman, L. S., Short, W. F., and Cooper, W. M., Barium enema septicemia: occurrence in a patient
with leukemia, JAMA, 226, 62, 1973.
6. Klein, B., Lewinsky, U. H., Cohen, A. M., Chaimoff, C., and Djaldetti, M., Liver abscess as a late
complication of percutaneous liver biopsy, Arch. Surg., 115, 1233, 1980.
7. Vicente, V. F. M., Ranz, F. M. H., Del Arbol, L. R., and Bouza, E. P., Septicemia as a complication
of liver biopsy, Am. J. Gastroenterol., 76, 145, 1981.
8. Postlethwaite, A. E. and Kelley, W. N., Uricosuric effect of radiocontrast agents: a study in man of four
commonly used preparations, Ann. Intern. Med., 74, 845, 1971.
9. Davis, J. L., Milligan, F. D., and Canieri, J., Septic complications following endoscopic retrograde
cholangiopancreatography, Surg. Gynecol. Obstet., 140, 365, 1975.
10. Levy, V. G., in Des Symptomes a la decision, Tchobroutsky, G., Ed., Medsi, Paris, 1983, 233.
11 Way, L. W., Abdominal pain, in Gastrointestinal Disease: Pathophysiology, Diagnosis, Management,
Sleisinger, M. H. and Fordtran, J. S., Eds., W. B. Saunders, Philadelphia, 1983, 207.
12. DeDombal, F. T., Leaper, D. J., Staniland, J. R., Harrocks, J., and McCann, A. P., Computer-aided
diagnosis of acute abdominal pain, Br. Med. J., 2, 9, 1972.
13. Brewer, R. J., Golden, G. T., Hitch, D. C., Rudolf, L. E., and Wangensteen, S. L., Abdominal pain:
an analysis of 1,000 consecutive cases in a university hospital emergency room, Am. J. Surg., 131, 219,
1976.
14. DeDombal, F. T., Analysis of symptoms in the acute abdomen, Clin. Gastroenterol., 14, 531, 1985.
14a. Roseau, G., Ulcerations gastroduodenales au cours d’une infection a cytomegalovirus sans immunodepres-
sion, Presse Med., 18, 319, 1989.
 121

15. Varay, A., Precis de Gastro-enterologie, Masson, Paris, 1966.

16. Sheft, D. J. and Shrago, G., Esophageal moniliasis: the spectrum of the disease, JAMA, 213, 1859, 1970.
17. Villar, L. A., Massanari, R. M., and Mitros, F. A., Cytomegalovirus infection with acute erosive
esophagitis, Am. J. Med., 74, 924, 1984.
18. Spiro, H. M., Clinical Gastroenterology, Macmillan, New York, 1977.
18a. Kaplan, L. M. and Compton, C. C., Case records of the Massachusetts General Hospital: case 4, 1989,
N. Engl. J. Med., 320, 235, 1989.
19. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report on 100 cases, Medicine, 40,
1, 1961.
20. Patwari, S. I., Choudhuri, G., and Tandon, R. K., Esophageal cancer: a cause of pyrexia of unknown
origin (letter), Am. J. Gastroenterol., 81, 837, 1986.
21. Parker, E. F. and Gregorie, H. B., Jr., Carcinoma of the esophagus, Curr. Prob. Surg., April 1967,
1.
22. Mannel, A., Carcinoma of the esophagus, Curr. Prob. Surg., 19, 553, 1982.
23. Miller, A. I., Smith, B., and Rogers, A. I., Phlegmonous gastritis, Gastroenterology, 68, 231, 1975.
24. LaForce, F. M., Diffuse phlegmonous gastritis: a rare complication of pneumococcal endocarditis, Arch.
Intern. Med., 120, 230, 1967.
25. Villadell, F., Gastritis, in Bockus Gastroenterology, Berk, J. E., Ed., W. B. Saunders, Philadelphia, 1985,
941.
26. Mathisen, A. H. S., Temperature and ESR in a patient with gastric ulcer, Nord. Med., 44, 1983, 1950.
27. Bang, S., Fever in gastric and duodenal ulcer, Arch. Intern. Med., 41, 808, 1938.
28. Kasich, A. M. and Miller, J. W., Prolonged pyrexia from penetrating benign ulcer on the greater curvature,
Gastroenterology, 39, 783, 1960.
29. Fouet, Gastro-enterologie, 2nd ed., Masson, Paris, 1983.
30. Keefer, C. S. and Laird, S. E., Prolonged and Perplexing Fevers, Little, Brown, Boston, 1955.
31. Olearchyk, A. S., Gastric carcinoma: a critical review of 243 cases, Am. J. Gastroenterol., 70, 25, 1978.
32. Witt, J. H., Marks, M. L, Smith, E. I., Altshuler, G., Wilson, D. A., and Humphrey, G. B.,
Leiomyoma presenting as prolonged fever, anemia and thrombocytosis, Cancer, 52, 2359, 1983.
33. Patel, R. M., DeSoto-LaPaix, F., and Mallaiah, L. R., Gastric infarction: a complication of endocarditis
due to Staphylococcus aureus, J. Clin. Gastroenterol., 5, 159, 1983.
34. Gleason, T., Prinz, R. A., Kirsch, E. P., Jablokow, V., and Greenlee, H. B., Tuberculosis of the
duodenum, Am. J. Gastroenterol., 72, 36, 1979.
35. Cooper, B. T., Diarrhoea as a symptom, Clin. Gastroenterol., 14, 599, 1985.
36. Krejs, G. J. and Fordtran, J. S., Diarrhea, in Gastrointestinal Disease: Pathophysiology, Diagnosis,
Management, Sleisinger, M. H. and Fordtran, J. S., Eds., W. B. Saunders, Philadelphia, 1983, 257.
37. Farmer, R., Infectious diarrhea: which culprit? what strategy?, Postgrad. Med., 73(6), 175, 1983.
38. DuPont, H. L. and Hornick, R. B., Clinical approach to infectious diarrheas, Medicine, 52, 265, 1973.
39. DeHovitz, J. A., Johnson, W. D., Jr., and Pope, J. W., Gastrointestinal infections, in Infectious Diseases:
Pathogenesis, Diagnosis and Therapy, Roberts, R. B., Ed., Year Book Medical, Chicago, 1986, 116.
40. Lishman, A. H., Al-Jumaili, I. J., and Record, C. O., Spectrum of antibiotic-associated diarrhoea, Gut,
22, 34, 1981.
4L Price, A. B. and Davies, D. R., Pseudomembranous colitis, J. Clin. Pathol., 30, 1, 1977.
42. Dickinson, R. J., Rampling, A., and Wight, D. G. D., Spontaneous pseudomembranous colitis not
associated with Clostridium difficile, J. Infect., 10, 252, 1985.
43. Moskovitz, M., Sullivan, S. N., and Troster, M., Recurrent pseudomembranous colitis unassociated with
antibiotic therapy, Arch. Intern. Med., 141, 663, 1981.
44. George, W. L., Rolfe, R. D., and Finegold, S. M., Treatment and prevention of antimicrobial agent-
induced colitis and diarrhea, Gastroenterology, 79, 366, 1980.
45. Vantrappen, G., Geboes, K., and Ponette, E., Yersinia enteritis, Med. Clin. North Am., 66, 639, 1982.
46. Kato, Y., Hattori, T., Oh-ya, H., Yoshino, S., Kato, H., and Noshikawa, H., Acute terminal ileitis
and Yersinia enterocolitica infection, Gastroenterol. Jpn., 12, 36, 1977.
47. Blaser, M. J., Berkowitz, I. D., LaForce, F. M., Cravens, J., Relier, L. B., and Wang, W.-L. L.,
Campylobacter enteritis: clinical and epidemiological features, Ann. Intern. Med., 91, 179, 1979.
48. Megraud, F., Campylobacter: nouveaux développements, Presse Med., 26, 1598, 1984.
49. Masur, H., Kovacs, J. A., Ognibene, F., Shelhamer, J., and Parillo, J. E., Infectious complications
of AIDS, in AIDS: Etiology, Diagnosis, Treatment and Prevention, DeVita, V. T., Jr., Heilman, S., and
Rosenberg, S. A., Eds., Lippincott, Philadelphia, 1985, 161.
50. Guerrant, R., Inflammatory enteritides, in Principles and Practice of Infectious Diseases, 2nd ed., Mandell,
G. L., Douglas, R. G., Jr., and Bennett, J. E., Eds., John Wiley & Sons, New York, 1985, 660.
51. Hruska, J. F., Gastrointestinal and intra-abdominal infections, in A Practical Approach to Infectious
Diseases, Reese, R. and Douglas, R. G., Jr., Eds., Little, Brown, Boston, 1983, 284.
52. Eras, P., Goldstein, M. J., and Sherlock, P., Candida infection of the gastrointestinal tract, Medicine,
51, 367, 1972.
122 Unexplained Fever

53. Kirsner, J. B., Chronic inflammatory bowel disease: overview of etiology and pathogenesis, in Bockus
Gastroenterology, 4th ed., Berk, J. E., Ed., W. B. Saunders, Philadelphia, 1985, 2093.
54. Bockus, H. L., Regional enteritis (Crohn’s disease). II. Clinical features, in Gastroenterology, 3rd ed.,
Bockus, H. L., Ed., W. B. Saunders, Philadelphia, 1976, 561.
55. Lee, F. I. and Davies, D. M., Crohn’s disease presenting as pyrexia of unknown origin, Lancet, 1, 1205,
1961.
56. Wolff, S. M., Fauci, A. S., and Dale, D. C., Unusual etiologies of fever and their evaluation, Annu.
Rev. Med., 26, 277, 1975.
57. Edwards, F. C. and Truelove, S. C., The course and prognosis of ulcerative colitis. I. Short-term prognosis,
Gut, 4, 299, 1964.
58. Molavi, A. and Weinstein, L., Persistent perplexing pyrexia: some comments on etiology and diagnosis,
Med. Clin. North Am., 54, 379, 1970.
59. Jacoby, G. A. and Swartz, M. N., Fever of undetermined origin, N. Engl. J. Med., 289, 1407, 1973.
60. Smith, J. N. and Winship, D. H., Complications and extraintestinal problems in inflammatory bowel
disease, Med. Clin. North Am., 64, 1161, 1980.
61. Cello, J. P., Ulcerative colitis, in Gastrointestinal Disease: Pathophysiology, Diagnosis, Management,
Sleisinger, M. H. and Fordtran, J. S., Eds., W. B. Saunders, Philadelphia, 1983, 1122.
62. Tedesco, F. J., Differential diagnosis of ulcerative colitis and Crohn’s ileocolitis and other specific in-
flammatory disease of the bowel, Med. Clin. North Am., 64, 1173, 1980.
63. Fingerhut, A., Eugene, C., Fourcher, J., Bergue, A., Terville, J. P., and Ronat, R., Les diverticules
acquis de l’intestin grele: presentation d’un cas de diverticulite ileale, Gastroenterol. Clin. Biol., 2, 299,
1978.
64. Almy, T. P. and Naitove, A., Diverticular disease of the colon, in Gastrointestinal Disease: Pathophys-
iology, Diagnosis, Management, Sleisinger, M. H. and Fordtran, J. S., Eds., W. B. Saunders, Philadelphia,
1983, 896.
65. Nemeth, J., Halphen, M., Hoang, C., Quillard, A., Guerin, J. M., Galian, A., and Le Charpentier,
Y., Pylephlebite suppuree et abcès hépatique par migration de materiel stercoral compliquant une diverticulite
sigmoidienne, Gastroenterol. Clin. Biol., 6, 688, 1982.
66. Gray, G. M., Rosenberg, S. A., Cooper, A. D., Gregory, P. B., Stein, D. T., and Herzenberg, H.,
Lymphomas involving the gastrointestinal tract, Gastroenterology, 82, 143, 1982.
67. Khojasteh, A., Haghshenass, M., and Haghighi, P., Immunoproliferative small intestinal disease — a
“ Third-World lesion’’, N. Engl. J. Med., 308, 1401, 1983.
68. Keddie, N. and Hargraves, A., Symptoms of carcinoma of colon and rectum, Lancet, 2, 749, 1968.
69. Kelleher, J. P. and Sales, J. E. L., Pyrexia of unknown origin and colorectal carcinoma, Br. Med. J.,
293, 1475, 1986.
70. Aderka, D., Hausmann, M., Weinberger, A., and Pinkhas, J., Unexplained episodes of fever: an early
manifestation of colorectal carcinoma, Isr. J. Med. Sci., 21, 421, 1985.
71. Klein, R. S., Association of streptococcus bovis with carcinoma of the colon, N. Engl. J. Med., 297, 800,
1977.
72. Tan, A. and Lau, P. H., Sonography of primary adenocarcinoma of the appendix with pathological
correlation, Am. J. Gastroenterol., 78, 488, 1983.
73. Pitcher, W. D. and Musher, D. M., Critical importance of early diagnosis and treatment of intra-abdominal
infection, Arch. Surg., 117, 328, 1982.
74. Lewis, F. R., Holcroft, J. W., Boey, J., and Dunphy, J. E., Appendicitis: a critical review of diagnosis
and treatment in 1000 cases, Arch. Surg., 110, 677, 1975.
75. Kassirer, J. P. and Kopelman, R. L, A young postman with abdominal pain and diarrhea, Hosp. Pract.,
20(11), 135, 1985.
76. Lebas, J., Pariente, D., Bletry, O., Pierkarski, J. D., Guillevisi, L., Couasnet, D., Plogert, F.,
Herson, S., Wechsler, B., Piette, J. C., Du hernot, T., Fermanian, J., Masselot, J., and Godeau, P.,
Fievres prolongées et syndromes inflammatoires inexpliqués: interet diagnostique de la tenodensitometrie
abdominale: etude propective randomisée de 36 observations, Presse Med., 14, 577, 1985.
77. Altmeier, W. A., Culbertson, W. R., Fullen, W. D., and Shook, C. D., Intra-abdominal abscesses,
Am. J. Surg., 125, 70, 1973.
78. Rault, P., Les fievre prolongées de diagnostique difficile, These Bischat Beaujon, Paris, 1973.
79. Wang, S. M. S. and Wilson, S. E., Subphrenic abscess: the new epidemiology, Arch. Surg., 112, 934,
1977.
80. Winblad, S., Nielehn, B., and Sternby, N. J., Yersinia enterocolitica (Pasteurella X) in human enteric
infections, Br. Med. J., 2, 1363, 1966.
81. Mair, N. S., Mair, H. J., and Stirr, E. M., Three cases of acute mesenteric lymphadenitis due to
Pastuerella pseudotuberculosis, J. Clin. Pathol., 13, 342, 1968.
82. Gordon, F., Starn1er, C., and Mills, J., Pyogenic psoas abscess: noninvasive diagnostic techniques and
review of the literature, Rev. Infect. Dis., 5, 1003, 1983.
 123

83. Sherman, S. J., Stern, J., and Neufeld, P., Recurrent psoas abscess, Postgrad. Med., 81(4), 96, 1987.
84. Byrd, W. E., Hunt, R. E., and Burgess, R., Retroperitoneal fibrosis as a cause of fever of undetermined
origin, West. J. Med., 134, 357, 1981.
85. Durst, A. L., Freund, H., Rosenmann, E., and Birnbaum, D., Mesenteric panniculitis: review of the
literature and presentation of cases, Surgery, 81, 203, 1977.
86. Meade, R. and Gang, D., Case records of the Massachusetts General Hospital: case 21, 1984, N. Engl.
J. Med., 310, 1374, 1984.
87. Strobe, W., Jr. and Richards, F., Case records of the Massachusetts General Hospital: case 13, 1984,
N. Engl. J. Med., 310, 839, 1984.
88. Dobbins, W. O., Ill, Current concepts of Whipple’s disease (editorial), J. Clin. Gastroenterol., 4, 205,
1982.
89. Laufman, H., Internal strangulation fever, Surg. Gynecol. Obstet., 135, 271, 1972.
90. Burt, R. W., Berenson, M. M., Samuelson, C. O., and Cathey, W. J., Rheumatoid vasculitis of the
colon presenting as pancolitis, Dig. Dis. Sci., 28, 183, 1983.
91. Becquemin, J. P., Fagnier, P. L., Soule, J. C., Chapelier, A., Bizard, T., and Julien, M., Infarctus
veineux entero-mesenterique: les difficultés d’un diagnostic précoce, Gastroenterol. Clin. Biol., 5, 992,
1981.
92. Chapman, R. S. and Mohamed, S. D., Pyrexia and elevated ESR in acute gastro-duodenal hemorrhage,
Postgrad. Med. J., 44, 238, 1968.
 125

Chapter 9

DISEASES OF THE HEPATOBILIARY TREE AND PANCREAS

ASSOCIATED WITH FEVER

Benedict Isaac and Michael Burke

APPROACH TO THE PATIENT WITH HEPATOMEGALY AND

FEVER
A frequent form of presentation of unexplained fever is in association with tender or
nontender hepatic enlargement. When faced with such a patient, the physician should carry
out a thorough history and physical examination having in mind the possible processes that
contribute to these features and paying special attention to certain accompanying findings
that may serve as clinical clues to the diagnosis. The principal mechanisms for “ febrile
hepatomegaly” are listed below. A list of causes of fever and hepatomegaly will be found
in Table 1.

1. Direct infection of the liver. Most forms of viral hepatitis as well many bacterial
infections of the liver may present with tender hepatomegaly and fever. Important
organisms to be considered in the differential diagnosis include hepatitis viruses A,
B, non-A, non-B, delta, EBV, CMV, and herpes simplex, Brucella, Salmonella typhi,
Treponema pallidum, Leptospira, Mycobacterium tuberculosis, Actinomyces, and the
protozoan Toxoplasma gondii.
2. Noninfectious processes producing inflammation and necrosis of the liver. Various
inflammatory conditions of the liver are characterized by hepatic enlargement and
fever. The best known examples are chronic active hepatitis, cirrhosis, alcoholic
hepatitis, granulomatous hepatitis, and some cases of drug-induced hepatitis.
3. Diseases resulting in hepatomegaly and fever by independent means. Finally there
is a heterogeneous group of conditions which cause liver enlargement and fever by
non-related mechanisms. A good example is cholangitis; obstruction to the biliary
outflow by a stone or a tumor results in hepatomegaly, and secondary infection may
cause fever. Another example is the secondary involvement of the liver by various
systemic disorders which themselves may present as unexplained fever: these diseases
may be neoplastic, such as lymphoma or metastatic carcinoma, or a collagen-vascular
disease, such as polyarteritis nodosa.
The following accompanying features should be sought:

1. Hepatic tenderness may suggest infection, including an abscess of the liver itself or
of a neighboring structure, e.g., subphrenic abscess, or it may be due to a congestive
liver, which occurs in heart failure and which occasionally may be accompanied by
fever.
2. Nodularity of the liver usually indicates hepatic tumor or cirrhosis, but may occa-
sionally be found in echinoccosis, gummatous syphilis, and polycystic disease of the
liver.
3. A friction rub may be heard over the liver in cases of hepatic tumors, but also in
perihepatitis and hepatic infarction.
4. Jaundice is an extremely important feature and will be discussed fully in the next
section.
5. Splenomegaly accompanies hepatomegaly in a large number of conditions of different
etiology, such as lymphoma, collagen diseases, and systemic infections, but not in
cases of primary or secondary tumors of the liver.
126 U nex p la in ed F e ve r

TABLE 1
Hepatomegaly and Fever

Infections
Viral Hepatitis A, B, NANB, Delta, EBV, CMV, HSV
Rickettsial Q fever
Chlamydial Psittacosis
Bacterial Ascending cholangitis, sepsis (aerobic and anaerobic), pylephlebitis, pyogenic liver and right
subphrenic abscess, salmonellosis, brucellosis, miliary tuberculosis
Spirochetal Leptospirosis, syphilis, relapsing fever
Protozoan Malaria, amebiasis, toxoplasmosis, babesiosis, visceral leishmaniasis
Helminthic Infected hydatid cyst, schistosomiasis, clonorchiasis, fascioliasis, toxocariasis
Inflammation
Chronic active hepatitis
Cirrhosis
Primary biliary cirrhosis
Granulomatous hepatitis
Inflammatory bowel disease
Neoplasia
Primary Benign—cavernous hemangioma
Malignant—hepatocellular carcinoma
Secondary Solid organ—metastatic carcinoma, renal carcinoma
Hematologic—lymphoma, leukemia, myeloproliferative syndrome
Collagen Diseases
Systemic lupus erythematosus
Polyarteritis nodosa
Progressive systemic sclerosis
Drugs and Toxins
Drug-induced hepatitis
Alcoholic hepatitis
Miscellaneous
Heart failure
Peliosis hepatitis
Wilson’s disease

6. Lymphadenopathy similarly points to infection, hematologic malignancy, or collagen

disease.
7. Features of chronic liver insufficiency, such as gynecomastia, testicular atrophy,
spider nevi, palmar erythema, and encephalopathy should be looked for.

APPROACH TO THE PATIENT WITH JAUNDICE AND FEVER

The febrile jaundiced patient is a frequent diagnostic and therapeutic dilemma in clinical
practice. Naturally the attending physician looks for a cause within the hepatobiliary tree
(which is in fact the usual situation). However, he should be aware of the possible occurrence
of unexplained fever and jaundice as the result of a remote, extrahepatic disorder.
The pathogenesis of jaundice in a particular clinical situation may be obscure or due to
a number of factors. The basic mechanisms leading to fever and jaundice are

1. Hemolysis. Certain diseases may cause hemolysis and fever. In this case anemia is
usally present and there is an elevation of the indirect bilirubin in the serum. The
conditions include infections, especially in association with hereditary disorders such
as glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and sickle cell hemoglo-
binopathy, as well as other conditions, which are listed in Table 2.
2. Hepatocellular damage. Parenchymal injury to hepatic cells occurs in many disorders,
including infections, inflammations, tumors, drug effects, collagen diseases (see Table
2). The jaundice is associated with an elevation of total serum bilirubin, especially
the direct fraction, and with bilirubinuria.
 Table 2
Causes of Fever and Jaundice

Mechanism Hemolytic Hepatocellular Obstructive Extrahepatic

Infections EBV infection Viral—Hepatitis Cholestatic hepatitis

A,B,NANB,Delta, yellow
fever, EBV, CMV, HSV
Rickettsial—Q fever, RMSF
Chlamydial—psittacosis
Clostridial sepsis Bacterial—miliary tuberculosis, Suppurative cholangitis Bacteremia (Gram neg)
Bartonellosis (Oroya fever) typhoid fever, brucellosis, Appendicitis
toxic shock syndrome, Pneumonia
Streptococcus Urinary tract infection
Spirochetal—secondary syphilis,
leptospirosis, relapsing fever
Malaria Protozoan—amebiasis, Metazoan—toxocariasis,
toxoplasmosis clorchiasis,
echinococciasis
Abscess Extrahepatic abscesses
Drugs and toxins Sulfonamides Halothane Erythromycin estolate
Alcoholic hepatitis Alcoholic hepatitis
Tumors Lymphoma Hodgkin’s disease Carcinoma of Extrabiliary Hodgkin’s
gallbladder disease
Lymphatic leukemia Hepatoma Biliary tract tumors
Métastasés Pancreatic carcinoma Carcinoma of kidney
Inflammatory Portal cirrhosis Biliary cirrhosis
Sarcoidosis Sclerosing cholangitis
Pancreatitis
Miscellaneous G-6DP deficiency Heart failure
Sickle-cell anemia
Thrombotic
thrombocytopenic
purpura
Ul
128 U nex p la in ed F ever

3. Biliary tract obstruction secondary to cholelithiasis, infection, inflammatory pro-

cesses, and tumors is a fairly frequent source of fever and jaundice, involving primarily
the direct serum bilirubin, and accompanied by markedly elevated serum alkaline
phosphatase, acholic stools and bilirubinuria. Pruritus is more common in obstructive
jaundice.
4. Extrahepatobiliary conditions. Infections outside the hepatobiliary tree, especially
in infants and occasionally in adults may cause jaundice,1 in addition to fever. The
pathogenesis is not clear and a variety of mechanisms, leading to intrahepatic bile
retention have been proposed. Bile stasis may be secondary to accumulation of in-
flammatory cells, swelling of Kupffer cells, the inhibitory effects of bacterial endotoxin
on parenchymal Na+, K +-ATPase‘ with subsequent interference with bilirubin excre-
tion, a form of inspissated syndrome,2 or abnormalities of bile duct epithelium.3 In
rare instances an extrahepatic tumor may be associated with fever, liver dysfunction,
and jaundice. The best known examples are Hodgkin’s disease4 and renal cell carci-
noma.5

ROLE OF LIVER BIOPSY IN UNEXPLAINED FEVER

The use of liver biopsy in the investigation of prolonged unexplained fever has its
proponents6 8 and opponents.910 In many cases of fever and hepatic dysfunction, diagnosis
may be made without liver biopsy. Yet some diseases may be determined with certainty
only after histologic examination of liver tissue has been performed.
The principal methods of liver biopsy are (1) blind percutaneous needle puncture, (2)
imaging-guided, (3) transjugular, (4) laparoscopy-directed, and (5) operative wedge biopsy.
Blind needle biopsy is useful in the investigation of diffuse hepatic disease, whereas guided
procedures are preferable for focal lesions. Percutaneous biopsy under CT or sonographic
guidance is also of value in the presence of ascites. Transvenous or transjugular liver biopsy
is indicated when massive ascites and/or a bleeding tendency is present.11 Laparoscopically
directed liver biopsy is advisable in patients in whom a previous blind biopsy was unsuc-
cessful. It is also useful for avoiding vascular lesions and for sampling tissue when lesions
are small. Although laparotomy for the specific purpose of obtaining hepatic histology is
not justified, wedge liver biopsy may be carried out during abdominal surgery for other
reasons.
The main indications for liver biopsy in patients with unexplained fever are

1. Persistent jaundice
2. Liver dysfunction, especially sustained elevations of SGOT and suspected diffuse
parenchymal disease, such as cirrhosis, primary biliary cirrhosis, chronic active hep-
atitis, NANB hepatitis, and alcoholic hepatitis
3. Anicteric (intrahepatic) cholestasis, characterized by pruritus, elevated serum alkaline
phosphatase and gamma-glutamyl transpeptidase
4. Hepatomegaly of obscure origin
5. Suspected tuberculosis, sarcoidosis, and other granulomatous diseases of the liver
6. Suspected liver tumor (metastases or primary)
7. Suspected drug-induced reaction
8. Suspected systemic disorders, such as collagen diseases and generalized infections

Liver biopsy is contraindicated in the following conditions:

1. Bleeding diathesis — clinical or laboratory (thrombocytopenia, prolonged prothrom-

bin, partial thromboplastin and bleeding times)
 129

2. Extrahepatic biliary obstruction, especially with cholangitis

3. Right subphrenic abscess, pleural empyema and lower lobe pneumonia
4. Ascites (except imaging-directed)
5. Severe hepatic cell necrosis
6. Cysts of the liver, including hydatid cysts
7. Vascular tumors, including hemangioma

Complications of liver biopsy are exceedingly rare. The morbidity is about 0.1 to 0.2%;
the mortality is approximately 0.015%,1213 and zero in one large series of 20,000 biopsies.14
Some complications, indicated by an asterisk (*) may be accompanied by fever.

1. Vascular lesions — (a) Intrahepatic hematoma,* (b) retroperitoneal or intraperitoneal

hemorrhage, (c) intrahepatic arteriovenous fistula
2. Infection* — (a) Liver abscess, (b) septicemia
3. Biliary — (a) Biliary peritonitis,* (b) biliary pleurisy*, (c) biliary embolism,* (d)
hemobilia

INFECTIONS INVOLVING THE LIVER

The liver may be involved in primary or secondary infection by a large number of
microorganisms — viral, rickettsial, bacterial, spirochetal, protozoan, or metazoan; the
clinical picture that emerges is often accompanied by fever, and occasionally, the patient
may present with unexplained fever. Infectious diseases have been described in detail in
previous chapters and only conditions relevant to hepatic infections will be discussed here.
Helminthiasis is discussed in the section on biliary disorders, subsection entitled “ Helminthic
Diseases of the Hepatobiliary System” .

VIRAL INFECTIONS
Viral Hepatitis
At least five distinct types of viral hepatitis have been recognized: A, B, two types of
non-A, non-B (NANB), or the recently described D or delta virus.15 These agents may
produce a wide range of clinical features, from asymptomatic infection, through anicteric
hepatitis, cholestatic jaundice, to acute fulminant hepatitis or chronic liver disease (in hepatitis
B, delta, and NANB). Fever and flu-like symptoms may predominate during the preicteric
phase of hepatitis, whose duration may range from 1 or 2 days to 3 weeks.1617 Fever and
chills occur in about 30% of adults and 40% of children with hepatitis A, and diarrhea is
common in children.18 The patient with anicteric hepatitis may complain of unexplained
fever, anorexia, nausea, and weakness; important clues to the correct diagnosis are abdominal
discomfort and brown urine. In hepatitis B, a febrile polyarthritis may develop and precede
other systemic features.19Fever may accompany several complications of hepatitis: fulminant
hepatitis, chronic active hepatitis, cirrhosis, hepatocellular carcinoma, aplastic anemia, nec-
rotizing vasculitis,20,21 and mixed cryoglobulinemia.22
HAV is usually transmitted by the fecal-oral route. Yet a clear distinction between
hepatitis A and other types cannot be made simply on epidemiologic criteria. HAV may be
transmitted during both heterosexual and homosexual23 contact, as well as parenterally. The
major route of the other hepatitis viruses is percutaneous, although sexual and other modes
of transmission may apply.The overall risk ratio of hepatitis viruses in transfusion hepatitis
is D:B:NANB = 1:30:3000.24 There appear to be several immunologically distinct NANB
agents.25 In general, the epidemiology of NANB hepatitis resembles hepatitis B. However,
reports from Central America and India suggest endemic26 or epidemic27 transmission. Preg-
nant females appear to be particularly susceptible to the epidemic form, which may cause
fulminant hepatitis in the third trimester.28
130 U nex p la in ed F ever

When a patient presents with fever, hepatomegaly, and evidence of liver dysfunction,
serologic testing for hepatitis A, B, and delta viruses should be carried out. Currently there
is no specific diagnostic test for NANB hepatitis. In certain cases in which diagnostic
difficulties still persist, liver biopsy may be necessary.

Herpes Viruses and the Liver

Several other viruses, especially herpes viruses, may produce a clinical picture similar
to viral hepatitis. The herpes viruses with hepatotropic qualities are EBV, CMV, and herpes
simplex. Even varicella has been reported to produce a hepatitis-like picture.29 31
Infectious mononucleosis — This condition may occasionally present with a predom-
inant hepatitis-like picture, namely, anorexia, nausea, vomiting, fever, jaundice and hepa-
tosplenomegaly, together with elevated serum aminotransferase.32 The clue may be provided
by the presence of lymphadenopathy, especially cervical, pharyngitis, and atypical lym-
phocytosis. The diagnosis may be confirmed by a positive heterophile antibody test and an
elevated IgM antibody titer to EBV.
Cytomegalovirus infection — CMV may produce a spectrum of disease, which may
be characterized by liver involvement: neonatal hepatitis, CMV mononucleosis syndrome,
and postperfusion syndrome, and rarely granulomatous hepatitis.33 Frank jaundice is unusual
in the mononucleosis syndrome, although a hepatitis-like picture may occur.34 35 A similar
condition may follow multiple blood transfusions.36,37 The diagnosis depends upon the
detection of the virus in the blood or body fluids, or a rising IgM antibody to CMV. Atypical
lymphocytosis may occur but heterophile antibody is negative. Liver biopsy reveals a his-
tologic picture similar to that of viral hepatitis.35
Herpes simplex — In recent years a significant number of cases of liver involvement
by herpes simplex viruses HSV1 and HSV2 have been reported. In these cases of herpetic
hepatitis, fever, hepatomegaly and mucocutaneous lesions are very common and jaundice
occurs in about V3. Most cases have a lethal outcome due to acute liver failure. Herpetic
hepatitis occurs mainly in the immunocompromised38,39 and in infancy,38 but has also been
described in pregnancy40 and in normal adults.4143 Clinical awareness and a search for
mucocutaneous lesions may aid in the diagnosis of a potentially lethal condition. Rapid tests
for the identification of antibodies to HSV, using ELISA, and early liver biopsy will detect
the cause and appropriate antiviral chemotherapy with acyclovir may be lifesaving.
A 46-year-old male, who had no evidence of immunosuppression or previous liver disease
was hospitalized41 in France for fever, chills, and dysuria of 4 days duration. On examination
the abdomen was diffusely tender and associated with meteorism; 2 days after admission he
went into shock. The serum amylase and aminotransferases were elevated. On a suspicion
of an acute abdomen, the patient underwent laparotomy, and succumbed shortly afterwards.
At autopsy, massive hepatic necrosis was revealed and found to be due to HSV.
Yellow fever — Occurring principally in Africa and in Central and South America, this
is a mosquito-transmitted infection characterized by fever, headache, nausea, epistaxis and
jaundice. Clues to diagnosis include relative bradycardia, albuminuria and early leukopenia.
Other viral infections may present occasionally with fever, jaundice and evidence of
liver dysfunction and be readily confused with “ classical” causes of the hepatitis syndrome
(such as HAV or leptospira). The ever-increasing list of agents includes rubeola,44,45 rubella,46
Coxsackie A and B,47-50 ECHO,51 reovirus,52 adenovirus,53 ebola,54 dengue,55 and Colorado
tick fever.56 The effects of human immunodeficiency virus (HIV) on the hepatobiliary tree
will be described in this chapter under the section “ Hepatobiliary Involvement in the Acquired
Immune Deficiency Syndrome” .
 131

RICKETTSIAL DISEASES

Certain rickettsial diseases may occasionally present with fever and hepatic dysfunction.
These include Q fever, Rocky Mountain spotted fever, and Boutonneuse fever.
Q fever — Liver involvement by Coxiella burnetti is quite common and is usually of
no serious consequence. Some patients will present without characteristic pulmonary man-
ifestations of Q fever, and a hepatitis-like picture may predominate.57,58 Liver biopsy may
reveal granulomatous lesions and a dense fibrin ring surrounding a central vacuole, presumed
to represent dissolved lipid.58,59 Okun59 reports a patient with FUO and liver dysfunction,
who was subsequently found to have granulomatous lesions in both liver and bone marrow
as a result of Q fever.
Rocky Mountain spotted fever60 62 — Hepatic involvement in this condition is uncom-
mon, but may forbear a poor prognosis. Although clinical jaundice is unusual, serum bilirubin
may be elevated by at least two mechanisms, namely, cholestasis and hemolysis. Liver
histology may reveal portal triaditis, vasculitis, sinusoidal erythrophagocytosis, and ductal
stasis. This potentially fatal yet curable disease should be suspected in endemic areas, even
if the typical rash is absent,63 and appropriate serologic testing should be performed.
Boutonneuse fever — In this condition serum elevations of hepatic enzymes are fre-
quently found. Histologically, nonspecific hepatitis or granulomatous hepatitis may be dem-
onstrated.64

BACTERIAL INFECTIONS
Bacteria may involve the liver directly, producing a hepatitis-like picture, granulomata,
or pyogenic abscess, or indirectly from a remote focus such as pneumonia, osteomyelitis,
appendicitis or urinary tract infection. The presentation in the latter event may include fever,
hepatomegaly and jaundice, thereby causing confusion and misdiagnosis. Occasionally the
major manifestation of systemic infection is as an elevated serum alkaline phosphatase.65
Liver biopsy in these cases usually reveals very mild preportal infiltrates or fibrosis. The
physician should not overlook a potentially serious primary (nonhepatic) febrile disorder
merely because of minor disturbances in liver function.

PYOGENIC LIVER ABSCESS

Pyogenic liver abscess is a life-threatening, potentially curable disease, which frequently
is manifest as unexplained fever or FUO.66 68 The pyogenic microorganisms reach the liver
via the biliary tract (usually), portal system, hepatic artery or through direct extension from
a neighboring organ. Pyogenic abscesses may complicate hepatic metastases undergoing
necrosis, hematoma following liver trauma, and rarely polycystic liver disease.69 In a small
group of cases the origin of the abscess is unknown or cryptogenic.
Diagnosis is often extremely difficult and an unfortunate delay in revealing this febrile
condition may have fatal consequences. The clinical picture may be protean: fever, chills,
anorexia, weight loss, and malaise. Useful clinical clues are right upper abdominal pain and
tenderness, hepatomegaly, and occasionally, jaundice. An abscess situated high in the right
lobe may produce respiratory symptoms such as cough, dyspnea, pleuritic pain radiating to
the right shoulder, and friction rub. The diagnosis should be entertained in the appropriate
clinical setting, such as previous disease or surgery of the biliary tract or bowel, liver trauma
and disease, especially alcoholic and metastatic, appendicitis, and pancreatitis, although a
relevant antecedent history may be lacking. Diabetes mellitus appears to be a predisposing
factor to liver abscess due to Yersinia enterocolitica.70-72
The main laboratory findings are leukocytosis with a left shift, elevated levels of serum
alkaline phosphatase, aminotransferases and occasionally, bilirubin. Blood culture should
132 U n ex p la in ed F e ve r

include incubation with special media to allow for anaerobes. Positive cultures may be
obtained in approximately half the cases, and are not infrequently polymicrobial.73,74 The
chest radiograph may reveal an elevation of the hemidiaphragm, a pleural effusion, atelectasis
or pulmonary infiltrates on the right side. A plain film of the abdomen displaying an unusual
collection of gas over the hepatic silhouette is highly suggestive.75
Hepatic scintography, using " mTc, 67Ga, or indium-labeled leukocytes, and ultrasono-
graphy (US) are the mainstay of detection and localization of hepatic abscesses. Computerized
tomography (CT) and more recently, magnetic resonance imaging (MRI) are both very
useful, but quite expensive, and not readily available in many developing countries, where
pyogenic liver abscess occurs more commonly. All of these methods have the advantage of
being noninvasive. US and CT are extremely accurate in directing percutaneous needle
aspiration for both diagnosis and treatment.68,76,77 The aspirated material should be sent for
aerobic and anaerobic culture. Hepatic arteriography has also been employed to delineate
an abscess as a central avascular area surrounded by a vascular rim, but this method has
been largely superseded by less invasive techniques.

HEPATIC TUBERCULOSIS
In many cases of hepatic tuberculosis, the principal clinical manifestations are of a
general and nonspecific nature, and liver involvement is often inapparent. Occasionally,
when the liver is severely affected, hepatic manifestations may predominate. It should be
appreciated that the primary site of tuberculosis may be hidden. Tuberculous involvement
of the liver may take one of several forms:

1. Miliary (micronodular)
2. Local
(a) Tuberculoma (macronodular)
(b) Abscess
(c) Granulomatous hepatitis (see section “ Inflammation Involving the Liver” , sub-
section “ Granulomatous Hepatitis” .)
(d) Tuberculous lymphadenitis

Miliary tuberculosis is the most common hepatic form of the disease, and is characterized
by fever, night sweats, anorexia, weight loss, hepatomegaly and occasionally, splenomegaly
and jaundice. The so-called “ primary” hepatic and miliary tuberculosis are not infrequent
causes of FUO.4 78 81 The serum alkaline phosphatase may be elevated. Liver biopsy com-
bined with culture is very useful in diagnosis, even in cases of miliary tuberculosis without
hepatic manifestations.
Hepatic tuberculoma may be solitary or multiple. The patient may present with prolonged
or recurrent fever, together with chills, weight loss, malaise and hepatomegaly. The condition
may simulate hepatic metastatic disease, and has been referred to as tuberculous pseudo-
tumor.82
Tuberculous liver abscess is a rare condition83 which may result from caseous necrosis
of a tuberculoma or from hematogenous spread. The clinical features are similar to those
of pyogenic and amebic abscess. Aspiration of purulent material will reveal acid fast bacilli.
Tuberculous lymphadenitis84 may involve the lymph nodes in the porta hepatis, producing
fever and other nonspecific clinical features, or the affected lymph nodes may cause biliary
tract obstruction.

HEPATIC INVOLVEMENT IN BRUCELLOSIS85 86

Brucella organisms tend to localize in the reticuloendothelial system, and hepatic in-
volvement is quite common pathologically but not clinically. Hepatomegaly is occasionally
 133

found and jaundice is very rare; disturbed liver enzyme function tests are found in about
10% of cases. The patterns of hepatic involvement are brucella hepatitis, granulomatous
hepatitis, and very rarely, abscess and cirrhosis. The diagnosis is based upon the isolation
of the organism in the blood and liver as well as brucella agglutinin titers.

THE LIVER IN SALMONELLA INFECTIONS

The clinical features of typhoid and paratyphoid fevers have been described previously.
An occasional patient presents with fever and predominant hepatobiliary symptomatology,
such as jaundice and hepatomegaly.87 89 Occasionally a clinical picture of suppurative cho-
langitis is present.90

HEPATIC ACTINOMYCOSIS
Involvement of the liver by A c tin o m y ces Israeli usually takes the form of a solitary
abscess, less commonly multiple abscesses and rarely, small nodules or granulomata. The
clinical features include abdominal or pleuritic pain, unexplained fever, weight loss and
tender hepatomegaly. Abscesses may be detected by isotopic scanning,91 ultrasonography,
or computerized tomography, and a specific diagnosis made after drainage and bacteriological
isolation following anaerobic culture. When not associated with large abscess formation,
hepatic actinomycosis may be very difficult to identify92 and may require repeated invasive
investigations, including biopsy and laparotomy.

OTHER BACTERIAL DISEASES

Other bacterial diseases may be associated with fever and hepatic dysfunction. Jaundice
and tender hepatomegaly may occur during pneumococcal pneumonia. S trep to co c cu s viri-
dan s was cultured from the liver of a patient presenting with FUO and elevated serum
alkaline phosphatase.93 N eisseria g o n o rrh ea e 94 may cause bacteremia, which is often as-
sociated with elevated serum aminotransferases, or they may be involved in the Curtis-Fitz-
Hugh syndrome (see below). In the staphylococcal toxic shock syndrome, liver involvement
may be extensive and is characterized by jaundice and very high serum aminotransferases.94
Severe infection by Gram-negative bacteria may cause cholestatic jaundice. In the typhoidal
form of tularemia, which simulates typhoid fever, hepatosplenomegaly is common and may
be accompanied by elevated serum aminotransferase and bilirubin levels.94

SPIROCHETAL DISEASES OF THE LIVER

Various spirochetes may involve the liver primarily or secondarily. Of principal interest
are B o rrelia , L e p to sp ira ,
and T repon em a p a llid u m .

BORRELIA
The clinical features and diagnosis of louse- and tick-borne relapsing fever will be
discussed in a subsequent chapter. However, tender hepatomegaly, jaundice, and disturbed
liver function frequently make an appearance during the course of the disease.

LEPTOSPIROSIS
Leptospirosis exists in two main clinical forms: a milder anicteric variety and a more
severe icteric type, Weil’s disease. The latter condition may present with obscure fever and
jaundice of several weeks duration, and the diagnosis may be suggested by the presence of
renal disease, hemorrhage, and hemolytic anemia. Liver enlargement is found in only 15
to 25% of cases, although tenderness is more frequent. Serum aminotransferases are only
moderately elevated, even in the presence of deep jaundice; however, the serum CPK is
markedly elevated. The diagnosis is confirmed by bacteriologic isolation and by serologic
testing. All leptospira serotypes may cause the disease.
134 Unexplained Fever

SYPHILIS
The liver may be involved in the congenital, and acquired secondary and tertiary forms
of syphilis. A febrile picture may occur in syphilitic hepatitis95 97 or granulomatous hepa-
titis.98' 100 The former is characterized by anorexia, nausea, upper right quadrant discomfort,
fever, tender hepatomegaly — features similar to those of viral hepatitis — together with
generalized lymphadenopathy and a maculopapular rash, which help to distinguish this entity.
A marked elevation of serum alkaline phosphatase with only a moderately raised amino-
transferase is a useful clue. Hepatic histology is variable.101 Differentiation of syphilitic
hepatitis from viral hepatitis may be very difficult, especially in the presence of jaundice.101 102
Identification of spirochetes in liver specimens103 and positive VDRL serology help to confirm
the diagnosis. The physician should obtain an appropriate sexual history and perform the
relevant physical examination. Most cases occur in young homosexual males. The presence
of genital or anorectal lesions is highly suggestive. One of the authors has seen a young
homosexual male who had secondary syphilis and hepatitis B concomitantly. It is conceivable
that such patients may have NANB hepatitis simultaneously with syphilis.
Granulomatous hepatitis with a febrile evolution caused by spirochetes resembles clin-
ically that caused by other organisms and must be differentiated by serology and histology.

FUNGAL DISEASES OF THE LIVER

CANDIDIASIS
Liver involvement is a well-documented complication of disseminated candidiasis. The
condition occurs mainly in patients with leukemia, lymphoma or immunosuppression. He-
patic candidiasis may be a cause of unexplained fever which can be diagnosed by percu-
taneous liver biopsy.104 Hepatic lesions may take the form of microabscesses, large abscesses105
or granulomatous hepatitis.106 When the serum aminotransferases are markedly elevated,
then a true “ Candida hepatitis” may occur.104

CRYPTOCOCCOSIS
Involvement of the liver by Cryptococcus neoformans usually occurs in the disseminated
form of the infection principally in the immunocompromised patient. Very infrequently, the
predominant features are fever together with hepatic manifestations, such as hepatomegaly,
liver dysfunction and ascites,107 hepatic failure,108 and acute hepatitis presenting as a surgical
emergency.109 A rare case of primary hepatic cryptococcosis simulating cholecystitis has
been recently described.110 Liver biopsy reveals granulomatous lesions which may exhibit
yeastlike organisms.

COCCIDIOIDOMYCOSIS
Hepatic coccidioidomycosis is an unusual manifestation of disseminated infection by
coccidioides immitis and most commonly characterized by a febrile hepatitis-pulmonary
syndrome with eosinophilia.111 The diagnosis may be made by detecting complement-fixing
antibodies in the serum. The organism may be cultured from the blood or sputum. Percu-
taneous liver biopsy may reveal granulomas, immature spherule-like structures, and rarely
specific mature endospherules.111
Histoplasmosis can produce hepatic granulomas, which may present with unexplained
fever.112

PROTOZOAL DISEASES OF THE LIVER

HEPATIC AMEBIASIS
Amebic liver abscess is the most common extraintestinal form of invasive amebiasis
and is observed in countries where intestinal amebiasis is common, such as South America,
 135

Africa, India, and the Far East, as well as in migrant populations and returning tourists in
more developed countries. The condition occurs most frequently in males (approximately 7
to 10 times more than females) in mid-adult life. It is uncommon in children, but when it
does occur this is usually in the under 3 years age group.113 The onset is variable and in
about one third to one half of cases there is an antecedent history of amebic dysentery.
The principal symptoms are right upper abdominal pain, fever, chills, sweating, weakness,
nausea, vomiting, and weight loss, frequently in association with respiratory complaints
such as cough, dyspnea, and pleuritic pain. Fever is present in 79 to 94% of cases.114 116
Atypical presentations include FUO, jaundice, acute abdomen and rarely, hepatic enceph-
alopathy. The occasional patient may be suspected of having primary hepatoma or metastatic
liver disease.
The physical findings include hepatic enlargement and tenderness. Jaundice is infrequent
and usually reflects the severity of the condition.117 Thoracic findings include friction rub,
decreased breath sounds and rales, usually over the right lung base.
Blood chemical investigations reveal slightly elevated aminotransferases, elevated al-
kaline phosphatase, decreased albumin and raised globulin. In addition, a slight leukocytosis
and an elevated ESR are present. Specific immunological testing using hemagglutination,
gel diffusion precipitation, counter immunoelectrophoresis and immunofluorescence are very
accurate; complement fixation is less sensitive. Stool examination for Entamoeba histolytica
is generally unrewarding.118
Various imaging techniques are useful in diagnosis of amebic liver abscess. The plain
film of the chest may reveal hump-like elevation of the diaphragm on the anteromedial
aspect of its right leaf. Radioisotopic imaging using Tc* and ultrasonography are very useful.
Computerized tomography may also be employed. Aspiration of an abscess under radiological
or ultrasonographic guidance will reveal thick “ anchovy paste’’-like material.
Certain complications of amebic liver abscess may result in an increase in the severity or
duration of fever. These include secondary pyogenic infection and rupture, which usually
occurs through the diaphragm, resulting in pulmonary sequelae, but occasionally occurs into
the peritoneal cavity, causing amebic peritonitis.119

MALARIA
The typical clinical features of malaria are well known. However, atypical presentations
of the disease may render difficulties in diagnosis. Within the framework of hepatobiliary
infection, three principal patterns of atypical malaria should be mentioned: malaria hepatitis,
bilious remittent fever, and blackwater fever. The important rules in diagnosis are clinical
awareness and repeated thin and thick blood films for malarial parasites, because of the
variability of their appearance in the blood.

1. Malaria hepatitis.120121 The patient presents with fever, chills, anorexia, vomiting,
hepatic tenderness and/or enlargement, with or without jaundice, with or without
splenomegaly, elevated serum aminotransferases and bilirubinuria. The clinical picture
mimics viral hepatitis and other hepatic infections. Liver biopsy demonstrates malarial
pigment, increased Kupffer cell activity, granulomatous lesions and hepatocyte ne-
crosis.
2. Bilious remittent fever. The condition is characterized by remittent fever, epigastric
pain, vomiting of bile, diarrhea, chocolate-colored stools, icterus, tender hepatosple-
nomegaly, and urobilinuria.122
3. Blackwater fever. This occurs almost exclusively in cases of Falciparum malaria. The
features include rigors, fever, intravascular hemolysis with icterus, and hemoglobinuria
as well as renal failure.
136 U nex p la in ed F ever

TOXOPLASMOSIS
Infection by T oxoplasm a g o n d ii is commonly asymptomatic. It may be transmitted from
mother to fetus, resulting in a congenital form, or it may be acquired postnatally by the
ingestion of contaminated soil or undercooked meat. About 40% of cases of congenital
toxoplasmosis are symptomatic with jaundice, hepatosplenomegaly, lymphadenopathy, fe-
ver, and retinochoroiditis as prominent manifestations.123 In acquired toxoplasmosis, a hep-
atitis-like picture with jaundice124125 or granulomatous hepatitis126 127 may occur. A prolonged
prodromal phase, which may be characterized by subfebrile temperature elevations and
fatigue, and the presence of generalized lymphadenopathy may suggest toxoplasma hepatitis.
Liver biopsy may disclose liver cell necrosis with an inflammatory infiltrate. A rising titer
in the Sabin-Feldman dye test establishes the diagnosis.

GIARDIASIS
Most patients with giardiasis are either asymptomatic or have symptoms referable to the
gut. Rarely, there may be features simulating cholelithiasis.128 An unusual case was reported
recently of a patient with prolonged fever subsequently found to be due to granulomatous
hepatitis and cholangitis associated with giardiasis.129

PERIHEPATITIS (CURTIS-FITZ-HUGH SYNDROME) 130

Perihepatitis is characterized by right upper quadrant pain, fever, and local tenderness.
Typically, the patient is a young sexually active female with a recent history of genital tract
infection or pelvic inflammatory disease. However, the syndrome has also been described
in males.131 132 The condition is frequently misdiagnosed as acute cholecystitis, and may
also be confused with pleurisy, pneumonia, pulmonary embolism, and rarely, perforation
of an abdominal viscus. The etiologic agents are N e isse ria g o n o rrh ea e and sometimes,
C h lam ydia tra c h o m a tis . The diagnosis may be confirmed by microbiologic analysis of swabs
from the cervix, urethra, rectum, and throat. Antichlamydial antibodies should be sought
in the blood and urogenital discharge. Laparoscopy may detect “ violin string” adhesions
between the anterior surface of the liver and the adjacent abdomen and/or white fibrous
plaques and tiny hemorrhagic spots on the liver.

HEPATOBILIARY INVOLVEMENT IN THE ACQUIRED IMMUNE

DEFICIENCY SYNDROME

Hepatobiliary involvement in AIDS133 134 is quite complex and may be due to many
causes. Fever is frequently present. Hepatic dysfunction with or without jaundice may be
related to concomitant viral infection, for example, HBV or EBV, or to opportunistic
infectious agents, including M y co b a c teriu m a v iu m -in tra c e llu la re , fungi, or CMV. In ad-
dition, these features may be associated with “ opportunistic” tumors, including Kaposi’s
sarcoma, lymphoma, or angiosarcoma of the liver. Peliosis hepatis may also be found.
Recently described febrile complications in the biliary tract are acalculous cholecystitis
and biliary tract obstruction due to papillary stenosis or sclerosing cholangitis. These con-
ditions are frequently associated with CMV infection or cryptosporidiasis. The clinical
features include fever, right upper quadrant pain, nausea, and vomiting; jaundice may or
may not be present. Sonography and ERCP are useful in the evaluation of such patients.
C a m p ylo b a c te r fe tu s infection and cystic duct obstruction caused by Kaposi’s sarcoma have
also been described in cholecystitis in patients with AIDS.
 137

INFLAMMATION INVOLVING THE LIVER

ALCOHOLIC HEPATITIS
Continuous consumption of alcohol may lead to several forms of hepatic injury, resulting
in three principal clinicopathological entities: fatty liver, alcoholic hepatitis, and portal
cirrhosis. Of these, fatty liver rarely, if ever, is associated with fever. Cirrhosis will be
discussed in the next section.
The clinical picture of alcoholic hepatitis may vary from asymptomatic hepatomegaly
with mild biochemical abnormalities to a severe febrile illness. The diagnosis should be
considered when an alcoholic complains of right upper quadrant pain, unexplained fever
and jaundice.135 The condition may simulate viral hepatitis, cholestasis136 or the presentation
may be with prolonged fever.137 138 The low-grade fever is often accompanied by weakness,
anorexia, nausea, vomiting, and weight loss. It is important to exclude respiratory or urinary
infections, which are very common sources of the fever in the alcoholic patient. Extrahepatic
manifestations, such as gastrointestinal bleeding, pancreatitis, and peripheral neuropathy
may serve to differentiate alcoholic hepatitis from other conditions. The definitive diagnosis
is made by liver biopsy, which reveals alcoholic hyaline deposition.

CHRONIC HEPATITIS
Chronic hepatitis may occur as a result of infection by hepatitis B, D, and NANB
viruses, drug toxicity, such as nitrofurantoin, perihexilene maleate, and oxyphenisatin,
occasionally in Wilson’s disease and as an autoimmune condition, so-called “ lupoid” hep-
atitis. Classification of chronic hepatitis into persistent or aggressive forms is not always
clear-cut.139 Chronic persistent hepatitis is usually benign, and characterized mainly by
persistent aminotransferase elevations. Chronic aggressive (or active) hepatitis (CAH) may
also be asymptomatic or it may present insidiously with jaundice, anorexia, abdominal pain,
fever, and arthralgia. Physical examination may reveal hepatosplenomegaly and palmar
erythema. The laboratory findings include elevated serum aminotransferases, alkaline phos-
phatase, and direct bilirubin, together with polyclonal hypergammaglobulinemia. Antinu-
clear, anti-smooth muscle, and antimicrosomal antibodies are frequently present. The diagnosis
is confirmed by histologic examination of liver biopsy material.

CIRRHOSIS OF THE LIVER

Fever may accompany all forms of cirrhosis, but most commonly alcoholic cirrhosis,
where it is claimed to be present in about V3 to V2 of patients. The fever may persist for
several weeks, thereby presenting as FUO.140 Low-grade fever is present in approximately
80% of patients with Indian childhood cirrhosis.141 A rare case of FUO was found to be
due to primary biliary cirrhosis.142
The mechanisms of fever in cirrhosis are complex and poorly understood. In essence,
fever may be secondary, i.e., related to a complication of cirrhosis such as infection or
neoplastic transformation, or it may be directly related to the cirrhotic process per se, in
which case it is termed primary.

Primary: Fever Due to Cirrhosis Per Se

About 40% of patients with advanced cirrhosis may exhibit a persistent, low-grade
fever.143 These febrile patients displayed a greater degree of active liver disease than their
afebrile counterparts, as demonstrated by a higher incidence of malnutrition, jaundice,
ascites, tender hepatomegaly, elevated serum alkaline phosphatase, and leukocytosis, as
well as parenchymal necrosis on histologic examination. The fever in these patients does
not seem to be affected by the administration of antibiotics or dietary protein, and appears
to be related to the liver disease itself.
138 U n ex p la in ed F e ve r

Rault144 describes a case of a 40-year-old alcoholic woman who had FUO of 2 months
duration. An extensive search failed to discover evidence of infection or neoplasia. Liver
biopsy revealed steatosis and cirrhosis. Supportive therapy resulted in a decline of the fever
and an abatement of disturbed liver function tests.

Secondary: Febrile Complications of Cirrhosis

Patients with cirrhosis have an increased tendency to infection, most frequently involving
the respiratory, urinary, and gastrointestinal tracts. These cases do not usually present much
difficulty in diagnosis. Septicemia or bacteremia may complicate intestinal infections, or
peritoneal infections following various manipulative procedures, such as paracentesis, lap-
aroscopy, and surgery. The patient may complain of fever, chills, abdominal pain, diarrhea,
and expanding ascites. Blood culture will usually permit the isolation of the causative
organism. Occasionally, the infection is confined to the portal system, resulting in pyle-
phlebitis, which is characterized by unexplained fever and increasing signs of portal hy-
pertension, especially gastrointestinal bleeding and ascites.
An important complication of cirrhosis which may present with unexplained fever is
spontaneous bacterial peritonitis. Whereas acute peritonitis, characterized by acute abdominal
pain and rigidity, and vomiting, is not difficult to diagnose, this form is uncommon in
cirrhosis. Usually, in spontaneous bacterial peritonitis there is an insidious onset of fever
in a cirrhotic patient who has recently undergone an acute infection, especially diarrhea, or
an investigative procedure, such as abdominal paracentesis. The diagnosis can be made by
examination of the ascitic fluid which reveals an exudate and bacteriological culture may
provide the microorganism.
Tuberculosis, whether of pulmonary or peritoneal origin or miliary in nature, may
supervene in cirrhosis and produce an unexplained febrile state.145 Even viral hepatitis may
occur during the course of chronic liver disease, and present a confusing picture characterized
by jaundice and markedly elevated serum transaminases.
Cholelithiasis is more prevalent in patients with cirrhosis,146 and hence, cholecystitis
and biliary sepsis occur more commonly.
Hepatocellular carcinoma is a well-known complication of cirrhosis, and its onset may
be heralded by unexplained fever and general deterioration.
Gastrointestinal hemorrhage is a frequent complication of cirrhosis and has sometimes
been associated with fever.147 On occasions, the bleeding may be occult and some patients
may present with fever and anemia during the course of chronic liver disease.

GRANULOMATOUS HEPATITIS148 150

The liver, which is endowed with a rich supply of reticuloendothelial cells, is particularly
susceptible to granuloma formation. Hepatic granulomata are characterized histologically
by discrete collections of modified macrophage or epithelioid cells, often fusing to form
Langerhans’ or foreign-body giant cells, and surrounded by a rim of mononuclear cells,
predominantly lymphocytes. Clearly, hepatic granulomas are formed in a wide and varied
range of disorders, and hence are largely nonspecific.
In recent years granulomatous hepatitis has emerged as a clinicopathologic entity which
may be characterized by prolonged or unexplained fever.148 According to Guckian and
Perry,149 fever occurs in over 40% of these patients, and may be accompanied by malaise,
chills, sweats, myalgia, arthralgia, anorexia, and weight loss. The list of causes of granu-
lomatous hepatitis is virtually endless. The most prominent ones are listed in Table 3. It
should be noted that in about 25% of cases the etiology is unknown.

DRUG-INDUCED HEPATIC INJURY151154

The central metabolic role of the liver renders this organ susceptible to injury to a vast
array of foreign agents. Many substances are metabolized in the liver before being excreted
 139

TABLE 3
Causes of Granulomatous Hepatitis

Infectious

Viral —Hepatitis A, B, CMV, EBV, influenza B

Chlamydia—Lymphogranuloma venereum, psittacosis
Rickettsial— Coxsiella burneti (Q fever), Boutonneuse fever
Bacaterial—Mycobacterium, Gram-negative bacilli, Spirochetes
Fungal—Coccidioidomycosis, histoplasma
Parasitic—Giardia, Toxocara, Schistosoma
Noninfectious

Primary liver disease—Cirrhosis, primary biliary cirrhosis, chronic active hepatitis, pericholangitis
Primary intestinal disease—Crohn’s disease, ulcerative colitis, Whipple’s disease, Sprue, jejuno-ileal bypass
Drug hypersensitivity—Sulfonamides, sulfonylureas, phenylbutazone, allopurinol, halothane, phenytoin, chlor-
promazine, carbamazepine, quinidine, hydralazine, methyldopa, penicillin
Immunologic disorders
Hypersensitivity—Sarcoidosis, erythema nodosum, berylliosis
Collagen disorders—Giant cell arteritis-polymyalgia rheumatica, Takayasu’s syndrome, SLE, rheumatoid ar-
thritis, Wegener’s granuloma, allergic granulomatosis
Immune defects—Agammaglobulinemia, chronic granulomatous disease (of childhood)
Neoplasia—Lymphoma, intraabdominal solid tumors (ovarian carcinoma), melanoma
Idiopathic

TABLE 4
Drugs Causing Fever and Liver Disease

Clinical Entity Examples Comments

Acute hepatitis Halothane Jaundice may occur

Isoniazid Jaundice may occur
Sulfonamides Rash and eosinophilia common
Diphenylhydantoin Mononucleosis-like picture
Hydralazine Jaundice may occur
Cholestasis Erythromycin estolate Rash and eosinophilia common
Chlorpromazine Pruritus and eosinophilia common
Chronic hepatitis Alpha-methyldopa May also cause acute hepatitis with jaundice
Propylthiouracil Rash, eosinophilia and neutropenia may occur
Nitrofurantoin May also cause cholestasis and granulomas
Granulomatous hepatitis Allopurinol Dermatitis may be present
Carbamazepine Very toxic, especially in elderly
Quinidine Hepatomegaly common
Peliosis hepatitis Synthetic androgens

in the bile. Orally ingested agents are absorbed in the intestine and pass through the portal
system on their way to the systemic circulation. The hepatic microcirculation permits the
exposure of materials in the blood to a large surface area of metabolically active cells.
During the passage from portal blood through the hepatocytes to the biliary canaliculi, a
variety of organelles and cells are exposed to potentially reactive substances. Furthermore,
fat soluble chemicals tend to concentrate in the liver.
Many drugs produce hepatic injury which is frequently accompanied by fever. Jaundice
is often present, but sometimes the only indication of hepatic dysfunction is serum enzyme
elevation. The mechanism of drug-induced liver injury is not always clear, but usually
involves direct hepatotoxicity, indirect hepatotoxicity via metabolites, hypersensitivity or a
mixture of these. In the accompanying table (Table 4) a representative list of drugs which
may produce hepatic injury and fever is presented. In many cases, and especially in the
140 U nex p la in ed F e ve r

elderly, the patient is taking more than one preparation at the time he is found to exhibit
fever and liver dysfunction, and it may be very difficult to uncover the “ culprit” . Whenever
possible, all medications should be ceased until the return of liver function to normal. Then
the least likely agents may be introduced serially and gradually.

FEBRILE HEPATOBILIARY COMPLICATIONS OF INFLAMMATORY BOWEL

DISEASE
Hepatobiliary involvement in inflammatory bowel disease (IBD) is quite common, but
usually asymptomatic. Up to 95% of liver biopsies carried out at surgery reveal some degree
of abnormality and approximately 15 to 25% of patients exhibit disturbed liver function
tests.150 However, certain patients suffering from IBD may present with fever and hepato-
biliary disorders, including pericholangitis, chronic active hepatitis, cirrhosis, cholelithiasis,
cholangiocarcinoma, and iatrogenic disease.
Pericholangitis,150 probably the most common hepatic disorder in IBD, is characterized
histologically by portal tract inflammation, bile duct proliferation, and periductal fibrosis.
The condition is generally asymptomatic, but may present with episodic jaundice, pruritus,
fever, and hepatomegaly. The serum alkaline phosphatase may be slightly elevated. The
diagnosis is established by liver biopsy. Although pericholangitis is usually found in asso-
ciation with IBD, it is not specific and may occur in other (febrile) conditions, including
abdominal sepsis, typhoid fever and pancreatitis.
Liver abscess is a very uncommon complication of Crohn’s disease155 156 and carries a
high mortality.
Chronic active hepatitis (CAH) occurs in about 2% of patients with ulcerative colitis157
and 2.5% of Crohn’s disease.158 The mechanism of CAH in these conditions is unknown,
but may be related to several factors, including surgery, blood transfusion, and immune
processes.
Cirrhosis may follow portal fibrosis associated with pericholangitis or CAH. The overall
incidence is 2 to 3%.158,159
Granulomatous hepatitis, sometimes observed in IBD, has the same clinical presentation
as that resulting from any other etiology. The diagnosis is made by histologic examination
of material obtained on liver biopsy.
Primary sclerosing cholangitis (see Fever in Diseases of the Extrahepatic Biliary Tract,
subsection Sclerosing Cholangitis) is a rare condition, which is nevertheless associated more
often with ulcerative colitis than any other disease. Its occurrence in Crohn’s disease is very
rare.
Cholelithiasis occurs with increased frequency in Crohn’s disease, but not in ulcerative
colitis. Presumably the result of bile salt deficiency with an interruption of the enterohepatic
circulation,160 the condition may predispose to cholecystitis and other febrile complications.
Patients with extensive terminal ileitis have a prevalence of stones about three to five times
than found in the normal population.161 The risk appears to be even greater following
ileostomy, especially in patients over the age of 50.162
Cholangiocarcinoma is a rare complication of ulcerative colitis, occurring about ten
times as often as in the normal population.163 In a recent report,164 a 31-year-old male with
ulcerative colitis complained of weight loss of 6 months duration, fever, night sweats,
nausea, and vomiting over the preceding 3 months, and jaundice during the last month.
Physical examination revealed smooth hepatomegaly. Serum levels of hepatic enzymes,
alkaline phosphatase, and the carcinoembyronic antigen (CEA) were elevated. ERCP re-
vealed a sclerosing cholangitis-like picture. CT demonstrated a diffuse infiltrating hepatic
tumor. Barium enema displayed features of ulcerative colitis with no evidence of colon
carcinoma. Percutaneous needle biopsy of the liver confirmed the diagnosis of sclerosing
cholangiocarcinoma.
 141

Iatrogenic diseases — Occasionally fever and hepatic dysfunction may be the result of
the treatment of IBD. Blood transfusions carry the hazard of hepatitis, especially of the
NANB type. Sulfasalazine may produce fever and jaundice by causing hemolysis or hep-
atotoxicity. Azothioprine may cause pancreatitis165 and leukopenia, which enhances suscep-
tibility to infection.

HEPATIC TUMORS AND CYSTS

TUMORS OF THE LIVER

Both primary and secondary tumors of the liver may present with unexplained fever.
Primary tumors may be benign or malignant. Secondary tumors are far more common.

Primary Tumors of the Liver

Benign tumors — Benign tumors are frequently asymptomatic and rarely attended by
fever. However there have been a few reports in the literature of benign liver tumors
presenting with fever. Hepatocellular adenoma may occasionally undergo infarction or hem-
orrhage and be manifested by the sudden onset of abdominal pain, nausea, vomiting, fever,
and leukocytosis. Such features occurred in three out of 75 cases reported from the United
States Armed Forces Institute of Pathology.166 A young female with FUO was subsequently
found to have an adenoma of the liver secondary to birth-control pill ingestion.157 Cavernous
hemangioma usually presents as an abdominal mass with or without pain. Sometimes, fever168
and chills are the predominant manifestations. Fever persisting after inability to resect the
tumor at laparotomy has been controlled by radiotherapy169 or prednisone.170 Mesenchymal
hamartoma was found in a 19-year-old female, who presented with abdominal pain, fever,
jaundice, and hepatomegaly, and who was initially thought to have a hepatic abscess.171
Leiomyoma of the liver was found at autopsy of an 87-year-old female who succumbed
after developing hematemesis, epigastric pain and fever.166
Malignant tumors — Hepatocellular carcinoma (HCC) is a common tumor in Africa,
the Orient, and the South Pacific Islands, and not uncommon in Western countries. The
most common manifestations of hepatocellular carcinoma are weight loss, malaise, anorexia,
abdominal pain and fullness, and low-grade fever. A history of hepatitis B, aflatoxin, or
other hepatotoxin ingestion may be contributory to the diagnosis. The presence of hepato-
megaly with one or more nodular masses is suggestive. Some patients may complain of
unexplained fever or FUO.172 173 The fever has been attributed to central necrosis174 or
bleeding within the tumor.175 A small percentage of patients have high fever and chills,
which may simulate liver abscess.174 Rarely, there is intermittent jaundice, associated with
colicky pain and fever, mimicking a common duct stone.175 Persistent HB antigenemia and
a positive alpha-fetoprotein test are significant. Hepatic scanning may demonstrate one or
more areas of decreased uptake when 99mTc-sulfur colloid is employed and increased activity
when 67Ga citrate is administered.176 Ultrasonography may be useful in detecting echogenic
masses. Computerized tomography alone is not usually diagnostic.177 Magnetic resonance
imaging shows promise. However, the most definitive method of diagnosis is through needle
biopsy of the liver, either blindly or under direct laparoscopic vision.
Cholangiocarcinoma — This tumor is usually extrahepatic in origin. It is more prevalent
in the Far East, especially Thailand,178 where it is characterized by its predominate hilar
location. Predisposing factors include fluke infestation, nitrosamine toxicity, hepatolithiasis
(in cases of peripheral liver location)179 and occasionally ulcerative colitis. The presentation
may be that of abdominal pain, fever, jaundice, and weight loss.
Sarcoma — Malignant mesenchymal tumors of the liver are very rare. They include
fibro-, angio-, leiomyo-, and undifferentiated or embryonal sarcoma. The presentation is
generally with abdominal swelling and pain. A few cases of embryonal sarcoma present
with fever or a picture simulating hepatic abscess.180181
142 U nex p la in ed F e ve r

Metastatic Tumors of the Liver

After lymph nodes, the liver is the commonest site of secondary tumors. Metastatic liver
disease is frequently asymptomatic, yet on occasions may produce a febrile presentation.
The fever is usually low grade and may be accompanied by night sweats.182 Other features
include right upper quadrant pain, jaundice, ascites, hepatomegaly (often nodular), friction
rub, portal hypertension with splenomegaly, and nonspecific symptoms such as anorexia,
weakness, and weight loss.182 Unexplained fever due to liver metastases most frequently
arises in cases of cancer of the pancreas and gastrointestinal tract,182 breast,183 mela-
noma,6182184 or unknown primary.182 The mechanism of the fever may be tumor necrosis
with phagocytic ingestion of debris or release of tumor pyrogen. It is important to exclude
an infectious origin of fever,183 such as septicemia or intra-abdominal abscess.185

CYSTIC CONDITIONS OF THE LIVER

Congenital Cysts
Congenital cysts of the liver may be parenchymal or ductal in origin. Parenchymal cysts
may be either solitary or multiple (polycystic) and are usually asymptomatic, although they
occasionally can become secondarily infected and may present with recurrent or low-grade
fevers.186 Ductal cysts are rare. Caroli’s disease consists of multiple cystic dilatations of
intrahepatic ducts, and may be associated with calculi, and various febrile conditions such
as cholangitis, cholecystitis, liver abscess,187 and cholangiocarcinoma.188 A recent report
describes two brothers with Caroli’s disease, who presented with FUO, one with a fatal
outcome.189

Peliosis Hepatitis
This is a rare condition characterized by the presence of multiple small, blood-filled
spaces in the liver.190 The etiology is unknown, although the condition may be associated
with androgenic steroid administration,191192 neoplasia,190 193 and other liver disease.194 It is
often asymptomatic, being discovered incidentally at autopsy. However, some patients pres-
ent with one or more episodes of jaundice and fever.194 Hepatomegaly may be found on
physical examination. The diagnosis may be made by identifying reddish-purple spots or
markings beneath a transparent liver capsule at laparoscopy, permitting liver biopsy to be
performed. Histologic examination demonstrates focal accumulations of dilated sinusoids
filled with erythrocytes.194

FEVER IN DISEASES OF THE EXTRAHEPATIC BILIARY TRACT

INTRODUCTION
Diseases of the gallbladder and extrahepaptic biliary ducts may present with prolonged
and obscure fever. The most common cause of unexplained fever is infection, usually
associated with stones in the biliary tract, but this is by no means universal. On occasions,
tumors or collagen-vascular diseases involving the biliary tract may evolve with a febrile
course.
The differentiation of extrahepatic biliary obstruction from primary hepatocellular disease
is often quite difficult. Classically, the serum glutamic oxaloacetic transaminase (SGOT) is
more markedly elevated in the latter, and usually only moderately raised in the former.
However, marked elevations of SGOT have been observed in extrahepatic biliary disease.195
In a recent review, patients presenting with upper abdominal pain, often with fever, nausea,
and vomiting, raised serum alkaline phosphatase, and markedly elevated SGOT were found
to have choledocholithiasis or cholelithiasis.196 Many patients with choledocholithiasis had
previously undergone cholecystectomy, giving rise to the theory that the gallbladder may
act as a safety valve to decrease intraductular pressure. A rapid rise and fall of the SGOT
may well represent extrahepatic biliary obstruction rather than intrahepatic disease.
 143

INFECTION
Cholecystitis
Acute cholecystitis — The classical clinical features of this condition are familiar to
both physicians and surgeons, and generally little difficulty is encountered in making a
diagnosis. Unexplained fever is an uncommon mode of presentation6 and more likely to
occur in the elderly. The most useful ancillary investigations are ultrasonography and radio-
nuclide imaging. Ultrasonography197 may demonstrate stones, focal tenderness over the
gallbladder, the sonographic Murphy’s sign, and a distended or enlarged gallbladder. Radio-
nuclide imaging using iminodiacetic substituted derivatives, is a simple, safe technique,
which may detect cystic duct obstruction in acute cholecystitis.197,198 The differential di-
agnosis of acute cholecystitis is extensive and includes liver abscess, hepatitis, congestive
hepatomegaly, appendicitis, pancreatitis, pneumonia, thoracic empyema, and myocardial
infarction as well as peptic ulcer.
Acalculous cholecystitis — This accounts for less than 5% of cases of inflammation
of the gallbladder. Infection primarily by Gram-negative organisms appears to be a major
factor. The condition may develop following surgery and trauma. Unexplained postoperative
fever is often the principal manifestation,199 and diagnosis often rests upon the clinical finding
of tenderness in the right upper quadrant. Imaging procedures will occasionally demonstrate
an enlarged, tense gallbladder, and blood cultures and febrile agglutinin titers may be useful.
However, the absence of abnormal findings should not deter the clinician from making the
diagnosis, since this condition carries a higher morbidity and mortality than the calculous
variety. Recently acalculous cholecystitis has been described with increasing frequency as
a complication of AIDS. 133,134 In these patients it is usually associated with infection with
CMV, Cryptosporidium, or Campylobacter fetus.
Empyema of the gallbladder — This refers to an intraluminal abscess of this organ.
The condition is usually characterized by severe upper right abdominal pain, fever, a tender
mass, and prostration. Empyema may appear to be a direct continuation of an attack of acute
cholecystitis, or it may develop insidiously, e.g., following infection of a mucocele. Very
occasionally, empyema can present as unexplained fever.6
Other febrile complications of acute cholecystitis — Certain complications of acute
cholecystitis, such as pericholecystic or hepatic abscess, perforation with biliary peritonitis,
cholangitis, and septicemia, may produce fever. An abscess secondary to cholecystitis may
rarely present as unexplained fever.80,200
Chronic cholecystitis — This is frequently asymptomatic or characterized by flatulent
dyspepsia. However, infrequently, chronic cholecystitis with cholelithiasis may present as
unexplained fever.201 203 In a report from Scotland, a 64-year-old male presented with FUO
accompanied by chest and abdominal pain, dyspnea, confusion, and sweating. Serum alkaline
phosphatase was markedly elevated and isoenzymes revealed a hepatic source. Ultrasonog-
raphy and isotopic indium scan were both negative. The final diagnosis was chronic cho-
lecystitis, associated with gallstones and polycythemia vera.204

Cholangitis
Clinical manifestations — Cholangitis secondary to common duct stones is typified by
Charcot’s triad, namely, biliary colic, jaundice, and fever (with chills). These may be
accompanied by hypotension and confusion, making a pentad, which Reynolds and Dargan
felt was characteristic of suppurative cholangitis and had a poor prognosis. However, the
term has limited value today, as pus may be found in the biliary tree at the time of surgery
in patients who do not have a toxic presentation. Vomiting occurs in about half the cases.
Charcot’s triad is not universally present. Colicky pain is occasionally absent and the patient
may present with prolonged unexplained fever.6,205,206 Another clinical variant is that of
fever, chills, and pruritus without jaundice or pain.
144 U n ex p la in ed F e ve r

Investigations — Dilated bile ducts may be demonstrated noninvasively by ultraso-

nography, isotopic scanning, or computerized tomography. Cholangiography may be per-
formed intravenously (provided that the serum bilirubin does not exceed 3 mg/dl),
transhepatically or by the increasingly popular technique of endoscopic retrograde cholan-
giopancreatography (ERCP). A surgical consultation is mandatory to determine the urgency
of common bile duct exploration.

Cholangitis not related to choledocholithiasis — Several diseases other than bile duct
stones may cause cholangitis and present with fever with or without pain or jaundice.
Extrahepatic biliary obstruction may be due to carcinoma207 or helminthiasis, and may present
with unexplained fever. Bacterial cholangitis is a common complication of hepatic portoen-
terostomy.208 Acute cholangitis may complicate Caroli’s disease and present as FUO.188

SCLEROSING CHOLANGITIS
Sclerosing cholangitis is characterized by obliterative inflammatory fibrosis of the intra-
and extrahepatic bile ducts.209 The condition may be primary or secondary. The latter is
usually related to calculi or biliary tract infection. Infection by CMV or C ryp to sp o rid iu m
has been implicated as a cause in patients with AIDS.134 Primary sclerosing cholangitis
(PSC) is most commonly associated with ulcerative colitis, but occasionally with other
diseases which frequently have some immunologic disorder or fibrotic component: retro-
peritoneal and mediastinal fibrosis, Peyronie’s disease, Riedel’s thyroiditis, thyrotoxicosis,
Weber-Christian disease, and a familial immune deficiency syndrome.210 PSC occurs prin-
cipally in males in the fourth decade. The clinical features include jaundice, right upper
abdominal discomfort, pruritus, weight loss, malaise and occasionally, fever and hepato-
megaly. The serum alkaline phosphatase is markedly elevated. The diagnosis is established
by transhepatic percutaneous cholangiography or preferably, ERCP, which demonstrate
irregular narrowing and dilatation of the intra- and extrahepatic bile ducts.

HELMINTHIC DISEASES OF THE HEPATOBILIARY SYSTEM

In the occasional patient helminthiasis of the hepatobiliary tree may produce unexplained
fever. Many of these conditions are endemic, but they may appear in other regions due to
migration and tourist travel. Hence as in all cases of unexplained fever, a good history is
essential for achieving the correct diagnosis.
Ascariasis — The tendency of adult ascarids to enter small openings permits their
invasion of biliary and pancreatic ducts. Uncomplicated ascariasis is not usually accompanied
by fever and jaundice. However, several complications may have a febrile evolution, in-
cluding suppurative cholangitis,211 liver abscess,212,213 biliary peritonitis, granulomatous hep-
atitis, and acute pancreatitis. The diagnosis of ascariasis can be made simply by performing
a fecal smear, which reveals characteristic eggs.
Clonorchiasis — This is caused by the Oriental liver fluke, C lo n o rch is sin e n sis , is
endemic in the Far East and may present with a febrile course. The most common compli-
cation is recurrent pyogenic cholangitis or Oriental cholangiohepatitis, which is characterized
by repeated bouts of abdominal pain and fever, associated with jaundice, hepatomegaly,
and frequently, eosinophilia. Intravenous cholangiography may demonstrate dilated intra-
hepatic bile ducts with partial filling defects which represent flukes. Tiny opercular ova
observed in the feces will confirm the diagnosis. The complications, pancreatitis and cho-
langiocarcinoma, may sometimes evolve with a febrile course.
Fascioliasis — Infection by the liver fluke, F a scio la h e p a tic a , may occur in sheep- or
cattle-raising areas. Humans acquire the infection by ingesting contaminated wild water-
cress.214,215 The clinical picture comprises upper abdominal pain, fever, diarrhea, pruritus,
jaundice, and eosinophilia. The condition may mimic choledocholithiasis. The diagnosis
 145

can be established by a complement fixation test and the detection of ova in the feces. Liver
biopsy may reveal granulomas,214 which occasionally contain an ovum of F. hepatica.216
Toxocariasis217 218— The ingestion of larvae of Toxocara canis leads to their penetration
of the intestinal wall and entrance into the bloodstream where they reach the liver, lung and
other tissues. The infection is often asymptomatic, but may be expressed clinically in the
form of visceral larva migrans, which is characterized by fever, tender hepatomegaly,
splenomegaly, pneumonitis and a skin rash. Eosinophilia and hypergammaglobulinemia are
frequently observed. Liver biopsy may reveal eosinophilic granuloma and larvae of Toxocara.
Echinococciasis219 — This condition is common in sheep-raising regions, in which dogs
can also be found. Larval forms of the tapeworm Echinococcus granulosa produce hydatid
cystic lesions in the liver, lungs, and other tissues in man. A large number of patients are
asymptomatic, and fever occurs only in the presence of complications, such as rupture,
obstruction, secondary infection, and hydatid allergy. Rupture into the biliary tract may
produce a clinical picture resembling acute cholecystitis.220 Cholangitis with jaundice and
fever may result from obstruction of the biliary tract by a hydatid cyst. A pyogenic abscess
can be caused by bacterial invasion of intrahepatic cysts. Rupture of a hydatid cyst can also
cause urticaria, anaphylaxis, and fever. The diagnosis of echinococciasis is suggested by
the finding of calcified hepatic cyst on plain abdominal radiography or ultrasonography,
which may also demonstrate daughter cysts. The most sensitive laboratory test is indirect
hemagglutination; the Casoni skin test is far less reliable. Sometimes scolices may be
identified in the stool, urine, or sputum.

VASCULITIS INVOLVING THE GALLBLADDER

Occasionally, polyarteritis nodosa may involve the gallbladder and produce a clinical
picture of right upper abdominal pain with recurrent fever, simulating acute cholecyst-
itis.221,222 In one case the presentation was of unexplained fever of 7 weeks duration.221
There was a suspicion of a right upper abdominal mass. The serum alkaline phosphatase
was elevated, and on oral cholecystography the gallbladder was not visualized. At laparot-
omy, signs of cholecystitis were observed. Histologic examination revealed fibrinoid necrosis
of the arteries of the gallbladder; similar changes were found in biopsy specimens of the
liver and the gastrocnemius muscle.
Similar features have been described in a patient who suffered from rheumatoid ar-
thritis.223 The patient complained of right upper quadrant pain radiating through to the back,
accompanied by fever and nausea. The gallbladder was not visualized on oral cholecysto-
graphy. Cholecystectomy was performed and panarteritis was demonstrated histologically.

TUMORS OF THE BILIARY TRACT

Primary carcinoma of the gallbladder is the most common biliary tract tumor. The
diagnosis is rarely achieved preoperatively.224 and the clinical features may suggest chole-
lithiasis or tumor of the liver or pancreas. The major manifestations are abdominal pain
(right upper quadrant or epigastric), nausea and vomiting, weight loss, hepatomegaly, and
jaundice. A small percentage of cases complain of fever, and occasionally FUO is the form
of presentation.200 201 225
Carcinoma of the bile ducts is usually manifested by secondary effects; bile duct ob-
struction may cause cholangitis with fever and jaundice, cystic duct obstruction may produce
a mucocele or cholecystitis; pancreatic duct obstruction may precipitate pancreatitis. Fever
is only an occasional symptom, but at times, it may be the dominant feature.6
The rare rhabdomyosarcoma of the biliary tree may manifest itself as intermittent (ob-
structive) jaundice, abdominal pain, fever, and anorexia. The mistaken impression that the
clinician is dealing with “ hepatitis” delays correct diagnosis and treatment. Ultrasonography
aids in diagnosis, which is confirmed at explorative laparotomy.
146 U nex p la in ed F e ve r

TABLE 5
Febrile Complications of Acute Pancreatitis

Local Systemic

Pancreatic phlegmon Thoracic

Pseudocyst Pneumonia
Abscess Pleural effusion
Peritonitis Mediastinal abscess
Cholangitis Metastatic fat necrosis
Sepsis

FEVER RELATED TO GALLBLADDER ANOMALY

In an unusual case described in Israel,226 a 4-year-old girl complained of recurrent attacks
of abdominal pain, vomiting, fever, and jaundice, progressing to biliary cirrhosis. At op-
eration, a duplication of the gallbladder was found. Apparently, intertwining of the two
cystic ducts had caused intermittent cystic duct obstruction and bile stasis. Both gallbladders
were resected and histologic examination revealed cholesterosis and chronic cholecystitis.
All symptomatology abated following surgery.

FEBRILE PANCREATIC DISORDERS

Unexplained fever is not a frequent problem in diseases of the pancreas. When fever
persists in a patient with suspected pancreatitis the condition may be one of protracted
pancreatitis, a complication, such as pseudocyst or pancreatic abscess, or the primary di-
agnosis may be incorrect.227
Acute pancreatitis is characterized by abdominal pain, nausea, vomiting, low-grade
fever, and sometimes, jaundice. Occasionally, pain and vomiting are absent, so-called silent
pancreatitis.228 and the patient first presents with a febrile complication, such as a pancreatic
abscess or pleural effusion. Prolonged fever following abdominal surgery may be the pre-
senting manifestation of postoperative pancreatitis. Physical examination usually reveals
abdominal tenderness, muscle rigidity, tachycardia, and in some cases, hypotension. The
diagnosis is supported by the presence of increased levels of amylase in the serum and urine
and elevated serum lipase. The amylase creatinine clearance ratio (ACCR) has not been
shown to be more accurate than conventional serum amylase testing, although the identi-
fication of the P isoenzyme in the serum is very sensitive for pancreatitis. Other laboratory
findings which may be present are leukocytosis, hyperglycemia, hypocalcemia, and hyper-
bilirubinemia. A plain X-ray of the abdomen may reveal air in the duodenum, sentinel loops
of dilated air-filled proximal jejunum, or intrapancreatic calcification. Diffuse enlargement
of the pancreas may be demonstrated by computerized tomography and ultrasonography;229
the latter frequently reveals stones and a dilated common bile duct.
The differential diagnosis is extensive since the “ typical” presentation may be simulated
by many intra-abdominal conditions, including acute cholecystitis, perforation of a hollow
viscus, mesenteric vascular occlusion, ruptured aortic aneurysm, and even nonsurgical dis-
orders such as familial Mediterranean fever (FMF). A further difficulty in diagnosis may
be encountered when pain occurs in an atypical site, such as the left thorax, or is absent
altogether. Elderly patients may complain of pressure discomfort rather than actual pain.
Although a prolonged fever of more than 20 days may occasionally occur in protracted
pancreatitis, the problem of unexplained fever is more likely to arise during one or other of
the complications of acute pancreatitis (see Table 5).
Pancreatic phlegmon refers to a solid mass of swollen, inflamed pancreas accompanied
by patchy areas of necrosis. The differentiation of this entity from protracted pancreatitis
and pancreatic abscess is frequently very difficult. Suggestive clinical features are prolonged
 147

fever, abdominal pain and mass and persistent leukocytosis.230 On ultrasonography and
computerized tomography the appearance is usually that of solid tissue.229
Pancreatic pseudocyst231 is a collection of necrotic tissue, blood, and pancreatic secre-
tions. Clinically, it is characterized by an epigastric mass or fullness, accompanied by
persistent abdominal pain, tenderness and low-grade fever. Ultrasonography demonstrates
an echo-free lesion with a well-defined posterior wall.229 Computerized tomography reveals
a smoothly marginated cystic lesion whose attenuation value approaches that of water.229
When a pseudocyst is complicated by hemorrhage, the ultrasonographic and CT appearance
may resemble that of a pancreatic abscess.
Pancreatic abscess is usually a complication of pancreatitis or pseudocyst;232 rare causes
include tuberculosis,233 and penetration of a peptic ulcer or duodenal diverticulum.234 The
symptoms and signs are frequently nonspecific, and diagnosis is often difficult. The presence
of moderate or spiking fever, accompanied by anorexia, weight loss, and abdominal (es-
pecially epigastric) tenderness, following pancreatitis (acute or chronic), abdominal trauma
or biliary tract surgery should raise the clinician’s suspicion of this potentially life-threatening
condition. CT scan may reveal gas within the pancreatic bed. Ultrasonography may disclose
fluid-filled cavities with numerous internal echoes in the lesser sac. In all cases of suspected
pancreatic abscess, radiologically guided percutaneous drainage is mandatory.235
Chronic pancreatitis does not usually have a febrile evolution. However, one subtype,
primary inflammatory pancreatitis,236 occurring in elderly patients, especially females, may
present with weight loss, steatorrhea, undulant fever, and only mild abdominal pain. Lab-
oratory tests may reveal elevated serum gamma globulin.
The clinical feature of pancreatic carcinoma are pain, weight loss, and jaundice. Fever,
fatigue, and weakness are present in about 25% of cases, although fever is a presenting
symptom in a much smaller percentage. Occasionally the disease presents with acute ab-
dominal pain, nausea, vomiting, and fever, simulating acute pancreatitis or cholecystitis.
About 1 to 2% of cases of FUO in several large series have been caused by pancreatic
cancer.6 80 Unexplained fever together with leukocytosis and elevated ESR usually indicates
metastases to the liver. Chills with fever may result from secondary infection in obstructed
biliary ducts, necrosis within the tumor or pancreatic abscess formation.
The diagnosis of pancreatic carcinoma is often very difficult, particularly in those cases
when the tumor involves the body or the tail rather than the head. Further, there may be no
laboratory abnormalities. Conventional radiography may be negative. Extrinsic compression
of the stomach or duodenum on barium meal examination is highly suggestive, but this sign
may be lacking. A most useful screening procedure is ultrasonography, which may detect
lesions of the pancreas as well as a dilated gallbladder. CT scanning may define lesions in
the body and tail in addition to the head. Selenomethionine-75 scanning is occasionally
helpful. More invasive techniques include selective angiography, ERCP, and percutaneous
aspiration biopsy of the pancreas under radiological guidance.237 Yet all of these procedures
may fail to detect small tumor masses.
Metastatic fat necrosis occurs in pancreatic disease as a result of hydrolysis of neutral
fat by lipase. The condition is characterized by fever, circumscribed tender red nodules,
polyarthritis, and occasionally pleural, pericardial, mediastinal, or peritoneal fat necrosis,238
and may be the presentation of pancreatitis or pancreatic carcinoma.

REFERENCES
1. Zimmerman, H. J., Fang, M., Utili, R., Seeffe, L. B., and Hoofnagle, J., Jaundice due to bacterial
infection, Gastroenterology, 77, 362, 1979.
2. Paton, A., Sepsis and cholestasis, Br. Med. J. 289, 857, 1984.
148 Unexplained Fever

3. Vyber, M. and Poulsen, H., Abnormal bile duct epithelium accompanying septicaemia, Virchows Arch.
A., 402, 451, 1984.
4. Finster, L. F., Reactive hepatopathy: liver signs without primary liver disease, Postgrad. Med., 76(7),
62, 1984.
5. Mohammed, S. D., Reversible non-metastatic liver-cell dysfunction and thrombocytosis from a hyper-
nephroma, Lancet, 2, 621, 1965.
6. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report on 100 cases, Medicine, 40,
1, 1961.
7. Brugera, M., Torres-Salinas, M., Bordas, J. M., Bru, C., and Rodes, J., La biopsia hepatica en el
estudio de una fiebre de origen desconocido, Med. Clin. (Barcelona), 77, 115, 1981.
8. Jimenez, M. L., Hernandez, F. J. B., Rodriguez, J. J. V., Sanchez de Ribera, J. M. P., Aguado,
A. G., Arnalich, F., Suarez, J., Larrauri, J., and Vazquez, J. O., Valor diagnostico de la biopsia
hepatica en la fiebre de origen desconocido, Gastroenterol. Hepatol., 6, 405, 1983.
9. Mitchell, D. P., Hanes, T. E., Hoyumpa, A. M., Jr., and Schenker, S., Fever of unknown origin:
assessment of the value of percutaneous liver biopsy, Arch. Intern. Med., 137, 1001, 1977.
10. Hidalgo, J. A. M., Alvarez, C. A., Rippe, M. L. F., and Garcia, E. S., Valor diagnostico de la biopsia
hepatica dirigida por laparoscopia en la fiebre de origen desconocido, Med. Clin. (Barcelona), 77, 386,
1981.
11. Lebrec, D., Degott, C., Rueff, B., and Benhamou, J. P., Transvenous (transjugular) liver biopsy: an
experience based on 100 biopsies, Am. J. Dig. Dis., 23, 302, 1978.
12. Thaler, H., Uber vorteil und Risiko der Leberbiopsiemethode nach Menghini, Wien Klin. Wochenschr.,
29, 533, 1964.
13. Lindner, H., Grenzen und Gefahren der perkutanen Leberbiopsie mit der Menghini, Nadel: Erfahrungen
bei 80,000 Leberbiopsien, Dtsch. Med. Wochenschr., 92, 1751, 1967.
14. Wildhirt, E. and Möller, E., Erfahrungen bei natezu 20,000 Leberblindpunktionen, Med. Klin., 76, 254,
1982.
15. Rizzetto, M., The delta agent, Hepatology, 3, 729, 1983.
16. Conrad, M. E., Schwartz, F. D., and Young, A. A., Infectious hepatitis: a generalized disease, Am. J.
Med., 37, 789, 1964.
17. Goodson, J. D., Taylor, P. A., Campion, E. W., Richter, J. M., and Wands, J., The clinical course
of acute hepatitis in the elderly patient, Arch. Intern. Med., 142, 1485, 1982.
18. Lemon, S. M., Type A viral hepatitis: new developments in an old disease, N. Engl. J. Med., 313, 1059,
1985.
19. Alarcon, G. S. and Townes, A. S., Arthritis in viral hepatitis: report of 2 cases and review of the literature,
Johns Hopkins Med. J., 132, 1, 1973.
20. Trepo, C. G., Zucherman, A. J., and Bird, R. C., The role of circulating hepatitis B antigen/antibody
immune complexes in the pathogenesis of vascular and hepatic manifestations in polyarteritis nodosa, J.
Clin. Pathol., 27, 863, 1974.
21. Sergeant, J. S., Lockshin, M. D., Christian, C. L., and Gorke, D. J., Vaculitis with hepatitis B
antigenemia: longterm observations in nine patients, Medicine, 55, 1, 1976.
22. Levo, Y., Gorevic, P. D., Kassab, H. J., Zucker-Franklin, D., and Franklin, E. C., Association
between hepatitis B and essential mixed cryoglobulinemia, N. Engl. J. Med., 296, 1501, 1977.
23. Corey, L. and Holmes, K. K., Sexual transmission of hepatitis A in homosexual men: incidence and
mechanism, N. Engl. J. Med., 302, 435, 1980.
24. Rosina, F., Saracco, G., and Rizzetto, M., Risk of posttransfusion infection with the hepatitis delta virus,
V. Engl. J. Med., 312, 1488, 1985.
25. Hollinger, F. B., Mosler, J. W., Szmuness, W., Aach, R. D., Peters, R. L., and Stevens, C.,
Transfusion-transmitted viruses study: experimental evidence for two non-A, non-B hepatitis agents, J.
Infect. Dis., 142, 400, 1980.
26. Villarejos, V. M., Provost, P. J., and Ittensohn, O. L., Seroepidemiologic investigation of human
hepatitis caused by A, B, and a possible third virus, Proc. Soc. Exp. Biol. Med., 152, 524, 1976.
27. Khuroo, M. S., Study of an epidemic of non A, non B hepatitis: possibility of another human hepatitis
virus distinct from posttransfusion non-A, non-B type, Am. J. Med., 68, 818, 1980.
28. Khuroo, M. S., Teli, M. R., Skidmore, S., Sofi, M. A., and Khuroo, M. L, Incidence and severity
of viral hepatitis in pregnancy, Am. J. Med., 70, 252, 1981.
29. Eschar, J., Reif, L., Waron, M., and Alkan, W. J., Hepatic lesion in chickenpox: a case report,
Gastroenterology, 64, 462, 1973.
30. Landay, S., Varicella hepatitis and Reye’s syndrome: an interrelationship?, Pediatrics, 60, 746, 1977.
31. Fleischer, G., Henry, W., and McSorley, M., Life-threatening complications of varicella, Am. J. Dis.
Child., 135, 896, 1981.
32. Stern, H., Cytomegalovirus and EB virus infections of the liver, Br. Med. Bull., 28, 180, 1972.
 149

33. Reller, L. B., Granulomatous hepatitis associated with acute cytomegalovirus infection, Lancet, 1, 20,
1973.
34. Lamb, S. G. and Stern, H., Cytomegalovirus mononucleosis with jaundice as presenting sign, Lancet,
2, 1003, 1966.
35. Toghill, P. J., Bailey, M. E., Williams, R., Zeegan, R., and Brown, R., Cytomegalovirus hepatitis in
the adult, Lancet, 1, 1351, 1967.
36. Armstrong, D., Balakrishnan, S. L., Steger, L., Yu, B., and Stenzel, K. H., Cytomegalovirus infections
with viremia following renal transplantation, Arch. Intern. Med., 127, 111, 1971.
37. Paloheimo, J. A., von Essen, R., Klemola, E., Kaariniainen, L., and Siltanen, P., Subclinical cyto-
megalovirus mononucleosis after open heart surgery, Am. J. Cardiol., 22, 624, 1968.
38. Anuras, S. and Summers, R., Fulminant herpes simplex in an adult: report of a case in renal transplant
recipient, Gastroenterology, 70, 425, 1976.
39. Holdsworth, S. R., Atkins, R. C., Scott, D. F., and Hayes, K., Systemic herpes simplex infections
with fulminant hepatitis post transplantation, Aust. N. Z. J. Med., 6, 588, 1976.
40. Young, E. J., Killam, A. P., and Greene, J. F., Jr., Disseminated herpesvirus infection association with
primary genital herpes in pregnancy, JAMA, 235, 2731, 1976.
41. Manoux, A., Ferchal, F., Bars, L., Beaugrand, M., Loirat, P., Chapman, A., Barbagelatta, Callard,
P., and Perol, Y., Hepatite herpetite mortelle chez un adulte apparemment sain, Gastroenterol. Clin. Biol.,
7, 340, 1983.
42. Rubin, M. H., Ward, D. M., and Painter, J., Fulminant hepatic failure caused by genital herpes in a
healthy person, JAMA, 253, 1299, 1985.
43. Goodman, Z. D., Ishak, K. G., and Sesterhenn, I. A., Herpes simplex hepatitis in apparently immu-
nocompetent adults, Am. J. Clin. Pathol., 85, 694, 1986.
44. Siegel, D. and Hirschman, S. Z., Hepatic dysfunction in acute measles infection of adults, Arch. Intern.
Med., 137, 1178, 1977.
45. McLellan, R. K. and Gleiner, J. A., Acute hepatitis in an adult with rubeola, JAMA, 247, 2000, 1982.
46. Zeldis, J. B., Miller, J. G., and Dienstag, J. L., Hepatitis in an adult with rubella, Am. J. Med., 79,
515, 1985.
47. Morris, J. A., Elisberg, B. L., Pond, W. L., and Webb, P. A., Hepatitis associated with Coxsackie
virus group A, type 4, N. Engl. J. Med., 267, 1230, 1962.
48. O’Shaughnessey W. J. and Buechner, H. A., Hepatitis associated with a Coxsackie virus B5 virus in
late pregnancy, JAMA, 179, 71, 1962.
49. Sun, N. S. and Smith, V. M., Hepatitis associated with myocarditis: unusual manifestation of infection
with Coxsackie virus group B, type 3, N. Engl. J. Med., 274, 190, 1965.
50. Gregor, G. R., Geller, S. A., Walker, G. F., and Campomanes, B. A., Coxsackie hepatitis in an adult,
with ultrastructural demonstration of the virus, Mt. Sinai J. Med., 42, 575, 1975.
51. Gitlin, N., Viveshwara, N., Kassel, S. H., Byock, I. R., Kishnakumar, B. R., and Weinberg, H. M.,
Fulminant neonatal hepatic necrosis associated with echovirus type 11 infection, West. J. Med., 138, 260,
1983.
52. Joske, R. A., Keall, D. D., Leak, P. J., Stanley, N. F., and Walters, M. N., I. Hepatitis-encephalitis
in humans with reovirus infection, Arch. Intern. Med., 113, 811, 1964.
53. Hartwell, W. V., Love, G. J., and Eisenbock, M.P., Adenovirus in blood clots from cases of infectious
hepatitis, Science, 152, 1390, 1966.
54. Ellis, D. S., Simpson, D. I. H., Francis, D. P., Knobloch, J., Bowen, E. T. W., and Deng, I. M.,
The ultrastructure of Ebola virus particles in human liver, J. Clin. Pathol., 31, 201, 1978.
55. Alvarez, M. E. and Ramirez-Ronda, C. H., Dengue and hepatic failure, Am. J. Med., 79, 670, 1985.
56. Loge, R. V., Acute hepatitis associated with Colorado tick fever, West. J. Med., 142, 91, 1985.
57. Hofmann, C. E. and Heaton, J. W., Jr., Q fever hepatitis: clinical manifestations and pathological
findings, Gastroenterology, 83, 471, 1982.
58. Pellegrin, M., Delsol, G., Auvergnat, J. C., Familiades, J., Faure, H., Guiu, M., and Voigt, J. J.,
Granulomatous hepatitis in Q fever, Hum. Pathol., 11, 51, 1980.
59. Okun, D. B., Sun, N. C. J., and Tanaka, K. R., Bone marrow granulomas in Q fever, Am. J. Clin.
Pathol., 71, 117, 1979.
60. Ramphal, R., Kluge, R., Cohen, V., and Feldman, R., Rocky Mountain spotted fever and jaundice:
two consecutive cases acquired in Florida and a review of the literature of this complication, Arch. Intern.
Med., 138, 260, 1978.
61. Green, W. R., Walker, D. H., and Cain, B. G., Fatal viscerotropic Rocky Mountain spotted fever:
report of a case diagnosed by immunofluorescence, Am. J. Med., 64, 523, 1978.
62. Adams, J. S. and Walker, D. H., The liver in Rocky Mountain spotted fever, Am. J. Clin. Pathol., 75,
151, 1981.
63. Westerman, E. L., Rocky Mountain spotless fever — a dilemma for the clinician, Arch. Intern. Med.,
142, 1106, 1982.
150 Unexplained Fever

64. Guardia, J., Vilaseca, J., Moragas, A., Martinez-Vasquez, J. M., Bombi, J. A., Calders, J., and
Bacardi, R., Hepatitis in exanthematous Mediterranean fever, Heapto-Gastroenterology, 28, 81, 1981.
65. Fang, M. H., Ginsberg, A. L., and Dobbins, W. O., Ill, Marked elevation in serum alkaline phosphatase
activity as a manifestation of systemic infection, Gastroenterology, 78, 592, 1980.
66. Rubin, R. H., Swartz, M. N., and Malt, R., Hepatic abscesses: changes in clinical, bactériologie and
therapeutic aspects, Am. J. Med., 57, 601, 1974.
67. Kaplan, S. L. and Feigin, R. D., Pyogenic liver abscess in normal children with fever of unknown origin,
Pediatrics, 58, 614, 1976.
68. McDonald, M. I., Corey, G. R., Gallis, H. A., and Durack, D. T., Single and multiple pyogenic
abscesses: natural history, diagnosis and treatment, with emphasis on percutaneous drainage, Medicine, 63,
291, 1984.
69. Du Toit, D. F., Van Schalkwyk, P., and Laker, L., Hepatic abscess in a patient with polycystic liver
disease: a case report, S. Afr. Med. J., 67, 559, 1985.
70. Mantse, L., West J., Cosman, H. H., and Mullens, J. E., Liver abscess due to Yersinia enterocolitica,
Can. Med. Assoc. J., 119, 922, 1978.
71. Viteri, A. L., Howard, P. H., May, J. L., Ramesh, G. S., and Roberts, J. W., Hepatic abscess due
to Yersinia enterocolitica without bacteremia, Gastroenterology, 81, 592, 1981.
72. Alberti-Flor, J. J., Jeffers, L. J., Iskandarani, and Schiff, E. R., Successful medical management of
a Yersinia enterocolitica liver abscess, Digestion, 29, 250, 1984.
73. Perera, M. R., Kirk, A., and Noone, P., Presentation, diagnosis and management of liver abscess, Lancet,
2, 629, 1980.
74. Sabbaj, J., Anaerobes in liver abscess, Rev. Infect. Dis., 6(S1), S152, 1984.
75. Kanner, R., Weinfeld, A., and Tedesco, F. J., Hepatic abscess, plain film findings as an early aid to
diagnosis, Am. J. Gastroenterol., 71, 432, 1979.
76. Kuligowska, E., Connors, S. K., and Shapiro, J. H., Liver abscess: sonography in diagnosis and
treatment, Am. J. Radiol., 138, 253, 1982.
77. Gerzof, S. G., Johnson, W. C., Robbins, A. H., and Nabseth, D. C., Intrahepatic pyogenic abscesses:
treatment by percutaneous drainage, Am. J. Surg., 149, 487, 1985.
78. Boettiger, L. E., Nordenstam, H. H., and Westen, P. L., Disseminated tuberculosis as a cause of fever
of obscure origin, Lancet, 1, 19, 1962.
79. Hersch, C., Tuberculosis of the liver: a study of 200 cases, S. Afr. Med. J., 38, 857, 1964.
80. Jacoby, G. A. and Swartz, M. N., Fever of undetermined origin, N. Engl. J. Med., 289, 1407, 1973.
81. Alvarez, S. Z. and Carpio, R., Hepatobiliary tuberculosis, Dig. Dis. Sci., 28, 193, 1983.
82. Zipser, R. D., Rau, J. E., Ricketts, R. R., and Bevans, L. C., Tuberculous pseudotumors of the liver,
Am. J. Med., 61, 946, 1976.
83. Essop, A. R., Segal, I., Posen, J., and Noormohamed, N., Tuberculous abscess of the liver, S. Afr.
Med. J., 63, 825, 1983.
84. Murphy, T. F. and Gray, G. F., Biliary tract obstruction due to tuberculous adenitis, Am. J. Med., 68,
452, 1980.
85. Young, E. J., Human brucellosis, Rev. Infect. Dis., 5, 821, 1983.
86. Williams, R. K. and Crossley, K., Acute and chronic hepatic involvement of brucellosis, Gastroenterology,
83, 455, 1982.
87. Ramachandran, S., Godfrey, J. J., and Perera, M. V. F., Typhoid hepatitis, JAMA, 230, 236, 1974.
88. Singh, D. S., Rajendran Nair, P. N., Krishnasamy, S., Aurora, A. L., Chandrasekar, S., and Bisht,
D. B., Jaundice in typhoid fever, J. Trop. Med. Hyg., 81, 68, 1978.
89. Rao, P. N., Bhusnurmath, S. R., and Naik, S. R., Typhoid fever manifesting with haematemesis,
hepatitis and haemolysis, J. Trop. Med. Hyg., 81, 146, 1978.
90. Sherlock, S., Diseases of the Liver and Biliary System, 6th ed., Blackwell, Oxford, 1985.
91. Chandalapaty, S. K. G., Dusol, M., Jr., Edwards, R., Pereiras, R., Jr., Clark, R., and Schiff,
E. R., 67Gallium accumulation in hepatic actinomycosis, Gastroenterology, 69, 752, 1975.
92. Meade, R. H., Ill, Primary hepatic actinomycosis, Gastroenterology, 78, 355, 1980.
93. Weinstein, L., Bacterial hepatitis: a case report on an unrecognized cause of fever of unknown origin, N.
Engl. J. Med., 299, 1052, 1978.
94. Cunha, A. B., Systemic infections involving the liver, Postgrad Med., 84(5), 148, 1988.
95. Haburchak, D. R. and Davidson, H., Anorectal lesions and syphilitic hepatitis, West. J. Med., 128, 64,
1978.
96. Tiliakos, N., Shamma’a, J. M., and Nasrallah, S. M., Syphilitic hepatitis, Am. J. Gastroenterol., 73,
60, 1980.
97. Keisler, D. S., Starke, W., Looney, D. J., and Mark, W. \y ., Early syphilis with liver involvement,
JAMA, 247, 1999, 1982.
98. Longstreth, P., Hoke, A. W., and McElroy, C., Hepatitis and bone destruction as uncommon manifes-
tations of early syphilis: report of a case, Arch. Dermatol., 112, 1451, 1976.
 151

99. Morrison, E. B., Norman, D. A., Wingo, C. S., and Henrich, W. L., Simultaneous hepatic and renal
involvement in acute syphilis: case report and review of the literature, Dig. Dis. Sci., 25, 875, 1980.
100. Koff, R. S. and Gang, D. L., Case records of the Massachusetts General Hospital: case 27-1983, N. Engl.
J. Med., 309, 35, 1983.
101. Veeravahu, M., Diagnosis of liver involvement in early syphilis: a critical review, Arch. Intern. Med.,
145, 132, 1985.
102. Sherlock, S., The liver in secondary (early) syphilis, N. Engl. J. Med., 284, 1437, 1971.
103. Feher, J., Somogyi, T., Timmer, M., and Jozsa, L., Early syphilitic hepatitis, Lancet, 2, 896, 1975.
104. Lewis, J. H., Patel, H. R., and Zimmerman, H. J., The spectrum of hepatic candidiasis, Hepatology,
2, 479, 1982.
105. Finkelstein, R., Wichtig, C., and Hashmonai, M., Candida albicans liver abscesses, Infection, 5, 243,
1985.
106. Jones, J. M., Granulomatous hepatitis due to Candida albicans in patients with acute leukemia, Ann. Intern.
Med., 94, 475, 1981.
107. Wilkins, R. H., Bennett, J. E., Wertlake, P. T., and West, J. T., Mesenchymoma and visceral
cryptoccocosis: report of a case, Arch. Surg., 88, 761, 1964.
108. Sabesin, S. M., Fallon, H. J., and Bethesda, V. T. A., Hepatic failure as a manifestation of cryptoccocosis,
Arch. Intern. Med., I l l , 661, 1963.
109. Procknow, J. J., Benfield, J. R., Rippon, J. W., Diener C. F., and Archer, F. L., Cryptoccocal
hepatitis presenting as a surgical emergency, JAMA, 191, 93, 1965.
110. Das, B. C., Haynes, I., Weaver, R. M., and Acland, P. R., Primary hepatic cryptoccocosis, Br. Med.
J., 287, 464, 1983.
111. Howard, P. F. and Smith, J. W., Diagnosis of disseminated coccidioidomycosis by liver biopsy, Arch.
Intern. Med., 143, 1335, 1983.
112. Lanza, F. L., Nelson, R. S., and Somayaji, B. N., Acute granulomatous hepatitis due to histoplasmosis,
Gastroenterology, 58, 392, 1970.
113. McCarty, E., Pathmanand, C., Sunakon, P., and Scherz, R. G., Amebic liver abscess in childhood,
Am. J. Dis. Child., 126, 67, 1973.
114. Barbour, G. L. and Juniper, K., Jr., A clinical comparison of amebic and pyopgenic abscess of the
liver in sixty-six patients, Am. J. Med., 53, 323, 1972.
115. DeBakey, M. E. and Jordan, G. L., Hepatic abscesses, both intra- and extrahepatic, Surg. Clin. North
Am., 57, 325, 337, 1977.
116. Shabot, M. J. and Patterson, M., Amebic liver abscess 1966, 1976, Dig. Dis., 23, 110, 1978.
117. Tim, L. Ou., Segal, I., and Hodgkinson, H. J., Amoebic liver abscess in patients presenting with
jaundice, S. Afr. Med. J., 55, 179, 1978.
118. Laverdant, C., Denee, J. M., Roue, R., Molinie, C., Daly, J. P., Flechaire, A., Valmary, J., and
Farret, O., Hepatic amebiasis: study of 152 cases, Gastroenterol. Clin. Biol., 8, 838, 1984.
119. Eggleston, F. C., Handa, A. K., and Verghese, M., Amebic peritonitis secondary to amebic liver abscess,
Surgery, 91, 46, 1982.
120. Dellar, J. J., Jr., Cifarelli, P. S., Berque, S., and Buchanan, R., Malaria hepatitis, Milit. Med., 132,
614, 1967.
121. Ramachandran, S. and Perera, M. V. F., Jaundice and hepatomegaly in primary malaria, J. Trop. Med.
Hyg. 79, 207, 1976.
122. Faliseval, J., Early diagnosis and clinical picture of malaria, Bull. WHO, 50, 159, 1974.
123. Frenkel, J. K., Toxoplasmosis, Pediatr. Clin. North Am. 32, 917, 1985.
124. Vischer, T. L., Bernheim, C., and Engelbrecht, E., Two cases of hapatitis due to Toxoplasma gondii,
Lancet, 2, 919, 1967.
125. Vethanyagam, A. and Bryceson, A. D. M., Acquired toxoplasmosis presenting as hepatitis, Trans. R.
Soc. Trop. Med. Hyg., 70, 525, 1976.
126. Martinez-Vazquez, J. M., Guardia, J., and Pattiss, A., Hepatite granulomateuse dans la toxoplasmose
acquise de l’adulte, Semin Hop. Paris, 51, 963, 1975.
127. Weitberg, A. B., Alper, J. C., Diamond, I., and Fligiel, Z., Acute granulomatous hepatitis in the course
of acquired toxoplasmosis, N. Engl. J. Med., 300, 1093, 1977.
128. Soto, J. M. and Dreiling, D. A., Giardia lamblia: a case presentation of chronic cholecystitis and
duodenitis, A. J. Gastroenterol., 67, 2635, 1977.
129. Roberts-Thomson, I. C., Anders, R. F., and Bhathal, P. S., Granulomatous hepatitis and cholangitis
associated with giardiasis, Gastroenterology, 83, 480, 1982.
130. Litt I. F. and Cohen, M. I., Perihepatitis associated with salpingitis in adolescents, JAMA, 240, 1253,
1978.
131. Kimball, M. C. and Knee S., Gonococcal perihepatitis in a male: the Fitz-Hugh-Curtis syndrome, N.
Engl. J. Med., 282, 1082, 1970.
152 Unexplained Fever

132. Francis, T. I. and Osoba, A. O., Gonococcal hepatitis (Fitz-Hugh-Curtis syndrome) in a male patient,
Br. J. Vener. Dis., 48, 187, 1972.
133. Schneiderman, D. J., Hepatobiliary abnormalities of AIDS, Gastroenterol. Clin. North Am., 17, 615,
1988.
134. Sievert, W. and Merrell, R. C., Gastrointestinal emergencies in the Acquired Immune Deficiency Syn-
drome, Gastroenterol. Clin. North Am., 17, 409, 1988.
135. Fallon, H. A., Alcoholic hepatitis, in Diseases of the Liver, 5th ed., Schiff, L. and Schiff, E. R., Eds.
Lippincott, Philadelphia 1982, 693
136. Maddrey, W. C., Alcoholic hepatitis, in Liver (Gastroenterology 4), Williams, R. and Maddrey, W. C.,
Eds., Butterworths, London, 1984, 226.
137. Gleckman, R., Crowley, M., and Esposito, A., Fever of unknown origin: a view from the community
hospital, Am. J. Med. Sci., 274, 21, 1977.
138. Smith, J. W., Southwestern Internal Medicine conference: fever of undetermined origin: not what it used
to be, Am. J. Med. Sci. 292, 56, 1986.
139. Reynolds, T. B., Chronic hepatitis: current dilemmas, Am. J. Med., 69, 485, 1980.
140. Conn, H. O., Cirrhosis, in Diseases of the Liver, 5th ed., Schiff, L. and Schiff, E. R., Eds., Lippincott,
Philadelphia, 1982, 847.
141. Nayak, N. C. and Ramalingaswami, Indian childhood cirrhosis, Clin. Gastroenterol., 5, 333, 1975.
142. Winter, R. J. D., Primary biliary cirrhosis presenting as pyrexia of unknown origin, J. R. Soc. Med., 76,
705, 1983.
143. Tisdale, W. A. and Klatskin, G., The fever of Laennec’s cirrhosis, Yale J. Biol. Med., 33, 94, 1960.
144. Rault, P., Les fievre prolongées de diagnostique difficile, These Bischat Beaujon, Paris, 1973.
145. Garcia, J. H., Han, S. V., Helman, C., and Wilkerson, J. A., Medical pathology conference: a 37-
year-old woman with liver dysfunction, abdominal pain, and fever, Ala. J. Med. Sci., 22, 411, 1985.
146. Nicholas, P., Rinaudo, P. A., and Conn, H. O., Increased incidence of cholelithiasis in Laennec’s
cirrhosis, Gastroenterology, 63, 112, 1972.
147. Garcia, M. A., Barque, P. B., Sanmartin, L. F., Lamoglia, R. S., Munujos, A.V., Aran, A. P., and
Suau, R. A., Fever in the patient with liver cirrhosis: 6-month prospective study, Med. Clin. (Barcelona),
84, 433, 1985.
148. Simon, H. B. and Wolff, S. M. Granulomatous hepatitis and prolonged fever of unknown origin: a study
of 13 patients, Medicine, 52, 1, 1973.
149. Guckian, J. C. and Perry, J. E., Granulomatous hepatitis: an analysis of 63 cases and review of the
literature, Ann. Intern. Med., 65, 1081, 1966.
150. Holdstock, G., Millward-Sadler, G. H., and Wright, R., Hepatic changes in systemic disease, in Liver
and Biliary Disease, Wright, R., Alberti, K. G., Karran, S., et al., Eds., W. B. Saunders, Philadelphia,
1982, 848.
151. Wilson, J. H. P., Drugs and the liver, in The Liver Annual 3, Elsevier, Amsterdam, 1983, 365.
152. Pessayre, D. and Larrey, D., Acute and chronic drug-induced hepatitis, Bailliere's Clin. Gastroenterol.,
2, 385, 1988.
153. Larrey D. and Erlinger, S. Drug-induced cholestasis, Bailliere's Clin. Gastrenterol., 2, 423, 1988.
154. Ishak, G. and Zimmerman, H. J., Drug-induced and toxic granulomatous hepatitis, Bailliere's Clin.
Gastroenterol., 2, 463, 1988.
155. Greenstein, A. J., Sachar, D. B., Lowenthal, D., Goldofsky, E., and Aufses, A. H., Jr., Pyogenic
liver abscess in Crohn’s disease, Q. J. Med., 220, 505, 1985.
156. Valero, V., Senior, J., and Watanakunakorn, C., Liver abscess complicating Crohn’s disease presenting
as thoracic empyema: case report and review of the literature, Am. J. Med., 79, 659, 1985.
157. Edwards, F. C. and Truelove, S. C., Course and prognosis of ulcerative colitis. III. Complications, Gut,
5, 1, 1964.
158. Perett, A. D., Higgins, G., Johnston, H. H., Masarella, G. R., Truelove, S. C., and Wright R., The
liver in Crohn’s disease, Q. J. Med., 158, 187, 1971.
159. Perett, A. D., Higgins, G., Johnston, H. H., Masarella, G. R., Truelove S. C., and Wright, R., The
liver in ulcerative colitis, Q. J. Med., 158, 211, 1971.
160. Heaton, K. W., The epidemiology of gallstones and suggested aetiology, Clin. Gastroenterol., 2, 67,
1973.
161. Heaton, K. W. and Read, A. E. Gallstones in patients with disorders of the terminal ileum and disturbed
bile salt metabolism, Br. Med. J., 3, 494, 1969.
162. Bluth, E. L, Merritt, C. R. B., Sullivan, M. A., Kurchin, A., and Ray, J. E., Inflammatory bowel
disease and cholelithiasis: the association in patients with an ileostomy, South. Med. J., 77, 690, 1984.
163. Ritchie, J. R., Allan, R. N., Macartney, J., Thompson, H., Hawley, P. R., and Cooke, W. T., Biliary
tract carcinoma associated with ulcerative colitis, Q. J. Med., 43, 263, 1974.
164. Levine, E. and Huntrakoon, M., Jaundice in a 31-year-old man with ulcerative colitis, Invest. Radiol.,
191, 361, 1984.
 153

165. Sturdevant, R. A. L., Singleton, J. W., Deren, J. J., Law, D. H., and McCleery, J. L., Azothioprine-
related pancreatitis in patients with Crohn’s disease, Gastroenterology, 77, 883, 1979.
166. Ishak, K. G. and Rabin, L., Benign tumors of the liver, Med. Clin. North Am., 59, 995, 1975.
167. Fiala, M., Chatterjee, S., Ellis, R., Imparato, B., Bahna S., and Saxon, A., Fever of undetermined
origin: role of cytomegalovirus and Epstein-Barr virus, West. J. Med., 129, 263, 1987.
168. Trastek, V. F., van Heerden, J. A., Sheedy, P. F., II, and Adson, M. A., Cavernous hemangiomas
of the liver: resect or observe?, Am. J. Surg., 145, 49, 1983.
169. Okazaki, N., Yoshino, M., Yoshida, T., Ohno, T., Kitagawa, T., and Hattori, N., Radiotherapy of
hemangioma cavemosum of the liver, Gastroenterology, 73, 353, 1977.
170. Fenster, L. F., Freeny, P. C., and Beebe, H. G., Cavernous hemangioma of the liver presenting with
fever, successful treatment with prednisone, West. J. Med., 129, 138, 1978.
171. Grases, P. J., Matos-Villalobos, M., Arcia-Romero, F., and Lecuna-Torres, V., Mesenchymal ha-
martoma of the liver, Gastroenterology, 76, 1466, 1979.
172. Ihde, D. C., Sherlock, P., Winawer, S. J., and Fortner, J. G., Clinical manifestations of hepatoma: a
review of 6 years experience at a cancer hospital, Am. J. Med., 56, 83, 1974.
173. Benner, E. J. and Labby, D. H., Hepatoma: clinical experiences with a frequently bizarre tumor, Ann.
Intern. Med., 54, 620, 1961.
174. Stein, C. M. and Gelfand, M., Hepatocellular carcinoma presenting as a fever of undetermined origin,
Cent. Afr. J. Med., 31, 21, 1985.
175. Lin, T. Y., Tumors of the liver. I. Primary malignant tumors, in Gastroenterology, Vol. 3, Bockus, H. L.,
Ed., W. B. Saunders, Philadelphia, 1976, 522.
176. Lomas, F., Dibos, P. E., and Wagner, H. N., Jr., Increased specificity of liver scanning with the use
of 67 gallium citrate, N. Engl. J. Med., 286, 1323, 1972.
177. Itai, Y., Nishikawa, J., and Tasaka, A., Computed tomography in the evaluation of hepatocellular
carcinoma, Radiology, 131, 165, 1979.
178. Juttijudata, P., Prichanond, S., Churnratanakul, S., et al., Hilar intrahepatic cholangiocarcinoma and
its etiology, J. Clin. Gastroenterol., 6, 503, 1984.
179. Chen, P. H., Lo, H. W., Wang, C. S., et al., Cholangiocarcinoma in hepatolithiasis, J. Clin. Gastroen-
terol., 6, 539, 1984.
180. Stocker, J. T. and Ishak, K. G., Undifferentiated (embryonic) sarcoma of the liver, Cancer, 42, 336,
1978.
181. Tanner, A.R., Boulton, P. M., and Powell, L. W., Primary sarcoma of the liver, Gastroenterology, 74,
121, 1978.
182. Fenster, L. F. and Klatskin, G., Manifestations of metastatic tumors of the liver: a study of eighty-one
patients subjected to needle biopsy, Am. J. Med., 31, 238, 1961.
183. Klastersky, J., Weerts, D., Hensgens, S., and Debusscher, L., Fever of unexplained origin in patients
with cancer, Eur. J. Cancer, 9, 649, 1973.
184. Bearhs, O. H. and Dahlin, D. C., Clinicopathologic conference: a patient with abdominal pain and fever,
Mayo Clin. Proc., 40, 260, 1965.
185. Aderka, D., Kidron, D., Weinberger, A., and Pinkhas, J., Absence of correlation between liver me-
tastases and unexplained fever episodes, Cancer, 55, 2830, 1985.
186. Symptoms, in Pediatric Clinical Gastroenterology, 3rd ed., Silverman, A. and Roy, C. C., Eds., C. V.
Mosby, St. Louis, 1983, 3.
187. Murray-Lyon, I. M., Shilkin, K. B., Laws, J.W., Illing, R. C., and Williams, R., Non-obstructive
dilatation of the intrahepatic biliary tree with cholangitis, Q. J. Med., 41, 477, 1972.
188. Dayton, M. T., Longmire, W. P., Jr., and Tompkins, R. K., Caroli’s disease: a premalignant condition?,
Am. J. Surg., 145, 41, 1983.
189. Frati-Munati, A. C., De La Riva, H., Gavino, J.F., Gonzalez-Angulo, J., and Hori-Milanes, S.,
Enfermedad de Caroli manifestada por fiebre de origen oscuro en dos hermanos, Gac. Med. Mex., 119,
415, 1983.
190. Karasawa, T., Shikata, T., and Smith, R. D., Peliosis hepatitis: report of nine cases, Acta Pathol. Jpn.,
29, 457, 1979.
191. Nadell, J. and Kosek, J., Peliosis hepatitis: twelve cases associated with oral androgen therapy, Arch.
Pathol. Lab. Med., 101, 405, 1977.
192. Meadows, A. T., Naiman, J. L., and Valdes-Dapena, M., Hepatoma associated with androgenic therapy
for aplastic anemia, J. Pediatr., 84, 109, 1974.
193. Naeim, F., Cooper, P. H., and Demion, A. A., Peliosis hepatitis: possible etiologic role of anabolic
steriods, Arch. Pathol., 95, 284, 1973.
194. Ito, T., Peritoneoscopy of peliosis hepatis, Endoscopy, 14, 14, 1982.
195. Shora, W. and Danovich, S. H., Marked elevation of serum transaminase activities in extrahepatic biliary
tract disease, Am. J. Gastroenterol., 55, 575, 1971.
154 Unexplained Fever

196. Fortson, W. C., Tedesco, F. J., Starnes, E. C., and Shaw, C. T., Marked elevation of serum transaminase
activity associated with extrahepatic biliary tract disease, J. Clin. Gastroenterol., 7, 502, 1985.
197. Laing, F. C., Diagnostic evaluation of patients with suspected cholecystitis, Surg. Clin. North Am., 64,
3, 1984.
198. Siddiqui, A. R., Hepatobiliary imaging, J. Indiana St. Med. Assoc., 76, 520, 1983.
199. Ottinger, L. W., Acute cholecystitis as a postoperative complication, Ann. Surg., 184, 162, 1976.
200. Fransen, H. and Bottiger, L. E., Fever of more than two weeks duration, Acta Med. Scand., 179, 147,
1966.
201. Geraci, J. E., Weed, C. A., and Nichols, D. R., Fever of obscure origin—the value of abdominal
exploration in diagnosis: report of seventy cases, JAMA, 169, 1306, 1959.
202. Ben Shoshan, M., Guis, J., and Smith, I. M., Explorative laparotomy for fever of unknown origin,
Surg. Gynecol. Obstet., 132, 994, 1971.
203. Petterson, T., Fever of obscure origin: a follow-up investigation of 88 cases, Acta Med. Scand., 171, 575,
1962.
204. Clinico-pathological conference: a case of P. U. O., Scott J. Med., 28, 82, 1983.
205. Caravati, C. M. and Cooke, C. L., Partial common duct obstruction presenting as fever of unknown
origin, Va. Med. Mon., 97, 99, 1970.
206. Taub, S. and Schiff, L., Common duct stone and cholangitis simulating fever of unknown origin, South.
Med. J., 74, 230, 1981.
207. Twidale, N., Mackinnon, M. and Watts, J., Recurrent cholangitis caused by hepatocellular carcinoma,
Aust. N. Z. J. Med., 15, 761, 1985.
208. Kuhls, T. L. and Jackson, M. A., Diagnosis and treatment of the febrile child following hepatic por-
toenterostomy, Pediatr. Infect. Dis., 4, 487, 1985.
209. Wiesner, R. H., La Russo, N. F., Ludwig, J., and Dickson, E. R., Comparison of the clinicopathologic
features of primary sclerosing cholangitis and primary biliary cirrhosis, Gastroenterology, 88, 108, 1985.
210. Record, C. O., Eddleston, A. L., Shilkim, K. B., and Williams, R., Intrahepatic sclerosing cholangitis
associated with a familial immunodeficiency syndrome, Lancet, 2, 18, 1973.
211. Yen ugo pal, S., Fletcher, P. R., and Carpenter, R., Biliary ascariasis, West. Ind. Med. J., 33, 45, 1984.
212. Reay, H. A. J., Dignan, A. P., and Maunder, C., Liver abscess caused by adult ascaris lumbricoides,
Br. Med. J., 2, 553, 1964.
213. Rossi, M. A. and Bisson, F. W., Fatal case of multiple liver abscesses caused by adult ascaris lumbricoides,
Am. J. Trop. Med. Hyg., 32, 523, 1983.
214. Ashton, W. L. G., Boardman, P. L., D’Sa, C. J., Everall, P. H., and Houghton, A. W. J., Human
fascioliasis in Shropshire, Br. Med. J., 3, 500, 1970.
215. Hardman, E. W., Jones, R. L. H., and Davies, A. H., Fascioliasis—a large outbreak, Br. Med. J., 3,
502, 1970.
216. Jones, E. A., Kay, J. M., Milligan, H. P., and Owens, D., Massive infection with fasciola hepatica in
man, Am. J. Med., 63, 836, 1977.
217. Huntley, C.C., Costas, M. C., and Lyerly, A., Visceral larva migrans syndrome: clinical characteristics
and immunologic studies in 52 patients, Pediatrics, 36, 523, 1965.
218. Zinkham, W. H., Visceral larva migrans, Am. J. Dis. Child., 138, 627, 1978.
219. Barros, J. L., Hydatid desease of the liver, Am. J. Surg., 135, 597, 1978.
220. Nagler, A., Enat, R., Brenner, B., Israel, O., and Argov, S., Hydatid cyst of the liver rupturing into
the biliary tract, mimicking acute cholecystitis on hepatobiliary scanning, Am. J. Gastroenterol., 80, 829,
1985.
221. LiVolsi, V.A., Perzin, K. H., and Porter, M., Polyarteritis nodosa of the gallbladder—presenting as
acute cholecystitis, Gastroenterology, 65, 115, 1973.
222. Katz, L. B. and Marchevsky, A., Polyarteritis nodosa presenting as acute cholecystitis, Mt. Sinai J. Med.,
5, 434, 1981.
223. Fayemi, A. O., Ali, M., and Braun, E. V., Necrotizing vasculitis of the gallbladder and the appendix:
similarity in the morphology of rheumatoid arthritis and polyarteritis nodosa. Am. J. Gastroenterol., 67,
608, 1977.
224. Hamrick, R. E., Jr., Liner, F. J., Hastings, P. R., and Cohn, I., Jr., Primary carcinoma of the
gallbladder, Ann. Surg., 195, 270, 1982.
225. Sheon, R. P. and Van Ommen, R. A., Fever of obscure origin: diagnosis and treatment based on a series
of sixty cases, Am. J . Med., 34, 486, 1963.
226. Granot, E., Deckelbaum, R. J., Gordon, R., Okon, E., Sherman, Y., and Schiller, M., Duplication
of the gallbladder associated with childhood obstructive biliary disease and biliary cirrhosis, Gastroenter-
ology, 85, 946, 1983.
227. Banks, P. A., Pancreatitis, Plenum Press, New York, 1979.
228. Falk, A., Gustafsson, L., and Gamklou, R., Silent pancreatitis: report of 4 cases of acute pancreatitis
with atypical symptomatology, Acta Chir. Scand., 150, 341, 1984.
 155

229. Neff, C. C. and Ferrucci, J. T., Jr., Pancreatitis, Surg. Clin. North Am., 64, 23, 1984.
230. Sostre, C. F., Flournoy, J. G., Bova, J. G., Goldstein, H. M., and Schenker, S., Pancreatic phlegmon:
clinical features and course, Dig. Dis. Sci., 30, 918, 1985.
231. Elliott, D. U., Pancreatic pseudocysts, Surg. Clin. North Am., 55, 339, 1975.
232. Warshaw, A. L., Pancreatic abscesses, N. Engl. J. Med., 287, 1234, 1972.
233. Stambler, J. B., Klibaner, M. I., Bliss, C. M., and LaMont, J. T., Tuberculous abscess of the pancreas,
Gastroenterology, 83, 922, 1982.
234. Wells, F., Pancreatic abscess complicating a perforated duodenal diverticulum, Br. J. Surg., 70, 292,
1983.
235. Barkin, J. S., Pereiras, R., Hill, M., Levi, J., Isikoff, M., and Rogers, A. I., Diagnosis of pancreatic
abscess via percutaneous aspiration, Dig. Dis. Sci., 27, 1011, 1982.
236. Sarles, H., Sarles, J. C., Muratore, R., and Guien, C., Chronic inflammatory sclerosis of the pancreas:
an autonomous pancreatic disease, Am. J. Dig. Dis., 6, 1, 1961.
237. Philllips, V. M., Hersh, T., Erwin, B. C., Torres, W. E., Sewell, C. W., Gedgaudas-McCIees, K.,
Clements, J. L., Jr., Baumgartner, B. R., and Bernardino, M.E., Percutaneous biopsy of pancreatic
masses, J. Clin. Gastroenterol., 7, 506, 1985.
238. Potts, D., Mass, M. F., and Iseman, M. D., Syndrome of pancreatic disease, subcutaneous fat necrosis
and polyserositis: case report and review of the literature, Am. J. Med., 58, 417, 1975.
 157

Chapter 10

UNEXPLAINED FEVER IN NEUROLOGICAL DISORDERS

N. Gadoth

INTRODUCTION
Facing the association of unexplained fever (UEF) and neurological impairment, one
has to consider three possible etiologies:

1. Neurological impairment is the result of prolonged fever (febrile convulsions, febrile

delirium, etc.).
2. Neurological impairment is caused by a systemic disorder manifested as UEF.
3. UEF is caused exclusively by a neural or neuromuscular impairment.

The following chapter will discuss these three possibilities in some detail and will dwell
mainly on the primary neuromuscular disorder as the other chapters of this book contain
most of the data on the first two subdivisions.

NEUROLOGICAL IMPAIRMENT DUE TO PROLONGED FEVER

Prolonged or even an acute febrile illness with abrupt rise in temperature can very often
cause change in alertness, clouding of consciousness, confusion, delirium, and sometimes
even changes in electroencephalographic pattern.1 This occurs mainly in the very young or
very old and may lead to alarm and unnecessary and, sometimes, invasive investigations.
In elderly patients with organic mental syndrome, Parkinson’s disease, or various chronic
neurological disabilities due to vascular or degenerative causes including epilepsy, fever can
cause a sudden deterioration in the neurological status. During infancy when febrile illnesses
are extremely common, mental changes and headaches may also be caused by fever itself
and do not indicate a primary neurological disorder. In both age groups, as well as in the
patients with various chronic neurological diseases, central nervous system (CNS) infections,
or subarachnoid hemorrhage might present only with mental symptoms without signs of
meningeal irritation, it is mandatory to include a properly performed lumbar puncture for a
complete evaluation of the cerebrospinal fluid (CSF). Two additional points are to be em-
phasized if the CSF is analyzed in such a case which will we consider as abnormal findings.
There is no need to stress the diagnostic significance to pleocytosis, xanthochromia, or
hypoglycorrhachia. The protein value is much less valuable if not excessively elevated. Mild
elevations might be found in advanced age or as part of the primary neurological chronic
impairment. Serological and immunological tests have a definite diagnostic value; however,
it may take a few days in most places to have the results and in a number of patients a
nonspecific reactivation of antibodies against several viruses might be detected.
A significant contribution is the CSF pressure. When performed in the supine position
with the patient in full relaxation, an elevated CSF opening pressure is indicative of CNS
pathology. There is only one condition to keep in mind and this is “ benign intracranial
hypertension.’’ In this condition, characterized by headaches and papilledema, increased
intracranial pressure is caused by a variety of systemic disorders, many of which might
present with UEF.2 3 Although papilledema is frequently present, this condition has been
described without papilledema.4
Signs resembling meningeal irritation (meningismus) may be misleading in UEF caused
by non-neurological systemic diseases. This phenomenon is well known in young children
158 Unexplained Fever

with apical pneumonia, enlarged cervical lymph nodes, in females with salpingitis as well
as in old individuals with severe cervical spondyloarthrosis, patients with severe extrapy-
ramidal rigidity and chronically bedridden institutional old patients with stiff joints from
prolonged immobilization (frozen-neck). Thus, we would recommend the performance of a
lumbar puncture as one of the laboratory tests of relatively noninvasive nature in the eval-
uation of UEF. This is in agreement with the suggestions made by Dinarello and Wolff who
claim that “ direct examination of blood and other body fluids are mandatory procedures
used in the evaluation of unexplained fevers“ .5 Thus, the following will concern conditions
in which the CSF examination was performed but failed to give an adequate explanation for
the prolonged fever.

PROLONGED FEVER AS A SOLE MANIFESTATION OF CNS

INFECTION
Infections of the CNS represent a group of life-threatening diseases which present a
formidable challenge to the physician. The development of effective antimicrobial agents
and modem surgical techniques has made the precise differential diagnosis of these infections
a panacea for the clinician rather than a simple academic exercise. CNS infections may
often present with fever only, thus any clinical evaluation of UEF should consider such a
possibility.

ACUTE BACTERIAL MENINGITIS AND OTHER NONVIRAL INFECTIONS

It is a “ rule of thumb” that acute meningitis is usually caused by bacteria while en-
cephalitis is due to viral infection. The mandatory lumbar puncture in cases of UEF makes
this diagnosis an easy one. Out of three main clinical signs (fever, neck rigidity, and cerebral
dysfunction) fever is secondary to bacterial invasion of the blood stream and spinal fluid,
eventually leading to release of leukocytic pyrogen and hypothalamic stimulation. An analysis
of five series of pediatric meningitis revealed that fever was present in 90% of the cases,
there was a stiff neck in 40%, and cerebral dysfunction signs such as nausea, vomiting,
headaches, irritability, excitability or depression of mental functions in 15 to 30% of the
cases.6 It is now clear why UEF workup should include a mandatory LP even when signs
of meningeal irritation are absent. This is especially true in stuporous patients, as well as
in alert very young and very old patients. The mortality rate of 75 to 100% in untreated
bacterial meningitis dictates the performance of a lumbar puncture.
This approach will yield abnormal fluid in practically every case of bacterial meningitis.
In cases of septicemia preceding meningitis, the initial spinal fluid may be normal, especially
in infants. Regarding the suggestion that the lumbar puncture may cause a conversion of
bacteremia to bacterial meningitis secondary to arachnoid trauma, we do believe that the
beneficial value of LP during the very early stage of septicemia is clear-cut.7 8To demonstrate
this point is the following case: a 19-year-old soldier was admitted with a history of fever
and chills lasting for 6 days. He had a normal physical and neurological examination and
lacked signs of meningeal irritation. His temperature was 39.3°C, and he complained of
headache and some nausea. Lumbar puncture was performed in the sitting position, thus
opening pressure was not measured. The fluid was crystal clear with normal sugar and
protein content. Gram stain was negative. There were 5 cells per mm3. However, all were
polymorphonuclears. A possible diagnosis of meningococcemia with meningeal involvement
was considered and he was started immediately on high doses of IV crystalline penicillin.
Subsequently, the blood and CSF grew Neisseria meningitides. He had an uneventful re-
covery. This case demonstrated an extremely important point. Five cells per mm3 is the
upper limit of normal, but only when they are mononuclear. It is always essential to perform
a differential count using a Wright or Giemsa stain. The differential count performed using
a vital stain on a standard counting chamber is misleading in the majority of the cases.
 159

Partially treated bacterial meningitis might raise a diagnostic problem. In this situation
the patient, frequently a child, presents with an undefined febrile illness and is otherwise
in good condition. It is a common and probably mistaken practice to treat such children
with low doses of antibiotics. When fever persists and the child is finally hospitalized the
possibility of partially treated meningitis should be considered. The spinal fluid may be
sterile and acellular and thus the diagnosis might be “ aseptic meningitis” . However, we
do recommend a repeated spinal tap 2 to 12 h (usually 6 h) after discontinuation of antibiotics,
at this time if bacterial meningitis is present, the spinal fluid will be diagnostic after such
an interval.9 Another difficult diagnostic problem is neonatal meningitis, especially related
to enteric Gram-negative bacteria. Meningeal signs in neonates are only rarely present.
However, if suspected and CSF is obtained, one must distinguish purulent meningitis from
normal neonatal spinal fluid, keeping in mind the fact that in noninfected newborns, up to
32 cells per mm3 may be present, 60% of them polymorphonuclears.10
In a study comparing CSF from high risk uninfected newborns and those with meningitis,
it was shown that any single spinal fluid value may not reliably identify the infant with
bacterial meningitis.10 In 80% of neonatal meningitis, Gram stain will demonstrate bacteria.
The combined use of counterimmunoelectrophoresis (CIE) and limulus lysate assay which
takes about an hour to perform may lead toward the correct diagnosis in the 20% of infants
in whom the Gram stain is negative and the CSF composition is noncontributary. These
techniques are useful in the detection of E. coli Kl.11

CHRONIC BACTERIAL MENINGITIS

Although etiological diagnosis is often difficult in such cases, and fever may precede
the appearance of meningitis in the majority of cases, the CSF is a reliable indicator of
meningitis.12

BRAIN ABSCESS
The diagnosis of supratentorial brain abscess remains one of the difficult problems in
clinical neurology. Fever may occur in brain abscess although its frequency is controversial.
Various studies reported fever in 13 to 69% of the patients at the time of admission.1315
The value of lumbar puncture in this condition is limited and the risk of herniation and
sudden death following LP is high.131518 In the era of CT scanning this procedure should
be abandoned. The following case report demonstrates clearly the nonspecific presentation
and the potential hazard of a spinal tap. A 17-year-old male left his home and joined a youth
gang. Three weeks prior to admission he noticed a small pustule on his lower gingiva which
he drained himself with a safety pin. He had a gradual onset of fever and mild nonlocalized
headache for which he took Tylenol. After 9 days of fever he visited his mother and asked
for help. He was described as behaving in an unusual way and he started to vomit. Two
visits on the same night at a local hospital emergency room resulted in two diagnoses (upper
respiratory infection, gastroenteritis). When vomiting continued, the mother took him to a
third hospital where he was found to be dehydrated, confused with normal neurological
status, normal fundi, but abnormal EKG which was read as “ possible myocarditis” . He
underwent a lumbar puncture and was admitted to the intensive cardiac care unit. We saw
him about 2 h following the spinal tap which showed mild monocytic pleocytosis leading
to a diagnosis of mumps with myocarditis. On examination he was comatose with complete
external and internal ophthalmoplegia, bilateral florid papilledema, and right flaccid hem-
iplegia. Immediate angiography disclosed a large frontal space-occupying lesion with signs
of transtentorial herniation. Craniotomy disclosed a large frontal,well-organized, encapsu-
lated abscess which was drained. After a long course of antibiotic and corticosteriod treatment
he recovered completely. The root of entry was found to be pyogenic pansinusitis.
Of special importance are multiple brain abscesses especially in infants and young
children with cyanotic heart disease. Fever and nonspecific signs of increased intracranial
160 U nex p la in ed F ever

pressure are usually present and frequently misdiagnosed. Focal signs might be absent when
abscesses are located in both hemispheres.

LEPTOSPIROSIS
Accurate history and the alertness of the physician usually results in the correct diagnosis.
However, in some cases, especially mild ones, during the first stage of the disease (3 to 6
days), high-grade fever, clouding of sensorium, and severe muscular pain are accompanied
by meningismus with normal spinal fluid. In the second stage which starts after a short
duration of fall in fever, organ involvement especially with leptospira icterohemorrhagica
would suggest the diagnosis. However, in milder cases serosal meningitis may be present.
This type of meningitis, seen very frequently with leptospirosis (up to 96% of cases), might
show normal CSF or slightly lymphocytic pleocytosis during the first febrile phase of the
disease, and the diagnosis should be reached by serological and direct dark field microscopic
examination.19 20 There may be a rapid rise in cell number in the CSF toward the end of
this stage, but in the short, fever-free interval, the cell count is again normal. During the
beginning of the second febrile stage, the CSF shows pleocytosis (7 to 10 days of illness)
and then the CSF slowly normalizes again.

SUBACUTE BACTERIAL ENDOCARDITIS (SBE)

Fever is a universal accompaniment of SBE. As there are cases with appropriate clinical
features but with sterile blood cultures while the estimated rate of neurological manifestations
is about 30% it seems useful to include a short discussion of SBE in this chapter. Among
the various neurological complications known to occur during the course of SBE, such as
cerebrovascular disease, meningitis, abscess, headaches and convulsions, and meningoen-
cephalitis, are of special interest. The meningoencephalitis is characterized by confusion
and stiff neck, however, the spinal fluid is sterile and may show only a dismal cellular
response.
Acute confusional state (acute brain syndrome), with delirium, hallucinations, confa-
bulations, disorientation, paranoid ideation, and other signs of psychosis are seen in the
severe form. Mild manifestations include drowsiness, insomnia, apathy, irritability, and
personality changes. These changes might be the presenting symptoms of SBE. The spinal
fluid is mostly normal and the EEG might show nonspecific abnormalities. However, if
SBE is overlooked, the consequences are quite clear-cut. In the older literature this syndrome
was attributed to encephalitis, however, at present this “ toxic encephalopathy” is believed
to be the expression of multiple thromboembolism or an immunoallergic process.21,22

DIPHTHERIA
Being extremely rare nowadays, it is important to mention its neurological complications
which may be again misleading when they appear early in the course of the disease. “ Paralytic
diphtheria” is well known and is always accompanied by abnormal spinal fluid; however,
toxic encephalopathy, seen in 2.2% of a large series of cases, frequently shows normal
spinal fluid.23

WHIPPLE’S DISEASE
This rare disorder, believed to be caused by rod-shaped bacilliform bodies, may be fatal
if the proper antibiotics are not used. It may frequently present with low-grade fever but
signs of multisystem disorder are usually present, including gastrointestinal malabsorption,
arthralgias and lymphadenopathy. However, this disease rarely presents solely with CNS
involvement,24 presenting as headaches, seizures, personality changes, signs of hypothalamic
disease, ataxia, etc.
The CSF is generally normal or contains only a few cells. Diagnosis may be reached
by brain biopsy, however, the characteristic lesions may be inaccessible.
 161

PARASITIC INFECTIONS

MALARIA
Cerebral malaria or malaria with neurological complications must always be borne in
mind in a patient who has been in the tropics or who has received a blood transfusion within
3 months of the onset of the disease, and who has a neuropsychiatric disorder associated
with UEF. Malaria may produce a wide range of CNS symptoms resembling, in many ways,
neurosyphilis. Altered state of consciousness, psychosis, and seizures may occur.The cerebral
form is predomonantly caused by Plasmodium falciparum. This clinical form is seen often
in children and decreases in frequency with aging.25 The common clinical presentation during
the first-time infections (“ primo-infection” ) as they usually occur in Europeans, is fever
with a distinct prodrome of headaches, myalgia,and anorexia. After 7 to 8 days of fever
many patients complain of influenza-like symptoms. Agitation and delirium may be followed
by coma and death within hours or days. Signs of meningeal irritation may be the first sign
of cerebral malaria or appear later in the course.26 However, unfortunately the spinal fluid
is usually normal or shows increased opening pressure with minimal changes in the CSF
content.

TRICHINOSIS
As the clinical presentation of trichinosis varies broadly and as many as 95% of cases
are only minimally ill and recover spontaneously, neurological signs during the course of
fever with no evident organ involvement might be confusing. The fever usually occurs in
the second week and peaks about 7 days later. Neurological complications occur in severe
cases only, and the diagnosis might be suggested by the typical multiple organ involvement
and the typical severe myalgia due to invasion of organisms into muscle tissue. During the
second week of infection (larval-migration), signs of meningoencephalitis may be present,
followed by multifocal neurological impairment affecting central and peripheral nervous
system. The CSF may be normal in as many as 50% of the cases, while larvae may be
found in about 30% of cases.

ACUTE VIRAL AND RICKETTSIAL INFECTIONS

The clinical signs and symptoms of acute viral infections of the CNS depend on which
neural cells are infected. Also, various cell types of the nervous system have different
susceptibility to different viruses. Infection limited to the meninges manifest with fever,
stiff neck, and CSF pleocytosis, compatible with the diagnosis of “ benign meningitis” .
When the infection spreads to the parenchymal cells of the brain, meningeal irritation will
be accompanied by depressed state of consciousness, seizures, focal neurological deficits
and increased intracranial pressure, a clinical picture designated as meningoencephalitis. If
signs of spinal cord involvement are present, the terms encephalomyelitis and meningoen-
cephalomyelitis are usually descriptive of the clinical picture.
Fever is a constant feature of such infections and may be the presenting symptom in as
many as 50% of patients but is usually accompanied by other symptoms such as myalgia,
rash, sore throat, or gastrointestinal signs. Fever can last as long as 2 weeks prior to the
appearance of abnormal neurological signs, although these usually appear earlier and lead
to the correct diagnosis. CSF is usually abnormal when examined with mild pleocytosis and,
sometimes, especially in mumps, hypoglycorrhachia. However, rarely, the CSF might be
initially entirely normal, indeed in Kennard’s review of viral encephalitis, among five patients
with proven viral encephalitis, one had a normal CSF.27
In general, viral infection of the CNS can easily be detected in cases in which the
presentation is UEF by performing a lumbar puncture. When neurological signs are present
162 U nex p la in ed F e ve r

the designation UEF should be logically abandoned and CNS infections should be seriously
considered and vigorously sought.

INFECTIONS OF SPECIAL INTEREST

Mumps
Mumps is responsible for as many as 15% of all cases with aseptic meningitis and
encephalitis.28 It is not well appreciated that only 50% of patients with mumps meningitis
and encephalitis also have parotitis.29 Sometimes meningitis can precede parotitis by a full
week.30 Thus, immunological studies of the CSF obtained should include mumps even in
the absence of parotitis. Interesting enough, encountering the combination of meningitis and
parotitis one should not forget lymphocytic choriomeningitis virus infection (arenavirus).

Herpes Virus (Type 1)

This virus causes nonepidemic, severe, and often fatal encephalitis. The onset may be
insidious with fever as high as 40 to 41 °C. Headache is prominent and appears early in the
course. The special localization of the virus to the temporal lobe may produce a clinical
picture of peculiar personality changes which may persist for a day or even a week before
focal signs evolve. Behavior changes include acute episodes of terror, hallucinations, or
other patterns of bizarre behavior which may lead to a psychiatric hospitalization before the
correct diagnosis is reached.31 In the cases without seizures or localizing signs, the diagnosis
may be enhanced by the examination of the sense of smell. Anosmia is very frequent in the
early stages of the disease, considering the entry of the virus by the olfactory route with
subsequent spread along the base of the brain.32 Early in the disease the CSF might be
normal except for some elevation of protein. The EEG is extremely helpful, being abnormal
but again nonspecific, in practically all cases early in the course, while the isotope scan and
computerized tomography (CT) might be entirely normal or show abnormalities only at a
later stage.33 Recently the value of MRI in early detection of cerebral involvement was
reported.34

Hemorrhagic Fever
This is an infection with arenavirus. In Argentina 13,000 cases have been reported in
Buenos Aires and adjacent provinces during one epidemic.35 The virus is carried in several
species of local rodents (cricetidae). This is a serious infection with a mortality rate of 10
to 20%. The clinical signs include high fever, headache, lymphadenopathy, and erythematous
exanthem. Varied neurological signs are found in fatal cases. Unfortunately, the spinal fluid
is frequently normal when atypical pathological signs of hemorrhagic encephalitis are usually
present. The virus can be recovered from the brain.35 A similar related disease has been
described in Bolivia and is due to Machupo virus while the Argentinian virus is known as
Junin virus.36 A related disorder is known as “ Lassa fever” , reported from Nigeria.

Rabies
Although it is not difficult to diagnose rabies when the classical clinical signs described
by Trousseau are present in an individual bitten by a rabid animal, this diagnosis is sometimes
tricky and may be overlooked for several reasons: (a) incubation period may last from 15
days to 1 year; (b) during the last several years only 50% of patients in the U. S. with rabies
have had a history of a bite; (c) following a prodrome of fever, headache, malaise, and
anorexia, in half of the patients a nonspecific clinical picture of encephalitis might be present;
(d) in 5 to 20% of cases ascending paralysis with areflexia similar to the Guillain-Barre
syndrome (GBS) may be present.37 This clinical presentation known also as “ dumb-rabies”
is seen mainly when transmitted by infected bats. The spinal fluid shows pleocytosis only
in 25% of patients but protein content is usually elevated, consistent with the classical
 163

albuminocytological dissociation seen in GBS, thus increasing the chances of completely

overlooking the possibility of rabies.

Cat Scratch Disease

This benign febrile adenitis is also believed to be caused by an undefined “ virus” ,
although recently pleomorphic Gram-negative bacteria have been implicated as a possible
causative agent.38 Fever is usually followed by a red raised papule and sometimes painful
regional lymphadenopathy. The diagnosis might be difficult as no definite diagnosis can be
made without the positive skin test. The history of cat scratch may be overlooked and the
lymph node biopsy shows nonspecific noncaseating granulomas. Neurological complications
in the form of encephalitis are rare, and usually appear 2 to 3 weeks following the skin
lesion. In the majority of the cases the cerebrospinal fluid is normal, and in mild cases the
EEG might be also normal, although it usually indicated encephalitis.39 40

Rickettsial Infections
Rocky mountain spotted fever is caused by Rickettsia rickettsi and is most frequent in
the mid-Atlantic states of the U.S. The onset of fever, headaches, typical rash, and gas-
trointestinal symptoms may be followed by neurological complications which may occur in
as many as 60% of the affected—mainly in the form of encephalitis—leading in many cases
to coma and severe neurological sequelae.41
The CSF shows a paucity of abnormalities. In only 20% is pleocytosis present and the
protein content is usually normal. The diagnosis is based mainly on the clinical picture and
the demonstration of hemagglutination inhibition (HI) antibodies to Proteus vulgaris 0X19,
0X2, OXK strains. A variety of tick-borne rickettsial diseases occur in the eastern hemi-
sphere, in the Mediterranean, Africa, Asia, and Australia. The clinical picture is similar but
less severe with fewer neurological complications and lower mortality.42

Epidemic Neuromyasthenia
This peculiar entity is thought to be caused by an undefined “ virus” although an
emotional cause and high rates among young woman with a paucity of objectives and
laboratory findings may mimic mass hysteria.43,44
This peculiar disease has been reported in the form of outbreaks, approximately 20
during the past 40 years. The outbreaks occur during the summer months and affect mainly
females in the third decade of life. Half of the cases are found among hospital staff. Low-
grade fever, which is present only in about 10% of cases, headaches, severe muscle pain,
and posterior cervical lymphadenopathy is usually followed by muscle paralysis.45 This
paralysis differs from poliomyelitis, lacking atrophy and is accompanied by hyperreflexia
and sensory symptoms. The cerebrospinal fluid is essentially normal and 95% of patients
show no pleocytosis. The course is rather protracted although the majority of patients recover
completely within 3 months.

CHRONIC INFLAMMATORY (SLOW VIRUS) CNS DISEASES

Among the so-called “ slow virus” infections of the CNS, subacute sclerosing panen-
cephalitis (SSPE) is a fatal disease affecting children and young adults. The disease is easy
to diagnose when a clinical picture of subacute and, rarely, acute onset of disorientation
and visual symptoms, mainly visual agnosia and myoclonic jerks, are present. A suggestive
electroencephalogram, high titer of anti-measles antibodies in serum and CSF and the pres-
ence of CSF oligoclonal IgG bands, will confirm the diagnosis. The patient is rarely febrile
during this stage but when he reaches the terminal stage of the disease and lapses into stupor
and rigid state, spiky fever, sweats, and cardiovascular instability are frequently observed.
164 Unexplained Fever

We have seen periods of 3 to 4 weeks of “ septic fever” in many of the patients, however,
a meticulous work-up for an infectious or toxic etiology was always negative. The combi-
nation of fever, perfuse bouts of sweating and cardiovascular instability points to autonomic
instability as the causative factor. A similar clinical entity is usually present in progressive
rubella panencephalitis.46

ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

Neurologic complications may appear early in the course of AIDS as a result of human
immunodeficiency virus (HIV) infection, secondary lymphoma, or opportunistic infection.47
Patients with AIDS may present with prolonged periods of fever while their CSF may
be entirely normal.48’49

PRIMARY, CENTRAL, AND PERIPHERAL NERVOUS SYSTEM

DISORDERS
Fever, as clinical manifestation of a neurological disorder, might be caused by central
brain lesions in sites responsible for temperature regulation, in the various peripheral path-
ways innervating temperature regulating organs such as sweat glands, and finally by affecting
the muscle in a way which will cause body temperature elevation due to its over-activity.

IMPAIRMENT OF CENTRAL TEMPERATURE REGULATION

Hypothalamic Damage
It is generally believed that the hypothalamus plays an important role in thermoregulation.
The anterior hypothalamus controls thermoregulatory sweating by serving as an internal
temperature sensing organ.50 The hypothalamus is capable of establishing the set point for
body temperature by inborn ionic mechanism within the region of its posterior part.51 Bauer
offered convincing clinical evidence by reporting abnormalities of body temperature in 13
out of 60 patients in whom hypothalamic disease was proven by biopsy. In four, fever was
the presenting symptom.52 Although the common presentation of abnormal hypothalamic
temperature regulation takes the form of bouts of hypothermia, hyperthermia has been
described. Following operations in the region of the floor of the third ventricle, the tem-
perature may rise to 41°C (106°F) or even higher. It usually remains elevated until death
some hours or days later and is resistant to treatment with common antipyretic drugs. The
temperature may, however, be reduced by the combination of phenobarbitol and physical
cooling of the body.
Wolff et al. described a 14-year-old boy with recurrent episodes of fever, nausea,
vomiting, and mental confusion lasting for 3 to 5 days, recurring irregularly every 1V2 to
3 months. The boy also experienced marked weight loss but regained his former weight
during the intervals between attacks. His disease was attributed to birth injury or undiagnosed
infectious disease during infancy. Numerous meticulous medical and endocrinological eval-
uations failed to localize the precise lesion; however, radiological signs of diffuse cortical
atrophy were present. Endocrine studies suggested periodic hypothalamic discharge.53 A
striking clinical example of hypothalamic disorder causing recurrent bouts of UEF was
described by Marilus et al. This was a 62-year-old male who had ten episodes of UEF for
which he was repeatedly hospitalized and evaluated during the course of 12 years. Various
symptoms and signs accompanied the bouts of unexplained fever leading to a wide spectrum
of diagnoses including septic and cardiogenic shock. A meticulous work-up disclosed hy-
pothalamic hypopituitarism most probably caused by encephalitis.54
In dealing with hypothalamic causes for UEF, one has to consider the wide spectrum
of conditions which may cause damage to that area. These may include tumors such as
craniopharyngioma and astrocytoma; vascular lesions such as A-V malformations, congenital
 165

hamartomata, vasculitis and traumatic hemorrhage; malformations of the third ventricle;

demyelination associated with metabolic disorders such as Wernicke’s encephalopathy, Leigh’s
encephalopathy, and the encephalopathy associated with acute intermittent porphyria in which
bouts of sweating, tachycardia, abdominal pain, and fever may occur. As mentioned above,
UEF is only rarely encountered as the cardinal or presenting sign of hypothalamic structural
damage.
For the purpose of demonstrating the role of metabolic changes in the hypothalamus
and other regions of the CNS, the following case report of acute intermittent porphyria is
instructive. A 21-year-old female suffered from personality changes following the use of
oral contraceptives. A year later she started to take phenobarbitol and phenytoin for severe
headaches and episodic vertigo and soon after she suffered severe abdominal pain, nausea,
and fever. Seizures and rapid decline in alertness initiated admission. Subsequently the
family history and laboratory work-up indicated acute intermittent porphyria. She sunk into
coma and the fever persisted. A complete fever work-up including CSF examination was
negative. In addition to encephalopathy she manifested with the syndrome of inappropriate
ADH secretion, as an additional manifestation of hypothalamic damage. She also showed
clinical and radiological evidence for bilateral temporal lobe function impairment (Kluver-
Bucy syndrome).55
Hypothalamic damage may be caused by a variety of obscure inflammatory processes
affecting the meninges of the base of the brain and causing the so-called ‘‘basilar meningitis” .
In sarcoidosis, granulomatous infiltration of the meninges and underlying parenchyma is
prominent at the base of the brain causing visual disturbances, polydipsia, polyuria, som-
nolence, and bouts of fever due to hypothalamic damage. CNS involvement in sarcoidosis
is relatively infrequent ranging from 1.1 to 7.9 %.56,57 The CSF may show mild lympho-
pleocytosis but may be entirely normal. Similarly, other causes of basilar meningitis such
as in Behcet disease, Vogt-Koyanagi Harada (VKH) syndrome, and carcinomatous meningitis
should be considered. In both Behcet and VKH syndromes, neurological manifestations may
be the presenting symptoms and ophthalmological and other systemic abnormalities may
appear later. UEF may be present while the CSF may be acellular and with normal amounts
of protein.58

Hypothalamic Damage Presenting as Psychosis

Of special interest is an obscure clinical entity known by the name, “ fatal catatonia” .
Cases with this ill-defined syndrome suffer from acute fatal agitated psychosis, and severe
hyperthermia.59 Since the early reports, a notion that the nature of this psychiatric illness is
related to infectious process gained support from similar cases.60,61
Neuropathological changes include diffuse perivascular cuffing, marked microglial ac-
tivation and neuronal loss involving also hypothalamic nuclei. Such changes are compatible
with nonspecific infections, probably viral encephalitis.62’63 In the same group one may
include patients in whom functional psychosis without signs of catatonia was the presenting
symptom and masked a clinical picture of UEF with subtle neurological signs. In such
patients the CSF is usually normal and EEG might show some slow activity. The following
case report is a typical presentation of fatal catatonia due to encephalitis.

Case Report (BMC 6869172)

A 27-year-old healthy male had the acute onset of paranoid psychosis 3 months prior
to the present admission. Antipsychotic treatment led to prompt improvement, but reap-
pearance of paranoid hallucinations initiated the present hospitalization. On admission he
was afebrile and in a state of agitated psychosis, but otherwise complete physical and
neurological examination was unremarkable. He was started on haloperidol, and subsequently
developed marked hyperthermia, leukocytosis, and catatonic posturing. An extensive work-
up for fever was unremarkable including several lumbar punctures. EEG and cerebral CT
166 U nex p la in ed F e ve r

were also normal. Malignant neuroleptic syndrome was considered, but treatment with
amantadine and several other anticholinergic agents was without benefit. Fatal catatonia was
finally considered and he received a course of 28 electroconvulsive shocks which were
ineffective. His condition deteriorated progressively during the 5 months of hospitalization.
Fever was continuous and did not respond to antipyretics, various antibiotics, or phenothi-
azines. A repeated CT scan close to the time of his death revealed mild dilation of the
cerebral ventricular system with slight cortical atrophy. Clinically, in addition to marked
catatonia, spasticity, primitive release reflexes, and pyramidal signs appeared, indicating
severe frontal lobe dysfunction. General autopsy findings were unremarkable. Microscopic
examination of the brain disclosed signs of encephalitis manifested by perivascular mono-
nuclear inflammatory cuffing, electron microscopy disclosed intraneural virus particles re-
sembling a virus of the herpes group.

“ Hysteric Fever”
UEF among hysterics is rare and yet controversial; however, among sporadic cases
suffering from UEF there are always a few hysterics. It is quite understandable that a major
proportion of these are students, fully trained nurses and nurses aides. When body temperature
is checked by a doctor or nurse it may be normal in some of them while others have
temperatures of 37 to 38°C (99 to 100°F) which may be their normal body temperature as
they may be individuals with exaggerated circadian temperature rhythm.64 Indeed only few
cases which have been well documented had their fever considered to be psychogenic.
However, the so-called “ admission fever” found frequently in patients when initial tem-
perature is taken on admission serves as a good example of fever due to an emotional factor.65
The possibility that an obscure hypothalamic disorder caused the fever and “ hysteric”
behavior cannot be completely excluded.66

Malignant Neuroleptic Syndrome

Malignant neuroleptic syndrome is a rare idiosyncratic side effect of neuroleptic drugs.
It usually appears during treatment with psychotropic drugs, mainly dopamine antagonists.
The cardinal clinical features are hyperpyrexia, reduced level of consciousness, motor ab-
normalities, mainly muscle hypertonia, diverse involuntary movements and severe autonomic
disturbances. It carries a significant morbidity and 20% mortality.67 Some direct evidence
suggests that D2 dopaminergic receptors are involved in the pathogenesis of this syndrome.68

Spinal Cord Trauma

Spinal cord traumatic lesion at the level of the fourth and fifth cervical segments cause
impaired temperature control due to denervation of sympathetic pathways which control
thermoregulatory sweating, vasomotion, and motor fibers responsible for shivering. Hypo-
thermia may develop, however, due to cutaneous vasodilatation and consequent heat loss,
especially in warm climates.69 70
This “ pan-dysautonomia” is usually transitory and represents one of the clinical expres-
sions of spinal shock. The phase of complete loss of autonomic innervation usually lasts
from 1 to 6 weeks. Following spinal shock a stage of heightened reflex activity develops.
Thermoregulation is again maintained mainly by sweating as paralysis rarely improves to
the extent of significant motor activity. Periods of unexplained hyperthermia and bouts of
hypothermia are caused by defective heat induced sweating while reflex evoked (spinal)
sweating may be profuse.71 This exaggerated sweating may be accompanied by cutaneous
flushing, pounding headache, hypertension, and reflex bradycardia. The combination of
these signs gained the name “ autonomic dysreflexia” . Its appearance is episodic and occurs
in response to specific stimuli such as bladder or rectal distention. The assumption that
autonomic denervation occurs below the level of spinal lesion is perplexing. Acquired pan-
dysautonomia reported in several well studied patients is not associated with abnormal
 167

thermoregulation and when infection occurs such patients are able to develop “ pyrogen
induced” fever.72 73

Spinal Epidural Abscess

This condition is a great clinical imitator and its diagnosis might be delayed endangering
motor functions and, sometimes, life. When spinal epidural abscess occurs in a young child
the diagnostic problem becomes even more difficult. Fortunately, it is rare under 12 years
of age and until 1972 only about 20 cases have been reported.74 Following an injury to the
back, often trivial, at the time of furunculosis or other skin infection, the spinal epidural
space may be seeded with bacteria, usually Staphylococcus aureus. Sometimes hematogenic
spread of bacteremia may lead to spinal osteomyelitis with extension to the epidural space.
The presenting symptoms are fever and pain in the back. Radicular pain may follow and
sometimes signs of acute abdomen may be the manifestation of referred pain from irritation
of lower thoracic sensory roots.74,75 This may lead to explorative laparotomy before the
correct diagnosis is reached. In children, fever and irritability were present in every case
while backache was evident in only 8 of the 20 reported cases. Meningismus was found in
seven children while abnormal neurological signs were found in ten. Thus, clinical signs of
meningitis might be present while the CSF can be entirely normal, contain a few cells
and/or elevated protein. When localized to the lumbosacral roots causing cauda equina
epidural abscess, pain may be severe while neurological symptomatology is minimal. This
important clinical entity has to be considered nowadays when epidural and spinal anesthesia
are frequently performed. When suspected, immediate myelography should be performed
in order to determine the operative site. CT scan and MRI imaging of the suspected area
may be extremely beneficial especially in youngsters in whom clinical signs are often
misleading.

IMPAIRMENT OF PERIPHERAL TEMPERATURE REGULATION

Malignant Hyperthermia
This metabolic polymyopathy should be mentioned here in spite of the fact that hyper-
pyrexia, which is the hallmark of the diagnosis, is acute and shortlived. First described about
28 years ago, its acute presentation is unforgettable.76 Usually during halothane anesthesia
when suxamethonium is administered to obtain muscle relaxation, the jaws become unex-
pectedly tense and general rigidity follows. A prompt elevation of body temperature as high
as 42 to 43°C leads—if untreated—to brainstem dysfunction and death. The cause of fever
is not entirely clear. It is probably due mainly to muscle spasm but a metabolic effect on
heat regulating centers cannot be excluded. It seems that several types of myopathy may
show susceptibility for malignant hyperthermia. The muscles from affected individuals are
abnormally sensitive to caffeine in vitro which causes muscle contraction. It seems that the
major “ toxic” anesthetic agents, such as halothane and succinylcholine, act similarly to
caffeine and release calcium from the sarcoplasmic reticulum thus interfering with muscle
relaxation.
Prompt treatment is lifesaving. Discontinuation of anesthesia should be followed by the
intravenous administration of dantrolene sodium (Dantrium®). Asymptomatic family mem-
bers should be carefully investigated as the mode of inheritance is thought to be autosomal
dominant.

Hyperthermia as a Result of Prolonged Muscle Contractions

Similar to the mechanism considered to play a major role in malignant hyperthermia,
we have observed UEF in patients with known Parkinson’s disease in whom severe extra-
pyramidal crisis expressed as extreme muscle rigidity was the cause of the hyperthermia.
The following case report serves to demonstrate this issue.
168 U nexplain ed F e ve r

Case Report (BMC 358715)

This 73-year-old male was known to suffer from Parkinson’s disease for the last 8 years
prior to the present evaluation. He was maintained on 750 mg levodopa + 75 mg carbidopa
(Dopicar®), 300 mg amantadine hydrochloride and 4 mg benztropine mesylate (Cogentin®)
daily. About a month prior to admission he sustained a fall and since then gradual deterioration
in his neurological condition occurred. Terrifying visual hallucinations caused abrupt dis-
continuation of his antiparkinsonian therapy. This resulted in rapid development of stupor
and akinesis. On admission he was stuporous with perfuse perspiration, severe blepharo-
spasm, extreme muscle rigidity, aphonia, and dysphagia. His body temperature was 37.6°C
and showed daily spiky elevations in spite of vigorous antipyretic treatment. Intensive medical
and neurological work-up including numerous urine, blood and CSF cultures failed to disclose
the cause of his fever. Adequate broad spectrum antibiotic treatment was uneffective and
only after control of his extrapyramidal crisis by intravenous amantadine sulfate and the
achievement of normal muscle tone, a dramatic drop in fever occurred. Serum creatine kinase
(CPK) activity was markedly increased during the febrile period and normalized when body
temperature and muscle tone returned to normal. On discontinuation of intravenous aman-
tadine sulfate, fever reappeared and cleared again on reinstitution of therapy.

Autonomic Dysautonomia
Generally, peripheral autonomic denervation, known also as pandysautonomia may be
congenital or acquired. Two major forms of acquired pandysautonomia are known: acute
with complete recovery and chronic progressive with poor recovery.
Although severe peripheral pandysautonomia and impaired sweating are present, ther-
moregulation is not impaired while other autonomic functions are abnormal.71,73 77
In contrast to the acquired dysautonomia, thermoregulation is markedly abnormal in the
congenital forms. The best documented disorder of this type is familial dysautonomia (Riley-
Day syndrome). It affects mainly children of Jewish Ashkenazi origin and may present at
birth, usually with hypotonia, depressed deep tendon reflexes, insensitivity to pain, lack of
tearing, dysphagia, skin blotching, and erratic temperature control.78 During infancy and
childhood, bouts of unexplained fever are a cardinal clinical sign and were present in 20 of
23 patients from Israel.79 The neurological abnormalities are confined to the peripheral
nervous system, in a similar distribution to the acquired forms.80 When comparing congenital
and acquired dysautonomias in regard to thermoregulation, one must conclude that the
explanation of UEF in congenital dysautonomia is not simple and cannot be attributed to
lack of sweating. On the contrary, in familial dysautonomia increased sweating is observed.
Thus, the pathophysiology of hyperthermia in familial dysautonomia deserved further studies.
Several cases with dysautonomia during early childhood, probably of a congenital nature
but different from classical familial dysautonomia, have been reported. In these, thermo-
regulation with bouts of UEF were also present.81,82

Autonomic Impairment in Fabry’s Disease

In this rare X-linked recessive storage disease, young boys may suffer from bouts of
unexplained fever and generalized joint tenderness which may last 2 to 3 weeks. Unrelated
to these attacks, paroxysms of lightning pain along the extremities occur. At this stage the
diagnosis of rheumatic fever is frequently considered. Only later, progressive renal failure,
cardiomyopathy and angiokeratoma corporis suggest the correct diagnosis which may be
confirmed by the demonstration of storage of ceramide bihexoside and trihexoside, and by
the deficiency of the enzyme ceramide-trihexosidase (a-galactosidase A) in leukocytes.
Storage of glycolipid causes damage to non-neural tissues such as kidneys, heart, skin, and
endothelium of cerebral blood vessels. Lesions in central and peripheral autonomic nervous
system may play a major role in the impaired thermoregulation in this syndrome.83,84
 169

FEVER AND STROKE

It is somewhat surprising that only single reports have described and analyzed fever in
patients with stroke, although fever is frequently encountered in such patients but hardly
can be regarded as UEF. Hindfelt considered such fever in stroke as an unfavorable prognostic
sign without evaluating the cause of fever.85 Recently, in a prospective study, which analyzed
the causes of fever in 104 ischemic stroke patients, fever occurred in 22% of the patients
and lasted not longer than 5 days. Fever was seen mainly in large infarcts and was never
related to a central cause but frequently associated with pulmonary disease.86

FEVER AND EPILEPSY

The simultaneous occurrence of seizures and unexplained fever in adults is extremely
rare. There are only four reports entitled fever and epilepsy.84 87 However, in the first three,
epilepsy was not confirmed. The claim for the coexistence of well documented febrile
episodes and epileptic phenomena is based on the presence of rage attacks or the demon-
stration of spikes in the EEG during the febrile episodes and the favorable response of the
fever to anticonvulsants.87 89 The only well-documented case had numerous febrile episodes
lasting from 24 to 72 h during which complex partial status epilepticus was observed.90
Extensive fever and neurological work-up was negative and only one out of a number of
EEGs was compatible with temporal lobe epileptic discharge.
Fever may also follow generalized tonic clonic seizures. In one study the fever last at
least 48 h after the seizure in 89% of the patients and in 66% of the patients no cause for
the fever could be found.91
This mode of UEF could be due to the combination of heat generation by sustained
muscle activity during the seizure and disruption of the thermoregulatory control of the
anterior hypothalamus caused by the excessive neuronal activity during the seizure.

REFERENCES
1. Ludmerer, K. M. and Kissane, J. M., Fever of unknown origin in a 71-year-old woman. Clinicopath-
ological Conference, Am. J. Med., 79, 373, 1985.
2. Bulens, C., De Vries, W. A. E. J., and Van Crevel, H., Benign intracranial hypertension, J. Neurol.
Sci., 40, 147, 1979.
3. Buchheit, W. A., Burton, C., Haag, B., and Shaw, D., Papilledema and idiopathic intracranial hyper-
tension, N. Engl. J. Med., 280, 938, 1969.
4. Lipton, H. L. and Michelson, P. E., Pseudotumor cerebri syndrome without papilledema, JAMA, 220,
1591, 1972.
5. Dinarello, C. A. and Wolff, S. M., Approach to the patient with fever of unknown origin, in Principles
of Practice of Infectious Diseases, Mandell, G. L., Douglas, R. G., Jr., and Bennett, J. E., Eds., John
Wiley & Sons, New York, 1985, 347.
6. Smith, H., Bannister, B., and O’Shea, M. J., Cerebrospinal fluid immunoglobulins in meningitis, Lancet,
2, 591, 1973.
7. Raskin, R. H., Repeat lumbar puncture in the diagnosis of meningitis, Pediatrics, 54, 34, 1974.
8. Fischer, G. W., Brenz, R. W., Alden, E. R., and Beckwith, B., Lumbar puncture and meningitis, Am.
J. Dis. Child., 129, 590, 1975.
9. Feigin, R. D. and Shackelford, P. G., Value of repeat lumbar puncture in the differential diagnosis of
meningitis, Med. Intell., 289, 572, 1973.
10. Sarff, L. D., Platt, L. H., and McCracken, G. H., Jr., Cerebrospinal fluid evaluation in neonates:
comparison of high risk infants with and without meningitis, J. Pediatr., 88, 473, 1976.
11. McCracken, G. H., Jr. and Sarff, L. D., Endotoxin in cerebrospinal fluid: detection in neonates with
bacterial meningitis, JAMA, 235, 617, 1976.
12. Ellner, J. J. and Bennett, J. E., Chronic meningitis, Medicine, 55, 341, 1976.
170 Unexplained Fever

13. Bonnal, J., Descuns, P., and Duplay, J., Les absces encéphaliques a l’ere des antibiotiques. Etude
statistique de 547 observations, dans Rapport Presente a la Reunion Annuelle de la Société de Neurochirurgie
de Langue Française, Masson, Paris, 1960.
14. Kiser, J. L. and Kendig, J. H., Intracranial suppuration. A review of 139 consecutive cases, with electron
microscopie observations in 3, J. Neurosurg., 20, 494, 1963.
15. Carey, M. E., Chou, S. N., and French, L. A., Experience with brain abscesses, J. Neurosurg., 36, 1,
1972.
16. Gregory, D. H., Messner, R., and Zinneman, H. H., Metastatic brain abscess, Arch. Intern. Med., 119,
25, 1967.
17. Morgan, H., Wood, M. W., and Murphy, F., Experience with 88 consecutive cases of brain abscess,
J. Neurosurg., 38, 698, 1973.
18. Garfield, J. S., Management of supratentorial intracranial abscess: a review of 200 cases, Br. Med. J., 2,
7, 1969.
19. Gsell, O., Leptospirosen, in Klinik der gegenwart, Vol. 2, Bock, H. E., Gerock, W., and Hartmann, F.,
Eds., Urban and Schwarzenberg, München, 1974, 121.
20. Beeson, P. B. and Hankey, D. D., Leptospiral meningitis, Arch. Intern. Med., 89, 575, 1952.
21. Perez, G. O., Rothfield, N., and Williams, R. C., Immunecomplex nephritis in bacterial endocarditis,
Arch. Intern. Med., 136, 334, 1976.
22. Arnold, S. B., Valone, J. A., Askenase, P. W., Kashgarian, M., and Freedman, L. R., Diffuse
glomerulonephritis in rabbits with streptococcus viridans endocarditis, Lab. Invest., 32, 681, 1975.
23. Gupta, O. K., Saksena, P. N., and Gupta, N. N., A clinical study of 856 patients with diphtheria, Indian
J. Pediatr., 40, 93, 1975.
24. Adams, M., Rhyner, P. A., Day, J., De Armond, S., and Smuckler, E. A., Whipple’s disease confined
to the central nervous system, Ann. Neurol., 21, 104, 1987.
25. Gelfand, M., Neurological complications of parasitic disease, in Tropical Neurology, Spillaine, J. D., Ed.,
London, 1973.
26. Hegglin, R., Differentialdiagnose innerer Krankheiten, 11th ed., Georg Thieme, Stuttgart, 1968.
27. Kennard, C. and Swash, M., Acute viral encephalitis, Brain, 104, 129, 1981.
28. Meyer, H. M., Jr., Johnson, R. T., Crawford, I. P., Dascomb, H. E., and Rogers, N. G., Central
nervous system syndromes of “ viral” etiology. A study of 713 cases, Am. J. Med., 29, 334, 1960.
29. Azimi, P. H., Cramblett, H. G., and Haynes, R. E., Mumps meningoencephalitis in children, JAMA,
207, 509, 1969.
30. Levitt, L. P., Rich, T. A., Kinde, S. W., Lewis, A. L., Gates, E. H., and Bond, J. O., Central nervous
system mumps. A review of 64 cases, Neurology, 20, 829, 1970.
31. Drachman, D. A. and Adams, R. D., Herpes simplex and acute inclusion body encephalitis, Arch.
Neurol., 7, 61, 1962.
32. Johnson, R. T. and Mims, C. A., Pathogenesis of viral infections of the nervous system, N. Engl. J.
Med., 278, 23; 87; 1968.
33. Davis, J. M., Davis, K. R., Kleinman, G. M., Kirchner, H. S., and Taveras, J. M., Computed
tomography of herpes simplex encephalitis, with clinicopathological correlation, Radiology, 129, 409, 1978.
34. Schroth, G., Gawehn, J., Thorn, A., Vallbracht, A., and Voigt, K., Early diagnosis of herpes simplex
encephalitis by MRI, Neurology, 37, 179, 1987.
35. Eisner, B., Schwarz, E., Mando, O. G., Maiztegui, J., and Vilches, A., Pathology of 12 fatal cases
of Argentine hemorrhagic fever, Am. J. Trop. Med. Hyg., 22, 229, 1973.
36. Child, P. L., MacKengre, R. B., Valverde, L. R., and Johnson, K. M., Bolivian hemorrhagic fever.
A pathologic description, Arch. Pathol., 83, 434, 1967.
37. Chopra, J. S., Banerjee, A. K., Murthy, J. M. K., and Pal, S. R., Paralytic rabies: a clinico-pathological
study, Brain, 103, 789, 1980.
38 Wear, D. J., Margileth, A. M., Hadfield, T. L., Fischer, G. W., Schlager, C. J., and King, F. M.,
Cat scratch disease: a bacterial infection, Science, 221, 1403, 1983.
39. Pollen, R. H., Cat scratch encephalitis, Neurology, 18, 1031, 1968.
40. Gadoth, N., Oren, A., Keynan, A., and Krugliak, L., Cat scratch disease presenting as status epilepticus,
Isr. J. Med. Sci., 15, 162, 1979.
4L Gorman, R. J., Saxon, S., and Snead, O. C., Neurologic sequelae of Rocky Mountain Spotted fever,
Pediatrics, 67, 354, 1981.
42. Miller, J. Q. and Price, T. R., Tick-bom typhus including Rocky Mountain Spotted fever, in Handbook
of Clinical Neurology, Vol. 34, Vinken, P. J. and Bruyn, G. W., Eds., Elsevier, Amsterdam, 1978, 651.
43. Lyle, W. H. and Chamberlain, R. N., Eds., Epidemic neuromyasthenia 1934— 1977: current approaches,
Postgrad. Med. J., 54, 705, 1978.
44. McEvedy, C. P. and Beard, A. W., Concept of benign myalgic encephalomyelitis, Br. Med. J., 1, 11,
1970.
 171

45. Dillon, M. J., Marshall, W. C., Dudgeon, J. A., and Steigman, A. J., Epidemic neuromyasthenia:
outbreak among nurses at children’s hospital, Br. Med. J., 1, 301, 1974.
46. Weil, M. L., Itabashi, H. H., and Cremer, N. E., Chronic progressive panencephalitis due to rubella
virus simulating subacute sclerosing panencephalitis, N. Engl. J. Med., 292, 994, 1975.
47. Case records of the Massachusetts General Hospital (Case 41 — 1987), N. Engl. J. Med., 317, 946, 1987.
48. Pitlik, S. D., Fainstein, V., Bolivar, R., Guarda, L., Rios, A., Mansell, P. A., and Gyorkey, F.,
Spectrum of central nervous system complications in homosexual men with acquired immune deficiency
syndrome, J. Infect. Dis., 148, 771, 1983.
49. Snider, W. D., Simpson, D. M., Nielsen, S., Gold, J. W. M., Metroka, C. E., and Posner, J. B.,
Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients, Ann. Neurol.,
14, 403, 1983.
50. Randall, W. C., Rawson, R. O., McCook, R. D., and Peiss, C. N., Central and peripheral factors in
dynamic thermoregulation, J. Appl. Physiol., 18, 61, 1963.
51. Myers, R. D. and Yaksh, T. L., Thermoregulation around a new “ set-point” established in the monkey
by altering the ratio of sodium to calcium ions within the hypothalamus, J. Physiol., 218, 609, 1971.
52. Bauer, H. G., Endocrine and other clinical manifestations of hypothalamic disease: a survey of 60 cases
with autopsies, J. Clin. Endocrinol., 14, 13, 1954.
53. Wolff, S. M., Adler, R. C., Buskirk, E. R., and Thompson, R. H., A syndrome of periodic hypothalamic
discharge, Am. J. Med., 36, 956, 1964.
54. Marilus, R., Leiba, S., Barkan, A., Arie, R., and Blum, I., Pyrexia of unknown origin. Presenting
sign of hypothalamic hypopituitarism, Postgrad. Med. J., 57, 310, 1981.
55. Guidotti, T. L., Charness, M. E., and Lamon, J. M., Acute intermittent porphyria and Kluver-Bucy
syndrome, Johns Hopkins Med. J., 145, 232, 1979.
56. Scadding, J. G., Sarcoidosis, Eyre and Spottiswoode, London, 1967.
57. Mayock, R. L., Bertrand, P., Morrison, C. E., and Scott, J. H., Manifestations of sarcoidosis, Am.
J. Med., 35, 67, 1963.
58. Manor, R. S., Vogt-Koyanagi-Harada syndrome and related diseases, in Handbook o f Clinical Neurology,
Vinken, P. J. and Bruyn, G. W., Eds., Vol. 34, Part II, North Holland, Amsterdam, 1978, 513.
59. Stauder, E., Lethal catatonia, Arch. Psychiatr. Nervenkr., 102, 614, 1934.
60. Shulack, N. R., Exhaustion syndrome in excited psychotic patients, Am. J. Psychiatry, 102, 466, 1945.
61. Malamud, N. and Boyd, D., Sudden “ brain death” in schizophrenia with extensive lesions in the cerebral
cortex, Arch. Neurol. Psychiatry, 41, 352, 1939.
62. Penn, H., Racy, J., Lapham, L., Mandel, M., and Sandt, J., Catatonic behavior, viral encephalopathy
and death, Arch. Gen. Psychiatry, 27, 758, 1972.
63. Wilson, L. G., Viral encephalopathy mimicking functional psychosis, Am. J. Psychiatry, 133, 165, 1976.
64. Dinarello, C. A. and Wolff, S. M., Molecular basis of fever in humans, Am. J. Med., 72, 799, 1982.
65. Weinstein, L., Clinically benign fever of unknown origin: a personal retrospective, Rev. Infect. Dis., 7,
692, 1985.
66. Adams, R. D. and Victor, M., Principles of Neurology, 2nd ed., McGraw-Hill, New York, 1981, 1023.
67. Caroff, S. N., The neuroleptic malignant syndrome, J. Clin. Psychiatry, 41, 79, 1980.
68. Hermesh, H., Huberman, M., Radvan, H., and Kott, E., Recurrent neuroleptic malignant syndrome
due to tiapride and haloperidol: the possible role of D-2 dopamine receptors, J. Nerv. Ment. Dis., 172,
692, 1984.
69. Comarr, A. E., Differential diagnosis of high fevers peculiar to spinal cord injury patients, J. Indian Med.
Prof, 5, 2223, 1958.
70. Pledger, H. G., Disorders of temperature regulation in acute traumatic paraplegia, J. Bone Jt. Surg., 44B,
110, 1962.
71. Kneisely, L. W., Hyperhydrosis in paraplegia, Arch. Neurol., 34, 536, 1977.
72. Young, R. R., Asbury, A. K., Corbett, J. L., and Adams, R. D., Pure pan-dysautonomia with recovery,
Brain, 98, 613, 1975.
73. Frank, Y., Kravath, R. E., Inoue, K., Hirano, A., Poliak, C. P., Rosenberg, R. N., and Weitzman,
E. D., Sleep apnea and hypoventilation syndrome associated with acquired nonprogressive dysautonomia:
clinical and pathological studies in a child, Ann. Neurol., 10, 18, 1981.
74. Avram, J., Freundlich, M., and Meirsdorf, A., Spinal epidural empyema in a child, Harefuah, 89, 323,
1975.
75. Miller, W. H. and Hesch, J. A., Nontuberculous spinal epidural abscess: report of a case in a 5-week-
old infant, Am. J. Dis. Child., 104, 269, 1962.
76. Denborough, M. A. and Lovell, R. R. H., Anaesthetic deaths in a family, Lancet, 2, 45, 1960.
77. Fagius, J., Westerberg, C. E., and Olsson, Y., Acute pandysautonomia and severe sensory deficit with
poor recovery. A clinical neurophysiological and pathological case study, J. Neurol. Neurosurg. Psychiatry,
46, 725, 1983.
172 Unexplained Fever

78. Gadoth, N., Margalith, D., Schlien, N., Svetliza, E., and Litwin, A., Presence of fungiform papillae
in classical dysautonomia, Johns Hopkins Med. J ., 151, 298, 1982.
79. Moses, S. W., Rotem, Y., Jagoda (Gadoth), N., Talmor, N., Eichhorn, F., and Levin, S., A clinical,
genetic and biochemical study of familial dysautonomia in Israel, Isr. J. Med. Sei., 3, 358, 1967.
80. Pearson, J., Axelrod, F., and Dancis, J., Current concepts of dysautonomia: neuropathological defects,
Ann. N.Y. Acad. Sei., 228, 288, 1974.
81. Esterly, N. B., Cantolino, S. J., Alter, B., and Brusilow, S. W., Pupillotonia, hyporeflexia and segmental
hypohidrosis: autonomic dysfunction in a child, J. Pediatr., 73, 852, 1968.
82. Wolfe, S. M. and Henkin, R. I., Absence of taste in type II familial dysautonomia: unresponsiveness to
methacholine despite the presence of taste buds, J. Pediatr., 77, 103, 1970.
83. Gadoth, N. and Sandbank, U., Involvement of dorsal root ganglia in Fabry’s disease, J. Med. Genet.,
20, 309, 1983.
84. Cable, W. J. L., Kolodny, E. H., and Adams, R. D., Fabry’s disease: impaired autonomic function,
Neurology, 32, 498, 1982.
85. Hindfelt, B., The prognostic significance of subfebrility and fever in ischemic cerebral infarction, Acta
Neurol. Scand., 53, 72, 1976.
86. Prezlomski, M. M., Roth, R. M., Gleckman, R. A., and Marcus, E. M., Fever in the wake of a stroke,
Neurology, 36, 427, 1986.
87. Alvarez, W. C., Practical Leads to Puzzling Diagnoses, Lipincott, Philadelphia, 1958, 367.
88. Berger, H., An unusual manifestation of epilepsy: fever, Postgrad. Med., 40, 479, 1966.
89. Cohn, D. F., Avrahami, E., and Dalos, E., Thermal epilepsy manifest as fever attacks, Ann. Intern.
Med., 101, 569, 1984.
90. Semel, J. D., Complex partial status epilepticus presenting as fever of unknown origin, Arch. Intern. Med.,
147, 1571, 1987.
91. Wachtel, T. J., Steele, G. H., and Day, J. A., Natural history of fever following seizures, Arch. Intern.
Med., 147, 1153, 1987.
 173

Chapter 11

UNEXPLAINED FEVER ASSOCIATED WITH

MUSCULOSKELETAL DISORDERS

Serge Kernbaum

INTRODUCTION
Pain and/or stiffness of joints, paraarticular structures, muscles, and tendons are in some
cases the unique symptoms associated with unexplained fever (U.F.). We shall of course
exclude the isolated myalgias frequent in febrile patients.
The approach to the patient with musculoskeletal symptoms and U.F. relies on a complete
history and physical examination as described in previous chapters, with particular attention
to the joint and muscle areas: as usual it follows a sequence of inspection, palpation, and
determination of the range of motion of each involved area; the involved joints and/or adjacent
structures should be compared with those of the examining physician or with his other
uninvolved contralateral joints, thus the range of motion will be precisely measured.
We shall first list in Table 1 the rheumatic diseases which may present as U.F., according
to the American Rheumatism Association classification.1
In addition to these rheumatic disorders in the present chapter, we shall also review the
bone lesions which could present as U.F., i.e., those of infectious or neoplastic origin.

RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a systemic, chronic disease of unknown etiology, affecting
patients over the age of 15, with a marked female predominance, characterized by a non-
specific, usually symmetric inflammation of the peripheral joints, which may result in a
progressive destruction of articular and paraarticular structures.
It is a rare cause of U.F., only when its mode of onset is atypical. Even in classic forms,
isolated constitutional symptoms may often precede the joint involvement.1They are usually
(in about 2/3 of cases) followed by insidious joint symptoms, with aching and stiffness of
wrists and fingers, grossly symmetrical, then followed by frank articular inflammation.
Neither can such a classical onset be mistaken among the U.F., nor Felty’s syndrome because
the splenomegaly and granulocytopenia occur in a long standing RA,2 in contrast to the
much rarer atypical modes of onset listed in Table 2.
The diagnosis of these manifestations is uneasy; one has to discuss rheumatic fever,
bacterial arthritis, gout, systemic lupus erythematosus, and other “ connective tissue” dis-
orders.
The search of rheumatoid nodules in the olecrane bursa and along the shaft of the ulna
must then be carefully undertaken.
The roentgenograms are of no diagnostic value at the onset of RA (revealing only slight
osteoporosis, effusions, and soft tissue swelling) nor are the biologic markers of inflammation
(elevated ESR . . . ). Some laboratory tests may be helpful:1,2

• The search of the rheumatoid factor with the latex agglutination test and the sheep
erythrocyte agglutination test
• The search of lupus erythematosus cell and fluorescent antinuclear antibody, which
may be present in RA
174 U nex p la in ed F e ve r

TABLE 1
Rheumatic Diseases Which may Present as U.F. (According to the ARA
Classification1)

Polyarthritis of unknown etiology

Rheumatoid arthritis
Juvenile rheumatoid arthritis
Adult Still’s disease
Ankylosing spondylitis
“ Connective tissue” disorders (except polymyositis and dermatomyositis)
Rheumatic Fever
Nonarticular rheumatism
Eosinophilic fasciitis
Various diseases with which arthritis is frequently associated
Sarcoidosis, relapsing polychondritis, regional enteritis, ulcerative colitis, Whipple’s disease, familial Mediter-
ranean fever
Arthritis associated with infectious agents
Arthritis associated with endocrine, metabolic and deficiency diseases, thyroid diseases, gout
Neoplasms
Allergy and drug reactions
Arthritis due to serum sickness, drug-induced lupus erythematosus
Arthritis due to drugs
Miscellaneous disorders
Behcet’s syndrome, erythema nodosum, relapsing panniculitis, erythema multiforme

TABLE 2
Atypical Modes of Onset of RA1-4

Acute or subacute polyarticular arthritis

Localized acute or subacute oligoarticular arthritis
Monoarthritis of many weeks duration
Tenosynovitis of many weeks duration
Knee or ankle post-traumatic arthritis
Palindromic rheumatism
Extraarticular initial manifestation
Subcutaneous nodules (rheumatoid granulomas)
Raynaud’s phenomenon
Pleurisy, with or without effusion
Pericarditis

In the case of arthritis of a large joint, the synovial fluid must be analyzed: it is an exudate:
10,000 cells/mm3; 35—50% granulocytes; proteins 4 g/100 ml.
Some findings are helpful, although nonspecific:

— a low complement level

— the presence of rheumatoid factor
— the presence of RA cells

It excludes other arthritis (bacterial, crystalline). When subcutaneous and subperiostal nod-
ules exist, their biopsy is of great value.
When a monoarticular arthritis of many months duration remains undiagnosed, a synovial
biopsy must be undertaken. It may show nonspecific but compatible abnormalities: lining
cell hyperplasia, edema and infiltration of the synovial membrane by various cells: granu-
locytes, plasmocytes, lymphocytes, and giant cells.
As the diagnosis may be difficult to affirm, the American Rheumatism Foundation has
established positive and exclusive criteria, more useful for classification than for bedside
diagnosis1 in order to rule out the other causes of arthritis; these are listed in Table 3.
 175

TABLE 3
Diagnostic Criteria for Rheumatoid Arthritis1

A. Classical RA
This diagnosis requires seven of the following criteria. In criteria 1 through 5 the joint signs or symptoms
must be continuous for at least 6 weeks
1. Morning stiffness
2. Pain on motion or tenderness in at least one joint (observed by a physician)
3. Swelling (soft tissue thickening or fluid) in at least one joint (observed by a physician)
4. Swelling (observed by a physician) of at least one other joint (any interval free of joint symptoms
between the two joint involvements may not be more than 3 months)
5. Symmetrical proximal joint swelling (observed by a physician) with simultaneous involvement of the
same joint on both sides of the body
6. Subcutaneous nodules (observed by a physician) over bony prominences, on extensor surfaces or in
juxta-articular regions
7. Roentgenographic changes typical of rheumatoid arthritis (which must include at least bony décalci-
fication localized to or most marked adjacent to the involved joints and not just degenerative changes
— which do not exclude patients)
8. Positive agglutination-test-demonstration of the “ rheumatoid factor” by any method positive in not
over 5% of controls
9. Poor mucin precipitate from synovial fluid
10. Characteristic histologic changes in synovium with $=3 of the following: marked villous hypertrophy;
proliferation of superficial synovial cells often will palisading; marked infiltration of chronic inflam-
matory cells (lymphocytes or plasma cells predominating) with tendency to form “ lymphoid nodules” ;
deposition of compact fibrin either on surface or interstitially
11. Characteristic histologic changes in nodules showing granulomatous foci with central zones of cell
necrosis, surrounded by a palisade of proliferated macrophages, and peripheral fibrosis and chronic
inflammatory cell infiltration, predominantly perivascular.
B. Definite RA
This diagnosis requires five of the above criteria, with the same length of time as A for criteria 1 through 5
C. Probable RA
This diagnosis requires three of the above criteria with the same length of time as A and B for criteria 1
through 5
D. Possible RA
Simplest, different criteria, with a shorter duration, are proposed. We shall not list them as, in our experience,
they are of no value in a patient with U.F.
E. Exclusions
1. Typical rash of systemic lupus erythematosus
2. High concentration of lupus erythematosus cells
3. Histologic evidence of periarteritis nodosa
4. Weakness of neck, trunk and pharyngeal muscles or persistent muscle swelling or dermatomyositis
5. Definite scleroderma (not limited to the fingers)
6. A clinical picture characteristic of rheumatic fever
7. A clinical picture characteristic of gouty arthritis
8. Tophi
9. A clinical picture characteristic of acute infectious arthritis
10. Tubercle bacilli in the joints or histological evidence of joint tuberculosis
11. A clinical picture characteristic of Reiter’s syndrome
12. A clinical picture characteristic of the shoulder-hand syndrome
13. A clinical picture characteristic of hypertrophic osteoarthropathy
14. A clinical picture characteristic of neuroarthropathy
15. Homogentisic acid in the urine
16. Histologic evidence of sarcoid or positive Kveim test
17. Multiple myeloma
18. Characteristic skin lesions of erythema nodosum
19. Leukemia or lymphoma
20. Agammaglobulinemia

Note: They are divided in classical, definite, probable and possible and any one of the features listed under
“ exclusions” will exclude RA.
176 Unexplained Fever

Beyond the scope of our chapter is the discussion of the diagnosis and the nosologic
place of the definite seronegative arthritis.

POLYMYOSITIS AND DERMATOMYOSITIS

Polymyositis is an inflammatory myopathy of unknown cause, called dermatomyositis
if the characteristic skin rash is present. It may be associated with neoplasia. As it is a
heterogeneous group of disorders, sometimes called “ polymyositis complex” , with overlaps
with other connective tissue diseases, many schemes of classification have been proposed,
and none of them has proved entirely satisfactory.5 6
It is a rare cause of U.F. Fever is frequent, usually of low grade, except in acute forms.6

CLINICAL FEATURES5 6
Polymyositis
Muscular deficiency is a prominent feature: symptoms appear within a few weeks or
more suddenly, affecting mainly the girdles, beginning usually in the pelvic one, with
progressive proximal muscular weakness, associated with local pain and objective muscular
abnormalities: edema followed by amyotrophia, preceding an inconstant myosclerosis.

Dermatomyositis
• Lilac discoloration of the upper eyelids
• Generalized facial or periorbital and/or mucosal edema
• Poikilodermia, i.e., erythema, scaling, dermal atrophy and dusky red patches or linear
streaks over the knuckles, elbows, knees, medial malleoli, forehead, face, neck, and
upper chest and back

SYSTEMIC FEATURES
• Arthralgia and arthritis
• Raynaud’s phenomenon
• Cardiac symptoms (mainly electric)
• Pulmonary fibrosis
• Varia: involvement of eyes, lymph nodes, endocrine glands, central nervous system6

CLASSIFICATION
None is entirely satisfactory, but a classification is needed because of the heterogeneity
of the disease as well as of its associations. We propose a synthesis of the classifications
of Bohan and Peters5 and of Serratrice and Schiano:6

• Adult primary idiopathic polymyositis

• Adult primary idiopathic dermatomyositis
• Dermatomyositis or polymyositis associated with neoplasm
• Childhood dermatomyositis or polymyositis associated with vasculitis
• Dermatomyositis or polymyositis associated with collagen-vascular disease
• Localized (to one muscle or one group of muscles) polymyositis, either inflammatory
or myositis fibrosa

DIAGNOSIS
It is often difficult, especially at the beginning of the disease, as there are no generally
accepted criteria. We shall present successively the criteria of the two most useful studies
in clinical practice we are aware of.
 177

Diagnostic Criteria of Bohan and Peter5

1. Symmetrical weakness of the limb-girdle muscles and anterior neck flexors, with or
without dysphagia or respiratory muscle involvement, progressive over weeks to months
2. Muscle-biopsy evidence of necrosis of Type I and Type II fibers, phagocytosis, de-
generation with basophilic large vesicular sarcolemmal nuclei and prominent nucleoli,
atrophy in a perifascicular distribution, variation in fiber size and an inflammatory,
often perivascular exudate.
3. Elevation in serum of musculoskeletal enzymes (mainly creatine phosphokinase).
4. Electromyographic triad of short, small, polyphasic motor units, fibrillations, positive
sharp waves and insertional irritability, and bizarre, high-frequency repetitive dis-
charges
5. Dermatologic features

Definite diagnosis — Requires three or four criteria (plus the rash) for dermatomyositis
and four (without the rash) for polymyositis; probable diagnosis requires two (plus the rash)
for dermatomyositis and three (without the rash) for polymyositis. Exclusions are

• Evidence of central or peripheral neurologic disease (although exceptionally, nervous

involvement has been described)6
• Evidence of familial muscular dystrophy
• Granulomatous myositis
• Infections: trichinosis, schistosomiasis, trypanosomiasis, toxoplasmosis, and staphy-
lococcal infection
• Recent use of various drugs (clofibrate . . . ) and toxins (alcohol . . . )
• Rhabdomyolysis
• Metabolic disorders such asMcArdle syndrome
• Various endocrinopathies (same remark as for neurologic disease)
• Myasthenia gravis

Diagnostic Criteria of Serratrice and Schiano6

They rely on a score:
Criteria Score

Clinical signs and symptoms

Proximal myalgia 2
Proximal weakness 1
Typical skin rash 3
Elevation of seric muscular enzymes or of 2
creatinuria
Electric signs
Fibrillation, increased irritability 1
Polyphasic potentials and high frequency 2
repetitive discharges
Histologic signs
Necrosis 1
Inflammatory exudate 1
Atrophy in a perifascicular distribution 4
Corticosteroid muscular response
Myalgias 1
Weakness 3

The definite diagnosis requires at least one clinical sign or symptom and a score ^ 6 .
178 Unexplained Fever

OTHER MYOSITIS WHICH MAY PRESENT AS U.F.

The inflammation of skeletal muscles is uncommon and a very rare cause of U.F. Among
the various causes found in reviews of myositis,7 9 we shall list:

• “ Tropical Myositis” or Staphylococcal Pyomyositis:9

It is an endemic disease in tropical areas, involving usually one muscle, which manifests
in one of three clinical syndromes or stages depending on the diagnostic interval: the
first stage, “ invasive” , is marked by increasing pain associated with edema, a hard
muscle and low-grade fever. Usually patients are seen at the second stage, 10—21
days from the onset, the “ suppurative” stage, marked by high fever, pain, muscle
edema, and tenderness, leukocytosis and eosinophilia; the “ late” stage includes hectic
fever, exquisite tenderness, and obvious fluctuance of the involved muscle(s). Needle
biopsy is usually diagnostic.
• A psoas isolated abscess8:
This is of hematogenous or adjacent origin usually confined to the psoas facia, may
follow the muscle and emerge in the groin. It usually complicates an intraabdominal
infection (diverticulitis, appendicitis), or a pyogenic or tuberculous vertebral osteo-
myelitis, or rarely a perinephric abscess or an infected retroperitoneal hematoma. Its
manifestations associate fever, pain (localized or irradiated and referred to the hip or
knee) and a limp; then appears a flexion deformity of the hip. Pain during the flexion
of the thigh is evocative. Roentgenograms may show a bulge of the psoas line, or
calcifications (evocative of tuberculosis), or gas (evocative of anaerobic bacteria).
• Trichinosis and Toxoplasmosis may uncommonly present as a febrile polymyositis
(see Chapter 20).
• Infective endocarditis may be associated with prominent myalgias, usually in con-
junction with arthralgias.814
• Tuberculous myositis is rare. Its diagnosis is difficult when it is the first manifestation
of the disease and presents as one tumor or as many muscular nodules. The presence
of calcifications is evocative. The diagnosis relies on histologic as well as bactériologie
data10
• A rhabdomyolysis associated with a systemic infection11 could theoretically present
as U.F.
• Noninfectious myositis7
Myositis can be the manifestation of connective tissue diseases as well as of
sarcoidosis (see Chapter 18).
Less well known are the myositis of Behcet’s syndrome12 (see Chapter 18) and
one case of association of poly synovitis, polymyositis, and hyperviscosity.13
• Pyogenic myositis particularly those due to anaerobic bacteria cannot present as U.F.
because the diagnosis is affirmed before the length of time necessary for the definition
of U.F.

DIFFUSE FASCIITIS WITH EOSINOPHILIA (SCHULMAN’S

SYNDROME)

This rare syndrome of unknown origin could theoretically be a cause of U.F. as among
the 72 cases known in 1972, 10 were associated with fever.15
It affects predominantly adult males, occurs more often in autumn and winter, and in
about V3 of cases follows strong physical exercise.1516
Symptoms usually include pain, muscular weakness, and a limitation of the articular
range of motion.
 179

TABLE 4
Viral Agents Associated with Arthritis and
a Fever Lasting at Least 2 Weeks

Hepatitis B virus
Epstein-Barr virus
Rubella virus
Adenovirus (type 7)
Mumps virus
Coxsackie B virus
HIV

Adapted from References 1, 17—20, and personal experi-

ence of the author.

The most evocative clinical sign is the palpation of the subcutaneous infiltration, sparing
skin and muscles, located electively in the proximal part of limbs, grossly symmetrical.1516
The hypereosinophilia is nearly constant.
The biopsy confirms the diagnosis, showing swollen fascias with a collagen hypertrophy
and a prominent infiltration of mononuclear cells (lymphocytes, plasmocytes, and histiocytes)
and sometimes of eosinophils.1516
Rare systemic manifestations can be associated with this syndrome:15 aplastic anemia,
hemolytic anemia, thrombopenic purpura, pericarditis, Sjogren syndrome, Raynaud’s phe-
nomenon, involvement of esophagus, lung and thyroid, and diabetes mellitus. Many recent
cases were described, associated with tryptophane ingestion.

INFECTIOUS ARTHRITIS
The septic involvement of synovitis is a rare cause of U.F.; it is associated with a
persistent fever, mainly when the affected joint(s) is(are) deeply located; the septic involve-
ment of bursae (bursitis) and/or of tendon sheath (tendinitis) although sharing some features
of septic arthritis is not a cause of unexplained fever.
To begin, we shall list in Table 4, the viral agents associated with arthritis and persistent
fever (see Chapter 19 for diagnosis); they cause mono- or polyarthropathies generally as-
sociated with systemic involvement.
Fungal arthritis — Supported by predisposing factors and serology, its diagnosis relies
on the isolation of the agent in the synovial fluid. Fungal arthritis is subacute or chronic
and its main etiologic agents are Candida species. Sporothrix schenkii, Coccidioides immitis,
and Cryptococcus neoformans. 17
Parasitic rheumatism21,22 — Joint manifestations are very rare in parasitic infections,
they are acute and transient, one or more joints being involved. They can have a triple
physiopathology:

• There can be parasites within the joint, demonstrable by aspiration and/or arthroscopy:
for example, filariasis (loa loa . . . )
• The equivalent of reactive arthritis exists (see below) due to Strongyloides stercoralis,
Taenia saginata . . .
• Finally, the parasite may have contributed to bacterial (mainly staphylococcal) super-
infection, as we have observed with Dracunculus medinensis.

The reader is referred to Chapter 20 for more details on the parasitic diseases.
Bacterial arthritis (mycobacteria excluded) — Only arthritis of deep joints can present
180 Unexplained Fever

as U.F., i.e., hip, sacroiliac, and pubic symphysis bacterial infections. The predisposing
factors are those of any bacterial arthritis:117

• Immunodépression: corticosteroid treatment, diabetes mellitus . . .

• Intraarticular therapeutic injection
• Preexisting arthritis (rheumatoid arthritis . . . ) or trauma
• Intravenous drug abuse
• Concomitant infectious focus

The étiologie agents are those of any bacterial arthritis.117’23’24

• Staphylococcal aureus is by far the most frequent; S. epidermidis is rare

• Hemophilus influenzae type b is frequent in patients under 2 years of age
• Gram-negative bacilli mainly in immunodepressed patients, in case of IV drug abuse . . .
• Gonococcus is frequent in adolescent and young adults, mainly females: a penicillin
trial may be helpful
• Anaerobic bacteria are probably underestimated
• Brucella species must be evoked in case of contact with cattle; the serodiagnosis is
helpful
• Streptococcus species, e.g., B in neonates . . .

Clinical features — They have in common fever and malaise, and the usual (but
inconstant) monoarticular involvement, contrasting with inflammatory rheumatism. The
complete clinical examination, always necessary, will focus on the predisposing factors, the
search of an abscess (psoas . . . ), the search of an occult infectious focus and the assessment
of the integrity of all the joints.

Specific Signs and Symptoms:

Hip arthritis of children and adults25 — The main localizing feature is local pain,
sometimes referred to the region of the knee, which appears healthy on examination. There
is a tenderness on hip movement, and the spasm of the muscles controlling the joint leads
to a reduction of its movements.
Hip arthritis in infants and newborns26 — There is for a long time no localizing sign
or symptom and the arthritis is often discovered late, manifested by an abscess, and/or
edematous thigh or only by destructions seen on systematic X-ray examination.
Saeroiliitis27 — A buttock pain is the first symptom, radiating in about half of the cases
to the posterior face of the thigh. A limp is often present. Pain may be induced by pressure
on the joint or (of greater value) by orthopedic maneuvers which produce sacroiliac joint
movement.
Pubic symphysitis32 — Formerly very unusual, it may be seen in drug addicts. Pain is
the localizing symptom.
Laboratory data:

• The usual elevated erythrocyte sedimentation rate and leukocytosis (inconsistent) are
of no value.
• Systematic blood cultures are usually negative.

Radiologic findings:
The comparative (with the contralateral one) study of the affected joint is disappointing
in the beginning of the process, as alterations usually appear after 2 weeks. But an edema
of soft tissue around the hip is often present. The first bone lesions are osteolytic: the
 181

demineralization starts at the margins of the subchondral bone, which appears blurred, then
there is a progressive narrowing of the joint space, later followed by new bone formation.
A C.T. scan is usually not necessary, but it allows the confirmation of the beginning
lesions as well as the existence of a small abscess.
Radionuclide studies may be of early diagnostic value as they can diagnose a diffuse
periarticular increase of fixation before any radiographic abnormality.29*31 However, it can
be normal in the first week, and there is a physiological hyperfixation in the sacroiliac area.27
Better results are obtained by the sequential use of technetium phosphate and gallium citrate
(99mTc and 67Ga) instead of the single use of one of these two compounds.30,31 The indium-
111-labeled polymorphonuclear technique is less sensitive than the previous techniques but
is much more specific for infection.60
Articular fluid aspiration is the next step. The examination of the fluid must in-
clude:23*28

• Microscopy for crystal elimination and the count of pus cells, (which typically exceeds
10,000/ml, but varies widely); overlaps may however exist between septic and in-
flammatory arthritis.
• Gram stain may inconstantly pinpoint bacteria.
• Chemical analysis may be useful when it shows a clear-cut lowering of glucose level
(normally equal to that of blood) and an elevation of the lactate concentration; but
inconclusive intermediate lactate levels may be found, mainly in an antibiotic-treated
patient or in gonococcal arthritis.28
• Systematic cultures of the fluid on various media must be undertaken. A delay of at
least 24 to 48 h is necessary and the cultures can be negative if antibiotics have been
given.

Lyme arthritis is a peculiar bacterial arthritis. Lyme disease (originally called lyme
arthritis) is characterized by erythema chronicum migrans (a typical expanding annular skin
lesion) occurring after a tick bite, sometimes accompanied by headache, stiff neck, myalgias,
arthralgias, lymphadenopathy, fatigue, and fever. Meningoencephalitis may occur weeks or
months later, as well as peripheral neuropathies, myocarditis, or heart block and frank
arthritis.38 It has recently been shown that if it is due to a newly recognized spirochete,
Ixodes dammini,39 a serodiagnosis is available.

REACTIVE ARTHRITIS

This term has been recently introduced to describe several forms of ill-understood joint
diseases with sterile joint fluid and infection elsewhere in the body, which occur preferentially
in HLA-B 27 antigen patients.33,59
According to our experience it is a true cause of U.F. The causal infectious agents as
well as the infectious focus are variable:

• The agent may be a bacteria (Yersinia species,34 Staphylococcus epidermidis35 . . .

or a parasite (5. stercoralis, T. saginata22 . . . )
• The infectious focus may be occult: digestive tract,22,34 lymph node,34 peritoneum,35
skin (e.g., Acne conglobata rheumatism, of which we have seen one case presenting
as U.F.;36 Hydradenitis suppurativa31).

To these infectious foci accompanied by reactive arthritis we could possibly add the sterile
arthritis of bacterial endocarditis.14
Moreover, the spectrum of the various reactive arthritis is not distant from Reiter’s
syndrome,59 whose diagnosis relies on the association of a predominantly axial severe
182 Unexplained Fever

polyarthritis with purulent conjunctivitis and either nongonococcal urethritis or bacterial

diarrhea (due to Shigella, Salmonella, Campylobacter, or Yersinia). It does not present as
U.F. because the classic triad is necessary to support the diagnosis.59 But one may assume
that it could be a cause of undiagnosed fever when the triad is not documented, and one of
the various extraarticular lesions is associated with reactive arthritis: cutaneous (keratoderma,
blennorrhagia, erythema nodosum), mucosal (oral ulcers, circinate balanitis) ocular (iritis,
conjunctivitis), neurologic lesions, myositis, nephritis, carditis . . . 59
The diagnosis of reactive arthritis relies on

• The sterile joint fluid

• The frequent but inconstant presence of HLA-B 27 antigen
• The demonstration by serodiagnosis (Yersinia . . . ) and/or by isolation in the other
body fluids (blood, stools, infectious focus . . . ) of the causal agent
• The demonstration of the infectious focus, whose cure leads to apyrexia and resolution
of arthritis

MYOBACTERIAL SKELETAL INFECTIONS

Among the various diseases briefly reviewed in this chapter, skeletal tuberculosis is the
most frequent cause of U.F. We shall describe tuberculous arthritis and osteomyelitis.
About 1% of patients with tuberculosis have skeletal involvement; of these approximately
50% have spinal disease, 30% inflammation of hips or knees, and 20% arthritis of various
other joints.40 Multiple sites of tuberculous involvement commonly occur;40 approximately
50% of the patients with bone tuberculosis do not have concomitant pulmonary tuberculosis,40
these patients may present only with U.F.
At an earlier time skeletal tuberculosis occurred mainly in children but it is now more
often seen in adults.1
The predisposing factors are1,40'42

• Any chronic debilitatingstate (including narcotic addiction)

• Alcoholism
• Diabetes mellitus
• History of local traumaor intraarticular injection of corticosteroids

The onset and course of skeletal tuberculosis can be so mild that it is not discovered
for months40'43 (and, as a consequence, a chronic monoarticular arthritis is evocative of
tuberculosis).
Pain is generally the most common complaint and tuberculosis should always be con-
sidered when evaluating the cause of skeletal pain.40 It may be associated with fatigue,
anorexia, weight loss, and rarely, local signs and symptoms: limitation of motion, neurologic
manifestations, or even rarer a cold abscess.
Atypical localizations and/or manifestations, although exceptional, may be a cause of
U.F.: tuberculosis of tendons sheaths and bursitis; cystic bone tuberculosis with many
osteolytic areas of various bones; diaphyseal bone tuberculosis;44 tuberculosis of the cos-
tochrondral junction, which may present as a cold abscess;40 and “ para-infective tuberculous
poly arthropathy” which seems to be a tuberculous-reactive arthritis.45 In the presence of an
elevated ESR associated with persistent skeletal pain, further investigations are necessary.
The diagnosis relies on one predisposing factor: The tuberculin skin test, often positive;
if not, a second test should always be done: its positivity would be of great value. It is a
routine part of the evaluation of any bone lesion as well as of any arthritis.
 183

Radiologic aspects are not specific:

• Spondylitis: There is a rarefaction and destruction of adjacent areas of two vertebral

bodies; loss of the intervening disc space and a tendency to anterior wedging or collapse.
• Arthritis: The destruction of cartilage occurs relatively late in the course of disease in
contrast to its rapid progression in pyogenic arthritis.
• Soft tissue around the lesions may show a swelling and/or the bulging of an abscess
• Radionuclide studies are also not specific except the indium-111 labeled polymorpho-
nuclear technique60 (see bacterial arthritis and osteomyelitis)

The synovial fluid study shows characteristically a leukocyte count greater than 10,000/
ml and a lowered glucose concentration.
Stained smears rarely reveal acid-fast organisms, for example, it was positive in only
20% of cases in one series, contrasting with positive cultures in 80% of cases,42 but culture
requires at least 3 weeks.
A biopsy of synovial tissue is then often necessary and very helpful because almost
always (e.g., in 19 of 20 cases in one series41) it shows the granulomatous reaction. Although
nonspecific, because of the frequency of tuberculosis it constitutes sufficient evidence to
begin therapy.40,41
Other biopsies include a bone biopsy which may be necessary in atypical cases40,44 or
a liver biopsy in case of associated cholestasis.43 Finally, in case of strong suspicion, if
bone biopsy is not performed, a specific therapeutic test (isoniazide plus ethambutol plus
pyrazynamide) can reasonably be prescribed.
Differential diagnosis includes pyogenic bacteria, brucella, fungi . . . : cultures and
serodiagnosis are necessary.
Other Mycobacteria (M. kansasii, M. marinum, M. intracellulare, M. fortuitum . . . )
are far less often the cause of similar lesions, except in AIDS where they are more common
than M. tuberculosis.
The rheumatic manifestations of leprosy are distinct, seen in about 1% of cases, mainly
in lepromatous form; they may reveal Hansen’s disease; they are often associated with
polyneuritis and can mimic rheumatoid arthritis.46

OSTEOMYELITIS (MYCOBACTERIA EXCLUDED)

Osteomyelitis continues to be a nonexceptional cause of U.F. because of the difficulties

of its early diagnosis as well as of its polymorphism.47
The classical distinction between acute or chronic osteomyelitis depending on either the
clinical course or the histologic findings is difficult to make because of the absence of abrupt
shift and consequent overlaps.47,48 We shall then divide this heterogeneous disease in four
main types according to the pathogenesis of the bone lesions (Table 5).
Because of the heterogeneity of osteomyelitis, in order to be clear and concise we shall
present its various aspects in Table 6.

DIAGNOSIS OF OSTEOMYELITIS
Clinical data — Presence of a predisposing factor, including another infectious focus
(ex. contiguous: urinary tract infection in case of lumbar spondylitis . . . )
Biologic data — An elevated ESR in association with a persisting skeletal localized
pain is of great value.
Radiologic aspects (always as compared with the contralateral bone) — No changes of
bone tissue are visible until 10 to 15 days after the onset of the disease. Early signs are
deep soft tissue swelling and obliteration of the planes between muscles.53 The first bone
 TABLE 5
184

Four Major Types of Osteomyelitis48,49’51’53’54

Secondary to continguous Secondary to vascular Secondary to animal

Hematogenous infectious focus insufficiency or human bite

Age distribution Peaks at 1— 15 and 50 years 40 years 50 years Any, mainly children
Bones involved Metaphyses of long bones; vertebrae Femur, tibia Feet Hand, feet . . .
Precipitating factor Trauma; bacteremia Surgery, radiation, soft tissue Peripheral vascular insuffi- Bite
infection ciency, mainly due to diabe-
Unexplained Fever

tes mellitus
Major clinical find- Initial episode: Recurrent: Ten- Initial episode: Recurrent: Drain- Pain, swelling, erythema, Wound tenderness,
ings (in addition Heat tenderness, derness, swell- Swelling, ery- age, swelling drainage, ulceration heat, swelling
to fever) swelling limita- ing, limitation of thema, heat Associated findings due to
tion of motion, motion sinus drainage causal disease: neuropathy,
erythema retinopathy, diffuse vascular
insufficiency
Bacteriology Usually one organism Usually mixed infection S. aureus, S. epidermidis, Pasteurella sp.,
S. aureus + +; Gram-negative S. aureus, Gram-negative bacilli Gram-negative bacilli, Staph, sp.,
bacilli anaerobic bacteria anaerobic bacteria
 185

TABLE 6
Various Forms of Osteomyelitis47'55

Symptomatic
Typical: abrupt onset of high fever, systemic toxicity, physical findings of local suppuration
Subacute: more frequent in adults and/or in chronic osteomyelitis: vague local symptoms (pain . . . ) with low
grade or intermittent fever with chills for many weeks
Drainage from a sinus tract with sometimes fever, and pain
“Toxic" forms with prostration, dehydration
Forms with inapparent onset revealed by febrile chronic lesions simulating neoplasms or by central bone abscess
(Brodie’s abscess)
"Neurologic" forms: paralytic forms due to bone pain; spinal forms revealed by paraplegia; pseudo-meningitis
forms
According to the localization
Typical: metaphyses of long bones: femur, tibia, humerus . . .
More than one bone in less than 10%
Spondylitis: typical: fever, back pain, stiffness; early diagnosis often difficult: limited to localized pain and
tenderness with fever and malaise; may be revealed by a complication: neurologic, abscess
Nontubular bones: pelvis, calcaneum, skull, clavicle, rib, sternum . . .
Evolutive forms (natural history)
Acute forms, rapidly destructive
Typical onset, resolution (nearly) complete and typical recurrence
Insidious, paucisymptomatic (e.g., due to Pseudomonas aeruginosa)
Forms with early abscess
According to underlying factors
Classical: occurs in healthy patients
Table 5 placed emphasis on two frequent types of predisposing factors:
• Contiguous infectious focus: osteomyelitis occurs after a surgical act, radiation therapy; or in contact with
soft tissue infections
• Vascular insufficiency: diabetes mellitus, atherosclerosis . . .
• Neurologic trophic ulcers due to tertiary syphilis, leprosy . . .
Sickle cell-disease: often due to Salmonella sp.; multiple sites of bone infection may coexist; early diagnosis
difficult: may mimic a thrombotic marrow crisis
Heroin addicts: often indolent; may affect any bone and/or joint due to various organisms: mainly Staphylococcus
sp., but also Gram-negative bacilli, yeasts . . .
Hemodialyzed patients: usually due to S. aureus\ may present as an U.F. (early local signs are slight); may
affect ribs, thoracic vertebral column . . .
According to the microorganism
Staphylococcus sp., mainly S. aureus, are predominant
Gram negative organisms: P. aeruginosa, E. coli, Proteus sp., Klebsiella — enterobacter sp., Salmonella
sp . . .
• Occurs mainly in patients with cancer, or collagen-vascular disease, or in heroin addicts . . .
• May affect any site (including femur, metatarsal bones . . . )
• Distinct are Brucella sp. which may cause spondylitis, value of contact with cattle, unpasteurized milk or
cheese ingestion
Anaerobic organisms: mainly Bacteroides sp. (B. fragilis, B. melaninogenicus)\ others after a bite, including
Actinomyces sp.)
• Possibly underestimated because of lack of optimal technique for isolation
• May affect long bones, skull and facial bones, hand bones
• Predisposing factors: atherosclerosis, diabetes mellitus, bites
Fungi: Candida sp., Cryptococcus neoformans, Blastomyces sp., frequently revealed by a cold abscess associated
with a lytic lesion
Polymicrobial: more frequent in osteomyelitis secondary to a contiguous infectious focus and in chronic osteo-
myelitis overestimated if the microbiologic specimen is contaminated by sinus tract and/or surface
material.

lesions include lysis, demineralization, cortical irregularity, and periosteal reaction. Later
new bone formation and sequestrum formation may be seen.
Radionuclide studies — These permit earlier detection of osteomyelitis foci than X-
ray examination. The choice is either indium-111-labeled polymorphonuclears60 or 99mTc
186 U nex p la in ed F e ve r

polyphosphate coupled with 67Ga citrate.29 31 There may be difficulties in differentiating

osteomyelitis from associated cellulitis.54 But radionuclide studies may be negative in the
first week in very rare cases of genuine osteomyelitis and as it does not differentiate bone
repair from bone infection, false positive results may be found.54 Magnetic resonance imaging
(MRI) is expensive but, if available, it is useful.
Microbiologic techniques — The importance of a precise microbiologic identification
is evident. Blood cultures are positive in about 50% of cases.54 Sinus tract specimens are
of poor value as they are often contaminated by commensal bacteria of the skin.55 Needle
bone aspirate is positive in about 2/3 of cases.53
Surgical exploration — This has precise indications:

• The identification of the microorganism when other techniques have failed to isolate
it, particularly in heroin addicts where there may be various causal agents53
• The biopsy of material in cases simulating neoplasms50

MUSCULOSKELETAL CANCERS

Musculoskeletal cancers are a very rare cause of U.F. They may present as U.F. only
if the affected muscle is profound, such as the heart or the psoas: one case of sarcoma of
the psoas revealed by an isolated fever of many weeks duration and diagnosed by gallium
scintigraphy has been published.56
Metastatic muscular cancers are not exceptional in the myocardium. They are usually
revealed by a pericarditis.
The primary malignant tumors of joints, synovioma, or synovial chondrosarcoma are
very rare.1 They could present as U.F. if they arised in a profound joint. Radionuclide
studies will be of value in their diagnosis.

BONE CANCERS
Metastatic bone cancers are not exceptional but from our experience as well as from
published data they do not appear to be a cause of U.F. because:

• Usually the primary tumor (kidney, breast, lung, thyroid, prostate, uterus, testicles)
is known and they are looked for in case of fever.
• Roentgen and radionuclide examination would then easily demonstrate a suspected
lesion, whose nature could be confirmed by bone puncture or aspiration biopsy best
guided by televised fluoroscopy or CAT scan.57
• Primary bone cancers are rarer and also an exceptional cause of U.F. as pain is usually
the first symptom. Their nature will be affirmed from their exact topography, the age
of the patient, their X-ray appearance and histopathology; biopsy of course the major
diagnostic procedure, demands considerable care both to obtain reliable data and to
avoid potentially serious complications.58

This chapter has briefly reviewed the various disorders that may present as fever as-
sociated with musculoskeletal signs and symptoms; the most frequent are occult bone in-
fections whose diagnosis is now greatly assisted by radionuclide studies and in the future
by MRI.
 187

REFERENCES
1. Rodnan, G., McEwen, C., and Wallace, S., Primer on the rheumatic diseases, JAMA, 224, 662, 1973.
2. Ryckwaert, A., Polyarthrite rheumatoide in Maladies Systemiques, 2nd ed., Kahn, M. F. and Peltier, A.,
Eds., Flammarion Paris, 1985, 135.
3. Lievre, J., Formes atypiques et associations morbides dans l’arthrite rhumatoide, Rev. Prat., XII, 1387,
1962.
4. Dudley-Hart, F., Rheumatoid arthritis: extra-articular manifestations, Br. Med. J., 3, 131, 1969.
5. Bohan, A. and Peter, J., Polymyositis and dermatomyositis, N. Engl. J. Med., 292, 334 and 403, 1975.
6. Serratrice, G. and Schiano, A., Dermatopolymyosites, in Maladies Systemiques, 2nd ed., Kahn, M. F.,
Flammarion, Paris, 1985, 324.
7. Hubault, A., Les Myosites, Rev. Prat., V, 917, 1955.
8. Swartz, M., Myositis, in Principles and Practice of Infectious Diseases, Mandell, G., Douglas, R. G.,
and Bennett, J., Eds., John Wiley & Sons, New York, 1979, 818.
9. Kallen, P., Nies, K., Louie, J., et al., Tropical myositis, Arthr. Rheum., 25, 107, 1982.
10. Bentata, M., Pasticier, A., Saimot, G., et al., La tuberculose musculaire, Med. Mal. Inf, 11, 540, 1975.
11. El Nahas, A., Farrington, K., Quyyumi, S., et al., Rhabdomyolysis and systemic infection, Br. Med.
J., 286, 349, 1983.
12. Arkin, C., Rothschild, B., Florendon, et al., Behcet’s syndrome with myositis: a case report with
pathologie findings, Arthr. Rheum., 23, 600, 1980.
13. Abruzzo, J., Heimer, R., Giuliano, V., et al., The hyperviscosity syndrome, polysynovitis, polymyositis
and an unusual serum IgG comparrent, Am. J. Med., 49, 258, 1970.
14. Rodriguez, C., Ryckewaert, A., and Dryll, A., Manifestations, articulaires et musculaires des endo-
cardities bactériennes, Nouv. Presse Med., 7, 411, 1978.
15. Kahn, M.-F. and Grossin, M., Fasciite avec éosinophilie (Syndrome de Shulman) in Maladies Systemiques,
2nd ed., Kahn, M. F. and Peltier, A., Eds., Flammarion, Paris, 1985, 318.
16. Schulman, L., Diffuse fasciitis with eosinophilia: a new syndrome, Arthr. Rheum., Suppl. 19, 205, 1976.
17. Smith, J., Infectious Arthritis, in Principles and Practice of Infectious Diseases, Mandell, G., Douglas,
R. G., and Bennet, J., John Wiley & Sons, New York, 1979, 933.
18. Sauter, S. and Utsinger, P., Viral arthritis, Clin. Rheum. Dis., 4, 225, 1978.
19. Ray, G., Gall, E., Minnick, L., et al., Acute polyarthritis associated with active Epstein-Barr virus
infection, JAMA, 248, 2990, 1982.
20. Hurst, N., Martynoga, A., Nudi, G., et al., Coxsackie B infection and arthritis, Br. Med. J., 286, 605,
1983.
21. Bocanegra, T., Espinoza. L., Bridgeford, P., et al., Arthritis due to parasitic infection, Arthritis Rheum.,
23, 638, 1980.
22. Doury, P., Parasitic rheumatism, Arthritis Rheum., 24, 638, 1981.
23. Wolski, P., Staphylococcal and other Gram-positive coccal arthritis, Clin. Rheum. Dis., 4, 181, 1978.
24. Goldenberg, D. and Cohen, A., Arthritis due to Gram-negative bacilli, Clin. Rheum. Dis., 4, 197, 1978.
25. Kelly, P., Martin, W., and Coventry, M., Bacterial arthritis of the hip in the adult, J. Bone Jt. Surg.,
47, 1005, 1965.
26. Weisberger, G., Boureau, M., and Bensahel, H., L’arthrite aigue de la hanche chez le nouveau-ne et
le nourrisson, Arch. Franc. Ped., 30, 83, 1973.
27. Vinceneux, P., Sacro-iliites infectieuses. Méthodes diagnostiques, Concours Med., 105, 998, 1983.
28. Anon., Synovial fluid lactate in septic arthritis, Lancet, 1, 261, 1982.
29. Namey, T. and Halla, J., Radiographic and nucleographic technics in the diagnosis and management of
septic arthritis and osteomyelitis, Clin. Rheum. Dis., 4, 95, 1978.
30. Horoszowski, H., Ganel, A., Kamhin, M., et al., Sequential use of technetium 99m MDP and gallium
67 citrate imaging in the evaluation of painful total hip replacement, Br. J. Radiol., 53, 1169, 1980.
31. Gaucher, A., Pere, P., Ethgen, D., et al., Exploration des infections ostéoarticulaires. Scintigraphie
séquentielle citrate de gallium 67 — complexes phosphates techneties, Presse Med., 12, 898, 1983.
32. Sequeira, W., Jones, E., Siegel, M., et al., Pyogenic infectious of the pubic symphysis, Ann. Intern.
Med., 96, 604, 1982.
33. Aho, K., Ahvonen, P., Lassus, A., et al., HLA-antigen 27 and reactive arthritis, Lancet, ii, 157, 1973.
34. Audran, M., Prost, A., Martin, M., et al., Arthrites aseptiques avec sérologie positive pour Yersinia
pseudotuberculosis, Rev. Rhum., 48, 477, 1981.
35. Hughes, B. and Hind, C., Reactive arthritis associated with Staphylococcus epidermidis peritonitis in a
patient undergoing continuous ambulatory peritoneal dialysis, Br. Med. J., 286, 188, 1983.
36. Bastin, R., Verliac, F., Kernbaum, S., et al., Manifestations rheumatismales de l’Acne conglobata,
Nouv. Presse Med., 7, 831, 1978.
37. Rosner, L, Richter, D., Huettner, T., et al., Spondyloarthropathy associated with Hidrandenitis sup-
purativa and Acne conglobata, Ann. Intern. Med., 97, 520, 1982.
188 U n ex p la in ed F e ve r

38. Steere, A., Malawista, S., Snydman, D., et al., Lyme arthritis in children and adults in three Connecticut
communities, Arthritis Rheum., 20, 7, 1977.
39. Steere, A., Grodzicki, R., Kornblatt, A., et al., The spirochetal etiology of Lyme disease, N. Engl. J.
Med., 308, 733, 1983.
40. Davidson, P. and Horowitz, I., Skeletal tuberculosis, Am. J. Med., 48, 77, 1970.
41. Berney, S., Goldstein, M., and Bishko, F., Clinical and diagnostic features of tuberculous arthritis, Am.
J. Med., 53, 36, 1972.
42. Wallace, R. and Cohen, A., Tuberculous arthritis, Am. J. Med., 61, 277, 1976.
43. Sen, P., Kapila, R., Salaki, J., et al., The diagnostic enigma of extra-pulmonary tuberculosis, J. Chron.
Dis., 30, 331, 1977.
44. Cywiner-Golenzer, C., Witvoet, J., Tayon, B., et al., Tuberculose osseuse Diaphysaire, Sem. Hop.
Paris, 43, 2481, 1977.
45. Bloxham, C. and Addy, D., Poncet’s disease: para-infective tuberculous polyarthropathy, Br. Med. J.,
10, 1590, 1978.
46. Bonvoisin, B., Martin, J., Bouvier, M., et al., Polyarthrite lepreuse, Presse Med., 12, 302, 1983.
47. Laurence, G., Formes cliniques de l’Osteomyelite, Rev. Praticien, XIII, 860, 1963.
48. Waldvogel, F., Medoff, G., and Swartz, M., Osteomyelitis: a review of clinical features, therapeutic
considerations and unusual aspects, N. Engl. J. Med., 282, 198, 260, 316, 1970.
49. Szalay, G. and Sommerstein, A., Innoculation osteomyelitis secondary to animal bites, Clin. Pediatr.,
11, 687, 1972.
50. Cabanela, M., Sim, F., Beabout, F., et al., Osteomyelitis appearing as neoplasms, Arch. Surg., 109,
68, 1974.
51. Quoc Dich, V., Nelson, J., and Haltalin, K., Osteomyelitis in infants and children, Am. J. Dis. Child.,
129, 1273, 1975.
52. Morrey, B., Bianco, A., and Rhodes, H., Hematogenous osteomyelitis at uncommon sites in children,
Mayo Clin. Proc., 53, 707, 1978.
53. Norden, C., Osteomyelitis, in Principles and Practice of Infectious Diseases, Mandell, G., Douglas, R. G.,
and Bennett, J., Eds., John Wiley & Sons, New York, 1979, 946.
54. Waldvogel, F. and Vasey, H., Osteomyelitis: the past decade, N. Engl. J. Med., 303, 360, 1980.
55. Mackowiak, P. and Smith, J., Polymicrobial infections in osteomyelitis, Rev. Infect. Dis., 5, 167, 1983.
56. Longchampt, M.-F., Wechsler, B., Goveau, P., et al., Diagnostic d’un fibrosarcome du Psoas a forme
febrile pure par la scintigraphie au citrate de Gallium, Nouv. Presse Med., 6, 3411, 1977.
57. Vinceneux, P. H., Cramer, E., Grossin, M., et al., Diagnostic des Métastasés Osseuses, Presse Med.,
12, 873, 1983.
58. Trifîaud, A., Circonstances de decouverte, demarche diagnostique et classification des tumeurs malignes
primitives des os, Rev. Praticien, 32, 3485, 1982.
59. Keat, A., Reiter’s Syndrome and reactive arthritis in perspective, N. Engl. J. Med., 309, 1606, 1983.
60. Martin, A., Moissan, A., Le Cloire, C. J., et al., Apport de la Scintigraphie aux polynucléaires marques
a l’indium 111 dans l’exploration des infections osseures et articulaires, Presse Med., 16, 1359, 1987.
 189

Chapter 12

UNEXPLAINED FEVER IN HEMATOLOGIC DISORDERS

SECTION 1. BENIGN HEMATOLOGIC DISORDERS

A. Hazani and B. Isaac

INTRODUCTION
Fever is a frequent presenting symptom in many varied hematologic disorders. It may
precede other manifestations of the disease process, for example, in lymphoma. Its presence
in hematologic neoplasms may be of prognostic value, as it often signifies a more advanced
disease or further malignant transformation. In addition, fever may be associated with
superimposed infections in the immunocompromised host.
The topic of unexplained fever in hematologic disorders will be divided into two sections:
(1) Benign hematologic disorders, to be discussed in Chapter 12, and (2) malignant he-
matologic disorders, which will be dealt with in Chapter 13. Essentially, the approach will
consider fever associated with hematologic diseases from two practical aspects: (a) the
diagnosis of a hematologic disorder in a patient with unexplained fever, and (b) the evaluation
and management of fever developing in a patient with a known hematologic disease. Al-
terations in hematologic parameters as a clue to the nature of otherwise “ nonhematologic”
pyrexia are presented in Chapter 32.

FEVER IN BENIGN LYMPHADENOPATHY AND

SPLENOMEGALY

The lymphatic system plays an important role in antibody production. This explains the
immune and histologic changes which occur in the lymph nodes and the spleen in the course
of diverse inflammatory, infectious, immune, and neoplastic conditions.
Benign nodal enlargement results from lymphocytic and/or macrophage hyperplasia.
Non-malignant lymphadenopathy and/or splenomegaly occur most frequently in infancy and
childhood. The appearance of lymphadenopathy, with or without splenomegaly, must always
raise the question of whether the condition is benign or malignant.1 Many of the infectious
diseases or collagen diseases are characterized by fever, night sweats, weight loss, and
fatigue. This makes the differentiation from malignant disorders, such as lymphomas, chronic
lymphocytic leukemia, and acute leukemias very difficult.
Careful history, physical examination, X-rays, and laboratory tests can provide clues to
the real etiology in many cases. Information about age, sex, the use of drugs, and exposure
to infection or animals is also very important.
The localization and character of the enlarged lymph nodes is of diagnostic value, e.g.,
retroauricular lymphadenopathy in rubella, or bilateral hilar adenopathy in sarcoidosis.
Computerized tomography and ultrasonography are very useful in the search for ab-
dominal and mediastinal lymph nodes. These techniques, together with spleen-liver radio-
isotope scan, give not only the location and size of the involved organs, but can demonstrate
the existence of an abscess, cyst, or tumor, as well.
If an infectious condition is suspected, appropriate bacteriological cultures should be
taken. In addition, serological tests for syphilis, toxoplasmosis, cytomegalic virus (CMV),
and infectious mononucleosis should be done. Positive nonspecific serologic tests, like anti-
nuclear antibodies and rheumatoid factor will suggest a connective tissue disorder. A positive
190 U nex p la in ed F e ve r

TABLE 1
Location and Causes of Lymphadenopathy

Location Causes

Anterior auricular Infections of eyelids, conjunctiva

Posterior cervical, submental Scalp and dental infections, TB, toxoplasmosis
Anterior cervical Infections of oral cavity and pharynx
Supraclavicular fossa Lymphoma, metastatic carcinoma
Axillary Infections of upper extremities, cat scratch fever, bru-
cellosis, lues, spirotrichosis, breast carcinoma
Unilateral epitrochlear Hand infection
Bilateral epitrochlear Viral diseases, sarcoidosis, secondary lues, tularemia
Inguinal Infections of the lower extremities, lymphogranuloma
venereum, lues, gonorrhea, herpetic urethritis
Mediastinal, hilar Lung infection with TB, coccidiomycosis, histoplas-
mosis, lung carcinoma, lymphoma
Intra-abdominal, retroperito- TB, mesenteric lymphadenitis, hematologic and non-
neal hematologic malignancies

Coombs test and the presence of polyclonal hyperglobulinemia are helpful in the diagnosis
of angioimmunoblastic lymphadenopathy. Bone marrow aspiration and biopsy can show a
leukemia or lymphoma infiltration, granulomatous disease, or a storage disease.
If lymphadenopathy persists for more than 4 to 6 weeks without an obvious cause, a
lymph node biopsy must be done. According to various series,1 50 to 60% of the biopsies
yield a positive diagnosis; 25% of cases with nondiagnostic biopsy, or “ atypical lymphoid
hyperplasia” (histologically suspicious but no clear-cut diagnosis of lymphoma) will develop
a lymphoproliferative disorder within a year. Careful follow-up and repeated biopsies should
be performed if the enlarged lymph nodes or the symptoms persist.

LOCAL OR GENERALIZED LYMPHADENOPATHY DUE TO INFECTION

Local Infections2,3
Acute pyogenic lymphadenitis (staphylococcal, streptococcal) — The lymph gland
is enlarged, soft and tender.
Chronic lymphadenitis — Considerable enlargement and fusion of the lymph glands,
without local inflammatory signs. The differentiation from lymphoma is very difficult in
these cases.
Chronic indolent enlargement of the lymph nodes with sinus formation and calcification
is seen in tuberculosis. Granulomatous lymphadenitis, lues, leprosy, and fungal infections
can produce the same clinical picture. Familiarity with the lymphatic drainage system is
necessary for the understanding of regional lymphadenopathy (Table 1).

Systemic Infections2,3
Generalized lymphadenopathy can be caused by systemic infections (Table 2). In some
cases an enlarged spleen may be present as well. One of the most common causes of
generalized lymphadenopathy and splenomegaly in young people is Epstein-Barr virus (EBV)
associated with infectious mononucleosis. Other viral infections, such as cytomegalic virus
infection (CMV), viral hepatitis, and influenza (Table 2) can produce a similar picture. In
all of these, atypical lymphocytes can be found in the peripheral blood. A high titer of EBV
is diagnostic of infectious mononucleosis.
The acquired immune deficiency syndrome (AIDS) is caused by the human immuno-
deficiency virus (HIV) which affects the helper/inducer T-lymphocytes (T4). AIDS is char-
acterized by general lymphadenopathy (cervical, axillary, and especially occipital),
 191

TABLE 2
Generalized Lymphadenopathy, With or Without Splenomegaly, Caused by
Systemic Infections

Viral
Infectious mononucleosis, viral hepatitis, influenza, cytomegalic virus (CMV) infection, rubella, rubeola, in-
fectious lymphocytosis, pertussis, adenovirus infection, roseola infantum, AIDS
Rickettsial
Typhus, Rocky Mountain spotted fever
Bacterial
Subacute bacterial endocarditis (SBE), brucellosis, salmonellosis, tularemia, listeriosis, diphtheria, tuberculosis
Spirochetal
Secondary lues, leptospirosis
Protozoan
Toxoplasmosis, malaria, leishmaniasis (Kala-Azar), amebiasis, schistosomiasis
Fungal
Histoplasmosis, coccidioidomycosis, blastomycosis, sporotrichosis, torulosis
Helminthic
Chronic parasitic infections

splenomegaly, atypical lymphocytosis, severe opportunistic infections, Kaposi’s sarcoma,

and the presence of HIV antibodies. General symptoms like fever, skin rash, and diarrhea
can be present, even in the absence of a superimposed opportunistic infection.4 5
“ AIDS-related complex” is reserved for patients with HIV antibodies, lymphadenopathy
(with or without general symptoms), and an immunologic disorder of T-lymphocyte subsets,
but without opportunistic infections or Kaposi’s sarcoma. The transmission of AIDS is
through sexual contact, or through blood and blood products. The population groups at risk
are homosexuals, drug addicts, and hemophiliacs.
Splenomegaly, fever, and anemia can be due to subacute bacterial endocarditis (SBE).
This picture can mimic lymphoma. Fever, splenomegaly, lymphadenopathy, and atypical
lymphocytes in the peripheral blood are present in many other bacterial, protozoan or
spirochetal diseases (Table 2). In the congenital form of toxoplasmosis, massive hepato-
splenomegaly, anemia, jaundice, and skin rashes are present and the course is fulminant.
Lymph gland biopsy may be diagnostic. A toxoplasmosis dye test is helpful in establishing
the diagnosis. The acquired form of the adult is milder; there is persistent lymphadenopathy
(especially cervical) and moderate splenomegaly.
Splenomegaly is common in the tropics, malaria being the most likely cause. The spleen
can be very enlarged, causing pancytopenia as a result of hypersplenism, but the lymph
glands are usually not enlarged. The fever in malaria is typically intermittent. Kala-Azar,
which is caused by Leishmania donovani, can produce huge splenomegaly, high fever and
pancytopenia. Fungal infections can cause lymphadenopathy. The spleen may also be en-
larged in histoplasmosis.

OTHER CAUSES OF BENIGN SPLENOMEGALY, LYMPHADENOPATHY, AND

FEVER
This is a group of syndromes characterized by lymphadenopathy and dysgammaglobulin-
emia.6

• Angioimmunoblastic lymphadenopathy
• Giant lymph node hyperplasia
• Sinus histiocytosis with massive lymphadenopathy
• Collagen-vascular diseases
• Drug-induced lymphadenopathy
• Sarcoidosis
• Vaccination and immunization
192 U n ex p la in ed F e ve r

Many of these conditions show a similar histological picture of pleomorphic infiltration

of the lymph nodes (lymphocytes, immunoblasts, plasma cells, and histiocytes) together
with vascular proliferation. The lymphadenopathy of infectious disease is also accompanied
by dysgammaglobulinemia. Malignant hematological diseases (macroglobulinemia, multiple
myeloma, heavy chain disease, lymphomas, leukemia) can present with lymphadenopathy,
dysgammaglobulinemia, and fever; they will be discussed in other chapters.
Angioimmunoblastic lymphadenopathy, giant lymph node hyperplasia and sinus histio-
cytosis will be discussed elsewhere.

Collagen-Vascular Diseases
These diseases have lymphadenopathy and diffuse hypergammaglobulinemia in com-
mon. In some of them, spleno- and hepatomegaly are also present. Fever can be one of the
symptoms. This group consists of:

• Rheumatoid arthritis (RA)

• Juvenile rheumatoid arthritis
• Felty syndrome (RA, splenomegaly, leukopenia)
• Systemic lupus erythematosus (SLE)
• Mixed connective tissue diseases
• Sjogren’s syndrome

The clinical and histological picture of these diseases may resemble lymphoma. In some of
them a true lymphoproliferative condition can ultimately develop.
Drug-induced lymphadenopathy — Lymph node enlargement can be caused by di-
phenylhydantoin and other anticonvulsive drugs. Systemic manifestations like fever, skin
rash, hepatosplenomegaly, anemia, leukopenia, plasmocytosis, and diffuse hypergamma-
globulinemia may also appear. The histoloy can mimic lymphoma. The lymphadenopathy
disappears rapidly after suspension of the drug.
Sarcoidosis — One out of three patients with sarcoidosis will develop lymphadenopathy.
Vaccination and Immunization — Lymphadenopathy can develop after vaccination
against various infectious diseases.
Other causes of lymphadenopathy — Dermatopathic lymphadenitis occurs in patients
with exfoliative dermatitis. Lymphadenopathy may be present in hyperthyroidism, at times
with splenomegaly as well. The manifestations of hypermetabolism are similar to those of
lymphoma.

BENIGN CONDITIONS ASSOCIATED WITH SPLENOMEGALY AND FEVER

In addition to the previously described infectious and inflammatory conditions which
can cause lymphadenopathy and/or splenomegaly, there are certain conditions which cause
splenomegaly preferentially.

Hemolytic Diseases
In thalassemia major,7 gross enlargement of the spleen and liver occurs as a result of
the intense destruction of red cells in the reticuloendothelial system. Such patients are prone
to infections and fever.
Sickle cell anemia:8 the rigidity of the erythrocytes which contain hemoglobin S (sickle
cells), results in hemolysis and the obstruction of blood vessels. The infarctive crises are
accompanied by pain and fever. The infarcts can occur anywhere; bones, chest, and ab-
dominal viscera, especially the spleen. The spleen, which is large initially, becomes small
and scarred (autosplenectomy). Such patients are effectively splenectomized and, hence,
prone to overwhelming infections, particularly encapsulated organisms, like pneumococcus,
 193

meningococcus, Haemophilus influenzae. Therefore, they must receive antipneumococcal

vaccine. Bacterial cultures should be taken and antibiotic therapy instituted whenever they
are febrile.

Storage Disease
Gaucher’s disease is a genetic disorder characterized by accumulation of glucocerebro-
sides in the macrophages (Gaucher cells), due to the lack of glucosylceramidase activity.
The infiltration of the spleen and the liver with these cells causes the enlargement of the
organs. Fever may occur associated with bone pain and without evidence of infection.9
Pulmonary infiltrates may also be present. Splenomegaly may also be found in other storage
diseases like Niemann-Pick disease, sea-blue histiocyte syndrome, etc.
Idiopathic infarction of lymph nodes is an uncommon condition which may cause dif-
ficulties in the diagnosis of an unexplained fever. Several cases have been published in the
English medical literature.1012 Most infarcted lymph nodes are located superficially, most
commonly in the axillary or inguinal regions. The main symptoms are a localized painful
mass associated with fever and without an obvious cause. Watts et al. published a case
report with infarction of intra-abdominal lymph nodes.13 The patient was a 56-year-old man,
hospitalized for nocturnal fever of 2 weeks duration, accompanied by chills, diaphoresis
malaise, anorexia, and slight weight loss. The patient had a single episode of abdominal
pain that might have coincided with the onset of infarction 1 week before admission.
Extensive clinical, laboratory, and radiologic studies could not define his illness and an
exploratory laparotomy was performed. Several enlarged, firm, matted lymph nodes meas-
uring 5 x 4 cm in greatest dimensions were found wrapped around the common duct. The
histologic examination showed ischemic necrosis of the central portions of the involved
lymph nodes.
The patient became afebrile on the 6th postoperative day. During the next 2 years, he
gained 24 lb. and had no recurrence of fever or abdominal pain.
The pathogenesis of this syndrome is still not well understood. It is important to em-
phasize that the histologic changes in the involved nodes are indistinguishable from those
produced experimentally by occlusion of the vascular supply of lymph nodes.
Splenic abscess — The spleen is sometimes the site of a purulent collection. The most
important routes of infection are (1) hematogenous spread from a site infection (infective
endocarditis, salmonellosis, urosepsis); (2) contiguous spread from another focus (perinephric
abscess or subphrenic abscess). The clinical picture is characterized by fever and pains in
the left upper abdomen, flank, or lower chest. If the patient’s condition deteriorates, one
should consider rupture of the spleen, which demands urgent splenectomy.

Work-Up For Fever and Splenomegaly1415

1. History, physical examination, laboratory tests, and imaging procedures may detect a
systemic disease (infectious, parasitic, immunologic), cirrhosis, tumor, chronic he-
molysis, and most cases of lymphoproliferative and myeloproliferative disorders.
2. If a definite diagnosis is not reached, a bone marrow aspiration and biopsy are necessary
(also a lymph node biopsy, if available) which may confirm a form of leukemia —
not revealed by the peripheral smear — or a medullar infiltration by malignancy.
3. If these procedures are negative, a liver biopsy, a laparoscopy, a lymphography and
eventually a splenic puncture should eliminate other hepatic and/or splenic disorders
(cirrhosis with portal hypertension, a splenic sarcoma with hepatic invasion, metastatic
intra-abdominal lymph nodes).
4. If all above-mentioned procedures are negative: exploratory laparotomy with splenec-
tomy.
194 U nex p la in ed F e ve r

TABLE 3
Main Causes of
Neutropenia

Stem cell disorders

Drugs
Infections
Immune mechanisms
Hypersplenism
Megaloblastic changes

FEVER IN BENIGN WHITE BLOOD CELL DISORDERS

The neutrophils provide an effective host defense against bacterial and fungal infections.
Marked neutropenia or severe defects in neutrophil function can cause aphtous ulcers of the
mucous membranes, severe gingivitis, recurrent pneumonias, and bacterial or fungal sepsis.
Fever in these cases is related to the infection. Changes in the number of the white blood
cells (WBC) may come as a reaction to a disease, like the increase in the number of neutrophils
in bacterial infections, lymphocytosis in viral infections, or monocytosis in infectious mono-
nucleosis.

NEUTROPHILIA
Neutrophilia is defined as an elevation of the number of neutrophils above 7500/p,l.
This value may vary in different age and race groups.16
Acute neutrophilia, or pseudoneutrophilia, is the result of the mobilization of neutrophils
from the marginal pool in reaction to various stimuli like stress, severe pain, exercise,
epinephrine, ethiocholanolone, and bacterial endotoxins. It may be as brief as 1 min, or last
several hours.
Chronic neutrophilia may persist for days or months. It is the result of the shift of
marrow neutrophils into the circulating pool. Chronic inflammatory or infectious conditions,
prolonged administration of corticosteroids, and chronic blood loss can be the cause of this
condition. Bacterial infections can cause a very accentuated neutrophilia (70,000 to 100,000
or higher per microliter) with young white cells present in the peripheral blood. This form
of neutrophilia is the “ leukemoid reaction” .
In severe tuberculosis the WBC may be very high, at times as high as 200,000/pl. Such
leukocytosis, together with hepatosplenomegaly, anemia, and high fever may make the
differentiation between tuberculosis and chronic myeloid leukemia quite difficult.
Chronic neutrophilia and fever may also be caused by fungal and protozoal infections.
Fever and persistent neutrophilia can be seen in some nonbacterial, chronic inflammatory
conditions like rheumatoid arthritis, or in cases of tissue damage due to eclampsia, azotemia,
liver necrosis, or necrotic tumors.

NEUTROPENIA
The term “ neutropenia” applies to a granulocyte count below 1500/pi. When the
granulocyte count is below 500/|xl the term “ agranulocytosis” is used.16The principal causes
of neutropenia are summarized in Table 3.

Neutropenia Due to Stem Cell Disorders

This is a group of rare diseases which are genetically determined and affect the pluripotent
or the committed stem cells.1617
Cyclic neutropenia is a disorder attributed to periodic pluripotent stem cell failure, which
usually occurs at 21-day intervals. The disease has an autosomal transmission and is seen
 195

in infancy or childhood. During the neutropenic episodes fever may be present for a few
days, as well as stomatitis, pharyngitis, cervical adenitis, skin infections and, at times,
vaginal and rectal ulcerations. Severe upper respiratory infections may also occur. Cyclic
neutropenia may also be accompanied by thrombocytopenia and reticulopenia.
Kostmann’s infantile agranulocytosis is a congenital disorder in which severe granulo-
cytopenia is present from birth. The committed progenitor cell assays are abnormal in some
cases; in some there is defective maturation of the myeloid precursors. The condition is
associated with severe infections and fever.
Reticular dysgenesis with congenital aleukocytosis is characterized by severe agranu-
locytosis and lymphopenia from birth, together with hypogammaglobulinemia. Thymic apla-
sia or thymoma may be associated with this disorder.
Neutropenia associated with congenital pancreatic insufficiency is a rare chronic neu-
tropenia and is usually manifest during the first year of life. Failure to thrive, steatorrhea,
and frequent episodes of infections (especially pneumonia) are characteristic of this disease.
Aplastic anemia18 is a pluripotent stem-cell disorder. The bone marrow in this condition
is hypoplastic or aplastic, resulting in various degrees of anemia, thrombocytopenia, and
neutropenia. The disease can be constitutional, like Fanconi’s anemia, or may appear later
in life, owing to damage caused by various agents, like chemical, physical, infectious,
immune, etc. In some cases the etiology remains unknown. Fanconi’s anemia is a familial
aplastic anemia which becomes manifest in the first decade of life and is associated with
various malformations. There is a high incidence of chromosomal abnormalities and of
leukemia in this disease. However, congenital bone marrow aplasia can occur without bone
or visceral malformations. In some cases, there is no familial history.
Bone marrow replacement by hematologic or nonhematologic malignancies, myelofi-
brosis, or storage diseases can also produce pancytopenia of varying severity. Bone marrow
aspiration and biopsy will differentiate between bone marrow aplasia and replacement.

Drug-Induced Neutropenia
This form of neutropenia1617 can be produced by virtually any drug or chemical sub-
stance. Some of these substances cause aplastic anemia, not just neutropenia, by damaging
all the hematopoietic lines.
Chemotherapeutic agents, irradiation, and chloramphenicol cause damage to the he-
matopoietic system in a predictable and dose-related way. They usually cause aplastic anemia.
With other drugs (phenothiazines, antithyroid drugs, phenylbutazone, sulfonamides, etc.)
the effect is idiosyncratic, based on a specific genetic susceptibility. Neutrophil destruction
may be secondary to an immune mechanism (drug-hapten-antibody interaction). Phenyl-
butazone and aminopyrine exert their effect by such a mechanism. In some cases more than
one mechanism may be involved in the induction of neutropenia. Drug-induced neutropenia
can be mild or severe and, at times, irreversible.

Neutropenia Due to Infection1617

Paradoxically, some infections may be accompanied by mild leukopenia. This can be
seen in the early stages of viral infections, bacillary dysentery, enteric fever, and brucellosis.
Sometimes, severe sepsis can produce neutropenia by increasing the peripheral destruction
of granulocytes and by causing maturation arrest and direct damage to the precursors of the
granulocytes in the bone marrow. This kind of myelotoxicity can be seen in staphylococcal,
pneumococcal, and Klebsiella infections. Infectious hepatitis and infectious mononucleosis
may cause aplastic anemia.

Immune Neutropenia
In some neutropenic patients, antibodies against neutrophils and/or their precursors can
be detected and correlated with the pathogenesis of this condition.
196 U n ex p la in ed F e ve r

Isoimmune neonatal neutropenia1617 — This condition is produced by the transfer of

maternal IgG antibodies against the infant’s neutrophils. The disease is self-limiting, lasting
6 to 8 weeks. The symptoms are those of bacterial infections, usually of the skin, of
respiratory and urinary tract infections and, at times, sepsis.
Autoimmune neutropenia1718 — The existence of specific antibodies to specific neu-
trophil antigens is well documented. In half of the patients with systemic lupus erythematosus,
who are neutropenic, antineutrophil antibodies can be detected.
Pure white cell aplasia — This can be produced by antibodies against the granulocyte-
macrophage progenitors.19 Serum from these patients will inhibit the growth of colony
forming units granulocyte-macrophage (CFU-GM) in vitro.
In addition to the humoral inhibition of granulopoiesis, there is also a cellular mechanism:
hemopoietic inhibitory T-cells were found, especially in patients with rheumatoid arthritis,
Felty’s syndrome, chronic hepatitis and other autoimmune diseases, and in myeloproliferative
disorders.20 Immune mechanisms are also found in some drug-induced neutropenias (see
above).
Sometimes cellular or humoral immune mechanisms are responsible for the damage to
the pluripotent stem cells, with aplastic anemia as a consequence.

Hypersplenism
The pancytopenia of hypersplenism is due to sequestration of blood cells by the enlarged
spleen.

Megaloblastic Anemia
This disorder is characterized by ineffective myelopoiesis, resulting in a decrease in the
number of neutrophils, as well as of the thrombocytes and erythrocytes. The neutropenia is
usually mild with no clinical consequences. Only rarely is there an increase in the incidence
of infections.

STRUCTURAL ABONORMALITIES OF THE NEUTROPHILS

Toxic gran u lation is seen in severe infections. It is due to the predominance in the
neutrophils of azurophilic granules which are larger and stain more deeply than usual.
D ôh le b o d ie s are small blue bodies which can be seen in the cytoplasm of the neutrophils
in severe infections. They can also be seen in pregnancy, cancer, and trauma.
The M a y-H eg g elin an o m a ly is a benign, inherited disorder, in which all the neutrophils
have Dôhle bodies. Giant platelets, mild neutropenia, and thrombocytopenia may be present
as well.

QUALITATIVE DISORDERS OF THE NEUTROPHILS

Biochemical or structural abnormalities of the neutrophils can impair the normal chemo-
taxis and phagocytosis of these cells resulting in increased susceptibility to infections.16
Fever in these cases is related to the infection. In some congenital abnormalities of the
neutrophils, specific biochemical defects have been documented.17

Deficiency of Adherence Related Glycoproteins

The process of neutrophil adherence to cells and surfaces involves the participation of
a group of glycoproteins, which includes the CR3 (iC3b), LFA-1 and pl50,95 glycoproteins.
CR3 deficiency is a rare autosomal recessive disorder, affecting the neutrophils, monocytes,
and lymphocytes. Patients with this disorder can exhibit all the symptômes of neutropenia
or impaired neutrophil function.

Disorders of Neutrophil Oxidative Metabolism

Activated neutrophils and monocytes produce large amounts of microbicidal oxidants.
 197

The result is the reduction of molecular oxygen to superoxide, which is rapidly converted
to hydrogen peroxide and hydroxyl radicals.

C hronic G ranulom atous D isease (CG D )

CGD is a genetically heterogeneous group of disorders of this oxidative metabolism, in
which the nitroblue tetrazolium dye reduction test, which measures the superoxides, is
negative. The neutrophils and monocytes ingest, but do not kill, catalase-positive micro-
organisms and fungi. The resolution of inflammatory foci is impaired, resulting in granuloma
formation. The severity of the disease is variable. Multiple types of inheritance — recessive,
sex linked, and autosomal — have been described.

S pecific G ranule D eficiency

The azurophilic granules of the neutrophils are denser and larger than the specific granules
and are peroxidase positive. On the other hand, the specific (secondary) granules are more
numerous and richer in glycoproteins. They also contain lysosomes, lactoferrins and vitamin
B12-binding proteins.
Patients with congenital deficiency of the specific granules have a depressed inflam-
matory response to infection resulting in recurrent severe bacterial infections of the skin and
of deep tissues.

M yeloperoxidase D eficiency
The myeloperoxidase is located in the azurophilic granules. In the presence of hydrogen
peroxide and a halide this peroxidase produces hypochlorous acid and chlorine which are
very effective in the destruction of microorganisms.
Hereditary deficiency of myeloperoxidase is an autosomal recessive disorder. The gene
responsible for this defect is localized on chromosome 17.
Nevertheless, susceptibility to infection is not enhanced in this disorder, probably due
to compensation by other microbicidal mechanisms.
“Chédiak Higashi Syndrome” is an autosomal recessive disorder, characterized by the
presence of giant cytoplasmatic granules in the neutrophils, lymphocytes, monocytes, and
in their precursors. Accompanying disorders are silvery-hair albinism, pancytopenia, bouts
of unexplained fever, and neuropathy. In this disorder the neutrophils kill the microorganisms
at a slow rate. As a result there are frequent infections of the skin, the mucous membranes
and the respiratory tract. In the accelerated phase of this syndrome there is an extensive
lymphohistiocytic infiltration of the viscera, with hepatosplenomegaly and fever, at times
without any evidence of infection.

Other Neutrophil Dysfunctions

Neutrophil Actine Dysfunction — Actine is a contractile protein. Neutrophils with this
disorder cannot migrate toward inflammatory sites.
Disorders of neutrophil motility — Neutrophil “ paralysis” with depressed chemotaxis
was observed in several conditions, like Felty’s syndrome, systemic lupus erythematosus,
bacterial sepsis, graft-versus-host disease and extensive bums. Drugs, like ethanol and
glucocorticoids, can impair neutrophil motility. Increased susceptibility to infections is no-
ticed in some systemic diseases, such as diabetes mellitus, malnutrition, uremia and alco-
holism. The mechanism is not fully understood.

THE EVALUATION OF THE NEUTROPENIC PATIENT21

In the neutropenic patient fever is almost always due to infection. A patient with neu-
tropenia and fever should have his case history taken carefully, with particular attention to
drugs, associated illnesses, and family background.
198 Unexplained Fever

A thorough physical examination and adequate bactériologie and viral studies should be
performed. Ultrasound, isotope, and radiologic investigations may assist in the diagnosis of
thoracic or abdominal infections.
A complete blood count (CBC) is extremely important. The presence of toxic granulation
and Dôhle bodies would suggest bacterial infection. When bone-marrow aplasia or malignant
replacement of the marrow is suspected, a bone marrow aspiration, or even bone biopsy,
should be performed.
Leukocyte alkaline phosphatase activity (LAPA) is high in infections but low in chronic
myeloid leukemia. This fact is of importance in the differential diagnosis of those diseases.
When an immune mechanism is suspected, tests for the detection of a neutrophil-specific
antibody, or serum antinuclear antibodies should be carried out.
Suppressors of cytotoxic T-cells may be found in excess, and in vitro assays for CFU-
GM (colony-forming unit-granulocyte macrophage) growth will be abnormal when these
progenitor cells are damaged. Studies of neutrophil kinetics can be helpful when abnormal
function of the neutrophils is suspected.

THE MANAGEMENT OF THE NEUTROPENIC FEBRILE PATIENT

The management of the neutropenic patient should be based on the correction of the
underlying cause, if there is one, and the treatment of the current infection. Any drugs that
might possibly be responsible for the neutropenia should be discontinued immediately.
Severe agranulocytosis is seen nowadays as part of total bone marrow failure, due to
aggressive chemotherapy and/or radiotherapy, as in preparation for bone marrow transplan-
tation, or as treatment of various hematologic and nonhematologic malignancies. Severe
aplasia of the bone marrow with eradication of the normal hematopoietic tissue will result
in anemia, agranulocytosis, and thrombocytopenia of varying duration. Broad-spectrum
antibiotic therapy should be instituted empirically and without delay22’23 in every case of
fever in a neutrogenic patient. In the past, the danger was especially that of overwhelming
Gram-negative infection.
Treatment was with a combination of an aminoglycoside with a broad-spectrum penicillin
or cephalosporin. However, in recent years, fungi, viruses, and Gram-positive organisms
have become more prevalent (especially coagulase-negative staphylococci). Therefore, if
the fever persists after 5 to 7 days of antibacterial treatment, antifungal therapy with am-
photericin-B should be instituted. The antibiotic regimen should be based on knowledge of
the current local ecology and the antibiotic resistance of the different strains of bacteria in
the particular hospital.
New drugs, like the quinolones, are currently in the curative and prophylactic treatment
of these patients.24,25 In addition to the antibiotic therapy, supportive therapy, including
blood and thrombocyte transfusions should be given. Granulocyte transfusions are no longer
used. Lithium carbonate can sometimes be helpful by stimulating the stem cells.
The role of hormones in governing hematopoiesis is becoming increasingly evident.
Molecular biology techniques are able to prepare and purify certain hormones on a large
scale. The recombinant (biosynthetic) human granulocyte-macrophage colony-stimulating
factor (GM-CSF) has been administered with beneficial results in several cases of leukopenia
in AIDS patients, and in patients with granulocytopenia after chemotherapy and/or radio-
therapy.26,27
In the case of aplastic anemia the treatment is that of replacement therapy, antibiotics,
androgens, corticosteroids, and/or immunosuppresive drugs. Good results have been obtained
in recent years with antithymocytic globulin (ATG)28 and cyclosporin.29
Severe aplastic anemia is treated at present with syngeneic or allogeneic bone marrow
transplantation (BMT) in those patients who have HLA-identical siblings. Very good results
are obtained in untransfused, and therefore unsensitized, patients 30 years of age or younger.
BMT has been performed also in some genetic diseases, like “ severe combined immuno-
 199

deficiency” , reticular dysgenesis, congenital agranulocytosis, functional abnormalities of

neutrophils, and Fanconi’s anemia.28 29

THE LYMPHOCYTES
Lymphocytes play a very important role in the immune response of the body. Functionally
they are divided into two classes:

1. Thymus dependent, or T-lymphocytes, which are mainly involved in cellular immunity

2. Bursa-equivalent, or B-cells, which are mainly responsible for humoral immunity

The lymphocytes represent 20 to 50% of the total leukocyte population.

LYMPHOCYTOSIS
Lymphocytosis1617 in adults is defined as a lymphocyte count greater than 4000/(xl.
Mild lymphocytosis in the peripheral blood is a very common finding in the course of most
viral infections. “ Atypical” lymphocytosis denoting a change in the appearance of the
leukocytes in addition to the increase in their numbers may be seen in infectious mononu-
cleosis, cytomegalic virus infection, infectious hepatitis, and hypersensitivity reactions.
Cytomegalic virus infection presents with fever, splenomegaly, and mild lymphocytosis
with atypical lymphocytes, as in infectious mononucleosis. The disease can be transmitted
by blood transfusions. In immunosuppressed patients the disease can be extremely severe,
particularly if there is pulmonary involvement as well. High titers of antibodies against
cytomegalic virus will be found.
The lymphadenopathic variety of Toxoplasmosis is characterized by fever, lymphade-
nopathy, and the presence of atypical lymphocytes in the peripheral blood. High titers of
antibodies against toxoplasmosis are diagnostic of the disease.
Lymphocytosis may be found in other infections such as tuberculosis, brucellosis, per-
tussis, and syphilis. In Bordetella pertussis infection the lymphocytosis may be as high as
15,000 to 25,000/pJ.

Acute Infectious Lymphocytosis

This type of lymphocytosis occurs mainly in children and young adults, and is of
unknown etiology. Mild elevation of body temperature may be the only clinical expression
of the disease. The lymphocytes, especially the T-cells, may reach levels of 20,000 to
100,000/pL

Infectious Mononucleosis
Infectious mononucleosis30 is a self-limited disease, occurring mainly in young patients.
The clinical signs are fever, lassitude, pharyngitis, lymphadenopathy (especially posterior
cervical) and splenomegaly. Atypical lymphocytes are found in the peripheral blood. The
etiologic agent is Epstein-Barr virus (EBV). The IgG antibody to the virus capsid antigen
(VCA) is the first antibody to be produced in EBV infection. Soon after, an IgM antibody
can be detected. After the acute phase a specific antibody against the EBV nuclear antigen
(EBNA) appears. The VCA and EBNA persist for life; the IgM antibody lasts only a few
months.
In the past the diagnosis used to be based on the demonstration of an elevated titer of
heterophil antibodies. Nowadays the disease is diagnosed by the demonstration of the above-
mentioned antibodies.
The antibodies occurring in infectious mononucleosis can cause immune hemolytic
anemia and thrombocytopenia. Mild abnormalities of liver function tests can be found. Other
200 Unexplained Fever

étiologie agents, like cytomegalovirus, herpesvirus, and toxoplasma can produce the same
syndrome. However, in such cases there is no elevation of the titer of specific antibodies
against EBV.

MONOCYTES
Monocytes in the peripheral blood are derived from the committed myeloid stem-cells
CFU-GM.17 The blood monocyte is a cell in transition from bone-marrow to tissues, where
it ultimately becomes a macrophage. Monocytes constitute 1 to 9% of the blood leukocyte
population.

MONOCYTOSIS
Monocytosis is present when the absolute monocyte count exceeds 800/(jl I. Monocytosis
occurs in the recovery phase of almost any infection and in chronic infections like tuber-
culosis, subacute bacterial endocarditis, and syphilis.
Monocytosis is seen in noninfective inflammatory disorders, such as ulcerative colitis
and collagen-vascular disease. Monocytosis may also be present in hematologic and non-
hematologic malignancies. Prolonged and intensive chemo- or radiotherapy can affect the
phagocytic capacity of the macrophages. As a result, fungal, protozoal, and bacterial in-
fections are more likely to occur.

EOSINOPHILS
Eosinophils constitute less than 6% of the total number of leukocytes. The absolute
count is 150/(jl 1. Eosinophils respond to chemotactic stimuli, they migrate to sites of allergic
reaction or parasitic infestation. Eosinophils are capable of phagocytosis. However, they are
less efficient than the neutrophils. Rather than attempt to engulf the large parasites, the
eosinophils fight them by secreting the content of their intracellular granules into the extra-
cellular space, where the parasites are to be found.

EOSINOPHILIA
The causes of eosinophilia are numerous1617 and include parasitic infestation, allergic
disorders, some dermatologic diseases, and gastrointestinal disorders (ulcerative colitis,
regional enteritis) as well as solid tumors, particularly those undergoing necrosis. In some
hematologic malignancies, like the lymphomas, myeloproliferative disorders, and eosino-
philic granuloma, the number of eosinophils may be increased. Eosinophilia can be found
during convalescence from infectious febrile diseases.
Massive eosinophilia is most commonly a manifestation of widespread parasitic invasion.
The term ‘'hypereosinophilic syndrome’’17 31 refers to a large group of different disorders
with prolonged eosinophilia and eosinophilic infiltration of one or more organs. These
disorders range from the benign “ Löffler’s Syndrome” to eosinophilic leukemia. The tend-
ency is to use this term for prolonged and life-threatening situations.
Hepatosplenomegaly, involvement of the central nervous system and endocardial fibrosis
are common. Other signs, like fever, anemia, and weight loss can be found. The accumulation
of eosinophils in the organs leads to tissue injury, due to intracellular substances that are
released by the disintegrating eosinophils (peroxidases, lysosomal enzymes, strongly cationic
proteins) into the surrounding tissues.

FEVER IN HEMORRHAGIC DISORDERS

The appearance of a hemorrhagic disorder during a febrile disease should raise the
possibility of thrombocytopenia with or without consumptive coagulopathy, or of vasculitis.
 201

The bleeding is usually into the skin (ecchymoses, petechiae) and mucous membranes, and
in the genitourinary and gastrointestinal tracts. Temperature may be raised at any time during
the resorption of a large hematoma, in the absence of infection.
When the thrombocytopenia is due to peripheral destruction of platelets (immune mech-
anisms, mechanical destruction, hypersplenism) an increase in the number of megakaryocytes
is seen in the bone marrow. When the thrombocytopenia is the result of damage to, or of
malignant infiltration into, the bone marrow, the number of megakaryocytes is decreased.
The bleeding time is prolonged, both in thrombocytopenic and in vascular purpura. In
consumptive thrombohemorrhagic disorders, decreased levels of plasma coagulation factors
and signs of activation of the fibrinolytic system may be found in addition to the throm-
bocytopenia.
The laboratory examination in every case of purpura during febrile disease should include
a complete blood count, bacterial, viral, and fungal cultures, serologic tests, a coagulogram
and, in some cases, a bone marrow aspiration as well.

THROMBOCYTOPENIC PURPURA ASSOCIATED WITH INFECTION

Viral, bacterial, and rickettsial infections can cause thrombocytopenic purpura by in-
terfering with platelet production, or by direct interaction with and destruction of platelets.32
Various immune mechanisms can be involved in such reactions.
Septicemia, especially with Gram-negative bacteria, is responsible for thrombocytopenia
in V3 of the patients. Febrile thrombocytopenia may also occur in acute or subacute bacterial
endocarditis. Infections with some rickettsias, typhoid fever, diphtheria, tuberculosis, his-
toplasmosis, and brucellosis can be complicated by thrombocytopenic purpura.
Another mechanism by which infections can produce thrombocytopenia is the syndrome
of disseminated intravascular coagulation (DIC).33 34The consumption of platelets and plasma
coagulation factors is secondary to the diffuse microvascular occlusions.
The laboratory tests will show a low thrombocyte count, low plasmatic fibrinogen,
prolonged prothrombin time and partial thromboplastin time, low plasmatic factors, espe-
cially VIII and V, and an elevation in fibrinogen degradation products. Fragmented eryth-
rocytes (schistocytes) can be seen in peripheral blood smears.
Acute meningococcal sepsis with the Waterhaus-Friederichsen syndrome is one of the
most dramatic clinical pictures, with a fulminant, fatal course in most of the cases. Pneu-
mococcal sepsis, as well as Gram-negative sepsis (Escherichia coli, Pseudomonas, Proteus,
Klebsiella, Aerobacter, etc.) may produce the same syndrome.
Rickettsial disease or viral infections can be also complicated by DIC. “ Purpura ful-
minans” , a disorder that can appear a few days after an acute infection (scarlet fever,
varicella, pneumococcal sepsis)35 is characterized by circumscribed ecchymoses, symmetrical
gangrene of the extremities, and the coagulation abnormalities of DIC. Malaria, fungal,36
and virtually any infection can be complicated by DIC. The symptomatology is predominated
by diffuse bleeding from various sites. Treatment of infectious thrombocytopenia should be
directed, first of all, at the underlying cause. If sepsis is suspected, antibiotic therapy should
be instituted immediately even before bacteriological proof is obtained.
In the presence of DIC, replacement therapy with transfusions of blood, fresh frozen
plasma, cryoglobulin, and platelets should be instituted.

THROMBOTIC THROMBOCYTOPENIC PURPURA

(MOSCHKOWITZ’S SYNDROME)
Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic he-
molytic anemia with changes in the fragmented erythrocytes (schistocytes), thrombocyto-
penia, and fluctuating neurologic abnormalities. Fever and renal involvement are usually
present as well.32 The characteristic pathologic lesions are widespread hyaline occlusions of
the small vessels, and microthrombi.
202 Unexplained Fever

There are many similarities between thrombotic thrombocytopenic purpura (TTP) and
the hemolytic uremic syndrome (HUS).37 39 However, HUS is more frequent in childhood
than in adults, fever occurs less often, and the neurologic signs are not as prominent. On
the other hand, the renal involvement in HUS is much more severe than in TTP.
The etiology is unknown. Factors such as circulating toxins, immune deregulation, or
abnormalities of prostacyclin metabolism with low serum levels have been incriminated
(prostacyclin is normally secreted by the vascular endothelium and has an anti-aggregating
effect on thrombocytes). TTP can be related to various infections: viral, Mycoplasma pneu-
moniae, Bartonella-like infection, vaccination, subacute bacterial endocarditis. The partially
occluded vessels damage the erythrocytes and thrombocytes which pass through them. The
clinical signs will be those related to the microangiopathic hemolytic anemia, the throm-
bocytopenic purpura, and the obliterated vessels in the particular organs. The fever, which
is present in 90% of patients, may be due to lesions in the hypothalamus.
The mortality from TTP in the past was very high. The treatment40,41 consists today of
a combination of glucocorticoids, platelet aggregation inhibitors (aspirin, dipyridamol, dex-
tran, sulfrinpyrazone) and plasma transfusion or plasmapheresis (to provide the missing
plasmatic factor or to eliminate the inhibitors of its synthesis).
Infusion of prostacyclin was also tried, but the available data is insufficient. Splenectomy
may be helpful in some cases. Improvement can be achieved by immunosuppressive drugs,
especially vincristine.

Fever in Benign Nonthrombocytopenic Purpura

Purpura with normal number and function of thrombocytes can be produced by a vascular
abnormality.42 Allergic purpura is a nonthrombocytopenic purpura produced by aseptic
vasculitis of the corium. This entity is seen especially in children. Malaise, fever, and
headache can precede the skin rash. Sometimes nonmigratory polyarthralgia and abdominal
pains can appear (Henoch-Schonlein purpura) with or without gastrointestinal bleeding. Renal
involvement can also be seen.
Purpura due to vasculitis accompanied by hyperglobulinemia and fever can occur in a
number of diseases of diverse etiologies: Sjogren’s syndrome, disseminated lupus erythe-
matosus, rheumatoid arthritis, and sarcoidosis, as well as in some lymphoproliférative dis-
orders and multiple myeloma.
Nonthrombocytopenic purpura can be seen in cryoglobulinemia, usually of the “ mixed”
type. The condition can be primary, or secondary to various collagen-vascular diseases or
to infectious disease. Exposure to cold causes the precipitation of the cryoglobulins and can
provoke Raynaud’s phenomenon, various skin lesions, and the hyperviscosity syndrome.

FEVER ASSOCIATED WITH ANEMIA

Pathophysiologically, anemia is the consequence of either diminished production or

accelerated destruction of the RBC, or of both.
With the advent of automated blood counting, the most practical categorization of
anemias from a clinical standpoint is by mean corpuscular volume (MCV) into normocytic,
microcytic, and macrocytic anemias.43 It should be stressed that anemia per se, except for
acute hemolysis, must be quite a rare, if ever, a cause of fever.

NORMOCYTIC ANEMIA (MCV = 90 ± 8 CUBIC MICRONS)

Isolated normocytic anemia may be seen in any chronic infectious inflammatory and
malignant disorder. Usually the anemia is not severe, but in chronic renal failure, hemoglobin
down to 7 g per dl may be quite commonly observed. Typically, the serum iron is low and
transferrin levels are also below normal. Thus, in contrast to iron deficiency anemias, iron
 203

saturation is often within normal limits, levels of ferritin are also normal or somewhat
elevated.
The underlying cause of both the fever and the anemia, such as tuberculosis, pyelo-
nephritis, rheumatoid arthritis, collagen disease, renal cell carcinoma, etc., is often disclosed
by the patient’s history, physical examination, appropriate cultures, serologic tests and X-
ray examination. The possibility of temporal arteritis, in which such tests are negative,
should also be looked into. If after a complete investigation, the cause of the fever is still
obscure, bone marrow biopsy and aspiration are indicated. By performing both biopsy and
aspiration, maximal information, with no additional risk or discomfort to the patient, may
be obtained. With local anesthesia, biopsy is performed first and followed immediately by
aspiration from the same site. The aspirate is examined for smear morphology and can also
be cultured for pathogens such as tubercle bacilli, brucella, etc. The bone marrow histology
may reveal a granulomatous process, metastasis, or a primary hematological malignancy,
such as leukemia, reticuloendothelial neoplasia, or multiple myeloma.44
Sometimes, as in malignancy, the anemia of “ chronic disease’’ may be compounded
by chronic blood loss or malabsorption leading to iron deficiency. Assessment of bone
marrow iron stores is of additional help in the evaluation of the anemia. Normal or increased
iron stores will be found in the anemia associated with chronic disease. The presence of
ringed sideroblasts will establish the diagnosis of idiopathic sideroblastic anemia. This disease
entity is not directly associated with pyrexia. However, it may sometimes be associated with
neoplastic or inflammatory conditions, the latter being the cause of pyrexia.
Spanish authors45 published a case of a 62-year-old woman hospitalized for a microcytic
hypochromic anemia associated with fever which lasted 3 months. After an extensive eval-
uation, the final diagnosis was hyperthyroidism. Treatment with carbimazol (30 mg/day)
suppressed the fever and the hematological disorder.
Hemolytic anemias are normocytic (occasionally slightly macrocytic) and regenerative
(the reticulocyte count is increased). Only the thalassemias are microcytic. They are due to
excessive red cell destruction. They are suggested by the occurrence of an anemia not
explained by bleeding, associated with signs and symptoms of hemolysis, which may be
acute, chronic, or episodic. Acute hemolysis is characterized by chills, fever, malaise,
abdominal and back pain, arthralgia, and in severe instances, tachycardia, dyspnea, jaundice,
splenomegaly, oliguria or anuria, prostration, and shock. In chronic hemolysis, anemia and
mild jaundice are exacerbated by a hemolytic crisis (aplastic crisis), usually related to an
infection.
The most important laboratory tests for evaluation of hemolytic anemias are routine
blood film, reticulocyte count, red cell morphology, bone marrow examination, Coombs
test, serum bilirubin and haptoglobin, osmotic fragility of RBCs, coagulation studies, urine,
bile pigments, and erythrocyte survival studies. Most forms of hemolytic anemias, whether
intra- or extracorpuscular, hereditary, or acquired, are associated with fever.46
Hemolytic anemias can be classified as intracorpuscular, or extracorpuscular, and con-
genital, or acquired. A more extensive discussion about the classification and clinical aspects
of the hemolytic anemias is beyond the scope of this chapter. We shall emphasize only some
features associated with fever.

INTRACORPUSCULAR HEMOLYTIC ANEMIAS

Membrane Defects
In hereditary spherocytosis, in addition to the above-described signs and symptoms of
chronic hemolysis, splenomegaly, hepatomegaly, and cholelithiasis are frequently observed.
The osmotic fragility of RBCs is increased, the Coombs test is negative.
In paroxysmal nocturnal hemoglobinuria (PNH), which is an acquired disorder of the
red blood cell membrane, an abnormal complement-sensitive clone is present; leukopenia
204 U nex p la in ed F e ve r

and thrombocytopenia are also frequently observed. Typically, there is hemosiderinuria and
the leukocyte alkaline phosphatase (LAP) score is reduced. Demonstration of complement
sensitivity (Ham test) and of reduced activity of acetylcholinesterase in the RBC will establish
the diagnosis. Patients with PNH are prone to thromboembolic disease. Occasionally, the
disease may evolve into acute leukemia. Both these conditions may be considered in a patient
with PNH and continuous fever.

Hemoglobinopathies
In sick le c e ll anemia, there may be aplastic crises associated with fever, arthralgia,
severe abdominal pain and various thromboses, especially cerebral.
The th a la ssem ia syn d ro m es are inherited disorders affecting the rate of synthesis of
hemoglobin (ineffective erythropoiesis). Thalassemia major (Cooley’s anemia) is a life-
threatening disease, in which a severe anemia may be associated with intramedullary and
peripheral hemolysis and with iron overload. The clinical aspect is characteristic: Mongolian
facies, stunted growth, jaundice, cholelithiasis, prominent abdomen, hepatosplenomegaly,
and leg ulcers. There is also an enhanced susceptibility to infection. The smear is charac-
teristic and suggests the diagnosis which is confirmed by hemoglobin electrophoresis.
Among the re d c e ll en zym e d efe cts, the most common is the G6PD deficiency which
affects about 10% of American Negroes and people from the Mediterranean basin (Italians,
Greeks, Arabs, and Sephardic Jews). The hemolysis occurs after exposure to oxidant drugs
or ingestion of fava beans. Drugs causing this form of hemolysis include sulfonamides,
phenacetin, antimalarials (primaquine, chloroquine, dapsone, pamaquine), nitrofurantoin,
Vitamin K derivatives, probenecid, p-aminosalicylic acid, nalidixic acid, quinine, quinidine,
and chloramphenicol. A large number of screening tests for G6PD are available.

EXTRACORPUSCULAR HEMOLYTIC ANEMIAS

The most important forms associated with fever are (1) auto-immune hemolysis47 (an-
tibodies directed against the patient’s own red blood cells — reactive at body temperature
or in the cold); (2) hemolysis by direct invasion of the red cells by infectious agents, or by
a direct toxic effect of some chemical agents; and (3) traumatic hemolysis in valve prosthesis.
Patients with auto-immune hemolysis may present without symptomatology, only with
a positive direct Coombs test or in a more severe form — sometimes fulminant or fatal —
with fever, hemoglobinemia, hemoglobinuria, and shock. These cases may represent a
complication of an underlying disease or may be related to the ingestion of certain drugs.
The underlying condition may be (a) infectious (mononucleosis, cytomegalovirus, myco-
plasma); (b) malignancy (non-Hodgkin lymphoma, chronic lymphocytic leukemia, Walden-
strom’s disease); (c) collagen-vascular disease (SLE, scleroderma); (d) rarely: syphilis,
cirrhosis, ovarian cyst). The following drugs are known to be involved: methyldopa, levo-
dopa, penicillin, and quinidine. Approximately 50% of auto-immune hemolytic anemias
are idiopathic (without a definite cause) but according to Bernard,48 most of them may be
related to a viral infection, difficult to confirm. Some organisms may produce hemolysis
by direct parasitization of red blood cells, e.g., malaria, bartonellosis, and babesiosis.
Hemolysis may occur also in septicemia with C lo strid iu m w elch ii and in bacteremia with
other organisms such as staphylococci, pneumococci, S alm on ella, and E. coli. There are a
great number of chemical agents which may cause hemolysis (most of them not associated
with fever). To mention a few, the list includes arsenic, lead, copper, aniline, naphthalene,
benzine derivatives, and intravenous injections of distilled water. In the w ork-u p f o r an
u nexplain ed fe v e r , on e sh o u ld co n sid e r a ll th ese a b o ve -m en tio n ed in fectious o r toxic c ir -
cu m stances, w hen an a sso c ia te d h em o ly tic an em ia is d e te c te d .49,50
A distinct form of severe anemia, usually normocytic or mildly macrocytic, is a p la stic
a n e m ia ,51 due
to bone marrow failure. The peripheral blood usually shows anemia associated
with leukopenia and thrombocytopenia (pancytopenia). The reticulocyte count is low. The
 205

bone marrow biopsy will reveal absent or reduced cellularity. The serum iron is elevated.
The clinical manifestations vary with the severity of the pancytopenia. Bleeding and infection
are the most common complications. Infection is usually associated with fever, but local
signs of inflammation may be absent. The differential diagnosis is important because pan-
cytopenia may occur in a variety of disorders, potentially evolving with fever, including
lymphoma, pre-leukemia, metastatic carcinoma to the marrow, granulomatous diseases,
parenchymal liver diseases with hypersplenism, and lipidoses. Two other diseases, usually
febrile, SLE and tuberculosis due to atypical mycobacteria, may be associated with pan-
yctopenia; some viral diseases, especially hepatitis and infectious mononucleosis, have also
been implicated. The main causes of aplastic anemia are ionizing irradiation and chemical
agents. The latter include chloramphenicol, phenylbutazone, hydantoin, sulfa drugs, phe-
nothiazines, quinacrune, colchicine, sulfonylureas, gold compounds, benzene, insecticides,
organic arsenicals, antineoplastic, and immunosuppressive drugs.

MICROCYTIC ANEMIA (MCV ^80 CUBIC MICRONS)

Iron deficiency anemia is the most common form. The diagnosis can be made with
certainty in a patient with low serum iron, elevated iron binding capacity and reduced
saturation of transferrin (=^10%). Transferrin saturation of 10 to 15% is also most probably
evidence of iron deficiency. In a doubtful case, the level of ferritin or bone marrow iron
stores should be estimated. Chronic blood loss from alimentary or genitourinary tract is a
frequent cause of such anemia and appropriate clinical investigation guided by patient’s
history and examination should be performed. Particular attention should be paid to men-
struation, postmenopausal bleeding, abdominal pain, rectal bleeding, weight loss, or a change
in diet and bowel habits. Tumors, such as renal, colon, or gastric carcinoma; or inflam-
mations, such as Crohn’s disease, may present with both iron deficiency anemia and pyrexia.
Malabsorption, associated with inflammatory or malignant lesions of the gastrointestinal
tract, may cause iron deficiency and also be associated with pyrexia. Thus, a complete GI
tract series and frequently, gastroscopy and colonoscopy, are indicated.
Sometimes, as in agammaglobulinemia, the cause of iron malabsorption is duodenal
giardiasis and in such cases, therapy with metronidazole is indicated. Though iron deficiency,
as such, does not cause pyrexia, severe iron deficiency is associated with increased tendency
towards microbial infections. Reduced granulocyte lactoferrin has been implicated as one
possible cause. One anecdotal case of pyrexia responsive to iron therapy was described in
the French literature.52
This 56-year-old male was hospitalized on several occasions for iron deficiency anemia
associated with fever, chills, myalgia, and arthralgia. Extensive investigation and empiric
antibiotic therapy were of no benefit. Therapy with intravenous iron brought about a complete
resolution of both the febrile episodes and of the anemia. Iron kinetics revealed a normal
plasma iron turnover with a defective utilization.
An infrequent cause of iron deficiency is massive hemosiderinuria. Loss of iron in the
urine is the result of repeated intravascular hemolysis. Such rare disorders as black water
fever due to malaria falciparum or paroxysmal nocturnal hemoglobinuria or valvular aortic
disease may cause iron deficiency. In such cases, there may be no reticulocytosis as the
hemolysis may be masked by an inadequate response of the iron deficient bone marrow. It
is to emphasize that bacterial virulence correlates with ability to acquire iron.53,54
The response to iron replacement therapy in an iron-deficient, febrile patient, is slower
than in uncomplicated iron-deficiency anemia. The administration of parenteral iron will not
be more effective, as the rate-limiting factor is not iron absorption, but its utilization.
Parenteral iron therapy may in itself be associated with pyrexia. Intravenous iron dextran
has been associated with fatal anaphylaxis, while intramuscular iron may cause pyrexia,
local pain, and lymphadenitis. Their use should be limited to very specific clinical situations,
in which an adequate intake or absorption of oral iron cannot be achieved.
206 Unexplained Fever

MACROCYTIC ANEMIA (MCV ^106 CUBIC MICRONS)

Macrocytic anemia with normal reticulocyte count may be either megaloblastic or non-
megaloblastic. Alcoholic hepatitis, in itself a cause of fever and of nonmegaloblastic ma-
crocytic anemia, is one such example. Additional disorders include other liver diseases and
hypothyroidism. Spuriously elevated MCV may be encountered in conditions in which red
cell aggregation is present, such as multiple myeloma or macroglobulinemia. Examination
of peripheral blood smear will clarify the cause of such “ macrocytosis” . In megaloblastic
anemias, the vast majority being either B12 or folic acid deficiency, the MCV is frequently
^110 cubic microns and leukopenia with hypersegmented neutrophils and thrombocytopenia
are also seen. The intramarrow death of defective hematopoietic precursors is reflected in
elevated levels of unconjugated bilirubin as well as in elevated levels of serum SGOT and
LDH, in particular the LDH, and LDH2 isoenzymes, and in increased serum muramidase.
This type of anemia may be accompanied by low grade fever. McKee,55 in his report of
122 patients suffering from megaloblastic anemia due to B12 or folate deficiency, mentioned
low grade fever in 40% of his cases, which became normal after appropriate vitamin re-
placement. Pyrexia and megaloblastic anemia during chemotherapy for a malignant disease
are discussed in Chapter 23.
Etiologic factors of megaloblastic anemia vary with respect to the age of the patient or
geographic region. Pernicious anemia is more frequent in the elderly; in France, alcoholism
and cirrhosis (even nonalcoholic) are prevalent; in Scandinavia, the fish tapeworm, Di-
phyllobothrium latum; in equatorial areas, tropical sprue. Ingestion of some drugs predispose
to vitamin B12 or folate deficiency, e.g., pentamidine, triamterene, and trimethoprim. The
diagnosis of megaloblastic anemia is suggested by prominent macrocytosis, accompanied
by hypersegmented, polymorphonuclear leukocytes and oval macrocytes in the smear. Ad-
ditional important tests are the determination of serum B12 and folate level, Schilling test
and, if available, the determination of serum antibodies to intrinsic factor or measurement
of intrinsic factor in gastric juice.
Many of the diseases we have discussed may be diagnosed and treated by the internist
or the general practitioner, depending certainly on the physician’s training in hematology.56
The evaluation and treatment of an anemia associated with fever may frequently require the
assistance of a hematologist. We refer the reader to Christensen’s comprehensive article,44
which contains a detailed discussion of the problems which call for referral to a hematologic
consultation.

REFERENCES
1. Straus, D. J., Lymphadenopathy, benign or malignant cause?, Primary Care of Cancer, May 15, 1986.
2. Weinstein, I. M., Lymph node enlargement and splenomegaly, in Hematology, 3rd ed., Williams, W. J.,
Ed., McGraw-Hill, New York, 1983, 937.
3. Haynes, B. F., Enlargement of lymph nodes and spleen, in Harrison s Principles of Internal Medicine,
Isselbacher, K. J., Petersdorf, R. G., Wilson, J. D., Maring, J. B., and Fauer, A. S., Eds., McGraw-Hill,
New York, 1987, 272.
4. Fauci, A. S., Mâcher, A. M., Longo, D. L., et al., Acquired immunodeficiency syndrome: epidemiologic,
clinical, immunologic and therapeutic considerations, Ann. Intern. Med., 100, 92, 1984.
5. Fauci, A. S., Masur, H., Gelmann, E. P., et al., The acquired immunodeficiency syndrome: an update,
Ann. Intern. Med., 1092, 800, 1985.
6. Pruzanski, W., Lymphadenopathy associated with dysgammaglobulinemia, Semin. Hematol., 17,41, 1980.
7. Weather hall, D. J. and Cleg, J. B., The Thalassémie Syndromes, 3rd ed., Blackwell Scientific, Oxford,
1981.
8. Serjean, G. R., Sickle Cell Disease, Oxford University Press, Oxford, 1985.
9. Mathot, Y., Zaizov, R., Hoffman, J., et al., Clinical and biochemical aspects of chronic Gaucher disease,
Isr. J. Med. Sci., 10, 1523, 1974.
 207

10. Davies, J. D. and Stansfeld, A. G., Spontaneous infarction of superficial lymph nodes, J. Clin. Pathol.,
25, 689, 1972.
11. De Franc, J. H. et al., Superficial lymph node infarction, Am. J. Surg., 132, 112, 1976.
12. Gorelkin, L. and Majmudar, B., Spontaneous primary lymph node infarction in a patient with lymphoma,
South Med. J., 71, 1451, 1978.
13. Watts, J. C. et al., Idiopathic infarction of intraabdominal lymph nodes. A new cause of fever of unknown
origin. Am. J. Clin. Pathol., 74, 687, 1980.
14. Bruckstein, A. H., Splenomegaly. When and how to treat, Postgrad. Med., 79, 289, 1986.
15. Bernard, J. et al., Hématologie, Masson, Paris, 1983.
16. Neutrophils, eosinophils and basophils, in Hematology, 3rd ed., Williams, W. J., Ed., McGraw Hill, New
York, 1983 (part 5).
17. Bunch, C., Leucocytes in health and disease, in Oxford Textbook of Medicine, 2nd ed., Oxford University
Press, 19, 156, 1987.
18. Erslev, A. J., Aplastic anemia, in Hematology, 3rd ed., Williams, W. J., Ed., McGraw Hill, New York,
1983, 151.
19. Levitt, L. J., Ries, C. A., and Greenberg, P. L., Pure white cell aplasia. Antibody mediated autoimmune
inhibition of granulopoiesis, N. Engl. J. Med., 308, 1141, 1983.
20. Bagby, G. C., Lawrence, J. H., and Neehrhout, R. C., T-lymphocyte-mediated granulopietic failure.
In vitro identification of prednisone responsive patients., N. Engl. J. Med., 309, 1073, 1983.
21. Malech, M. L. and Gallin, J. L, Neutrophils in human diseases, N. Engl. J. Med., 31, 68, 1987.
22. Barnes, R. W. and Rogers, T. R., An evaluation of empirical antibiotic therapy in febrile neutropenic
patient, Br. J. Haematol., 66, 137, 1987.
23. Brenner, B., Nagler, A., Finkelstein, R., Raz, R., and Tatarsky, L, Fever and neutropenias, Harefuah,
109, 319, 1985.
24. Dan, M., The new quinolones, Harefuah, 112, 452, 1987.
25. Groopman, J. E., Mitsuyasu, R. T., DeLeo, M. J., Oette, D. H., and Golde, D. W., Effect of re-
combined human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired im-
munodeficiency syndrome, N. Engl. J. Med., 317, 593, 1987.
26. Champlin, R., Ho, W., and Gale, R. P., Antithymocytic globulin treatment in patients with aplastic
anemia: a prospective randomized trial, N. Engl. J. Med., 308, 113, 1983.
27. Bern, M. M., Roberts, M. S., and Yoburn, D., Cyclosporine treatment for aplastic anemia; a case
demonstrating a second response to second exposure to cyclosporine, Am. J. Hematol., 24, 307, 1987.
28. Storb, R., Prentice, R. L., Buckner, C. D., et al., Graft-versus-host disease and survival in patients
with aplastic anemia treated by marrow grafts from HLA identical siblings. Beneficial effect of protective
environment. N. Engl. J. Med., 308, 302, 1983.
29. Rappoport, J. M., Smith, B. R., Parkman, R., and Rosen, F. S., Application of bone marrow trans-
plantation in genetic diseases, Clin. Hematol., 12, 755, 1983.
30. Christie, A. B., Infectious mononucleosis, in Infectious Diseases, 3rd ed., Churchill Livingstone, Edin-
burgh, 1980, 890.
31. Fauci, A. S., Harley, J. B., Roberts, W. C., et al., The idiopathic hyperéosinophilie syndrome: clinical,
pathophysiologic, and therapeutic considerations, Ann. Intern. Med., 97, 78, 1982.
32. Aster, R. H., Thrombocytopenia due to enhanced platelet destruction, in Hematology, 3rd ed., Williams,
W. J., Ed., McGraw-Hill, New York, 1983, 1298.
33. Marder, V. J., Consumption thrombohemorrhagic disorders, in Hematology, 3rd ed., Williams, W. J.,
Ed., McGraw-Hill, New York, 1983, 1433.
34. Hamilton, P. J., Stalker, A. L., and Douglas, A. S., Disseminated intravascular coagulation, a review,
J. Clin. Pathol., 31, 609, 1978.
35. Hautekeete, M. L., Berneman, Z. N., Bieger, R., et al., Purpura fulminans in pneumococcal sepsis,
Arch. Intern. Med., 146, 497, 1986.
36. Silverman, R. A., Rhodes, A. R., and Dennehy, P. H., Disseminated intravascular coagulation and
purpura fulminans in a patient with Candida sepsis. Biopsy of purpura fulminans as an aid to diagnosis of
systemic Candida infection, Am. J. Med., 80, 679, 1986.
37. Kaplan, B. S. and Prosemans, W., The hemolytic uremic syndrome in childhood and its variants, Semin.
Hematol., 24, 148, 1987.
38. Byrness, J. S. and Moake, J. L., Thrombotic thrombocytopenic purpura and the hemolytic uremic
syndrome: evolving concepts of pathogenesis and therapy, Clin. Haematol., 15, 413, 1986.
39. Drummond, K. N., Hemolytic uremic syndrome then and now, N. Engl. J. Med., 312, 116, 1985.
40. Schepard, K. U. and Bukowski, R. M., The treatment of thrombotic thrombocytopenic purpura with
exchange transfusion, plasma infusions and plasma exchange, Semin. Hematol., 24, 178, 1987.
41. Liu, E. T., Linker, C. A., and Shuman, M. A., Management of treatment failures in thrombotic
thrombocytopenic purpura, Am. J. Hematol., 23, 347, 1986.
42. Gottlieb, A. J., Disorders of hemostasis — non-thrombocytopenic purpura, in Hematology, 3rd ed.,
Williams, W. J., Ed., McGraw-Hill, New York, 1983, 1363.
208 Unexplained Fever

43. Crosby, W. H., Certain things physicians do: red cell indices, (editorial), Arch. Intern. Med., 139(1), 23,
1979.
44. Christensen, D. J., Diagnosis of anemia — clues to greater precision, Postgrad. Med., 73, 293, 1983.
45. Lucas, A. M., Ordi, F., et al., Anemia microciltica severa y fiebre prolongada como forma de presentación
de un hipertiroidismo, Rev. Clin. Esp., 172(1), 53, 1984.
46. Zittoun, R., Une anémié in Tchobroutsky G. Des symptômes a la decision, Medsi, (Paris), 1983.
47. Frank, M. M., Schreiber, A. D., et al., Pathophysiology of immune hemolytic anemia, Ann. Intern.
Med., 87, 210, 1977.
48. Bernard, J., Hématologie, Masson, Paris 1983.
49. Kalderon, A. E., Kikkawa, T., and Bernstein, J., Chronic toxoplasmosis associated with severe hemolytic
anemia, Arch. Intern. Med., 114, 95, 1964.
50. Horgaard, L. and Karle, H., Fever and hemolysis in Hodgkin’s disease, Acta Med. Scand., 197, 311,
1975.
51. Camitta, B. M., Storb, R., and Thomas, E. D., Aplastic anemia: pathogenesis, diagnosis, treatment and
prognosis, N. Engl. J. Med., 306, 645, 1982.
52. Rault, P., Les fievres prolongées de diagnostique difficile. These Paris, Université Bichat, Beaujon. No.
90, 1973.
53. Payne, S. M. and Finkelstein, R. A., The critical role of iron in host-bacterial interactions, J. Clin.
Invest., 61, 1428, 1978.
54. Barrett-Connor, E., Anemia and infection, Am. J. Med., 52, 242, 1972.
55. McKee, C., Jr., Fever in megaloblastic anemia, South Med. J., 72(11), 1423, 1979.
56. Meisler, A. and Mittal, R., Hematologic and oncologic problems, in Samiy-Douglas-Barondess — Textbook
of Diagnostic Medicine, Lea and Febiger, Philadelphia, 1987.
 209

Chapter 13

UNEXPLAINED FEVER IN HEMATOLOGIC DISORDERS

SECTION 2. MALIGNANT HEMATOLOGIC DISORDERS
D. Meytes and A. Ballin

INTRODUCTION
Fever in malignant hematologic disorders is of considerable clinical significance. It may
constitute a systemic manifestation of the disease, be related to treatment, or be associated
with severe infections.

TUMOR ASSOCIATED FEVER

The role of malignancy-associated fever is not clear. There is evidence that cell-mediated
immunity improves when temperatures are raised from 32 to 37°C.1,2 Other immunologic
reactions have also been reported to be temperature sensitive: these include antibody synthesis3
and mixed lymphocyte reaction.4 Several immunological mediators have been found to be
pyrogenic. Thus, monocyte-derived endogenous pyrogen has been recently identified as
interleukin 1 (II^).4-6 ILj initiates fever by increasing synthesis of thermogenic amines,
including prostaglandin (PGE2) in or near the anterior hypothalamus.6 11^ possesses other
biologically important activities such as stimulation of T cells,7 increasing hepatic acute-
phase protein synthesis,8 activation of neutrophils,9 and a cytotoxic effect for tumor cells
in vitro. 10 Purified human monocyte ILj has a stimulatory effect on natural killer cells as
well as a direct antitumor activity for certain tumor targets.11
Cachectin, or tumor necrosis factor (TNF) is another endogenous pyrogen. It is produced
by macrophages and is capable of inducing fever both directly by acting on hypothalamic
neurons, and indirectly by induction of the peripheral production of ILP12 Also, TNF has
been considered by some to be an endogenous antineoplastic agent.13
Human interferon, another leukocyte product, also produces fever,14 and has a proven
antineoplastic activity.
The mechanisms through which pyrogenic immunostimulants may enhance host defenses
against malignant cells are not known. Elevated temperatures have been shown to retard the
proliferation of certain tumor cells both in vitro15 and in vivo.16'11 Nevertheless, exogenously
raised temperatures in vitro do not absolutely mimic fever of endogenous origin. No cor-
relation has yet been found between endogenous pyrogen levels and any cytotoxic effect in
hematologic malignancies in humans.

DRUG FEVER
Drugs used in the treatment of malignant hematologic disorders are an important cause
of short-term pyrexia. They may cause a generalized allergic reaction with fever.18 Some
of the more common examples are as follows. The use of procarbazine, a constituent of
treatment protocols for Hodgkin’s disease and non-Hodgkin lymphoma, is associated with
up to 10% incidence of allergic skin reaction with fever. Agents of bacterial origin such as
L-asparaginase are commonly associated with anaphylactoid reactions and fever. Pyrexia of
24 h duration is quite prevalent in patients who are treated with 5-azacytidine or bleomycin.
Though usually mild to moderate, the allergic reaction may lead to hypotension and death,
210 U nex p la in ed F e ve r

as has been reported for bleomycin.19 A flu-like syndrome with fever, arthralgia, myalgia,
and rash may follow the administration of cytosine arabinoside and of dacarbazine (DTIC).
In the case of the latter drug the symptoms may be dose related. They have a typical onset
at 7 days and may last for 1 to 3 weeks. Other agents which infrequently may also cause
fever include methotrexate, etoposide (VP-16), nitrogen mustard, and 6-mercaptopurine.
Fever induced by chemotherapy is difficult to prove, as any agent used whether cytotoxic
or other, such as allopurinol antimicrobial agents etc., may be pyrogenic in the occasional
patient. It has been estimated to be the cause of the abnormal temperature elevations in over
45% of febrile episodes in nongranulocytopenic leukemia patients.20
Except in extremely severe reactions, drug fever seldom requires the discontinuation of
an otherwise effective chemotherapy. Sometimes, as with procarbazine or nitrogen mustard,
fever may be encountered with initial treatment, without recurrence upon subsequent read-
ministration.

INFECTION
Bacterial, viral, in particular cytomegalovirus21 and herpesvirus,22 fungal,23 and other
opportunistic infections are the most common cause of fever in patients being treated for
hematologic malignancies. Fever in a neutropenic patient will be caused by significant
infection in over 70% of temperature elevations which exceed 38.3°C and are not associated
with transfusion of blood products. Accordingly, elevated temperatures in patients with
responsive disease can seldom be attributed to the malignancy. Other causes, primarily
infection or drug fever, should be seriously considered. From a clinical standpoint it is
important to note that because of inadequate inflammatory response, localizing signs of
infection may not be evident.
In many hematologic malignancies host defense mechanisms are impaired even before
the administration of chemotherapy. Intercurrent infections are often the presenting event
in such patients, and should be looked for in each febrile episode.
The differentiation between fever secondary to active malignant disease from that due
to infection may be difficult. Naproxen, a nonsteroidal anti-inflammatory agent may be
useful. It has produced a rapid and sustained resolution of fever in patients with cancer
without infection.24

MALIGNANT LYMPHOMA
Recurrent, unexplained fever is a common manifestation of malignant lymphoma. In a
patient with fever of unknown origin (FUO), the likelihood of occult malignancy increases
with duration of the symptom. Thus, in about V3 of adults with prolonged FUO, malignancy,
in particular lymphoma, will be disclosed.25

HODGKIN’S DISEASE (HD)

Fever is more common at the initial presentation in Hodgkin’s Disease (HD) than in
non-Hodgkin’s lymphoma (NHL). It was present in 27% of the patients with HD in the
Stanford series.26 Though usually low-grade, high, spiking fevers were also reported. The
classic Pel-Ebstein fever, described in HD, with recurrent hyperpyrexia of 1 to 2 weeks
duration alternating with afebrile periods is rather infrequent. However, if present, it may
be associated with bouts of hemolytic anemia.27 It may also be in synchrony with fluctuations
in the size of the involved lymph nodes.28 The rapid enlargement and tenderness of such
nodes during the febrile episodes may mimic a viral infection.
The occurrence of fever in HD has been ascribed to any or all of the following: areas
of necrosis within the involved nodes, circulating immune complexes29 and to the elaboration
 211

of endogenous pyrogens. One such agent, a relatively cationic protein, has been identified
in the plasma30 and urine of febrile patients with HD. A statistical correlation between the
severity of the pyrexia and the plasma content of the protein has been described.
The presence of fever in HD has important clinical implications in terms of patient
management. The treatment strategy is based on the accurate staging of patients according
to the extent of the disease. In about 90% of cases the disease spreads contiguously via
lymphatic channels from the initially involved lymph nodes to adjacent lymphatic areas.
Based on the extent of the disease, patients are allocated into stages I to IV. Each stage is
further subdivided into A and B categories: B for those with manifestations such as unex-
plained fever, significant weight loss, and night sweats and A — for those patients without
systemic manifestations. The presence of B symptoms has been associated with vascular
invasion31 and noncontiguous involvement. In one series32 only 5 of 95 patients in the A
category had evidence of noncontiguous spread, as opposed to 10 of 36 patients with B
symptoms. Also, B symptoms were more frequent in mixed cellularity and lymphocyte
depleted HD than in the other histologies. Because of these considerations the presence of
fever in apparent stage I or II disease calls for a meticulous re-examination in order to rule
out the possibility of any missed intrathoracic, intra-abdominal, splenic, hepatic, or bone-
marrow involvement with HD.
Abdominal HD has a low survival rate. Patients with this disease have a unique clinical
presentation with high fever and drenching night sweats. Frequently there is no peripheral
adenopathy. Computerized tomography and/or lymphangiography may demonstrate enlarged
retroperitoneal lymph nodes. Laparotomy may reveal lymph nodes involved with lympho-
cyte-depleted HD and areas of necrosis. The clinical course is notorious for early bone
marrow and hepatic dissemination with resultant panycytopenia and lymphocytopenia.33
Radiotherapy alone is curative in most HD patients with localized stage A disease. The
presence of B symptoms usually calls for the additional use of chemotherapy. This should
result in a rapid resolution of the lymphoma-associated fever. Nevertheless, chemotherapy
or even steroid therapy alone before the completion of staging is unadvisable. The fever as
such poses no real danger to the patient and should be symptomatically treated until the
stage of the disease has been accurately determined. Only after this has been accomplished
should radio- and/or chemotherapy begin.
High fever may be extremely troublesome in patients who have relapsed with uncon-
trollable disease. Steroids may be useful for some time. Prostaglandin inhibitors such as
indomethacin and in particular naproxen34 35 may control the fever in some patients and may
have a steroid sparing effect in others.
Cell-mediated immune dysfunction in untreated patients with HD is common. Humoral
response to recall antigens appears to be unaffected, at least until advanced stages of the
disease.36 The derangements in the immune system become more pronounced following
treatment. The immunological impairment underlies the increased susceptibility to infection
such as herpes zoster/varicella,37 cytomegalovirus, tuberculosis, and disseminated fungal
infections.38 Opportunistic infections are frequent in patients with uncontrolled disease.
Indeed, infection has been found to be the cause of death in over half of the patients.39
Fever due to infection should be differentiated from fever due to the lymphoma.
Immediate attention should be given to high fever in patients who have undergone
splenectomy for staging. In one such series,40 82 serious infections occurred among 59 of
210 splenectomy patients; 4.3% were due to Streptococcus pneumoniae.

NON-HODGKIN LYMPHOMA (NHL)

Fever in NHL is less frequent than in HD. It has been observed in 14 to 24%4142 of the
patients. NHL may present with rapidly enlarging lymph nodes, local heat, pain, redness,
swelling and fever, symptoms which may sometimes mimic inflammatory conditions.
212 U nex p la in ed F e ve r

Although usually associated with widespread disease and a more malignant histological
pattern, fever in NHL is of less clinical importance than in HD and of little therapeutic
implication. The main difference between HD and NHL is that the latter is frequently
widespread, i.e., stage III and IV disease at the initial presentation, with frequently non-
contiguous dissemination. Moreover, in NHL of high-grade histology, in apparent stage I
or II disease, the current approach demands multiagent aggressive chemotherapy even in
the absence of systemic symptoms.
Patients with low- and intermediate-grade malignancy are usually afebrile. Notable
exceptions are isolated lymphomas of the spleen,43 which are frequently associated with
fever, and peripheral T-cell lymphomas, in particular those with angioimmunoblastic-like
histology. The appearance of unexplained fever during the course of low-grade NHL may
signify its transformation into a more malignant histological pattern.
Death from infection occurs in 17% of patients with HD and 52% of NHL. In HD there
was a positive correlation between mortality, staphylococcal infection, and monocytopenia.44

LYMPHOMA-MIMICKING DISORDERS
Fever is the presenting symptom in most patients with syndromes which, by virtue of
idiopathic significant lymph node enlargement, mimic malignant lymphoma.
These diverse entities manifest common clinical features such as prominent lymph-
adenopathy, fever, skin rash, dysgammaglobulinemia, and autoimmune phenomena. They
are considered to represent a spectrum of lesions ranging from benign lymphoprolifération
with final evolution into highly malignant lymphoma45 to malignancy at initial presentation.
The diagnosis is based on typical histological features in a lymph node biopsy specimen.
Recent advances in immunohistological techniques and in DNA hybridization analysis allow
a more precise delineation of the cellular composition in the involved lymph nodes. It has
been suggested that many cases of angioimmunoblastic lymphadenopathy and lymphomatoid
granulomatosis represent peripheral T-cell lymphoma at their onset.46 The evolution into a
histologically recognizable malignant lymphoma could be envisaged as a sufficient prolif-
eration of the neoplastic lymphocytes to allow the formation of cell clusters.47 A B-cell
lymphoma could then be caused by the prolonged stimulation of B-cells by neoplastic helper
T-cells.

ANGIOIMMUNOBLASTIC LYMPHADENOPATHY
This disease48 49 commonly occurs after exposure to a drug, dilantin (phenytoin sodium)
being one notable example. High fever, lymphadenopathy, hepatosplenomegaly, skin rash,
autoimmune hemolytic anemia, lymphocytopenia, and polyclonal hypergammaglobulinemia
are the salient clinical features. Autoantibodies such as antinuclear factor, rheumatoid factor,
and anti-smooth muscle antibodies as well as circulating immune complexes may be found.50
The fever occasionally subsides without specific treatment but usually will respond to steroids
when needed. The clinical outcome may range from a complete recovery, through steroid
resistant unremitting fever and uncontrollable hemolysis to overt high grade non-Hodgkin
lymphoma, which may occur in up to 18% of the patients.49
In patients who require high doses of steroids various chemotherapeutic regimens have
been tried. Although no formal clinical trials have so far been presented, it appears that
treatment with steroids and cyclophosphamide offers better results than steroids alone.51 At
present there are no clear guidelines concerning treatment.

GIANT ANGIOFOLLICULAR LYMPH NODE HYPERPLASIA

This entity, originally described by Castleman et al.,52 is an atypical lymphoproliférative
disease lacking features of monoclonality. The classical Castleman’s Disease presents as a
 213

solitary mass, most commonly in the mediastinum. There are two histological variants. The
more common, hyaline vascular type, is usually not associated with systemic manifestations
whereas the plasma cell type is typically accompanied by fever and other clinical signs and
symptoms of a similar nature to those present in angioimmunoblastic lymphadenopathy.53
Local treatment has been associated with a full clinical recovery.
A systemic lymphoproliferative disorder affecting multiple lymph nodes with multiple
organ dysfunction has been described.54'55 High fever, weight loss, and night sweats are
frequent presenting signs. Hepatosplenomegaly with abnormal liver function tests, autoim-
mune hemolytic anemia, and thrombocytopenia may be seen. Polyclonal hypergammaglob-
ulinemia is typical, although monoclonal proteins have also been observed. Signs of renal
disease with proteinuria and a vague central nervous system disorder may occur. The course
may be persistent or episodic. Significant infections may further complicate the disease and
be a prominent cause of fever and morbidity. Treatment, including steroids, splenectomy,
and various combinations of cytotoxic drugs, has been attempted;54 55 however, many patients
succumb to this seemingly nonmalignant disorder. An association with Kaposi’s sarcoma54,56
has been described. In a recently published series, malignancy developed in 27% of the
patients.54

LYMPHOMATOID GRANULOMATOSIS
Lymphomatoid granulomatosis was initially described in 1972 as “ angiocentric — an-
giodestructive lymphoreticular proliferative and granulomatous disease involving predomi-
nantly the lungs” .57 Subsequently a form of benign lymphocytic angiitis and granulomatosis
has been separated from other cases.58 The malignant disease is considered to represent
lymphoma, identified as helper T-cells in some patients.59 Typical organ involvement in-
cludes lung, skin, nasopharynx and mesentery as well as the central nervous system.54'60
Here again the outcome may range from spontaneous regression or intermittent symptom-
atology to steroid responsive or relentlessly progressive, lethal disease.61

MULTIPLE MYELOMA AND MACROGLOBULINEMIA

Infections are a major cause of morbidity and mortality in patients with multiple myeloma
(MM) and macroglobulinemia. Frequently bacterial infection is the presenting symptom of
MM, ranging from 0.8 to 2.22 infections per patient per year.62 Though Streptococcus
pneumoniae continues to be a significant problem, Gram-negative microorganisms presently
account for over 2/3 of the infectious episodes.63 Sinopulmonary and urinary tract infections
are the most common. Tumor mass, azotemia, and refractory disease have all been associated
with an increased risk of infection.64 While the depression of normal marrow elements, in
particular granulocytes, is an important feature of MM, a lack of correlation between infection
and neutropenia has been noted.65 Patients with macroglobulinemia have less infectious
episodes than those suffering from MM.66
The mechanism of immunosuppression in MM has been studied in plasmacytoma-bearing
mice and in humans. A defective primary antibody response has been found.62 Based on
animal studies, it is believed that the B-cells in MM are intrinsically normal, but that they
are inhibited by suppressor macrophages and/or by suppressor T-lymphocytes. It appears
that the catabolism of antibodies in MM is also accelerated. Inability of MM patients to
mount adequate antibody response to bacterial antigens may lead to repeated infections with
the same microorganisms. A decreased complement activity in MM sera has also been
described, but its clinical significance is uncertain.
Very infrequently, in a rapidly progressive, aggressive MM, fever may occur. However,
in general, fever in patients with MM and macroglobulinemia should not be attributed to
the malignant disease per se. The vast majority of febrile episodes are in fact due to bacterial
214 U n ex p la in ed F e ve r

infection. It should be remembered that overwhelming infections account for up to 20 to

50% of deaths in the patients.67 Management of the infectious episodes should include
meticulous attention to adequate hydration, as dehydration may precipitate hypercalcemia.
Although cell-mediated immunity is usually not impaired in MM, the administration of
corticosteroids, sometimes in large doses, in treatment may be associated with a spectrum
of opportunistic infections.

CHRONIC LYMPHOCTYIC LEUKEMIA (CLL)

Clonal transformation of B-lymphocytes with surface immunoglobulin (Ig) restricted to
a single Ig class and subclass is present in most CLL patients. T-CLL accounts for 5% of
CLL worldwide. The latter typically presents with prominent hepatosplenomegaly and marked
lymphocytosis. Skin infiltration is frequent. There is often poor response to treatment.
Prolymphocytic leukemia, another variant of less maturely appearing lymphocytes, typically
presents with massive splenomegaly, high lymphocyte count, and insignificant enlargement
of peripheral lymph nodes. A particular form of lymphoproliférative disease with granulo-
cytopenia and recurrent infections is associated with proliferation of large granular lympho-
cytes.68
Fever in the absence of infection is rare in (CLL). Infection-related pyrexia is the
presenting symptom in many patients.69 Over 50% of CLL patients die of infection.
B-CLL lymphocytes are immunologically dysfunctional. Severe hypogammaglobuli-
nemia may be present in patients who have asymptomatic disease and will eventually develop
in some 50% of the patients. Inversion of T-helper/T-suppressor ratio, a decreased T-helper
function and increased numbers of T-suppressor cells have been described in B-CLL.70 The
absent or inadequate antibody response underlies the marked susceptibility of CLL patients
to infections, commonly with encapsulated microorganisms.70*71 In patients with severe
hypogammaglobulinemia and recurrent infections, administration of gammaglobulin, in par-
ticular intravenous immunoglobulin, may be of benefit.72 Paradoxically, autoantibodies,
autoimmune hemolytic anemia and immune thrombocytopenia occur with increased fre-
quency.
Fever in CLL should be approached in a similar way as in multiple myeloma. A similar
spectrum of pathogens and types of infection occur. Opportunistic and fungal infections as
a cause of pyrexia are more frequent. They may be related to an inherently abnormal cell-
mediated immunity72 as well as to the more extensive use of steroids in CLL as opposed to
MM.
An important cause of fever in CLL is its evolution into a more malignant disease,
Richter’s Syndrome,73 which is a pleomorphic large cell lymphoma of localized lymph nodes
in association with pre-existing CLL. It is characterized by persistent fever, weight loss and
elevated levels of serum lactic dehydrogenase. Richter’s Syndrome may be diagnosed by
lymph node biopsy or by a positive aspirational cytology in a patient who presents with the
appropriate clinical picture. In less than 1% of the patients transformation into acute lym-
phocytic leukemia will occur.70

HAIRY CELL LEUKEMIA

Hairy cell leukemia (HCL) is a B-lymphocyte lymphoproliférative disease characterized
by pancytopenia, splenomegaly and the presence of charactertic mononuclear “ hairy cells’’
in peripheral blood, bone marrow and other lymphoreticular tissues. T-HCL, related to
human T-cell leukemia virus (HTLV-II) has been described.74
The incidence of febrile episodes caused by infection is very high. These are related to
the severe granulocytopenia and monocytopenia. In contrast to CLL, immunoglobulin levels
 215

in HCL are usually normal. Pneumonia and septicemia due to P seu d o m o n a s and E. co li
organisms are common.75 Death may be attributed to infection in 40 to 66% of HCL patients.
Treatment with interferon has dramatically changed the prognosis of patients with HCL.76
Prolonged complete or partial remissions are now to be expected in about 75% of the patients
receiving interferon, with regression of splenomegaly and a marked improvement of all
peripheral blood elements. Before the advent of interferon therapy, splenectomy was offered
to symptomatic patients. Splenectomy reduced the risk of infection in the responding patients,
presumably by increasing the blood neutrophil counts. Treatment with interferon has been
also associated with reduced infection rate, an increase in monocyte counts, and an increased
ability of the cells to elaborate tumor necrosis factor.77 Whether interferon has changed the
incidence of unusual types of infection, such as disseminated atypical mycobacterial or
fungal disease is not yet known. 2-Deoxycoformycin (pentostatin) appears to be very effective
in this disease. However its use has been associated with severe infections and its role as
first line treatment has not yet been determined.
Immune complex disease has been recently described in HCL.78 Whether it can cause
fever is not presently known.

ACUTE LEUKEMIA
Fever is a well-known symptom in patients with acute leukemia (AL).79 Pizzo et al.20
have prospectively examined 1001 febrile episodes registered in their cancer patients during
a 5-year period. The risk of developing a fever in pediatric and young adult patients with
acute lymphoblastic leukemia (ALL) receiving cytotoxic therapy was 31 % and that of acute
myeloblastic leukemia (AML)—45% . Boggs reports that fever was registered in about 25%
of 5169 hospitalization days in 70 ALL patients.80 Fifty-three AML patients had fever in
more than 40% of 2463 hospitalization days.
The main clinical problem in a febrile patient with AL is to establish whether the pyrexia
is due to the disease or to one of the infectious episodes which so frequently complicate
AL. Unfortunately, neither the character nor the severity of the fever is of any help in
determining the cause of the pyrexia. The presence of frank, shaking chills is helpful as
they are much more common when infection is the cause of the fever.81

ETIOLOGY OF FEVER
In the presence of a normal granulocyte count, about 60 to 70% of febrile nongranu-
locytopenic episodes in leukemia patients can be assigned to a noninfectious etiology, some
are associated with the administration of chemotherapy (when fever occurs within 12 h
following the completion of chemotherapy and the patient defervesces during the subsequent
24 h period). On the other hand, of the episodes of fever associated with granulocytopenia,
(>500 PMN per mm3) an infectious etiology can be defined in 50 to 60%.20,82,83
Microbiological confirmation is obtained in about half of the infections, the remaining
being diagnosed by clinical evidence alone.20 Laboratory isolates reveal the following patho-
gens: Gram-positive bacteria (40 to 45%), Gram-negative bacteria (30%), anaerobic (3%),
viruses (5 to 30%), mycoplasma (1 to 11%), fungi (1 to 8%) and P n e u m o cy stis ca rin ii (3
to 4%).20,84-86
The main bacterial pathogens in leukemia patients are E. c o li , S ta p h y lo co c cu s a u re u s ,
and P seu dom o n a s a e r u g in o sa * 4 *1 Less common are S trep to co c cu s virid a n s, S erra tia spp.,
K le b s ie lla , E n te ro c o c c u s , and H a em o p h ilu s in fluenzae. The principal causes for febrile
episodes in pediatric leukemia patients are bacteremia, pneumonia, skin and soft tissue
infections, and upper respiratory tract infections.62,84,85,87
The spectrum of viruses documented in children with acute leukemia and fever includes
herpes simplex, varicella-zoster, adenovirus, cytomegalovirus, rhinovirus, parainfluenza
216 U nex p la in ed F e ve r

types 1, 2, and 3, enterovirus, influenza A and B and respiratory syncytial.88 Viral infection
rates in children with AML are considerably higher than those in children with ALL.88 The
incidence of bacterial infections85 as well as viral infections88 in leukemia pediatric patients
is higher at the stages of “ active disease” (induction therapy and relapse) as compared to
“ inactive disease” (“ remission” ). With the improvement of chemotherapy and antibiotic
protocols, surgical procedures and the use of total parenteral nutrition, fungal infections are
more frequently documented. In one study89 fungi alone or in combination with bacteria
accounted for 40% of infectious fatalities during the initial remission induction period of
AML patients. Most fungal infections in AL patients are caused by C a n d id a and A sp erg illu s
Sp 82,89,90 other fungal pathogens are C r y p to c o c c u s , T o ru lo p sis g la b r a ta , T rich o sp o ro n cu-
tan eu m , M u co r sp. and F u sariu m sp. The recently described hepatosplenic candidiasis
presents with spiking fever, leukocytosis, and splenomegaly with abnormal liver function
tests. Typically, it evolves in a recently treated leukemic patient who entered a complete
hematological remission
The underlying malignancy can be implicated only rarely as a cause of fever in patients
with AL.21 It is suggested that in neoplastic diseases, as in infections, endogenous pyrogen
serves as the final common pathway in producing fever. Whether the pyrogen comes from
necrotic tumor cells from granulocytes or from macrophages infiltrating the tumor remains
a matter of controversy.5 Other causes fever in leukemia patients are infected central line
catheter, transfusion reaction, and splenic infarction.91

THE “ FEVER WORK-UP” AND MANAGEMENT OF INFECTIONS

The “ fever work-up” includes a complete physical examination and the following
laboratory investigation: complete hematologic analysis, aerobic and anaerobic blood cultures
(three consecutive samples are usually taken over a few-hour period), urine cultures and
urinalysis, cultures of stools and chest roentgenogram.20-92 If the patient is not granulocy-
topenic (polymorphonuclears >500 per mm3) and no cause of the fever is found, a broad
spectrum antibiotic such as amoxycillin is prescribed. If, on the other hand, granulocytopenia
is present, further investigation takes place while the patient is hospitalized. Urine, sputum,
and stools are examined for the presence of additional pathogens. Blood cultures and serologic
investigation for antibodies to viruses (herpes simplex, herpes zoster, adenovirus, cytomeg-
alovirus, respiratory syncytial, influenza, parainfluenza) psittacosis, mycoplasma, and HBsAg
are carried out. Evidence of C a n d id a and A sp erg illu s infection is also looked for. Abdominal
ultrasonography, CT scan, and other radiological and laboratory investigations are undertaken
according to the physician’s suspicion.
Concomitantly, an empiric antibiotic regimen is initiated. Various combinations of ami-
noglycosides and beta lactams have been studies to combat bacterial infections.93 97 Others
tried the combination of two beta-lactam antibiotics.98101 Some have approached the problem
of avoiding various toxicities, such as the ototoxicity and nephrotoxicity of aminoglycosides,
by attempting to exploit the broad spectrum of some of the “ third generation” cephalosporins,
such as moxalactam, ceftazidine, and cefoperazone as monotherapy.102104 Currently, the
combination of an aminoglycoside and beta-lactam antibiotic remains the standard treatment
for infections in leukemia patients. Persistence of the pyrexia and granulocytopenia beyond
7 days requires the addition of amphotericin B. Documented skin infections should prompt
antibiotic coverage for staphylococcus, namely, cloxacillin or vancomycin.

PREVENTION OF INFECTION
Trimethoprim — sulfamethoxazole, colistin, neomycin, and nalidixic acid have been
tried — with equivocal success — to prevent infections in leukemia patients.105"108 However,
side effects, emergence of resistant microogranisms109 and poor compliance limit their use.
Quinolones have a broad spectrum of activity and adequate tissue levels may be achieved.
 217

Some studies indicate that ciprofloxacin and norflotacin, new quinolones, are appropriate
for gut decontamination.110 115 The increasing frequency of fungal infections in AL patients
has led to the evaluation of antifungal prophylaxis. Amphotericin B116 and ketocona-
zole117118 were shown to be effective in preventing fungal gut colonization in leukemia
patients.

CHRONIC MYELOGENOUS LEUKEMIA

Low-grade fever is frequently present at diagnosis in chronic myelogenous leukemia

(CML). It was present in 31% of 152 patients 119 and only 5% had documented infections.
Controversy exists whether CML granulocytes are functionally normal; nevertheless, the
incidence of severe infections does not seem to be increased during the chronic phase. An
increased metabolic rate, which is proportional to tumor burden and immaturity of leukocytes
underlies the systemic manifestations, which also include weight loss and night sweats.
When the hyperleukocytosis is controlled by drugs, patients are usually afebrile. An important
cause of fever may be splenic infarction in uncontrolled disease.
Unexplained fever appearing when CML seems to be under moderately good control
may herald blastic transformation, which is accompanied by fever in 45 to 60% of CML
patients.120 122 Documented infection, however, is uncommon. Other signs of accelerated
phase in CML include swinging blood counts, cytopenias, an increase in the proportion of
basophils and immature granulocytes. Leukocyte alkaline phosphatase, which is typically
very low in the chronic phase, may increase. Increasing splenomegaly, splenic infarction,
lymphadenopathy and prominent bone pain are other clinical features. In addition to the
classic Philadelphia chromosome, other chromosomal abnormalities, including a double
Philadelphia chromosome, may be seen.123 Pyrexia is believed to be related to the blastic
transformation, since patients defervesce following successful chemotherapy of blast crisis.

MYELODYSPLASTIC SYNDROMES
Myelodysplastic Syndromes (MDS) are clonal disorders of the bone marrow hemato-
poietic stem cells. They all are characterized by peripheral blood cytopenias with hyper-
cellular bone marrow. Various degrees of ineffective hematopoiesis are present. The course
is subacute or chronic with evolution into acute leukemia in a variable proportion of the
cases. Terms such as preleukemia, which have been previously used, have largely been
abandoned.
The French-American-British cooperative group has defined five categories of MDS.124
These include refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS),
refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in
transformation (RAEV-T), and chronic myelomonocytic leukemia (CMML).
Anemia, bleeding, and fever are the most common presenting features. Fever is due to
bacterial infection in most cases. In addition to granulocytopenia, neutrophil function has
been found to be abnormal in about half of all patients.125 Aberrations in host-defense
mechanisms, such as defective natural killer activity,126 have also been described.
The various categories differ with respect to prognosis.127 On one extreme, patients may
survive for many years — on the other, death may occur within a few months. So far no
effective treatment has been found. Derivatives of ds-retinoic acid and low-dose cytosine
arabinoside have been claimed to be of limited value in some studies.128 Aggressive chemo-
therapy has been associated with marked toxicity and no study has demonstrated survival
advantage. Trials with hematopoietic growth factors are currently under investigation.
Infection and hemorrhage are the major causes of death.129' 130
218 U n ex p la in ed F e ve r

MYELOPROLIFERATIVE SYNDROMES

Myeloproliferative syndromes, i.e., polycythemia vera (PV), esssential thrombocy-

themia (ET), and agnogenic myeloid metaplasia are neoplastic disorders affecting the he-
matopoietic stem cell and its progeny. Except for myeloid metaplasia in which granulocytopenia
may be present, myeloproliferative disorders in their chronic phase are not associated with
increased incidence of infections. Granulocytosis with a shift to the left is a feature of the
disease and should not be interpreted as an evidence of infection.
An important cause of otherwise “ unexplained” fever may be thrombosis and throm-
bophlebitis. Mesenteric, hepatic portal, and splenic vein thrombosis may occur in patients
in whom the disease has not been adequately controlled. Phlebothrombosis with pulmonary
embolism is quite common. Splenic infarction may occur.
The appearance of prolonged FUO in the course of the disease may herald acute leukemic
transformation. The inherent liability to develop acute leukemia in patients with PV is further
increased by treatment with radioactive phorphorus and alkylating agents.131 A preleukemic,
pancytopenic phase with secondary sideroblastic anemia, bone pain, and unexplained fever
has been described.132

THE HISTIOCYTOSES
The histiocytoses are a diverse group of disorders involving cells of the mononuclear
phagocyte series. These disorders are characterized by proliferation and activation of mac-
rophages and are caused by external stimuli or by an intrinsic cellular abnormality.133 Fever
is one of the main clinical features.133
Cell cultures originating from surgically collected skull lesions of patients with eosi-
nophilic granuloma elaborated interleukin 1 (ILj) and prostaglandin E2.134 ILj was detected
in neoplastic cells from patients with true histiocytic lymphoma and malignant histiocyto-
sis.135
ILj, which is identical to endogenous pyrogen,6 10 is known to be the product of mac-
rophages and monocytes,6136 macrophage-derived endogenous pyrogen is presumed to par-
ticipate in the pathophysiology of the clinical features of histiocytic disorders.133
Decreased production of ILj by a patient with familial hemophagocytic lymphohistio-
cytosis and high fever137 suggests that other substances also participate in the pathogenesis
of fever in these disorders. Alternatively, hyperactive macrophagaes are able to suppress
ILj activity by elaboration of PGE2.138
Histiocytic disorders are divided into two main categories: malignant histiocytosis (his-
tiocytic medullary reticulosis) as a primary neoplastic disease of the phagocytic cell line and
reactive histiocytosis. The latter may be caused by agents such as bacterial, viral, fungal,
or parasitic infections, or unknown, as in familial erythrophagocytic lymphohistiocytoses,
sinus histiocytosis with massive lymphadenopathy, eosinophilic granuloma, and other gran-
ulomatous diseases.133 Morphologically, the histiocytoses may be divided into two groups;
those in which the proliferating cells have definite cytologic features of malignancy and
show some degree of hemophagocytosis and disorders in which the proliferating histiocytes
lack malignant characteristics and manifest prominent hemophagocytosis.139
High fever is common to all forms of histiocytosis. In malignant histiocytosis it is
believed to be a constant characteristic and its absence makes the diagnosis unlikely.140
Other common features in both the malignant and the benign reactive disorders are the
presence of constitutional symptoms and organomegaly. The overlapping clinical charac-
teristics among disorders of such diverse etiologies may be explained by similarities in
behavior of the activated macrophages in both benign and malignant disorders, notably
hemophagocytosis, osteolysis, tissue invasion, and release of endogenous pyrogens.133
 219

Although fever is an inherent characteristic of the histiocytoses, the presence of secondary

infection should be always suspected and searched for.

REFERENCES
1. Purtilo, D. T., Walsh, G. P., Storrs, E. E., and Banks, I.S., Impact of cool temperatures on transfor-
mation of human and armadillo lymphocytes (Dasypus novemcintus Linn.) as relatead to leprosy, Nature,
248, 450, 1974.
2. Lauwasser, M. and Shands, J. W., Depressed mitogen responsiveness of lymphocytes at skin temperature,
Infect. Immun,, 24, 454, 1979.
3. Brucher, J., Teodorescu, M., Gaspar, A., Stefanescu, D. T., and Badelscu, A. A., Different optimum
temperatures for the biologic activity of rabbit and human lymphocytes in vitro, Arch. Rheum. Pathol. Exp.
Microbiol., 32, 297, 1973.
4. Smith, J. G., Knowlton, R. P., and Agarwal, Human lymphocyte responses are enchanced by culture
at 40°C, J. Immunol., 121, 691, 1978.
5. Hanson, D. F., Murphy, P. A., Silicano, R., and Shin, H. S., The effect of temperature on the activation
of thymoctyes by interleukins I and II, J. Immunol., 130, 216, 1983.
6. Jam pel, H. D., Duff, G. W., Gershon, R. K., Atkins, E., and Durum, S. K., Fever and immunoreg-
ulation, J. Exp. Med., 157, 1229, 1983.
7. Dinarello, C. A., Cannon, J. G., Wolff, S. M., Bernheim, H. A., Beutler, B., and Cerami, A., Tumor
necrosis factor (Cachectin) is an endogenous pyrogen and induces production of interleukin I, J. Exp. Med.,
163, 1433, 1986.
8. McAdam, K. P. W. J. and Dinarello, C. A., Induction of serum amyloid A synthesis of human leukocytic
pyrogen, in Bacterial Endotoxins and Host Response, Agarwal, M. K., Ed., Elsevier/North-Holland,
Amsterdam, 1980, 167
9. Klempner, M. S., Dinarello, C. A., and Gallin, J. I., Human leukocytic pyrogen induces release of
specific granule contents from human neutrophils, J. Clin. Invest., 61, 1330, 1978.
10. Dinarello, C. A., Conti, P., and Mier, J. W., Effects of human interleukin I on natural killer cell activity:
is fever a host defense mechanism for tumor killing?, Yale J. Biol. Med., 59, 97, 1986.
11. Onozak, K., Matsushima, K., Aggarwal, B. B., and Oppenheim, J. J., Human Interleukin I is a
cytocidal factor for several tumor cell lines, J. Immunol., 135, 3962, 1985.
12. Beutler, B. and Cerami,A., Cachectin: more than a tumor necrosis factor, N. Engl. J. Med., 316(7), 379,
1987.
13. Sugarman, B. O. and Schreiber, H., Tumor necrosis factor: potent effector molecule for tumor cell killing
by activated macrophages, Proc. Natl. Acad. Sci. U.S.A. 83, 5233, 1986.
14. Dinarello, C. A., Bernheim, H. A., Duff, G. W., Le, H. V., Nagabhushan, T. L., Hamilton, N C.,
and Coceani, F., Mechanisms of fever induced by recombinent human interferon, J. Clin. Invest., 74,
906, 1984.
15. Hall, E. J. and Roizin-Towle, L., Biological effects of heat, Cancer Res., 44, 4708s, 1984.
16. Li, D. J. and Hahn, G. M., Responses of RIF tumors to heat and drugs: dependence on tumor size,
Cancer Treat. Rep., 68, 1149, 1984.
17. Irish, C. E., Brown, J., Galen, W. P., and Gallucci, J. J., Thermoradiotherapy for persistent cancer
in previously irraditated fields, Cancer, 57, 2275, 1986.
18. Dorr, R. T. and Fritz, W. L., Common toxicities, in Cancer Chemotherapy Handbook, Elsevier, New
York, 1982, 101.
19. Dorr, R. T. and Fritz, W. L., Bleomycin Sulfate, in Cancer Chemotherapy Handbook, Elsevier, New
York, 1982, 274.
20. Pizzo, P. A., Robichaud, K. J., Wesley, R., and Commers, J.R., Fever in pediatric and young adult
patients with cancer, Medicine, 61, 153, 1982.
21. Griffiths, P.D., Diagnostic techniques for cytomegalovirus infection, Clin. Haematol, 113, 631, 1984.
22. Saral, R., Burns, W. H., and Prentice, H. G., Herpes virus infections: clinical manifestations and
therapeutic strategies in immunocompromised patients, Clin. Haematol., 13, 645, 1984.
23. Hawkins, C. and Armstrong, D., Fungal infections in the immunocompromised host, Clin. Haematol.,
13, 599, 1984.
24. Azeemuddin, S. K., Vega, R. A., Kim, T. J., and Ragab, A. H., The affect of naproxen on fever in
children with malignancies, Cancer, 59, 1966, 1987.
25. Larson, E. B., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow up of 105 cases, 1970 — 1980, Medicine, 61, 269, 1982.
220 Unexplained Fever

26. Kaplan, H. S., Clinical Evaluation in ‘'Hodgkin’s Disease’’, 2nd ed., Harvard University Press, Cambridge,
1980, 117.
27. Eisner, E., Ley, A. D., and Mayer, K., Coombs positive hemolytic anemia in Hodgkin’s disease, Ann.
Intern. Med., 66, 258, 1967.
28. Kaplan, H. S., Clinical Evolution in "Hodgkin’s Disease” , 2nd ed., Harvard University Press, Cambridge,
1980, 124.
29. Amlot, P. L., Slaney, J. M., and Williams, B. D., Circulating immune complexes and symptoms in
Hodgkin’s disease, Lancet, 1, 449, 1976.
30. Young, C. W., Hodas, S., Dessources, W., and Korngold, L., Observations on trace proteins in plasma
of febrile patients by cationic disc electrophoresis in acrylamide gel at pH 3.8, Cancer Res., 35, 1985,
1975.
31. Hoerni, B., Chauvergne, J., and Parsi, M., La fievre de la maladie de Hodgkin, hypothese pathogenique,
Presse Med., 78, 1317, 1970.
32. Johnson, R. E., Thomas, L. B., and Chretien, P., Correlation between clinicohistologic staging and
extranodal relapse in Hodgkin’s disease, Cancer, 25, 1071, 1970.
33. Neiman, R. S., Rosen, P. J., and Lukes, R. J., Lymphocyte depletion Hodgkin’s disease. A clinico-
pathologic entity, N. Engl. J. Med., 288, 751, 1973.
34. Chang, J. C. and Gross, H. M., Utility of naproxen in the differential diagnosis of fever of undetermined
origin in patients with cancer, Am. J. Med., 76, 597, 1984.
35. Geisler, C., Gotzche, T. C., Schade-Hansen, S., Yuul, K., Plesner, A. M., and Nissen, N. I., Naproxen
has greater antipyretic effect on Hodgkin’s disease related fever than on other tumors or infection, Scand.
J. Haematol., 35, 325, 1985.
36. Romagnani, S., Rossi-Ferrini, P. L., and Ricci, M., The immune derangement in Hodgkin’s disease,
Semin. Hematol., 22, 41, 1985.
37. Souhami, R. L., Babbage, J., and Sigfusson, A., Defective in vitro antibody production to varicella
zoster and other virus antigens in patients with Hodgkin’s disease, Clin. Exp. Immunol., 53, 297, 1983.
38. Casazza, A. R., Duvall, C. P., and Carbone, P. P., Summary of infectious complications occurring in
patients with Hodgkin’s disease, Cancer Res., 26, 1290, 1966.
39. Colby, T. V., Richard, T. H., and Roger, A. W., Hodgkin’s disease and autopsy, Cancer, 47, 1852,
1981.
40. Coker, D. D., Morris, D. M., Coleman, J. J., Schimpff, S. C., Wiernik, P. H., and Elias, E. G.,
Infection among 210 patients with surgically staged Hodgkin’s disease, Am. J. Med., 75, 97, 1983.
41. Rosenberg, S. A., Diamond, H. D., Jaslowitz, B., and Craver, L., Lymphosarcoma, a review of 1269
cases, Medicine, 40, 31, 1961.
42. Jones, S. E., Fuks, Z., Bull, M., Kadin, M. E., Dorfman, R. F., Kaplan, H. S., and Rosenberg,
S. A., Non Hodgkin’s lymphoma, clinicopathological correlations in 405 cases, Cancer, 31, 806, 1973.
43. Ahmann, D. L., Kiely, J. M., Harrison, E. G., and Payne, W. S., Malignant lymphoma of the spleen,
Cancer, 19, 461, 1966.
44. Shaikh, B. S., Moore, R. D., Tier, J. J., Gorg, M. L., and Appelbaum, P. C., Mortality association
factors in infected lymphoma patients, Cancer, 59, 1635, 1985.
45. Lukes, R. J. and Tindle, B. H., Immunoblastic lymphadenopathy: A prelymphomatous state of immu-
noblastic sarcoma, Recent Results Cancer Res., 64, 241, 1978.
46. Weis, J.W., Winter, M. W., Phyliky, R. L., and Banks, M. D., Peripheral T cell lymphomas: histologic,
immunologic and clinical characterization, Mayo. Clin. Proc., 61, 411, 1986.
47. Nathwani, B. N., Rappaport, H., Moran, E. M., Pangalis, G. A., and Kim, H., Malignant lymphoma
arising in angioimmunoblastic lymphadenopathy, Cancer, 41, 578, 1978.
48. Frizzera, G., Moran, E. M., and Rappaport H., Angioimmunoblastic lymphadenopathy with dyspro-
teinaemia, Lancet, 1, 1070, 1974.
49. Pangalis, G. A., Moran, E. M., Nathwani, B. N., Zelman, R. G., Kim, H., and Rappaport, H.,
Angioimmunoblastic lymphadenopathy: longterm follow up study, Cancer, 52, 318, 1983.
50. Archimbaud, E., Coiffier, N., Bryon, P.A., Vasselon, C., Brizard, P. C., and Viala, J. J., Prognostic
factors in angioimmunoblastic lymphadenopathy, Cancer, 59, 208, 1987.
51. Koo, C. H., Nathwani, B. N., and Weinberd, C. D., Atypical lymphoplasmacytic and immunoblastic
proliferation in lymph nodes of patients with autoimmune disease, Medicine, 63, 274. 1984.
52. Castleman, B., Iverson, L., and Menendex, V., Localised mediastinal lymph node hyperplasia resembling
thymoma, Cancer, 9, 822, 1956.
53. Keller, A. R., Hochholzer, L., and Castleman, B., Hyaline — vascular and plasma cell types of giant
lymph node hyperplasia of the mediastinum and other locations, Cancer, 29, 670, 1972.
54. Frizzera, G., Peterson, B. A., Bayrd, E. D., and Goldman, A., A systemic lymphoproliferative disorder
with morphologic features of Castleman’s disease: clinical findings and clinicopathologic correlations in 15
patients, J. Clin. Oncol., 3, 1202, 1985.
 221

55. Weisenburger, D. D., Nathwani, B. N., Win berg, C. D., and Rappaport, H., Multicentric angiofol-
licular lymph node hyperplasia. A clinicopathologic study of 16 cases, Hum. Pathol., 16, 162, 1985.
56. Kessler, E., Multicentric giant lymph node hyperplasia. A report of seven cases, Cancer, 56, 2446, 1985.
57. Liebow, A. A., Carrington, C. R. B., and Friedman, P. J., Lymphomatoid granulomatosis, Hum.
Pathol., 3, 457, 1972.
58. Saldana, M. J., Patchefsky, A.S., Israel, H. I., and Atkinson, G. W., Pulmonary angiitis and granu-
lomatosis: the relationship between histologic features, organ involvement and response to treatment, Hum.
Pathol., 8, 391, 1977.
59. Harrist, T. J., Bahn, A. K., Murphy, G. F., Sanchez, N. P., and Mihm, M. C., Jr., Lymphomatoid
papulosis and lymphomatoid granulomatosis: T cell subset populations, refined light microscopic morphology
and direct immunofluorescent observations (abstract), J. Invest. Dermatol., 76, 326, 1981.
60. Katzenstein, A. L. A., Carrington, C. R. B., and Liebow, A. A., Lymphomatoid granulomatosis: a
clinicopathologic study of 152 cases, Cancer, 43, 360, 1979.
61. Fauci, A. S., Haynes, B. F., Costa, J., Katz, P., and Wolff, S. M., Lymphomatoid granulomatosis —
prospective clinical and therapeutic experience over 10 years, N. Engl. J. Med., 306, 68, 1982.
62. Jacobson, D. R. and Zolla-Pazner, S., Immunosuppression and infection in multiple myeloma, Semin.
Oncol., 13, 282, 1986.
63. Espersen, F., Birgens, H. S., and Hertz, J. B., Current patterns of bacterial infection in myelamatosis,
Scand. J. Infect. Dis., 16, 169, 1984.
64. Perri, R. T., Hebbel, R. P., and Oken, M. M., Influence of treatment and response status on infection
risk in multiple myeloma, Am. J. Med., 71, 935, 1981.
65. Savage, D. G., Lindenbaum, J., and Garrett, T. J., Biphasic pattern of bacterial infection in multiple
myeloma, Ann. Intern. Med., 96, 47, 1982.
66. Fahey, J. L., Scoggins, R., Utz, J. P., and Szwed, C. F., Infection, antibody response and gammaglobulin
components in multiple myeloma and macroglobulinema, Am. J. Med., 35, 698, 1963.
67. Kyle, R. A., Subject Review: Multiple myeloma — review of 869 cases, Mayo Clin. Proc., 50, 29, 1975.
68. Reynolds, C. W. and Foon, K. A., T-gamma lymphoproliferative disorder in man and experimental
animals: a review of the clinical, cellular and functional characteristics, Blood, 64, 1146, 1984.
69. Twomey, J. J., Infections complicating multiple myeloma and chronic lympocytic leukemia, Arch. Intern.
Med., 32, 562, 1973.
70. Gale, R. P. and Foon, K. A., Chronic lymphocytic leukemia — recent advances in biology and treatment,
Ann. Intern. Med., 103, 101, 1985.
71. Miller, D. G. and Karnofsky, D. A., Immunologic factors and resistance to infection in chronic lymphatic
leukemia, Am. J. Med., 31, 748, 1961.
72. Foon, K. A. and Gale, R. P., Staging and therapy of chronic lymphocytic leukemia, Semin. Hematol.,
24, 264, 1987.
73. Long, J.C. and Aisenberg, A.C., Richter’s syndrome: a terminal complication of chronic lymphocytic
leukemia with distinct clinical pathologic features, Am. J. Clin. Pathol., 63, 768, 1975.
74. Wachsman, W., Golde, D. W., and Chen, I. S. Y., Hairy cell leukemia and human T-cell leukemia
virus, Semin. Oncol., 11, 446, 1984.
75. Golomb, H. M. and Hanner, S. B., Infectious complications associated with hairy cell leukemia, J.
Infect. Dis., 143, 639, 1981.
76. Quesada, J. R., Reuben, J., Manning, J. T., Hershe, M., and Gutterman, J., Alpha interferon for
induction of remission in hairy cell leukemia, N. Engl. J. Med., 310, 15, 1984.
77. Aderka, D., Levo, Y., Ramot, B., Michalewicz, R., Meytes, D., Shaklai, M., Hahn, T., Holtmann,
H., Revel, M., and Wallach, D., Reduced production of tumor necrosis factor by mononuclear cells in
hairy cell leukemia patients and improvement following interferon therapy, Cancer, 60, 2208, 1987.
78. Westbrook, C. A. and Golde, D. W., Autoimmune disease in hairy cell leukemia: clinical syndromes
and treatment, Br. J. Haematol., 61, 349, 1985.
79. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report on 100 cases, Medicine (Bal-
timore), 40, 1, 1961.
80. Boggs, D. R., The significance of fever and infection in malignant neoplastic disease, Med. Sci., 14, 64,
1963.
81. Boggs, D. R. and Frei, E., Clinical studies of fever and infection in cancer, Cancer, 13, 1240, 1960.
82. Pizzo, P. A., Infectious complications in the child with cancer, I. Pathophysiology of the compromised
host and the initial evaluation and management of the febrile cancer patient, J. Pediatr., 98, 513, 1981.
83. Pizzo, P. A., Infectious complications in the child with cancer. II. Management of specific infections, J.
Pediatr., 98, 513, 1981.
84. Kosmidis, H., Lusher, J. M., Shope, T. C., Ravindranath, Y., and Dajani, A. S., Infections in
leukemic children: a prospective analysis, J. Pediatr., 96, 814, 1980.
85. Nachman, J. B. and Honig, G. R., Fever and neutropenia in children with neoplastic disease, an analysis
of 158 episodes, Cancer, 45, 407, 1986.
222 Unexplained Fever

86. Wolk, J. A., Stuart, M. J., Stockman, J. A., and Oski, F. A., Neutropenia, fever and infection in
children with acute lymphocytic leukemia, Am. J. Dis. Child., 131, 157, 1977.
87. Brown, A.E., Management of the febrile, neutropenic patient with cancer: therapeutic considerations, J.
Pediatr. 106, 1035, 1985.
88. Wood, D. J. and Corbitt, G., Viral infections in childhood leukemia, J. Infect. Dis., 152, 266, 1985.
89. Estey, E. H., Keating, M. D., McCredie, K. B., Body, G. P., and Freireich, E. J., Cases of initial
remission induction failure in AML, Blood, 60, 309, 1982.
90. Bodey, G., Fungal infection and fever of unknown origin in neutropenic patients, Am. J. Med., 80 (Suppl.
5C), 112, 1986.
91. Wintrobe, M.M., Complications of neoplastic diseases of the hematopaietic system and their treatment,
in Clinical Hematology, 8th ed., 1981, 1299.
92. Debusscher, L., Fever of unexplained origin in patients with cancer, Eur. J. Cancer, 9, 649, 1973.
93. Gaya, H., Rational basis for the choice of regimes for empiric therapy of sepsis in granulocytopenic patients,
Schweiz. Med. Wochenschur, 113 (Suppl. 14), 49, 1983.
94. EORTC International Antimicrobial Therapy Project Group: Three antibiotic regimens in the treatment of
infection in febrile granulocytopenic patients with cancer, J. Infect. Dis., 137, 14, 1978.
95. Wade, J. C., Schimpff, S. C., Newman, K. A., Furtner, C. L., Standiford, H. C., and Wiernik,
P. H., Piperacillin or ticarcillin plus amikacin: a double-bind prospective comparison of empiric anatibiotic
therapy for febrile granulocytopenic cancer patients, Am. J. Med., 71, 983, 1981.
96. De Jongh, C. A., Wade, J. C., Schimpff, S. C., Newman, K. A., Finley, R. S., Salvatore, P. C.,
and Moody, M. R., Empiric antibiotic therapy for suspected infection in granulocytopenic cancer patients,
Am. J. Med., 73, 89, 1982.
97. Winston, D. J., Ho, W. G., Young, L.S., Hewitt, W. L., and Gale R. P., Piperacillin plus amikacin
therapy in febrile granulocytopenic patients, Arch. Intern. Med., 142, 1663, 1982.
98. Brown, A. E., Quesado, O., Murrer, J. A., Eason, J. V., Clarkson, B., and Armstrong, D., Empiric
combinationantibiotic therapy of febrile, neutropenic patients with neoplastic disease: results of a randomized
study, Proc. 13th Int. Cong. Chemotherapy, Vienna, Austria, 1983.
99. De Jongh, C. A., Joshi, J. H., Newman, K. A., Danhauer, F., Finley, R., Moody, M. R., Wiernik,
P., and Schimpff, S. C., Moxalactam plus piperacilin or amikacin: empiric antibiotic therapy for febrile,
neutropenic cancer patients, Proc. 22nd Interscience Conf. Antimicrobial Agents and Chemotherapy, Miami
Beach, October 4 to 6, 1982, abstr. 943.
100. Winston, D. J., Barnes, R. C., Ho, W. G., Young, L. S., Champlin, R. E., and Gale, R. P.,
Moxalactam plus piperacillin versus moxalactam plus amikacin in febrile neutropenic patients, Am. J. Med.,
77, 442, 1984.
101. Fainstein, V., Bodey, G. P., Bolivar, R., Elting,I., McCreadie, K. B., and Keating, M.J., Moxalactam
plus ticarcillin or tobramycin for treament of febrile episodes in neutropenic cancer patients, Arch. Intern.
Med., 144, 1766, 1984.
102. Joshi, J., Ruxer, R., Newman, K., Finley, R., Moody, M. R., Drusano, G., Tenney, J., and Schimpff,
S., Double beta-lactam versus an aminoglycoside plus beta-lactum combination as empiric therapy for
granulocytopenic cancer patients, Proc. 24th Interscience Conf. Antimicrobial Agents and Chemotherapy,
Washington, D. C., October 8 to 10, 1984, abstr. 383.
103. Sanders, C. C. and Sanders, W. E., Jr., Emergence of resistance during therapy with the newer beta-
lactum antibiotics: role of inductible beta-lactamases and implications for the future, Rev. Infect. Dis., 5,
639, 1983.
104. Brown, A. E., Quesada, O., and Armstrong, D., Empiric moxalactam therapy in febrile, neutropenic
patients with cancer on nephrotoxic chemotherapy, Proc. 21st Interscience Conf. Antimicrobial Agents and
Chemotherapy, Chicago, November 4 to 6, 1981, abstr. 318.
105. Quesada, O., Brown, A. E., Won D., and Armstrong, D., Efficacy of ceftazidime in the treatment of
selected cancer patients with serious infections, Proc. I4th Int. Congr. Chemotherapy, Kyoto, Japan, June
24 to 28, 1985.
106. Wade, J. C., Schimpff, S. C., Hargadon, M. T., Fortner, C. L., Young, V. M., and Wiernik,
P. H., A comparison of trimethoprimsulfamethoxazole plus nystatin with gentamicin plus nystatin in the
prevention of infections in acute leukemia, N. Engl. J. Med., 304, 1057, 1081.
107. Dekker, A. W., Rozenberg-Arska, M., Sixma, J. J., and Verhoef, J., Prevention of infection by
trimethoprim-sulfamethoxazole plus amphotericin B in patients with acute nonlymphocytic leukemia, Ann.
Intern. Med., 95, 555, 1981.
108. Wade, J.C., De Johgh, C. A., Newman, K. A., Crowley, J., Wiernik, P. H., and Schimpff, S. C.,
Selective antimicrobial modulation as prophylaxis against infection during granulocytopenia; trimethoprim-
sulfamethoxazole vs. nalidixic acid, J. Infect. Dis., 147, 624, 1983.
109. Gualtieri, R. J., Donowitz, G. R., Kaiser, D. L., Hess, C. E., and Sande, M. A., Double-blind
randomized study of prophylactic trimethoprim/sulfamethoxazole in granulocytopenic patients with hema-
tologic malignancies, Am. J. Med., 74, 934, 1983.
 223

110. Wilson, J. M. and Guiney, D. G., Failure of oral trimethoprim-sulfamethoxazole prophylaxic in acute
leukemia: isolation of resistant plasmids from strains of Enterobacteriaceae causing bacteremia, N. Engl.
J. Med., 306, 16, 1982.
111. Dekker, A. W., Rosenberg-Arska, M., and Verhoef, J., Infection prophylaxis in acute leukemia: a
comparison of ciprofloxacin with Trimethoprim-sulfamethotazole and colistin, Ann. Intern. Med., 106, 7,
1987.
112. Rozenberg-Arska, M., Dekker, A. W., and Verhoef, J., Ciprofloxacin for selective decontamination of
the alimentary tract in patients with acute leukemia during remission induction treatment: the effect on fecal
flora, J. Infect. Dis., 152, 104, 1985.
113. Winston, D. J., Ho, W. G., Nakao, S. L., Gale, R. P., and Champlin, R. E., Norfloxacin versus
vancomycin/polymyxin for prevention of infections in granulocytopenic patients, Am. J. Med., 80, 884,
1986.
114. Karp, J. E., Hendricksen, C., Redden, T., and Bartlett, J., Double-blind randomized trial of oral
prophylactic norfloxacin on infection in acute leukemia (abstract 149), in Proc. 25 th Interscience Conf.
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Washington, D. C., 1985.
115. Bow, E. J., Louie, T. J., Rayner, E., and Pitsanuk, J., Norfloxacin (N) versus trimethoprim/sulfa-
methoxazole (T/S) for infection prevention in patients (pts) wtih acute leukemia (AL) (abstr. 150), in Proc.
25th Interscience Conf. Antimicrobial Agents and Chemotherapy, American Society for Microbiology,
Washington, D. C., 1985.
116. Ezdinli, E. Z., O’Sulllivan, D. D., Wasser, L. P., Kim, U., and Stutzman, L., Oral amphotericin for
candidiasis in patients with hematologic neoplasms. An autopsy study, JAMA, 242, 258, 1979.
117. Brincker, H., Prevention of mycosis in granulocytopenic patients with prophylactic ketoconazole treatment,
Mykosen, 26, 242, 1983.
118. Estey, E., Maksymiuk, A., and Smith, T., Infection prophylaxis of acute leukemia: comparative effec-
tiveness of trimethoprim-sulfamethoxazole, ketoconazole, and trimethoprim-sulfamethoxazole plus keto-
conazole, Arch. Intern. Med. 144, 1562, 1984.
119. Prabhu, M., Kochupillai, V., Sharma, S., Ramachandram, P., Sundaram, K. R., Bijlani, L., and
Ahuja, R. K., Cancer, 58, 1356, 1986.
120. Marks, S. M., McCaffrey, R., Rosenthal, D. S., and Mohoney, W. C., Blastic transformation in chronic
myelogenous leukemia: experience with 50 patients, Med. Ped. Oncol., 4, 159, 1978.
121. Pedersen-Bjergaard, J., Worm, A. M., and Hainau, B., Blastic transformation of chronic myelocytic
leukemia: clinical manifestations, prognostic factors and results of therapy, Scand. J. Haematol., 18, 292,
1977.
122. Rosenthol, S., Canellos, G. P., DeVita, V. T., and Gralnick, H. T., Characteristics of blast crisis in
chronic granulocytic leukemia, Blood, 49, 705, 1977.
123. Barton, J. C. and Conrad, M. E., Current status of blastic transformation in chronic myelogenous
leukemia, Am. J. Hematol., 4, 281, 1978.
124. Bennett, J. M., Classification of the myelodysplastic syndrome, Clin. Haematol., 15, 909, 1986.
125. Boogaerts, M. A., Nellisen, V., Roelant, C., and Goossens, W., Blood neutrophil function in primary
myelodysplastic syndromes, Br. J. Haemataol., 55, 217, 1983.
126. Kerndrup, G., Mayer, K., EUegard, J., and Hokland, P., Natural killer (NK) activity and antibody
dependent cellular cytoxicity (ADCC) in primary preleukemia syndrome, Leukemia Res., 8, 239, 1984.
127. Mufti, G. J. and Galton, D. A. G., Myelodysplastic syndromes: natural history and features of prognostic
importance, Clin. Haematol., 15, 953, 1986.
128. Spriggs, D. R., Stone, R. M., and Kufe, D. W., The treatment of myelodysplastic syndromes, Clin.
Haematol., 25, 1081, 1986.
129. Tricot, G., Vlietnick, R., and Verwilghen, R. L., Prognostic factaors in the myelodysplastic syndromes
— a review, Scand. J. Haematol., 36 (Suppl. 45), 107, 1986.
130. Koeffler, H. P., Myelodysplastic syndromes (Preleukemia), Semin. Hematol., 23, 284, 1986.
131. Berk, P. D., Goldberg, J. D., Silverstein, M. N, Weinfeld, A., and Donovan, P. B., Increased incidence
of acute leukemia in polycythemia vera associated with cholorembual therapy, N. Engl. J. Med., 304, 441,
1981.
132. Meytes, D., Katz, D., and Ramot, B., Preleukemia and leukemia in polycythemia vera, Blood, 47, 237,
1976.
133. Groopman, J. E. and Golde, D. W., The histiocytic disorders: a pathophysiologic analysis, Ann. Intern.
Med., 94, 95, 1981.
134. Arenzana-Seisdedos, F., Histiocytosis x, J. Clin. Invest., 77, 326, 1986.
135. Hsu, S. M. and Zhao, X., Expression of Interleukin 1 in Reed-Stemberg cells and neoplastic cells from
true histiocytic malignancies, Am. J. Pathol., 125, 221, 1986.
136. Gerrard, T. L., Siegel, J. P., Dyer, D. R., and Zoon, K.C., Differential effects of interferon and
interferon on IL,, secretion by monocytes, J. Immunol., 138, 2535, 1987.
224 Unexplained Fever

137. Friedman, E., Levin, S., Vogel, R., Schlesinger, M., and Zaizov, R., Immunologic dysrégulation in a
patient with familial hemophagocytic lymphohistiocytosis, Cancer, 60, 2629, 1987.
138. Monick, M., Glazier, J., and Hunninglake, G. W. Human alveolar macrophages suppress ILt activity
via the secretion of PGE2, Am. Rev. Respir. Dis., 135, 72, 1987.
139. Risdall, R. J., McKenna, Nesbit, M.E., and Krivit, W., Virus-associated hemophagocytic syndrome,
Cancer, 44, 993, 1979.
140. Lanzkowsky, P., Histiocytosis Syndromes in Pediatric Oncology, 1st ed., McGraw-Hill, New York, 1982,
330.
 225

Chapter 14

FEVER IN ENDOCRINOLOGIC DISORDERS

Y. Gilboa, E. Horer, and B. Isaac

INTRODUCTION
Although the endocrine system plays an important role in thermoregulation, fever as
the manifestation of endocrine abnormalities is quite rare with the exception of some thyroid
disorders.
However, isolated cases of unexplained fever have been reported, in which the ultimate
cause was hyper- or hypofunction of endocrine glands.1 A detailed discussion on the role
of the endocrine system in thermoregulation appears in the chapter on pathophysiology of
fever. Here we shall mention only some essential data. There are thermosensitive neurons
in the skin, certain deep tissues, the spinal cord, and in various parts of the brain, as well
as heat gain and heat loss centers within the preoptic area of the interior hypothalamus, near
the floor of the third ventricle.2 Different lesions in this area of the hypothalamus (vascular,
traumatic, infections, tumors) can produce failure of thermoregulation and sometimes unex-
plained fever which is considered as “ central fever” , especially after vascular or tumoral
lesions. Only very seldom is this hypothalamus fever accompanied by endocrine manifes-
tations.
The endocrine factors involved in heat regulation and production are now better under-
stood. The major source of basal heat production is thyroid hormones thermogenesis through
activation of the adenosinic triphosphatase (ATPase) on the sodium pump of the cellular
membranes throughout the body. This action is probably one of the main physiological
effects of the thyroid hormones, thyroxine and triiodothyronine.3
Another example of hormonal effects on temperature regulation is the elevation of basal
temperature on the second half of the menstrual cycle under the influence of progesterone,
or the hot flushes and diaphoresis experienced by many menopausal women, probably under
the effect of endocrine changes, at this period of life.
In the pathogenesis of any type of fever produced by exogenous pyrogens, there is an
interaction with the endogenous pyrogen — interleukin-1, which is produced by macrophages
and monocytes and has a central role in mobilizing T and B lymphocytes, myeloid cells,
fibroblasts, and in stimulating hepatocytes and cerebral neurons — and the temperature
regulation centers of the hypothalamus. Increased synthesis of prostaglandins, especially
PGE! and PGE2, is observed in the hypothalamus as well as synthesis of cyclic AMP, under
the influence of interleukin-1.
Interleukin-1, like many other lymphokines, can be considered a hormone of the im-
munologic system and as such, it is involved in all the fever producing mechanisms of the
body, probably by changing the “ set point” of the temperature regulating centers of the
hypothalamus.4
After this brief introduction we will review published data as well as personal experience
with fever accompanying endocrine disorders.

HYPOTHALAMUS, PITUITARY GLAND, AND FEVER

The proximity of thermoregulatory centers to the pituitary physiotropic areas of the

hypothalamus would lead us to suspect a frequent combination of fever and pituitary dis-
turbances. However, this combination is quite rare and perusal of the literature revealed
only two cases. In the many patients suffering from “ central fever” , usually after a vascular
226 U nex p la in ed F e ve r

accident, the life prognosis is very poor, and there is no time for the development of
hypopituitarism. Fever as a sign of pituitary hyperfunction is not known. However, with
hypofunction, fever has been described.
Hypopituitarism is a partial or total failure of the anterior hypophysis. One has to
differentiate between:

1. Primary hypopituitarism, due to intrinsic pituitary gland disease as in surgical ablation,

radiation, nonsecretory pituitary tumors, metastatic tumors, infection of the pituitary
(commonly associated with postpartum hemorrhage), infiltrative or granulomatous
processes, hypophysitis, mycoses, tuberculosis (very rare nowadays), maldevelopment
of the pituitary gland.
2. Secondary hypopituitarism due to damage of the hypophysiotropic area of the hypo-
thalamus as in craniopharyngioma, trauma, infections, hydrocephalus, granulomatous
lesions, congenital malformations.

Apart from hypophysectomy without replacement therapy or pituitary apoplexy, the

onset of pituitary failure is slow and insidious. The clinical manifestations of hypopituitarism
are usually absent until more than 75% of the gland is destroyed. The symptoms are those
of the target organ failure (adrenal, thyroid, gonads); high prolactin appears only in secondary
hypopituitarism. Fever as a sign of hypopituitarism is very rare. One case was described by
Marillus et al.5 A 62-year-old man had a history of recurrent episodes of fever — ten times
over 12 years. The patient complained of loss of libido, impotence, loss of hair, hypersomnia
and severe mental disturbances. A defect on visual fields was found. Dynamic endocrine
tests revealed hypothalamic hypopituitarism. The etiology of the disorder was believed to
be previous encephalitis. Substitution therapy with prednisone and testosterone was started.
During 16 months follow-up, all the clinical signs disappearead, including fever.
An additional case was recently described by Mann6 in a 29-year-old woman with
Sheehan syndrome and recurrent high fever. The patient had hypothyroidism, hypogonadism,
and hypocortisolism of primary pituitary origin as revealed by dynamic endocrine tests.
Substitution therapy with thyroxine, hydrocortisone, and sex hormones restored her well
being and the fever disappeared.

THE THYROID GLAND AND FEVER

The role of thyroid hormones in body heat regulation has already been mentioned.3 An
increased secretion of thyroid hormones — thyroxine (T4) and triiodothyronine (T3) is
followed by increased heat production, but fever is not a common finding in thyrotoxicosis,
probably due to increased loss of heat through peripheral vasodilatation and perspiration.
Occasionally, patients suffering from thyrotoxicosis have a basal body temperature higher
by 0.5 to 0.7°C than what is considered normal.

THYROTOXICOSIS AND FEVER

The thyroid gland secretes thyroxine (T4) and small amounts of triiodothyronine (T3).
Most of the T3 is derived from peripheral conversion of T4 to T3 and is considered the active
hormone of the thyroid although T4 has biological activity of its own. Hyperfunction of the
gland is due to excessive production of these hormones leading to thyrotoxicosis which can
appear in different clinical forms such as Graves’ disease, toxic multinodular goiter, auto-
nomous toxic adenoma, factitious thyrotoxicosis, iatrogenic thyrotoxicosis, TSH secreting
pituitary tumors, struma ovarii, hyperfunctioning thyroid carcinoma, and thyroiditis. The
symptoms and signs of thyrotoxicosis are the direct result of the metabolic effects of the
 227

thyroidal hormones and present as weight loss with increased appetite, nervousness, tachy-
cardia, rhythm disturbances, muscle weakness, diarrhea, tremor, emotional instability, ex-
cessive perspiration, to mention only a few.
Because thyroid hormones are directly involved in heat production one could expect
that fever will be a common manifestation in thyrotoxicosis but it is not so. It is probable
that excessive heat production is offset by increased loss brought about by regulatory mech-
anisms.1
No appropriate study on the prevalance of fever in thyrotoxicosis has been performed
but it appears that the basal temperature and its circadian variation is slightly elevated,
especially in severe cases. Rault7 described two patients hospitalized because of prolonged
fever (3 to 4 months duration) of unknown origin. One of them was a 62-year-old man who
was suspected of having amebiasis and the other a 47-year-old woman suspected of having
bacterial endocarditis. In these two patients the fever ranged between 37 to 39°C, and in
addition they had weight loss, tachycardia, weakness, tremor, muscular pains, exophthalmos
in one of the cases and a goiter in the second one. The final diagnosis was thyrotoxicosis
with high levels of T3 and T4 and high uptake of 13*1. Fifteen days after 1311 treatment
(7 me) the fever disappeared and all the other clinical signs disappeared after 2 months.

THYROTOXIC CRISIS
The thyrotoxic crisis is a rare condition. There is an exaggeration of the usual features
of hyperthyroidism, accompanied by some manifestations not found in the uncomplicated
disease.8 Possible causes to be considered in the genesis of thyroid crisis are

1. A change in the normal proportion of T4 and T3 secretion with higher T39

2. Diminished protein binding with increased amounts of free hormones10
3. Alterations of peripheral degradation or uptake of hormones or interaction with other
hormones11

The diagnosis is established mainly by the clinical picture. Fever is always present and
may be extreme. It is an important hallmark of this condition, since circulating levels of
the thyroid hormones are similar in hyperthyroidism and thyroid storm. A possible expla-
nation for the higher fever during the thyrotoxic crisis is that infection and stress, which
often precipitate this condition, are responsible for its occurrence.
The other clinical manifestations of the thyroid crisis are severe tachycardia or atrial
fibrillation, congestive heart failure, severe perspiration, and diarrhea and vomiting leading
to dehydration. Neuropsychiatric manifestations are also present, manifested by anxiety,
tremor, stupor, and even convulsions.
Thyrotoxic crisis arises usually in patients already known to be hyperthyroid, virtually
confined to cases of Graves’ disease. Crisis is almost always evoked by a precipitating factor
such as surgery of the thyroid, especially if the patient is not rendered euthyroid prior to
the operation, but also by surgical procedures not involving the thyroid. Medical crisis is
precipitated by injuries, diabetic keto-acidosis, myocardial infarction, severe infections (viral
and bacterial) or cessation of antithyroid therapy. Thyrotoxic crisis may appear after admin-
istration of a therapeutic dose of radioactive iodine, probably by producing radiation thy-
roiditis.12 Iodine in contrast media can also give rise to thyrotoxic crisis.13 Treatment is by
large amounts of antithyroid drugs (propylthioracil, methimazol), kalium iodate, beta block-
ers, rehydration, and supportive therapy.
Thyroid crisis is a medical emergency and if not properly treated the mortality is very
high. It should be suspected in every thyrotoxic patient presenting with an exacerbation of
the usual signs of the disease and fever.
228 U nex p la in ed F e ve r

SUBACUTE THYROIDITIS (De Quervain, Granulomatous)

Subacute thyroiditis is usually caused by a viral infection.14There is strong circumstantial
evidence of a preceding viral illness. As etiologic agents different viruses were found:
mumps,15 Coxsackie virus,16 measles,17 adenovirus,18 and EB virus.19 Women are far more
affected than men with a 5:1 ratio with maximal incidence in the fourth and fifth decades.
The clinical picture is characterized by pain in the region of the thyroid gland which radiates
up to the angle of the jaw and to the ear of the affected side. In addition to the pain, there
may be fever, which is generally low to moderate, but there are also cases with fever as
high as 40°C and severe systemic reaction. Other clinical signs are nervousness, palpitations,
lassitude which is often extreme; hoarseness and dysphagia are sometimes present. On
palpitation, the thyroid is slightly to moderately enlarged, painful, firm, often nodular, one
lobe being generally more severely affected than the other. Laboratory evaluation reveals
increased ESR, and normal or slightly increased blood levels of thyroid hormones. In a few
cases, the ESR may be normal which makes the diagnosis difficult.20
Subacute thyroiditis classically evolves through four phases.21

(A) H yp erth y ro id p h a s e :This starts concurrently or shortly after the onset of thyroidal
pain and the T4 and T3 are normal or high. The destruction of the thyroid caused by
the inflammation discharges colloid and hormones; the thyrotoxic signs are less prom-
inent than in Graves’ disease because the levels of T3 are less elevated.
(B) E u th yro id p h a se : This is transient and due to exhaustion of the stored thyroid hormones.
(C) H yp o th y ro id ism : In this phase high TSH and low T4 and T3 can be found.
(D) R e co v e ry p h a se : A normal range of T4 and T3 is found

The 1311 uptake is suppressed even if only a part of the gland is involved and this may be
partially due to suppression of pituitary TSH by the elevated levels of T4 and T3. In the
recovery stage the 13T uptake returns to normal.22

CASE REPORTS

1. A 53-year-old woman was hospitalized because of pain in the thyroid region irradiating
to the ears, a fever of 38°C and general malaise. A painful nodule was palpated in
the right lobe of the thyroid gland. The ESR was 88 mm/ 1st hour and 110 mm/2nd
hour. There was no 131I uptake by the thyroid. The titer of antibodies to mumps was
increased. The diagnosis was subacute thyroiditis and treatment with decreasing doses
of prednisone brought a complete cure. Two months after starting the treatment the
ESR and 13‘I scan were normal. Comment — This is a normal course of subacute
thyroiditis.
2. A 60-year-old man was admitted because of high fever of 6 weeks duration, up to
41°C. Besides the fever, loss of weight, sweating, and general malaise, there were no
complaints directed towards the thyroid. Previous to his admission he received large
amounts of various antibiotics without any effect. On examination there were no clinical
findings but on pressure on his thyroid, severe pain was elicited, although there was
no spontaneous pain. An elevated ESR and lack of 131I uptake by the gland confirmed
the diagnosis of subacute thyroiditis. Thirty-six hours after starting prednisone 60 mg/
day, the fever disappeared and the patient made an uneventful recovery. Comment —
Fever was the only manifestation of the disease and only pressure on the thyroid
elicited pain. The lack of spontaneous thyroid pain delayed the diagnosis for 6 weeks
and malignancy was thought as a probable cause, after failure of the antibiotic treat-
ment.
 229

ACUTE THYROIDITIS
This condition is very rare nowadays and is the result of a bacterial infection of the
thyroid gland. In some cases, thyroid infection was preceded by infection elsewhere in the
body such as pyelonephritis, otitis, mastoiditis, erysipelas, pharyngitis, or upper respiratory
tract infection.23
The typical symptoms are high fever, local tenderness, and swelling of the thyroid. The
infection may involve the whole gland or only a portion of it. The thyroid function tests are
normal. There is a high ESR and leukocytosis. On thyroid scan, there is decreased uptake,
corresponding to the involved portion.

HYPERPARATHYROIDISM AND FEVER

The prevalence of hyperparathyroidism in the general population is 1/1000 and the

diagnosis is usually made by the unexpected finding of hypercalcemia in an asymptomatic
patient or confirmed by it in patients with appropriate signs and symptoms. The classic
symptoms of hyperparathyroidism are nephrolithiasis (55%), bone demineralization (33%),
personality disturbances, hypertension, gastrointestinal manifestations, and the laboratory
findings of elevated serum parathyroid hormone, hypercalcemia, hypophosphatemia, and
elevated nephrogenous adenosine 3'5' cyclic monophosphate (NCAMP). Fever as a mani-
festation of hyperparathyroidism is rare: only a few cases have ever been described in the
literature.
Blair and Fekety24 reported a case of a 28-year-old woman who presented with fever
and intractable headache, persisting for over a year, before hyperparathyroidism was di-
agnosed. Intenstive evaluation for intracranial disease, collagen-vascular disease, and occult
malignancy was unrevealing. After 1 year of investigation, the patient was operated and a
solitary parathyroid adenoma was removed. After surgery, serum calcium and serum phos-
phate levels returned to normal. The fever and the headache gradually diminished and
disappeared. She has remained afebrile and symptom free for 5 years.
Ricci et al.25 also reported a case of a 36-year-old woman who presented with hyper-
calcemia, hypercalciuria, elevated serum parathyroid hormone levels and prolonged fever.
Surgical removal of the hyperplastic and adenomatous parathyroid glands led to reversal of
the biochemical abnormalities, as well as return of normal temperature.
There are no data, experimental or clinical, that explain the association of hyperpara-
thyroidism and fever. There is no evidence that parathyroid hormone can produce fever by
either a direct effect on the hypothalamus or other mechanisms. The high CAMP found in
hyperparathyroidism has not been shown to act on the central nervous system to alter
temperature. Calcium does not appear to have a major role in regulating thermal homeostasis.
In view of the two above-reported cases, in the presence of fever of unknown origin,
the diagnosis of primary hyperparathyroidism, although very rare, should also be considered
in the differential diagnosis.

HYPOGLYCEMIA AND FEVER

Although hypoglycemia is usually associated with hypothermia26 there are some reports
of its association with hyperthermia.27 The principal factors involved in the hyperthermia
of hypoglycemia are cerebral edema, dehydration, hypothalamic dysfunction, and increased
levels of catecholamines.
Molnar et al.27 described cases of insulin induced hypoglycemic coma accompanied by
hyperthermia. The coma was usually severe and prolonged, lasting between 2 to 14 days.
The outcome was fatal and at autopsy, cerebral hyperemia and edema were present. Similar
230 U n ex p la in ed F e ve r

findings were reported by Ramos et al.28 and in one case mannitol administration, which
reduces the cerebral edema, was life saving.
Dehydration induced in dogs with hypoglycemia led to a rise of the body temperature
and similar observations were made on hypoglycemic patients who were dehydrated and
developed fever.27 Another explanation for the hyperthermia which appears in some patients
with hypoglycemia is given by Chorcinov et al.29 who showed hypothalamic dysfunction
and impaired control mechanism of heat regulation. This type of fever is similar to “ central
(hypothalamic) fever” mentioned at the beginning of this chapter.
Finally, in response to hypoglycemia, there is a significant rise in plasma and urinary
catecholamines.30 31 Increased levels of catecholamines are known to produce fever by several
mechanisms: increased metabolic rate and decreased heat dissipation because of vasocon-
striction.

CASE REPORT
A 47-year-old man with diabetes of 26 years duration had many episodes of ketosis and
hypoglycemia. He underwent hypophysectomy because of malignant diabetic retinopathy,
without any effect on its progression. He also developed diabetic peripheral neuropathy.
After hypophysectomy, he developed insulin hypersensitivity although he received full re-
placement therapy: thyroxine, glucocorticosteroids, and testosterone. Over the following
years the patient underwent several episodes of fever, chills, perspiration, shakiness, nausea,
vomiting, and impaired consciousness. On clinical and laboratory grounds these episodes
were diagnosed as severe hypoglycemia and fever was a constant complication. There were
no signs of infection or response to antibiotics. The clinical signs disappeared after admin-
istration of glucose or glucagon.

CASE REPORT
A 29-year-old known diabetic was admitted to the emergency ward in deep coma. The
blood glucose was 18 mg/dl, the eye fundi revealed grade III diabetic retinopathy and no
reflexes could be elicited. Treatment with large amounts of intravenous concentrated glucose
was started and quite rapidly his blood glucose levels reached 300 mg/dl but without any
effect on his level of consciousness. Simultaneously, a high fever appeared and signs of
cerebral edema were detected on repeated fundoscopy. It was thought that the severe hy-
poglycemia had produced cerebral edema and fever. Mannitol and other diuretics were of
no help. Only the addition of glucocorticoids brought on recovery of his consciousness and
disappearance of fever. It was later found that on the day of his coma he received 100 U
of intermediate and short-acting insulin but had neglected to eat appropriately.

ADRENAL DISEASE AND FEVER—PHEOCHROMOCYTOMA

AND FEVER

The clinical manifestations of pheochromocytoma are variable and fever is mentioned

by some authors in 70% of patients.32,33 The fever is generally of low grade but can rise up
to 40°C during a crisis, and masquerade as an overwhelming infection.34 When the pheo-
chromocytoma secretes mainly epinephrine it may cause symptoms such as palpitations,
tremor, sweating, tachypnea, and fever which may be misdiagnosed as biliary colic, shock,
pulmonary embolism, or sepsis. Failure of early recognition of the true cause of the symptoms
has often led to severe complications and death.35
The fever in pheochromocytoma can be explained by both increased heat production,
due to excess of catecholamines and decreased heat loss, due to generalized vasoconstriction.
Recently,36 the case of a 34-year-old man with a five year history of episodes of
paroxysmal hypertension, nausea, flushing, and polyuria was reported. The episodes occurred
 231

at 1 to 2 month intervals, lasted for a few hours and were accompanied by leukocytosis,
erythrocytosis, hypoglycemia, lactic acidosis, renal failure, encephalopathy, and fever. Of
interest were the repeated episodes of fever and leukocytosis without apparent infection.
After an extensive investigation, a pheochromocytoma of the adrenal gland was found and
its removal stopped the clinical manifestations.
An additional case presenting with shock and fever and considered to have septic shock
was found at autopsy to have a pheochromocytoma.1 Hamvin37 reported a case in which the
presenting symptoms were abdominal pain, vomiting, normal blood pressure, azotemia,
neutrophilia, erythrocytosis, and high fever. A renal artériographie examination was per-
formed because of suspicion of a perinephric abscess and a pheochromocytoma was found.

ADRENAL INSUFFICIENCY AND FEVER

Adrenal insufficiency is most commonly caused by idiopathic adrenal atrophy and less
frequently by tuberculosis. Other rare causes are bacterial (especialy meningococcemia) or
mycotic infection, sarcoidosis, amyloidosis, hemochromatosis, bilateral adrenalectomy, ab-
dominal irradiation, anticoagulant therapy, and adrenolytic drugs. Fever is a well-known
manifestation of adrenal insufficiency and cases have been reported by Simon and Daniels.1
It is not known what role, if any, the glucocorticoids play in thermoregulation, and the fever
which accompanies acute adrenal insufficiency from any cause remains poorly understood.
Withdrawal from steroid hormone therapy is associated with a syndrome characterized
by fever, anorexia, nausea, lethargy, weakness, arthralgias, and myalgias (steroid withdrawal
symptom).38
Fever is also one of the manifestations of Addisonian crisis and is sometimes the
presenting sign of imminent adrenal crisis. Because infection is one of the trigger mechanisms
of Addisonian crisis, one has to differentiate between Addisonian crisis with fever and fever
associated with adrenal insufficiency, as the therapeutic approach is different. Fever caused
by adrenal insufficiencey per se disappears after administration of steroids only, while in
superimposed infections triggering the adrenal crisis, antibiotics should be added to the
steroids.

ADRENAL HYPERPLASIA AND FEVER

This is a very uncommon occurrence but several cases have been reported by Gardner
and Migeon,39 Care and Gardner,40 and Gilboa et al.41 In all these cases the usual manifes-
tations of congenital adrenal hyperplasia, usually the 21-hydroxylase defect type, were
accompanied by continuous or periodic fever. At the time of their publication it was spec-
ulated that the fever was produced by an increased secretion of etiocholanolone.
In some of these patients the fever responded to small amounts of glucocorticosteroids,
in others, the fever was unaffected.

STEROIDS AND FEVER

It has been found that some steroids, like cortisol and estradiol, are antipyrogenic while
etiocholanolone, a known metabolite of the androgens, is a potent pyrogen in man.42 43
Bondy44 and Kappas45 described the pyrogenic effect of etiocholanolone as well as increased
levels of this steroid in some cases of congenital adrenal hyperplasia associated with fever.
The problem of the connection of etiocholanolone with different types of prolonged or
periodic fevers has had its ups and downs. In most of the cases in which etiocholanolone
was estimated, no increase was found. However, occasionally cases of fever and increased
etiocholanolone levels have been described, one as recent as 1981.46 In the opinion of most
authors etiocholanolone is no more considered in the differential diagnosis of obscure fever.47
232 Unexplained Fever

Progesterone is an inducer of fever as known from the elevation of the basal temperature
by 0.5°C immediately after ovulation, when it is secreted by the corpus luteum. The mech-
anism involved in the elevation of the basal temperature by progesterone is not known just
as the mechanism for the production of hot flushes of menopause is not well understood.48

REFERENCES
1. Simon, H. B. and Daniels, G. H., Hormonal hyperthermia, endocrinologie causes of fever, Am. J. Med.,
66, 257, 1979.
2. Dinarello, C. A. and Wolff, S. M., Pathogenesis of fever in man, N. Engl. J. Med., 298, 607, 1878.
3. Ismail-Beigi, F. and Edelman, I. S., The mechanisms of thyroid calorigenesis: role of active sodium
transport, Proc. Natl. Acad. Sci. U.S.A., 67, 1071, 1970.
4. Petersdorf, R. G. and Root, R. K., Disturbances of heat regulation, in Harrison s Principles of Internal
Medicine, Braunwald, E., Issellacher, K. J., Petersdorf, R. G., Wilson, J. D., Martin, J. B., and Fauci,
A. S., Eds., McGraw-Hill, New York, 1987, section 2, chap. 8.
5. Marilius, R., Barkan, A., Leiba, S., Arie, R., and Blum, I., Pyrexia of unknown origin. Presenting
signs of hypopituitarism, Postgrad. Med. J., 57, 310, 1981.
6. Mann, K., Rezidivirende, hochfieberhafte Infekte mit Bewusstlosigkeit, Der Internist, 25, 135, 1984.
7. Rault, P., Les fievres prolongées de diagnostique difficile. These No. 90, Bichat-Beaujon, Paris, 1973.
8. McArthur, J. W., Rawson, R. W., and Means, J. H., Thyrotoxic crisis, JAMA, 134, 868, 1947.
9. Brooks, M. H., Waldstein, S. S., Bronsky, D., and Sterling, R., Serum triiodothyronine concentration
in thyroid storm, J. Clin. Endocrinol. Metab., 40, 339, 1975.
10. Brooks, M. H. and Waldstein, S. S., Free thyroxine concentration in thyroid storm, Ann. Intern. Med.,
93, 694, 1980.
11. Hoffenberg, R., Thyroid emergencies, Clin. Endocrinol. Metab., 9, 503, 1980.
12. Sheeler, L. R., Skilern, and Schumacher, O. P., Radio-iodine induced thyroid storm. A point of
controversy, Am. J. Med., 76, 98, 1984.
13. Wu, S. Y., Chopra, I. J., and Solomon, D. H., Changes in circulating iodothyronines in euthyroid and
hyperthyroid subjects given ipodate (orografin), an agent for oral cholecystogrpahy, J. Clin. Endocrinol.
Metab., 46, 691, 1978.
14. Fraser, R. and Harrison, R. J., Subacute thyroiditis, Lancet, 1, 382, 1952.
15. Eylan, E., Zmucky, R., and Sheba, C., Mumps virus and subacute thyroiditis. Evidence of a causal
association, Lancet, 1, 1062, 1954.
16. Liberman, U., Djaldetti, M., and DeVries, A., A case of herpangina pleurodynia and subacute thyroiditis,
Harefuah, 67, 342, 1964.
17. Candel, S. Acute non-suppurative thyroiditis following measles, U.S. Navy Med. Bull., 46, 1109, 1946.
18. Hintze, G. Fortelius, P., and Railo, J., Epidemic thyroiditis, Acta Endocrinol., 45, 381, 1964.
19. Mosony, I. L., Thyroiditis, Br. Med. J., 1, 1132, 1960.
20. Volpe, R., Subacute thyroiditis, Clin. Endocrinol. Met., 8, 81, 1979.
21. Czerniak, P. and Harell-Steinberg, A., The chronology of events in the development of subacute thy-
roiditis, studies of radioactive iodine, J. Clin. Endocrinol. Metab., 17, 2448, 1957.
22. Lewitus, Z., Rechnic, J., and Lubin, E., Sequential scanning of the thyroid as an aid in diagnosis of
subacute thyroiditis, Isr. J. Med. Sci., 3, 847, 1967.
23. Berger, S. A., Zonszein, J., Villamena, P., and Mittman, N., Infectious diseases of the thyroid gland,
Rev. Infect. Dis., 5, 108, 1985.
24. Blair, D. C. and Fekety, R., Primary hyperparathyroidism presenting as fever of unknown origin with
unremitting headache, Ann. Intern. Med., 91, 575, 1979.
25. Ricci, J., Vlasschaert, J., and Salit, I. E., Prolonged fever associated with primary hyperparathyroidism,
Can. Med. Assoc. J., 131, 459, 1984.
26. Kedes, L. H, and Field, T. B., Hypothermia, a clue to hypoglycemia, N. Engl. J. Med., 271, 785, 1964.
27. Molnar, G. W. and Read, R. C., Hypoglycemia and body temperature, JAMA, 227, 916, 1974.
28. Ramos, E., Zorilla, E., and Hadley, W. B., Fever as a manifestation of hypoglycemia, JAMA, 205,
590, 1968.
29. Chorcinov, R. and Daughaday, W. H., Marked hyperthermia as a manifestation of hypoglycemia in
long-standing diabetes mellitus, Diabetes, 24, 859, 1975.
30. Joung, J. B. and Landsberg, L., Catecholamines and intermediary metabolism, J. Clin. Endocrinol.
Metabol., 6, 599, 1977.
 233

31. Garber, A. J., Cryer, P. E., Santago, J. V., Haymond, M. W., Pagliara, A. S., and Kipnis, D. M.,
The role of adrenergic mechanism in the substrate and hormonal response to insulin induced hypoglycemia
in a man, J. Clin. Invest., 58, 7, 1976.
32. Smithwick, R. H., Greer, W. E. R., Robertson, C. W., and Wilkins, R. W., Pheochromocytoma, a
discussion of symptoms, signs and procedures of diagnostic value, N. Engl. J. Med., 242, 252, 1950.
33. Leather, H. M., Shaw, D. B., Cates, J. E., and Walker, R. M., Six cases of pheochromocytoma with
unusual clinical manifestations, Br. Med. J., 1, 1373, 1962.
34. Fred, H. L., Alfred, D. P., and Garber, H. E., Pheochromocytoma masquerading as overwhelming
infection, Aw. Heart J., 73, 149, 1967.
35. Martin G., Myos, S. A., and Arshinog, F., Infection and pheochromocytoma, JAMA, 237, 2095, 1977.
36. Scully, R. E., Mark, E. J., and McNeely, B. V., Weekly clinicopathological exercises, N. Engl. J.
Med., 314, 431, 1986.
37. Hamvin, B., Sustained hypotension and shock due to an adrenaline-secreting pheochromocytoma, Lancet,
2, 123, 1962.
38. Dixon, R. B. and Christy, N. P., On the various forms of corticosteroid withdrawal syndrome, Am. J.
Med., 68, 224, 1980.
39. Gardner, L. I. and Migeon, C. J., Unusual plasma 17-ketosteroid pattern in a boy with congenital
hyperplasia and periodic fever, J. Clin. Endocrinol. Metab., 19, 226, 1959.
40. Cara, J. and Gardner, L. I., Two new subvariants of virilizing adrenal hyperplasia, J. Pediatr., 57, 461,
1960.
41. Gilboa, Y., Rumney, G., and Ber, A., “ Virilizing” adrenal hyperplasia in an elderly man, Arch. Intern.
Med., 114, 475, 1964.
42. Dillard, G. M. and Bodel, P., Studies on steroid fever. II. Pyrogenic and antipyrogenic activity in vitro
of some endogenous steroids of man, J. Clin. Invest., 49, 2418, 1970.
43. Bodel, P. and Dillard, G. M., Suppression of periodic fever with estrogen, Arch. Intern. Med., 131, 189,
1973.
44. Bondy, P. K., Cohn, G. L., and Gregory, P. B., Etiocholanolone fever, Medicine, 44, 250, 1965.
45. Kappas, A., Soybel, W., Fukushima, D., and Gallagher, T., Studies on pyrogenic steroids in man,
Trans. Assoc. Am. Physicians, 72, 54, 1959.
46. Goerz, G., Bedfur, M., and Graef, V., Urticaria in association with etiocholanolone fever, Br. J.
Dermatol., 105, 109, 1981.
47. Larson, E. B., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow-up of 105 cases, Medicine, 61, 269, 1982.
48. Meldrum, D. R., Erlik, Y., Lu, K. H., and Judd, H. L., Objectively recorded hot flushes in patients
with pituitary insufficiency, J. Clin. Endocrinol. Metab., 52, 684, 1981.
 235

Chapter 15

FEVER IN INHERITED AND METABOLIC DISORDERS

Menahem Fainaru

INTRODUCTION
Among the rare conditions leading to unexplained fever, one may encounter patients
with inherited and metabolic disorders.12 When, following extensive investigations, the
cause of fever cannot be categorized into one of the three main groups of FUO (i.e.,
infectious, collagen-vascular, or neoplastic), one of the remaining possibilities is to look
into metabolic and inherited abnormalities. Although these consist of very rare causes of
unexplained fever, such a search may be rewarding in view of the recent advances, which
make them amenable for effective treatment.

FAMILIAL MEDITERRANEAN FEVER (FMF)

Familial Mediterranean fever, also called familial or recurrent polyserositis, and periodic
fever or disease, is most probably a single autosomal recessive inherited disease characterized
by acute self-limited attacks of fever accompanied by signs of serositis. The disease occurs
predominantly in patients of Mediterranean or Middle Eastern origin, in non-Ashkenazic
Jews, Armenians, Arabs, and Turks. However, patients of other ethnic extraction may
become involved. The homozygote prevalence is about 1/2000 in Iraqi Jews in Israel.3
Numerous pathologic mechanisms have been proposed but its etiology remains un-
known.3 Recently, a deficiency in C5-a inhibitor has been reported in both synovial and
peritoneal fluids of these patients.4 It is conceivable that the deficiency of this protein
complex, which is known to antagonize the chemotactic activity of the complement fragments
C5a, may lead to inadequate suppression of the inflammatory response to C5a released
accidentally, or as a result of a minor stimulus in patients with FMF.
The basic pathologic finding, during acute attacks, show acute nonspecific, nonbacterial
exudative inflammatory reactions in the affected membranes. The most striking findings are
hyperemia, nonpurulent cellular perivascular infiltrates with neutrophils, lymphocytes,
monocytes, and more rarely eosinophils and plasma cells. Repeated attacks may result in
secondary fibrous adhesions.
Clinical manifestations usually start in the first two decades of life. The acute attacks
are of short duration, lasting from 24 to 48 h, but occasionally may last longer, up to 1
week. The frequency of the attacks vary among patients and in the same patient, most often
1 to 2 per month. Between the attacks the patients are normal.
The acute attack is characterized in most cases by fever, which may reach as high as
39 to 40°C, signs and symptoms of serositis: peritonitis, arthritis, pleuritis, or pericarditis,
reaching their peak within 12 h.
Acute serous peritonitis is most frequent, up to 95% of patients, and is manifested as
an “ acute surgical abdomen” indistinguishable from any other cause of abdominal catas-
trophe.
Pleuritis occurs in 75 to 85% of patients resembling other forms of acute febrile pleuritis
with effusion.
Acute arthritis may be seen in up to 75% of patients in Israel and are less frequent in
other parts of the world.3 Typically, it is nondestructive and asymmetric. Usually, one large
joint is affected, particularly the knee or ankle, and may assume a more protracted course
236 U nex p la in ed F e ve r

of weeks to months. The synovial fluid is turbid, sterile, forms a good mucin clot, and
contains 15,000 to 30,000 polymorphonuclear cells.
In 10 to 20% of patients an “ erysipelas like” rash is observed over the extensor aspects
of the lower limbs.
Uncommon findings include pericarditis, perimyocarditis, myalgias, and headaches.
Rarely, one may observe a patient whose attacks consist of fever only.
Amyloidosis is rarely seen in patients outside the Mediterranean basin. In Israel it is
frequent and occurs in up to 31% of patients with FMF.3 The amyloidosis is of the AA
type, and is deposited in the intima and media of both arterioles and venules in all organs
involved. Amyloid deposits are seen characteristically in glomeruli, adrenal cortex, spleen,
and pulmonary septa sparing usually the liver and heart muscle. The main clinical conse-
quence is nephrotic syndrome and renal failure.
Laboratory findings during acute attacks include elevated erythrocyte sedimentation rate,
neutrophilic leukocytosis (up to 30,000/cmm) and elevated acute phase reactants (C-reactive
protein, fibrinogen, etc.). In remission, between attacks, all laboratory abnormalities return
to normal.
The diagnosis is difficult during the initial attacks for two main reasons: the absence of
pathognomonic laboratory findings and the extensive differential diagnosis. Thus, one has
to rely on the recurrence of typical attacks that include short bouts of fever and serositis,
laboratory signs of acute inflammation (transient elevation in ESR, leukocytosis, and high
fibrinogen), positive family history and exclusion of common clinical conditions listed below.
The diagnosis is even more difficult in patients lacking symptoms or signs of serositis. In
these rare patients, who present with fever only, a systematic approach for “ fever of unknown
origin” should be undertaken. Recently, a possible specific diagnostic test was reported by
Barakat et al.5 In a placebo-controlled, double blind study, they have demonstrated that the
intravenous infusion of Metaraminol (10 mg in 500 ml of normal saline) was followed by
the precipitation of a typical “ disease like” attack in all patients with FMF. If this test
proves itself, also in other hands, as specific, sensitive, and safe, it may become a pillar
for the diagnosis until a specific biochemical test is developed.
The differential diagnosis includes acute appendicitis, acute cholecystitis, acute pan-
creatitis, diverticulitis, primary pneumococcal peritonitis, etc., for patients presenting with
abdominal attacks; pulmonary embolism and various causes of infectious and inflammatory
pleuritis; various causes of infectious (e.g., gonorrhea, brucellosis, etc.) and inflammatory
(e.g., rheumatic fever, rheumatoid arthritis—Still’s disease in particular, systemic lupus
erythematosus, etc.) arthritis. Of particular interest, although very rare, are certain conditions
associated with periodic fever—see below.
Treatment for acute attacks is symptomatic with antipyretics, analgesics, and nonsteroidal
anti-inflammatory drugs. Corticosteroids are of no effect in either acute attacks or in their
prevention.
In the last decade, an effective treatment for prevention of acute attacks has been
introduced. Controlled studies have established that colchicine reduces the number or may
completely prevent acute attacks.6 A daily dose of 1.0 to 2.0 mg of the drug is effective in
about 95% of the patients. Moreover, it has been demonstrated recently that such treatment
may prevent the development of amyloidosis—the fatal complication.7Thus, such a treatment
is currently indicated “ for life” . Cessation of therapy is indicated only for 3 months prior
to a planned pregnancy in both spouses, to prevent possible chromosomal aberrations.

PERIODIC FEVER
Many “ cyclic fevers” have been described in the past, but most have been reclassified
into newly described nosological entities. Currently, we are still left with patients who suffer
from periodic fevers that are unclassifiable. It has recently been reported in 18 out of 85
 237

patients with recurrent fever of unknown origin.8 It is characterized by bouts of fever lasting
for 1 to 3 days with remissions of many weeks, associated with arthralgia, splenomegaly,
and laboratory findings of acute inflammation. This nosological entity differs from the
classical FMF by the lack of serous membrane involvement.
Hibernian Fever9—This periodic syndrome described in an Irish family consists of
attacks of fever, localized myalgia, and painful erythema. Additional features include ab-
dominal pains, pleurisy, leukocytosis, and elevated ESR during acute attacks. Therefore,
this autosomal dominant disease resembles FMF, but differs from it by its prompt response
to corticosteroids, and absence of amyloidosis.9
Deafness, Urticaria and Amyloidosis10’11—An inherited, dominant, and sex-linked
syndrome consisting of the manifestations detailed in its name, was first described by Muckle
et al.10 The clinical course is characterized by recurrent transient attacks of fever, severe
constitutional symptons associated with amyloidosis, nephropathy, and hyperglobulinemia.
Thus, it resembles closely FMF with deafness.
Cyclic Neutropenia12—This is an additional cause of periodic fever, associated with
bacterial infections precipitated during periods of cyclic neutropenia. These patients exhibit
cyclic inhibition of hematopoiesis at the pluripotential or early committed stem cells. Con-
sequently, this leads to depression in all the formed elements of blood: neutrophils, mono-
cytes, eosinophils, reticulocytes, and platelets. Thus, neutrophils disappear from circulation
at a strikingly periodic rhythm—every 21 days. During some of these cycles, bacterial
infections manifested with fever may occur.12

DISORDERS OF PORPHYRIN METABOLISM—ACUTE INTERMITTENT

PORPHYRIA13
This is an autosomal dominant disorder of porphyrin metabolism, caused by a deficiency
in porphobilinogen (PGB) deaminase (uroporphyrinogen synthase), with a gene frequency
of 1 to 10/100,000.
The clinical expression is variable and is influenced in part by exogenous factors, such
as steroid hormones, certain drugs (e.g., barbiturates) and nutrition. These conditions affect
y-aminolevulinic acid (ALA) synthase and porphyrin-heme synthetic rates in the liver.
The clinical presentation, which rarely occurs before puberty, is characterized by re-
current attacks of abdominal pains, vomiting, constipation, and accompanied often by fever
(in 9 to 37% of the patients) and leukocytosis, resembling other inflammatory abdominal
conditions. Most of these symptoms ascribed to autonomic neuropathy, leading to abnormal
gastrointestinal motility, but the origin of the fever is not well understood.
The acute attacks, which last from a few days to several months, include in addition,
other signs of autonomous nervous system impairment, peripheral and cranial nerve neu-
ropathies, and cerebral dysfunction. Cardiac rhythm and blood pressure disturbances (postural
hypotension or systemic hypertension), neurogenic muscle weakness, sensory loss, con-
vulsions and mental symptoms are among the frequent manifestations.
The diagnosis is based on the detection of excessive secretion of ALA and PBG in the
urine during acute attacks. During latent periods of diagnosis may be established by dem-
onstrating low levels of PBG deaminase, in either erythrocytes or lymphocytes.
Treatment of acute attacks include intravenous administration of 5% dextrose and He-
matin solutions. This regimen, by suppressing hepatic ALA synthase activity, will lead in
most patients to clinical improvement within 48 h. In addition, careful monitoring and
correction of blood pressure and fluid and electrolyte disorders are mandatory.

GLYCOLIPID STORAGE DISEASES

FABRY’S DISEASE14
This is a sex-linked, dominant disorder of glycosphingolipid metabolism, caused by
238 U nex p la in ed F e ve r

defective activity of a-galactosidase A activity (an intralysosomal enzyme). Consequently,

glycosphingolipids with the terminal a-galactosyl moiety (predominantly globotriaosylcer-
amide) accumulate in lysosomes of most visceral tissues and body fluids. Hemizygous males
have extensive deposition of glycosphingolipid in the endothelium and smooth muscle of
blood vessels; in ganglion cells; in heart, kidney, and eyes.
The onset of symptoms starts during childhood of affected males, and consists of periodic
severe neuritic pain in the extremities accompanied often with a low grade fever; cutaneous
angliokeratomas; corneal dystropy, vascular thrombosis, and progressive renal failure. Het-
erozygous females are affected in a milder form. The attacks of episodic pain (Fabry’s crises)
may last from minutes to several days and because of the accompanying fever and elevated
erythrocyte sedimentation rate may be confounded with other collagen-vascular diseases.
The diagnosis of hemizygotes may be suggested by the history of Fabry’s crises, char-
acteristic skin lesions, and corneal dystrophy; and established by the demonstration of
characteristic lipid inclusions (Maltese crosses) in blood vessels of skin biopsy. Confirmation
of diagnosis may be achieved through quantification of the deficient a-galactosidase A
activity in biospied tissues.
Treatment of the Fabry crises or their prevention may be achieved by diphenylhydantoin.
Hopeful approaches include enzyme replacement15 and kidney or bone marrow transplan-
tation.

GAUCHER’S DISEASE16
This is the most common, inherited metabolic disorder of glycolipid metabolism. Ex-
cessive quantities of glucocerebroside accumulate in the cells of the reticuloendothelial
system (Gaucher’s cells), due to an inherited abnormal activity of glucocerebrosidase (an
intralysosomal enzyme), which catalyzes the hydrolytic cleavage of glucose from gluco-
cerebroside. This abnormal recessive trait results in hepatosplenomegaly and bone lesions,
and in certain forms involvement of the central nervous system.
The clinical manifestations reflect the degree and the sites of organs involved: from
hypersplenism to the neuropathic infantile form, the latter leading to early death. Febrile
episodes are infrequent, but may occur in association with bone infarction,17 similar to the
crises associated with sickle cell disease.
The diagnosis may be made on the basis of hepatosplenomegaly, bone lesions, and the
presence of Gaucher’s cells in either bone marrow or other tissues. Confirmation of the
diagnosis may be achieved through the demonstration of reduced glucocerebrosidase activity
in liver tissue, skin fibroblasts, or blood leukocytes.
The treatment to date is supportive, but bone marrow transplantation may restore the
enzymatic defect, and is currently indicated in the more severe forms of this disease.18

HYPERLIPIDEMIA

HEREDITARY HYPERTRIGLYCERIDEMIA19
Fever may be observed in patients with acute pancreatitis complicating extreme hyper-
triglyceridemia.19 The fever originates from the inflammatory process and fat necrosis,
accompanying acute pancreatitis of any cause. Additional symptoms and signs of pancreatitis,
such as pain and “ surgical abdomen’’ prevail.
The mechanism for acute pancreatitis in hypertrigliceridemia is not clear, but it is likely
that blood flow through pancreatic capillaries becomes impaired, and in turn leads to necrosis
and leak of pancreatic enzymes. Recurrent acute pancreatitis may be associated with hered-
itary disorders of triglyceride metabolism caused either by increased plasma influx or im-
paired catabolism.
Increased plasma triglyceride influx results from an increased synthesis in the liver of
 239

very low density lipoproteins (VLDL), associated with an autosomal dominant inheritance
(a gene frequency of 1 to 2/1000)—hyperlipidemia type IV.19
Decreased triglyceride catabolism is associated with two extremely rare autosomal re-
cessive disorders: (1) lipoprotein lipase deficiency, a congenital absence of the main intra-
vascular triglyceride hydrolytic enzyme;19 (b) apolipoportein C-II deficiency—the protein
cofactor of lipoprotein lipase.20 These two conditions result in diminished catabolism of
plasma lipoprotein triglycerides, and thus lead to the accumulation in plasma of very large
lipoprotein particles: Chylomicrons (type-I) or Chylomicrons + VLDL (type-V, hyperli-
pidemia).
The increase in triglycerides in either or both of these particles (>1000 mg/dl), lead to
lipemia retinalis, eruptive type of skin xanthomata, and attacks of acute pancreatitis, making
this nosological entity easily recognized. The presence of “ milky” appearing plasma, and
an overlying creamy layer in refrigerated plasma obtained from a fasting patient, establish
the correct diagnosis. Confirmation may be achieved through analysis of plasma triglycerides
(>1000 mg/dl), cholesterol (within normal limits), plasma lipoproteins (elevated VLDL),
and quantification of lipoprotein lipase and apolipoprotein C-II.19’20
Treatment of acute attacks of pancreatitis is conservative and supportive. Prevention of
recurrent attacks may be achieved through dietary intervention (low in fat with substitution
of the regular fat by medium chain triglycerides, for hyperchylomicronemia—types I or V).

ACQUIRED HYPERTRIGLYCERIDEMIA OF MALIGNANCY

Hypertriglyceridemia may be associated with neoplastic conditions,2123 and therefore
may be accompanied also by fever. This elevation in serum triglycerides has been shown
to result from a decrease in the main intravascular lipolytic enzyme—lipoprotein lipase.19
This decrease is caused by a suppression in synthesis of lipoprotein lipase in adipose tissue,
induced by a recently discovered monokine—cachectin or tumor necrosis factor (TNF).24
Therefore, fever in association with elevated plasma triglycerides may point to an un-
derlying neoplastic condition, such as leukemia,25,26 lymphoma,22 or solid tumors.21,23

GOUT27

This is a clinical disorder, congenital (primary) or acquired (secondary), of uric acid

metabolism manifested by hyperuricemia, recurrent attacks of acute arthritis, kidney stones,
and tophaceous deposits of monosodium urate.
Primary gout may be caused by inborn errors of urate metabolism. In the majority of
patients, the exact biochemical abnormality has not been yet elucidated, but a polygenic
propensity to urate overproduction (in 85% of cases) or reduced fractional renal urate ex-
cretion (in 10 to 15% of patients) may be demonstrated. In rare instances specific enzyme
defects have been demonstrated, such as the sex-linked partial deficiency of hypoxanthine-
guanine phopsphoribosyl transferase deficiency.27
Secondary gout occurs in conditions associated with increased nucleic acid turnover
(e.g., hemolysis, leukemia, induction of chemotherapy, etc.).
Acute gouty attacks are triggered by the deposition of monosodium urate crystals in
affected joints. Consequently, these crystals are ingested by phagocytes and in turn activate
an intense local inflammatory reaction. In some cases, fever is a prominent symptom and
may be due to a mediator (interleukin-1) produced by stimulated macrophages in the affected
joints.28
Treatment includes colchicine or other nonsteroidal anti-inflammatory drugs for acute
attacks, followed by allopurinol for reduction of urate blood levels and thus preventing the
clinical manifestations of this disease.
240 U n ex p la in ed F e ve r

MISCELLANEOUS
Hypematremic dehydration may be associated with high fever, in addition to other major
clinical manifestations (i.e., irritability, mental dullness, ataxia, hypotension, or coma). Its
main etiology being diabetes insipidus of either pituitary or nephrogenic origin.29 Hyper-
natrémie dehydration should be considered in the differential diagnosis of patients presenting
with fever and impaired cerebral function.
Prolonged hypoglycemia, although usually associated with hypothermia,30 may result
in rare instances in fever.31 It is conceivable that cerebral edema leads to catecholamine
release which in turn may result in hyperthermia.
Diabetic nonketotic hyperosmolar coma, similar to hypoglycemia, is usually associated
with hypothermia,32 but it may present in rare instances with fever, as a result of associated
hypematremic dehyrdration or infection.33

REFERENCES
1. Dinarello, C. A. and Wolf, S. M., Fever of unknown origin, in Principles and Practices of Infectious
Diseases, Vol. 1, Mandell, G., Bennet, J. E., and Douglas, R. G., Eds., John Wiley & Sons, New York,
1979, 407.
2. Larson, E. B., Featherson, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow-up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
3. Eliakim, M., Levy, M., and Ehrenfeld, M., Recurrent Polyserositis (Familial Mediterranean Fever,
Periodic Disease), Elsevier/North-Holland, Amsterdam, 1981.
4. Matzner, Y. and Brzezinski,A., C5a-inhibitor deficiency in peritoneal fluids from patients with familial
Mediterranean fever, N. Engl. J. Med., 311, 287, 1984.
5. Barakat, M. H., El-Khawad, A. O., Gumma, K. A., et al., Metaraminol provocative test: a specific
diagnostic test for familial Mediterranean fever, Lancet, 1, 656, 1984.
6. Zemer, D., Revach, M., Präs, M., et al., A controlled trial of colchicine in preventing attacks of familial
Mediterranean fever, N. Engl. J. Med., 291, 932, 1974.
7. Zemer, D., Präs, M., Zohar, E., et al., Colchicine in the prevention and treatment of the amyloidosis
of familial Mediterranean fever, N. Engl. J. Med., 314, 1001, 1986.
8. Winckelmann, G., Lutke, A., and Löhner, J., Recurrent fever of unknown origin for more than 6 months,
Detsch. Med. Wochensch., 107, 1003, 1982.
9. Williamson, L. M., Hull, D., Mehta, R., et al., Familial Hibernian fever, Q. J. Med., 51, 469, 1982.
10. Mückle, T. J. and Wells, M., Urticaria, deafness and amyloidosis: a new heredo-familial syndrome, Q.
J. Med., 31, 235, 1962.
11. Andersen, V., Buch, N. H., Jensen, M. K., and Killmann, S. A., Deafness, urticaria and amyloidosis:
a sporadic case with a chromosomal aberration, Am. J. Med., 42, 449, 1967.
12. Guerry, D., Dale, D. C., Omine, M., et al., Periodic hematopoiesis in human cyclic neutropenia, J.
Clin. Invest., 52, 3220, 1973.
13. Kappas, A., Sassa, S., and Anderson, K. E., The porphyrias, in The Metabolic Basis of Inherited Disease,
Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., et al., Eds., McGraw-Hill, New York, 1983,
chap. 60.
14. Desnick, R. J. and Sweeley, C. C., Fabry’s Disease, in The Metabolic Basis of Inherited Disease, Stanbury,
J. B., Wyngaarden, J. B., Fredrickson, D. S., et al., Eds., McGraw-Hill, New York, 1983, chap. 45.
15. Desnick, R. J., Dean, K. J., Grabowski, G., et al., Enzyme therapy in Fabry disease: differential in
vivo plasma clearance and metabolic effectiveness of plasma and splenic-galactosidase A isozymes, Proc.
Natl. Acad. Sei. U.S.A., 76, 5236, 1979.
16. Bradie, R. O. and Barranger, J. A., Glucosylceramide lipidosis: Gaucher’s Disease, in The Metabolic
Basis of Inherited Disease, Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., et al., Eds., McGraw-
Hill, New York, 1983, chap. 42.
17. Billings, A. A., Post, M., and Shapiro, C. M., Febrile reaction of Gaucher’s disease, III. Med. J., 144,
222, 1970.
18. Parkman, R., The application of bone marrow transplantation to the treatment of genetic diseases, Science,
232, 1373, 1986.
 241

19. Nikilla, E. A., Familial lipoprotein lipase and related disorders of Chylomicron metabolism, in The Met-
abolic Basis of inherited Disease, Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., et al., Eds.,
McGraw-Hill, New York, 1983, chap. 30.
20. Breckenridge, W. C., Little, J. A., and Steiner, G., Hypertriglyceridemia associated with deficiency of
apolipoprotein C-II, N. Engl. J. Med., 298, 1265, 1978.
21. Barclay, M., Calathes, D. N., DiLorenzo, J. C., et al., The relation between plasma lipoproteins and
breast carcinoma: effect of degrees of breast disease on plasma lipoproteins and the possible role of lipid
metabolic aberrations, Cancer, 12, 1163, 1959.
22. Spiegel, J., Schaefer, J., Magrath, I. T., and Edwards, B. K., Plasma lipid alterations in leukemia and
lymphoma, Am. J. Med., 72, 775, 1982.
23. Theologides, A., Anorexins, asthenins, and cachectins in cancer, Am. J. Med., 81, 696, 1986.
24. Beutler, B. and Cerami, A., Cachectin and tumor necrosis factor as two sides of the same biological coin,
Nature, 320, 584, 1986.
25. Blackett, P. R., Koren, E., Blackstock, R., et al., Hyperlipidemia in acute lymphoblastic leukemia, Ann.
Clin. Lab. Sci., 14, 123, 1984.
26. Dodds, R., Rappaport, E., Ladd, D., et al., Hypertriglyceridemia and lipid inclusions in a case of
Philadelphia chromosome positive, acute nonlymphocytic leukemia, Arch. Pathol. Lab. Med., 110, 159,
1986.
27. Wyngaarden, J. B. and Kelly, W. N., Gout, in The Metabolic Basis of Inherited Disease, Stanbury,
J. B., Wyngaarden, J. B., Fredrickson, D. S., et al., Eds., Mc-Graw-Hill, New York, 1983, chap. 50.
28. Dugg, G. W., Atkins, E., and Malawista, S. E., The fever of gout: urate crystals activate endogenous
pyrogen production from human and rabbit mononuclear phagocytes, Trans. Assoc. Am. Phys., 96, 234,
1983.
29. Culpepper, R. M., Hebert, S. C., and Andreoli, T. E., The posterior pituitary and water metabolism,
in Williams Textbook of Endocrinology, 7th ed., Wilson, J. D. and Foster, D. W., Eds., W. B. Saunders,
Philadelphia, 1985, 614.
30. Kedes, L. H. and Field, J. B., Hypothermia: a clue to hypoglycemia, N. Engl. J. Med., 271, 785, 1964.
31. Ramos, E., Zorilla, E., and Hadley, W. B., Fever as a manifestation of hypoglycemia, JAMA, 205,
118, 1968.
32. Unger, R. H. and Foster, D. W., Diabetes mellitus, in Williams Textbook of Endocrinology, 7th ed.,
Wilson, J. D. and Foster, D. W., Eds., W. B. Saunders, Philadelphia, 1985, 1018.
33. Rayfield, E. J., Ault, M. J., Keusch, G. T., et al., Infection and diabetes: the case for glucose control,
Am. J. Med., 72, 439, 1982.
 243

Chapter 16

UNEXPLAINED FEVER ASSOCIATED WITH CUTANEOUS

MANIFESTATIONS
I. Alteras

INTRODUCTION

The skin is the site of the most diverse and unforseen eruptions which sometimes may
be accompanied by an unknown onset of fever, lasting during the entire evolution of the
respective rash or partially disappearing a few days before or after. In order to establish a
connection between the fever and the skin eruption, one should have some knowledge about
the main skin disorders which tend to be associated with a febrile state. When examining
the skin in such cases, it is valuable to study the form of the individual lesions, their pattern,
and distribution over the body surface. Considering the individual lesions (maculae, papules,
vesicles and/or bullae, pustules, nodules, ulcers, scales, crusts, atrophy, sclerosis, etc.), it
is to be retained that the skin eruption may be composed sometimes either from only one
type or from a combination of such elements, thus making the diagnosis more difficult.
There is also a possibility that each of the respective lesions can become purpuric, so we
have to deal with purpuric papules or vesicles. Therefore, it would be helpful to present a
brief list of the most important cutaneous manifestations, which may be associated with
fever, taking into account their classification based upon the predominant individual lesions
found. Moreover, keeping in mind that many types of skin rash may be very similar in their
clinical aspect, it is very important to establish, as quickly as possible, the presumptive
diagnosis, in order to prevent critical eventualities. All the available diagnostic procedures
should be used immediately in such cases.
Among the manifold skin manifestations there are some with precise etiology, others
with still unknown origin. Both groups have a series of cutaneous disorders, in which
unexplained fever may also be found.

BACTERIAL INFECTIONS

STAPHYLOCOCCAL ORIGIN
The pathogenic strains of staphylococci, collectively known as Staph, a u re u s , are fre-
quently important causes of skin infection, being able also to colonize all sorts of lesions.
The fever may accompany:

1. The common im p etig o (a contagious superficial infection of the skin caused by strep-
tococci or staphylococci or by both organisms) in the severe state, when regional
adenitis or other constitutional symptoms are also present. The two main recognized
clinical forms: Im p etig o co n ta g io sa (of Tilbury-Fox) and bu llo u s im p etig o are vesi-
culous bullous eruptions affecting mainly the face, limbs, sometimes scalp and, more
rarely, other areas of the body skin. In im p etig o n eo n a to rm , a variant of the latter that
occurs in newborn infants, fever may also be present. The same constitutional symp-
toms can be found in Ritter’s disease, a severe form of impetigo neonatorum.
2. F u ru n cu lo sis , an acute, usually necrotic infection of a hair follicle, starting as a deep-
seated inflammatory nodule, soon becoming a pustule, single or multiple, may be
associated with fever and mild constitutional symptoms. When a group of contagious
follicles is invaded by S taph, au reu s producing intense inflammatory changes in the
244 U nex p la in ed F e ve r

underlying connective tissue, called a carbu n cle or ca rb u n cu lo sis, the fever may be
higher, even preceding by some hours the development of the respective infection.
3. S ta p h ylo co c cu s toxic e p id e rm o ly sis , a diffuse, erythematous, leading to bullous, erup-
tion, most commonly seen in newborns, is due to Staph, aureus with 71 phage type—may
be associated with fever which appears a few hours before the onset of the rash.

STREPTOCOCCAL ORIGIN

1. E r y sip e la s ,a common skin infection usually caused by Streptococci of group A,

occasionally of group B. The abrupt onset of fever is followed, on the second day,
by the strongly diffused, slightly elevated erythema of the affected area.
Very similar to the former infection is cellu litis or p h leg m o n a diffusa caused by
S trep to co c cu s p y o g e n e s , in which the fever may accompany the onset of the suppurative
inflammation of the subcutaneous tissues.
2. In S tre p to c o c c a l g a n g ren e or necrotizing fa s c iitis which may develop rapidly in a
patient debilitated by predisposing factors (diabetes, arteriosclerosis), fever, sometimes
high, is usual. Very soon, the hemorrhagic bullae are followed by ulcerations.

M ENINGOCOCCAL ORIGIN
In the chronic septicemic form of M e n in g o co c ca l se p tic e m a , in which purpura is char-
acteristic, with small, scanty petechiae spread on limbs or trunk, sometimes developing into
maculopapular or nodular type, an indetermined febrile illness may be present for a couple
of weeks. From the early purpuric legions, N e isse ria m e n in g itis , a Gram-negative diplo-
coccus, may be isolated.

GONOCOCCAL ORIGIN
In the bacteremic form of g o n o rrh ea —gonococcemia—associated sometimes with non-
specific transient skin lesions (hemorrhagic vesicles, pustules, or bullae), scattered over the
limbs, knees, or ankles, fever is intermittent and may even be high, mainly in the rare
septicemic forms with signs of meningitis or endocarditis.
Among va rio u s uncom m on b a te ria l in fections o f the skin one should keep in mind:
Erysipeloid of Rosenbach —An acute, localized, self-limiting, infection, caused by
E rysip elo th rix in sid io sa a Gram-positive bacillus, affecting the hand, fingers or forearm, in
which the fever may accompany the mild constitutional symptoms in 10% of the cases.
Listeriosis —Caused by L iste ria m o n o cyto g en es (Gram-positive microaerophilic bacil-
lus) has an extremely variable clinical picture, sometimes with generalized erythema or
bluish papules on the trunk and legs, closely simulating mononucleosis and associated with
unexplained fever.
Hemophilus cellulitis —Caused by H . in flu en za , the fever is associated by a diffuse
area of bluish red cellulitis localized on the cheeks, neck, hand, or leg.
In the se p tic e m ic fo r m s o f P seu d o m o n a s a e ru g in o sa , fever may be associated with many
variable skin eruptions from scarlatiniform erythema through persistent bullae in the axillae
and lower abdomen up to necrotic ulcers ectym a gan gren osu m . This entity occurs mainly
in patients with chronic debilitating diseases.
In L ep to sp iro sis (Fort Bragg fever, pretibial fever, or Weil’s disease) fever may start a
few days before appearance of the purpuric elements on skin and mucous membrane (con-
juctivitis). The causative agents are L. ic tero h em o rrh a g icu s and L. au tum nalis.
In tu la re m ia , a sporadic infection caused by P a ste u re lla tu la re n sis , affecting mostly
sportsmen, campers, and laboratory workers, fever may accompany a maculopapular erup-
tions resembling erythema multiforme, or profuse nodules, usually on the limbs. The clinical
manifestations of the ulceroglandular type depends on the portal of entry.
 245

B ru c e llo sis , a widespread infection, caused by various species of B ru cella spread through
milk products of cattle, sheep, and goats, affecting mainly farmers or veterinary surgeons,
may present with nonpathognomonic skin lesions (roseola, exanthema, or hemorrhagic le-
sions) and intermittent fever.
R ick ettsio sis due to various species of Rickettsiae:
R ocky M ou ntain S p o tte d F e v e r , caused by R ick ettsia ric k e ttsii , an endemic disease,
in which the fever may precede by a few days the maculopapular or purpuric rash,
localized first on the wrists, ankles, palms, and soles and spread very quickly on trunk
and face.
E pidem ic ty p h u s , characterized by a macular hemorrhagic eruptions on the entire body
skin, sparing palms, soles, and face.
Tick ty p h u s , caused by R. c o n o rii , similar to the former R ick e ttsia l p o x , due to R.
a ca ri, in which the fever appears 3 to 4 days before the onset of the maculo-papular
or vesicular eruption.

SPIROCHETAL INFECTIONS
The most important clinical entities caused by various species of T rep o n em a , accompanied
by unexplained fever are

1. R elapsin g f e v e r due to B o rrelia re c u rre n tis , transmitted by various ticks, where high
fever may accompany a generalized erythema or macularpurpuric lesions on the trunk
and limbs.
2. L e p to sp iro sis , caused by L ep to sp ira sp., affecting sewer workers and people having
direct contact with animals with an acute fever, headache, and respiratory symptoms,
together with purpura or blotchy erythema mainly on the legs.
3. The ra t-b ite fe v e r , due to S pirillu m m inus and S trep to b a cillu s m o n ilifo rm is , which
affect people exposed to rat bites. A widespread macular or maculopapular eruption
may be associated with fever and tender-enlarged regional lymph nodes.
4. Y a w s , a disease particularly of warm climates and rural environments, whose identity
with syphilis is still being discussed, because its etiological agent— T repon em a p e r -
tenue—is almost morphologically indistinguishable from T repon em a p a llid u m and
T repon em a ca ra teu m . It occurs predominantly in children and fever may accompany
the respective cutaneous lesions in the primary stage (large, raised, vegetative, easy
bleeding lesions) or preceding the eruption in secondary stage (lenticular, hyperemic
macules).
5. S yph ilis in its secondary stage, manifests on skin (macular, maculopapular, papulos-
quamous and even pustular lesions) and mucous membranes (macurated papules), and
always positive serological tests. The rash may be generalized, including palms and
soles and the nonspecific constitutional symptoms—mainly the nocturnal headache,
are sometimes accompanied by a low-grade fever. The H erx h eim er re a c tio n , which
occurs when penicillin is first given to the syphilitic patient, should also be kept in
mind.

VIRAL INFECTIONS
The list of viral infections with skin manifestations is very large and the factors influ-
encing the areas of distribution of a rash are still not completely understood. It may be said
that all sorts of individual skin lesions may occur in the numerous viral infections known
up to now, starting from macular type (see measles, infectious mononucleosis, etc.) maculo-
papular (measles, vesicular (herpes simplex), vesiculopastular (varicella-zoster), papulo-
vesicular-pustular (vaccinia, variola).
246 U n expla in ed F e ve r

The most frequent virus infections in which fever is associated with such as the above
mentioned skin manifestations are

H erpan gin a , caused by group A Cocksackie virus, with groups of minute vesicles
developing on pharynx, tonsils, and soft palate.
H a n d , f o o t , a n d m outh d is e a s e , due to several Cocksackie A types, especially A-16,
occurring mostly in young children, with slight fever of short duration and small
vesicles on fingers and toes, sometimes on buttocks and in the mouth, where it
resembles herpangina.
M e a sles (morbili) with its characteristic Koplik’s spots, photophobia and the macu-
lopapular reddish exanthema diffusely confluent.
R u bella —in which a pinky, macular eruption on face and trunk is seen rapidly dis-
appearing.
V aricella and z o s te r , caused by the same virus—H . v a ric e lla e with the centripetal
distribution of unilocular vesicles and fever of variable duration for the former, and
the dermatomas vesiculopustular eruption in the latter. In h erp es sim p le x , caused by
two major antigenic types of H . hom in is (type 1 and type 2), the fever may subside
after 3 to 5 days in primary infection or can be higher in disseminated cases. In
recurrent herpes of the hand or forearm and more rarely of the face and lips, fever,
pain, and lymphangitis are sometimes also associated.
K a p o si s va ricellifo rm eru p tio n , also more informative and commonly called eczem a
vaccinatu m and eczem a h erp e tic u m , is a manifestation of primary infection, usually
found in infancy, and fever, which may be high, develop 2 to 3 days after the onset
of the vesiculopustular eruption, appearing in massive crops and simulating smallpox.
Patients suffering from active or recent atopic dermatitis are mostly affected.
E ryth em a in fectious or fifth d is e a s e , assumed to be caused also by a virus, may be
associated with a slight fever, which accompanies the rose-red coalescing papules on
the cheeks and on the proximal extremities, forming lace-like patterns up to the palms
and soles.
E ryth em a ch ron icu m m ig ra n s (Lyme arthritis) is regarded by some authors as a variety
of nodular vasculitis, by others due to a rickettsia or spirochete, as confirmed by
agglutination tests. The fever may appear simultaneously with the occurrence of a
single or several spreading bands of elevated erythemas with central clearing, which
may relapse at various periods.
R o seo la in fan tu m , also considered a viral infection, very common in children, may
be associated with very high fever and when it falls, after 3 to 5 days, a discrete rose-
pink, maculopapular eruption develops on the neck and trunk, spreading later to the
arms, face, and legs, leaving no scaling or pigmentation.
M on on u cleo sis syn d ro m e caused by Epstein-Barr (EB) virus begins also with a rising
and sometimes high persisting fever, accompanying a maculopapular eruption, dis-
tributed on trunk and upper arms, in 10 to 15% of the cases.
K a w a sa k i d ise a se —presumed to be of viral etiology, fever may precede by 3 to 5
days the polymorphous rash, sometimes accompanied by edema.
C a t-scra tc h d ise a se whose causative agent has not yet been identified is characterized
by persisting fever in 75% of the cases, accompanying the primary lesion, (a reddish-
brown papule or nodule which may ulcerate), appearing on hands or arms in individuals
handling cats or kittens. In tu b erc u lo sis of the skin or le p ro sy (Hanseniasis) unexplained
fever accompanying the respective symptoms is very rarely to be seen. In the former,
fever may be occasionally marked, but more often to slight at the onset of the primary
lesion: the tu b ercu lo u s ch an cre. In the latter disease—hanseniasis—an intermittent
fever can be associated with the type 2 reaction or eryth em a n odosum le p ro su m , an
immune complex syndrome complicating lepromatous leprosy.
 247

The fu n g a l in fections most commonly seen in daily practice, are occasionally accom-
panied by unexplained fever. Those of worldwide distribution like d e rm a to p h yto sis (tinea),
candidiasis, pityriasis versicolor, etc., are practically developing without fever or other
constitutional symptoms; the exceptions are severe superimposed bacterial infections or in
K erio n -lik e lesions (severe pattern of reaction caused by a dermatophytic invasion, known
as Kerion) or in acute, dysidrotic type of tin ea p e d is and/or tin ea m anuum with erysipellas,
etc. The situation may change in some of the mycoses with possible systemic involvement,
where a low-grade fever can occur together with other constitutional reactions. Such situ-
ations, as those mentioned above, may often be found in immunocomprised as well as in
immunocompetent patients. Various opportunistic fungi, like C a n d id a spp., A sp e rg illu s spp.,
C ryp to c o cc u s n eoform an s, H isto p la sm a spp., other species producing Z y g o m yco sis (from
genus M u co ra le s , viz,: A b sid ia , M u c o r , R h izo p u s , etc.) then from genus P en icilliu m (P.
m a rn efei , P . cru staceu m or species producing p h a elo h yp h o m yc o sis (Alternaría, Wangiella,
Bipolaris, etc.), etc. etc., may cause all types of cutaneous lesions, starting with erythematous
macules, passing through vesicles, papules, and pustules and reaching subcutaneous nodules.
Cellulitis and panniculitis can also appear in these cases.
Fever may also occur sometime in b la sto m y c o sis , mainly in the pulmonary type, in the
primary pulmonary form of c o c c id io id o m y c o sis and in systemic p a ra c o c c id io id o m y c o s is.
A clinical picture simulating pulmonary or meningeal tuberculosis can also be found in
pulmonary involvement associated with cutaneous lesions of N o c a r d io s is , when fever de-
velops together with cough, dyspnea and sometimes hemoptysis.
It was to be mentioned that the accurate diagnosis of the fungal manifestations mentioned
above is not all easy and needs the collaboration of skilled mycologists.
Considering the im m u n o co m p ro m ised h o st with skin lesions due to bacteremic Gram-
negative b a cilla ry in fections (P seu d o m o n a s a e ru g in o sa , E sch erich ia c o li , the febrile state
may appear a couple of days prior to the development of skin manifestations.

PARASITIC DISEASES
Some of the skin manifestations caused by parasitic worms and protozoa, particularly
found in the tropic and subtropic areas, may be accompanied by unexplained fever. For
instance:

O n ch o cerca sis —(a filarial disease caused by O n ch o cerca volvu lu s) from Central Amer-
ica, in which fever is associated with an acute eruption on the face resembling ery-
sipellas, described as “ erisipela déla costa” .
D ra n cu lo sis —due to the nematode worm— D ra n cu lu s m ed in en sis —in which the ur-
ticarial rash develops very quickly into blisters and occurs together with fever and
other toxic symptoms.
F ila ria sis —a disease due to the two varieties of filaría: W u sch ereria b a n cro fti and
B ru gia m a la y i , clinically almost indistinguishable in which the acute stage is marked
by lymphadenitis and “ filarial fever” accompanying urticaria and swelling.
T rich in o sis , a worldwide spread disease, caused by T rich in ella s p ir a lis , may occur
sometimes like an acute food poisoning with fever, muscle pain and a transient ma-
culopapular rash of the extremities.
African T ryp a n o so m a sis (syn. “ sleeping sickness” caused by T. g a m b ie n se in West
Africa and T. rh o d esien se in East Africa, in which the fleeting erythematous-annular
eruption on chest and back is accompanied sometimes by fever and other constitutional
symptoms.
V iscera l le ish m a n ia sis , (syn. Kala-azar, “ death fever” caused by L eish m an ia d o n o va n i
widely distributed in warm climates, may occur with prolonged irregular fever, ac-
companying the patchy discoloration of various areas of the skin.
248 Unexplained Fever

OTHER NONINFECTIOUS CUTANEOUS MANIFESTATIONS, OF (MORE OR

LESS) DOUBTFUL ETIOLOGY, ASSOCIATED WITH UNEXPLAINED FEVER

a. Miliaria (heat rash may be very rarely associated with a light fever starting a few
hours prior to the minute vesicular eruption occurring on covered areas of body skin).
b. Drug allergy widely known as drug eruption in which the type of the rash is highly
variable (from macular to urticarial) may also be associated with fever, viz., serum
sickness reaction, etc.
c. Cutaneous vasculitis, whose classification is still unsatisfactory, may be associated
with fever accompanying the onset or during the course of the various types of lesions,
where necrosis can occur spontaneously, as a result of hemorrhage and purpura.
d. In Henoch-Schonlein purpura (syn. anaphylactoid purpura), the fever may precede,
together with other prodromal symptoms, the papular, urticarial, and purpuric lesions,
associated with polyarthralgia and abdominal symptoms.
e. Pyoderma gangrenosum, a necrotizing, noninfective ulceration of the skin, usually of
the legs, may occur sometimes with a sustained fever in the course of its active stage.
f. Sweet's syndrome (acute febrile neutrophilic dermatitis) is an explosive eruption of
dull-red nodules or plaques with common neutrophilia, in which the patient usually
has a high persistent fever.
g. Erythema multiforme is a very common skin reaction, mostly of unknown etiology,
the rest of precipitating factors being associated with a preceding herpes simplex or
mycoplasma infection, bacterial infection, or drug sensitivity. The fever, usually high
and lasting for up to 2 to 3 weeks, may be observed in the severe bullous form (Steven-
Johnson syndome), showing extensive bullous-erosions formation on oral mucous
membranes and cornea.
h. Erythema nodosum, a nodular erythematous eruption, affecting mainly the skin about
the knees and ankles and recognized as an immunopathological process or a hyper-
sensitivity vasculitis (“ type reaction” ), which may occur in a wide variety of triggering
factors (infectious causes or noninfectious), starts with high fever also, mainly in the
acute onset of an attack.
i. Acne fulminans is one of the clinical varieties of Acne conglobata (a chronic, sup-
purative type of Acne vulgaris), also called the acute febrile ulcerative Acne conglobata,
in which the respective inflammatory nodules, occurring mainly on chest and back,
may be accompanied by fever, arthralgia and leukocytosis.
j. Polyarteritis nodosa, in which cutaneous and subcutaneous nodules around the knees
and anterior leg are also found, may be accompanied by fever at the onset in about
50% of the cases and even more, at some stage of the disease.

CONNECTIVE TISSUE DISEASES

Fever of uncertain origin may be found in:

Systemic lupus erythematosus, mainly in fulminanting cases with other marked con-
stitutional disturbances, like loss of weight, anorexia, joint pains, etc. Pulmonary
involvement in SLE simulating acute pneumonitis or recurrent pulmonary infection is
associated with fever. Febrile upsets with polyarthritis are also included in the stage
when hepatic lesions, rarely occurring in this disease, are found.
Dermatomyositis, translated cutaneously by the characteristic heliotrope rash on the
face and erythematous changes on the back of the hands, is sometimes associated with
fever and malaise.
 249

DISORDERS OF KERATINIZATION
Among the main skin diseases in this group, an unexplained fever may be found in:

(von Zumbush), a dramatic change in the nature of the

G en era lize d p u stu la r p so ria sis
common psoriasis, with an abrupt onset of high fever, increasing leukocytosis and
severe malaise, accompanying the pinpoint pustules which develop on pre-existing
psoriatic lesions.
Im petig o h erp e tifo rm is , a rare minute pustular eruption starting on acutely inflammed
areas of body skin, occurring especially in pregnant women, may be associated with
a continuous or remittent fever, increasing with successive waves of the disease.

BULLOUS ERUPTIONS
The fever is uncommon in the well-known major bullous diseases of worldwide distri-
bution like pemphigus, bullous pemphigoid, or dermatitis herpetiformis. An exception may
be offered by F o g o S elva g em (wildfire), an endemic bullous disease found in certain areas
of Brazil, very similar to p em p h ig u s fo lia c e u s or p em p h ig u s e ry th e m a to su s , in which the
flacid bullae progress, in the majority of cases, to a generalized erythema associated with
evening fever.
In the other group of more rarely found bullous diseases, the fever may occur in:

H erp es g e s ta tio n is ,
a rare polymorphous bullous eruption appearing in the first or
subsequent pregnancies and resembling bullous pemphigoid or dermatitis herpetifor-
mis. Pyrexia, which may rise up to 40°C occurs in exacerbations together with the
bullous lesions.
Toxis ep id erm a l n ecro lysis (scalded skin syndrome or Lyell’s disease), a clinical entity
in which the cutaneous manifestations (placid bullae and tender erythema with dramatic
separation and wrinkling of epidermis) demand immediate treatment and may be
accompanied by slight malaise and fever. The association with staphylococcal septi-
cemia, well-known in children, may rarely occur in adults.
It should be emphasized that in immunocompromised patients, such as those
suffering from leukemia, or who have undergone renal transplantation, fever may
precede the development of skin lesions in bacterial infection of the skin.

DISORDERS OF THE ORAL CAVITY AND LIPS

Fever may be found in the following conditions:

1. Behcet’s syndrome is a chronic disorder, characterized by recurrent ulcerations of the

mouth and genitalia, associated with uveitis and follicular or nonfollicular pustules on
the genitalia and trunk; fever may be moderate or severe during periods of activity.
2. Melkerson-Rosenthal syndrome is a recurrent and chronic condition manifested by a
diffuse swelling of the upper lip, facial palsy, and scrotal tongue (the latter may precede
attacks of edema); mild fever may accompany episodes of the cutaneous lesions.

In the accompanying table (Table 1) various skin manifestations accompanied by fever

are listed.
 TABLE 1
250

Cutaneous Manifestations Associated with Fever

Laboratory clue or Remarks (areas of body

Clinical entity Type of rash Causative agent other procedures skin involved)

Bacterial Infections

Impetigo Vesicles, bullae Staph, aureus Clinical culture Face, limbs, sometimes
scalp
U nex p la in ed F ever

Furunculosis Nodules, pustules Staph, aureus Clinical culture Various areas

Staphylococcus toxic epider- Eythema, bullae Staph, aureus, 71 phage Culture Nikolski sign + most
molysis type common in newborn
Erysipelas Raised erythema, sometimes Strept. group A, occasion- Clinical culture Extremities, face, etc.
bullae ally B
Cellulitis Erythema Strept. pyogenes Clinical Extremities
Necrotizing fasceitis Bullae, ulcerations Strept. pyogenes Biopsy Extremities
Meningococcemia Macules, papules, petechiae, Neisseria meningitis Blood and CSC cul- Limbs and trunks
nodules ture
Gonococcemia Hemorrhagic vesicles, pustules, Neisseria gonorhoea Smears culture Limbs, knees, ankles
bullae
Erisipeloid Rosenbach Erythema, swelling vesicles Erysipelothrix insidiosa Culture Fingers, forearms
Listeriosis Erythema, papules, pustules Listeria monocytogenes Serology Trunk, legs
Ectyma gangrenosum Erythema, bullae, ulceration Pseudomonas aeruginosa Blood culture Axillae, abdomen, ex-
tremities
Leptospirosis Macular, papular, purpuric le- L. icterohemorrhagicus, L. Blood culture Mucous membrane, con-
sions autumnatis juctivities, trunk, arms,
neck
Tularemia Macules, papules, nodules, ul- Pasteurella tularensis Smears P. A., culture Limbs
cers
Brucellosis Erythema, papules, pustules, B. abortus, B. melitensis, B. Smears, culture Upper extremities, face,
hemorrhagic lesions suis neck

Ricketsial Infections

Rocky Mt. Spotted Fever Macular, papular, purpuric R. ricketsii C.F.T. Ankles, wrist, palms,
soles, trunk
Epidemic typhus Macular, hemorrhagic R. p ro va czeck i Agglutinin for OX-19 Trunk, axillae, not on
face, palms and soles
Tick typhus Macular, vesicular, papular R. can ori C.F.T. Trunk, palms and soles
Rickettsial pox Macular, papular, vesicular R. akari C.F.T. Various areas

Spirochetal Infections

Relapsing fever Erythema, macular, purpuric Borellia recurrentis C.F.T. Trunk, limbs
Rat bite fever Macular, papular, vesicular S p ir illu s
minus S tr e p to b a c il- Blood culture Trunk, extremities,
lu s m o n o lifo m s is palms + soles
Yaws (primary stage) Vegetative lesions, hypochromic T r e p o n e m a p e r te n u e Clinical, endemic, Predominantly in chil-
macules reactive STS dren, face, extremities
Syphilis (secondary stage) Macular, papular, papulosqua- T r e p o n e m a p a llid u m Serology Generalized rash palms
mous, pustules (on skin), ma- and soles
cerated papules on mucous
membranes

Viral Infections

Hand, foot and mouth dis- Vesicular, ulcerations Cocksackie virus A-16 Throat culture, serol- Fingers and toes, but-
ease ogy tocks, mouth
Measles Macular, papular RNA virus Clinical serology Face, neck, shoulders,
Koplik spots in the
mouth
Rubella Macular, mainly Rubella virus Serology Face, trunk
Varicella herpes zoster Vesicular, umbilicated pustules, H. v a r ic e lla e Clinical E. M. exam- Face, trunk
vesicular, pustular ination of vesical
fluid
Herpes simplex Papular, vesicular, pustular H. h o m in is type and type 2 Clinical, culture his- Cutaneous and mucous
tology, serology membrane areas
Eczema herpeticum Vesicular, pustular H. h o m in is type and type 2 Clinical, culture, his- Complicat. atopic derma-
tology, serology titis, seborrheic derma-
titis, impetigo
Erythema infectisum (5th Papular Virus? Clinical Cheeks, proximal ex-
disease) tremities
Roseola infantum Macular, papular Virus? Clinical Common in children,
neck, trunk, arms
251

Infectious mononucleosis Macular, papular EBV or CMV Serology Trunk, upper arms
(Mononucleosis Syndrome)
 TABLE 1 (continued)
252

Cutaneous Manifestations Associated with Fever

Laboratory clue or Remarks (areas of body

Clinical entity Type of rash Causative agent other procedures skin involved)

Kawasaki disease Erythmatous, macular, Virus ? Clinical Conjuctiva, pharyngitis

polymorphous

Parasitic Diseases
U nexplain ed F ever

Onchocercasis Erytheme papular, nodules O n c h o c e r c a v o lv u lu s Clinical, Mazziti test Face, scalp

Draneulosis Papular, vesicles, ulcers D r a n e u lu s m e d in e n s is Clinical Legs, hand
Filariasis Papular hypertrophy of the skin W u sh e r e ria b a n c r o fti, B r u - Clinical, specimens Legs, scrotum, lymphad-
elephantiasis g ia m a la y i of blood from finger enitis
or ear
Trichinosis Macular, papular, edema T r ic h in e lla s p ir a lis Immunofluoresc. an- Muscle pain, eosinophi-
tibody test, biopsy lia, eyelids, conjuctiva
of muscle
Trypanosomiasis Erythematous annular angio- T. g a m b ie n s e , T. r h o d e n - Clinical Chest, back, lymphade-
edema ie n s e nopathy
Leishmaniasis (visceral) Discolorated macules L e is h m a n ia d o n o v a n i Blood smears, bone Various cutaneous areas
marrow exam.

Infections by Fungi

Kerion-like tinea (capitis, Boggy, inflammatory papules, T ric h o p h y to n spp. (menta- KOH-treating scrap- Scalp, beard
barbae) nodules grophytes), T. v e r r u c - ings, culture
c o su m , T. v io la c e u m , etc.,
M ic r o s p o r u m spp., M.
c a n is , etc.)
Tinea pedis and or manuum Papular, vesicullous bullous T r ic h o p y to n r u b ru m , T. in - Similar Soles and palms
(inflammatory type, acute) te r d ig ita le , E p id e r m o p h y to n
f lo c c o s u m
Systemic (opportunistic) my- Macular, papular, vesicular
coses eventually nodules, granuloma-
tous lesions
 Blastomycosis Nodules, “ chancroid-like” le- Blastomyces dermatidis Culture Face, arms
sions
Paracoccidioidomycosis Ulcerative crusty lesions P a r a c o c c id io d e s b r a s ilie n s is Smears, culture Secondary to hematoge-
(mixed type) nous dissemination,
face
Coccidioidomycosis Verrucous lesions, subcutaneous C o c c id io id e s im m itis Smears, cultures Face, abdomen
abscesses
Cryptococcosis Acneiform, ulcerative, granu- C r y p to c o c c u s n e o f o r m a n s Direct preparations, Face, arms
lomatous lesions, subcuta- culture
neous, tumor-like abscesses
Candidiasis (systemic or Papular, verruccous crusty le- C a n d id a a lb ic a n s
(more Scrapings, culture, Face, trunk, extremities,
macro-chronic cutaneous sions rarely other C a n d id a spp.) serology axillae, oral cavity
Aspergillosis Pustular, necrotic lesions, cellu- A s p e r g illu s spp. Smears, cultures Trunk, extremities, face
litis
Histoplasmosis Papules, pustules, hemorrhagic H is to p la s m a c a p s u la tu m Culture, biopsy Trunk, extremities
lesions, cellulitis
Zygomycosis Necrotic ulcers, cellulitis R h iz o p u s spp. (S a k s e n a e a Culture, biopsy Face, extremities
spp.)
Phaeohyphomycosis Erythematous macular, hemor- A ite r n a r ia spp. (A lte r n a ta ) Culture, biopsy Extremities, trunk
rhagic lesions
Hyalohyphomycosis Cellulitis Paecyclomyces spp. (P . v a r- Smears, culture Face, trunk
io ttii, etc.)
Protothecosis Papules, nodules, cellulitis Proteotheca spp. (P . w ic h e r - Biopsy, culture Extremities
a m i, etc.)

Noninfectious Cutaneous Manifestations

Miliaria Superficial vesicles Occlusion of sweat ducts Clinical Covered areas of body
skin
Drug allergy Variable, from vesicular papular Drugs Clinical, MIF reac- Mainly face and trunk
to urticarial tion
Cutaneous vasculitis Variable: papular, purpuric, Drugs Biopsy, clinical Limbs, trunk, extremities
pustules, ulcerative, necrotic
Henoch-Schonlein purpura Papular, urticarial, purpuric Unknown Clinical, biopsy Extremities, limbs,
trunk, buttocks, poly ar-
thralgia
Pyoderma gangrenosum Papular, pustular, nodular, nec- Unknown Clinical Essential with ulcerative
253

rotizing ulcerations collitis

 TABLE 1 (continued)
254

Cutaneous Manifestations Associated with Fever

Laboratory clue or Remarks (areas of body

Clinical entity Type of rash Causative agent other procedures skin involved)

Sweet’s syndrome Papular, nodular, edematous le- Unknown Clinical, biopsy Back, face, arms
sions
Erythema multiforme Papular, vesicular, bullous + Drug sensitivity, bacterial or Clinical, biopsy Hands, feet, trunk,
erosion formation systemic fungal infection mouth, cornea
U nex p la in ed F ever

Erythema nodosum Erythematous nodules Hypersensitivity type reac- Clinical, biopsy Shins
tion
Acne fulminans Ulcerative nodules Clinical Chest, back
Periarteritis Nodular, subcutaneous Drug or internal allergy Clinical, biopsy Legs, knees, lower ex-
trem.

Connective Tissue Diseases

SLE Erythematous, papular, erosions Still in doubt ANA immunofluores- Polyarthrit., face, trunk,
telangiectasia cent band anti-DNA extremities, oral cavity
Dermatomyositis Heliotrope erythema, urticarial Unknown Biopsy muscle elec- Face, eyelids, polymyo-
patches tromyogram sitis, muscle weakness

Bullous diseases

Herpes gestationis Vesicular, papular, bullous Unknown Clinical? Face, hands, palms and
soles, first or subse-
quent pregnancies
Toxic epidermal necrolysis Erythema, bullae, wrinkling of Drugs Biopsy Nikolski sign + face,
(Lyell’s disease) epidermis trunk, oral mucosae,
conjuctiva

Disorders of keratinization

Pustular psoriasis (general- Generalized erythema, pustules Unknown Clinical, biopsy On psoriatic lesions, mu-
ized) cous membranes
Impetigo herpatiformis Pustules Unknown Biopsy In pregnant women,
groin, flexures, mucous
membranes
255
256 Unexplained Fever

REFERENCES
1. Areno, F. C., Perlin, M., Brahman, H., Weiser, B., and Armstrong, D., Fever, rash and myalgias of
disseminated candidiasis during antifungal therapy, Arch. Intern. Med., 141, 1233, 1981.
2. Avedisian, R. and Adelizzi, R. A., Cutaneous polyarthritis nodosa: report of a case and literature review,
J. Am. Osteopath. Assoc., 85(2), 93, 1985.
3. Balandran, L., Rotschild, H., Pugh, N., and Seabury, J., A cutaneous manifestation of systemic
candidiasis, Ann. Inter. Med., 78, 400, 1973.
4. Bateman, C. P., Umland, E. T., and Becker, L. E., Cutaneous zygomycosis in a patient with lymphoma,
J. Am. Acad. Dermatol., 8, 890, 1983.
5. Berger, B. V., Erythema chronicum migrans of Lyme disease. Arch. Dermatol., 20(8), 1017, 1984.
6. Bodey, G. R. and Luna, M., Skin lesions associated with disseminated candidiasis, JAMA, 229, 1466,
1974.
7. Bodey, P. G., Infection in cancer patients, Am. J. Med., 81, 11, 1986.
8. Braverman, I. M., Skin Signs of Systemic Diseases, 2nd ed., W. B. Saunders, Philadelphia, 1981, 476.
9. Carlile, G. R., Millet, R. E., Cho, C. T., and Vats, T. S., Primary cutaneous aspergillosis in a leukemic
child, Arch. Dermatol., 114, 178 1973.
10. Davies, S. F., Sarasi, G. A., and Peterson, P. K., Disseminated histoplasmosis in renal transplant patients,
Am. J. Surg., 137, 686, 1979.
11. O’Dorino, T. M., Jasper, D. A., and Sullivan, J., A cutaneous manifestation of untreated disseminated
histoplasmosis, Chest, 67, 616, 1975.
12. Edungbok, L. D., Drancuneuliasis in Igbon, Oyo State, Nigeria, J. Trop. Med. Hyg., 87(41), 153, 1984.
13. Epstein, E. H., Flynn, P., and Davis, R. J., Adult toxic epiderman necrolysis with fatal Staphylococcal
septicemia, JAMA, 229(4), 425, 1974.
14. Everard, G. O. R., Edwards, C. N., and Webb, G. B., The prevalence of severe leptospirosis among
humans in Bamados, Trans. R. Soc. Trop. Med. Hyg., 78(5), 596, 1984.
15. Fishbein, D. B., Kaplan, J. E., Bernard, K. W., and Winkler, W. G., Surveillance of Rocky Mountain
Spotted Fever in the United States, J. Infect. Dis., 159(4), 609, 1984.
16. Greone, S. L., Su, W. P. D., and Muller, S. A., Ectyma gangrenosum—report of clinical, histopathologic
and bactériologie aspect, J. Am. Acad. Dermatol., 19(51), 781, 1984.
17. Green, M. H., Mader, A. M., Hernandez, A. D., Tomecki, K. J., and Chabner, G., Disseminated
cryptococcosia presenting as palpable purpurs, Arch. Inter. Med., 138, 1412, 1978.
18. Grossman, M. E., Silvera, D. N., and Walther, R. R., Cutaneous manifestations of disseminated
candidiasis, J. Am. Acad. Dermatol., 2, 111, 1980.
19. Hattwick, M. A. W., O’Brien, R. J., and Hanson, B. F., Rocky Mountain Spotted Fever, Ann. Intern.
Med., 84, 732, 1976.
20. Hay, R. J., Campbell, C. K., Marshall, W. M., Reis, B. J., and Pincott, J., Disseminated zygomycosis
caused by Saksenaea, vasiformis, J. Infect., 7, 145, 1983.
21. Hardie, R. and Roberts, W., Adult listeriosis presenting an acute hepatitis, J. Infect., 8(3), 256, 1984.
22. Isaac, B. and Kernbaum, S., Fievres prolongées inexpliquées, Presse Med., 10(40), 3311, 1981.
23. Harp, P. L., Rocky Mountain Spotted Fever in children in Kansas, J. Infect. Dis., 151(2), 361, 1985.
24. Leonard, J. C., Humphrey, G. B., and Basmedjian, G., Lymphedema secondary to filariasis, Clin.
Nucl. Med., 10(3), 203, 1985.
25. Lin, G. Y. C., Bailowitz, A., and Koslowe, P., Kawasaki syndrome, Am. J. Dis. Child., 139(3), 277,
1985.
26. Meyer, R. D., Kaplan, M. H., Ony, M., and Armstrong, D., Cutaneous lesions in disseminated
mucormycosis, JAMA, 225, 737, 1973.
27. Meyer, R. D. and Armstrong, D., Mucormycosis-changing status, Crit. Rev. Clin. Lab. Sei., 4, 421
1973.
28. Meinhof, W., Acne fulminans, eine schwere Akneform mit Fieber ausgeprazte leukozytose und Gelenk-
beleitang, Therapiewoch, 34(43), 6178, 1984.
29. Morenz, D. M. and O’Brien, R. J., Kawasaki disease in the United States, J. Infect. Dis., 137, 91,
1978.
30. Mandel, D. R., Streptobacillary fever—an unusual case of infectious arthritis, Cleveland Clin. Q., 52(2),
203, 1985.
31. Navin. T. R., Roberto, R. R., and Juramek, D. D., Human and sylvatic Trypanosoma cruzi infection
in California, Am. J. Public Health, 75(4), 360, 1985.
32. Okabe, N., Koboyashi, S., Tabazane, O., and Mortimer, P. P., Detection of antibodies to human
parvovirus in erythema infectiosum, Arch. Dis. Child., 59(11), 1016, 1984.
33. Powel, F. C. and Perry, H. O. Pyoderma gangrenosum in childhood, Arch. Dermatol., 120(6), 757,
1984.
 257

34. Procowicz, D., Boron, P., and Szakowska, D., Changes in the incidence of trichinosis and its clinical
picture in the bialystov region in the last 16 years (pols.), Wiad. Lek., 38(5), 352, 1985.
35. Panida Jaynetra, Pravat Nitiyanant, Ajello, L., Padhye, A. A., and Lolehka, S., Penicillosis mameffei
in Thailand—report of five human cases, Am. J. Trop. Hyg., 33(4), 637, 1984.
36. Ray, T. L., Cutaneous signs of systemic disease. Fungal infections in immunocompromised hosts, Med.
Clin. North Am., 64, 955, 1980.
37. Schwan, T. G., Thompson, J., and Nelson, B. C., Fever on roof rats in six areas of Los Angeles County.
Their potential role in the transmission of plague and murine typhus in humans, Am. J. Trop. Med. Hyg.,
34(2), 372, 1985.
38. Sengupta, S., Musculo-skeletal lesions in Yaws, Clin. Orthop. Relat. Res., 192, 193, 1985.
39. Schweinfarth, V. Filarial diseases in Ceylon—a geographic and historical analysis, Biol. Dis., 2(4), 309,
1983.
40. Syrjala, H., Harvorum, J., and Salminem, A., Skin manifestations of tularemia: a study of 88 cases in
Northern Finland during 16 years, Acta Dermatovenerol., 64(6), 513, 1984.
41. Taylor, N. R., Recent developments in the treatment of onchocercosis, Bull. W. H. O., 62(4), 509, 1984.
42. Trunnell, T. N., Waisman, M., and Trunnell, T. L., Contact dermatitis caused by Brucella, Cutis,
35(4), 379, 1985.
43. Toews, W. H. and Bass, J. W., Skin manifestations in meningococcal infection, Am. J. Dis. Child., 127,
173, 1974.
44. Venezia, F. R., Lavoo, E., and William, J. E., Progressive cutaneous protothecosis, Arch. Dermatol.,
104, 430, 1982.
45. Walter, D. H. and Gea, J. N. S., Correlation of the distribution of Rickettsia conorri, microscopic lesions
and clinical picture in South African tick bite fever, Am. J. Trop. Med. Hyg., 34(2), 361, 1985.
46. Wieden, A., Steinbronn, M., Karen, K., Padhye Arvind, A., Ajello, L., and Chandler, F. W.,
Zygomycosis caused by Apophysomyces elegans, J. Clin. Microbiol., 22(4), 522, 1985.
47. Wolfson, J. S., Sober, J. A., and Rubin, R. H., Dermatologic manifestations in immunocompromised
patients, Medicine, 64(2), 115, 1985.
48. Yagupsky, P. and Moses, S., Neonatal Borellia species infection (relapsing fever), Am. J. Dis. Child.,
139(1), 74, 1985.
Part III
Environmental and Biologic Causes of Unexplained
Fever
 261

Chapter 17

IATROGENIC AND OCCUPATIONAL FEVER

David Schlossberg

Iatrogenic and occupational causes of fever are likely to be overlooked. The effects of
medical care and possible deleterious effects of the workplace may result in febrile states
that elude detection by the unwary. One must think of these entities to diagnose them, and
frequently it is a seemingly minor historical point that explains a puzzling and prolonged
febrile course. Iatrogenic fever results, of course, from iatros, the physician. As physicians,
we administer medications to patients and perform procedures on them. When fever arises
during the course of an illness, it is usually attributed to the illness itself. Thus, when a
therapeutic or diagnostic modality is itself responsible for causing fever, it may complicate
the course of an illness, obfuscate the diagnosis, and potentially threaten the patient if the
iatrogenic contribution is not recognized.
Administration of medication, especially antimicrobials, frequently causes fever.16 A
list of agents most commonly associated with drug fever is provided in Table 1, though the
clinician is safest in assuming that any medication may cause fever. In medication-related
fever, the fever may be accompanied by other dramatic symptomatology which makes drug
reaction likely. These other phenomena may be the syndrome of serum sickness, the classic
signs of immediate hypersensitivity such as urticarial rash and eosinophilia, adenopathy,
joint pains, bronchospasm, and edema of face, hands, feet, and genitalia. At other times,
a drug hypersensitivity or toxicity may focus on a particular organ system as with the dilantin-
induced hepatitis or pseudolymphomas, or with beta-lactam antibiotic-induced nephritis. A
variety of types of pulmonary injury may be seen with antineoplastic drugs, including
interstitial fibrosis (acute and chronic forms), pleural effusions, and patchy areas of con-
solidation.7 Sterile meningitis has been attributed to several medications, including anti-
inflammatory agents and antibiotics, especially in patients with systemic lupus erythema-
tosus.8 11 All of these acute drug reactions may be accompanied by fever; the history and
associated abnormalities should suggest drug toxicity as a possible etiology.
However, other drug reactions may be manifested primarily by a febrile response, and
these tend to be more confusing in that the fever may be considered part of the underlying
disease or may be misinterpreted as a failure of the patient to respond to effective therapy.
Some drugs rarely are associated with production of fever, i.e., the tetracyclines, digitalis,
and insulin. Other medications frequently induce a febrile response, and the clinician’s index
of suspicion should be raised when a patient develops fever while receiving one of the drugs
in this group, including the penicillins, sulfonamides, pronestyl, and quinidine.
It is important to identify allergic reactions even if fever is the only manifestation, as
the fever may be a harbinger of more severe manifestations if the drug is not discontinued.
On the other hand, some apparently allergic reactions represent idiosyncratic responses that
will not recur on readministration of the drug; the classic example of this response is the
fever and rash that may be induced in patients with infectious mononucleosis (caused by
EB virus or, less frequently, by other causes of the mono syndrome such as cytomegalovirus)
when administered ampicillin or a related compound.
Although fever as a sole manifestation of a drug reaction presents a diagnostic challenge,
certain clinical characteristics may be helpful.
Patients whose fever results from a drug reaction tend to lack signs of systemic toxicity,
though they may demonstrate rigors (probably from rapid defervescence). Eosinophilia is
not common. Relative bradycardia is helpful when found, but is usually absent. There may
be no history of prior allergy. Although some authors have described drug fever as beginning
262 U nexplain ed F e ve r

TABLE 1
Agents Responsible for Episodes of Drug Fever“

Cardiovascular (38) Central nervous system (30)

Alpha methyldopa (16) Diphenylhydantoin (11)
Quinidine (13) Carbamazepine (3)
Procainamide (6) Chlorpromazine
Hydralazine Nomifensine (2)
Nifedipine Haloperidol
Oxprenelol Triamterene
Benztropinet
Antimicrobial (46) Thioridazine (2)
Penicillin G (9) Trifluoperazinet
Ampicillin (2) Amphetamine (2)
Methicillin (6) Lysergic acid (5)t
Cloxacillin (2)
Cephalothin (7) Anti-inflammatory (3)
Cephapirin Ibuprofen
Cephamandole Tolmetin
Tetracycline (2) Aspirin
Lincomycin
Sulfonamide (2) Other (19)
Sulfa-trimethoprim Iodide (6)
Streptomycint Cimetidine (2)
Vancomycin Levamisole
Colistin Metoclopramide
Isoniazid (5) Clofibrate
Para-aminosalicylic acid Allopurinol
Nitrofurantoin (2) Folate
Mebendazole Prostaglandin E2 (2)
Ritodrine
Antineoplastic (12) Interferon (2)
Bleomycin (3) Propylthiouracil
Daunorubicin
Procarbazine
Cytarabine
Streptozocin (2)
6- Merc aptopuri ne
L-Asparaginase
Chlorambucil
Hydroxyurea

a Numbers in parentheses show number of episodes induced by drugs re-

sponsible for several epsiodes.
t Fever seen during drug overdose.

From Mackowiak, P. A. and LeMaistre, C. F., Ann. Intern. Med.. 106, 728,
1987. With permission.

typically on the 7th-to-10th day, a recent review1 corroborates this for antimicrobial-asso-
ciated fever but noted a shorter lag time with antineoplastic agents and a longer one for
cardiac medications. Other recent observations stress the variability of duration of drug
administration before a febrile response.2
No particular fever pattern is diagnostically helpful, and the observations throughout the
literature that age, female sex, atopic dermatitis, systemic lupus erythematosus, and severe
infection all predispose to drug fever have not been the experience of all observers1 and
remain controversial.
Discontinuation of the offending agent should result in defervescence, though it should
be remembered that agents that persist in the body for long periods of time may cause
 263

TABLE 2
Mechanisms o f Fever Produced by
Medication

Hypersensitivity
Altered thermoregulation
Pharmacologic action
Idiosyncratic response
Administration-related
Withdrawal

Modified from References 12 and 13.

correspondingly protracted febrile responses. Thus, while most drug fevers will resolve
within several days of discontinuation of the offending agent, some contrast materials, iodine,
and depots of injected drugs like benzathine penicillin may take much longer to be eliminated
from the body and for their secondary fever to resolve.
A variety of mechanisms may be responsible for drug fever and are classified in Table
2.
Fever as a response to a medication may result from a change in thermoregulation. This
may be a direct effect, as is seen with administration of cocaine or amphetamines, or may
be a result of deficient heat loss, induced by atropine, epinephrine, and phenothiazines.
Other medications may induce a hypermetabolic state, with resultant fever. Examples of
this last phenomenon include MAO inhibitors, thyroid hormone, and cimetidine.34
An additional mechanism for production of fever by medication administration includes
the pharmacologic action of the drug itself. The Herxheimer reaction, seen after penicillin
administration for the treatment of syphilis, includes fever, chills, and sometimes exacer-
bation of the underlying disease, such as accentuation of the rash of secondary syphilis or
focal neurologic symptoms. Attributed to the spirochetocidal effect of the penicillin, it has
been explained by some investigators as due to entotoxin release. The Herxheimer reaction
is not unique to syphilis, as it may be seen in treatment of other spirochetal diseases and
some bacterial infections, i.e., brucellosis. The pharmacologic action of chemotherapeutic
agents in the treatment of malignancy may also result in a febrile response, and this may
be the result of liberation of endogenous pyrogen from destruction of tumor cells.
In addition to the pharmacologic actions described above, antibiotic administration may
alter the patient’s normal flora enough to allow overgrowth (C. difficile) or infection (Sal-
monella) with pathogens. Similarly, immunosuppressive medication may permit the devel-
opment of opportunistic infection.
Some idiosyncratic reactions on the part of patients may result from hereditary bio-
chemical defects. The syndrome of malignant hyperthermia, life-threatening fever and rhab-
domyolysis seen after administration of certain anesthetics, is the result of a defect in calcium
metabolism. The related entity, the neuroleptic malignant syndrome, is seen after admin-
istration of psycho-active drugs. Both malignant hyperthermia and neuroleptic malignant
syndrome have been treated with various agents, including dantrolene, bromocriptine, and
pancuronium.1214 Similarly, in G6PD deficiency, an oxident drug may result in massive
hemolysis with release of pyrogen from red blood cells and resultant fever. Malignant
hyperthermia and hemolytic response in G6PD-deficient patients represent preventable drug
reactions that can be avoided by in vitro testing.
The act of medication administration may of course result in fever. Sepsis may be
induced via intravenous administration, and local irritation or phlebitis with or without a
purulent response may develop at the infusion site. This has been noted especially with the
infusion of Vancomycin, Amphotericin B, and Bleomycin. In addition, administration of
medications intramuscularly, particularly analgesics, may cause fever even without signs of
tissue injury.15
264 U nex p la in ed F e ve r

Finally, it is not just drug administration that can produce fever, but sometimes with-
drawal of medication. Withdrawal of chronic barbiturate administration may result in an
acute illness accompanied by fever, an etiology frequently overlooked when a patient is
hospitalized and medications he had been taking are inadvertantly discontinued. Similarly,
withdrawal from corticosteroids, frequently an iatrogenic event on admission to the hospital
or postoperatively, may result in a syndrome resembling sepsis, with hypotension and fever.
Other than administration of specific medications, iatrogenic fever can be induced by
other procedures, both diagnostic and therapeutic, to which patients are subjected. The very
admission to a hospital may result in a short-lived mild temperature elevation on a psycho-
genic basis. After admission to the hospital, patients are susceptible to nosocomial infection.16
Nosocomial infection affects 3.5% of hospital patients and approximately 1/1000 hospital
patients die per year of nosocomial infection. The vast majority are bacterial and involve
the urinary tract, surgical wounds, lower respiratory tract and the bloodstream. (Postoperative
infection is discussed in Part IV of this book.)
Nosocomial infection may occur as supra-infection because of a change in a patient’s
own flora. It may result from communicable diseases acquired from other patients and staff
in the same manner that such diseases are acquired outside the hospital. However, recent
note has been made of less frequent pathogens causing disease in this setting, and the
clinician must be aware of the vast potential for nosocomial spread of unusual as well as
common diseases. Thus, for example, direct contact may result in soft-tissue infection due
not only to streptococci, but also to M y co b a c teriu m fo rtu itu m -c h e lo n e i , the JK bacillus, and
L eg io n ella p n eu m o p h ila .
Infection introduced by infusion of blood and blood products is due not only to non-A
non-B hepatitis and the “ post-pump” culprits CMV, EBV, and toxoplasma, but also to
AIDS (Factor VIII, blood), salmonellosis (platelets), and babesia, trypanosoma, filaria,
borrelia, and syphilis (blood).
Airborne spread also has expanded its potential, and risks from this route include not
only the previously appreciated varicella, TB, rubeola and meningococcal infection, but also
L is te r ia , N o c a r d ia , P n e u m o c y stis , and C h la m yd ia via person-to-person spread, and legi-
onellosis and aspergillosis from environmental airborne spread.
In addition, specific procedures performed on patients are associated with febrile re-
sponses, either from the procedure itself or from complications thereof.
Bronchoscopy and gastrointestinal endoscopy both have the potential for introducing
pathogens into the respiratory and gastrointestinal tract directly, as well as disruption of
mucosal membrane and sometimes actual performation, with resultant local infection due
to the patient’s own flora. ERCP may allow infection to ascend proximal to biliary tract
obstruction. Interventional radiologic techniques may allow infection usually associated with
the patient’s skin flora, e.g., staphylococci, and some of the modalities used via intraventional
radiologic techniques may of themselves produce a brief self-limited febrile response, i.e.,
the infusion of streptokinase for acute myocardial infarction.7
Unlike the procedures in the preceding paragraph, which represent transient invasion of
the patient, there are other types of mechanical intervention which induce a prolonged
impairment of a patient’s local host defenses. For example, endotrachial intubation allows
easier entry of organisms into the lower respiratory tract with resultant infection and has
also been associated with the complication of conjunctivitis. Nasal catheters, by obstructing
sinus drainage, may produce a sinusitis and a mysterious fever of unknown origin in the
intubated patient.17 Indwelling urinary catheters allow entry of organisms into the urinary
tract with resultant infection, especially with open drainage systems.
Prosthetic devices implanted permanently in patients may form a nidus for infection and
resultant fever. These include the intra-uterine devices, which have recently been associated
with infection due to actinomyces, permanent intravascular apparatuses such as AV fistulae
and grafts, central nervous system shunts, Leveen shunts, and the Hickman catheter, and
 265

prosthetic heart valves, joints, breast implants, and intra-ocular lenses. The major threats
to these prostheses are coagulase-negative and coagulase-positive staphylococci and occa-
sionally Gram-negative bacilli, although unusual organisms such as atypical mycobacteria
may infect prostheses such as the intra-ocular lenses. Infection of prosthetic material and
intravascular accesses are problematic not only because of the resultant sepsis, but also
because of the nearly universal requirement for removal of the synthetic material to effect
eventual cure.18 Exceptions to the requirement for such removal include the frequent ability
to treat bacterial infection on prosthetic heart valves, the occasional cure of early joint
infection with irrigation and antibiotic therapy, and reported efficacy in some instances of
treatment of intravascular access materials by prolonged bactericidal antibiotic therapy alone.
Infusions administered to patients are fraught with potential for production of fever with
or without infection. Infecting organisms are noted above in the discussion on nosocomial
infections. But transfusions of blood or blood products may induce a leukoagglutinin-related
febrile response. These reactions happen immediately, as opposed to the delayed mono-
nucleosis-type illness seen after perfusion or multiple transfusions.
Transplantation of organs, aside from opportunistic infections seen as a result of the
immunosuppressive therapy used, may result in a febrile response upon rejection of the
transplant or when infecting organisms transmitted via the transplant (e.g., CMV) begin to
produce symptoms.
Radiation therapy produces several syndromes which are often accompanied by fever.7
This response is usually obvious in that the injury occurs in the irradiated tissue, but radiation
pneumonitis may mimic infectious pneumonitis (with fever, infiltrate) and may not be
restricted to the irradiated portal; the infiltrates may be widespread, making difficult the
distinction between infection and radiation injury. Irradiation-induced pneumonitis is en-
hanced when cytotoxic drugs are given during the period of irradiation or after it is completed.
If corticosteroid treatment is withdrawn during a course of irradiation, pulmonary damage
may also be facilitated.
Thus, a patient receiving cytotoxic medication and irradiation,who develops pulmonary
infiltrates and fever, has a complicated differential diagnosis. Possibilities include “ routine”
pneumonia, opportunistic infection, cytotoxic lung injury, radiation pneumonitis, drug-in-
duced lupus, graft-vs.-host disease if the patient received a transplant, hemorrhage, and
spread of an underlying malignancy.
This chapter discusses both iatrogenic and occupational causes of fever because of areas
of etiologic overlap. The most prominent such area involves health care and laboratory
workers, whose occupation subjects them to communicable diseases.
The secretions of patients expose health care workers to infectious pathogens. Table 319
outlines the salient points of the prominent infectious diseases encountered by hospital
employees.
Laboratory workers are at additional risk when working with a specific pathogen.20,21
The most frequent infections acquired by the laboratory worker are brucellosis, Q fever,
hepatitis, typhoid fever, tuberculosis, dermatomycosis, Venezuelan equine encephalitis,
psittacosis, and coccidioidomycosis. Other infections that may be spread nosocomially range
from the trivial (respiratory viruses such as RSV, para-influenza, adenovirus, and rhinovirus)
to serious and potentially life-threatening infections like legionellosis, Jacob-Creutzfeldt
disease, and a group of viruses principally from Africa: Lassa, Marburg, Ebola, and Congo-
crimean hemorrhagic fever viruses. This last group may cause nosocomial outbreaks and,
because of their prolonged incubation period and lengthy period of virus excretion, may
easily be imported into nonendemic areas.22
Infections that affect non-health-care workers include a vast collection of illnesses from
a variety of sources.4,23 26 Table 4 is a selected list, identifying the exposure and some
associated infections. It can be seen that many occupations may be associated with a certain
exposure, such as soil. Also, consideration of geography, climate, and season should be
 TABLE 3
266

Infectious Diseases Encountered by Hospital Employees

Period of
Infectious agent Incubation period communicability General precautions Diagnostic tests Vaccines or prophylaxis

Hepatitis B 6 to 24 weeks While HBsAg-positive Blood precautions for pa- HBsAg = acute or Passive prophylaxis: HBIG
tients, HBsAg-positive per- chronic infection or car- 0.06 mg/kg bodyweight for
sonnel are informed, rier; HBeAg = increased HBsAG-positive needle-
counseled to wear gloves, infectivity; anti-HBs = sticks. Repeat at 1 month if
U nexplain ed F e ve r

but not usually removed immunity; anti-HBc = not vaccinated Active pro-
from work unless critically acute, chronic or previous phylaxis: hepatitis B vac-
ill infection cine, 20 —pg doses at 0.1
and 6 months
Non-A, non-B hepa- 3 to 18 weeks Unknown Same as for hepatitis B None available No therapy or possibly ISG
titis (0.06 mg/kg body weight)
for needlestick injuries
ISG, 0.02 ml/kg
Hepatitis A 2 to 7 weeks 2 to 3 weeks before Stool precaution for patients. Anti-HAV: IgM (acute);
jaundice; until 7 days Good handwashing by em- IgG (immune)
after onset of jaundice ployees; remove from work
for 7 days after onset of
jaundice
Rubella (German 14 to 21 days 7 days before to 5 days Employee history is unrelia- HA to screen; HAI (four- Rubella vaccine. Women
measles) after onset of rash ble, respiratory isolation for fold rise) to diagnose should not conceive for 3
patients; remove infected acute disease months after vaccination
employee from work for
period of communicability
Rubeola (Measles) Adults 8 to 15 days; 5 to 21 days after expo- Respiratory isolation for pa- Usually not necessary Measles vaccine ISG, 0.25
from the onset of sure tients; employee history is ml/kg, may be helpful for
the catarrhal stage reliable, exposed suscepti- exposed patients and per-
to 4 days after the ble employees should be sonnel
onset of rash removed from work 5 to 21
days after exposure
Mumps 12 to 26 days 7 days before to 9 days Respiratory isolation for pa- Usually not necessary Mumps vaccine
after parotitis tients; positive history is
reliable; if negative may
still be immune; employee
 usually removed from work
for period of communica-
bility
Influenza 1 to 3 days 1 day before to 5 days Respiratory precautions for CF and HAI antibody tests Influenza vaccine is given
after clinical onset patients; remove employees available; viral isolation yearly; amantidine 100 mg
from work for period of possible orally twice a day, is effec-
communicability tive prophylaxis against in-
fluenza A
Varicella-zoster Usually 14 to 21 10 to 21 days after expo- Patients with chickenpox re- FAMA most sensitive test; VZIG may attenuate or pre-
(Chickenpox) days after exposure sure quire strict isolation; pa- false-negative tests occur vent disease and should be
tients with localized herpes with CF considered for given to high-risk patients
zoster are placed on contact personnel and
precautions; history of
chickenpox is reliable; ex-
posed susceptible employ-
ees should not work;
infectious employees are
removed until lesions dry
and crust; employees with
localized herpes zoster
should cover lesions and
not care for high-risk pa-
tients
Herpes simplex (Her- Variable Until lesions crust over Employee history is sugges- Not helpful; viral culture None
petic whitlow) tive. Employees should use available
gloves when caring for in-
fected patients; infected
employees should avoid
contact with immunosup-
pressed patients or neonates
Acquired immunode- 6 months to 2 years Unknown Blood, secretion, and excre- HTLV-1I1 or LAV anti- None
ficiency syndrome tion precautions are stan- body tests available
dard; additional precautions
depend on the patient’s ill-
ness
267
 TABLE 3 (continued)
268

Infectious Diseases Encountered by Hospital Employees

Period of
Infectious agent Incubation period communicability General precautions Diagnostic tests Vaccines or prophylaxis

Tuberculosis Usual 3 to 5 weeks; Until 3 consecutive sputa Evaluate contacts and moni- Tuberculin skin tests; acid Isoniazid prophylaxis if indi-
range 2 to 8 weeks are free of tubercle ba- tor employees with PPD fast smears; cultures cated. BCG not recom-
cilli or the patient is on skin test. Respiratory pre- mended.
adequate therapy for 2 cautions for patients. Ven-
Unexplained Fever

weeks tilation. UV lights in high

risk areas
Meningococcal men- Variable: 1 to 10 Variable Close prolonged exposure Culture on blood or choco- Rifampin 600 mg orally
ingitis days required for transmission late agar twice a day for 2 days (sul-
mouth to mouth resuscita- fonamide if sensitive); vac-
tion or prolonged exposure cine against meningococcal
to infected secretions. Res- groups A.C.Y. and W135
piratory precautions. is available.
Salmonella, Shigella, Variable: 1 to 5 days While organism is pres- Enteric precautions for pa- Culture on selected agar or Antibiotic treatment for se-
Campylobacter ent in stool (days to tients. Employees should broth lected or severely ill em-
week) be removed while they are ployees
symptomatic; employees
with salmonella should not
have contact with high-risk
patients
Staphylococcus au- Variable: 4 to 10 During skin infection or Patients placed on contact Culture on blood agar Topical or oral antibiotics
reus days as a nasal “ dissemina- precautions; infected per- are sometimes used to treat
tor” sonnel should be evaluated carriers
by employee health service
and may be removed from
work
Scabies Days to weeks Until mites or eggs are Patients should be isolated None Topical lindane as directed.
destroyed until treated All clothes and bedding
should be decontaminated
by washing in hot, soapy
water
HBsAg = hepatitis B surface antigen; HBIG = hepatitis B immune globulin; HBeAg = hepatitis B e antigen; anti-HBs = antibody to HBsAg; anti-HBc = antibody
to hepatitis B core antigen; ISG = immune serum globulin; HAV = hepatitis A; HAI = hemagglutination inhibition antibody; CF = complement fixation; FAMA
= fluorescent antibody membrane antigen; VZIG = varicella-zoster globulin; HLTV-III = human T-cell lymphotropic virus type III; LAV = lymphadenopathy-
associated virus; PPD = purified protein derivative; BCG = bacille Calmette-Guerin; UV = ultraviolet.

From Patterson, W. B., Craven, D. E., Schwartz, D. A., Nardell, E. A., Kasmer, J., and Noble, J., Ann. Intern. Med., 102, 658, 1985. With permission.
269
270 Unexplained Fever

TABLE 4
Exposure-Related Infections

Exposure Infectious agent

Soil A s c a r is
C o c c id io id e s
H is to p la s m a
S p o r o tr ic h u m
Hookworm
Construction C o c c id io id e s
H is to p la s m a
L e g io n e lla
Cotton mill C o c c id io id e s
Forests, the great outdoors Rocky Moutain Spotted Fever
Tularemia
B o r r e lia
G ia r d ia
Lyme Disease
Livestock Q fever
B r u c e lla
Milker’s nodules
Rabies
Anthrax
Rocky Mountain Spotted Fever
L e p to s p ir a
Plague
Tularemia
E c h in o c o c c u s
C a m p y lo b a c te r
Wild animals Rocky Mountain Spotted Fever
Plague
Tularemia
Rabies
Rats L e p to s p ir a
Murine typhus
Rat bite (S p ir illu m m in u s and S tr e p to -
b a c illu s m o n ilifo r m is )
Plague
Cats and dogs Cat scratch bacillus
P a s te u r e lla m u lto c id a
Rabies
Tularemia
L e p to s p ir a
Rocky Mountain Spotted Fever
T o x o c a r a c a n is
D ir o f d a r ia
T o x o p la sm a
C a m p y lo b a c te r
S a lm o n e lla
DF-2
Fish Erysipeloid
M . m a rin u m
Birds (poultry and pets) and Psittacosis
their roosts Newcastle Disease
H is to p la s m a
Erysipeloid
Furs, hides, wool Q fever
Anthrax
Tularemia
Orf
Plague
 271

TABLE 4 (continued)
Exposure-Related Infections

Exposure Infectious agent

Animal carcasses Erysipeloid

Brucella
Salmonella
Leptospira
Q fever
Tularemia
Anthrax
Flowers Sporotrichum
Caves Rabies
Histoplasma
Salt water Marine vibrios
M. marinum
Aeromonas
Legionella
Fresh water Legionella
Aeromonas
Pharyngoconjunctival fever
Shigella
Pseudomonas
Proteus
Leptospira
Aeromonas
Actinetobacter
Herpes simplex
Schistosoma
Acanthamoeba
Naegleria
Prototheca

applied individually. This list is not all-inclusive, as that would involve a separate com-
pendium beyond the scope of this chapter. The reader is referred to detailed works on the
subject.2728
Not all of the occupationally related febrile illnesses result from infection. Polymer or
fume fever is due to breakdown products of heated Teflon. Nonproductive cough, chills,
and chest pain may result and the Teflon may contaminate cigarettes with later production
of the syndrome when the cigarette is lit. A related syndrome is caused by metal fumes and
may be accompanied by a metallic taste. Exposure to the combustion products of metals
produces a typical influenza-like clinical picture; copper, zinc, nickel, and many other
industrial metals have been implicated.27
Extrinsic allergic alveolitis16,29'32’34 (hypersensitivity pneumonitis) may produce a febrile
response to inhaled antigens, characterized by fever and nonproductive cough but without
the wheezing and asthma. X-rays range from normal to diffuse interstitial infiltrates. A clue
to etiology is the characteristic lag of 4 to 8 h between exposure and symptoms, and lung
biopsy demonstrates granulomas. There are many antigens that have been implicated, and
the list grows constantly. A representative list is provided in Table 5.
Diagnosis is suspected by history, but may be confirmed by specific serum precipitant
assays. This is an important entity, as the offending antigen may be constantly in the victim’s
environment (i.e., hairspray, hot tubs, air conditioning ducts) and the patient may be mis-
diagnosed as having the chronic pulmonary disease he may ultimately develop if exposure
to the antigen is not terminated.
The common denominator and the diagnostic clue to iatrogenic and occupational causes
of fever is a thorough history. Simpler than our current technologic revolution would suggest
possible, this alone frequently solves a perplexing and dangerous clinical puzzle.
272 U nexplain ed F ever

TABLE 5
Etiology of Hypersensitivity Pneumonitis

Antigen Antigen source Name of disorder

Thermophilic actinomycètes
M ic r o p o ly s p o r a f a e n i Moldy hay Farmer’s lung
T h e r m o a c tin o m y c e s v u lg a r is Moldy sugarcane (bagasse) Bagassosis
T h e r m o a c tin o m y c e s s a c c h a r i Moldy compost Mushroom worker’s lung
T h e r m o a c tin o m y c e s c a n d id u s Contaminated humidifiers and air- Humidifier lung and air-condi-
conditioning ducts tioner lung
Cattle Hog fever
Moldy cork Suberosis
Thermoactinomyces viridis Vineyards Vineyard sprayer’s lung
Ventilation systems
True fungi
A s p e r g illu s c la v a tu s Moldy barley Malt worker’s lung
A s p e r g illu s c la v a tu s Moldy cheese Cheese washer’s lung
C r y p to s tr o m a c o r tic a le Moldy maple logs Maple bark lung
C ra p h iu m Moldy wood dust Sequoiosis
P u llu la r la Moldy wood dust Sequoiosis
A ite r n a r ia Moldy wood pulp Wood pulp worker’s lung
M u c o r s to lo n ife r Moldy paprika pods Paprika sheer’s lung
C r y p to s tr o m a c o r tic a le Maple bark Maple bark stripper’s lung
C la d o s p o r iu m Hot tub Hot tub pneumonitis
Animal products
Pigeon serum proteins Pigeon droppings Pigeon breeder’s lung
Duck proteins Feathers Duck fever
Turkey proteins Turkey products Turkey handler’s lung
Parrot serum proteins Parrot droppings Budgerigar fancier’s lung
Chicken proteins Chicken products Feather plucker’s lung
Bovine and porcine proteins Pituitary snuff Pituitary snuff taker’s lung
Rat serum protein Rat urine
Bat serum protein Bat droppings Bat lung
Insect products
A c a r u s s ir o (mite) Dust
S ito p h ilu s g r a n a r iu s (wheat wee- Contaminated grain Miller’s lung
vil)
Amebae
N a e g le r ia g r u b e r i
A c a n th a m o e b a p o ly p h a g a Contaminated water
A c a n th a m o e b a c a s te lla n i
Sawdust (redwood, maple, red ce- Sequoiosis
dar
Cereal grain Grain measurer’s lung
Vegetable products Dried grass and leaves Thatched roof lung
Tobacco plants Tobacco grower’s lung
Tea plants Tea grower’s lung
Cloth wrappings of mummies Coptic lung

Modified from Reference 33.

 273

REFERENCES
1. Mackowiak, P. A. and LeMaistre, C. F., Drug fever: a critical appraisal of conventional concepts, Ann.
Intern. Med., 106, 728, 1987.
2. Young, E. J., Fainstain, V., and Musher, D. M., Drug induced fever: cases seen in the evaluation of
unexplained fever in a general hospital population, Rev. Infect. Dis., 4, 69, 1982.
3. Kumar, K. L. and Reuler, J. B., Drug fever, West. J. Med., 144, 753, 1986.
4. Lipsky, B. A. and Hirschmann, J. V., Drug fever, JAMA, 245, 851, 1981.
5. Patterson, R. and Anderson, J., Allergic reactions to drugs and biologic agents, JAMA, 248, 2637, 1982.
6. Van Arsdel, P. P., Jr. Diagnosing drug allergy, JAMA, 247, 2576, 1982.
7. Preger, L., Ed., Iatrogenic Diseases, Vols. 1 and 2, CRC Press, Boca Raton, FL, 1986.
8. Haas, E. J., Trimethoprim-sulfamethoxizole: another cause of recurrent meningitis, JAMA, 252, 1984.
9. Derbers, S. J., Trimethoprim induced aseptic meningitis, JAMA, 252, 2865, 1984.
10. Von Reyn, C. F., Recurrent aseptic meningitis due to sulindac, Ann. Intern. Med., 343, 1983.
11. Burnstein, R. F., Ibuprofen-related meningitis in mixed connective tissue disease, Ann. Intern. Med., 92,
206, 1980.
12. Sangal, R. and Dimitrijevic, R., Neuroleptic malignant syndrome, JAMA, 254, 2795, 1985.
13. Nelson, T. E. and Flewellen, E. H., The malignant hyperthermia syndrome, N. Engl. J. Med., 309, 416,
1983.
14. Mueller, P. S., Vester, J. W., and Fermaglich, J., Neuroleptic malignant syndrome, JAMA, 249, 386,
1983.
15. Semel, J. D., Fever associated with repeated intramuscular injections of analgesics, Rev. Infect. Dis., Jan/
Feb 1986, 68.
16. Harris, A. A., Levin, S., and Trenholme, G. M., Selected aspects of nosocomial infections in the 1980’s,
Am. J. Med., July 31, 1984, 3.
17. Knodel, A. R. and Beekman, J. F., Unexplained fevers in patients with tracheal intubation, JAMA, 248,
868, 1982.
18. Sugarman, B., Infections in prosthetic devices, Am. J. Med., 81 (Suppl. 1A), 78.
19. Patterson, W. B., Craven, D. E., Schwartz, D. A., Nardell, E. A., Kasmer, J., and Noble, J.,
Occupational hazards to hospital personnel, Ann. Intern. Med., 102, 658, 1985.
20. Pike, R. M., Laboratory associated infections, Annu. Rev. Microbiol., 33, 41, 1979.
21. Pike, R. M., Past and present hazards of working with infectious agents, Arch. Pathol. Lab. Med., 102,
333, 1978.
22. Hopkins, C. C. and McCormick, J. B., Isolation in management of contageous, highly lethal diseases,
Curr. Clin. Topics Infect. Dis., 86.
23. Barbaro, D. J. and Mackowiak, P. A., Infections in hunters, Infect. Med., Sept/Oct 1985, 246.
24. Rolnick, M., Stear, T., and Silfen, E., Aquatic pathogens: source of disease, Consultant, July 1980, 34.
25. Fite, G. L., Canine zoonoses, JAMA, 231, 1975.
26. Elliot, D. L., Toll, S. W., Goldberg, L., and Miller, J. B., Pet associated illness, N. Engl. J. Med.,
313, 985, 1985.
27. Gantz, N. M., Infectious agents, in Occupational Health, Levy, B. S. and Wegman, D. H., Eds., Little,
Brown, Boston, 1983.
28. Hubbert, W. T., McCulloch, W. F., and Schnurrenberger, P. R., Diseases Transmitted from Animal
to Man (6), Charles C Thomas, Springfield, IL, 1975.
29. Brooks, S. M., An approach to patients suspected of having an occupational pulmonary disease, Clin.
Chest Med., 2, 171, 1981.
30. Toogood, J. H. and Payton, K. B. Homing in on the cause of hypersensitivity in pneumonitis, J. Resp.
Dis., April 1983, 58.
31. Dyer, E. L., Farmers lung: industrial hazard for rural inhabitants, South. Med. J., 73, 353, 1980.
32. Hollick, G. E. and Kurpu, V. P., Isolation and identification of thermalphylic actinomyci associated with
hypersensitivity pneumonitis, Lab. Med., 14, 39, 1983.
33. Pitlik, S., Berger, S. A., and Huminer, D., Non-enteric infections acquired through contact with water,
Rev. Infect. Dis., 9, 54, 1987.
34. Salvaggio, J. E., Diagnosis and management of hypersensitivity pneumonitis, Hosp. Pract., November
1980, 93.
 275

Chapter 18

UNEXPLAINED FEVER ASSOCIATED WITH

HYPERSENSITIVITY AND AUTO-IMMUNE DISEASES

Serge Kernbaum

INTRODUCTION

In this vast and heterogeneous chapter we will briefly describe various diseases which
represent, after infections and malignancies, the third main cause of U.F. (see Chapter 1).
Many of these diseases have common or overlapping clinical and/or histological features.
Most of them are of unknown etiology, and are mediated by immune mechanisms. Some
of the diseases reviewed here overlap with others, but among them, two genuine, well-
defined illnesses may be associated. Finally, in all of these diseases, fever can either be a
symptom of the disease itself, including the fever resulting from the withdrawal of steroid
therapy, or reveal a superimposed infection.

CONNECTIVE TISSUE DISEASES

Connective tissues are responsible for the form and the mechanical function of the body.
They are present in all tissues, including large blood vessel walls. They are made up of
specialized cells responsible for their formation, as they command synthesis and organization
of the extracellular material which characterizes the tissue. This material is made up of
various proteins, including a fibrillar one, collagen, the major protein of most connective
tissues: hence the ancient and now inappropriate term of “ collagen diseases” to characterize
all the disorders affecting mainly the connective tissues.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

There is no useful and universally accepted definition of SLE because of the polymor-
phism of its presenting features and of the inconsistency and lack of specificity of the various
autoantibodies found in the serum of affected patients, the most valuable being the anti-
native DNA antibodies.1*2
Fever is very frequent in SLE: it is present in all series, in about four fifths of patients
(83% of 520 patients of Dubois).1 Fever is of all types, sometimes accompanied by shaking
chills; the frequency of associated anorexia and weight loss varies greatly from 50%1 to
nearly 100%.2
Our experience as well as that of Larson3 shows that SLE is no longer a cause of U.F.
We believe this is due to the use of the revised diagnostic criteria4 (see below) and also to
the detection of various antinuclear antibodies in the blood of the patient.
SLE is indeed a very protean disease (nearly all viscera can be affected) and its initial
manifestations may be difficult to diagnose, but usually, as time elapses, in most cases if
its diagnosis is evoked it will be confirmed with only a reasonable delay.
To sum up its clinical features we shall list the incidence of visceral involvement in the
largest published sery, that of Dubois1which compiles visceral involvement during the whole
life of the patients; any one of these manifestations can be a presenting syndrome.
In Table 1 are listed the main clinical manifestations of SLE, in Table 2 its cutaneous
manifestations and in Table 3 its revised diagnostic criteria.
The association of four criteria supports the diagnosis of SLE. The diagnostic probability
is higher when more criteria are present. Unfortunately, hypocomplementemia is not listed,
although it is of great value, especially when it is associated with anti-DNA antibodies.2
276 Unexplained Fever

TABLE 1
Main Clinical Manifestations of SLE According to Dubois1
(Fever — Present in 83% — Excluded)

% of 520
Manifestations patients Comments

Arthritis or arthralgia 91.6 Arthralgia occurs in about one fourth of cases and is
often a presenting feature
Mucocutaneous symptoms 71.5 Were the presenting symptom in 23% of patients
Adenomegaly 58.6 Lymph nodes are not tender; splenomegaly is pres-
ent in about 15% of patients
Anemia 56.5 Usually “ inflammatory” ; sometimes hemolytic, or
exaggerated by renal insufficiency or due to ery-
throblastopenia . . .
Gastrointestinal manifestations 53.2 Anorexia, nausea, abdominal pain; not to be con-
fused with lupoid hepatitis
Myalgia 48.2
Kidney involvement 46.1 Mainly glomerulonephritis, (possible nephrotic syn-
drome) responsible for one third of deaths
Pleurisy 45 Lung disease is very rare (interstitial)
Pericarditis 30.5 Myocarditis and verrucous endocarditis are much
less frequent
Nervous system involvement 25.5 Behavioral disturbances; psychosis organic brain
damage: convulsions (about 15%), paresias; ocular
paresias and cotton wool spots

TABLE 2
Cutaneous Manifestations of SLE in 120 of 520 Patients of Dubois1

% of 520
Manifestations patients Comments

Discoid lupus 10.8 The lesion scale is associated with follicular plug-
ging and heals with atrophy, scarring, hyper- or
hypopigmentation
Butterfly rash 3.4 Scaly erythematous maculopapular rash located on
both cheeks and the nose bridge
Butterfly erythema 2.1 Blush and swelling of same topography
Various nonspecific dermatosis 2.1
Raynaud’s phenomenon 1.7 As some lesions listed below it demonstrates the
frequency of vasculitis (also responsible for some
mucous syndromes, e.g., oral ulcerations)
Photosensitivity 1.3 The photosensitivity explains the topography of the
lesions
Alopecia 0.4
Thrombophlebitis 0.4
Digital gangrene 0.2
Ecchymoses 0.2
Sjogren’s syndrome 0.2
Periorbital edema 0.2

We will review briefly the laboratory abnormalities:

• Nonspecific — ESR elevation, anemia, polyclonal hypergammaglobulinemia . . .

• Evocative — Leukopenia in a febrile patient; presence of the rheumatoid factor (IgM
immunoglobulin with antibody activity for IgG): its occurrence varies between 4% of
275 patients5 and 57% of 520,1 it is present in about 30% of patients;2 hypocomple-
mentemia (decreased total hemocytic complement as well as lowered C4 and C3 levels)
 Ill

TABLE 3
The 1982 Revised Criteria for the Classification of Systemic Lupus
Erythematosus4

1. Facial erythema
2. Discoid lupus
3. Photosensitivity
4. Oral or nasopharyngeal ulcerations
5. Nonerosive polyarthritis
6. Pleuritis or pericarditis
7. Renal dysfunction: proteinuria >0.5 g/24 h (or + + + ) or cellular casts
8. Neurologic dysfunction: psychosis or convulsions
9. Hematologic dysfunction: hemolytic anemia with reticulocytosis or leukopenia <4000/
mm3 or lymphopenia < 1500/mm3 or thrombocytopenia < 100,000/mm3
10. Immunologic disorder: presence of LE cells or of anti-native DNA antibodies or of anti-
SM antibodies or of a chronic false-positive serologic test for syphilis
11. Presence of significant antinuclear antibodies (detected by immunofluorescence)

TABLE 4
Main Patterns of Nuclear Fluorescence2,6

Aspect Name Comments

<3? Homogeneous or diffuse The most frequent aspect; detects insoluble nucleoproteins
C s) Peripheral Seen mainly in active SLE; detects DNA antigens
Cg) Speckled Detects soluble nucleoproteins of three main types: Sm specific,
seen in 30% of SLE patients; RNP (ribonucleoprotein): not spe-
cific; HA or SS-B: like SS-A seen mainly if Sjogren syndrome
associated
<3? Nucleolar Seen in 26% of SLE patients and 54% of cases of systemic scle-
rosis

is present mainly in patients with severe vasculitis, as well as two often associated
abnormalities, circulating immune complexes and/or cryoglobulinemia: their frequency
(which depends on the severity of the disease and of the method of detection) varies
between about one fourth and two thirds of the patients.2 Finally, a false-positive
syphilitic serology is also of great value.
• Rather specific — Detection of antinuclear and anti-DNA antibodies: (The list of all
the antibodies detectable in the sera of SLE patients can be found in a recent com-
prehensive review.2 Only those of diagnostic value will be discussed here.)

Hargraves in 1948 demonstrated the presence of an antibody, later identified as an anti-

nucleoprotein responsible for the LE cell.1,2’5 This cell is inconstant in SLE, it was detected
in 75.7% of the patients of Dubois;1 technical progresses in its detection can find it in up
to 90% of patients2 and even in 100% of the 275 patients of Haserick,5 who described its
search in the serum and not in the whole blood. But its presence is not specific as it can be
found in 1.6 to 15.8% of cases of chronic discoid lupus, 3.6 to 33% of cases of rheumatoid
arthritis, 4% of cases of systemic sclerosis and 15 to 42% of cases of chronic active hepatitis.2
The indirect immunofluorescent assay is usually the initial screening test used to detect
antibodies to nuclear antigens (ANA). Neither the fluorescent sera nor the nuclear substrates
are standardized. The four main patterns of fluorescence are described in Table 4.
The ANA are present in at least 90% of SLE and more often as well as in a higher
degree if the disease is active.2But they lack specificity, they are detected in all the connective
tissue diseases (systemic sclerosis: 75 to 81%; rheumatoid arthritis: 14 to 32%; juvenile
rheumatoid arthritis: 13 to 33%; Felty’s syndrome: 100%; Sjogren’s syndrome: 37 to 67%;
278 Unexplained Fever

dermatopolymyositis: 8 to 29%; vasculitides: 17 to 25%) and are present moreover in chronic

discoid lupus (13 to 53%), in control patients (20 to 60 years old: 2.9 to 3.6%; older than
60: 12.2 to 23.9%), in the family of SLE patients (first degree relative 33%, second degree
21%), and in various disorders (chronic active hepatitis: 100%; post-hepatitis cirrhosis: 44%;
myasthenia: 25 to 53% . . . 2
Anti-DNA antibodies — Two techniques are usually performed. The radioimmuno-
logical Farr test (which uses immunoglobulin (IgG) precipitation by ammonium sulfate) is
a sensitive detector of all antibodies capable of binding to DNA, independent of their
biological properties. It is positive in 80 to 98% of SLE cases, in 0 to 6% of patients with
rheumatoid arthritis and in 0 to 2% of normal subjects.2 The second technique used in the
routine clinical detection is an immunofluorescent method detecting antibodies to double-
stranded DNA employing the kinetoplast of the flagellate Crithidia luciliae as a substrate.
It allows determination of the antibodies according to their nature (IgG, IgM, IgA) and their
complement fixing ability (IgGl, IgG3); it may give false-positive results; it is positive in
up to 96% of SLE sera.2 Then the diagnosis of SLE relies on the association of evocative
clinical lesions with immune abnormalities.
Significance of fever in a patient known to have a SLE — Fever is both common
and hard to manage because of its various etiologies: it is a well-known manifestation of
increased disease activity and will quickly respond to corticosteroids but it also can reveal
the presence of an occult infection.12’5’7 Lupus patients are highly susceptible to infection;
all infectious agents, including the opportunistic ones, have been implicated (see Chapter
2). A prospective study of 223 patients concluded that the frequency of infections increased
with increasing steroid dosage and if active renal disease was present.8 A retrospective study
of fever observed in 160 patients concluded that leukocytosis, neutrophilia, shaking chills,
and normal levels of anti-DNA antibodies were associated with infection.7 To these clinical
clues, we may add the complement assay: a frank lowering is a strong argument in favor
of SLE activity and the elevation of the CRP (C Reactive Protein) observed in infections.
Finally, fever may be due to drug allergies which are more frequent in SLE patients than
in controls: for example, contraceptive pills65 or nonsteroidal anti-inflammatory agents66 67
have been reported to be the cause of U.F. in such patients.

SCLERODERMA (SYSTEMIC SCLEROSIS)

Scleroderma is a disease of unknown etiology, affecting predominantly women, and
which produces vascular insufficiency (because of abnormalities of small arterioles and
capillaries) and a hardness of the skin associated with fibrosis and loss of smooth muscle
of internal viscera (particularly esophagus, lungs, and kidney), leading to a progressive loss
of cutaneous and visceral functions.
It is an exceptional cause of U.F. when it atypically begins as an acute febrile disease
and when visceral involvement precedes the typical cutaneous symptoms: then the patient
consults for pain of small joints (inaugural symptom in 12% of cases9) and/or dysphagia
(another early symptom) and/or dyspnea and/or proteinuria . . .
The diagnosis relies first on clinical data. Search of skin abnormalities (mainly on hands
and face): the skin is hard, sometimes infiltrated, rarely edematous, and has lost its elasticity.
Three evocative signs must be looked for: dyspigmentation, telangiectasia, and a beginning
Raynaud’s phenomenon.
Roentgenograms are important for diagnosis:

• The hands may exhibit soft tissue atrophy, subcutaneous calcinosis, resorption of the
tuft of the terminal phalanges without loss of apparent joint spaces between phalanges.
• Upper gastrointestinal films of esophageal manometry may reveal a dilated hypotonic
esophagus.
• Chest-lung can disclose the fibrosis and/or an enlarged heart.
 279

Biology — There is no specific abnormality. Elevation of ESR and polyclonal hyper-

gammaglobulinemia are very frequent. LE cells are rare (about 10%). Rheumatoid factor is
present in about 40% of cases.9A false-positive test for syphilis is rare. Antinuclear antibodies
of the speckled (mainly) or of the nucleolar type are present in 75 to 81% of patients.2
There is no specific histologic abnormality. In these acute febrile sclerodermas with
prominent visceral involvement the course is often acute and the diffusion and aggravation
of lesions in a few weeks or months helps greatly the diagnosis, which is always difficult
at the beginning.

MIXED CONNECTIVE TISSUE DISEASE

It is well known that some connective tissue disease can coexist, succeed to one another
(e.g., SLE succeeding to scleroderma) and even more, overlap.10 In 1972, Sharp et al.
described a new entity with a combination of clinical features of SLE, scleroderma, and
polymyositis and a distinct serum antibody directed against a nuclear ribonucleoprotein.11
It then appeared that this syndrome had a relatively good prognosis. More than 200 cases,
predominanting in women (80% of cases) are known.10 It can sometimes present as U.F.,
the patient complaining of a distal symmetrical polyarthralgia sometimes associated with a
nondestructive arthrosynovitis. The two evocative clinical findings may occur later, namely,
Raynaud’s phenomenon and large sausage-shaped fingers. The diagnosis must then be evoked
and the distinct antibodies be looked for, as well as visceral involvement (lung, esophagus,
liver, kidney, central nervous system . . . ).

DERMATOPOLYMYOSITIS, RHEUMATOID ARTHRITIS

These two diseases will be reviewed in Chapter 11.

JUVENILE RHEUMATOID ARTHRITIS

This condition will be reviewed in Chapter 30.

VASCULITIDES
Vasculitis is a clinicopathologic process characterized by inflammation and necrosis of
blood vessels. These lesions are supposed to be mediated by circulating immune complexes,
although in most cases the offending antigen is unknown.1215 Vasculitides are a major cause
of U.F.
Their classification is not easy because they encompass a broad spectrum of overlapping
disorders, involving vessels of different types, sizes, and location and they can exist either
as the primary manifestation of various clinical syndromes or as a minor component of other
primary diseases. Moreover, an etiologic classification is not possible for two reasons: first,
as previously said, most of them are of unknown origin; second, one antigen, such as
hepatitis B virus, can cause three different vasculitides (true polyarteritis nodosa; essential
mixed cryoglobulinemia; and a serum sickness-like disease at the prodromal stage of viral
hepatitis).1215

Anatomic Nosology1315
Vasculitis means inflammation of the vascular wall, infiltrated by leukocytes which may
overflow in the perivascular space. These leukocytes can predominantly be neutrophils (in
most cases) or eosinophils, lymphocytes, plasma cells, macrophages, or giant cells. These
infiltrating cells can be intact or lysed as in leukocytoclastic angiitis, where the term of
nuclear dust is used.
The qualifying word necrotizing is added when fibrinoid necrosis of the vascular wall
and/or the surrounding tissue is a regular feature. The qualifying word granulomatous is
added when the inflammatory exudate assumes a nodular pattern and is rich in cells distinct
280 U nex p la in ed F e ve r

TABLE 5
Vasculitis Which May Present as UF1215

Involved vessel Disease

(size and main pathologic lesion)

Large- and medium-sized vessels: giant cell arteritis Takayasu’s arteritis; temporal arteritis; thromboangiitis
obliterans
Medium-sized muscular arteries (often associated with Polyarteritis nodosa (classical and secondary forms);
small-sized ones) Kawasaki’s syndrome
Predominant involvement of small vessels — granu- Wegener’s granulomatosis; lethal midline granuloma;
lomatous angiitis allergic granulomatosis; lymphomatoid granulomato-
sis; granulomatous angiitis
Hypersensitivity vasculitis Various subgroups (serum sickness essential mixed cry-
oglobulinemia . . . )
Miscellaneous vasculitides Erythema nodosum: Cogan’s syndrome; Behcet’s dis-
ease . . .

from polymorphonuclear leukocytes. We will list our own classification of vasculitis in Table
5 as it will resume our general plan.
Before an analytical review of the diseases listed in Table 5, as far as they can present
as U.F., we wish, according to Peltier15 to present broadly the common clinical picture of
the various vasculitis, as all these disorders associate more or less three main clinical features:
the first ones are systemic features (fever, weight loss, proteinuria . . . ) the second are
cutaneous symptoms (palpable purpura, subcutaneous nodules, urticaria, livedo, localized
necrosis . . . ) and finally, vascular symptoms (palpation of an indurated or nodular artery,
venous thrombosis, absence of pulse(s), ischemic cutaneous lesions . . . ).

TAKAYASU’S ARTERITIS (AORTIC ARCH SYNDROME)

Under that name, perhaps improper but everywhere employed, (synonymously called
“ pulseless* disease” ) are grouped one or various chronic inflammatory arteriopathies of
unknown etiology affecting large vessels, leading to occlusion of the vessels arising from
the arch of the aorta.1416,85
This rare, universal (but more common in the Orient) disease predominates in young
women, usually in the third decade of life, but can also begin in some cases at a later age.16
Its course can be divided into two stages, a preocclusive one (which seems to be frequent
in Europe,16 17 rare in the rest of the world) and the chronic, occlusive stage of vascular
insufficiency.
Fever is present only in the first stage. The disease is usually of abrupt onset with
myalgias, arthralgias, and mimics influenza, rheumatic fever, or presents as fever of unknown
origin.1617 A weight loss was present in 38% of 32 patients seen at the Mayo Clinic; it was
the second most frequent symptom (44%) after arthralgias present in 56% of cases.85 When
early aortic symptoms occur, a bacterial endocarditis is discussed.18 Sometimes lung and
cutaneous symptoms (rashes, erythema nodosum . . . ) may occur.16
Biologic nonspecific inflammatory symptoms are present: inflammatory anemia, leu-
kocytosis, ESR elevation, and even, though exceptionally, monoclonal gammapathy.18 If
the diagnosis is suspected, digital intravenous arteriography must be performed.
This stage usually lasts a few weeks and is followed by the chronic, occlusive phase of
the disease, marked by various symptoms of vascular insufficiency, with normal tempera-
ture.16 Almost all patients have multiple sites of arterial involvement.85 Sometimes the
occlusive stage occurs in a patient with a long-standing erosive arthropathy and is manifested
initially by a febrile recrudescence of joint pains.19
The diagnosis relies on aortography (enlargement of the aorta, and/or irregular limits of
aorta, stenosis, and dilatation and/or linear calcifications) and moreover, on the biopsy of
 281

an involved vessel, which typically shows the lesions of panarteritis14 16 or only of the media
and the adventitia:85 the infiltrate is mainly made up of mononuclear cells, there is an intimal
proliferation and fibrosis, associated with scarring and vascularization of the media, dis-
ruption and degeneration of the elastic lamina; giant cells are typical but less commonly
seen than in temporal arteritis;1416 the lesions may be indistinguishable from those of temporal
arteritis.85
The response to corticosteroid treatment is usually very good, with dramatic improvement
of both vascular symptoms and avascular ones.85

TEMPORAL ARTERITIS
It is one major cause of U.F. in patients over 60 years of age.20'23 In one series of U.F.
occurring in 111 patients over 65, temporal arteritis was demonstrated in 18 of them.28
Instead of the classical (and most frequent) symptoms due to the diseased temporal
artery (headache, mandibular claudication, visual disorders, tender cranial arteries) many
patients (in one series 12 of 7421) may present with a prolonged fever of all types, sometimes
with asthenia, weight loss, depression, and malaise.20 21
The disease predominates slightly in women, usually affects patients over 60 (but may
occur in young adults), with increasing frequency as the patients get older.
We will briefly discuss some atypical modes of presentation of the disease, distinct from
typical temporal symptoms:

• The disease may suggest an occult malignancy (in 7 of 74 patients21) because of

anorexia, weight loss, anemia, fever, abnormal liver function tests.
• The disease may present as an inflammatory (normocytic, normochromic) isolated
anemia (3 of 74 patients21). A bone marrow biopsy can disclose a vasculitis.20
• Or as a neurologic syndrome (diplopia . . . ) (4 of 74 patients21)
• Or as a limb claudication (mainly of one arm).
• Or as a hepatic disease: an elevated alkaline phosphatase level was present in 44%
and an elevation of SGOT-SGPT in 25% of 47 patients.22 The histology discloses fatty
metamorphosis or rarely an epithelioid granuloma.20
• Exceptionally, temporal arteritis presents as a febrile intractable dry cough with weight
loss, which evokes a lung cancer.68
• Temporal arteritis has close relationships with polymyalgia rheumatica,23 which is one
of its classical modes of presentation: the patient complains of proximal musculoskeletal
discomfort lasting several weeks, leading to pain and stiffness in the region of the
axial skeleton, more often the shoulder than the pelvic girdle.23 But it rarely happens
that polymyalgia rheumatica is the presenting feature not of temporal arteritis, but of
a malignancy, rheumatoid arthritis, or infective endocarditis.24

Whatever heralding symptoms are present in a febrile patient over 60, one must always
think about temporal arteritis.

• Medical history must seek evocative signs (pain . . . )

• Careful examination of both arteries must be done, seeking tenderness, a decreased
pulse, or local inflammatory symptoms, which are often lacking in genuine cases.
• Laboratory tests: a frank elevation of ESR is the main abnormality, but it can be absent
as it was in 4 of 47 patients (8.5%).22
• As the diagnosis is then anatomic, a temporal artery biopsy must be undertaken, but
the nature of the process is to be kept in mind: the lesions are limited to isolated foci
(the so-called “ skip lesion” 26) and not present all the artery long. For example, skin
lesions were present in 17 of 60 patients and some foci of arteritis were as short as
330 m in length in an otherwise normal biopsy.26 Then long segments of artery must
282 Unexplained Fever

TABLE 6
Various Forms of Polyarteritis Nodosa (P.N.)1215’30’90

• Classical polyarteritis nodosa (Kussmaul Maier)

• Limited and/or occasional and/or associated polyarteritis nodosa
• Localized forms: pure cutaneous, digestive tract . . .
• P.N. with hepatitis B antigenemia: possible liver disease with a spectrum from subclinicalto chronic active
hepatitis
• P.N. with features of allergic granulomatosis (occurrence in allergic diathesis, high eosinophilia, lung
involvement . . . ): the so-called “ overlap syndrome’’ of Fauci14
• P.N. accompanying various systemic disorders: SLE, rheumatoid arthritis, dermatomyositis, temporal ar-
teritis, polychondritis
• P.N. associated with some infective processes: bacterial, streptococci, or fungal; P.N. of bacterial endo-
carditis
• P.N. due to irritating intravascular embolic material: cotton, gauze, smashed pills . . .
• P.N. complicating various arterial diseases — Malignant hypertension, pulmonary hypertensive vascular
disease, P.N. occurring in the aorta after the cure of a coarctation.

be biopsied and multiple histologic sections must be examined. Where is the biopsy
to be performed if there are no local signs? Some authors seek help in carotid
arteriography22 or in less traumatic Doppler Flow Studies.25 Unfortunately, negative
results of these examinations do not exclude diagnosis. Then if the first biopsy is
negative, it is safe to perform a second one (usually contralateral).

The typical histopathology is a panarteritis with inflammatory mononuclear cell infil-

trates; giant cells are frequent (more than in Takayasu’s arteritis) within the cell wall, with
disruption or fragmentation of the internal lamina, and proliferation of the intima.14,22 26
Exceptionally, another type of vasculitis can be disclosed.27
Because of the frequency of the disease, which responds to treatment, it is safe to
consider early the performance of a temporal artery biopsy in febrile patients over 60, even
in the absence of clinical local arteritis, if the initial blood and radiographic tests were
unrewarding.20

THROMBOANGIITIS OBLITERANS (BUERGER’S DISEASE)

Thromboangiitis obliterans is a rare disease of young (under 40) and heavy smoker men.
It can also affect women.29 It is an exceptional cause of U.F. Its classical presentation is
variable, insidious, or abrupt, with a venous superficial thrombosis, limited, which tends
to recur, and can mimic erythema nodosum. Some fever usually accompanies the thrombosis
(see Chapter 25).
Then future attacks will add the arterial thrombosis manifested by coldness, dysesthesias,
color changes or excruciating pain, ulceration, gangrene, or atrophy of the distal extremi-
ties.14,29 The attacks usually last a few weeks and then the disease runs an indolent and
recurrent course.14
Its diagnosis is anatomic: it involves arteries and veins in a segmental fashion; in the
acute phase the vessel wall and thrombus are infiltrated by polymorphonuclear leukocytes;
in the subacute phase mononuclear cells and giant cells may be seen.14

POLYARTERITIS NODOSA
Classical polyarteritis nodosa is a necrotizing vasculitis of small- and medium-sized
muscular arteries with segmental lesions, sometimes leading to aneurysmal dilatation up to
1 cm in size in medium-sized intraabdominal arteries, sparing the lungs.14,30 Recently, some
new aspects of polyarteritis nodosa have been outlined. We will only list them in Table 6
as all can be febrile and have to be known.
We shall review the most frequent classical form. It affects equally both sexes, in all
 283

age groups, with a predominance between 40 and 60. The disease begins in about two thirds
of cases by malaise, weight loss, and fever.30 Various constitutional signs and symptoms
occur more or less quickly: arthralgias (arthritis is rare); myalgias, mononeuritis multiplex;
cutaneous symptoms of vasculitis (see supra), abdominal pain, renal involvement (related
to vasculitis in about 70% of cases, to glomerulonephritis in 30%), hypertension, lesions of
various viscera: heart, liver, digestive tract, lungs (may be affected in genuine P.N.),
testes . . . 14’30’31
Much more puzzling are cases inaugurated by an isolated fever, of all types. In a recent
comprehensive review of the literature as well as 95 personal cases, Godeau et al. believed
that it occurred in about 10% of cases.30 The diagnosis is very difficult to affirm and can
be supported by:

• The careful palpation of arterial axis, in search of nodosities.

• The presence of hypereosinophilia but it is not specific and inconstant, present in 18
to 45% of various series.30
• The presence of HBS antigen in the serum, variable and nonspecific.
• The presence of various immune abnormalities: rheumatoid factor, circulating immune
complexes . . . (inconsistent and not specific, see supra).
• The presence of aneurysms of celiac axis and/or renal arteriograms; but they are usually
lacking at the beginning of the disease.14’30’31,32
• Usually the diagnosis relies on typical histopathology of a muscular biopsy. But it is
often negative at the beginning and moreover, the site of the biopsy is not evident to
choose.

Some authors then do not perform arteriograms and biopsies and wait until the appearance
of the first evocative signs, usually myalgias and arthralgias.30 Electromyographic exami-
nations will then help to localize the diagnostic biopsy (in a site different from that of the
electrodes). Often the muscle exhibits inflammatory lesions in and around the vessels, but
atypical ones. We do not wish to discuss here the difficulties of the anatomic diagnosis of
the disease which sometimes needs another biopsy; the reader is referred to References 14
and 30.
For the above reasons, P.N. (in contrast with SLE) is still a great cause of U.F. and a
diagnostic challenge to the physician.

KAWASAKI SYNDROME (MUCOCUTANEOUS LYMPH NODE SYNDROME)

This acute febrile exanthematous childhood illness occurring mainly in the first 2 years
of life, of unknown etiology, described in Japan (where it is very frequent) is present
worldwide. It is benign in about 98% of cases, but in the other 2% imprevisible death due
to coronary artery vasculitis happens. Histologically the lesions are not very different from
those of polyarteritis nodosa.14 30’33
Its clinical course is triphasic: an acute febrile phase with high fever persisting for more
than 5 days, (average duration 11 days, range 5 to 23 days) followed by a subacute and by
a convalescent phase.33
As there is no pathognomonic abnormality, the diagnosis is based upon the adherence
to clinical criteria together with exclusion of other similar diseases. These criteria are listed
in Table 7.
Some associated features illustrate the extension of the disease: central nervous system
symptoms are nearly constant (irritability, mood instability . . . ); pyuria and urethritis occur
in 70% of cases, arthritis in 40%, diarrhea in 25%, and clinical cardiac disease in 20%.33
Differential diagnosis during the acute phase includes: toxic shock syndrome, scarlet
fever, atypical measles, septicemias.
284 Unexplained Fever

TABLE 7
Diagnostic Criteria of Kawasaki Syndrome33

• Fever persisting more than 5 days

• Conjunctival injection
• Mouth abnormalities: erythema, Assuring and crusting of the lips, diffuse oropharyngeal erythema, straw-
berry tongue
• Peripheral extremities abnormalities: induration of hands and feet, erythema of palms and soles, desqua-
mation of fingers and toetips, about 2 weeks after onset, transverse grooves across fingernails 2 to 3
months after onset
• Erythematous rash
• Enlarged lymph node greater than 1.5 cm in diameter

WEGENER’S GRANULOMATOSIS
Wegener’s granulomatosis is a disease characterized clinicopathologically by necrotizing
granulomatous vasculitis of the upper and lower respiratory tracts, glomerulonephritis and
varying degrees of small vessel vasculitis.14 34
It affects middle aged patients and is slightly more frequent in males.
It may present as U.F., but usually the apyretic patient complains of manifestations of
the upper respiratory tract: severe rhinorrhea, nasal mucosal ulceration or sinus pain or
drainage. At the beginning, pulmonary symptoms and signs are unusual as are renal or
peripheral manifestations, such as arthralgias, skin ulcerations, malaise, weight loss, eye,
or middle ear problems.34
More or less rapidly fever appears in about 80% of patients, in part due to infections
of the affected respiratory tract. Later on multiple nodular cavitary infiltrates of lungs will
be present in 95% of cases, pansinusitis in 90%, glomerulonephritis in 85%, mucosal
pharyngeal ulcerations, saddle nose deformity in 75%, keratoconjunctivitis in 60%, arthral-
gias in 50%, and serous otitis media in 35%.14,34
Limited forms of the disease, without kidney lesions, have been described.14’35-36
The diagnosis relies on a biopsy of one of the affected viscera.

LETHAL MIDLINE GRANULOMA

This is a chronic destructive disease of unknown etiology affecting the midline structures
of the face. Its diagnosis relies on clinical and anatomic lesions.
It is an often less frequent disease than Wegener’s granulomatosis, characterized by
granulomatous lesions of the upper respiratory tract, which can present as U.F., as we have
seen in one patient.36 This disease could be a limited form of Wegener’s granulomatosis.35 36
We have listed in Table 8 its main features as well as those of Wegener granulomatosis.

ALLERGIC GRANULOMATOSIS AND ANGIITIS (CHURG AND STRAUSS

SYNDROME)
This disease strongly resembles classical polyarteritis nodosa (P.N.)14 and then can
present as U.F. But in contrast with P.N., it occurs in patients with allergic diathesis (usually
severe asthma of long duration). Pulmonary symptoms are constant and predominant and
there is always a high level hypereosinophilia.14 37 The vasculitis can affect peripheral nerves,
skin, kidney . . . ,37
Its diagnosis is histologic: there is necrotizing vasculitis of small arteries and veins with
extravascular granulomas and infiltration of vessels and perivascular tissues with eosino-
philia.37
GRANULOMATOUS ANGIITIS
It is a very rare and and frequently fatal necrotizing vasculitis limited to the central
nervous system.38,39’90 It affects both sexes, with a wide age range, the majority of cases
occurring between the fifth and the eighth decade.39
 285

TABLE 8
Main Features of Lethal Midline Granuloma (LMG) and of Wegener’s
Granulomatosis (WG)36

LMG WG

Beginning Often unilateral nasal obstruction Often bilateral infection of nose

and/or rhinorrhea (purulent bloody) and/or sinuses
Constitutional symptoms Occur late Occur rapidly
Fever During acute phases of extension Long standing
Destruction of upper respiratory Destruction of nasal septum, para- Destruction of the palate, the exten-
tract nasal sinuses, hard or soft palate, sion is more posterior
orbital cavities
Cutaneous destruction +++ Absent
Diffusion to
Lungs Absent +++
Kidneys Absent + + + (except in limited forms)
Various: skin
digestive tract, + ++
genitourinary . . .
Histology
Granuloma +++ ++
Vasculitis + /- +++
Giant cells —(possible ++
Spindle histiocytes ++ Absent
Natural duration of the disease A few years Less than 1 year
Cause of death Hemorrhage, infection, cachexia Renal insufficiency, respiratory in-
sufficiency, infection, cachexia

It presents as an unexplained, often febrile, acute, progressive encephalopathy in the

absence of extracranial systemic vasculitis. Angiography discloses intracranial arteritis.
The biopsy (of lepmeninges always involved, or of the brain) discloses the segmental
necrotizing granulomatous vasculitis.38,39’90

LYMPHOMATOID GRANULOMATOSIS
It is a severe, poorly understood, very rare disease characterized by inflammatory angiitis
with histological similarities with Wegener’s granulomatosis as well as with a lymphopro-
liférative disease (hence its name).40,41 Patients may present with U.F. or with atypical
lymphoma.
The associated features cannot be summarized, depending on the site of the affected
viscera.40,41
The diagnosis is anatomic: the disease is characterized by infiltration of various organs
with a polymorphic cellular infiltrate consisting of atypical lymphocytoid and plasmacytoid
cells together with granulomatous inflammation in an angiocentric and angiodestructive
pattern.41

HYPERSENSITIVITY VASCULITIS
It is a large and heterogeneous group of clinical syndromes that have in common the
predominant small vessel involvement, usually of the skin, with a recognizable precipitating
event or exposure. It was also called leukocytoclastic vasculitis, characterized by its typical
involvement of postcapillary venules.14
The skin is the main organ involved, typically with the palpable purpura. Various lesions
of various sizes can also be seen (papules, nodules, vesicles, bullae, ulcers, relapsing chronic
urticaria . . . ).144243
Serum sickness is the model of all these vasculitis, which are believed to be mediated
by circulating immune complexes.12,14 It is characterized by the association of fever, urticaria,
286 U n ex p la in ed F e ve r

TABLE 9
Underlying Diseases Presenting as Erythema Nodosum46-49

The three major ones:

• Tuberculosis (essentially primo-infection)
• Streptococcal infection (pharyngitis, otitis, sinusitis, tooth lesion . . .
• Sarcoidosis (often presenting as Lòfgren syndrome — erythema nodosum, hilar lymphadenopathy, tuberculin
anergy — which is evocative but not specific of sarcoidosis)
Others:
• Bacterial diseases: syphilis, leprosy reaction (peculiar topography: limbs, face . . . ), yersiniosis, gonorrhea,
leptospirosis, Campylobacter colitis, cat-scratch disease . . .
• Viral and chlamydial diseases: ornithosis, lymphogranuloma venereum, measles . . .
• Fungal diseases: trichophytosis, histoplasmosis, blastomycosis, coccidioidomycosis
• Parasitic diseases: Toxoplasmosis, malaria, trypanosomiasis, various helminth infections
• Digestive diseases: Ulcerative colitis, Crohn’s disease
• Articular diseases: beside the above listed ones — sarcoidosis, syphilis, Crohn’s disease, ulcerative coli-
tis . . . we must add Behcet’s disease and spondyloarthropathy associated with Hidradenitis suppurativa
and Acne conglobata.
• Drugs: Sulfonamides, iodides, bromides, salicylic acid, phenacetin, oral contraceptives, arsphenamine . . .

arthralgias, lymphadenopathy 7 to 10 days after primary exposure or 2 to 4 days after

secondary exposure to serum. If the exposition to heterologous serum cannot be dismissed,
it can be a cause of U.F. when it is a manifestation of drug allergy (penicillin, sulfonam-
ide . . . ) hence the importance of a good medical history.
Henoch-Schònlein purpura cannot be a cause of U.F. as fever is either absent or transient
and its clinical picture easy to diagnose.14’42
Essential mixed cryoglobulinemia is characterized by asthenia, fever, purpura, anemia,
hypergammaglobulinemia, glomerulonephritis and usually mixed IgM-IgG cryoglobulin-
emia.1442 Hepatitis B virus is frequently found in the serum and cryoprecipitates of the
patients.44
Chronic urticaria with necrotizing vasculitis and very frequently hypocomplementemia
(the so-called McDuffie syndrome) is characterized by attacks of associating fever, weight
loss, urticaria, nearly constant arthralgias and sometimes abdominal pain. Inconstant and
variable are the decrease of Clq, C4, C3, and C5. The diagnosis relies on the exclusion of
connective tissue diseases and on histology.43 45
Finally, various febrile hypersensitivity vasculitis can be associated with connective
tissue diseases, malignancies, and dysglobulinemia.1442 They are confirmed by biopsy spec-
imens, are a secondary component of the associated disease, probably not the cause of the
fever, and will not be described here.

ERYTHEMA NODOSUM
It is a vasculitis affecting predominantly small venules and it is easy to diagnose. We
will not describe its painful and highly colored lesions occurring usually over the shins,
with fever, malaise, and arthralgias.
Usually its clinical aspect is evident and one has not to discuss othersubcutaneous nodules:
erythema induratum (lesions of the calves more indolent and often ulcerated), Weber Chris-
tian disease (see below), migratory thrombophlebitis (sometimes diagnosed by biopsy),
sarcoidosis, metastatic neoplasm, pancreatic fat necrosis or polyarteritis nodosa.
In fact, its interest lies in the fact that it may reveal various underlying disorders,
sometimes hard to diagnose, sometimes associated.46 These are listed in Table 9.

COGAN’S SYNDROME
This syndrome is defined by the association of vestibulo-auditory symptoms to a non-
syphilitic interstitial keratitis. It affects young adults of both sexes. Its etiology is unknown.
 287

It is very rare, less than 100 cases are known.50 51 In about 15 to 20% of cases50 it begins
with fever and upper respiratory symptoms, or tooth infection. During the course of this
vasculitis which may affect the nervous system, the heart, the digestive tract, the skeleton,
the lymph nodes, and the lung, fever is present in about 25% of cases.50-51

BEHCET’S DISEASE
Behcet’s disease can be defined as the association with aphtae (ulcers) of the mouth and
the genitalia, of multisystemic disease: ocular symptoms (relapsing iritis), vascular throm-
bosis (thrombophlebitis) cutaneous, articular, nervous system lesions . . .
Its etiology is unknown; it affects young adults and is predominant in males; although
it is present worldwide, it predominates around the Mediterranean Sea and in Japan.52-53 It
is accepted that two distinct forms of the disease exist: the classical form, predominant in
males and associated with HLAB 5 gene and the Anglo Saxon form predominant in females
and not linked with one HLA gene.53
In our experience Behcet’s disease presented as U.F. in three patients, because the
cutaneous accompanying symptoms were not attributed to this entity. A similar case had
been published.86
The earliest manifestations of the disease were aphtous stomatitis in 30 of 41 patients;
ocular lesions were the presenting symptoms in 5, and joint, cutaneous, or genital lesions
initiated the disease in the others.52
A low-grade fever accompanies most bouts of Behcet’s disease; fever is more prominent
in case of thrombophlebitis and in case of severe systemic involvement.87
Besides the HLA predominance in non-Anglo-Saxon patients (the majority), the diag-
nosis is clinical; it is based on the association of:

1. Painful recurrent oral genital ulcers (aphtae)

2. Cutaneous lesions which associate52-53
3. Vesicles and papules, pustules; pseudofolliculitis; acne; furuncles; erythema nodosum

One peculiar feature is the nonspecific skin reactivity manifested by bullous lesions at
the site of any scratch or intracutaneous injection as well as venipunctures. One of our three
patients was said to have tuberculosis as a nonspecific bulla occurred in the site of a tuberculin
test.
Ocular lesions52-53: Relapsing iridocyclitis; conjunctivitis; corneal ulcerations; choroiditis;
vitreous involvement; optic papillitis; and retinal vessel involvement.
Thrombophlebitis, deep or superficial, of any localization, sometimes following veni-
puncture is also a cardinal manifestation of the disease.52-53
Finally, various manifestations can be present due to vasculitis of the central nervous
system, the heart, the large arteries (aneurysms), the digestive tract (ulcerative colitis . . . ),
the lung . . .
To conclude, Behcet’s syndrome may, not infrequently, present as U.F. Its diagnosis
is based on the oral and genital aphtae, on spontaneous mucosal and cutaneous symptoms,
on skin reactivity, on the ocular lesions, on thrombophlebitis, and on the presence of the
gene HLAB 5 in non-Anglo-Saxon patients.

SPANISH TOXIC EPIDEMIC SYNDROME 1981

In Spain in 1981 more than 800 patients developed a disease probably caused by ingestion
of an illegally marketed cooking oil (denaturated rapeseed oil), leading to a peculiar non-
necrotizing vasculitis affecting primarily the intima. The presenting symptoms were acute
pleuropneumopathy, fever, itching exanthema, myalgias, and eosinophilia. Later appeared
scleroderma-like lesions, pulmonary hypertension, neuromyopathy, respiratory failure, Sicca
288 Unexplained Fever

TABLE 10
Main Bacteria, Fungi and Viruses Associated with
Granulomatous Reactions

• Mycobacteria
• Brucella, Salmonella, Listeria, Francisella, Yersinia . . .
• Nocardia, Actinomycètes
• Chlamydia
• Coxiella burnetii
• Candida, Histoplasma, Aspergillus,Coccidioides, Blastomyces . . .
• Cytomegalovirus, Epstein-Barr virus, Hepatitis B virus . . .

syndrome, alopecia, hypertrichosis, and weight loss.54 We are aware of some French cases.
Such vasculitis, if its occurrence is not epidemic, could present as U.F.

GRANULOMATOUS DISEASES
A common anatomic lesion links various diseases which are a great cause of U.F.
particularly when the fever lasts for many months (see Chapter 1).
Granulomas are defined by the coalescence of various cells: polymorphonuclear neu-
trophils and/or eosinophils and/or macrophages and/or plasmocytes and/or lymphocytes;
sometimes the monocytes and macrophages cells aggregate into epithelioid cells (large
mononuclear cells with a diameter of about 20 m) and into giant cells (up to 300 m in
diameter, multinucleated). Central necrosis may occur. They can be present in all organs.55
Granulomas are thought to be due to the interaction of indigestible antigen(s) with
macrophages, T lymphocytes and antibodies.55

GRANULOMA-FORMING DISORDERS898
Infectious agents are the commonest etiology. The causative agents may be intracellular
(obligate or facultative) bacteria, fungi, and viruses, listed in Table 10.
Granulomas may be the result of the host reaction to various stages of the development
of many parasites (eggs, larvae as well as adult forms) as well as facilitation or rejection
host phenomena.56 These parasites are listed in Table 11. A tissue eosinophilia is suggestive
but inconstant and nonspecific.
Granulomas may be a reaction to chemicals: chronic beryllium disease mimics sarcoid-
osis; zirconium, talc, and silicon may rarely be the causative agents.
Granulomas may be found in various immunological disorders:

• AIDS, Crohn’s regional enteritis, primary biliary cirrhosis

• Hypogammaglobulinemia
• Systemic lupus erythematosus and various vasculitis
• Various unclassified disorders: Histiocytosis X, Peyronie’s disease, granulomatous
cheilitis (Rosenthal-Melkerrson syndrome)

A leukocyte oxidase defect is the basis of chronic granulomatous disease of children.

Granulomas may be associated with neoplasia, reticulosis, and reticulum cell sarcoma, lymph
node draining carcinoma, pinealoma, dysgerminoma, seminoma, and malignant nasal car-
cinomas.
Granulomas are present in extrinsic allergic alveolitis or hypersensitivity pneumonitis:
a thorough occupational history is a key to the diagnosis. The disorders are farmer’s lung,
bagassosis, mushroom picker’s lung, maltworker’s lung, bird fancier’s lung, pituitary snuff-
taker’s lung, wheat weevil disease, maple stripper’s lung, sequoisis, suberosis, woodworker’s
lung, cheese washer’s lung, paprika splitter’s lung, humidifier or air conditioner lung.
 289

TABLE 11
Parasites Associated with Granulomatous Reactions56

Protozoa

Entamoeba histolytica
Trypanosoma gambiense, T. rhodensiense
Leishmania donovani, L. braziliensis, L. tropica
Toxoplasma gondii

Helminths

Ascaris lumbricoides
Visceral larva migrans (Toxocara canis, T. cati)
Strongyloides stercoralis
Hookworms: Necator americanus, Ancylostoma duodenale
Filaria
Shistosoma mansoni, S. haematobium, S. japonicum
Fasciola hepatica
Clonorchis sinensis
Capillaria hepatica
Tapeworms: Taenia solium, T. saginata, Diphyllobotrium latum

Others

Pentastomes
Agents of myasis (development of maggots of flies)

Miscellaneous disorders: These which may present as U.F. are Whipple’s disease,
panniculitis, some allergic reactions to drugs, granulomatous hepatitis.
Sarcoidosis, which has many clinical and histological features with previous listed
diseases, will be described as will granulomatous hepatitis because of their high incidence.
Crohn’s disease is described in Chapter 8.

SARCOIDOSIS
An international subcommittee defined sarcoidosis in 1976 as:

A multisystem granulomatous disorder of unknown etiology most commonly affecting young adults and pre-
senting most frequently with bilateral hilar lymphadenopathy, pulmonary infiltration and skin or eye lesions. The
diagnosis is established most securely when clinico-radiographic findings are supported by histologic evidence of
widespread non-caseating epithelioid cell granulomas in more than one organ or a positive Kveim-Siltzbach skin
test.

U.F. is a rare mode of presentation as in three personal patients.57 Fever had been
estimated to be present in 2 to 28% of patients.61 When present it is associated with gran-
ulomatous hepatitis, polyarthritis, erythema nodosum, uveoparotitis, and acute meningitis.
The various modes of presentation of sarcoidosis are listed in Table 12.
When it is suspected, the various clinical localizations must be searched, as well as the
cutaneous anergy, present in about 80% of patients. According to the definition the diagnosis
relies on biopsies. To avoid biopsies various diagnostic tests were recently introduced. The
serum level of angiotensin-converting enzyme was found to be elevated in 19 of 22 (86%)
patients but false-positive results may be found, if the patient has another granulomatous
disease.58
Gallium-67 scintigraphy has a greater diagnostic value than the enzyme level.89bc This
isotope accumulates in rapidly dividing cells such as those of sarcoid granulomas.60 Its
diagnostic value is excellent when the isotope concentrates, grossly symmetrically, only
within three targets: the orbits, the parotids, and the hilar areas; a new quantitative scoring
290 U n ex p la in ed F e ve r

TABLE 12
Modes of Presentation of Sarcoidosis57

• Respiratory symptoms and hilar lymphadenopathy

• Cutaneous symptoms: erythema nodosum, lupus pernio, plaques, scars . . .
• Ocular symptoms: iridocyclitis, keratoconjunctivitis sicca, choroidoretinitis, Sjogren’s syndrome . . .
• Neuromeningeal symptoms: cranial nerve palsy, neuropathy, myopathy, meningitis, space-occupying le-
sions, often associated with diabetes insipidus.
• Digestive symptoms: granulomatous hepatitis, splenomegaly, features similar to Crohn’s disease
• Myocarditis and/or heart block.
• Rheumatic symptoms: polyarthritis, dactylitis, bone cysts (distal)
• Renal and urological symptoms: hypercalciuria, renal calculi, nephrocalcinosis
• Peripheral lymphadenopathy
• Parotid enlargement
• Fever of unknown origin

method improves its usefulness;890 finally it may be a guide to biopsy.89bc But its usefulness
had been denied by some authors.59
A bronchoalveolar lavage is helpful because of the abundance of T lymphocytes (more
than 10% of cells) in the fluid; although its diagnostic value is claimed, that abundance of
T lymphocytes is not specific of sarcoidosis, and may be seen in extrinsic allergic alveolitis
and lymphoid interstitial pneumonia.60
To conclude, we believe that in patients with U.F. the value of these three new tests is
not properly appreciated. We wonder if their positivity would avoid the repetition of the
biopsies of various tissues: accessory salivary glands, hepatic, skin lesions, bronchial mu-
cosa . . . and/or the performance of the Kveim test which unfortunately is read at the sixth
week, a long delay in febrile patients and whose results depends moreover on the quality
of the antigen: with an excellent one it was positive only in 78.6% of 583 patients with
sarcoidosis but in only 0.07% of 164 patients without that disease.89d

GRANULOMATOUS HEPATITIS
As previously said, granulomas represent a nonspecific reaction to various antigens. As
the liver is rich in phagocytic cells, receives all the blood of the digestive tract and is a
major detoxification organ, it is particularly suited for clearing the body of antigenic sub-
stances, and is then a major localization site for granuloma formation.62'64 Granulomatous
hepatitis is a great cause of U.F. and particularly of U.F. of many months duration (see
Chapter 1).
Granulomatous hepatitis is usually clinically latent but a slight icterus may be present.
The liver is not enlarged in the majority of cases.
Liver tests may be normal, but usually exhibit incomplete cholestasis (elevation of
alkaline phosphatase and of gamma glutamyltransferase) or complete cholestasis with the
addition of hyperbilirubinemia and hypercholesterolemia to the above abnormalities.
The diagnosis relies on hepatic biopsy, which has large indications in the management
of patients with U.F.
The first etiology of granulomatous hepatitis discovered in patients with U.F. is tuber-
culosis, which accounts for about 40 to 50% of cases.62 64 Its prevalence is higher (70%) in
febrile granulomatous hepatitis. A specific culture of a fragment of the liver tissue must
always be performed.
Other infectious etiologies are listed in Tables 13 and 14. Noninfectious causes of
granulomatous hepatitis are62'64 sarcoidosis; acquired immunodeficiency syndrome; Crohn’s
disease; lymphogranulomatous disease of childhood; the granulomatous connective tissue
diseases (see supra); some primary liver diseases easy to diagnose on the basis of the
accompanying abnormalities such as primary biliary cirrhosis; some drugs allergies (listed
in Table 13) and idiopathic granulomatous hepatitis, cured by corticosteroids.62
 291

TABLE 13
Hepatic Granulomas Due to Drug Allergy64

• Sulfonamides, penicillin, paraaminosalicylic acid

• Allopurinol, phenylbutazone, oxyphenbutazone
• Halothane, phenytoin, diazepam
• Hydralazine, procainamide, quinidine, hydrochlorothiazine, methyldopa
• Clofibrate, progesterone, estrogen contraceptive
• Cromolynsodium
• Sulfonylurea derivatives

TABLE 14
Atypical Presentations of Rheumatic Fever

• Fever of unknown origin

• Atypical arthritis: monoarticular; spine joint localization; sacro-iliac joint localization; muscular and ten-
dinous pain predominance
• Atypical visceral forms: affecting lung; pleura; digestive tract (diarrhea; abdominal pain simulating appen-
dicitis . . . ); kidney (glomerulonephritis); eye; central nervous system (meningitis, psychosis . . . )

Although the existence of the latter disease is admitted by medical authorities, we wonder
if it is a genuine entity or a melting pot of unrecognized entities and/or of overlapping
syndromes. In fact some patients with multiorgan granulomas (located in liver, lung . . . )
do not conform to any single disease: their clinical, serologic and histologic features overlap
with sarcoidosis, primary biliary cirrhosis, Sjogren’s syndrome, celiac disease, and mixed
connective tissue disease; they seem to belong to a continuum that links these conditions.83
To conclude, the existence of granulomatous hepatitis justifies a large use of hepatic
biopsy in febrile patients. It must be performed at an early stage, and a fragment of par-
enchyma has to be cultured on various media including Loewenstein medium.
In case of a strong suspicion the importance of tuberculosis may justify a specific trial
of 4 to 12 weeks duration. If fever persists some authors try steroids in the absence of any
diagnosis.62 64
We cannot give general guidelines applicable to all patients. In our own ones, because
of the importance of tuberculosis, we agree with the specific trial but we are generally
reluctant with the nonspecific steroid course, which could mask many disorders and/or may
promote the acute transformation of a latent infection.

MISCELLANEOUS DISORDERS
In that last part we will discuss four unrelated diseases which belong to the vast and
rather kaleidoscopic chapter of hypersensitivity and autoimmune diseases.

RHEUMATIC FEVER
Rheumatic fever is a delayed sequel of an upper airway infection caused by a group A
hemolytic streptococcus, characterized by a febrile inflammation of the joints and the heart,
and rarely, of the subcutaneous tissue. It has a natural tendency to recur.
Its clinical manifestations are very variable, each sign and symptom may be either severe
or mild and has a variable severity, and no typical clinical presentation can be described.
As there is no pathognomonic feature, a list of signs and symptoms was proposed, the Jones
criteria, revised in 1965,73 have not been universally accepted. Rheumatic fever affects
children over 2 years of age, with a predominance between 6 and 8 years, and may affect
adults up to 59 years old, either recurrently or as an apparent first attack; in adults polyarthritis
is the nearly unique major manifestation.71
We will not describe the various aspects of this proteinmorph disease (the reader is referred
292 Unexplained Fever

TABLE 15
Differential Diagnosis of Rheumatic Fever

• Rheumatoid arthritis, systemic lupus erythematosus

• Still’s disease
• Postinfectious arthritis of viral diseases
• Subacute bacterial endocarditis with arthritis
• Bacterial arthritis (streptococcal, gonococcal . . . ), osteomyelitis
• Sickle cell anemia, acute aleukemic leukemia
• Serum sickness, Henoch-Schönlein’s purpura
• Benign idiopathic pericarditis

to References 69, 70, and 71) but will list some atypical presentations in Table 15.
As previously said, diagnosis is not easy, because of the absence of specificity of all
the listed criteria, none of them being pathognomonic. Their combination is, in contrast,
very evocative. But the arthritis can simulate other diseases affecting the joints (see Table
15); the cardiac murmur may be nonorganic in a febrile patient; chorea may have another
etiology, erythema marginatum may be confused with a nonspecific rash occurring in a
febrile patient; subcutaneous nodes may be present in juvenile rheumatoid arthritis70 and
even the antistreptolysin O titer may be confusing: in one of the greatest rheumatology units
of Paris only 25 of 100 cases of elevated antistreptolysin O titer were due to a streptococcal
rheumatism (including rheumatic fever erythema nodosum with arthritis, and streptococcal
pyogenic arthritis).74 The same conclusions can be drawn for the minor manifestations, in
particular arthralgia: after a recent streptococcal angina, the joint disease can be rapidly
additive, sometimes symmetrical, with a lower extremity and large joint predominance,
associated with tenosynovitis; all these features characterize the poststreptococcal arthritis
distinct from rheumatic fever (predominance in adults, abscence of heart, central nervous
system and subcutaneous involvement).72 74
In Table 15 we have listed the differential diagnosis of rheumatic fever.
Therapeutic test: formerly when salicylate was available, a load was given to the patient:
it leads to a dramatic fall of temperature in rheumatic fever. Now other anti-inflammatory
drugs can be given, at high dosage. But such a trial is devoid of specificity.

ADULT STILL’S DISEASE

Although a rare disease, it is a frequent newly recognized cause of U.F.3
The juvenile rheumatoid arthritis, which will be reviewed in Chapter 30, can present
either with involvement of a few joints or as a systemic febrile illness in which joint disease
may be initially a minor manifestation; this second variant is called Still’s disease and in
1971 Bywaters described such a picture in young or middle-aged adults of both sexes.75 76
Clinical manifestations can be divided into three major and various minor ones. The
three major ones are: (1) hectic fever with evening spikes, of sudden onset, which lasts
many weeks, sometimes with weight loss, with negative bacterial cultures.75*76 Kahn et al.
found in all of their 21 cases a permanent sinusal tachycardia, present even in the morning
when the patient was not febrile.76 (2) Inflammatory polyarthritis affects all joints, sometimes
initially migratory, then fixed, symmetrical. Myalgias are often associated, sometimes se-
vere, of various topography.75*76 (3) Recurrent, fugacious, morbilliform-like pink maculas,
small, with a clear center, present in the trunk and on the proximal limbs; they appear during
the hectic pyrexia, then vanish, but usually persist, very pale in the morning. Their histology
is nonspecific.75*76
A recent comprehensive review has listed the various manifestations of the disease:76
Although very rarely present76 (see Table 16), meningoencephalitis, conjunctivitis, glo-
merulonephritis, Sjogren’s syndrome, acute hepatitis, and intravascular disseminated co-
agulation may be observed.
 293

TABLE 16
Clinical Manifestations of Adult Still’s Disease
in 73 Cases76

Percentage

Fever ^40°C 86
Arthralgia, myalgia 100
Typical rash 90
Adenopathy 57
Sore throat 53
Splenomegaly 44
Hepatic abnormalities 39
Pleuritis and/or pneumonitis 27
Pericarditis 24
Manifestations similar to those occurring in 17
childhood
Abdominal pain 12

There is no specific biologic abnormality: the elevated erythrocyte sedimentation rate

is constant, hyperleukocytosis and absolute neutrophilia are very frequent, as well as hy-
poalbuminemia, anemia and elevation of immunoglobulins are frequent.
As Kahn et al.76 stated, we believe that Wissler’s “ subsepsis hyperergica” is a variant
of adult Still’s disease. Then it is recommended to look for an occult infectious focus (see
Chapter 25) in patients with adult Still’s disease. A dental infection was found in one of
our four personal cases, and in another one typical Still’s disease appeared in a man 35
years old, associated with Buerger’s disease (glomerulopathy characterized by intermittent
hematuria and local IgA deposits), known to often succeed an upper airway infection,
sometimes due to a streptococcus.
The diagnosis of adult Still’s disease is either easy to establish if the three major symptoms
are present, or very difficult if one of them is lacking.76 In the latter circumstance one must
think of it and, when an infectious process is certainly discarded, a therapeutic corticosteroid
trial (0.5 to 1 mg/kg/d) must be initiated for a few days: its dramatic and lasting efficacy
is evocative of the diagnosis, but not specific.
If the disease is ignored, nearly all the diseases reviewed in many chapters of that book
can be discussed.

ANKYLOSING SPONDYLITIS
This is a chronic inflammatory disease, of unknown etiology with a predominance in
males (90%), which involves prominently sarcoiliac joints, spinal articulations, and par-
avertebral soft tissues. It is strikingly associated with HLA-B27 antigen.
Although the initial symptoms are usually low back pain and stiffness, it may present
as U.F.77 Four patients were described with fever ^38°5, weight loss, sacroliitis and HLA-
B27 antigen.77 It is an exceptional mode of presentation.
The diagnosis is based on:

• The sex (one of the four patients of Kinsella et al. was however a woman77).
• The topography of pain.
• A chest expansion under 5 cm.
• Eventually systemic manifestations: iritis, aortic insufficiency . . .
• Sacroiliitis on excellent X-ray. When the diagnosis is highly suspected and conventional
radiographs are not demonstrative, computed tomography may be helpful.79
• The presence of HLA-B27 antigen present in 77 to 97% of patients in contrast to 3.9
to 12.4% of controls.78
294 U nex p la in ed F e ve r

RELAPSING POLYCHONDRITIS
It is a very rare disorder characterized by recurrent inflammation and destruction of
cartilage, with a predominance in nose, ears, and laryngotracheal structures. It affects both
sexes, occurs at all ages with a predominance in the middle of life.80,81
It may present, in 5% of published cases, as U.F. ,80 sometimes associated with arthralgia
and myalgia.81 The usual presenting features are ear chondritis (26% of 181 published cases),
arthritis (22%), nose chondritis (16%), laryngotracheal chondritis (14%), ocular manifes-
tations (13%), various manifestations and audiovestibulatory symptoms (4%).80
Its diagnosis is based on the involvement of at least two cartilaginous structures (one
must be either nose or ear) and on compatible histologic lesions of the cartilage: loss of
metachromasia, necrosis, and calcification; associated with inflammation and granulation
tissue.80
Me Adam et al. proposed six criteria: relapsing chondritis of ears; nonerosive polyarthritis;
nose chondritis; cochlear and/or vestibular lesion.81 The diagnosis relies on the presence of
three of these criteria associated with typical histologic lesion.
For Damiani et al. the diagnosis can be supported either by the association of a unique
clinical criteria to histopathologic lesions or, if biopsy is not performed, by two distinct
chondritis which respond either to corticosteroids or to dapsone.82

GOODPASTURE’S SYNDROME
This syndrome associates alveolar hemorrhages with a proliferative glomerulonephritis,
and anti-basal membrane autoantibodies with an elective deposition in alveoli and glomer-
uli.87
Two-hundred ten cases were recently reviewed.87 It affects young adults with a pre-
dominance in males; a low-grade fever is present in about 15 to 24% of cases.
The syndrome may present as a mild respiratory tract infection until hemoptysia, the
key symptom, appears.
We have deliberately excluded from our discussion Sjogren’s syndrome (sicca syndrome)
associating xerophthalmia with xerostomia, because a recent comprehensive review excluded
fever as an initial manifestation of the syndrome when it is isolated.88 Obviously, later in
the course of the syndrome, particularly if it is associated with a “ connective tissue’’ disease,
fever may be present.

REFERENCES
1. Dubois, E., Lupus Erythematosus. A Review of the Current States of Discoid and Systemic Lupus Erythe-
matosus and their Variants, 2nd ed., Univ. South Calif. Press, Los Angeles, 1974, 798.
2. Meyer, O., Margulis, J., and Kahn, M.-F., Lupus erythemateaux dissemine in Maladies Systemiques,
2nd ed., Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 202.
3. Larson, E., Featherstone, H., and Petersdorf, R., Fever of undetermined origin: diagnosis and follow-
up of 105 cases 1970— 1980, Medicine, 61, 269, 1982.
4. Fan, E., Cohen, A., Fries, J., et al., The 1982 revised criteria for the classification of systemic lupus
erythematosus, Arthritis Rheum., 25, 1271, 1982.
5. Haserich, J., Modem concepts of systemic lupus erythematosus. A review of 126 cases, J. Chron. Dis.,
1, 317, 1955.
6. Bloch, K. and Salvaggio, J., Use and interpretation of diagnostic immunologic laboratory tests, JAMA,
248, 2734, 1982.
7. Stahl, N., Klippel, J., and Decker, J., Fever in systemic lupus erythematosus, Am. J. Med., 67, 935,
1979.
8. Ginzler, E., Diamond, H., Kaplan, D., et al., Computer analysis of factors influencing frequency of
infection in systemic lupus erythematosus, Arthritis Rheum., 21, 37, 1978.
 295

9. de Prost, Y. and Touraine, R., Sclerodermies in Maladies Systémiques, 2nd ed., Kahn, M.-F., and Peltier,
A., Eds., Flammarion, Paris, 1985, 296.
10. Appelboom, T. and Kahn, M.-F., Connectivities mixtes (syndrome de Sharp), in Maladies Systémiques,
2nd ed., Kahn, M.-F., and Peltier, A., Eds., Flammarion, Paris, 1985, 400.
11. Sharp, G., Irvin, W., Tan, E., et al., Mixed connective tissue disease — an apparently distinct rheumatic
disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA), Am. J. Med.,
52, 148, 1972.
12. Christian, C. and Sergent, J., Vasculitis syndromes: clinical and experimental models, Am. J. Med., 61,
385, 1976.
13. Lie, J., Nosology of pulmonary vasculitides, Mayo Clin. Proc., 52, 520, 1977.
14. Fauci, A., The spectrum of Vasculitis, Ann. Intern. Med., 89, 660, 1978.
15. Peltier, A., Vascularities nécrosantes: généralités, in Maladies Systemiques, 2nd ed., Kahn, M.-F. and
Peltier, A., Eds., Flammarion, Paris, 1985, 409.
16. Fiessinger, J.-N., Housset, E., Aorto-arterite non spécifique (maladie de Takayasu) in Maladies Syste-
miques, 2nd ed., Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 518.
17. Ask-Upmark, E. and Fajers, C., Further observations on Takayasu’s syndrome, Acta Med. Scand., 155,
275, 1956.
18. Roberts, W., McGregor, R., Deblanc, H., et al., The prepulseless phase of pulseless disease or pulseless
disease with pulses. A newly recognized cause of cardiac disease, monoclonal gammapathy and fever of
unknown origin, Am. J. Med., 46, 313, 1969.
19. Wilson, W., Morgan, O., Bain, B., et al., Takayasu’s arteritis: association with Still’s disease in an
adult, Arthritis Rheum., 22, 684, 1979.
20. Calamia, K. and Hunder, G., Giant cell arteritis (temporal arteritis) presenting as fever of undetermined
origin, Arthritis Rheum., 24, 1414, 1981.
21. Healey, L. and Wilske, K., Presentation of occult giant cell arteritis, Arthritis Rheum., 23, 641, 1980.
22. Godeau, P., Aubert, L., Guillevin, L., et al., Aspect clinique, evolution et pronostic de la maladie de
Horton, Ann. Med. Intern. (Paris), 133, 393, 1982.
23. Ettlinger, R., Hunder, G., and Ward, E., Polymyalgia rheumatica and giant cell arteritis, Annu. Rev.
Med., 29, 15, 1978.
24. Huskisson, E., Dieppe, P., and Balme, H., Complicated polymyalgia, Br. Med. J., 4, 1459, 1977.
25. Barrier, J., Potel, G., Renaut-Ovasse, H., et al., The use of Doppler Flow Studies in the diagnosis of
giant cell arteritis, JAMA, 248, 2158, 1982.
26. Klein, R., Campbell, J., Hunder, A., et al., Skip lesions in temporal arteritis, Mayo Clin. Proc., 51,
504, 1976.
27. Morgan, J., and Harris, E., Non-giant cell temporal arteritis, Arthritis Rheum., 21, 362, 1978.
28. Esposito, A. and Gleckman, R., Fever of unknown origin in the elderly, J. Am. Geriatr. Soc., 26, 498,
1978.
29. Fiessinger, J.-N. and Housset, E., Thrombangeite oblitérante (maladie de Buerger), in Maladies Syste-
miques, 2nd ed., Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 526.
30. Godeau, P. and Guillevin, L., Periarterite noueuse systemique, in Maladies Systemiques, 2nd ed., Kahn,
M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 415.
31. Zizic, T., Classen, J., and Stevens, M., Acute abdominal complications of systemic lupus erythematosus
and polyarteritis nodosa, Am. J. Med., 73, 525, 1982.
32. Helenon, C., Bigoy, J., Jacri, P., et al., Aspects de l’artériographie au cours de l’évolution des lesions
de la periarterite noueuse, J. Radiol. Electrol., 58, 45, 1977.
33. Melish, M., Kawasaki syndrome (The mucocutaneous lymph node syndrome), Annu. Rev. Med., 33, 569,
1982.
34. Fauci, A. and Wolff, S., Wegener granulomatosis: studies in eighteen patients and a review of the literature,
Medicine, 52, 535, 1973.
35. De Remee, R., McDonald, T., Harrison, E., et al., Wegener’s granulomatosis. Anatomic correlates. A
proposed classification, Mayo Clin. Proc., 51, 111, 1976.
36. Kernbaum, S., Debrabander, C., Bouton, C., et al., Granulome malin centrofacial et cyclophosphamide,
Ann. Med. Intern. (Paris), 127, 429, 1976.
37. Chumbley, L., Harrison, E., and Deremee, R., Allergic granulomatosis and angiitis (Churg-Strauss
Syndrome), Mayo Clin. Proc., 52, 477, 1977.
38. Vincent, F., Granulomatous angiitis, N. Engl. J. Med., 296, 1977.
39. Sabharwal, U., Keogh, L., Weisman, M., et al., Granulomatous angiitis of the nervous system: case
report and review of the literature, Arthritis Rheum., 25, 342, 1982.
40. Patton, W. and Lynch, J., Lymphomatoid granulomatosis, Medicine, 61, 1, 1982.
41. Fauci, A., Haynes, B., Costa, J., et al., Lymphomatoid granulomatosis, N. Engl. J. Med., 306, 68,
1982.
42. Clauvel, J.-P., Yeni, P., and Leibowitch, M., Purpuras vasculaires, in Maladies Systemiques, 2nd ed.,
Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 551.
296 Unexplained Fever

43. Saurat, J. and Sohier, J., Urticaires systémiques, in Maladies Systemiques, 2nd ed., Kahn, M.-F. and
Peltier, A., Eds., Flammarion, Paris, 1985, 564.
44. Garcia-Bragado, F., Villardell, M., Fonollosa, V., et al., Cryoglobulinémie mixte essentielle: relations
avec le virus de l’hepatite B, Nouv. Presse Med., 10, 2955, 1981.
45. Soter, N., Chronic urticaria as a manifestation of necrotizing venulitis, N. Engl. J. Med., 296, 1440, 1977.
46. Manigand, G., L’erytheme noueux de l’adulte, Rev. Practicien (Paris), XVI, 1167, 1966.
47. Lofgren, L., Erythema nodosum studies on etiology and pathogenesis in 185 adult cases, Acta Med. Scand.
Suppl., 174, 1, 1946.
48. Longmore, H., Toxoplasmosis and erythema nodosum, Br. Med. J., 1, 490, 1977.
49. Rosner, I., Richter, D., Huettner, T., et al., Spondyloarthropathy associated with hidradenitis suppurativa
and Acne conglobata, Ann. Intern. Med., 97, 520, 1982.
50. Vinceneux, P., Syndrome de Cogan, in Maladies Systemiques, 2nd ed., Kahn, M.-F., and Peltier, A.,
Eds., Flammarion, Paris, 1985, 544.
51. Haynes, B., Kaiser-Kupfer, M., Mason, P., et al., Cogan’s syndrome: studies on thirteen patients, long-
term follow-up, and a review of the literature, Medicine, 59, 426, 1980.
52. Chajek, T. and Fainaru, M., Behcet’s disease — report of 41 cases and a review of the literature,
Medicine, 54, 179, 1975.
53. Hamza, M., Ayed, K., and Ben Ayed, H., Maladie de Behcet, in Maladies Systemiques, 2nd ed., Kahn,
M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 668.
54. Toxic Epidemic Syndrome Study Group, Toxic Epidemic Syndrome, Spain, 1981, Lancet, II, 697, 1982.
55. James, G., Sarcoidosis, in Textbook of Medicine, 14th ed., Beeson, P. and McDermott, W., Eds., W. B.
Saunders, Philadelphia, 1975, 164.
56. Quenum, C. and Destombes, P., Les granulomes provoques par les parasites animaux, Ann. Anat. Pathol.
(Paris), 21, 75, 1976.
57. Leclerc, P., Kernbaum, S., Delfraissy, J., et al., Fievre prolongée relevant une sarcoidose extrathoracique,
Nouv. Presse Med., 9, 713, 1980.
58. Shultz, T., Miller, W., and Bedrossian, C., Clinical application of measurement of angiotensin converting
enzyme level, JAMA, 242, 439, 1979.
59. Ackart, R., Munzel, T., Rodriguez, J., et al., Efficacy of 67Ga scintigraphy in predicting the diagnostic
yield of transbronchial lung biopsy in pulmonary sarcoidosis, Chest, 82, 7, 1982.
60. Poole, G., The diagnosis of sarcoidosis, Br. Med. J., 285, 321, 1977.
61. Nolan, J. and Klatskin, G., The fever of sarcoidosis, Ann. Intern. Med., 61, 455, 1964.
62. Simon, H. and Wolff, S., Granulomatous hepatitis and prolonged fever of unknown origin, Medicine, 52,
I, 1973.
63. Vilaseca, J., Guardia, J., Cuxart, A., et al., Hepatite granulomateuse. Etude étiologique de 107 cas,
Nouv. Presse Med., 7, 3323, 1978.
64. Harrington, P., Gurierrez, J., Ramirez-Ronda, C., et al., Granulomatous hepatitis, Rev. Infect. Dis.,
4, 638, 1982.
65. Garovith, M., Agudelo, C., and Pisko, E., Oral contraceptives and systemic lupus erythematosus, Arthritis
Rheum., 23, 13906, 1980.
66. Finch, W. and Strottman, M., Acute adverse reactions to ibuprofen in systemic lupus erythematosus,
Ann. Rheum. Dis., 39, 50, 1980.
67. Ruppert, G. and Barth, W., Tolmetin-induced aseptie meningitis, JAMA, 245, 67, 1981.
68. Siame, J.-L. and Duquesme, B., Maladie de Horton a forme tussigene, Nouv. Presse Med., 11, 3576,
1982.
69. Prieur, A.-M. and Griscelli, C., Maladie systemiques chez l’enfant: rhumatisme articulaire aigu et con-
nectivités, in Maladies Systemiques, 2nd ed., Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985,
603.
70. Kaplan, E., Acute rheumatic fever, Pediatr. Clin. North Am., 25, 817, 1978.
71. Pader, E. and Elster, S., Studies of acute rheumatic fever in the adult, Am. J. Med., 26, 424, 1959.
72. McDonald, C. and Weisman, M., Articular manifestations of rheumatic fever in adults, Ann. Intern.
Med., 89, 917, 1978.
73. Stollerman, G., Markowitz, Taranta, A., et al., Jones’ criteria (revised) for guidance in the diagnosis
of rheumatic fever, Circulation, 32, 664, 1965.
74. Lemaire, V., Le rhumatisme post-streptococcique de l’adulte, Concours Med. (Paris), 102-8, 983, 1980.
75. Esdaille, J., Tannenbaum, H., and Hawkins, D., Adult Still’s disease, Am. J. Med., 68, 825, 1980.
76. Kahn, M. F., Delaire, M., Maladie de Still de l’Adulte, in Maladies Systemiques, 2nd ed., Kahn, M.-
F. and Peltier, A., Eds., Flammarion, Paris, 1985, 197.
77. Kinsella, P., Ebringer, R., Hooker, J., et al., Ankylosing spondylitis presenting as F.U.O., Br. Med.
J . , 2, 19, 1978.
78. Bourgeaois, P., Aspects systemiques de la spondylarthrite andylosante, in Maladies Systemiques, 2nd ed.,
Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 619.
 297

79. Kozin, F., Carrera, G., Ryan, L., et al., Computed tomography in the diagnosis of sacroiliitis, Arthritis
Rheum., 24, 1479, 1981.
80. Vinceneux, P., Polychondrite atrophiante, in Maladies Systemiques, 2nd ed., Kahn, M.-F., and Peltier,
A., Eds., Flammarion, Paris, 1985, 532.
81. McAdam, L., O’Hanlan, M., Bluestone, R., et al., Relapsing polychondritis. Prospective study of 23
patients and review of the literature, Medicine, 55, 193, 1976.
82. Damiani, J. and Levine, H., Relapsing polychondritis. Report of ten cases, Laryngoscope (St. Louis),
89, 929, 1979.
83. Fagan, E., Moore-Gillon, J., and Turner-Wawick, M., Multiorgan granulomas and mitochondrial an-
tibodies, N. Engl. J. Med., 308, 572, 1983.
84. Jabs, D., Houk, L., Bias, W., et al., Familial granulomatous synovitis, eitis and cranial neuropathies,
Am. J. Med., 78, 801, 1985.
85. Hall, S., Barr, W., Lie, J., et al., Takayasu arteritis, Medicine, 64, 89, 1985.
86. Pines, A., Kaplinsky, N., Olchovsky, D., et al., Fever of undetermined origin as the presenting symptom
of Behcet’s Disease: a favorable response to colchicine, South. Med. J., 77, 802, 1984.
87. Even, P., Dennewald, G., Sors, H., et al., Syndrome de Goodpasture et syndromes analogues, in Maladies
Systemiques, 2nd ed., Kahn, M.-F. and Peltier, A., Eds., Flammarion, Paris, 1985, 484.
88. Kaplan, G., Syndrome de Gougerot-Sjogren, in Maladies Systemiques, 2nd ed., Kahn, M.-F. and Peltier,
A., Eds., Flammarion, Paris, 1985, 359.
89. Johns, C., 10th Int. Conf. on Sarcoidosis and other Granulomatous Disorders, Ann. N.Y. Acad. Sci., 465,
1986, (a) James, D. and Williams, J., Report on granulomatous diseases, p 304; (b) Israel, H., Gushue,
G., and Park, C., Assessment of Gallium-67 scanning in pulmonary and extrapulmonary sarcoidosis, p
455; (c) Rizzato, G. and Blasi, A., A European survey on the usefulness of 67Ga lung scans in assessing
sarcoidosis, p 463; (d) Teirstein, A., The Kveim test after Siltzbach, p. 744.
90. Sigal, L., The neurologic presentation of vasculitic and rheumatologic syndrome, Medicine, 66, 157, 1987.
 299

Chapter 19

UNEXPLAINED FEVER IN INFECTIOUS DISEASES

SECTION 1: VIRUSES, CHLAMYDIA, MYCOPLASMA,
RICKETTSIAE, HIGHER BACTERIA, CELL-WALL DEFICIENT
BACTERIA, AND FUNGI
Serge Kernbaum

INTRODUCTION
Viral infections are usually benign, self-limited and of short duration and are then a rare
cause of U.F., which is a more frequent mode of presentation in children than in adults.46
U.F. due to HIV virus is described in Chapter 21. The two viruses most often implicated
are Epstein-Barr virus (EBV) and cytomegalovirus (CMV). They both belong to the Her-
pesvirus group, therefore they can remain in the human host as silent agents for indefinite
periods following primary infection. They can produce the mononucleosis syndrome, are
immunosuppressive and at the same time able to stimulate some functions of T lymphocytes.1

EBV INFECTIONS PRESENTING AS U.F.

The various strains of this DNA virus have a very narrow host range: they infect mainly
B lymphocytes and a few other cells among which are those of the salivary glands: saliva
is the major reservoir for the spread of EBV.2 Only a few cells containing the viral genome
are capable of producing fully infectious viral particles. It is unique among human viruses
in that it produces disease by immortalizing or transforming cells.12
Infections with this ubiquitous agent occur in all populations throughout the world.2
These infections manifest in different ways, often in relation to the age at primary exposure:
in children they are usually mild and most often inapparent; in adolescents or young adults
of Western societies who remain noninfected until the teenage years, the primo-infection is
expressed as infectious mononucleosis.2
Infectious mononucleosis (I.M.) is a frequent and well-known disease,2 4 which could
be the cause of U.F. in two circumstances. In the first one, fever is the main presenting
symptom: it lasts usually 2 to 3 weeks4 and its cause can be hidden because either accom-
panying clinical features are faint, for example, in the elderly5 or exceptionally, when the
development of both heterophil and specific antibodies (see below) is delayed for several
weeks.
In the second one, I.M. may be misdiagnosed if its presenting manifestations are
overshadowed by a fulminant complication, or when such a complication exists without the
usual hematologic abnormalities or even precedes the typical disease as it was described for
example in a case of meningoencephalitis.7 These complications are nonspecific and rare:
for example, five occurred in a sery of 200 consecutive cases.4 Their nature and comments
thereof, including their frequency in other series, are listed in Table 1.
The EBV infection has protean manifestations, distinct from I.M., and more common
in childhood. First, it can evolve for many months, with fever, weight loss, and spleen,
liver, and lymph node enlargement.13 In one child a selective defect of immune interferon
secretion was demonstrated.14Two recent series report the case of 2350 and 4451 adult patients
with a long-standing illness characterized by low-grade fever associated with profound
fatigue, myalgia, mild pharyngitis, and tender adenopathy. The clinical importance of these
persistent infections with EBV, which may be a cause of U.F., was emphasized in two
recent editorials.47 48
300 U nex p la in ed F e ve r

TABLE 1A
Complications of Infectious Mononucleosis

Nature Comments

Neurologic3,6,7

Cerebellitis, encephalitis, meningitis meningoencephal- Occurs in approximately 1.6% of patients,3 are rarely
itis, lowering of seizure threshold, transverse myelitis, the presenting symptoms7
cranial nerve palsy, peripheral neuropathy, Guillain-
Barre syndrome

Cardiovascular3’6’8

Myocarditis, pericarditis Electrocardiographic abnormalities (nonspecific ST and

T wave changes occur in up to 6% of patients.8 Heart-
block is very rare;6 20 cases of pericarditis reported by
19693

Hematologic3,6

Hemolytic anemia, agranulocytosis, granulocytopenia, All are transient and reversible.3 The frequency of he-
thrombocytopenia molytic anemia is up to 3%, that of the other compli-
cations is up to 0.2%3

Hepatic3,6’9

Severe hepatitis with coma, massive necrosis Mild hepatitis, seen in more than 80% of I.M. cases,
is a symptom of the disease

Splenic rupture3,4’6

Abdominal pain, simulating appendicitis6 Occurs in up to 0.2% of patients3 late in the course of
the disease.6 It is due to mesenteric adenomegaly

Respiratory3610

Acute pharyngeal obstruction, interstitial pneumonitis, Interstitial pneumonitis occurs in up to 5% of patients3

mass in the anterior mediastinum

Renal3

Glomerulonephritis, nephrotic syndrome Abnormal urinary findings varied from 0 to 13% in

different series;3 one case of nephrotic syndrome known
in 1978;3 absence of permanent renal impairment6

Varia

Dermatitis of various types including one including one Up to 7.6% of patients had cutaneous manifestations;
genital ulcer6 80 to 100% had some if they received ampicillin; a
Ocular: papilledema without detectable neurological in- rash is also more frequent in patients receiving allo-
volvement, conjunctivitis, uveitis6 purinol
Glandular: salivary gland4 orchitis6
Arthritis: mainly monoarticular3
Occurrence of various antibodies: anti-smooth muscle,
antinuclear, cold reactive rheumatoid factor . . . 11
Myoglobinuria, muscle atrophy and acute renal failure12 One case published

Note: The differential diagnoses of I.M. are listed in Table IB.

 301

TABLE IB
Differential Diagnosis of Infectious Mononucleosis Presenting as Undiagnosed Fever

The most often confused diseases are two diseases that may induce a mononucleosis-like illness
Cytomegalovirus infection — Pharyngitis is rare
Toxoplasmosis — Hepatic abnormalities are nearly always absent
Hypersensitivity reactions
Serum sickness and/or drug hypersensitivity (paraaminosalicylic acid, phenytoin sodium . . . )
Value of a good (repeated) medical history
Lymphomas — Value of lymph node biopsy
Viral hepatitis — Use of serum markers
Other diseases cannot be confused with infectious mononucleosis presenting as U.F.
Streptococcal pharyngitis; viral pharyngitis; Vincent’s angina; diphtheria; rubeola; infectious lymphocytosis (Carl
Smith’s disease); secondary syphilis . . .

In addition, infectious mononucleosis may fail to recover completely and the symptoms
may persist or recur for several years; this entity has been called chronic mononucleosis
syndrome.53
Second, the simultaneous infection with multiple herpes-virus, EBV and CMV15' 17 or
EBV and herpes simplex type l 15 lead to an atypical, long-lasting disease (2 years in one
child).16 Serologic results suggest either the reactivation by the other co-infesting virus of
a latent EBV1517 or that of a latent CMV.16
Third, EBV infection can be associated with malignant diseases. The oncogenic potential
of EBV is now well known.2 We will not discuss here two typical human cancers arising
in localized areas which cannot be mistaken (Burkitf s lymphoma and nasopharyngeal car-
cinoma)2 but we have to mention the various EBV-induced lymphomas, as lymphoma is a
major cause of U.F. Some sporadic cases of I.M. (which can be considered as a “ self-
limited lymphoproliferative disorder) progressed to lymphomas, particularly in immuno-
depressed patients.1820 Such an evolution sometimes occurs in families. The best known is
the XLP syndrome: male subjects with the X-linked lymphoproliferative syndrome (XLP)
inherit a progressive combined variable immunodeficiency which after infection by EBV
results in fatal or chronic I.M., and/or in agammaglobulinemia and/or in aplastic anemia
and/or in malignant B cell lymphomas.21 The occurrence of similar phenomenons was
observed in one another family which differed by the inheritance (not X-linked), the fact
that the affected members had a history of recurrent bacterial infections and that the survivors
recovered completely, and by the different immune response to EBV.22

DIAGNOSIS OF EBV INFECTIONS

There is no problem in young adults. The diagnosis is based on clinical data (sore throat,
fever and cervical lymphadenopathy), hematological changes over (50% lymphocytes and
monocytes with at least 10% atypical lymphocytes), elevated hepatic enzyme levels and
serological data (elevated heterophile antibody titers after the guinea pig absorption test or
elevated beef cell hemolysin titers).
In childhood (where heterophile antibodies can remain low or rise only after several
weeks) and moreover, in various other clinical conditions, the diagnosis is based on specific
EB antibodies, available only in few laboratories.
Nearly all acute phase sera contain antibodies to viral capsid antigen (VCA), which
persist throughout life and appear to be associated with permanent immunity.2 Sera from
about 80% of newly infected persons reveal antibodies to early antigen (EA), which are
undetectable 6 months later.2 The EBV-IgM disappears within 2 to 3 months following the
acute infection; this highly sensitive test is difficult to perform.2
Antibodies to EB nuclear antigen (EBNA) appear in some patients in the third or fourth
week which follows I.M. and are present in all patients in the sixth month, and probably
persist for life.2
302 U nexplain ed F ever

CMV INFECTIONS PRESENTING AS U.F.

The various strains of the CMV are DNA viruses relatively host specific affecting animals
and man.23 The infected host cell enlarges and presents two eosinophilic inclusions, one
intranuclear and one intracytoplasmic. CMV produces permissive lytic infections in numerous
tissues and organs; its target cell and the site of viral latency have not yet been found.1
As CMV may invade virtually any organ or tissue, it produces a spectrum of protean
clinical manifestations ranging from an inapparent infection (the primo-infestation is usually
asymptomatic) to a disseminated fatal one.
Depending on the host, CMV infections can be divided into fetal and neonatal infections
which are beyond the scope of our U.F. review, infections of the normal host and of the
immunocompromised patient; in the latter case CMV infection is both more frequent and
more likely to result in symptomatic and severe disease.24
In contrast with EBV, the CMV diseases which can be associated with U.F. seem to
be more frequent in adults.49,54
In healthy adults, the most frequent symptomatic CMV disease is an I.M.-like illness.
Affected patients (usually young adults) have a moderate fever the characteristics of which
in 62 patients from the literature were recently reviewed:49 fever was present in 98% of 54
patients; it was of low-grade type, with a mean maximum of 39°3C (range, 38 to 41°0C);
its mean duration was 18 days (range 3 to 35 days) and it persisted 3 weeks in 26% of 42
patients.49
The fever was associated mainly with myalgias present in 28/46 patients (61%) and
malaise in 16/29 (55%).49
The other signs and symptoms were less frequent: sore throat 38%. Such a high incidence
contrasts with our own experience as well as with that of French authors,41,46 splenomegaly
38%; headache 34%, rash 31%, adenopathy 28%, hepatomegaly 25% (once again in our
own experience of 17 unpublished patients it was present in only one case) . . .
The most frequent laboratory abnormalities were the SGPT and SGOT elevation —
91%, the presence of atypical lymphocytes — 88%, and the elevation of lymphocytes —
72%.49
Typical blood changes may not appear until the second week of illness.25 Complications
(see below) may be present. Heterophil antibodies are absent. CMV appears to be responsible
for 8% of IM-like illness.24
The post-perfusion CMV infection occurs 2 to 5 weeks after the transfusion of fresh
blood. It is not different from the spontaneous disease.
Localized granulomatous lesions are a rare form of CMV infection, which may reveal
the disease. Among the affected organs are the liver26 (granulomatous hepatitis is a major
cause of U.F.), the parotid gland.27
In the immunodepressed patients, CMV disease evolves as a severe prolonged febrile
illness with various complications. These compromised hosts are essentially renal and bone
marrow transplants, but also AIDS patients, splenectomized and multiply transfused pa-
tients.28 CMV infection had been described as the cause of U.F. in four bum patients.44
Complications of CMV infection can be confusing as they can reveal the disease or
overshadow the typical clinical disease. They are listed in Table 2.
The atypical presentation of coincident CMV and EBV infections had been quot-
ed.15'17
Finally, mainly CMV, and also EBV may be associated with a very rare disease which
may present as U.F., the virus-associated hemophagocytic syndrome characterized by fever,
hepatosplenomegaly, pancytopenia, and erythrophagocytosis by histiocytes that appear be-
nign by histologic criteria, but the clinical course may be fatal.42,43
 303

TABLE 2
Complications of CMV Infections

Nature Comments

Liver23,25,49

Severe hepatitis Mild hepatitis is a symptom of the disease. Occasionally

jaundice is the presenting sign: it was present in 2%
of 62 patients.49

Lung23 2549

Interstitial pneumonitis Frequent in immunodepressed patients; in others it was

present in 6% of cases.49

Nervous system23,24,29,49

Meningitis and/or encephalitis CMV is implicated in approximately 10% of cases of

Peripheral neuritis the Guillain Barré syndrome. It causes more often pe-
Guillain Barré syndrome ripheral than central nervous disease.
Cranial nerve palsy: VIII

Cardiac23 2449

Pericarditis Usually only nonspecific ECG changes

Myocarditis

Hematologic23'25,30

Hemololytic anemia The hematologic changes are among the most frequent
Leukopenia complications of CMV infections.
Thrombopenia
Occurrence of various autoantibodies
Benign histiocytic proliferation

Ocular31

Retinitis and/or choroiditis and/or anterior segment in- Mainly in immunodepressed patients
volvement

Digestive24

Gastritis, colitis Only in immunodepressed patients

Skin24

Various rashes mainly in patients taking ampicillin In one personal unpublished case the disease in a healthy
and/or allopurinol adult who ingested both drugs evolved during 6 weeks
as an exfoliative dermatitis.

DIAGNOSIS OF CMV INFECTIONS

Laboratory confirmation can be obtained by several methods, not all need to be per-
formed. The virus can be isolated from blood or urine. Its presence in the saliva of im-
munodepressed patients is of no diagnostic help as its saliva excretion can last for months
or years.24
Of low value in non-congenital infections are microscopic urine examinations: classical
(for typical cells) or ultramicroscopic (for the virus).24 In contrast, these examinations are
very valuable for the study of infected tissues.24
The indirect proof of the presence of the virus is linked with serology. The complement
304 U nex p la in ed F e ve r

fixation test is usually performed as it is group- and not strain specific. As usual, a fourfold
rise in titer is required. The detection of CMV IgM is also indicative of recent, active
infection but this assay has several pitfalls.24
In fact, because CMV can persist many years in the host, neither its presence in blood
and/or in urine nor the rising serologic titers definitely prove that fever is causally related
to CMV infection, if the patient is immunosuppressed, even if IgM antibodies are present.
It only demonstrates the reactivations of a latent persistent intracellular organism.
The best diagnostic clue then, not always available, is the characteristic histologic
response: the finding of the cytomegalic cell with its large acidophilic inclusions.24
In conjunction with viral isolation and/or positive serologic clue, the presence of these
cells in a biopsy specimen supports the diagnosis.

U.F. ASSOCIATED WITH OTHER VIRAL INFECTIONS

OTHER HERPESGROUP VIRUSES
Herpes simplex type 1 and 2 viruses (HSV) are exceptionally the cause of an infection
presenting as U.F. As HSV is the most common cause of sporadic severe encephalitis, we
believe that only atypical cutaneous manifestations and/or visceral involvement in immu-
nodepressed patients could be misdiagnosed,32 as well as HSV erythema multiforme,33 or
hepatitis. HSV can also be the cause of myoglobinuria with muscle atrophy and renal failure,12
and was once associated with EBV infection.15
It can be speculated with herpes zoster infection could present as U.F. in “ Zoster sine
zostere” , i.e., when the infection takes place only in the neural cells and not in the skin
ones. The topography of the pain must lead to the serology.
Hepatitis viruses are also exceptionally the cause of U.F. except perhaps hepatitis B
virus (HBV) in a few circumstances: during the prodromal phase of type B hepatitis which
may last 28 days with its possible skin and articular symptoms, if hepatic enzymes are not
measured.34 Moreover, when HBV is the cause of diseases different from viral hepatitis:
periarteritis nodosa,35 polymyositis,35 glomerulonephritis,35 polymyalgia rheumatica,35 es-
sential mixed cryoglobulinemia,36 and papular acrodermatitis of childhood.37 We will de-
scribe here only the latter as it is nearly specific of HBV infection and far less well known.
This infectious disease of childhood of low infectivity is characterized by the association of
a nonrelapsing erythematopapular dermatitis localized to the face and limbs and lasting 3
weeks, to an acute hepatitis which is usually anicteric, which lasts at least 2 months and
may progress to chronic liver disease. A paracortical hyperplasia of lymph nodes may be
demonstrated. In the serum, an HBV surface antigenemia of subtype ayw is detected and
may persist for a long time.37 But some cases associated with EBV infection have been
described recently.45
Non-A, non-B hepatitis is not a reported cause of U.F.38
The atypical measles syndrome can present as U.F. It is due to the occurrence of measles
in previously vaccinated patients; more than 200 cases were known by 1979.39 It associates
inconstantly: fever, upper and low respiratory tract infection; macular rash, sometimes
purpuric, seen initially on the distal extremities, and then spread to involve the proximal
ones; and in more than three fourths of the patients, abnormal chest roentgenogram: hilar
adenopathy; patchy, diffuse, or lobar infiltrates; pleural effusions; and residual nodular
lesions.39,40 Myocarditis, liver involvement, thrombocytopenia, and disseminated intravas-
cular coagulation are very rarely seen.39,40 In all cases, measles serology leads to diagnosis.
An adenovirus infection was the cause of two cases of prolonged fever in 82 children.46
On a theoretical basis, epidemic pleurodynia (due to a group B Coxsackie virus) could
be a cause of U.F., as fever may last 3 weeks and even relapse, but we are not aware of
any published case. In fact, in our experience the spasmodic and paraoxysmal character of
the pain is typical and evokes strongly the diagnosis. Other clinical manifestations of en-
 305

TABLE 3
Human Diseases Caused by Chlamydiae56,57,71

Species Serotypes Disease Extent of disease

C . p s itta c i Many unidentified Psittacosis; Reiter syndrome Often hematogenous dissem-

ination with vasculitis and
multisystem involvement
C . p n e u m o n ia e So-called “ TWAR” Atypical pneumonia, clinically Localized ?
strain similar to M . p n e u m o n ia e
C . tr a c h o m a tis L-l, L-2, L-3 Lymphogranuloma venereum Localized
C . tr a c h o m a tis A, B, Ba, C Hyperendemic blinding; tra- Localized (but C. tr a c h o m a -
choma tis present in various sites
of the body)
C . tr a c h o m a tis D, E, F, G, H, I, J, Inclusion conjunctivitis; Localized
K nongonococcal urethritis; Loco-regional diffusion
cervicitis, salpingitis; proctitis, Localized ?
epididymitis; pneumonia of
newborn

terovirus infection, although they can present as an isolated fever, and are not a cause of
U.F. as they spontaneously resolve in a few days.
Finally, if the disease is unknown, hemorrhagic fever with renal syndrome may present
as an U.F.: cases were described in Asia, Europe, and North America. They occur in patients
exposed to rodents; the disease is due to Hantaan virus or related viruses. The disease begins
abruptly with fever, chills, weakness, and dizziness; headache, myalgia, and lumbar pain
are not rare; renal failure may occur; and thrombocytopenia is rare.
The disease may then mimic leptospirosis. Its diagnosis is serologic. Usually the fever
lasts about 1 week or more.53

UNDIAGNOSED FEVER ASSOCIATED WITH CHLAMYDIAL

INFECTION
The Chlamydiae are a group of obligate intracellular organisms individualized by two
virulence factors: enhanced ingestion by a susceptible host cell and inhibition of phagoly-
sosomal fusion.55
The genus is divided into two species: C. psittaci is a common pathogen in avian species
and lower mammals, C. trachomatis affects nearly only man.55 Recently a third one, C.
pneumoniae (ex. TWAR) was described.
All chlamydiae share a common genus — specific antigen and C. trachomatis also share
species and type-specific antigens.55
The diseases they cause in man are summarized in Table 3.
Some of these diseases can be associated with U.F. either because of their typical features:
nongonococcal urethritis and most genital infections, lymphogranuloma venereum, tra-
choma, and atypical pneumonia, or because of the benignity and the short duration of the
disease, most patients being on the way to recovery within a week.

CHLAMYDIAL INFECTIONS POSSIBLY REVEALING AS U.F.

Genital Infections
Some of these can present as an isolated fever; they are also various and constitute a
major health problem in Western society.59
In men only some cases of proctitis could present as U.F. C. trachomatis is a common
cause of proctitis in men who practice anal intercourse; local symptoms are usually prominent,
but they can be absent.60
306 Unexplained Fever

In women it is reasonable to assume that some cases of acute or subacute salpingitis

can present as U.F.; as it happens for salpingitis of other etiologies.
The clinical symptoms can be more puzzling when the acute salpingitis is complicated
by perihepatitis (Fitz-Hugh syndrome).61 Typical symptoms include fever, pain (usually of
sudden onset, in the right upper abdomen) which can sometimes overshadow the symptoms
of salpingitis and simulate a surgical emergency (cholecystitis . . . ). In the acute stage a
localized peritonitis of the anterior liver surface and the adjacent peritoneum exists. Later
“ violin string” adhesions may develop. The diagnosis is verified by laparoscopy or lapa-
rotomy.61

Systemic Symptoms
In some patients the multisystem involvement can be puzzling, the disease affecting
mainly the respiratory, cardiovascular, and nervous systems.53
Some cases are very severe: the mortality was 20% in the pre-antibiotic era, and is now
below 5%. These cases associate respiratory insufficiency and/or circulatory collapse
and/or shock and/or disorientation and coma and/or renal insufficiency and/or pancreatitis.
The various disorders they can mimic include Gram-negative septicemia (including typhoid
fever), Legionnaire’s disease . . .
In a human renal allograft recipient one case was described where slight respiratory and
neurologic symptoms were associated with renal insufficiency and hepatosplenomegaly with
elevation of serum aspartate transaminase.63 In other patients the disease is localized but
atypical.

Subacute Chlamydial Endocarditis

A few cases of C. psittaci endocarditis have been reported.64 65 Their existence is un-
questionable as in one case chlamydiae were identified in aortic valve vegetations by electron
microscopy and immunofluorescent staining.65 They all presented as culture-negative en-
docarditis: in these patients when Coxiella burnetii and fungi have been excluded by serologic
tests and, for the latter, by cultures on appropriate medium, the possibility of chlamydia
endocarditis must be investigated.
Polyarthritis can be the presenting syndrome of a chlamydial infection, either mimicking
Reiter’s syndrome66 or rheumatic fever, because of the associated migratory arthritis and
erythema marginatum rash.67 Reactive inflammatory arthritis is not an uncommon sequella
of genital C. trachomatis infection.72
Chlamydiae are one of the causative infectious agents which, in HLA-B 27 patients,
one case Reiter’s syndrome with its classic tetrad of nongonococcal urethritis, seronegative
asymmetrical polyarthritis, conjunctivitis and/or uveitis and mucocutaneous lesions (see
Chapter 11).
Cases that were even more atypical included one case of C. trachomatis infection
presenting as a meningoencephalitis followed by arthritis68 and the possible hematologic
complications: immune hemolysis due to cold agglutinines69 or disseminated intravascular
coagulation.70

DIAGNOSIS
Medical history is of help when it discloses a contact with birds. Clinical data are
nonspecific, but the absence of respiratory symptoms is a strong argument against C. psittaci
infection. Cytology (usually using the Giemsa stain) is useful when it demonstrates inclusions
(intracellular colonies of Chlamydiae) in conjunctival scrapings or genital tract specimens.
But as its sensitivity is poor, negative results will not rule out the diagnosis.55
With respect to serology, the microimmunofluorescent test is much more sensitive than
the complement fixation test and allows determination of the immunoglobulin class of
antibody.55 It may fail to diagnose TWAR infection if TWAR antigen is not available.71
 307

It is especially useful in the chlamydial infections presenting as U.F. with systemic

complications, as they result in high antibody titers, and because of the limits of cultural
methods in these cases.55
As usual, the presence of IgM antibodies is associated with a recent infection, but also
with a reinfection.55
A fourfold rise in IgG titers is the usual diagnostic method of the cases involving systemic
complications.
Isolation procedures of cultures are ideal but their sensitivity is unknown55 and they are
limited to some laboratories able to perform tissue cultures.
Systemic infections are harder to diagnose by isolation procedures because of sampling
errors (the involved anatomic site, and not the discharge must be sampled) as well as
difficulties in sample collection timing; serodiagnosis therefore is preferable.55

UNDIAGNOSED FEVER ASSOCIATED WITH MYCOPLASMA

INFECTIONS

Mycoplasmas are pathogens of the respiratory tract, urogenital tract, and joints of man,
animals, plants, and arthropods; they are the smallest and simplest self-replicating prokary-
otes.73
Among Mycoplasma species only M. pneumoniae is known to be associated with U.F.
This agent, of which man is the sole reservoir, is a frequent cause of pneumonia in children
and young adults.74 M. hominis and Ureaplasma urealyticum, also pathogenic in humans,
can induce genital infections; they are not known to be associated with U.F.
The course of M. pneumoniae infections is often subclinical; most clinical infections
are upper respiratory tract infections, tracheitis or bronchitis.75 Of infected individuals, most
frequently children 5 to 19 years of age,74 375 to 18%74develop a primary atypical pneumonia.
Severe mycoplasmal respiratory diseases are uncommon; they often mimic necrotizing bac-
terial pneumonia.75
U.F. may be due only to the nonrespiratory manifestations of M. pneumoniae infection,
when they are the presenting symptoms. They are listed in Table 4. All can occur alone or
in association in the same patient.

DIAGNOSIS
The diagnosis relies on laboratory tests. Definite diagnosis should be based on the
isolation, possible only in specialized laboratories, of the organism, (from the respiratory
tract or other sites, including bronchial secretions, cerebrospinal fluid, skin vesicles . . . )
and on a fourfold rise in specific antibody; the complement fixation test being most often
used. The increase is seen 7 to 9 days after infection with a peak after 3 to 4 weeks.75
A single titer of 1/64 or higher is suggestive but not conclusive.75 In such a case, the
absence of isolation of another pathogen likely to cause the same manifestations would be
of great help.

UNEXPLAINED FEVER ASSOCIATED WITH RICKETTSIAL

INFECTION

The small nonmotile bacteria of the family Rickettsiaecea belong to three genera. The
genus Rickettsia: the Gram-negative coccobacilli can multiply and grow only within the
host’s cell, which is penetrated by a process of “ induced phagocytosis’’. They multiply in
the endothelial cells of small blood vessels of various tissues, mainly the skin and the
subcutaneous tissue and the central nervous system. They are transmitted to man by arthro-
pods, with rare exceptions (aerosol cases of Rocky Mountain spotted fever).
The genus Rochalimaea, whose typical representative species is R. quintana, is able to
308 U nex p la in ed F ever

TABLE 4
Nonrespiratory Manifestations of M . pn eu m on iae Infections

Manifestations Comments

Neurologic75'78

Meningoencephalitis Cerebrum, cerebellum, spinal cord and nerve roots can

be affected singly or in combination77
Brain stem encephalitis
Aseptic meningitis
Cerebellar ataxia
Ascending paralysis (Guillain-Barre like) 21% of 50 patients had no previous respiratory
symptoms77
Transverse myelitis
Peripheral and cranial nerve palsie(s) More than 130 cases known in 198075
More than half of the reported patients in 1979 were
from 6 to 21 years of age78

Hematologic75'77

Cold hemogglutinin hemolytic anemia A cold agglutinin anti-IgM antibody occurs in 33 to 76%
Intravascular coagulation (with possible complications: of M. pneumoniae infected patients75
thrombocytopenic purpura; paroxysmal cold hemoglo- Positive Coombs test in 83% and reticulocytosis in 64%76
binuria; Raynaud’s disease; peripheral gangrene; renal
failure)

Gastrointestinal75,76,78

Gastroenteritis Occurs in 12 to 44% of M. pneumoniae infected patients76

Cytolytic hepatitis (some cases associated with antibod-
ies to smooth muscles)
Pancreatitis
Hepatomegaly, weight loss, diarrhea One case presented as U.F.80

Mucocutaneous75,76

Two most common: erythematous maculopapular and Occurs in 25% of M. pneumoniae infected patients76,78
vesicular exanthems sometimes associated with ulcer- 17 cases of Stevens-Johnson syndrome due to M. pneu-
ative stomatitis and conjunctivitis (Stevens-Johnson moniae were known in 198075
syndrome)
Macular, petechial, morbilliform and papulovesicular
exanthems
Scaly erythema
Pytiriasis rosea
Erythema nodosum
Varicella like rashes
Urticaria
Musculoskeletal75,76,79

Myalgia and arthralgia Occurs in 15 to 45% of patients76

Arthritis 29 cases of arthritis known in 1979.79 They are often
initially considered as rheumatic fever or rheumatoid
arthritis.76

Cardiac75,76,78

Pericarditis Over 45 cases reported in 1979,78 some having required

Myocarditis intensive care (heart block . . . )
Generalized lymphadenopathy76 Said to be uncommon76
Splenomegaly76 Reported in 4 patients76
Acute glomerulonephritis75 Reported in 3 patients78
 309

multiply outside a cell, and is the agent of trench fever, an anarthrope-bom disease.
The genus Coxiella whose typical representative species, C. burnetii the agent of Q.
fever (the only disease in which no rash occurs) is an obligate intracellular organism trans-
mitted by inhalation of aerosol.
The rickettsial diseases are characterized by a common pathologic lesion and widespread
peripheral vasculitis which is very similar and differs only in intensity. They fall into four
categories: the typhus group; the spotted fever group; Q fever; trench fever.
They rarely present as an U.F., probably because of their typical well known clinical
features as well as of their usual benignity and spontaneous short duration.
Some of their features are listed in Table 5.
The three diseases of the typhus group are very similar (except for their epidemiology);
their differences bear only on the intensity of the symptoms and signs and on the severity
of the clinical course.81 They all associate fever, severe (and sometimes intractable) headache
and, typically a few days to 2 weeks later, a rash, often absent in Brill-Zinsser’s disease.
Epidemic typhus was in the pre-antibiotic era a cause of U.F. and may still be one, especially
because some cases can be sporadic.82
The diseases of the spotted fever group could present as an U.F. in the absence of typical
symptom, such as the rash which is said to be absent in less than 10% of all patients but
in as many as 86% of ultimately fatal cases of Rocky Mountain spotted fever.85
The unusual cases of Q fever, those presenting without the atypical pneumonia, may
present as true U.F.; these atypical cases are mild hepatitis and culture-negative endocarditis.
Moreover, in untreated cases, fever may last as long as 57 days.96
Finally, trench fever is a benign, often epidemic disease of variable (often short) duration
with possible recurrence; it is not a cause of obscure fever.
The complications and/or atypical localizations of rickettsial diseases, which can be
misdiagnosed when they are the presenting symptom, are listed in Table 6.
As isolation of rickettsial organisms is complex. The diagnosis relies on serologic testing.
The Weil Felix reaction and microagglutination test were useful but the complement-fixation
reaction is preferred. All rickettsial organisms (except for the antigenically heterogenic strains
of scrub typhus) produce complement fixing antibodies. Some are group specific, others
type specific, allowing the determination of the rickettsial species involved. As usual, a
fourfold rise in the titer is necessary.
Although more difficult to realize, the indirect immunofluorescence reaction is more
sensitive, and allows also, as usual, the detection of early IgM antibodies. A rising antibody
titer in serum samples taken during the acute phase and during the convalescence phase is
of course required.

UNEXPLAINED FEVER ASSOCIATED WITH ACTINOMYCOSIS

AND NOCARDIOSIS

These infections are caused by organisms morphologically similar and closely related
by taxonomy: both are actinomycetes, higher bacteria.

ACTINOMYCOSIS
This section will only deal with visceral actinomycosis, because cervicofacial actino-
mycosis as well as cutaneous mycetomas (due to different bacteria) are not associated with
U.F.
Actinomycosis is a subacute or chronic suppurative granulomatous infection, which may
affect all the viscera; it occurs in healthy patients.
The causative anaerobic Gram-positive filamentous bacteria is usually Actinomyces is-
raelii, sometimes A. bovis, very infrequently A. propionicus or A. naeslundii. The infection
in man is endogenous; it requires an insult to the mucosa of the mouth or of the digestive
 TABLE 5
310

Major Features of Rickettsial Diseases of Man81*87

Natural cycle
Disease Agent Arthropod Reservoir Transmission to man

Epidemic typhus R. prow azecki Body louse Man, squirrels Infected louse feces in broken skin
Brill-Zinsser disease R. prow azecki Recurrence of epidemic ty-
phus years after original
attack
U nex p la in ed F ever

Endemic typhus R . ty p h i Flea Rodents Infected flea feces into broken skin
R o c k y m o u n ta in R . r ic k e tts ii Ticks Wild rodents, dogs Tick bite
s p o tte d f e v e r
A fr ic a n tic k ty p h u s R . c o n o r ii Ticks Wild rodents, dogs Tick bite
B o u to n n e u s e f e v e r
R ic k e tts ia lp o x R. akari Blood-sucking mites House mouse, other rodents Mite bite
S c r u b ty p h u s R . ts u ts u g a m u s h i Tromiculid mites Wild rodents Mite bite
Q u e n s la n d tic k ty p h u s R . a u s tr a lis Ticks Marsupial wild rodents Tick bite
North Asian R . s ib ir ic a Ticks Wild rodents Tick bite
tick-borne
rickettsiosis
Q fever C o x ie lla b u r n e tii Ticks Small mammals, cattle, Inhalation of dried, contaminated ma-
sheep, goat terial
Trench fever R o c h a lim a e a q u in ta n a Body louse Man Infected louse feces into broken skin
Worldwide Trunk, then extremities Macular, maculopapular Absent No — epidemic nature, typical asso-
ciation of high fever, intractable
headache, myalgia, followed by rash
Worldwide Identical to the precedent Absent No — history of epidemic typhus
or absent
Worldwide Trunk, then extremities Macular, maculopapular Absent Possible, if disease ignored and/or
(harbors . . . ) presenting complication
Western hemisphere Extremities, then trunk Macular, maculopapular, Absent Possible if the rash is absent, or dis-
purpuric ease ignored or presenting complica-
tion
Africa, South of Europe, Extremities, then trunk Papular, macular Frequent Probably no. Mild disease of short
Middle East, India duration
North America Europe Trunk, face, extremities Pustulo vesicular Frequent No — except the primary skin lesion
Macular all signs resolve in a week
Asia, Australia Trunk, then extremities, Macular maculopapular Frequent No — typical symptoms. High fever,
Pacific Islands generalized headache, rash, eschar, lymphade-
nopathy
Australia Trunk, extremities Macular Possible ? Probably not
Siberia, Mongolia Trunk, extremities Macular Possible ? Probably not
Worldwide Absent Absent Yes — in case of absence of atypical
pneumonia and presence of endocar-
ditis or hepatitis . . .
Europe, North America, Trunk, extremities Macular Absent No — mild disease often epidemic of
Africa short duration. But possible recur-
rences
311
312 Unexplained Fever

TABLE 6
Complications and/or Atypical Localization of Rickettsial Diseases

Nature Comments

Cardiovascular

Endocarditis, essentially due to Q fever88 More than 90 cases reported.88 The serology of Rick-
ettsia must always be performed in culture negative
endocarditis
Myocarditis,84 89 pericarditis,91 and arteritis90 Very rare

Neurologic

Aseptic meningitis and/or encephalitis and/or myelitis Meningitis is the most frequent complication. Convul-
and/or cerebellitus and/or Guillain-Barré polyneuritis sions may occur,
and/or mononeuritis86 92

Hepatitis

Mainly due to Q fever, with granuloma, sometimes vas- Granulomatous hepatitis is a major cause of U.F.
culitis, and nonspecific lesions of hepatocytes.93 94

Varia

Pleurisy,91 interstitial pneumonitis,84 acute renal fail- We have not mentioned the very frequent myalgias,
ure," glandular localization: parotitis,84 skin ulceration arthralgias (in RSMF) and less frequent lymphadenop-
due to vasculitis84 athy, splenomegaly and hepatomegaly83 84

tract, where the organisms are saprophytic. As it is the rule in anaerobic infections, acti-
nomycosis is often a mixed infection and anaerobic streptococci or bacilli, including Acti-
nobacillus actinomycetemcomitans, are commonly associated.
We will describe briefly the frequency of the affected viscera; it varies according to the
published series.98
The most classic form, which is beyond the scope of this section, is cervicofacial
actinomycosis (involvement of soft tissues of the face, neck, and oral cavity); it accounts
for one third to more than 90% of cases.98
The thoracic cases vary from 2% to one third of cases.98 The lung is the most frequent
infected viscus, mainly the lower lobes, because of the deglutition of oral bacteria. Two
main modes of presentation are described: a pseudotuberculous and a pseudotumoral one.
The pleura, chest wall (with cold abscesses), and pericardium can be infected by contiguity.98
The abdominal involvement is also frequent, accounting for 5 to 28% of reported cases.98
It usually occurs in a setting of prior appendicitis, cholecystitis or diverticulitis or following
surgery. All the digestive tract can be involved, but the most frequent and classic localization
is a febrile pseudotumoral lesion of the cecum, which can lead to occlusion and/or fistulas.98
Some cases of liver abscesses are reported.98
The female genital tract is often involved, following pelvic infection or occurring in
women using intrauterine contraceptive devices: ovarian abscesses and/or salpingitis, and/
or endometritis are described.98
In 1970, 17 cases of unilateral kidney actinomycosis were known and in 1974, 9 cases
of orchi-epididymitis.98
The other localizations are mainly cerebral abscesses: 125 published cases in 1970.98
Involvement of bones, thyroid, lymph nodes (one personal case) . . . 98100 is rare.
Actinomycosis is an uncommon disease, but its frequency is probably underestimated.100
It progresses slowly: 90% of the 181 cases reviewed by Brown had a duration of 1 month
to 2 years.99
 313

DIAGNOSIS
The diagnosis relies on bacteriologic and more particularly on histologic examinations.

BACTERIOLOGY
Actinomyces are extremely difficult to culture because of their fastidious growth re-
quirements and the frequent isolation of other associated bacteria: for example, A. isra e lii
or A . b o vis were isolated in 16 of 67 cases."

HISTOPATHOLOGY
The diagnosis then relies on histologic studies of needle aspiration product or of biopsy
material.98101
A ctin o m y ces isra e lii is usually not acid fast,101 is frequently associated with other bacteria
(in contrast with N o ca rd ia a ste ro id e s) and with sulfur granules.
Sulfur granules can be missed unless multiple blocks are embedded and serial step-
sections obtained. This helps to explain the underestimation of the disease. The granules
are round or oval masses, basophilic or amphiphilic, with a radiating fringe of eosinophilic
clubs." 101 They contain the Gram-positive branching filamentous bacilli. Similar granules
can be seen in nocardiosis, but only in the skin, not in the viscera.101

NOCARDIOSIS

We will only discuss infections due to N o c a r d ia a s te r o id e s ; other Nocardia species cause

localized afebrile mycetoma.
N o ca rd ia a ste ro id e s is an aerobic Gram-positive filamentous bacteria widely distributed
as a soil and vegetation saprophyte which can be inhalated and, mainly in immunodeficient
patients, can create a primary necrotizing pneumonia, with a possible hematogenous spread
to viscera, mainly to central nervous system.
Formerly considered as an infrequent disease, nocardiosis is in fact no so rare if adequate
clinical management and microbiological procedures are performed: Palmer et al.102reviewed
230 cases in the English literature between 1961 and 1972 and 13 personal patients. They
analyzed these 243 cases as a whole — 62% occurred in males; the lung was the primary
site in 73% of cases;102 the second sites were mainly the brain, meninges, and spinal cord
(23%), the skin and subcutaneous tissue (9%), the pleura and chest wall (8%), the kidney
(8%), then the eye, the liver, and lymph nodes (3%).102 Half the patients (51%) were
immunodepressed: 23% received steroid therapy; 17% had either a leukemia or lymphoma
or an immune deficit of any type; 12% had a preexistent pulmonary disease, 5% had a
“ chronic collagen-vascular” disease; visceral transplantation, diabetes mellitus, trauma, or
surgery, carcinoma and pulmonary alveolar proteinosis were less frequent.102 Five cases
(affecting bone and subcutaneous tissues) presented as U.F.103

DIAGNOSIS
There are no pathognomonic clinical, laboratory, or roentgenographic signs of nocar-
diosis.103
The diagnosis relies on the association of the identification of the bacteria and of objective
lung or other viscera involvement. In the abscence of visceral lesion one must discuss either
a mild upper respiratory tract infection (if the bacteria is present in the sputum) or a sap-
rophytic presence of Nocardia.104
The isolation of Nocardia can be made in sputum, and/or abscess fluid and/or tissue
biopsy102 104 exceptionally in blood.105 Histopathology and Gram stain — the hyphae-like
filaments of N . a ste ro id e s resemble A . isr a e lii , but display a right angle branching. Sulfur
granules are absent in viscera.101
Bacteriologic demonstration is the usual mode of diagnosis. N . a ste ro id e s grows slowly
314 Unexplained Fever

on aerobic-enriched media for bacteria or for fungi.105 The cultures must be incubated
aerobically at 37°C with C 02 atmosphere and observed frequently for 4 weeks.102
Visceral involvement with one of these two higher bacteria can be ignored if not actively
looked for; they both are a minor but not exceptional cause of fever of unknown origin.

UNDIAGNOSED FEVER ASSOCIATED WITH INFECTIONS DUE

TO CELL WALL-DEFICIENT BACTERIA (L-FORMS,
MICROBIAL SPHEROPLASTS)
Cell wall-deficient bacteria (C.W.D.), or L-forms, or microbial spheroplasts, have atyp-
ical morphologic forms because they are derived from parent (classical) bacteria that have
lost their rigidity owing to defective cell wall.106 They are very sensitive to osmotic forces:
they swell and often burst in media of low osmolality and can be isolated in hypertonic
ones.106
They can be pathogenic in humans, but less than parent bacteria.106' 108 They may be
survival forms of pathogenic bacteria in the face of therapy with beta-lactam antibiotics.106
In contrast, antibiotics whose target is not the cell wall, for example, macrolides agents,
are curative agents. C.W.D. bacteria may be also induced by host factors, for example,
they can develop and survive in the hyperosmotic renal medulla.
Louria, using hypertonic media, found cell wall-deficient bacteria in 6 of 300 febrile
patients whose routine blood cultures were negative, and published five of such cases.107
Of these C.W.D. bacteria, two were Corynebacterium strain, two alpha hemolytic strep-
tococci (one associated with Staphylococcus epidermidis) and one Cryptococcus neoformans.
In four of the five patients serologic studies supported the bactériologie findings. Irwin108
isolated one C.W.D. variant of a Corynebacterium strain in the blood of a patient with U.F.,
who was cured by a macrolide. However, C.W.D. bacteria are probably a very unusual
cause of U.F. as the routine culture on hypertonic media of blood of 65 patients with F.U.O.
failed to detect any L-form.109

UNEXPLAINED FEVER ASSOCIATED WITH DEEP MYCOSES

The fungi are chlorophyll free, heterotrophic, eukaryotic, thallophytic organisms.110
They can be divided into two groups:111 the cosmopolitan ones, (Candida, Cryptococ-
cus . . . ) saprophytic of man, pathogen only when host defenses are impaired, are called
opportunistic; in contrast other fungi (Histoplasma, Coccidioides . . . ) which infect people
living in hot areas, are true pathogens; they are less often a cause of infection presenting as
U.F. than the opportunistic fungi.
Deep mycoses have in common to be a rare cause of U.F., but have a growing incidence
as the majority occurs in patients with serious underlying disorders (that they occasionally
reveal); they preferentially involve lungs and are never transmitted to man from man nor
from animals.110111
Before carrying out an analytical survey, we shall briefly list, in Talbe 7 the factors
predisposing to fungal infections. The presence of one of these predisposing factors must
alert the physician confronted with the febrile patient and lead him to consider the possibility
of a mycotic infection (as well as bacterial and viral ones) (see Chapter 21).

SYSTEMIC CANDIDOSIS

Only systemic candidosis can present as U.F.; we are not aware of any case of U.F.
due to chronic mucocutaneous candidiasis.113
The diagnosis of visceral candidal infection is still an enigma,113 a challenge114 for the
 315

TABLE 7
Deep Mycose-Promoting Factors111112

Predisposing factors Opportunistic fungi

Physiologic Age: newborn C. a lb ic a n s

Pregnancy >4th month C . a lb ic a n s
Host dependent Leukemia, aplastic A s p e r g illu s , C a n d id a ,
intrinsic factors anemia C r y p to c o c c u s
Pathologic Polymorphonuclear C a n d id a , A s p e r g illu s Z y g o m y c e s
leukocyte defects
Defects of cell-mediated Cryptococcus, mainly, C a n d id a ,
immunity; Hodgkin’s A s p e r g illu s H is to p la s m a ,
disease, sarcoidosis . . . C o c c id io id e s
Diabetes mellitus and Z ygom yces (diabetic acidosis)
other endocrine C a n d id a , T o r u lo p s is ,
disorders A s p e r g illu s , C r y p to c o c c u s
AIDS C a n d id a , A s p e r g illu s ,
C r y p to c o c c u s
Host dependent Parenteral drug abuse C a n d id a , A s p e r g illu s Z y g o m y c e s
extrinsic factors
Extrinsic Drugs Broad spectrum C a n d id a , G e o tr ic h u m
iatrogenic antibiotics (in sterilized
A s p e r g illu s
factors Antituberculous cavitary lesions)
antibiotics
Corticosteroids, other A s p e r g illu s , C r y p to c o c c u s
immunosuppressive C a n d id a , T o r u lo p s is ,
drugs Z ygom yces
Contraceptive pills C . a lb ic a n s (vaginal infection)
Catheters Intraarterial or C a n d id a , T o r u lo p s is
intravenous C a n d id a , T o r u lo p s is ,
hyperalimentation M a la s s e r ia fu r fu r
Surgery Cardiac C a n d id a , A s p e r g illu s
Abdominal C a n d id a , A s p e r g illu s
Physical agents, radiation C a n d id a , M u c o r , Z y g o m y c e te s ,
therapy, bums F u s a riu m

clinician. It remains primarily clinical but definite confirmation can be made only by his-
topathologic demonstration of organisms invading visceral tissues.113
The first clue is afforded by the presence of one or more of the promoting factors listed
in Table 7: the patient may have recently received broad-spectrum antibiotics, sometimes
pursued and inactive on fever (such inefficiency must alert the physician); have lowered
antimicrobial defenses (the major ones, when Candida had entered the bloodstream, are the
polymorphonuclear leukocytes112 has an intravascular catheter and/or receives hyperalimen-
tation; or is in the first months of life, or has been recently operated.110*118 Sometimes all
these factors can be absent.
The second clue is the rare discovery of a possible portal of entry: thrush, or other
cutaneo-mucous mondial infections (intertrigo, vaginal infection). Usually the portal of entry
is digestive and not clinically detectable. It must be remembered that in man C. albicans is
a saprophyte only of the digestive tract, not of the skin.111 The physician is then confronted
with one or more visceral localization(s) of Candida infection, which becomes more and
more frequent, mainly in immunodepressed patients.113115119' 121
The first to be searched routinely is hematogenous candidal endophthalmitis, because
it is frequent, often associated with other visceral localizations, and severe, necessitating
urgent systemic treatment. The lesions are white (cottonball-like), sometimes surrounded
by hemorrhage (then simulating Roth spots), chorioretinal in origin, and then extending in
the vitreous.113
In bronchopulmonary candidiasis110120122,123 lung tissue can be invaded by Candida
316 U nex p la in ed F e ve r

species during hematogenous dissemination or rarely after aspiration from the upper airways,
although the lung tissue does not favor transformation of yeast cells to mycelial, invasive
form.110 As Candida can be contaminants of the airways, diagnosis relies only on histol-
o g y . 110,122 Usually, when lung involvement is extensive, the patient is terminally ill from
various other factors.123 There are neither clinical nor radiologic specific features.
Candida endocarditis is very uncommon but is often associated with U.F.124 Vegetations
are large and crumbly. The clinical picture is nonspecific; it depends on the mechanical
effect on the affected valve (natural or often artificial valve) which may be obstructed, and
on the occurrence of embolism. The diagnosis relies essentially on positive blood cultures
in Sabouraud’s medium; cultures may require many days to be positive. Negative cultures
do not exclude the diagnosis. Presence of high titers of precipitins in the patient’s serum is
helpful.139 A fungus must always be searched for in every patient with endocarditis and
negative bacterial cultures.
Small microabscesses of the myocardium are frequent but usually without clinical man-
ifestation.113120125
A sustained candidemia persisting after the removal of all intravenous devices, without
patent local venous symptoms, can be due to a candidal suppurative peripheral thrombo-
phlebitis.125
The kidney is the target metastasis involved in septicemia, but its lesions are usually
subclinical. Pyelonephritis rarely induces renal insufficiency. Anuria due to obstruction by
fungus ball is exceptional.111112
The Candida infection of the digestive tract, mainly the esophagus, is not associated
with U.F.,128129 except in some AIDS patients.
In contrast, Candida meningitis can present as U.F. as it is a febrile disease with slight
meningeal symptoms at its onset; thus, the mean diagnostic interval in 28 patients was 17
weeks.127 The CSF shows a lymphocytic pleocytosis with elevated proteins and in 60% of
cases hypoglycorrhea; in 43% of cases organisms were visible on Gram stain.127
Cerebral abscesses are said to be present (but usually asymptomatic) in up to 50% of
patients.113
Candidal arthritis is subacute or chronic, indolent, with marked synovial proliferation,
then can mimic tuberculosis.130 Osteomyelitis is less rare and affects mainly the spine, and
also the limb bones.131,132
Finally, skin lesions can help the diagnosis as they are accessible to punction or biopsy.
The large macronodular lesions, of 0.5 to 1 cm in diameter, unique or multiple, described
in leukemic patients, can be seen in the scalp of heroinomans. Some lesions are clinically
identical to ecthyma gangrenosum.133
Other Candida species can be invasive, mainly C. p a ra p silo sis and C. tro p ica -
//j110 112134 135 as well as another yeast, T o ru lo p sis g la b r a ta xu and less often T . fa m a ta or
T. g lo b o s a .111
The diagnosis relies on the identification of the fungus in the blood (by culture, excep-
tionally on Gram stain) and/or in tissues. Serologic reactions are less valuable: the best one
is the detection of precipitins.111,113,137 139 Some authors emphasize the differences in studied
populations of patients, the differences in techniques, as well as the absence of standardization
of antigens, and finally the existence of false-negative and false-positive reactions. False-
negative results can sometimes be due to the patients, but false positive ones are less easy
to explain; to conclude we agree with the balanced opinion of Edwards that “ a positive
candidal precipitin test, in a population where disseminated candidiasis is likely, increases
the likelihood of the presence or the disease.” 113 Perhaps in the future, the detection of
antigenenemia will be helpful; it is still too soon to appreciate its diagnostic value.140
 317

CRYPTOCOCCOSIS

Cryptococcosis is a cosmopolitan subacute or chronic disease caused by the encapsulated

yeast Cryptococcus neoformans. The organism is found abundantly in pigeon excreta and
less often in other avian excreta and in the soil. The presumed portal of entry is the respiratory
tract, then the lung is the initial focus of the infection, which usually spontaneously resolves
but is sometimes hematogenously disseminated to any part of the body, primarily the central
nervous system.111 142,143,145
In terms of incidence, Cryptococcosis is the second fungal cause of U.F.
At least two thirds of cases occur in immunodepressed patients, in patients with cancer
(hematologic or solid), receiving corticosteroids, or having AIDS, cirrhosis, or diabetes
mellitus.111,142146
The disease occurs mainly in young adults111,142 equally in both sexes111 or more often
in males.142,144
The most frequent clinical finding is meningitis, which can present as U.F. at its onset
because fever is constant; neurologic symptoms may be absent or limited to headache;111
for example 2 of 15 patients in one sery were investigated for U.F.149 More or less quickly
altered states of consciousness appear, ranging from bizarre behavior to psychosis and coma.
Depending on the location and extent of the cryptococcal involvement, symptoms and signs
of meningitis, meningoencephalitis or a space-occupying lesion (due to a granulomatous
reaction) can be present.111,142,145 The CSF shows a lymphocytic reaction and usually a
reduced glucose level.
Fever is less frequent and often minimal or absent in the second localization, lung
involvement.112,141
The third ones are the skin lesions:111 subcutaneous nodules or papulopustulous, acnei-
form or ulcerative lesions, symmetrical, present in the extremities; as usual they are of great
diagnostic help because their punction can identify the yeast.
The other localizations affect the kidneys (pyelonephritis and papillary necrosis),
the bones, the synovial membrane, the spleen lymph nodes, liver, muscles, endocrine
glands130,141144,146
The diagnosis relies mainly on the identification of the yeast. Repeated samples are
often necessary: in one patient multiple lumbar cultures were negative but cisternal culture
was positive.148 As failure of identification can be due to the presence of only a few yeasts;
a cytocentrifugation of the CSF, or its examination on a Millipore filter, can be useful. The
India ink preparation is often negative, in two thirds of cases of Sen and Louria.112
The detection in blood and/or CSF of a circulating cryptococcal polysaccharide antigen
with a latex agglutination reaction is of great diagnostic value; it is positive in 96% of
cases.112 False-positive reactions can be due to a circulating rheumatoid factor, and can be
eliminated by pretreatment of samples with dithiothreitol.145,147
This latex reaction is said to have both diagnostic and prognostic value.145
We recommend the use of this simple and quick screening procedure in every patient
with U.F. when cryptococcosis is suspected.

ASPERGILLOSIS
Aspergilli are cosmopolitan opportunistic fungi. Their spores, present in air, are very
often inhaled by healthy individuals; the alveolar macrophages destruct easily these spores
which are then eliminated with the bronchial mucus.111
Aspergillosis is the second most frequent fungal disease in immunosuppressed pa-
tients.112,150 All types of immunosuppression can be a promoting factor, including patients
with respiratory, renal, or hepatic failure.157 But it can occur also in healthy individuals.111,157
It is a possible, albeit rare, cause or U.F.
318 Unexplained Fever

Aspergillus fumigatus is reasponsible for at least three quarters of cases: A. flavus and
A . glaucus are also implicated.111112
As overlaps exist between the different clinical types, Aspergillosis can be seen as a
continuum disease.153 These types are Aspergilloma, not associated with U.F.; allergic
bronchopulmonary aspergillosis; acute pulmonary and disseminated aspergillosis; and chronic
necrotizing pulmonary aspergillosis.
Allergic bronchopulmonary aspergillosis151152 is probably not a cause of U.F. because,
if indeed a chronic low-grade fever exists, other features are distinctive: its preferential
occurrence in atopic patients, the episodes of wheezing and the expectoration of fungus-
laden mucus plugs associated with eosinophilia. Finally, when aspergillus antigen is injected
into the skin, it leads to a double response, an immediate and an “ Arthus” one.
Chronic necrotizing pulmonary aspergillosis could be a cause of U.F. as fever of many
months duration, sometimes with weight loss, without any respiratory symptoms, was the
first manifestation of the disease in 2 of 21 patients.153 The chest roentgenogram shows
infiltrative and cavitary lesions, which evoke tuberculosis or anaerobic infection.153
The acute pulmonary and disseminated form of aspergillosis is sometimes presenting as
U.F.: not when pulmonary lesions are severe and extensive (with infarction, abscesses,
pleural empyema . . . ) but when they are mild or even absent, and associated with visceral
diffusion of the disease.150
The portal of entry of that entity is usually the lung, but could also be the skin.154
The other affected viscera are the brain with hemorrhagic infarction and/or abscesses
(meningeal localization is rare3) and the endocardium, mainly on artificial valves: 50 cases
of endocarditis were known in 1978;112 the kidney: abscesses; the skin: large dermal nec-
rotizing lesions;111 the bone: 19 cases of osteomyelitis were known in 1982;154 the gastroin-
testinal tract, liver, thyroid . . . can be involved,155 and even a granulomatous mediastinitis
was described in a nonimmunodepressed patient.112

DIAGNOSIS
Antemortem diagnosis of invasive aspergillosis is very difficult. The recovery from
sputum, urine, or feces of aspergillus is very difficult to interpret, as it can be a saprophyte;157
but in immunodepressed patients caution is necessary.158 In fact most patients with invasive
aspergillosis usually have no fungi in sputum, even after bronchoscopic washings.112 Or-
dinarily, Aspergillus species cannot be cultivated from blood or CSF. Some authors stated
that the presence of Aspergillus flavus on nose culture is “ predictive” for aspergillosis,
even more if the patient had received a prolonged treatment with carbenicillin.159
To conclude, isolation of aspergillus from body fluids in a healthy subject is valueless
and in an immunocompromised patient it may suggest that but not prove the diagnosis.
Serologic tests are not standardized and give various results: the detection of antibodies
in the serum (for example precipitins in immunodiffusion) are said to be helpful.111112158 It
is too soon to appreciate the value (which seems to be great) of the detection of antigene-
mia.160161

HISTOPLASMOSIS
There are two types of histoplasmosis: The American type due to Histoplasma capsu-
latum, a little yeast of 1 to 4 m and the African type, localized in Central and Occidental
Africa, due to Histoplasma duboisii, a big yeast of 10 to 15 m .111 Both are a very rare but
possible cause of U.F. Geographical overlaps may exist.

AMERICAN HISTOPLASMOSIS
This is a common mycosis (found in 80 to 90% of the population in endemic areas of
the U.S., as evidenced by skin test, but usually subclinical.162163) The agent is present in
 319

soil and usually enters the body by inhalation of spore-containing dust. The primary complex
is located in the lung or exceptionally in skin or mucous membranes (vagina, eye), leading
to granulomatous lung and lymph node lesions which subsequently calcify.163 The primary
infection is not a cause of U.F. as it is benign (often subclinical) and self limited, although
complications may occur, such as pericarditis.163 Hematogenous dissemination is said to
occur however in at least 70% of asymptomatic cases.163 In fact, U.F. could be the presenting
feature either of late manifestations of the primary disease, such as mediastinal granulomas
or of one or more visceral atypical localizations seen in the progressive secondary dissem-
inated histoplasmosis.164 It is a rare occurrence (for example 25 cases in one series of 530
patients with active histoplasmosis162), occurring sometimes in immunodepressed pa-
tients.112162 Many organs may be involved:162 skin, oral cavity, gastrointestinal tract, liver,
spleen, lymph nodes, genitourinary tract, heart and great vessels, blood and bone marrow,
central nervous system, endocrine glands (adrenals . . . ).162 Any of these lesions can be
the presenting manifestation of the disease, and is usually associated with fever.162 The
diagnosis relies on identification of the yeast in the tissues.

COCCIDIOIDOMYCOSIS
This is a very rare cause of U.F. The disease is encountered chiefly in California and
the Southwestern parts of the U.S. and Mexico, and Central and South America. In these
regions the microorganism, present in the soil, enters the body by inhalation of spore-
containing dust; the lung is the portal of entry, exceptionally the skin or mucous mem-
branes.110162166
Exceptionally the disease can manifest outside endemic areas; it is easy to diagnose if
it occurs in tourists or as a laboratory contamination, but far more difficult if it is due to
contamination of imported dry commodities such as cotton.110 In this case it can be a cause
of U.F.
The primary disease is asymptomatic in 60% of cases, limited to skin-test conversion;166
in symptomatic cases fever associated with cough, headache, and chest pain is one of the
most frequent symptoms.166 Rare but atypical and misleading symptoms can be associated:
the so-called “ toxic erythema” of short duration is a macular diffuse rash covering the trunk
and extremities, sometimes associated with oral enanthem;166 the so-called “ Valley Fever”
associates, erythema nodosum, erythema multiforme, arthritis and arthralgia and a mild
conjunctivitis sometimes accompanied by episcleritis or keratitis. Eosinophilia, sometimes
very high, is frequent. Skin tests and serodiagnosis are very helpful. The pulmonary man-
ifestations may also present as U.F.
In some patients (pregnancy, diabetes mellitus, corticosteroid treated patients, cancer
patients . . . ) the disease may disseminate and may involve any organ of the body with the
general exception of the gastrointestinal tract:166 skin, bones, joints, meninges, genitourinary
tract, liver, spleen, adrenals, lymph nodes . . . 166
The diagnosis relies on identification of the agent in the tissues, but the complement
fixation test and the precipitin test (which is positive sooner than the complement fixation
test) are helpful in contrast with skin tests except if they show a conversion; their positivity
is valueless in people living in endemic areas.137

SPOROTRICHOSIS

Sporotrichum schenckii is a cosmopolitan biphasic fungus which exists in nature as a

mold and in the body as a yeast. Found in soil, it is present on a variety of plants and
cutaneous sporotrichosis (not a cause of U.F.) and is an occupational disease of florists and
gardeners.167
320 Unexplained Fever

General dissemination of the disease is very rare and usually skin lesions are present
and help the diagnosis. This dissemination occurs in immunodepressed patients: cancer,
AIDS, alcoholic patients, or is associated with tuberculosis or sarcoidosis. . . . 167 168 It
affects mainly the lungs (with cavitary lesions) and bones (of the extremities) and joints.130 167 168
It can be postulated that, when skin lesions are absent, the disease can present as U.F.
The close contact with plants and flowers may be helpful as is the skin test but only
when it shows a conversion; more valuable are the detection of precipitins in the patient’s
serum and, as usual, the biopsy which shows the fungi.

ZYGOMYCOSIS (MUCORMYCOSIS)
Two orders of Zygomycotes can cause human disease: Entomophthera not associated
with U.F. and the family Mucoraceae of the Mucorales.
Zygomycosis is a severe systemic infection, occurring only in immunodepressed patients
(diabetes mellitus, renal insufficiency, leukemia and lymphoma, chronic malnutrition, ex-
tensive bums, shock . . . ) caused by members of the genera Rhizopus, Mucor, and Obsidia,
which have a great affinity for blood vessels.111112169170
The most common form is the rhinocerebral syndrome, typically occurring in patients
with uncontrolled diabetes mellitus. The disease is severe and acute, with high fever. It is
believed to be derived from inhalation of airborne organisms and the portal of entry is usually
unilateral in the nose; the mycotic arterial occlusion leads to an hemorrhagic coryza and an
eschar. Some ischemic lesions may occur in the palate, sinuses, orbit . . . The severity of
the disease is due to the frequent neurologic involvement with pachymeningitis, paresis of
cranial nerve, frontal lobe abscesses.
The second most common occurrence, usually present in hematologic malignancy, is
necrotizing pneumonia.112169>170
Focal involvement of the gastrointestinal tract is nearly always due to Rhizopus. Initial
symptoms are nonspecific; later hemorrhages and perforation may occur. More than half of
the cases affect the stomach and duodenum, one fifth the bowel and one tenth the esoph-
agus.112,170
Disseminated zygomycosis can associate lesions of the above listed viscera to endocar-
ditis, mycotic aneurysms, skin lesions (which may mimic ecthyma grangrenosum), lesions
of the spinal medulla, bones, kidney, larynx, adrenals112,169,170
The diagnosis is only anatomic.

BLASTOMYCOSIS
This is an exceptional but possible cause of U.F. The North American type is due to
the yeast Blastomyces dermatitidis. It predominates in Canada and the U.S., but cases were
reported in Mexico, Venezuela, Europe, and Central and North Africa.171
It usually gives a chronic skin disease, sometimes a chronic pulmonary lesion which
cannot present as U.F. But dissemination in various viscera may occur: liver, spleen, brain,
prostate, and bones.
Of diagnostic value is the occurrence of skin fistulas or of subcutaneous abscesses and
the absence of digestive disorders (unlike in Crohn’s disease) in the South American form
and histoplasmosis.172
The South American blastomycosis is due to Blastomyces brasiliensis. It is endemic in
South America but cases were reported in the U.S., Portugal, Italy, Bulgaria, and Morocco.171
Neither the usual pathognomonic oropharyngeal localization, nor the cutaneous form
can present as U.F. Most probably it is the same with isolated lymph node or lung involve-
ment.
But disseminated localizations may be misleading: the progressive lesions of the large
 321

bowel and the rectum; the localization to the adrenal glands, genital glands, and the men-
inges.171
The diagnosis relies on the identification of the yeast; a serodiagnosis (precipitins,
complement fixing, and fluorescent antibodies) may be helpful.

OTHER EXCEPTIONAL DEEP MYCOSES

We shall just list these diseases: meningoencephalitis, or endocarditis due to Cephalo-
sporium.111
Brain or thyroid gland involvement by Petriellidium boydiP12
Brain involvement by pénicillium112
Geotrichum septicemia112
Pulmonary vasculitis due to Malasseria furfur112
Panophthalmitis due to Fusarium solani173

REFERENCES
1. Ho, M., The lymphocyte in infections with Epstein-Barr virus and cytomegalovirus, J. Infect. Dis., 143,
857, 1981.
2. Andiman, W., The Epstein-Barr virus and EB virus infections in children, /. Pediatr., 95, 171, 1979.
3. Rapp, C. and Hewetson, J., Infectious mononucleosis and the Epstein-Barr Virus, Am. J. Dis. Child.,
132, 78, 1978.
4. Hoagland, R., The clinical manifestations of infectious mononucleosis. A report of two hundred cases,
Am. J. Med. Sci., 240, 21, 1960.
5. Carter, J., Edson, R., and Kennedy, C., Infectious mononucleosis in the older patient, Mayo Clin.
Proc., 53, 146, 1978.
6. Erwin, W., Weber, R. and Manning, R., Complications of infectious mononucleosis, Am. J. Sci., 238,
699, 1959.
7. Dibenedetto, R. and Jurgensen, P., Infectious mononucleosis meningoencephalitis, South. Med. J., 67,
736, 1974.
8. Lowry, P., Edwards, C., and Goldberg, M., Serious cardiac morbidity in infectious mononucleosis, Br.
Med. J., 192, 285.
9. McMahon, J., Elliott, C., and Green, R., Infectious mononucleosis complicated by hepatic coma, Am.
J. Gastroenterol., 51, 200, 1969.
10. Waterhouse, B. and Lapidus, P., Infectious mononucleosis associated with a mass in the anterior me-
diastinum, N. Engl. J. Med., Ill , 1137, 1967.
11. Sutton, R., Edmons, R., Thomas, D., et al., The occurrence of autoantibodies in infectious mononucleosis,
Clin. Exp. Immunol., 17, 427, 1974.
12. Schlesinger, J., Gandara, D., and Bensch, K., Myoglobinuria associated with herpes-group viral infec-
tions, Arch. Intern. Med., 138, 422, 1978.
13. Tobi, M., Morag, A., Ravid, Z., et al., Prolonged atypical illness associated with serological evidence
of persistent Epstein-Barr virus infection, Lancet, 1, 61, 1982.
14. Virelizier, J., Lenoir, G., and Griscelli, C., Persistent EBV infection in a child with hypergamma-
globulinemia and immunoblastic proliferation associated with a selective defect in immune interferon se-
cretion, Lancet, ii, 231, 1978.
15. Lemon, S., Hutt, L., Huang, Y.-T., et al., Simultaneous infection with multiple herpesviruses, Am. J.
Med., 66, 270, 1979.
16. Jones, J., Minnich, L., Jeter, W., et al., Treatment of childhood combined Epstein-Barr virus cyto-
megalovirus infection with oral bovine transfer factor, Lancet, ii, 122, 1981.
17. Charmot, G., Kernbaum, S., and Bastin, R., Reactivation du virus d’Epstein-Barr lors de la primo-
infection a cytomegalovirus chez l’adulte sain, Nouv. Presse Med., 11, 280, 1982.
18. Abo, W., Takada, K., Kamada, M., et al., Evolution of infectious mononucleosis into Epstein-Barr
virus carrying monoclonal malignant lymphoma, Lancet, ii, 1272, 1982.
19. Hanto, D., Frizzerà, G., Gajt-Peczalska, K., et al., Epstein-Barr virus-induced B-cell lymphoma after
renal transplantation, N. Engl. J. Med., 306, 913, 1982.
322 Unexplained Fever

20. Snydman, D., Rudders, R., Daoust, P., et al., Infectious mononucleosis in an adult progressing to fatal
immunoblastic lymphoma, Ann. Intern. Med., 96 (part 1), 737, 1982.
21. Purtilo, D., Sakamoto, K., Barnabei, V., et al., Epstein-Barr virus-induced diseases in boys with the
X-linked lymphoproliférative syndrome (XLP), Am. J. Med., 73, 49, 1982.
22. Fleisher, G., Starr, S., Koven, N., et al., A non-X-linked syndrome with susceptibility to severe Epstein-
Barr virus infections, J. Pediatr., 100, 727, 1982.
23. Weller, T., The cytomegaloviruses: ubiquitous agents with protean clinical manifestations, N. Engl. J.
Med., 285, 203 and 267, 1971.
24. Friedman, H., Cytomegalovirus: subclinical infection or disease?, Am. J. Med., 70, 215, 1981.
25. Klemola, E., Kaariainen, L., Von Hessen, R., et al., Further studies on cytomegalovirus mononucleosis
in previously healthy individuals, Acta Med. Scand., 182, 311, 1967.
26. Clarke, J., Craig, R., Saffro, R., et al., Cytomegalovirus granulomatous hepatitis, Am. J. Med., 66,
264, 1979.
27. Balfour, H., Speicher, C., McReynolds, D., et al., Juvenile xanthogranuloma associated with cytomeg-
alovirus infection, Am. J. Med., 50, 380, 1971.
28. Baumgartner, J., Glauser, M., Burgo-Black, A., et al., Severe cytomegalovirus infection in multiply
transfused splenectomised, trauma patients, Lancet, ii, 63, 1982.
29. Baruch, D., Bouvet, E., Calamy, G., et al., Complications neurologiques de l’infection a cytomegalovirus
(CMV) chez l’adulte sain, Med. Mal. Inf., 12, 470, 1982.
30. Zuelzer, W., Mastrangelo, R., Stulberg, C., et al., Autoimmune hemolytic anemia, Am. J. Med., 49,
80, 1970.
31. England, A., Miller, S., and Maki, D., Ocular findings of acute cytomegalovirus infection in an im-
munologically competent adult, N. Engl. J. Med., 307, 94, 1982.
32. Muller, S., Herrmann, E., and Winkelmann, R., Herpes simplex infections in hematologic malignancies,
Am. J. Med., 52, 102, 1972.
33. Kazmierowski, J., Peizner, D., and Wuepper, H., Herpes simplex antigen in immune complexes of
patients with erythema multiforme, JAMA, 247, 2547, 1982.
34. Veyre, B. and Brett, R., L’Hepatite B a la Phase prémonitoire, Nouv. Presse Med., 4, 1349, 1975.
35. Mihas, A. and Conrad, M., Hepatitis B Antigen and the liver, Medicine, 57, 129, 1978.
36. Garcia-Bragado, F., Vilardell, M., Fonollosa, V., et al., Cryoglobulinémie mixte essentielle: relations
avec le virus de f hepatite B., Nouv. Presse Med., 10, 2955, 1981.
37. Gianotti, F., Popular acrodermatitis of childhood and other papulosicular acro-located syndromes, Br. J.
Dermatol., 100, 49, 1979.
38. Robinson, W., The enigma of non-A, non-B hepatitis, J. Infect. Dis., 145, 387, 1982.
39. Martin, D., Weiner, L., Nieburg, P., et al., Atypical measles in adolescents and young adults, Ann.
Intern. Med., 90, 877, 1979.
40. Annunziato, D., Kaplan, M., Hall, W., et al., Atypical measles syndrome: pathologic and serologic
findings, Pediatrics, 70, 203, 1982.
41. Calamy, G., Vesinet, F., Hincky, J. M., et al., Syndromes mononucleosiques spontanes a cytomegalovirus
survenant chez des individus sains. Etude prospective de 28 Observations, Nouv. Presse Med., 10, 29,
1981.
42. Risdall, R., McKenna, R., Nesbitt, M., et al., Virus associated hemophagocytic syndrome: a benign
histiocytic proliferation distinct from malignant histiocytosis, Cancer, 44, 993, 1979.
43. Danish, E., Dahms, B., and Kumar, M., Cytomegalovirus-associated hemophagocytic syndrome, Pe-
diatrics, 75, 280, 1985.
44. Deepe, G., MacMillan, B., and Linnemann, C., Unexplained fever in bum patients due to cytomegalovirus
infection, JAMA, 248, 2299, 1982.
45. Joaquin, V. and Marks, M., Gianotti disease or Gianotti-Crosti syndrome?, J. Pediatr., 101,216, 1982.
46. Lassale, C., Lemerle-Gruson, S., Dernardin, F., et al., Les fièvres prolongées de l’enfant, Concours
Med., 10528, 3103, 1983.
47. Niederman, J., Chronicity of Epstein-Barr Virus Infection, Ann. Intern. Med., 102, 119, 1985.
48. Anon., EBV and persistent malaise, Lancet, i, 1017, 1985.
49. Cohen, J. and Corey, R., Cytomegalovirus in the normal host, Medicine, 64, 100, 1985.
50. Strauss, S., Tosato, G., Armstrong, G., et al., Persisting illness and fatigue in adults with evidence of
Epstein-Barr vims infection, Ann. Intern. Med., 102, 7, 1985.
51. Jones, J., Ray, C., Minnich, L., et al., Evidence for active Epstein-Barr vims infection in patients with
persistent, unexplained illnesses: elevated anti-early antigen antibodies, Ann. Intern. Med., 102, 1, 1985.
52. Lallement, P., Moriniere, B., Kaloustian, E., et al., Fièvre hémorragique avec syndrome renal: quatre
cas autochtones, Med. Mal. Infect., 14, 425, 1984.
53. Anon., Enervating illness and Epstein-Barr vims, Lancet, 11, 141, 1986.
54. Jeantils, V., Lemaître, M. O., Krivitzky, M., et al., Cytomegalovims et fièvre au long cours chez
l’adulte, Ann. Med. Intern., 138, 358, 1987.
 323

55. Schächter, J. and Grossman, M., Chlamydial Infections, Annu. Rev. Med., 32, 45, 1981.
56. Schächter, J., Chlamydial Infections, N. Engl. J. Med., 298, 428, 490, 540, 1978.
57. Hieber, P., Infections due to Chlamydia, J. Pediatr., 91, 864, 1977.
58. Editorial, Psittacosis, Br. Med. J., 1, 5791, 1972.
59. Richmond, S. and Oriel, J., Recognition and management of genital chlamydial infection, Br. Med. J.,
2, 480, 1978.
60. Quinn, T., Goodell, S., Mkrtichian, E., et al., Chlamydia trachomatis proctitis, N. Engl. J. Med., 305,
195, 1981.
61. Wilner-Hanssen, P., Westrom, L., and Mardh, P.-A., Perihepatitis and chlamydial salpingitis, Lancet,
i, 901, 1980.
62. Byrom, N., Walls, J., and Mair, J., Fulminant psittacosis, Lancet, i, 353, 1979.
63. Griffith, P., Lechler, R., and Treharne, J., Unusual chlamydial infection in a human renal allograft
recipient, Br. Med. J., 4, 1264, 1978.
64. Editorial, Chlamydial endocarditis, Lancet, 1, 132, 1980.
65. Jones, R., Priest, J., and Kuo, C.-C., Subacute chlamydial endocarditis, JAMA, 247, 655, 1982.
66. Bopal, R. and Thomas, G., Psittacosis presenting with Reiter’s syndrome, Br. Med. J., 284, 1606, 1982.
67. Simpson, R., Huang, C., and Grahame-Smith, D., Psittacosis masquerading as rheumatic fever, Br.
Med. J., 1, 694, 1978.
68. Myhre, E. and Mardh, P.-A., Chlamydia trachomatis infection in a patient with meningoencephalitis,
N. Engl. J. Med., 304, 310, 1981.
69. Vanherweghem, J.-L., De Jonghe, M., and Van Gell, P., Syndrome hémolytique aigu par agglutinimes
froides manifestations inhabituelle d’une omithose, Nouv. Presse Med., 6, 851, 1977.
70. Peyramond, D., Thomas, L., Robert, D., et al., Coagulation intravasculaire disséminée au cours d’une
omitho-psittacose, Nouv. Presse Med., 6, 4142, 1977.
71. Grayston, J., Kjo, C., Wang, S., et al., A new Chlamydia psittaci strain, TWAR, isolated from acute
respiratory tract infections, N. Engl. J. Med., 315, 161, 1986.
72. Keat, A., Thomas, B., and Dixey, J., Chlamydia trachomatis and reactive arthritis: the missing link,
Lancet, 1, 72, 1987.
73. Razin, S., Mycoplasmas: the smallest pathogenic procaryotes, Isr. J. Med. Sei., 17, 510, 1981.
74. Brunner, H., Mycoplasmas pneumonia infections, Isr. J. Med. Sei., 17, 516, 1981.
75. Cassel, G. and Cole, B., Mycoplasmas as agents of human disease, N. Engl. J. Med., 304, 80, 1981.
76. Murray, H., Masur, H., Senterfit, L., et al., The protean manifestations of Mycoplasma pneumoniae
infection in adults, Am. J. Med., 58, 229, 1975.
77. Lerer, R. and Kalavsky, S., Central nervous system disease associated with Mycoplasma pneumoniae
infection, Pediatrics, 52, 658, 1973.
78. Ponka, A., The occurrence and clinical picture of serologically verified Mycoplasma pneumoniae infections
with emphasis on central nervous system cardiac and joint manifestations, Ann. Clin. Res., Suppl. 24, 11,
1, 1979.
79. Ponka, A., Arthritis associated with Mycoplasma pneumoniae infection, Scand. J. Rheumatol., 8, 27,
1979.
80. Lam, K. and Bayer, A., Mycoplasma pneumoniae as a cause of the “ fever of unknown origin’’ syndrome,
Arch. Intern. Med., 142, 2312, 1982.
81. Murray, E., Rickettsial Diseases. The Typhus Group, in Textbook of Medicine, 14th ed., Beeson, P. and
McDermott, W., Eds., W. B. Saunders, Philadelphia, 1975, 249.
82. Kaplan, J., McDade, J., and Newhouse, V., Suspected Rocky Mountain spotted fever in the winter.
Epidemic typhus?, N. Engl. J. Med., 305, 1648, 1981.
83. Haynes, F., Sanders, D., and Cramblett, H., Rocky Mountain spotted fever in children, J. Pediatr.,
76, 685, 1970.
84. Vianna, N. and Hinman, A., Rocky Mountain spotted fever on Long Island, Am. J. Med., 51, 725, 1971.
85. Westerman, E., Rocky Mountain spotless fever, Arch. Intern. Med., 142, 1106, 1982.
86. Miller, J. and Price, T., The nervous system in Rocky Mountain spotted fever, Neurology, 22, 561, 1972.
87. Wong, B., Singer, C., Armstrong, D., et al., Rickettsialpox, JAMA, 242, 1998, 1979.
88. Tobin, M., Cahill, N., Gearty, G., et al., Q fever endocarditis, Am. J. Med., 72, 396, 1982.
89. Sheridan, P., McCaig, J., and Hart, R., Myocarditis complicating Q fever, Br. Med. J., 2, 155, 1974.
90. Rigaud, J., Sirol, J., Bara be, P., et al., Arterite rickettsienne due a Coxiella Bumetti, Arch. Mal. Coeur,
2, 185, 1977.
91. Pieron, R., Coppin, M., Develoux, M., et al., Pericarditers et Pleuresies Rickettsiennes, Sem. Hop.
Paris, 52, 621, 1976.
92. Larribaud, J., Chevrel, M., Colonna, P., et al., Contribution a l’etude des formes neurologiques des
Rickettsioses, Presse Med., 70, 527, 1962.
93. Dupont, H., Hornick, R., Levin, H., et al., Q fever hepatitis, Ann. Intern. Med., 14, 198, 1971.
324 Unexplained Fever

94. Faure, J., Escande, J., Grataloup, et al., Hepatitite Granulomateuse Rickettsienne, Nouv. Presse Med.,
6, 2896, 1977.
95. Bernheim, J., Myers, B., and Griffel, B., Insuffisance renale qigue complication de Rickettsiose, Nouv.
Presse Med., 3, 826, 1974.
96. Warren, J. and Hornick, R., Coxiella burnettii (Q fever), in Principles and Practice of Infectious Diseases,
Mandell, G., Douglas, R. G., and Bennett, J., Eds., John Wiley & Sons, New York, 1979, 1516.
97. Sawyer, L., Fishbein, D., and McDade, J., Q fever: current concepts, Rev. Infect. Dis., 9, 935, 1987.
98. Kernbaum, S., Les Actinomycoses, in Maladies Infectieuses, Bastin, R., Ed., Flammarion, Paris, 1975,
885b, 885i.
99. Brown, J., Human actinomycosis, Hum. Pathol., 4, 319, 1973.
100. Cope, V., Visceral actinomycosis, Br. Med. J., 2, 1311, 1949.
101. Robboy, S. and Vickery, A., Tinctorial and morphologie properties distinguishing actinomycosis and
nocardiosis, N. Engl. J. Med., 282, 593, 1970.
102. Palmer, D., Harvey, R., and Wheeler, J., Diagnostic and therapeutic considerations in Nocardia aster-
oides infection, Medicine, 53, 391, 1974.
103. Frasier, A., Rosenow, E., and Roberts, G., Nocardiosis: a review of 25 cases occurring during 24 months,
Mayo Clin. Proc., 50, 657, 1975.
104. Young, L., Armstrong, D., Blevins, A., et al., Nocardia asteroides infection complicating neoplastic
disease, Am. J. Med., 50, 356, 1971.
105. Roberts, G., Brewer, N., and Hermans, P., Diagnosis of nocardiosis by blood culture, Mayo Clin. Proc.,
49, 293, 1974.
106. Feingold, D., Biology and pathogenicity of microbial spheroplasts and L-forms, N. Engl. J. Med., 281,
1159, 1969.
107. Louria, D., Kaminski, T., Grieco, M., et al., Aberrant forms of bacteria and fungi found in blood or
cerebrospinal fluid, Arch. Intern. Med., 124, 39, 1969.
108. Irwin, R., Seith, W., Woelk, W., et al., Cell wall deficient bacterial variant cultural surveillance, Am.
J. Med., 59, 129, 1975.
109. Gleckman, R., Esposito, A., and Madoff, S., Fever of unknown origin: attempts to isolate L-forms and
other aberrant bacterial forms, J. Clin. Microbiol., 5, 225, 1977.
110. Kahanpaa, A., Bronchopulmonary occurrence of fungi in adults, Acta Pathol. Microbiol. Scand., Suppl.
227, 147, 1972.
111. Drouhet, E., Les Mycoses Profondes Viscerales: un problème d’actualité, Rev. Med., 11, 605, 1978.
112. Sen, P. and Louria, D., Higher Bacterial and Fungal Infections, in Infections in the Abnormal Host,
Grieco, M., Ed., Yorke Medical Books, 1980, 325.
113. Edwards, J., Severe candidial infections, Ann. Intern. Med., 89, 91, 1978.
114. Hughes, J. and Remington, J., Systemic candidiasis. A diagnostic challenge, Calif. Med., 116, 8, 1972.
115. Young, R., Bennett, J., Geelhoed, G., et al., Fungemia with compromised host resistance, Ann. Intern.
Med., 80, 605, 1944.
116. Rapp Curry, C. and Quie, P., Fungal septicemia in patients receiving parenteral hyperalimentation, N.
Engl. J. Med., 282, 1221, 1971.
117. Richards, K., Pierson, C., Bucciarelli, L., et al., Monilial sepsis in the surgical patient, Surg. Clin.
North Am., 52, 1399, 1972.
118. Keller, M., Sellers, B., Melish, M., et al., Systemic candidiasis in infants, Am. J. Dis. Child., 131,
1260, 1977.
119. Rose, H. and Varkey, B., Deep mycotic infection in the hospitalized adult: a study of 123 patients,
Medicine, 54, 499, 1975.
120. Parker, J., McCloskey, J., and Knauer, K., Pathobiologic features of human candidiasis, Am. J. Clin.
Cardiol., 65, 991, 1976.
121. Klein, J. and Watanakunakorn, C., Hospital-acquired fungemia, Am. J. Med., 67, 51, 1979.
122. Rose, H. and Sheth, N., Pulmonary candidiasis, Arch. Intern. Med., 138, 964, 1978.
123. Masur, H., Rosen, P., and Armstrong, D., Pulmonary disease caused by Candida species, Am. J. Med.,
63, 914, 1977.
124. Rubinstein, E., Noriega, E., Simberdoff, M., et al., Fungal endocarditis: analysis of 24 cases and review
of the literature, Medicine, 54, 331, 1975.
125. Franklin, W., Simon, A., and Sodeman, T., Candida myocarditis without endocarditis, Am. J. Cardiol.,
38, 924, 1976.
126. Torres-Rojas, J., Stratton, C., Sanders, C., et al., Candidal suppurative peripheal thrombophlebitis,
Ann. Intern. Med., 96, 431, 1982.
127. Bayer, A., Adwards, J., Seidel, J., et al., Candida meningitis, Medicine, 55, 477, 1976.
128. Eras, P., Goldstein, M., Sherlock, P., Candida infection of the gastrointestinal tract, Medicine, 51, 367,
1972.
129. Kodsi, B., Wickremesinghe, P., Kozinn, P., et al., Candida esophagitis, Gastroenterology, 71, 715,
1976.
 325

130. Goldenberg, D. and Cohen, A., Arthritis due to tuberculous and fungal microorganisms, Clin. Rheum.
Dis., 4, 211, 1978.
131. Edwards, J., Türkei, S., Elder, H., et al., Hematogenous Candida osteomyelitis, Am. J. Med., 59, 89,
1975.
132. Simpson, M., Merz, W., Kurlinski, J., et al., Opportunistic mycotic osteomyelitis: bone infections due
to Aspergillus and Candida species, Medicine, 56, 475, 1977.
133. Fine, J., Miller, J., Harris, T., et al., Cutaneous lesions in disseminated candidiasis mimicking ecthyma
gangrenosum, Am. J. Med., 70, 1133, 1981.
134. Wingard, J., Merz, W., and Sarai, R., Candida tropicalis: a major pathogen in immunocompromised
patients, Ann. Intern. Med., 91, 539, 1979.
135. Wall, B., Weinblatt, M., Damall, J., et al., Candida tropicalis arthritis and bursitis, JAMA, 248, 1098,
1982.
136. Marks, M., Langston, C., and Eickhoff, T., Torulopsis glahrata — An opportunistic pathogen in man,
N. Engl. J. Med., 283, 1131, 1970.
137. Baum, G. and Schwarz, J., Diagnosis and treatment of systemic mycoses, Med. Clin. North Am., 58,
661, 1974.
138. Axelsen, N., Analysis of human Candida precipitins by quantitative immunoelectrophoresis, Scand. J.
Immunol., 5, 177, 1976.
139. Iannini, P., Everett, D., Pappas, G., et al., Candida precipitins as a diagnostic aid in Candida endocarditis,
JAMA, 236, 2518, 1976.
140. Weiner, M. and Coats-Stephen, M., Immunodiagnosis of systemic candidiasis: mannan antigenemia
detected by radioimmunoassay in experimental and human infections, J. Infect. Dis., 140, 989, 1979.
141. Littman, M. and Walter, J., Cryptococcosis: current status, Am. J. Med., 45, 922, 1968.
142. Lewis, J. and Rabinovich, S., the wide spectrum of cryptococcal infections, Am. J. Med., 53, 315, 1972.
143. Schroter, G., Temple, D., Husberg, B., et al., Cryptococcosis after renal transplantation: report of ten
cases, Surgery, 79, 268, 1976.
144. Kaplan, M., Rosen, P., and Armstrong, D., Cryptococcosis in a cancer hospital, Cancer, 39, 2265,
1977.
145. Editorial, Cryptococcosis, Lancet, i, 944, 1982.
146. Randall, R., Stacy, W., Toone, E., et al., Cryptococcal pyelonephritis, N. Engl. J. Med., 279, 60, 1968.
147. Goodman, J., Kaufman, L., and Koenig, G., Diagnosis of cryptococcal meningitis, N. Engl. J. Med.,
285, 434, 1971.
148. Berger, J. and Paz, J., Diagnosis of cryptococcal meningitis, JAMA, 236, 2517, 1976.
149. Saimot, G., personal communication.
150. Meyer, R., Young, L., Armstrong, D., et al., Aspergillosis complicating neoplastic disease, Am. J.
Med., 54, 6, 1973.
151. Rosenberg, M., Patterson, R., Mintzer, R., et al., Clinical and immunologic criteria for the diagnosis
of allergic bronchopulmonary aspergillosis, Ann. Intern. Med., 86, 405, 1977.
152. Patterson, R., Greenberger, P., Radin, R., et al., Allergic bronchopulmonary aspergillosis: staging as
an aid to management, Ann. Intern. Med., 96, 285, 1982.
153. Binder, R., Faling, J., Pugatch, R., et al., Chronic necrotizing pulmonary aspergillosis: a discrete clinical
entity, Medicine, 61, 109, 1982.
154. Prystowsky, S., Vogelstein, B., Ettinger, D., et al., Invasive aspergillosis, N. Engl. J. Med., 295, 655,
1976.
155. Tack, K., Rhame, F., Brown, B., et al., Aspergillus osteomyelitis, Am. J. Med., 73, 295, 1982.
156. Park, G., Drummond, G., Lamb, D., et al., Disseminated aspergillosis occurring in patients with
respiratory, renal and hepatic failure, Lancet, ii, 179, 1982.
157. Ahmad, M., Weinstein, A., Hughes, J., et al., Granulomatous mediastinitis due to Aspergillus flavus in
a nonimmunosuppressed patient, Am. J. Med., 70, 887, 1981.
158. Fisher, B., Armstrong, D., Yu, B., et al., Invasive aspergillosis: progress in early diagnosis and treatment,
Am. J. Med., 71, 571, 1981.
159. Aisner, J., Murillo, J., Schimpff, C., et al., Invasive aspergillosis in acute leukemia: correlation with
nose cultures and antibiotic use, Ann. Intern. Med., 90, 4, 1979.
160. Shaffer, P., Kobayashi, G., and MedofF, G., Demonstration of antigenemia in patients with invasive
Aspergillosis by solid phase radio immunoassay, Am. J. Med., 67, 627, 1979.
161. Weiner, M., Antigenemia detected by radio immunoassay in systemic aspergillosis, Ann. Intern. Med.,
91, 793, 1980.
162. Vanek, J. and Schwarz, J., The gamut of histoplasmosis, Am. J. Med., 50, 89, 1971.
163. Reddy, P., Gorelick, D., Grasher, C., et al., Progressive disseminated histoplasmosis as seen in adults,
Am. J. Med., 48, 629, 1970.
164. Strimlan, V., Dines, D., and Payne, S., Mediastinal granuloma, Mayo Clin. Proc., 50, 702, 1975.
326 Unexplained Fever

165. Dupont, B., Drouhet, E., and Lapresle, C., Histoplasmose generalisee a Histoplasma duboisii, Nouv.
Presse Med., 3, 1005, 1974.
166. Drutz, D. and Catanzaro, A., Coccidioidomycosis. II, Am. Rev. Respir. Dis., 117, 727, 1978.
167. Baum, G., Donnerberg, R., Stewart, D., et al., Pulmonary sporotrichosis, N. Engl. J. Med., 280, 410,
1969.
168. Gladstone, J. and Littman, M., Osseous sporotrichosis, Am. J. Med., 51, 121, 1971.
169. Agger, W. and Maki, D., Mucormycosis, Arch. Intern. Med., 138, 925, 1978.
170. Dupont, B., Les Mucormycoses, Concours Med., 9831, 3892, 1976.
171. Silva, D., Blastomycoses, Encycl. Med. Chir. (Paris) Mal. Infect., 8126B, 10, 1977.
172. Redline, R. and Dahms, B., Malasseria pulmonary vasculitis in an infant on long-term intralipid therapy,
N. Engl. J. Med., 305, 1395, 1981.
173. Cho, C., Vats, T., Lowman, J., et al., Fusarium solani infection during treatment for acute leukemia,
J. Pediatr., 83, 1028, 1973.
 327

Chapter 20

UNEXPLAINED FEVER IN INFECTIOUS DISEASES:

SECTION 2: COMMONLY ENCOUNTERED AEROBIC,
FACULTATIVE ANAEROBIC, AND STRICT ANAEROBIC
BACTERIA, SPIROCHETES, AND PARASITES
Benedict Isaac

INTRODUCTION
Bacterial disease is a common problem in clinical practice. Despite progress over the
last few decades in public health measures such as sanitary engineering and immunization
programs, as well as the ever-growing list of specific antibacterial agents, the clinical impact
of bacterial infections is still considerable. An increasing number of patients may develop
bacterial and other infectious complications during the course of underlying noninfectious
diseases. Fever is a prominent and almost constant feature of bacterial infection.
When the characteristic manifestations of specific and localized bacterial infections are
fully developed, diagnosis is fairly obvious. However, in many situations to be discussed
in this chapter, a standard work-up fails to disclose the source of fever. These include
bacteremia, infections by “ culture-negative” organisms, atypical or new presentations and
rapidly evolving life-threatening bacterial infections. Prompt diagnosis and treatment of
these conditions are essential and sometimes lifesaving. The clinician should keep in mind
the vast spectrum of febrile diseases and complications caused by commonly encountered
bacteria. At the same time he should consider uncommon clues and difficult problems of
differential diagnosis.

BACTEREMIA, SEPSIS, AND SEPTICEMIA

These terms are frequently used interchangeably, although there are slight differences
which require precise definition. Bacteremia implies the presence of viable bacteria in the
blood, as demonstrated by a positive blood culture.1 Sepsis may be defined as bacteremia
coupled with host response to the circulating microorganisms.2 Septicemia is a severe in-
fection, spread via the bloodstream and caused by many different microbes and characterized
by a persistent presence of bacteria in the blood; it may be associated with a portal of entry
or as a primary focus, with systemic signs or symptoms of toxicity and with septic metastases.
Some authors denote the appearance of septic metastases as septicopyemia. Septicemia
implies a sense of gravity and urgency. Sepsis is a term frequently used to denote a symp-
tomatic infection not necessarily in the bloodstream (e.g., wound sepsis, urinary sepsis,
etc.)
Bacteremia may be transient, intermittent, or continuous. A transient bacteremia lasts
for several minutes; it can occur in healthy people, shortly after meals, during mastication
or brushing the teeth, as well as during menstruation or defecation. Intermittent bacteremia
occurs in cases of intermittent obstruction (pulmonary, biliary, or genitourinary) or repeated
manipulations of diagnostic procedures. Continuous bacteremia may be observed especially
in intravascular infections (endocarditis, thrombophlebitis), in intra-abdominal abscesses,
and in the initial phase of some diseases, such as typhoid fever, brucellosis, leptospirosis,
and tularemia. However, the latter diseases are of a transient nature and may disappear
spontaneously.
According to Braude3 “ the diagnosis of septicemia is largely dependent on subjective
interpretation and bacteremia is a more precise term that is preferable for clinical use” . A
328 U nex p la in ed F ever

TABLE 1
Etiologie Factors in Bacteremia416,18,119

Site or organ-system
of origin Procedure or manipulation Organisms most often involved

Skin and subcuta- Inadequate treatment of furuncle, infected S ta p h y lo c o c c u s a u r e u s ; group A

neous tissue wound; soft-tissue infection or bum streptococci Gram-negative bacilli
Oropharynx Dental extraction; periodontal surgery; dental Anaerobic mouth flora; viridans
care measures; tooth brushing; mastication for streptococci; group A streptococci;
30 min in individuals with caries or severe S ta p h y lo c o c c u s a u r e u s ; Gram-neg-
gingival lesions; chewing candy; oral irriga- ative bacilli
tion device
Respiratory tract Nasotracheal suction or intubation; puncture of viridans
S ta p h y lo c o c c u s a u r e u s ;
sinus; endotracheal intubation; tracheostomy; streptococci; group A streptococci;
transtracheal aspiration bronchoscopy (rigid); anaerobic upper respiratory tract
cold and heated nebulizers; mechanical venti- flora; Gram-negative bacilli
latory aids; tonsilectomy
Cardiovascular Venous cutdown; intravenous catheters; cardiac Streptococci (S . v ir id a n s , entero-
system catheterization; intracardiac pacemaker; par- cocci); S ta p h y lo c o c c u s e p id e r m i-
enteral nutrition; arterial catheterization and d is ; S ta p h y lo c o c c u s a u r e u s ; Gram-
angiographic procedures; hemodialysis shunt; negative bacilli { P s e u d o m o n a s ,
prosthetic valve; infection of vascular graft K le b s ie lla , E . c o li, A c tin e o b a c te r ,
S e r r a tia ,etc.); B a c te r o id e s , mixed
infections, C a n d id a sp., T o r u lo p -
s is g la b r a ta , A s p e r g illu s sp.
Gastrointestinal and Endoscopic procedures; barium enema; percu- Enteric Gram-negative bacilli;
biliary tract taneous liver biopsy; jejunal biopsy; laparos- S ta p h y lo c o c c u s a u r e u s ; entero-
copy; peritoneal dialysis; procedures for cocci, S tr e p to c o c c u s b o v is ; Anaer-
diagnosis and treatment of tumors, stones, obic bowel flora (B a c t e r o id e s ,
abscesses (with obstruction and perforation); C lo s tr id ia )
abdominal surgery
Urogenital tract Urethral catheterization; urethral dilatation; in- Enteric Gram-negative bacilli; an-
ternal urethrotomy; removal of in-dwelling aerobic bowel flora; S ta p h y lo c o c -
catheter; retropubic transurethral prostatec- c u s a u r e u s; streptococci
tomy; cystoscopy; insertion or removal of (enterococci, group B, group A,
I.U.D.; biopsy of cervix; artificial abortion; S tr e p to c o c c u s b o v is )
curettage
Bones, joints, Invasive diagnostic and therapeutic procedures; S ta p h y lo c o c c u s a u r e u s ; group A
meninges sternal puncture; C.S.F. shunts streptococci; D ip lo c o c c u s p n e u -
m o n ia e ; E . c o li, P r o te u s , P s e u d o -
m o n a s a e r u g in o s a , N e is s e r ia
m e n in g itid is , H a e m o p h ilu s in flu e n -
zae

considerable proportion of bacteremiae present as unexplained fever, e.g., 20% of staphy-

lococcal septicemia. Despite the enormous medical progress over recent years, mortality
still ranges between 15 and 50% in septicemia.
Table 1 shows the circumstances in which bacteremia may arise and the organisms most
often involved.
In addition to the procedures mentioned in Table 1, other predisposing conditions for
bacteremia are: (a) factors leading to immune deficiency (see Chapter 21); (b) antecedent
infections in the gastrointestinal, biliary, and urinary tract; (c) underlying heart diseases
(congenital, rheumatic, arteriosclerotic), splenectomy; (d) intravenous drug abuse; and (e)
neonates, pregnancy, and the elderly. In fact, the severity of the underlying disease is
frequently a more important determinant of survival than the species of organism isolated
from the blood. The patient with bacteremia may be asymptomatic or may have only a low-
grade temperature, but the manifestations of sepsis (bacteremia) are usually diverse in their
 329

TABLE 2
Clinical and Laboratory Findings Suggestive of Sepsis

Fever and/or shaking chills; body temperature >38.6°C rectally or hypothermia (<35.6°C rectally)
A previous surgical or invasive procedure, or the presence of an obvious primary septic site or other clinical
evidence of infection
At least one of the following manifestations of inadequate organ perfusion or organ dysfunction:
Altered mental ability
Hypoxemia (p02 <75 mmHg) while breathing room air, in the absence of pulmonary disease; hypocapnia (pC02
<32 mmHg)
Acid-base disorders: unexplained respiratory alkalosis (early sign), lactic acidosis (late)
Signs and symptoms in various organ-systems
Cardiovascular and respiratory
Tachycardia (heart rate >100/min)
Hypotension (cuff systolic pressure in arm <90 mmHg, patient in supine position); cardiovascular collapse
Tachypnea (>24 breaths/min)
Pulmonady edema
Adult respiratory distress syndrome (ARDS)
Gastrointestinal and hepatobiliary
Nausea, vomiting, diarrhea
Abdominal distension, ileus
Jaundice
Renal — Oliguria (output <30 ml or 0.5 ml/kg for at least 1 h)
Central nervous system
Obtundation
Coma
Elevated intracranial pressure
Hematologic — Disseminated intravascular coagulation
Dermatologic
Hyperemia — vasoconstriction
Rash
Acrocyanosis — digital gangrene
Laboratory findings
Hematologic abnormalities: WBC >15,000 or <3500; abnormal neutrophil count (>85% or <35%); abnormal
immature neutrophil count (band forms >20%); myeloid leukemoid reaction; thrombocytopenia (<100,000
platelets per mm3)
Hyperbilirubinemia; elevated serum transaminases
Elevated serum creatinine; decreased creatinine clearance
Hyperglycemia or hypoglycemia

range and presentation. The clinical diagnosis of sepsis requires various criteria, which are
listed in Table 2.
The clinical suspicion of bacteremia should be promptly confirmed by blood cultures.
In a recent study on the treatment of severe sepsis and septic shock,4 the presence of sepsis
was considered to be confirmed if one positive culture from blood, or an intraperitoneal
source, was obtained within 48 h of the patient’s study entry. Two positive cultures were
required if a patient had bacteroides or Staphylococcus epidermidis infections. Unlike the
conventional method of transferring 5 ml blood into each culture bottle, some authors5
propose using three independent collections, each of 10 ml, claiming a success rate of over
90% detection of bacteremia.
Polymicrobial bacteremia comprises cases in which two or more species are isolated
from the blood. Various reports6'8 indicate the prevalence between 6 and 13% of all bac-
teremiae. Polymicrobial bacteremia may occur in the following settings: the immunocom-
promised host, especially in malignancies (most often hematologic), the surgical or obstetric
patient, intra-abdominal abscesses, alcoholics, decubitus, and child abuse. Occasionally, it
may be observed in an otherwise healthy individual or it may be a diagnostic clue for
factitious or self-induced fever. The overall mortality is quite high (over 35%).
In brief, signs and symptoms suggesting bacteremia, include fever and/or shaking chills,
330 U nex p la in ed F e ve r

tachycardia, tachypnea, hypotension and, less commonly, nausea, vomiting, changes in

mental status, hepato- and/or splenomegaly, skin lesions, and oliguria. Fever may be absent
or mild in the immunocompromised host. It may be the only symptom in patients with
venous or bladder catheter. No specific clinical signs or symptoms exist distinguishing Gram-
negative rod from Gram-positive coccal bacteremia.
The clinical setting for sepsis can be divided into two major groups: in one group there
is a known focus or source, in the other, there are no localizing symptoms, physical or
baseline laboratory findings which suggest the source of the fever. Such a case is said to
have sepsis of obscure etiology, especially when there are concomitant leukocytosis and/or
an elevated ESR. If a pathogen is isolated, the patient is said to have occult bacteremia.
The clinician should attempt to make an educated guess in the emergency room, in order
to differentiate between patients with occult bacterial infection, from those with nonbacterial
illness.9 In addition, he should endeavor to distinguish the bacteremic at-risk patient, because
fever may be the initial or only sign of a potentially catastrophic illness.10' 13
Some clinical features, especially mucocutaneous manifestations, may suggest certain
organisms, such as the generalized purpura due to meningococcemia; the petechiae, pustulae,
papulae, or hemorrhagic lesions of fingers and fingertips of the disseminated gonorrheal
infection; the malar hemorrhage of pregnancy due to E. co li infection, the ecthyma gan-
grenosum of psueodomonas bacteremia, and the peripheral signs of infective endocarditis
(Osier nodes, splinter, or subconjunctival hemorrhages).
Sometimes the portal of entry is obvious and in itself suggests the diagnosis. This is
true for cases of cutaneous suppuration, infected wound or bums, septic sore throat and
adenitis, pulmonary, gynecologic and urinary infections, and surgery involving a septic
focus. However, it is often necessary to search for an infected thrombus, particularly in
patients with venous catheters. Thrombophlebitis is characterized by microabscess formation
in the cannulated vein and repeated bacterial embolization into the circulation, which can
be life-threatening.14 Septic thrombophlebitis may be superficial or deep. In descending order
of frequency, it arises in the saphenous system, antecubital veins, jugular veins, and iliac
veins. The most common pathogens, again in descending order, are K le b sie lla , E n te ro b a c te r,
Staph, aureu s, providencia, P ro te u s, E. coli, S erra tia , and P s. a eru g in o sa . In immuno-
compromised patients, frequently no primary focus is apparent. An example of a primary
focus very difficult to detect, is an infected intramural myocardial thrombus after a myocardial
infarction.21 The signs and symptoms linked to secondary foci may sometimes dominate the
clinical picture and mimic primary disorders of the organs where septic métastasés have
developed. This can lead to errors in diagnosis as the associated bacteremia is not appreciated.
In multiple studies of Gram-negative bacteremia, E. co li was the étiologie agent in 37%
of cases.15 The K le b sie lla -E n te ro b a c te r-S e rra tia groups were the next most common, ac-
counting for approximately 20% of isolates, followed by P seu d o m o n a s and P ro te u s. The
frequency and severity of complications make Gram-negative bacteremia a major problem
today, particularly in hospital-acquired infections. However, Gram-positive bacteremia can
also be very serious and in some reports had an even higher mortality rate than Gram-
negative bacteremia — (42 vs. 29% in a community hospital).11
As Young states16 “ The distinction between primary manifestations and complications
in bacteremia is arbitrary; such complications as hypotension, bleeding, hypoxia, acidosis
and jaundice may be the major clues that first suggest the diagnosis” . Gram-positive bac-
teremia has been incriminated in up to one third of patients and Gram-negative in the
remainder. Target organs for complications in bacteremia are especially the lung (pulmonary
edema, hemorrhage, cyanosis); the kidney (oliguria, anuria, acidosis, tubular or cortical
necrosis); the cardiovascular system (congestive heart failure, patchy necrosis of the myo-
cardium, generalized thrombi in the capillaries, hypotension); the blood (bleeding, throm-
bocytopenia, leukopenia); the liver (jaundice); and the gastrointestinal tract (superficial
ulcerations).
 331

The most severe complication of bacteremia is septic shock, related to release of endo-
toxin into the circulation. The transition from the clinical picture of bacteremia to that of
septic shock may be sudden or insidious. The appearance of oliguria, confusion, coagulation
abnormalities or metabolic-acidosis strongly suggests such a transition. An important sign
is the sudden fall of blood pressure: systolic less than 90 mmHg and diastolic less than 60
mmHg. (In a previously hypertensive individual, a decrease of more than 50 mmHg in the
systolic pressure). Septic shock occurs in the setting of impaired resistance to infection and
performance of diagnostic procedures, especially invasive. When faced with a patient in the
first hours of fever and shock, one may observe the manifestations of so-called warm shock:
mild hypotension, warm, dry skin, tachycardia, normal or increased cardiac output, respi-
ratory alkalosis, leukocytosis, and hypokalemia. Without adequate treatment, some patients,
especially those with Gram-negative rod bacteremia, develop the full-blown syndrome of
cold shock, characterized by absence of fever, severe hypotension, altered sensorium, aci-
dosis, moist, cold extremities, oliguria or anuria, hyperkalemia, decreased cardiac output,
and increased serum lactate concentrations.1718
Complications of septic shock, usually severe, include DIC (disseminated intravascular
coagulation), shock lung (acute respiratory distress syndrome), gastrointestinal hemorrhage,
marked leukopenia, renal failure, cardiac failure, and jaundice. A detailed discussion of
these complications is beyond the scope of this chapter.

PERSISTENT BACTEREMIA AND FEVER

In some cases, fever persists or recurs while blood cultures remain positive, despite
administration of the appropriate antibacterial agents. Some authors1920 designate this con-
dition as “ break-through” bacteremia. Persistent bacteremia may be a severe or even life-
threatening condition. Significant causes are inappropriate antibiotic therapy, immuno-
suppression (especially patients receiving high doses of corticosteroids, liver transplant
recipients, renal failure, diabetics) and those with an intra-abdominal primary focus of
infection. Breakthrough bacteremia is more likely to be caused by facultative or aerobic
Gram-negative rods (e.g., Enterobacteriaceae and Pseudomonas species) than by anaerobes.
Staphylococci and Streptococci are uncommon breakthrough isolates. Mortality is high (ap-
proximately 60%). Intensive therapy includes intravenous infusions of appropriate bacteri-
cidal antibiotics, leukocyte transfusion; surgical assistance (when necessary) and supportive
measures are required in severe cases.
Some patients may be able to tolerate protracted bacteremia until a definitive cure is
achieved. Younkin et al.22 described a case of well-tolerated bacteremia of 5 years duration,
due to Streptococcus epidermidis.
Concerning fungemia, we refer the reader to Chapter 19. In this chapter we emphasized
the features of Gram-negative bacteremia. Characteristics of bacteremia with other organisms
will be discussed in the following pages.

THE SPECTRUM OF FEBRILE DISEASES CAUSED BY COMMONLY

ENCOUNTERED BACTERIA
We shall follow a systematic approach: Gram-positive, Gram-negative bacteria, anaer-
obes, spirochetes, and mycobacteria. The major discussions of the infectious agents are
given in connection with their febrile evolution and with the organ-system or tissue most
often affected.

Staphylococcus
The incidence of staphylococcal infections remains fairly high due to the inherent and
acquired resistance of the genus, combined with nosocomial factors and the large number
of asymptomatic carriers. Infection, either localized or disseminated, occurs frequently in
332 U nex p la in ed F e ve r

an immunocompromised host, but severe forms may occur even in an otherwise healthy
individual. Medically important staphylococci are

1. Staph, a u reu s (coagulase positive). The main febrile manifestations are (a) cardio-
vascular: endocarditis, pericarditis, thrombophlebitis; (b) pleuropulmonary: pneu-
monia, lung abscess, empyema; (c) genito-urinary: pyelonephritis, renal-cortical abscess,
perinephric abscess, prostatic abscess; (d) musculoskeletal: osteomyelitis, spondylod-
iscitis, septic arthritis, spinal epidural abscess, suppurative myositis (in the tropics);
(e) neuromeningeal: meningitis, brain abscess, intracranial thrombophlebitis; (f) ENT,
especially as suprainfection after viral diseases: tonsillar abscess, sinusitis, otitis,
parotitis; (g) toxic syndromes (associated with toxin-producing strains): toxic shock
syndrome, food poisoning, toxic epidermal necrolysis; (h) septicemia.23-25
2. Staph, e p id e rm id is causes infections especially in patients with prostheses (heart
valves, orthopedic), in-dwelling urethral catheters and various other foreign bodies.
It is often antibiotic-resistant and can cause severe septicemia.26 28 S taph, ep id erm id is
previously considered a common saprophyte or innocuous contaminant, if isolated on
several cultures, should be assumed to be a pathogen, especially in patients with
prosthetic devices.
3. Staph, sa p ro p h yticu s is a common cause of urethrocystitis in sexually active young
females.

Approximately 20% of staphylococcal septicemias present as fever of unknown origin:

50% are hospital-acquired; 40% develop septic metastases. Early signs and symptoms of
staphylococcal bacteremia are not specific: chills, fever, nausea, vomiting, tachycardia,
dyspnea. In geriatrics, cyanosis associated with confusion may be suggestive; staphylococcal
septicemia in the elderly may sometimes be fulminant, particularly after influenza epidemics.
Some clinical manifestations related to secondary foci may suggest the diagnosis, for ex-
ample: pustulonecrotic cutaneous lesions, bullous bronchopneumonia, septic renal infarction
with abscess formation, osteomyelitis, particularly vertebral and septic arthritis. One should
emphasize that staphylococcal infections can exhibit considerable latency, to the extent that
the initiating event may no longer be evident. There are prolonged clinical forms (months
or even years) evolving with relapses, associated with fever and cachexia.29 30
The blood culture may occasionally be positive. Cachexia, amyloidosis, renal insuffi-
ciency, and septic metastases aggravate the prognosis of these forms. A high index of
suspicion, a correct diagnosis without delay and an aggressive antibiotic and supportive
treatment may be lifesaving.
Staphylococcal infection has a broad spectrum of clinical forms, ranging from mild with
minimal fever and constitutional symptoms, to severe with high fever, cyanosis, gastroin-
testinal symptoms, and vascular collapse. The patient may succumb in 12 to 24 h.31 A
variable evolution, from mild ambulatory cases to coma, may be observed in a syndrome
caused by certain exotoxin-producing staphylococci, the toxic shock syndrome, which was
primarily detected in menstruating women who used vaginal tampons. Later, it was also
described in children, in men, and nonmenstruating women. Signs and symptoms include
fever over 38.9°C (102°F); hypotension, diffuse macular erythroderma or polymorphic ma-
culopapular rash, with desquamation of palms or soles 1 or 2 weeks after the onset of the
illness; vomiting or diarrhea; severe myalgia; vaginal, oropharyngeal or conjunctival hy-
peremia; change in consciousness; thrombocytopenia, abnormal liver tests, high creatinine
or BUN, abnormal metabolic laboratory data (serum proteins, calcium and phosphorus).32,33
A recent report34 describes nine cases of severe toxic shock syndrome (marked hypo-
tension, five deaths), following influenza or influenza-like illness. The syndrome may recur
in about 30% of cases; subsequent attacks are generally less severe.
The diagnosis of staphylococcal infection may sometimes be only clinical (toxic shock
 333

TABLE 3
Group and Species of Streptococci. Clinically Important Streptococcal Diseases

Lancefield Group He- Localized or generalized infec-

molytic reaction Species Habitat tions

Group A — beta he- S tr . p y o g e n s Respiratory; skin; uro- Pharyngotonsilitis; scarlet fever;

molysis, alpha hemo- genital; feces otitis; sinusitis; bacteremia; en-
lysis docarditis; puerperal infection,
skin infection; pulmonary in-
farction; osteomyelitis; septic
arthritis; meningitis; brain ab-
scess
Group B — beta he- S tr . a g a la c tia Oropharynx; bowel; Infections: skin, pleuropulmon-
molysis urogenital ary, puerperal, osteoarticular,
urinary tract, endocarditis,
meningitis, bacteremia
Group C — beta he- S tr. e q u is im ilis Oro-pharynx; skin Bacteremia; respiratory infec-
molysis tions
Group D — no hemo- (Enterococcal) S tr. Respiratory; bowel; Bacteremia; endocarditis; infec-
lysis (gamma) b o v is , S tr. eq u in u s, urogénital tions: pulmonary; biliary tract;
(nonenterococcal) urogenital; osteomyelitis
Group F—G — beta S tr . a n g in o su s, S tr. Respiratory; skin; uro- Abscesses; sinusitis; meningitis;
hemolysis; alpha he- c a n is génital; feces puerperal sepsis
molysis; gamma he-
molysis
Group H — (viridans S tr. s a n g u is Respiratory, feces Endocarditis (subacute bacte-
group) alpha hemoly- rial); bacteremia of dental ori-
sis gin
Group K — alpha he- S tr . s a liv a r iu s Oropharynx Pulmonary infections; endocar-
molysis, gamma he- ditis; meningitis — brain ab-
molysis scess
Microaerophilic and P e p to s tr e p to c o c c i Oropharynx; intestinal Sinusitis; brain abscess; bacterial
anaerobic streptococci tract; abscess cavi- endocarditis; pulmonary ab-
ties; vagina scess; gynecologic infections

syndrome, spinal epidural abscess), but most cases require laboratory confirmation: cultures
(blood, urine, CSF and other body fluids), smear and stain techniques, teichoic acid anti-
bodies, countercurrent-immunoelectrophoresis (CIE), latex agglutination, ELISA test, and
coagglutination of Staph. aureus.

S treptococci
Streptococci are responsible for a wide variety of common and uncommon febrile syn-
dromes. The incidence of streptococcal infections has dropped considerably over the last
few decades in the developed countries, but is still very high in many parts of the world,
notably so in some subtropical areas. Streptococci include numerous strains, both pathogenic
and nonpathogenic. They are currently grouped A through H and K through T on the basis
of serologic cell wall properties. A discussion on their classification and antigenic grouping
is beyond the scope of this chapter.
In accordance with the design of this book, the main aspects for the consideration of
the clinician are (a) the spectrum of diseases caused by streptococci (see Table 3); (b) the
clinical picture of streptococcal diseases or complications which may arise as a result of
unexplained fever; and (c) the work-up for a correct diagnosis in these problematic cases.35
Nonsuppurative delayed sequelae of infections caused by Str. pyogenes (rheumatic fever
and acute glomerulonephritis) are discussed in other chapters.
Acute invasive streptococcal infections and bacteremia are usually associated with fever.
If an enterococcus is isolated on blood culture, infective endocarditis must first be considered.
334 Unexplained Fever

If Streptococcus bovis is isolated, there are two important considerations: (a) infective
endocarditis and (b) an investigation of the gastrointestinal tract, since recent studies36 have
shown that underlying carcinoma and polyps of the colon may serve as a portal of entry for
this organism.
The source and the setting of streptococcal infections are various, often local and obvious,
e.g., fingerprick, tonsilitis, skin ulcers, or soft-tissue abscesses; conversely, the source may
be obscure or overlooked, e.g., an intra-abdominal or prostatic abscess. In the latter, the
setting is frequently an immunocompromised host, with the organism acting as an oppor-
tunistic pathogen.
Beta-hemolytic streptococci (groups A and B), can occasionally cause a fulminant bac-
teremia. The clinical picture of streptococcal bacteremia in the initial phase, may include
the following signs and symptoms: high fever, shaking chills, nausea, vomiting, diarrhea
(in severe forms) or constipation, petechiae or purpura, anemia, confusion or delirium, and
splenomegaly.37,38
The work-up for establishing a correct diagnosis comprises: (a) the isolation and char-
acterization of streptococcus species from appropriate cultures (blood or samples taken from
the inflammatory site); and (b) the presence and significant rise of streptococcal antibodies
in the serum. The usual test is ASO (antistreptolysin titer) which rises in only 70 to 80%
of patients. A rising titer is indicative only of current or recent streptococcal infection.
Antibodies appear about 2 weeks after infection. Serum need not be taken more than once
every 2 weeks. For completion of the ASO test, a hemagglutination test (streptozyme) may
be made, being more sensitive in early detection of antibody responses; but, although rapid
and simple to perform, it has some limitations (sensitive only for pharyngeal infection).1
In the work-up for a case of unexplained fever, the clinician should be cautious in
interpreting the isolation of group A streptococci from pharyngeal cultures, because the
patient may be an asymptomatic carrier in the presence of a febrile state of another etiology.

P n eum ococcus (Streptococcus pneu m on iae)

This can produce pneumonia, empyema, endocarditis, meningitis, otitis, sinusitis, ar-
thritis (with contiguous osteomyelitis, especially in the elderly) and peritonitis (common
mostly in young girls, but also in patients with cirrhosis, liver carcinoma, or nephrotic
syndrome). The very rare instances of septicemia generally involve immunocompromised
patients. Special mention must be made of severe septicemia in individuals with asplenia
(anatomically or functionally absent spleen)39 and sickle-cell disease. Diagnosis can be made
quickly using C.I.E. (counter-immuno-electrophoresis). This bacterium is not usually as-
sociated with prolonged fever. Despite the progress in antibiotic therapy, mortality in pneu-
mococcal bacteremia is still high.

M en ingococcus
Meningococcal disease can induce problems of unexplained fever in the following cir-
cumstances: chronic meningococcemia (without meningitis). This clinical form is manifested
initially by a prodromal episode of upper respiratory illness, or a viral exanthem. A few
days or weeks after so-called recovery, the patient develops fever, weakness, headache,
petechial rash, splenomegaly, arthralgia or arthritis and, in severe cases, hypotension and
prostration. The pattern of fever is intermittent and the infection may last for weeks or
months, with afebrile periods lasting up to 10 days. Without adequate diagnosis and treat-
ment, severe complications may appear, e.g., carditis, nephritis and, especially, meningitis.
This clinical picture must be distinguished from that of recurrent meningococcal meningitis.40
The diagnosis of chronic meningococcemia requires a high index of suspicion.4142 The
differential diagnosis includes infective endocarditis, Schonlein-Henoch purpura, rheumatic
fever, gonococcal septicemia, malaria, secondary syphilis, and hypersensitivity diseases.
Fulminant meningococcemia (Waterhouse-Friderichsen syndrome) is a severe bacteremic
 335

infection which can kill an otherwise healthy adult within 4 to 6 h of onset of initial clinical
symptoms.10 The onset is abrupt with high fever, profound prostration, and a severe hem-
orrhagic syndrome (petechiae, purpura) which may evolve over a few hours. Signs of
meningeal irritation may appear later or are often absent. This clinical picture is associated
with vasomotor collapse (acute adrenal insufficiency) which may rapidly develop into shock,
myocarditis, disseminated intravascular coagulation, coma, and death. In such a catastrophic
situation, intravenous chloramphenicol 4 to 8 g/day and intravenous penicillin 20 to 24
million U/day may sometimes be lifesaving.10
The laboratory diagnosis of meningococcal infection requires the bactériologie isolation
of Neisseria meningitides from body fluids such as blood, cerebrospinal, synovial, pleural,
or pericardial fluid. The organism may also be recovered from material aspirated from skin
lesions and may be seen in Gram-stained smears of nodular petechiae or the buffy coat of
blood from patients with bacteremia. Counter-immunoelectrophoresis and latex agglutination
studies of the spinal fluid are also capable of detecting meningococcal antigens within a few
minutes of admission to the hospital.

G onococcus
Infection with Neisseria gonorrhoeae may generate problems of unexplained fever in
disseminated gonococcal infection (D.G.I.). This clinical designation includes gonococcal
bacteremia often associated with complications such as septic arthritis, endocarditis, toxic
hepatitis, and meningitis. Bacteremia occurs in approximately 1 to 3% of infected patients,
with a female predominance. Dissemination may occur from genital, rectal (especially in
male homosexuals), or pharyngeal sites of infection and, in women, usually at the onset of
menstruation; it should be emphasized that local infections are often asymptomatic before
dissemination.43 Inborn defect of complement production increases the risk for bacteremia,
especially with certain types of gonococci.44
In the first days, bacteremia is characterized by fever, polyarthralgia, tenosynovitis, and
a rash (petechial or pustular lesions on the extremities). In this phase, gonococci can be
isolated in blood cultures or demonstrated by immunofluorescent staining of gonococcal skin
lesions. In the second week, cutaneous signs subside, septic arthritis of one or two joints
is prominent and low-grade or high fever may persist. Gonococci may be isolated from
synovial fluid and, with more difficulty, from blood. The course of the infection is generally
subacute and the disease of moderate severity, but both endocarditis and meningitis have a
very poor prognosis.
The gonococcus is one of the étiologie factors of perihepatitis (Fitz-Hugh-Curtis syn-
drome). Fever, tenderness or pain in right upper quadrant (or bilateral upper abdominal pain)
and a hepatic friction rub may characterize the clinical picture. This syndrome may mimic
acute cholecystitis and may be associated with transient nonvisualization of the gallbladder
and mild liver function abnormalities. For further details, we refer the reader to Chapter 9.

L isteria m onocytogenes
Infection with this organism is of worldwide distribution and is being diagnosed with
increased frequency. Thus, in the University Hospital of Lausanne (Switzerland), 20 patients
were hospitalized during a 6-year period (1974 to 1980); 10 adults and 10 children.45 This
infection may create problems of unexplained fever with difficulties in clinical and bacte-
riological diagnosis.
The organism has been isolated from nonhuman mammals, birds, ticks, and crustaceae.
The infection may follow ingestion of contaminated milk or meat, or inhalation of infected
dust. Predisposing factors are immunosuppression (especially patients with neoplasia and
cirrhosis), pregnancy (mostly in the third trimester) and some professions, such as veteri-
narians and abattoir workers. The infection may also be observed in patients of apparently
good health.
336 U nex p la in ed F e ve r

The onset is nonspecific, characterized by fever, headache, nausea, and vomiting. There
are many clinical syndromes: the most frequent presentation is meningitis or meningoen-
cephalitis, generally indistinguishable from viral meningoencephalitis. Other clinical man-
ifestations associated with fever are pericarditis, osteomyelitis, peritonitis, abscesses in
various organs; the typhoidal form, with high fever and without localizing signs and symp-
toms requires a high index of suspicion. Transplacental transmission from mother to fetus
results in abortion, premature birth or stillbirth. In pregnant women, infection may be mild
and self-limited or even asymptomatic; however, if there is fever, pain in the back or loins,
diarrhea, or cutaneous itching, L iste ria infection should be suspected and blood cultures
requested.
Swiss authors45 emphasize the association of fever with neurologic deficits (damage of
various cranial nerves), without meningeal signs. Such a clinical picture should immediately
suggest L iste ria infection.
On bacteriologic examination, the organism and its colonies may easily be confused
with diphtheroids and streptococci and may be dismissed as an insignificant contaminant.
The laboratory must be alerted that L iste ria infection is suspected, so that selective culture
media be used. Serologic tests are of no value, due to nonspecific reactions (so-called natural
antibodies).

E rysipeloth rix rhusiopathiae

This Gram-positive bacillus is the causative agent of the Erysipeloid of Rosenbach, an
acute skin infection common in butchers and fish-handlers, but also as a result of scratches
caused by fish or mammal bones. The clinical picture of Erysipeloid is characteristic — a
purplish-red inflammation, especially of the fingers. Problems of unexplained fever may
arise from this rare bacteremic form in which there may be endocarditis, arthritis, meningitis,
and involvement of various organs. The skin lesions may have completely healed by the
time these complications appear. The diagnosis is made by blood cultures and by the presence
of specific agglutinins. The difficulties in diagnosis are reflected in a clinical pathologic
conference46 in which the discussion inclined toward Y ersin io sis or leptospirosis in a case
of E rysip elo th rix bacteremia.

A n aerobes
Anaerobic infections may generate problems of unexplained fever and are responsible
for 8 to 10% of general hospital bacteremias and 85% of suppurative brain infections.47
They are often polymicrobial in nature: the anaerobes may be associated with aerobes,
especially E. c o li , or with A c tin o m yces. Anaerobes can be allocated to one of two classes,
according to their origin: (1) exogenous species — generally found in soil, but also residing
in man (skin, buccal cavity, gastrointestinal tract, female genital tract). They are spore-
bearing rods, virulent, extremely toxic, their principal representative being C lo strid iu m ; (2)
endogenous species — nonsporing, a normal part of the body flora, and found particularly
in the intestines and pelvis. Their main representative is B a c te r o id e s fr a g ilis . Most exogenous
anaerobes cause nonfebrile diseases; a small proportion cause febrile infections: bacteremia,
pulmonary, biliary, intra-abdominal and post-abortion genital infections. C lo strid iu m bac-
teremia may develop in the setting of a septic surgical operation, a puerperal or post-abortum
infection, an underlying neoplastic disease, or decubitus ulcers, and may have a fulminant
evolution. The clinical features are high fever with chills, abdominal pain, intravascular
hemolysis with oliguria or anuria, jaundice and shock. Aggressive treatment with high doses
of intravenous aqueous penicillin or, in penicillin-allergic patients, clindamycin, a cepha-
losporin or chloramfenicol, may sometimes be life-saving.
Bacteremia with B a c te ro id e s f r a g ilis may also be severe, the main clinical features
being: abdominal abscesses, jaundice, thrombophlebitis and septic metastases (especially
 337

TABLE 4
Infections Due to Endogenous Anaerobes

1. Central nervous system: brain abscess, meningitis (rare)

2. Oral cavity, neck and respiratory system: periodontitis, space infections (lateral neck and retropharyngeal
area), middle ear infection, sinusitis, Ludwig’s angina, lung abscess, aspiration pneumonia, empyema
3. Abdomen: subphrenic abscess, liver abscess, peritonitis, paracolic collections, appendicitis, diverticulitis,
postoperative infections
4. Urogenital: puerperal fever, endometritis, salpingitis, renal abscess
5. Others: septicemia, endocarditis, osteomyelitis, perirectal abscess, infected decubitus ulcer

pulmonary). Table 4 lists the infections due to nonsporing endogenous anaerobes. Most of
these infections are associated with fever.48,49
The often forgotten anaerobic bacteremia, with F u so b a cteriu m n ecroph oru m following
oropharyngeal infection, deserves special mention. Besides the oral cavity, the primary focus
of infection may be in the respiratory or female genital tract, or may remain occult. The
classical clinical presentation of Lemierre’s post anginal septicemia, caused by this organism,
is a young patient with fever, chills, pain and swelling at the angle of the jaw, dysphagia,
and local septic thrombophlebitis. A characteristic feature of this infection is metastatic
abscess formation, most frequently involving the lungs and the large joints. The outcome
may sometimes be fatal. Treatment with appropriate bactericidal antibiotics and, when
indicated, associated with surgical drainage of metastatic abscesses, may be lifesaving.50'52
In patients with the clinical presentations described above, anaerobic infection or bac-
teremia should always be considered and isolation of the organism is mandatory. Collabo-
ration between the clinician and the bacteriologic laboratory is very important. Specimens
for culture include blood, various aspirates (transtracheal, abscess cavity) pleural fluid and
other tissues or fluids. Proper and accurate specimen collection, transport and handling in
the laboratory and rapid processing of samples are essential.

C am pylobacter fe tu s
C a m p ylo b a c te r fe tu s (formerly V ibrio fe tu s) is a lesser-known, yet ubiquitous agent
which can cause obscure fever and human infectious diarrhea. C a m p y lo b a c te r fe tu s may
cause a prolonged relapsing illness characterized essentially by fever, abdominal pain, con-
stitutional symptoms (myalgia, headache, arthralgia), nausea and vomiting, purulent dis-
charge with pain in the rectum, tenesmus, anemia, dehydration, and splenomegaly. In a
small percentage of cases, the illness may manifest as a typhoid-like syndrome, without
diarrhea. Transmission occurs through ingestion of contaminated food or water, or contact
with infected animals. Risk factors are immunodeficiency, pregnancy, and hypochlorhydria.
Infants and young adults, homosexuals, and hikers in the wilderness are at greater risk.
The spectrum of febrile syndromes or complications of C a m p y lo b a c te r infection is wide
and include bacteremia (often with septic thrombophlebitis), lung abscess, empyema, bac-
terial endocarditis, pericarditis, spontaneous bacterial peritonitis, cholecystitis, septic ar-
thritis, osteomyelitis, urinary tract infection, meningoencephalitis, brain abscess, subarachnoid
hemorrhage, cerebrovascular accidents, and fever and abortion in pregnant women. When
there are difficulties in establishing the diagnosis in the above-mentioned conditions, one
should suspect a C a m p y lo b a c te r infection, especially when abdominal pain and diarrhea are
associated symptoms in the course of the disease. The physician should alert the laboratory,
because special selective medium is required to identify C. f e tu s from stool cultures. Routine
blood cultures may be useful in bacteremic patients. Cultures must be kept for extended
periods of time. In some cases, Gram-staining of the stool may promptly identify the
organism.53,54
338 U nex p la in ed F ever

G ram -negative bacilli

The largest and clinicially most important family of Gram-negative bacilli is Entero-
bacteriaceae, and includes the following groups: E sch erich ia c o li , S a lm o n ella , A r izo n a ,
C itro b a cter, S h ig e lla , E n te ro b a c te r , H a fn ia , S e r r a d a , P ro te u s , and P ro vid en cia . Most of
these groups may generate febrile diseases, which may pose problems of unexplained fever,
in some period of their evolution.55
£■. c o li , a normal commensal in the gastrointestinal tract, is responsible for a wide variety
of clinical infections and is the leading cause of Gram-negative bacteremia in adults. It is
one of the most important opportunistic invaders in immunodeficient patients. The usual
portals of entry are the urogenital and gastrointestinal tract, the gallbladder, lung and skin;
less often, diagnostic procedures (intravenous catheter and others) may be involved. Fre-
quently, the portal of entry cannot be found in patients with immunodeficiency; the onset
of bacteremia may be abrupt, with chills, high fever, confusion, dyspnea, hypotension.
Evolution and complications of Gram-negative bacteremia have been discussed above. Not-
able E. c o li febrile infections include acute cholecystitis with gangrene and perforation,
multiple liver abscesses, pylephlebitis, acute nonsuppurative hepatitis, acute cholangitis,
subphrenic abscess, urinary tract infection, intra-abdominal abscess, perirectal abscess, septic
arthritis, suppurative thyroiditis, sinusitis, endocarditis, osteomyelitis and brain abscess. In
some of these above-mentioned infections surgery, associated with antibiotics, is manda-
tory.56 57
The other Enterobacteriaceae listed above are important agents of nosocomial infection,
but rarely cause primary infection. The clinical picture is very similar to that of E. c o li ;
however, a few distinguishing features exist. K le b sie lla tends to produce severe pulmonary
infections, particularly in alcoholics: severe pneumonia, pulmonary abscess, necrotizing
pneumonitis, pleural effusion and empyema. S e rra d a may be responsible for infection
associated with in-dwelling intravenous and intraperitoneal catheters, urinary tract instru-
mentation, and flexible fiberbronchoscopy.58,59
P ro teu s infections are generally nosocomial and involve multirésistant strains. They are
difficult to control, partly because of frequent antibiotic resistance and partly because they
predispose to urolithiasis which may cause urinary stasis, thereby maintaining bacterial
viability despite appropriate antibiotic treatment. Most P ro te u s bacteremias are linked to
urinary tract infection or instrumentation and a smaller part to biliary, gastrointestinal, and
ENT infections.
The most severe Gram-negative bacillary bacteremia is caused by P seu d o m o n a s a e ru -
g in o sa , which especially affects immunocompromised patients, particularly those with un-
derlying malignancy and bums; it is often hospital-acquired and may supervene in patients
on broad-spectrum antibiotics. The mortality is high (nearly 70%). Fever is associated with
bacteremia and various septic localizations. In infections with this organism, apart from the
usual manifestations of Gram-negative bacteremia, there may also be some unusual features:
(a) skin manifestations (ecthyma gangrenosum, rose spots, hemorrhagic cellulitis). Puncture
of skin lesions, followed by culture, may help isolate the organism, (b) P seu d o m o n a s
a eru g in o sa often invades blood vessels, causing mural necrosis as a result of vasculitis,
hence bacteremia may be associated with thrombosis or hemorrhage. Soave et al.60 described
a fatal pseudomonal bacteremia mimicking pulmonary thromboembolism and infarction in
a patient with immunodeficiency. Such cases underline the importance of blood cultures in
the investigation of febrile thromboembolism of obscure origin, (c) in some cases of P se u -
do m o n a s b a c te re m ia , the urine may be green due to excretion of a hemoglobin pigment,
verdoglobin. Localized P seu d o m o n a s infections are endocarditis, pneumonia, urinary tract
infections, osteomyelitis, pancreatic abscess, brain abscess, and nosocomial meningitis.

Yersinia gen u s
This includes three species of medical interest: Y. p e s d s , Y. e n te ro c o lid c a , and Y.
 339

p se u d o tu b ercu lo sis. Y. p e s tisis the causative agent of plague, a disease which in the past
centuries caused severe pandemics, but currently causes only sporadic cases, particularly in
hunters. Plague still exists in wild rodent populations in several areas of the world, including
the American West. Mann and Shaw61 report a case of a 5-year-old boy hospitalized for
fever (40.6°), pain in his left knee and leg and an exquisitely tender lymphadenitis in the
left groin. The patient lived in a small rural community in north-central New Mexico. The
affected lymph node was aspirated and smears were sent to the state laboratory where, within
hours, fluorescent antibody staining established a presumptive diagnosis of plague, later
confirmed by culture. Subsequent investigations showed evidence of active, rodent plague
in the vicinity of the patient’s home. Recovery was obtained after treatment with strepto-
mycin. The infection was transmitted through the bite of an infected flea. From 1970 to
1980, 121 cases of human plague were reported in the U.S. About 15% of plague cases are
primary septicemic (in which no palpable lymphadenitis is detected). Such cases may generate
problems of unexplained fever. The clinical picture is of a severe septicemia and potential
complications are meningitis and pneumonia.
Y ersinia e n te ro co litic a and pseudotuberculosis, usually animal pathogens, may cause a
variety of syndromes, manifested especially by fever, abdominal pain, diarrhea, and po-
lyarthritis. Transmission may be by contact with infected animals or contaminated food or
water. The reported incidence has strikingly increased in recent years: many thousands of
human cases were reported especially in Scandinavia and other parts of Europe. The most
important clinical manifestations are similar in both species and include septicemia, or
septicopyemia: rare but severe cases especially in immunosuppressed, debilitated patients
and in those with iron overload.
The septic localizations may be in (a) liver, meninges, spleen, lungs, kidney, heart (with
mycotic aneurysm); (b) gastrointestinal: enterocolitis (in young children); mesenteric adenitis,
which mimics appendicitis in older children; terminal ileitis, which mimics Crohn’s disease.
Facing a case presenting fever, pain in right lower quadrant, and leukocytosis in an older
child or adolescent, one suspects an acute appendicitis. At laparotomy, the appendix is
usually normal and large, inflamed, mesenteric lymph nodes are found; (c) miscellaneous:
septic arthritis (rare) and febrile reactive polyarthritis. This latter syndrome is linked to an
immunologic mechanism and manifested by an episode of acute diarrhea, followed a month
later by inflammatory arthropathies, involving large and small joints. Symptoms may persist
for some months and may mimic Reiter’s syndrome; this reactive polyarthritis is observed
especially in patients who carry the antigen HLA-B27. Other clinical manifestations are
erythema nodosum, carditis, granulomatous hepatitis, glomerulonephritis, in which the role
of Y ersinia has been incriminated only on the basis of positive serology. In such unexplained
clinical syndromes and also in cases when prolonged fever is the only symptom, serology
for Y ersinia should be included in the work-up.62 64 A Swedish author65 reports the case of
a 14-year-old girl presenting fever for 3 weeks without associated signs or symptoms. As
part of the serological investigation, an agglutination test for Y. e n te ro c o litic a was ordered.
The titer was 1:3000. On the basis of this high serological titer, tetracycline was administered.
Within a few days the temperature returned to normal and Y ersinia antibody titer was 1:200.
It was later found that the girl had been in contact with a chinchilla 4 or 5 days before the
onset of the fever.
Confirmation of Y ersinia infection is based on the isolation of the organism from blood,
stool, lymph node, C.S.F. or peritoneal fluid. Serologic tests may also be very useful.
P a ste u re lla m u lto c id a , a Gram-negative coccobacillus, may cause localized infections
and also, rarely, life-threatening septicemia. A large number of domestic animals (cats or
dogs) harbor this organism in their mouth. Localized infections are common after bites from
these animals. Bacteremia may arise even in the absence of a local lesion and may be
complicated by pneumonia, empyema, sinusitis, arthritis, pyelonephritis, peritonitis, and
meningitis. Rarely, this organism may cause severe septicemia in patients with chronic
340 U nex p la in ed F e ve r

disease (especially liver diseases) or cancer, with no animal contact. Over a 25-year period,
at the Memorial Sloan-Kettering Cancer Center in New York, P a ste u r ella m u lto cid a was
isolated in 11 patients, 2 of whom had bacteremia.66

H aem ophilus influenzae

H a em op h ilu s influenzae infections occur most often in children, but in recent years, an
increased rate of attack has been observed in adults. This organism is an important cause
of respiratory tract infections and may be invasive, causing epiglottitis, pericarditis, septic
arthritis and meningitis. There may be acute as well as subacute and prolonged clinical
forms. Problems of unexplained fever due to superinfection with H em o p h ilu s may arise in
patients on increased risk: post-splenectomy, sickle-cell disease and adults during and after
chemotherapy for Hodgkin’s disease, who may have bacteremia without local disease. In
these patients, “ the clinical course may progress to septic shock, often with death, within
hours of the initial medical evaluation. Early diagnosis and therapy are critical’’.67 Fever
with chills, anorexia, anxiety, and lethargy may be the main symptoms. Cultures of blood
and various other body fluids may confirm the diagnosis, but in emergency cases, C.I.E.
(counter-immunoelectrophoresis) may provide the diagnosis within hours.68

T ularem ia
Tularemia is a rare infection caused by a Gram-negative coccobacillus, F ra n cisella
tu laren sis.It is characterized by high fever and severe constitutional symptoms that may
persist for weeks to several months, if not treated appropriately. There are four clinical
types: the most frequent, ulceroglandular, comprises over 80% of cases; the remainder being
the glandular, oculoglandular and typhoidal forms. Problems of unexplained fever may arise
in the typhoidal and ulceroglandular forms: the former, because the disease may be manifested
only by fever without a primary lesion; the latter, because the primary lesion at the site of
infection (papule, ulceration of the skin or mucous membrane) may be overlooked. In these
two forms, the clinical and the differential diagnosis may be very difficult. The onset occurs
suddenly 3 to 7 days after the infective contact, with high fever, chills, headache, nausea,
vomiting, drenching sweats, severe prostration, regional lymph nodes, and splenomegaly.
The patient’s profession (farmer, hunter), the epidemiologic data (contact with infected
mammal, especially rabbit, or the bite of an infected arthropod), and the presence of pleu-
ropulmonary complications may suggest the diagnosis. In the work-up for an unexplained
fever with bizarre manifestations, one should always request an agglutination test for Fr.
tu laren sis which becomes positive after the second week of illness. A titer of 1:160 is
diagnostic of past or current infection. In most cases, skin tests become positive after the
third day. The difficulties in diagnosing tularemia were well expressed in a clinicopathologic
conference at the Barnes and Wohl Hospital (Washington University School of Medicine).69

Salm onellosis
The clinical picture in S a lm o n ella infection falls into three categories, namely, acute
gastroenteritis, enteric fever, and bacteremia. Fever is a major symptom in the last two.
The most important enteric fever is typhoid (Group D S a lm o n ella ) which is on the decline
in developed countries, but on the increase in others, such as India and Mexico, where it
is endemic. This epidemiological factor should be borne in mind when nonvaccinated pa-
tients, returning from a visit to these areas, present with fever. The diagnosis should also
be considered in patients who have recently eaten shellfish.
Apart from typhoid fever, other bacteria of the genus S a lm o n ella may raise problems
of unexplained fever, namely, 5. en te ritid is (serotypes paratyphi A and B) and S. c h o le r -
a esu is. These organisms may produce a clinical picture similar to typhoid fever, or food
poisoning or bacteremia. If blood and stool cultures are taken at an early stage, diagnosis
may be soon established. However, atypical forms, bacteremia and various septic metastases
 341

may create baffling problems. Thus, nontyphoid salmonella bacteremia, characterized by

spiking fever with rigors, sweats, anorexia, and weight loss, may last for weeks or months.
Rose spots and leukopenia may be absent. Blood cultures are often negative because discharge
of organisms into the bloodstream is intermittent. Stool cultures are also usually negative.
Repeated blood cultures are required. S a lm o n ella circulating in the blood may localize in
any organ or tissue and give rise to local infections with a possible febrile evolution, such
as bronchopneumonia, empyema, endocarditis, osteomyelitis, septic arthritis, meningitis,
pyelonephritis and various abscesses. The diagnosis is established by isolation of salmonella
from blood, feces, pus, or other body fluids.70"72
Agglutination tests on sera from acute and convalescent cases are often not useful, unless
the titer is high 01:560) or rising. S alm on ella is also one of the etiological agents of food
poisoning, which may have a febrile evolution. The contaminated food may include meats,
e.g., hamburger and precooked roast beef (S. n e w p o rt), powdered milk (5. n ew b ru n sw ick ),
chocolate (S. eastbourne ), marijuana (S. munchen ), inadequately pasteurized milk (S. dubliri),
that may cause severe or blood stream infections, and eggs or egg products.
The enteric fevers of which 5. typ h i is a common serotype are usually of 3 or 4 weeks
duration, but may be short and continue for only a week, or prolonged and last for several
months. It may be prolonged due to a complication or a metastatic abscess (cholecystitis,
pyelonephritis, mycotic aneurysm, pericarditis, arthritis, meningitis, osteomyelitis). Fever
may recur after a relapse and there may even be several relapses. Recurrent S alm o n ella
bacteremia in the presence of appropriate antibiotic therapy suggests an intra-arterial focus.
One third of patients with enteric fever are predisposed to metastatic infections by underlying
diseases, e.g., malignant lymphoma, SLE, cirrhosis, biliary tract diseases, cysts, aneurysms,
hematomas, various effusions, intramuscular injection sites, hematologic malignancies and
sickle cell disease (in which salmonellae are a frequent cause of osteomyelitis). In later
years, an increased frequency of S a lm o n ella infections has been observed in patients with
AIDS. Thus, S a lm o n ella bacteremia should always be considered in cases of obscure fever
and repeated blood cultures are required, because discharge of Salmonellae into the blood-
stream is intermittent.
The recovery of typhoid bacilli in the feces, in a febrile patient, should be considered
with circumspection and caution, because the patient may be a chronic carrier and the fever
due to another cause. The history can be misleading, as a number of chronic carriers may
have had subclinical episodes, not diagnosed at the time. In such situations, the test for Vi
antigen may frequently be helpful, since it may be positive (titer greater than 1:5) in 70%
of carriers. Prolonged S a lm o n ella bacteremia may occur in patients with schistosomiasis,
e.g., in Brazil (hepatosplenic form due to S ch ist, m an soni) or in Egypt (urinary tract infections
due to Schist, h a em a to b iu m ). In the latter form, patients are urinary carriers. Eradication of
schistosomiasis should also eliminate the bacteria lodged in the parasite’s intestine.
Some authors73 76 emphasize the changing pattern of typhoid fever. The disease has
considerably attenuated over the last few decades. Fever is the most frequent symptom,
followed by diarrhea. There is a notable decrease in other classical symptoms (abdominal
pain, asthenia, cough, myalgias, and sore throat). S a lm o n ella may be isolated from blood,
stool, urine, bile, bone marrow, liver biopsy material, skin snips from rose spots, and
purulent secretions (particularly in osteomyelitis, even several years after the initial infec-
tion).
The differential diagnosis of persistent fever due to S alm on ella species is extensive. The
most common conditions to be discussed are septicemia, miliary tuberculosis, brucellosis,
infective endocarditis, leptospirosis, rickettsiosis, Campylobacter infection, Yersiniosis,
rheumatic fever, inflammatory bowel disease and intraabdominal abscesses.

B rucellosis
Brucellosis is a disease with multisystem manifestations, often presenting as unexplained
342 Unexplained Fever

fever. It is on the decline, particularly in developed countries, but still has a worldwide
distribution and is endemic around the Mediterranean basin, in Mexico, Argentina, and
other areas. It should be suspected in certain occupations entailing livestock contact (slaugh-
terhouse workers, butchers, veterinarians, farmers), or, when unpasteurized dairy products
have been ingested. The principal species and their hosts are B. abortus (cattle), B. melitensis
(goats), B. suis (pigs), and B. canis (dogs). Human beings are secondary hosts. Two factors
may facilitate the diagnosis: (1) the epidemiologic data (70% of cases are occupational) and
(2) the laboratory investigations (blood culture, agglutination tests and others). However,
diagnosis can sometimes be very difficult, as symptoms may be masked by blind antibiotic
therapy; blood cultures may be negative even in the absence of antibacterial drug treatment;
Wright’s sérodiagnostic test may be negative for a long time, even when no interfering
antibodies exist. Fever may persist, despite suitable drug therapy, because of a deep focus
of infection which is difficult to identify. When faced with a febrile patient suspected of
brucellosis, one should establish which localization (or complication) maintains the fever,
in addition to the clinical and bacteriological diagnosis. Acute septicemic brucellosis is
frequently devoid of localized findings. The onset is rarely acute, most often insidious with
febrile periods lasting 15 to 20 days and separated by short symptom-free periods. Fever is
well-tolerated and associated with copious nocturnal sweating, diffuse pain, often spleno-
megaly, sometimes hepatomegaly and local or generalized lymphadenopathy. A pseudoty-
phoidal form with sustained fever exists and, in the immunocompromised patient, brucellosis
may take a polyviscéral, malignant form with severe complications, especially endocarditis.
Septic metastatic foci in various organs or tissues are occasionally observed in the acute
phase, but generally appear in the following months. A subacute or chronic form ensues
(after a year), with repeated febrile periods and remissions.
Septic métastasés may involve one of the following locations: (a) cardiovascular: en-
docarditis, thrombophlebitis; (b) hepatobiliary: granulomatous hepatitis, cholecystitis; (c)
osteoarticular: septic arthritis, spondylodiscitis, sacroiliitis; (d) glandular: orchi-epididymitis,
parotitis, mastitis; (e) pleuropulmonary: pneumonia, empyema; (f) neurologic: meningitis,
encephalitis, neuritis; (g) urological: glomerulonephritis, hematuria; (h) splenomegaly and
adenopathies are frequent features.
A French author70 cites two illustrative cases in which rare vascular complications of
brucella infection were the cause of prolonged fever. In the first case, the localization of
the infection was on an aneurysm of the posterior wall of the aorta, above the kidney. The
patient went into shock, which suggested rupture of the aneurysm. The diagnosis was
established at laparotomy. In the second case, a thrombophlebitis of the right calf appeared
after 5 weeks of unexplained fever. Wright’s agglutination test, which was initially negative,
rose to the titer 1:320. Cure was obtained with tetracyclines.
In a study published by Young,77 the author states that: “ Before we assume that human
brucellosis is now a rare disease in the United States, we must remember that the disease
is vastly under-diagnosed and under-reported. Some authorities78 have estimated that for
each case reported, another 26 are unrecognized and unreported’’. According to the author’s
documentation, certain states, namely, California, Iowa, Virginia, and Texas, account for
the majority of cases of human brucellosis in the U.S. The article contains nine reports of
documented active cases of brucellosis of humans (plus an additional case of chronic bru-
cellosis) discovered and treated in Houston, Texas between June 1981 and June 1982. These
cases express the great variation of clinical forms of the disease. We quote some of the
clinical features of the case reports: fever, urinary obstruction and leukopenia; fever, depres-
sion and orchitis in a part-time farmer; sweats and sciatica following a laboratory accident:
chronic meningitis and psychosis; fever and septic arthritis; fever, back pain and hepatitis.
The author emphasizes the frequency of nervousness and depression which may exist in up
to one half of patients with brucellosis.
The diagnosis of chronic brucellosis is often difficult to establish. The condition may
 343

persist for months or years giving rise to many “ functional” symptoms (pain, sweating,
asthenia, depression) and apart from mild splenomegaly, no abnormal physical findings.
Febrile episodes may reappear intermittently. Suppuration may occur in the liver, spleen or
kidneys and extensive investigation is required for detection and eradication. In fact, chronic
forms are rare. Are they really chronic or are they re-infections? It is not always easy to
tell. Laboratory tests are often helpful in determining the phase of the disease. The pathogen
should be isolated either from the blood, or occasionally, from biopsy material such as
lymph node, bone marrow, liver, or a metastatic focus.
Wright’s agglutination test is reliable, specific, and very rarely gives false negatives. A
titer of 1/80 or more is positive. False-positive results may be due to antigenic similarity
with tularemia, Y. e n te ro c o litic a , and cholera vaccination. False negatives are due to the
prozone phenomenon and interfering antibodies. The complement fixation test is sensitive
and reveals IgG antibodies present in chronic forms. Immunofluorescence is also useful in
chronic cases.
The laboratory should be alerted to the possibility of brucellosis; the cultures must be
preserved for 4 to 6 weeks. The differential diagnosis of brucellosis is very extensive due
to the polymorphism of the disease. It is most frequently confused with miliary tuberculosis,
typhoid fever, rheumatic fever, malaria, amebiasis, lymphoma, and collagen-vascular dis-
eases. In some instances, a low or false-positive agglutination test for brucellosis may lead
to an erroneous diagnosis of undulant fever.

R at-bite F ever
Rat-bite fever represents two febrile diseases caused by two distinct Gram-negative rods,
and S pirillu m m in o r , both following a rodent bite. When a
S trep to b a cillu s m on iliform u s
definite history of rodent or cat bite is obtained, the abrupt appearance of fever, local wound
and a rash, after an incubation of 3 to 21 days, obviously suggest the diagnosis. Problems
of unexplained fever may arise when the patient is unaware of the bite or when the infection
is associated with ingestion of milk contaminated by rats (Haverhill fever). The infection
in laboratory workers also may be overlooked as a viral illness. The diagnosis is difficult
on clinical grounds alone. The characteristics of these infections are

1. S trep to b a cillu s m on iliform is — Incubation 3 to 10 days, abrupt onset with fever, chills,
headache, myalgias, weakness. After several days, a morbiliform or petechial rash
appears involving the palms and soles. Arthritis, with joint effusion and lymphade-
nopathy, develop frequently. The primary wound usually heals. Fever may subside
after 3 to 4 days, but arthritis may persist. After an apyrexia of 3 to 6 days, the
temperature may rise again with return of constitutional symptoms, rash and lymph-
adenopathy. If untreated, relapses may occur for weeks or months. Febrile compli-
cations may also appear, such as: bacterial endocarditis, pericarditis, broncho-pneumonia,
parotitis, and brain abscess.
2. Spirillu m m in or — Incubation of 7 to 21 days. The clinical picture resembles the
preceding form: onset with a viral-like syndrome, with rash and evolution in relapses.
The difference is that, with the onset of fever, pain returns at the site of the bite, scar
breaks down and becomes an ulcer with lymphangitis and lymphadenitis. Arthritis is
uncommon. Confirmation of the diagnosis is based on the recovery of the organism
for S tre p to b a c illu s , culture of blood or joint fluid and serology (agglutination test);
for S p irillu m , darkfield examination of exudate from an infected site, or intraperitoneal
inoculation of mice or guinea pigs with blood or exudate. The differential diagnosis
includes: rocky mountain spotted fever, Coxsackie B virus infection, malaria, men-
ingococcemia, relapsing fever (Borrelia), infective endocarditis, acute rheumatic fever,
rickettsial infection, secondary syphilis, and drug fever.79
344 U n ex p la in ed F e ve r

B artonellosis
B a rto n ello sis (syn. Carrion’s disease) is caused by a small, motile aerobic Gram-negative
bacillus, B a rto n e lla b a c illifo rm is . The disease is endemic in Peru, Ecuador, and Colombia.
The organism invades the erythrocytes and reticuloendothelial cells. Various species of the
sandfly vector, Phlebotomus, transmit the infection. There are two clinical forms: febrile
(Oroya fever) and cutaneous (Verruga peruana). The former deserves a short mention because
it may create problems of unexplained fever. After an incubation of approximately 20 days,
or more, may appear a fever with shacking chills, malaise, headache, arthralgias, myalgias,
changes in mentation, adenopathies, and severe anemia. Some critical forms may develop
dyspnea, delirium, coma, and death. Intercurrent infections are common, especially sal-
monellosis, which may account for the prolongation of fever and adversely affect the prog-
nosis. During the acute febrile stage, the organism may be identified on Giemsa-stained
smears of the peripheral blood or by blood culture.80

SPIROCHETAL DISEASES
Spirochetal diseases may create problems of unexplained fever. The most important are
leptospirosis, relapsing fever, syphilis, and Lyme diseases.

Leptospirosis
L ep to sp iro sis is transmitted to man from animals (rodents, cats, dogs, pigs, cows) by
direct contact or during recreational activities (swimming in contaminated water). This
infection is widely spread throughout the world and is often forgotten in the differential
diagnosis of obscure fevers. The protean nature of symptoms and the frequency of atypical
clinical forms contribute to a low index of suspicion. Infection occurs at any age and may
vary from inapparent or clinically self-limited cases to life-threatening forms. Thus, lepto-
spirosis with jaundice is included in a recent study of fulminant community-acquired infec-
tious diseases.10 In fact, there are two important clinical forms: (a) anicteric leptospirosis
— the common milder form and (b) icteric leptospirosis (Weil’s disease) a severe form.

1. The anicteric form comprises 90% of cases and has a great variety of signs and
symptoms including: fever (97%), chills, headache, myalgia, nausea, diarrhea, ab-
dominal pain, conjunctivitis, hepato- and/or splenomegaly, rash, and lymphadenop-
athy. The evolution of this form is characteristically biphasic: a septicemic phase, with
most of the above-mentioned signs and symptoms, especially recurrent chills associated
with conjunctival suffusion, lasting 4 to 9 days; it follows an immune phase, in which
fever is usually not present or is low grade and lasts for only a few days. Severe
headache, myalgia, and meningismus may be presenting symptoms in this phase.
2. In the icteric form, jaundice may appear in the first week associated with oliguria or
anuria, hemorrhagic manifestations (petechiae, purpura, bleeding gums, epistaxis,
hematemesis, subarachnoid hemorrhage), vascular collapse, and mental confusion. In
this form, the high fever lasts approximately 5 days; subsequently, fever and jaundice
gradually diminish and apyrexia is reached in about three weeks. Mortality is still high
(5 to 30%).

Some clinical forms should be mentioned: (1) Fort Bragg Fever (L. au tu m n alis). Char-
acteristics are pretibial slightly raised 1 to 5 cm erythematous lesions; (2) Japanese 7-day
fever (L. h e b d o m a d is ); (3) Canefield’s fever in Queensland, Australia (L. a u stra lis); (4)
Swineherd’s disease (L. p o m o n a ) carried by pigs; (5) Canicola fever (L. ca n ic o la ) transmitted
by dogs. There are clinical febrile forms which may be diagnosed only by serological
investigation: aseptic meningitis, or jaundice which may suggest a viral origin. In cases of
jaundice, a very high creatine phosphokinase should call attention to the possibility of
leptospirosis.8182
 345

Laboratory diagnosis includes in the first week, blood and CSF cultures; after the first
week, urine culture, animal inoculation of blood and other specimens; Serology: microscopic
agglutination test; indirect fluorescent antibody test. The differential diagnosis includes
meningitis or meningoencephalitis, influenza, hepatitis, acute cholecystitis, nephritis, toxic
shock syndrome, Legionnaires disease, and Kawasaki syndrome.
Most cases of leptospirosis are recognized after 5 to 7 days of illness. Since a small
percentage of patients (average 6%) are diagnosed on the basis of positive cultures, and
serologic positive results may appear late, empiric antibiotic therapy should be considered
in suspected cases, when there are high fever, meningitis, severe liver dysfunction or he-
molysis. According to Levin et al.,10 in such cases doxycycline given early might modify
the fatal outcome of some of the more severely ill patients.

Relapsing Fever
A disease characterized by recurrent attacks of fever separated by periods of apyrexia
and caused by many strains of arthropod-borne spirochetes of the genus Borrelia. The human
body louse (Pediculus humanus) transmits the epidemic form of the disease and the ticks
of the genus Omithodorus, transmit the endemic form. There are not great variations in the
clinical picture of both forms, but generally the louse-borne disease is more severe. In the
U.S. tick-borne disease occurs mostly in Western and Southwestern areas. Other geographic
locations are for the tick-borne disease — foci throughout the world, especially in Central
Africa and South America; for the louse-borne disease — Egypt, Ethiopia, Sudan, India,
South America, and the Far East. Following an incubation of about 7 days, a sudden onset
of fever with chills which may be associated with nonspecific signs and symptoms (headache,
myalgias, arthralgias, cough, tachypnea, tachycardia, abdominal pain, vomiting, diarrhea,
conjunctival suffusion and petechiae). Some patients may also develop jaundice, bleeding,
neck stiffness, hepato- and/or splenomegaly, prostration and delirium.
Diagnosis is easy during epidemics and in an endemic area. Problems of unexplained
fever, especially in tick-borne disease, may arise in patients after traveling for occupational
or recreational reasons in an endemic area, where they may be exposed to contamination.
The tick bites are usually painless and the patient may not be aware of the exposure.
The differential diagnosis of relapsing fever is extensive and difficult: meningococcemia,
rickettsiosis, infectious hepatitis, leptospirosis, Q-fever, salmonellosis, rat-bite fever, ma-
laria, dengue, yellow-fever, and Colorado-tick fever. Diagnosis is suggested by the recurrent
paroxysms of fever and knowledge of travel in an endemic area. Confirmation is obtained
by demonstration of spirochetes in the blood, during a paroxysm, through darkfield ex-
amination, or thick or thin Wright or Giemsa stained blood smears. Other laboratory pro-
cedures are intraperitoneal injection of the patient’s blood into a mouse or rat. A complement-
fixation test may be positive in approximately 50% of patients with tick-borne disease. Initial
blood smears for spirochetes may be positive in approximately 70% of cases and this
emphasizes the importance of staining methods in diseases with abrupt onset of fever and
chills and associated with nonspecific constitutional symptoms.83

Syphilis
Syphilis (caused by the spirochete Treponema pallidum) continues to be a major problem,
although AIDS today represents the most important concern regarding sexually transmitted
diseases. Problems of unexplained fever may arise in syphilis in the second stage and
exceptionally also in the latent (tertiary) stage. The secondary stage appears within 6 to 12
weeks after the primary infection (chancre) and its manifestations may be transitory, or
persist for months. Young, sexually active persons and male homosexuals are commonly
affected. Secondary syphilis may present as flu-like, or as a variable systemic illness
characterized by fever, headache, sore throat, arthralgia, aching pains in the bones, nontender
rubbery lymph nodes, hepato- and/or splenomegaly, jaundice, neck stiffness, and cranial
346 Unexplained Fever

nerve lesions. In 80% of cases may appear mucocutaneous lesions (macules, papules, pus-
tules, squamous lesions and greyish-white mucous patches in the mouth or in the anal canal).84
In the absence of a history of a primary chancre, the clinical picture may mimic drug fever,
infectious mononucleosis, erythema multiforme or rubella. In Spain, Corral85 published two
cases of prolonged obscure fever, in which, after an extensive workup, the final diagnosis
was secondary syphilis: in the first case the presenting symptoms were fever, a macular rash
and uveitis; in the second case (who had brucellosis in the past), the presenting symptoms
were fever, lymphadenopathy, and weight loss, which suggested lymphoma.
In late (tertiary) syphilis, gummas in the liver may cause fever, hepatic tenderness and
a form of cirrhosis, with a characteristic shape of the organ (hepar lobatum). Serologic tests
(rapid plasma reagin, V.D.R.L., FTA-ABS, microhemagglutination assay) may confirm the
diagnosis. Failure to consider syphilis in the evaluation of obscure fever, especially in cases
associated with a rash, may be critical.84

Lyme Disease
Lyme disease is caused by the spirochete Borrelia burgdorferi, first recognized in Lyme,
Connecticut in 1975. The hallmarks of the disease are (a) skin lesion: erythema chronicum
migrans (an annular lesion developing at the site of the tick bite); (b) protean, clinical
manifestations: fever and chills, headache, malaise, pharyngitis, rash, arthralgias, myalgias,
lymphadenopathy and splenomegaly; (c) in a later stage (weeks to months, or even years)
complications may occur, such as febrile arthritis, intermittent, involving large joints, my-
ocarditis, meningoencephalitis, peripheral neuritis. The disease is not rare in the U.S. and
is known to occur also in Europe and in Australia. Visceral complications may occur,
especially in patients with B-cell alloantigen DR2. The vector is an Ixodes tick. The patient
contracts the disease on travel to areas of infestation by the vector. Diagnosis is made by
serology (indirect immunofluorescence) using the Lyme spirochete. Early diagnosis is im-
portant because early treatment may prevent complications later.86,87 Therapy: high-dose
aqueous penicillin G intravenous or tetracycline.

TUBERCULOSIS
Tuberculosis (TB) is a protean disease that can involve almost every organ system,
either singly or multiply. Over the past three decades, morbidity rates of TB have declined
progressively in developed countries. In the U.S. in recent years, the case rate has been
falling at a rate of 5 to 6% per year. Although morbidity and mortality have declined steadily
in most countries, the disease continues to be an important health problem. Case rates vary
with respect to age, sex, race, geographic location and socioeconomic factors. In developed
countries, the highest incidence of active disease is in aged nonwhite adults; in U.S. in
1985, the rate for nonwhites (blacks, Asian/Pacific Islanders, American Indians, and His-
panics), was 5.2 times that for whites.88 However, in many impoverished countries new
case rates are still very high. According to Daniel,89 half the population of the world is
infected with M. tuberculosis, there are 30 million new cases of active TB in the world,
ten million new cases occur annually and three million die of TB each year.
In most series published over the last decades, TB was a major infectious cause of fever
of unknown origin. However, as TB case rates have fallen, so has general awareness of the
disease and the index of suspicion of the attending clinicians. TB should be considered in
the differential diagnosis of any obscure illness characterized by unexplained fever, positive
PPD skin test and especially in indigent residents of inner cities, in immigrants from Southeast
Asia, Korea, Africa, India, in drug addicts, alcoholics, prisoners, nursing home residents,
and health care workers with potential prior contact with TB.90 Some granulomatous diseases,
without a definite diagnosis and some infections refractory to antibiotic treatment, especially
in immunocompromised host, should also raise suspicion of TB.90
 347

Of clinically active TB, 85% is pulmonary and the remainder are extrapulmonary.91 The
various aspects of pulmonary and miliary TB are discussed in Chapter 7. We shall consider
some basic concepts and diagnostic clues in extrapulmonary TB.
Disseminated TB can occur either together with the primary or the postprimary phase
of pulmonary TB. Tubercle bacilli from the primary focus may drain to regional lymph
nodes and subsequently reach the systemic circulation, through the lymphatics with the
potentiality of seeding in various organ-systems. Granuloma formation may occur, especially
in areas characterized by high local 0 2 tension (kidney, bone, spine, brain).
By far the most common outcome of the initial infection is healing with granuloma
formation, in which the bacilli may remain latent, yet viable for the life of the host. In a
small proportion of cases, one of the granulomas breaks down and the tuberculous infection
may be reactivated. This process can occur in a few months, or many decades after the
initial infection. More commonly in the adult, disseminated TB (after the post-primary phase)
may take the form of a chronic illness, with low-grade fever and few or no pulmonary signs
or symptoms.
Factors leading to reactivation include (1) old-age; (2) a family history of TB; (3) previous
tuberculous exposure; (4) male sex; (5) general deterioration in health; (6) alcoholism; (7)
steroid and other forms of immunosuppressive therapy; (8) postgastrectomy states and post
ileojejunal by-pass; (9) poorly controlled diabetes; (10) renal failure; (11) preexisting lung
damage (silicosis, pulmonary resection, lung abscess); (12) trauma (especially bone injury);
(13) race (Negroid or Asian, although here re-infection may also be involved); and (14)
blood dyscrasias. Extrapulmonary TB may involve any organ system and may occur without
pulmonary symptoms and without a suspicious chest X-ray. TB can resemble other lesions
and present in a rather atypical pattern. Especially in the elderly, other disorders may coexist
and alter the clinical presentation.
In 1985, Weir and Thornton92 stated that “ Although the incidence of pulmonary TB
throughout the United States is declining at a rapid rate, the number of cases of extrapul-
monary tuberculosis has remained constant” . They investigated all new cases of active
tuberculous infection identified at a 522-bed community hospital over an 11-year period.
Forty-five foci of extrapulmonary infection were diagnosed in 38 patients. Extrapulmonary
tuberculosis accounted for 37% of all new cases of active TB. Involvement of the geni-
tourinary, lymphatic, and respiratory systems (other than the lung) was most frequent and
accounted for 58% of all infections. The most common presenting symptoms were malaise,
fever, weight loss, and fatigue. There was a wide range in delay of diagnosis, which varied
from days to many years: the median delay was 2 months.
Extrapulmonary TB may result from hematogenous and/or lymphogenous spread or
direct extension from pulmonary or nonpulmonary lesion. The tuberculin test is nearly always
positive and ESR is usually elevated. The signs and symptoms depend on the organ involved,
and their evaluation corroborated with factors leading to reactivation of old TB (above
mentioned) can lead to the correct diagnosis.
Extrapulmonary tuberculosis occurs principally in the following organ systems or lo-
cations:

1. Respiratory: main bronchi, trachea and larynx

2. Cardiovascular: myocardium, pericardium
3. Alimentary tract: buccal cavity and tongue, tonsils, esophagus, stomach, small bowel,
ilio-cecal, fistula-in-ano, ischio-rectal (abscess); peritoneum, liver
4. Hematopoietic: lymph nodes, spleen
5. Osteo-articular: tuberculous osteomyelitis, tuberculous spondylitis (Pott’s disease);
articular TB (especially hip, knee, elbow or wrist)
6. Genitourinary: kidney, bladder, epididymis, salpinx
7. C.N.S.: meningitis, intracranial tuberculoma
348 U n ex p la in ed F e ve r

8. Exo- and endocrine: adrenal, breast, thyroid

9. ENT and eyes: otitis media, mastoiditis, chloroidal tubercles, phlyctenular conjunc-
tivitis
10. Skin: erythema nodosum

Most of these locations are discussed on a larger scale in the chapters dealing with fever
in various organ-systems. Some of them have particular aspects, especially concerning the
differential diagnosis. Thus, the issue of TB is sometimes misdiagnosed as cancer. In 1984,
Pitlik et al.93 published a study concerning 26 patients with TB who were referred to a
Cancer Center in Houston, Texas with a presumptive diagnosis of malignant disease. The
most frequent initial diagnosis in this series were lung cancer, lymphoma, and breast cancer.
The final diagnoses were 12 pulmonary TB, 7 TB lymphadenitis, 3 TB mastitis, 1 miliary
TB, 1 Pott’s disease, 1 pharyngeal, pulmonary and renal TB. In 1977, Dent and Weber94
emphasized the tendency of mammary TB to mimic breast cancer. They report on 21 patients
who were seen at Groote Schuur Hospital (Cape Town) with breast TB presenting with fixed
subcutaneous nodules, large fixed, central masses with edema and ulceration. The initial
diagnosis was either breast abscess or advanced carcinoma. Histological and bacteriological
investigations confirmed the diagnosis of breast TB. Two other studies95 96 emphasize the
importance of this differential diagnosis especially when a lump is found in patients partic-
ularly at risk for TB.
TB myocarditis should be considered when cardiac arrhythmias occur in a young man
with an active tuberculous process elsewhere in the body and even in an otherwise healthy
immigrant.97 The cause of this complication is direct spread of TB from mediastinal lymph
nodes to the myocardium.
In the evaluation of upper airway obstruction, endotracheobronchial TB must be con-
sidered;98 tuberculous laryngitis is frequently misdiagnosed as carcinoma of the larynx.
There are many similarities between TB and sarcoidosis as well as between intestinal
TB and Crohn’s disease. If, after an extensive work-up, doubt persists as to the correct
diagnosis, it is safer to treat the condition as though it were TB, rather than administer
corticosteroids which may involve critical complications.99
Tuberculous lymphadenitis may present difficult differential diagnosis especially when
intra-abdominal or retroperitoneal. In 1984 at a clinicopathologic conference in Paris, the
case of a 47-year-old man with an unexplained fever lasting for 2 months, and without any
associated symptoms, was discussed.100 The final diagnosis, after exploratory laparotomy,
was tuberculosis of the peripancreatic lymph nodes.
In another case, a 42-year-old woman was extensively evaluated for fever of 8 months
duration. The only diagnostic clues were calcification of the adrenals and paralumbar ret-
roperitoneal lymph nodes, and raw-milk ingestion from non-tuberculin-tested cattle in her
youth. There was a dramatic and complete response to antituberculous therapy.101
Tuberculous meningitis is fortunately rare, as it is potentially a very serious disease.
Cranial nerve palsies (particularly sixth nerve), severe headache, seizures, mental disorders,
often associated with fever, in an individual with previous tuberculous exposure are sugges-
tive of the diagnosis, which must be considered promptly, because early treatment may be
lifesaving. Tuberculomas, also often associated with fever, tend to present in adult life,
have symptoms associated with space-occupying lesions, and may be diagnosed by brain
scanning or CT. Osteoarticular TB is becoming more common in adults and should always
be considered in the work-up for unexplained fever. Pain, local swelling, and tenderness
may suggest osteomyelitis, which should be confirmed by X-ray (local and chest), a tub-
erculin skin test and needle or open biopsy of the suspected bone lesion (tissue for histo-
pathology and culture).
In 50% of patients with skeletal TB there is also concomitant pulmonary TB; the presence
of chronic draining sinuses resistant to antibiotic therapy may suggest osteoarticular TB.
 349

Delays in diagnosis are frequent. Weight-bearing joints and vertebral bodies are frequently
involved.102104
TB of the alimentary tract (gastrointestinal, hepatic) is discussed in detail in Chapters
7 and 9. Certain hematologic and serum chemical abnormalities, associated with features
predisposing to TB, may suggest tuberculous infection:105106 anemia, thrombocytopenia or
pancytopenia, monocytic leukemoid reaction, increased serum IgG, increased serum calcium,
increased serum prolactin levels and increased alkaline phosphatase. Hyponatremia should
suggest meningeal disease or adrenal insufficiency. Atypical mycobacteria, known as MOTT
organisms (mycobacteria other than tuberculosis) may produce disseminated diseases in
severely immunocompromised hosts (patients with AIDS or organ transplantation). They do
not spread from person to person, in contrast to tubercle bacilli.91
Pulmonary and extrapulmonary TB are common among patients with AIDS and human
immunodeficiency virus infection (HIV). Among patients with AIDS, the most frequently
isolated agent is the atypical bacteria Mycobacterium avium (intracellular), but in some
groups as Haitians and intravenous drug users, M. tuberculosis is more common. Dissem-
inated (miliary) form of TB and lymph node TB are the most frequent extrapulmonary forms
affecting these patients in whom the tuberculin skin test may often be falsely negative,
because of immunosuppression associated with HIV infection. Appropriate specimens to
establish a culture-confirmed diagnosis of TB include respiratory secretions, urine, blood,
lymph node, bone marrow, liver, or other tissue or body fluid that is clinically indicated.107
Extrapulmonary TB is frequently overlooked because (1) the protean nature of the
disease; (2) lack of a simple screening test; (3) associated nontuberculous disorders or
concomitant illnesses that may alter the clinical presentation. Failure to diagnose TB in due
time, may lead to deterioration and ultimately, death. A Scandinavian autopsy series108 and
an American study,109 discuss the causes of active TB, undiagnosed until autopsy. They
indicate the value of the various diagnostic procedures, the possible errors in the evaluation
of suspected cases, especially in the elderly, and the causes of the long delays between the
onset of symptoms and the final diagnosis. TB is an elusive disease, even in countries with
advanced medical technology. In the evaluation of a case of unexplained fever, the physician
must always keep TB on the suspect list.110

FEVER IN PARASITIC DISEASES

Infection by certain parasites may create problems of unexplained fever. Some infes-
tations due to protozoa and worms may evolve with fever and they should be considered in
the differential diagnosis of many illnesses. Of particular importance in the medical history,
are animal contact, ingestion of infected food, socioeconomic status, and transfusions.
Parasitic diseases are relatively easily confirmed by detection of ova and/or parasites in stool
specimen or by serologic tests. Eosinophilia is frequent and is an important ancillary test in
diagnosis. Once diagnosed, we have at our disposal several effective therapeutic agents.
Many of the protozoan and helminthic diseases are discussed in Chapters 7 and 18. Here,
we shall comment only on some diseases not fully discussed elsewhere.

Toxoplasmosis
Toxoplasmosis is caused by Toxoplasma gondii, a small intracellular protozoan parasite
that can infect any warm-blooded animal, especially cats, as well as some species of reptiles
and birds. It has worldwide distribution. The prevalence of positive serologic reactions in
normal adults in the U. S. varies from 20 to 70% depending on age and region.111 Transmission
may occur by ingestion of unpasteurized milk, raw eggs or undercooked meat, by blood or
leukocyte transfusion, by transplantation of organs from infected donors, by exposure to cat
feces (emptying kitty litter or playing in contaminated sandboxes), by exposure to cock-
roaches (passive vector), by accidental self-inoculation in laboratory workers and transpla-
centally, from mother to fetus (in 33% of acute infections).
350 U nex p la in ed F e ve r

The main clinical features of this infection are (1) acute acquired toxoplasmosis; (2)
congenital form; and (3) ocular involvement. However, the acute acquired variety (in the
immunocompetent, as well as the immunocompromised patient), frequently associated with
fever, deserves to be discussed.1121,3 It should be emphasized that 85% of the acquired
forms are usually asymptomatic. In the immunocompetent host, about 15% of adults with
this infection may develop a syndrome that resembles infectious mononucleosis with fever,
local or general lymphadenopathy (especially cervical), malaise, hepato- and/or splenomeg-
aly, maculopapular rash (which spares palms and soles), myalgia, arthralgia, stiff neck,
confusion, and a peripheral lymphocytosis with atypical forms. Rarely, in this group, severe
pulmonary, cardiovascular or neurologic manifestations may occur.
In immunocompromised patients, an acute disseminated infection may be fulminant or
even fatal. The clinical picture includes high fever with chills, prostration, CNS involvement
(change in mental status, focal neurologic deficits, cerebral mass lesions, meningoence-
phalitis), pneumonitis, myocarditis, pericarditis, and hepatitis. Toxoplasmic encephalitis is
a severe opportunistic complication in patients with AIDS.114115 T oxoplasm a infection in
pregnancy is symptomatic in only about 10 to 20% of cases.
Since the manifestations of toxoplasmosis are protean, a definite diagnosis cannot be
established on clinical grounds alone. The diagnostic procedures and laboratory tests are (1)
isolation of T. g o n d ii in body fluids, inoculated intraperitoneally into mice or isolation from
tissues obtained by biopsy; (2) histologic diagnosis by lymph node biopsy. Both these
techniques are not available routinely. Serological tests are useful: the Sabin-Feldman dye
test is a useful screening tool. The IgM immunofluorescent antibody (IgM-IFA) may detect
early disease within the first 2 to 4 months of illness; in recent years, the IgG indirect
immunofluorescent antibody test (IgG-IFA) has replaced the Sabin-Feldman dye test in
virtually all laboratories. It is also indicative of acute infection. As Dinarello and Wolff
stated116 “ Toxoplasmosis can manifest as FUO and is often discovered in patients with
lymph-node enlargement during lymph-node biopsy. A few patients have minimal lymph-
node swelling and may have fever as the predominant symptom. Rising antibody titers can
detect the disease when it is suspected” . A syndrome of retroperitoneal lymphadenopathy
with fever mimicking lymphoma, in reality may be toxoplasmosis, a disease which should
always be kept on the suspect list.

Babesiosis
Babesiosis is a disease which often evolves with fever. It is caused by intraerythroeitic
protozoan parasites of the genus B a b e sia . This infection is common in both domestic and
wild animals. The parasite is transmitted from animal to man by the bite of ticks (of the
genera Ixodes, D e rm a c e n to r , R h ip icep h a lu s). The most important causative agents are bovine
parasites (B . b o vis, B. d iv erg e n s) or rodent parasites (B . m ic ro ti). Babesiosis should be
considered in any patient with fever, a history of tick bite, a prior splenectomy, a blood
transfusion, or sojourn in endemic areas (in U.S.: Nantucket, Massachusetts, New York,
Long Island Sound; in Europe: Yugoslavia, USSR, France, Scotland, Ireland). An associated
hemolytic anemia is very suggestive.117
Human babesiosis may present as (1) a severe febrile illness, with jaundice, hemoglo-
binuria and occasionally, a fulminant fatal evolution, especially in splenectomized patients;
(2) a moderate-to-severe clinical infection characterized by fever with shacking chills, drench-
ing sweats, splenomegaly, arthralgia, myalgia, nausea, vomiting, mental depression, and
abnormal liver tests. Symptoms may wax and wane for several weeks before the diagnosis
is made; (3) mild illness not suggestive of a specific infection; (4) subclinical infection
detected through serologic surveys and retrospective study. The incubation period ranges
from 7 to 16 days. In patients with fever and hemolytic anemia, one must always search
for and identify the intraerythrocytic parasite in Giemsa-stained peripheral blood smears.
Confirmation of the diagnosis may also be obtained through serologic tests (indirect fluo-
 351

rescent antibody and/or ELISA test) or inoculation of the patient’s blood into a susceptible
laboratory animal.

Trichinosis
Trichinosis is a disease caused by the nematode Trichinella spiralis. The infection
develops when undercooked pork or bear meat, contaminated with larvae of the nematode,
is eaten. Trichinosis may sometimes create difficult problems of differential diagnosis.118
Many patients remain asymptomatic. Within 1 to 2 days after ingestion of the infected meat,
a slight fever may appear, associated with diarrhea, abdominal pain, nausea and vomiting.
During the second week, the most important signs and symptoms may appear: (1) periorbital
edema, followed by subconjunctival and retinal hemorrhage and photophobia; (2) fever,
which is generally remittent, rising to 39°C (102.2°F) or higher; it is of variable duration
and is present in 70 to 100% of cases (according to reported outbreaks); (3) painful myositis
predominantly in extraocular muscles, masseter, neck muscles, limb flexors and lumbar
muscles; (4) eosinophilia, which reaches its height (40% or more) in the third or fourth
week. Additional signs and symptoms are represented by dyspnea (sometimes severe),
headache, dysphagia, sweating, weakness, prostration and a macular or petechial rash.
Invasion of lung, heart or CNS may cause severe complications: pneumonia, pleurisy,
hemoptysis, myocarditis, congestive heart failure, meningitis, encephalitis, polyneuritis,
pareses, psychosis and coma. The clinical picture may be confused with a wide variety of
diseases, including angioneurotic edema, sinusitis, sepsis, tuberculosis, brucellosis, typhoid
fever, polyarteritis nodosa, dermatomyositis, glomerulonephritis, and rickettsiosis. Serologic
tests may help to confirm the diagnosis. ELISA test may detect the specific antibodies in
the first week of infection. The bentonite flocculation test (most widely used) and other
serologies, may detect antibodies starting from the third week. A muscle biopsy (deltoid or
gastrocnemius), may detect larvae or cysts after the third week.

REFERENCES
1. Reese, R. E. and Douglas, R. G., A Practical Approach to Infectious Diseases, Little, Brown, Boston,
1986.
2. Jacobs, E. R. and Bone, R. C., Clinical indicators in sepsis and septic adult respiratory distress syndrome,
Med. Clin. North Am., 70(4), 921, 1986.
3. Braude, A. T. etal., Infectious Diseases and Medical Microbiology, 2nded., W. B. Saunders, Philadelphia,
1986.
4. Bone, R. C. et al., A controlled clinical trial of high-dose méthylprednisolone in the treatment of severe
sepsis and septic shock, N. Engl. J. Med., 317(11), 653, 1987.
5. Casey, K. K. and Weinstein, M. P., Gram-negative bacteremia: detection, diagnosis and management,
J. Crit. Illness, 1(2), 28, 1986.
6. Hermans, P. E. and Washington, J. A., Polymicrobial bacteremia, Ann. Intern. Med., 73, 387, 1970.
7. Jacobi, G. A., Jr. and Hyslop, N. E., Jr., Intermittent polymicrobial bacteremia and fever, N. Engl. J.
Med., 301, 488, 1979.
8. Elting, L. S. et al., Polymicrobial septicemia in the cancer patient, Medicine, 65(4), 218, 1986.
9. Mellors, J. W. et al., A simple index to identify occult bacterial infection in adults with acute unexplained
fever, Arch. Intern. Med., 147, 666, 1987.
10. Levin, L. and Goodman, L. J., Fulminant community-acquired infectious diseases: diagnostic problems,
Med. Clin. North Am., 70(5), 967, 1986.
11. Setia, U. and Gross, P., Bacteremia in a community hospital, Arch. Intern. Med., 137, 1698, 1979.
12. McCabe, W. R. et al., Pathophysiology of bacteremia, Am. J. Med., 75 (Suppl.), 7, 1983.
13. Cates, K. L., Host factors in bacteremia, Am. J. Med., 75 (Suppl.), 19, 1983.
14. Maki, D. G. et al., Semi-quantitative culture method for identifying intravenous catheter related infection,
N. Engl. J. Med., 296, 1305, 1977.
352 Unexplained Fever

15. Bryan, C. S. et al., Analysis of 1186 episodes of gram-negative bacteremia in non-university hospitals:
the effects of antimicrobial therapy, Rev. Infect. Dis., 5, 629, 1983.
16. Young, L. S., Gram-negative sepsis, in Principles and Practice of Infectious Disease, Mandell, G ., Douglas,
R. G., and Bennett, J., Eds., John Wiley & Sons, New York, 1979, 575.
17. Fisher, L., Infectious disease emergencies, West. J. Med., 125, 131, 1976.
18. The Veterans Administration Systemic Sepsis Cooperative Study Group, Effect of high-dose glucocorticoid
therapy on mortality in patients with clinical signs of systemic sepsis, N. Engl. J. Med., 317(11), 659,
1987.
19. Weinstein, M. P. and Relier, L. B., Clinical importance of “ breakthrough” bacteremia, Am. J. Med.,
76, 175, 1984.
20. Anderson, E. T. et al., Simultaneous antibiotic levels in “ breakthrough” gram-negative rod bacteremia,
Am. J. Med., 61, 493, 1976.
21. Weinberg, A. N. and Scully, R., C.P.C. sepsis of unusual origin in a middle-aged woman, N. Engl. J.
Med., 18, 932, 1970.
22. Younkin, S. V. et al., Well-tolerated bacteremia of five years’ duration, JAMA, 248(18), 2310, 1982.
23. Bayer, A. S. et al., Staphylococcus aureus bacteremia, Arch. Intern. Med., 147, 457, 1987.
24. Bryan, C. S. et al., Staphylococcal bacteremia: current patterns in non-university hospitals, South Med.
J., 77, 693, 1984.
25. Gransden, W. R. et al., Staphylococcus aureus bacteremia: 400 episodes in St. Thomas’s Hospital, Br.
Med. J., 288, 300, 1984.
26. Lowy, F. D. and Hammer, S. U., Staphylococcus epidermidis infections, Ann. Intern. Med., 99, 834,
1983.
27. Sitges-Serra, A. et al., Catheter sepsis due to Staph, epidermidis during parenteral nutrition, Surg. Gynecol.
Obstetr., 1515, 481, 1980.
28. Christensen, G. D. et al., Nosocomial septicemia due to multiple antibiotic-resistant Staphylococcus
epidermidis, Ann. Intern. Med., 96, 1, 1982.
29. Nolan, C. U. and Beaty, H. N., Staphylococcus aureus bacteremia: current clinical problems, Am. J.
Med., 60, 495, 1976.
30. Sheagren, J. N., Staphylococcus aureus: the persistent pathogen, N. Engl. J. Med., 310, 1437, 1984.
31. Armengaud, M., Varieties sémiologiques des infections a staphylocoques, Rev. Prat. (Paris), 49, 3135,
1982.
32. Tofte, R. W. and Williams, D. N., Clinical and laboratory manifestations of toxic shock syndrome, Ann.
Intern. Med., 96 (Part II), 843, 1982.
33. Greenman, R. L. and Immerman, R. P., Toxic shock syndrome, Postgrad. Med., 81(4), 147, 1987.
34. MacDonald, K. L. et al., Toxic shock syndrome. A newly recognized complication of influenza and
influenza-like illness, JAMA, 257(8), 1053, 1987.
35. Francioli, P. et al., Septicémies a Streptocoques du groupe B, Schweiz. Med. Wschr., 113(2), 40, 1983.
36. Klein, R. S. et al., Streptococcus bovis septicemia and carcinoma of the colon, Ann. Intern. Med., 91,
560, 1979.
37. Hable, K. A. et al., Group A-beta-hemolytic streptococcemia, Mayo Clin. Proc., 48, 336, 1973.
38. Baker, C. J., Group B streptococcal infections, Adv. Intern. Med., 25, 475, 1980.
39. Gransden, W. R. et al., Pneumococcal bacteremia: 325 episodes diagnosed at St. Thomas’s Hospital, Br.
Med. J., 290, 505, 1985.
40. Peltola, H., Meningococcal disease: still with us, Rev. Infect. Dis., 5(1), 71, 1983.
41. Benoit, F. L., Chronic meningococcemia. Case Report and review of the literature, Am. J. Med., 35, 103,
1963.
42. Hoffman, R. and Schomerus, H., Chronische Meningokokkensepsis als Ursache unklaren Fiebers, Der
Intern., 24, 648, 1983.
43. Holmes, K. K. et al., Disseminated gonococcal infection, Ann. Intern. Med., 74, 979, 1971.
44. Walker, L. C. et al., Circulating immune-complexes in disseminated gonorrheal infection, Ann. Intern.
Med., 28, 89, 1978.
45. Yersin, B. R. et al., Infections a Listeria monocytogenes chez l’adulte, Schweiz. Med. Wschr., iii, 1596,
1981.
46. Clinico-pathologic conference, No. 16/1978, N. Engl. J. Med., 298, 957, 1978.
47. Gorbach, S. L. and Barlett, J. G., Medical progress: anaerobic infections, N. Engl. J. Med., 290, 1177,
1974.
48. Finegold, S. U. et al., Management of anaerobic infections, Ann. Int. Med., 83, 375, 1975.
49. Finegold, S., Anaerobic Bacteria in Human Disease, Academic Press, New York, 1977.
50. Sharon, H. et al., Bacteremia due to Fusobacterium species, Am. J. Med., 75, 225, 1983.
51. Seidenfeld, S. M. et al., Fusobacterium necrophorum septicemia following oro-pharyngeal infection, JAMA,
248/ii, 1348, 1982.
52. Hirschel, B. et al., Septicemie a anaerobes apres infections oropharyngees (septicémie post-angine de
Lemierre): un syndrome oublie, Schweiz. Med. Wschr., 113, 2008, 1983.
 353

53. Amin, M. N., Campylobacter-caused diarrhea, Postgrad. Med., 75(5), 89, 1984.
54. Megraud, F., Campylobacter, nouveaux développements, Presse Med. (Paris), 13(26), 1598, 1984.
55. Krieger, B. E. et al., Gram-negative bacteremia, Am. J. Med., 68, 332, 1980.
56. Sack, R. B., Human diarrheal disease caused by enterotoxigenic Esch, coli, Annu. Rev. Microbiol., 29,
333, 1975.
57. Saksouk, F. and Salti, S., Acute suppurative thyroiditis caused by Esch, coli, Br. Med. J., 2, 23, 1977.
58. Goldenberg, D. L. et al., Acute arthritis caused by gram-negative bacilli, Medicine, 53, 197, 1974.
59. Steinhauer, B. W. et al., The Klebsiella-Enterobacter-Serratia division. Clinical and epidemiologic char-
acteristics, Ann. Intern. Med., 65, 1180, 1966.
60. Soave, R. et al., Bacterial invasion of pulmonary vessels. Pseudomonas bacteremia mimicking pulmonary
thromboembolism with infarction, Am. J. Med., 65, 864, 1978.
61. Mann, J. M. and Shaw, R. F., Febrile lymphadenitis in the American West, Hosp. Pract., 18(1), 51,
1983.
62. Leina, R. and Kalliomak, J. L., Yersiniosis as an internal disease, Ann. Intern. Med., 81, 458, 1974.
63. Kohl, S., Yersinia enterocolitica: a significant “ new” pathogen, Hosp. Pract., 13(12), 81, 1978.
64. Canton, Ph. et al., Manifestations cliniques imputées aux Yersinia, Rev. Prat. (Paris), 33(45), 2403,
1983.
65. Bliddal, J. and Kaliszan, S., Prolonged monosymptomatic fever due to Yersinia enterocolitica, Acta Med.
Scand., 201, 387, 1977.
66. Stein, A. A. et al., Pasteurella multocida septicemia, JAMA, 249(4), 508, 1983.
67. Smith, D. H., Haemophilus influenzae, in Principles and Practice of Infectious Diseases, Mandell, G.,
Douglas, R. G., and Bennett, J., Eds., John Wiley & Sons, 1979, 1763.
68. Crowe, H. M. and Levitz, R. E., Invasive Haemophilus influenzae disease in adults, Arch. Intern. Med.,
147, 241, 1987.
69. Clinicopathologic Conference, Fever, leukopenia, acute renal failure and death in a 65-year old man, Am.
J. Med., 77, 117, 1984.
70. Rault, P., Les fievres prolongées de diagnostique difficile, These Paris, Université Bichat, Beaujon, No.
90, 1973.
71. Mandai, B. K., Typhoid and paratyphoid fever, Clin. Gastroenterol., 8, 715, 1979.
72. Blaser, M. J. and Newman, L. S., A review of human salmonellosis, Rev. Infect. Dis., 4, 1096, 1982.
73. Chérubin, E. C. et al., Septicemia with non-typhoid salmonella, Medicine, 53, 365, 1974.
74. Rubin, R. H. and Weinstein, L., Salmonellosis, Stratton Intercontinental, New York, 1977.
75. Verghese, A., The “ Typhoid State” revisited, Am. J. Med., 79, 370, 1985.
76. Klotz, S. A. et al., Typhoid fever. An epidemic with remarkably few clinical signs and symptoms, Arch.
Intern. Med., 144, 533, 1984.
77. Young, E. J., Human brucellosis, Rev. Infect. Dis., 5(5), 821, 1983.
78. Wise, R. T., Brucellosis in the United States: past, present and future, JAMA, 244, 2318, 1980.
79. McCormack, R. C. et al., Endocarditis due to Streptobacillus moniliformis, JAMA, 200, 77, 1967.
80. Ricketts, W. E., Clinical manifestations of Carrion’s disease, Arch. Intern. Med., 84, 751, 1949.
81. Gould, K., Leptospirosis: an oft-forgotton disease, in Infectious Diseases — Current Topics, Gilbert, D. P.
and Sanford, J. P., Eds., Grune and Stratton, New York, 1979.
82. Peter, G., Leptospirosis: a zoonosis of protean manifestations, Pediatr. Infect. Dis., 1, 282, 1982.
83. Southern, P. M., Jr. and Sanford, J. P., Relapsing fever. A clinical and microbiologie review, Medicine,
48, 129, 1969.
84. Siegel, D. and Washington, A. E., Syphilis. Updated approach to an old disease, Postgrad. Med., 81(1),
83, 1987.
85. Corral, C. C. et al., Fiebre prolongada y sifilis oculta, Rev. Clin. Espan., 167(6), 409, 1982.
86. Shrestha, M. et al., Diagnosing early Lyme disease, Am. J. Med., 78, 235, 1985.
87. Meyerhoff, J., Lyme disease, Am. J. Med., 75, 663, 1983.
88. MMWR, Centers for Disease Control, Atlanta, Vol. 36, No. 6, 1987, and Vol. 36, Nos. 13 and 14, 1987.
89. Daniel, Th. M., Tuberculosis, in Harrison s Principles of Internal Medicine, 11th ed., McGraw-Hill, New
York, 1987, 625.
90. Glassroth, J. et al., Tuberculosis in the 1980’s, N. Engl. J. Med., 302, 1441, 1980.
91. Stumacher, R. J., Clinical Infectious Diseases, W. B. Saunders, Philadelphia, 1987.
92. Weir, M. R. and Thornton, G. F., Extrapulmonary tuberculosis, Am. J. Med., 79, 467, 1985.
93. Pitlik, S. D. et al., Tuberculosis mimicking cancer — A reminder, Am. J. Med., 76, 822, 1984.
94. Dent, D. M. and Webber, B. L., Tuberculosis of the breast, S. Afr. Med. J., 51, 611, 1977.
95. Guillet, J. L. et al., Mammary tuberculosis, Lancet, ii, 166, 1982.
96. Modai, D. et al., Breast mycobacterial infection in a hemodialysis patient, Postgrad. Med. J., 60, 164,
1984.
97. Jason, M. K. et al., Tuberculosis of the myocardium, N. Y. State J. Med., 81(3), 368, 1981.
98. Liu, A. C. et al., Upper airway obstruction due to tuberculosis, Postgrad. Med., 78, 275, 1985.
99. James D. G., The changing pattern of tuberculosis, Postgrad. Med. J., 60, 92, 1984.
354 Unexplained Fever

100. Cabane, J. et al., Fievre prolongée inexpliquée chez un Haitien de 47 ans. (C.P.C.), Ann. Med. Intern.
(Paris), 135(3), 235, 1984.
101. McCue, J. D., Fever of unexplained origin and retroperitoneal calcifications, J. Maine Med. Assoc., 70,
454, 1979.
102. Gorse, G. J. et al., Tuberculous spondylitis, Medicine (Baltimore), 62, 178, 1983.
103. Davidson, P. T. and Horowitz, J., Skeletal tuberculosis, Am. J. Med., 48, 77, 1970.
104. Waldvogel-Medoff-Swartz, Osteomyelitis, Charles C Thomas, Springfield, IL, 1971, 78.
105. Twomey, J. J. and Leavell, B. S., Leukemoid reactions to tuberculosis, Arch. Intern. Med., 116, 21,
1965.
106. Glasser, R. M. et al., The significance of hematologic abnormalities in patients with tuberculosis, Arch.
Intern. Med., 125, 691, 1970.
107. Centers for Disease Control. Diagnosis and management of mycobacterial infection and disease in persons
with Human Immunodeficiency Virus infection, Ann. Intern. Med. 106, 254, 1987.
108. Linell, F. and Ostberg, G., Tuberculosis in autopsy material, Scand. J. Respir. Dis., 47, 200, 1966.
109. Bobrowitz, T. D., Active tuberculosis undiagnosed until autopsy, Am. J. Med. 72, 650, 1982.
110. Alvarez, S. and McCabe, W. R., Extrapulmonary tuberculosis revisited, Medicine (Baltimore), 63(1),
25, 1984.
111. Anderson, S., Toxoplasma gondii, in Principles and Practice of Infectious Diseases, Mandell, G ., Douglas,
R. G.,and Bennett, J., Eds., John Wiley & Sons, New York, 1979, p 2127.
112. Remington, R. S., Toxoplasmosis in the adult, Bull. N.Y. Acad. Med., 50, 211, 1974.
113. Faruqui, A. M. A. et al., Acute acquired toxoplasmosis, S. Med. J., 69, 1234, 1976.
114. Luft, B. J. et al., Toxoplasmic encephalitis in patients with AIDS, JAMA, 252, 913, 1984.
115. Wong, B. et al., CNS toxoplasmosis in homosexual men and parenteral drug abusers, Ann. Intern. Med.,
100, 36, 1984.
116. Dinarello, Ch. A. and Wolff, S. M., Fever of unknown origin, in Principles and Practices of Infectious
Diseases, Mandell, G., Douglas, R. G., and Bennett, J., Eds., John Wiley & Sons, New York, 1979,
407.
117. Dammin, G. J., Babesiosis, Semin. Infect. Dis., 1, 169, 1978.
118. Gould, S. E., Trichinosis in Men and Animals, Charles C Thomas, Springfield, IL, 1970.
119. Johnson, D. Y. and Tonnesen, A. S., The abdomen as a source of occult sepsis, Gastroenterol. Clin.
North Am., 17, 419, 1988.
 355

Chapter 21

UNEXPLAINED FEVER IN THE IMMUNOCOMPROMISED

PATIENT

Serge Kernbaum

INTRODUCTION
Undiagnosed fever is frequent in patients with altered immune defenses. Fever in these
patients may be due to the underlying disease and to many various causes (adverse drug
reactions, vascular thrombosis . . . ) among which infections are the most frequent.
Four major points are to be outlined at this point: infections are not infrequently due to
more than one pathogen; infections due to common pathogens occur more frequently; in-
fections can be due to opportunistic agents (organisms which infect only immunocompro-
mised patients) and as these patients may have an altered capability to produce an inflammatory
response (because of neutropenia . . . ), the usual diagnostic clues may be absent.
As we do not wish to duplicate the other chapters of this book, we will first summarize
the approach of the febrile patient in two steps: what is the nature of the immune depression?
and according to it, which organisms may be involved?, with a special emphasis on a true
opportunistic agent, Pneumocystis carinii. In the second part, the noninfectious causes of
fever in these patients will be listed. Finally, we will discuss HIV-1 infections.

THE IMMUNOCOMPROMISED HOST

The first critical step is to define whether the febrile patient has altered defenses. We
have listed in Table 1 the most common factors that compromise host defenses.
The infectious agents that most often complicate these various host defense alterations
are listed in Table 2.
As the infectious complication may reveal the underlying disease and also in order to
summarize the previous tables, we will briefly list in Table 3 the most frequently isolated
infectious agents according to the host defense alteration present.
Localization of the infectious process: it may be unique and/or multiple. The major
tissue localizations of the infectious processes are the lungs, the skin and subcutaneous
tissues, the central nervous system and the gastrointestinal tract . . . But other tissues may
be involved, e.g., bacterial endocarditis was present in 2 of 47 cancer patients with U.F.9
It must be remembered that in one of the most frequent situations of immunosuppression,
namely, neutropenia, fever occurs frequently in the absence of any localizing sign or symptom
because of the lack of a normal inflammatory response.
Because of its importance in AIDS we shall briefly discuss one ubiquitous protozoan,
true opportunistic agent, Pneumocystis carinii: it causes an interstitial and alveolar pneumonia
in various mammals with altered immunity, mainly AIDS, where about 60% of patients are
affected, some with exceptional extra-lung manifestations.11 14
The disease begins slowly (in weeks) with nonspecific signs or symptoms: dyspnea, dry
cough, inconstant cyanosis, fever, rales, hypoxemia. Chest X-ray films typically exhibit
bilateral pulmonary infiltrates of alveolar and interstitial types.
Diagnostic problems may occur because of the not infrequent association of another
opportunistic agent (cytomegalovirus . . . ) which adds its own signs and symptoms and/or
the frequent atypic X-ray findings;1415 asymmetric lung involvement; pure alveolar lesion;
round lung lesion, unique or not, sometimes excavated; pleurisy . . . and even (mainly in
AIDS patients) a normal X-ray contrasting with tachypnea and blood gasses abnormali-
ties.15’16
356 Unexplained Fever

TABLE 1
Major Etiologie Factors of Immunosuppression1’310

Host Factors

Malnutrition
Various cancers
Hodgkin’s disease and various lymphomas
Leukemias
Multiple myeloma and other malignant dysproteinemia
Carcinomas and sarcomas
Connective tissue diseases
Systemic lupus erythematosus
Rheumatoid arthritis
Other “ collagen” diseases
Inherited and acquired primary immunodeficiency diseases
Phagocyte disorders
Complement defects
B cell defects (humoral immunity defect)
T cell defect (cellular immunity defect)
Splenic insufficiency
Others: severe combined deficiency . . .
Sickle cell disease
Metabolic diseases
Diabetes mellitus
Chronic renal disease
Cystic fibrosis
Various: polyendocrinopathy
Exogenous abuses
Alcohol
Various recreational drugs
Burned patients
Bypasses of the skin and mucosal barrier
Dermal sinus tract
Lesions of the base of the skull

Iatrogenic Factors

Altered endogenous microbial flora

Broad-spectrum antibiotic therapy
Depressed leukocyte number and functions
Cytotoxic chemotherapy
Irradiation
Various drugs: some anti-inflammatory agents; some antibiotics; cytotoxic agents . . .
Impaired B and/or T cell-mediated immunity
Corticosteroid therapy
Antilymphocyte globulin
Cytotoxic chemotherapy
Irradiation
Lesions of the skin and mucosal barrier
In-dwelling intravenous or intra-arterial and urethral catheters
Intestinal mucosal toxicity of cytotoxic drugs
Inhalation therapy equipment and/or positive pressure breathing apparatus

Help may be obtained from an inconstant elevation of blood level of the angiotensin
converting enzyme and/or from a gallium scan which may exhibit abnormal lung fixation.
As most (if not all) subjects have met the agent in infancy the serodiagnosis is of no
value. The diagnostic help afforded by the detection of an inconstant antigenemia, if it is
available, may be useful.17 In fact, the diagnosis relies upon the demonstration of the
organism.
 357

TABLE 2
Microbial Pathogens M ost Often Isolated According to the Predisposing
Disorder1710

Predisposing cause Infectious agents most frequently isolated

Malnutrition Viruses (severity of measles . . . )

Mycobacteria
Cancers Enterobacteriaceae; P s e u d o m o n a s a e r u g in o s a ; Gram-positive cocci;
anaerobic bacteria; M y c o b a c te r ia ; L i s te r ia ; S a lm o n e lla ; N o c a r d ia
Viruses: varicella-zoster, herpes simplex; CMV, papova; C a n d id a
sp.; C r y p to c o c c u s ; A s p e r g illu s sp.; P n e u m o c y s tis c a r in ii; T o x o -
p la s m a g o n d ii
Connective tissue diseases S ta p h y lo c o c c u s ; L i s te r ia ; S a lm o n e lla ; M y c o b a c te r ia ; C o r y n e b a c -
te r ia ; P . a e r u g in o s a , N o c a r d ia : Enterobacteriaceae CMV; vari-
cella-zoster; herpes simplex; Hepatitis viruses: C a n d i d a ;
A s p e r g illu s ; M u c o r ; P . c a r in ii; G ia r d ia la m b lia ; S tr o n g y lo id e s
s te r c o r a lis ; T. g o n d ii
Depressed leukocytes
Number S ta p h y l o c o c c u s ; Enterobacteriaceae; P . a e ru g in o s a ; N o c a r d ia ;
C a n d id a
Function
Chronic granulomatous disease Same as above
Myeloperoxidase deficiency C a n d id a
Glucose-6-phosphate dehydrogenase S ta p h y lo c o c c u s ; S e r r a tia
deficiency
Chédiak Higashi syndrome Various pyogens
Job syndrome S. a u r e u s
Complement defects: C3 pyogenes;
S tr e p to c o c c u s S. p n e u m o n ia e ; S. a u r e u s
C6, C7, C8 Gram-negative cocci
B cell defects S ta p h y lo c o c c u s ; S tr e p to c o c c u s ; Gram-negative bacilli; anaerobes;
P . c a r in ii
T cell defects M y c o b a c te r ia ; L is te r ia ; S a lm o n e lla ; N o c a r d ia ; A c tin o m y c è te s ;
CMV; varicella-zoster
C a n d id a ; A s p e r g illu s ; C r y p to c o c c u s ; P . c a r in ii
Splenic insufficiency S. p n e u m o n ia e ; S a lm o n e lla
Acquired immunodeficiency syndrome P . c a r in ii; M y c o b a c te r ia ; S a lm o n e lla ; CMV; C a n d id a ; C r y p to -
s p o r id iu m ; S tr o n g y lo id e s ; C r y p to c o c c u s ; T. g o n d ii
Sickle cell disease S. p n e u m o n ia e ; S a lm o n e lla
Diabetes mellitus S ta p h y lo c o c c u s ; S tr e p to c o c c u s ; E . c o li; P r o te u s ; C lo s tr id iu m ; M y -
c o b a c te r ia ; C a n d id a ; M u c o r
Chronic renal disease Gram-positive Cocci; Enterobacteriaceae; Bacteroides; Mycobac-
teria; C a n d id a ; varicella-zoster; herpes
Cystic fibrosis P . a e r u g in o s a ; S ta p h y lo c o c c u s
Polyendocrinopathy C a n d id a
Alcohol abuse Pulmonary infections: S. p n e u m o n ia e ; anaerobic bacteria; Myco-
bacteria (mainly M . tu b e r c u lo s is )
Drug abuse S ta p h y lo c o c c u s , C a n d id a , C o r y n e b a c ie r ia ; Hepatitis B and non-
A, non-B viruses
Bums P s e u d o m o n a s sp.; S ta p h y lo c o c c u s ; C a n d id a
Bypasses of the skin and mucosal barrier S. e p id e r m id is ; S. a u r e u s, C o r y n e b a c te r ia , C a n d id a
Lesion of the base of the skull Recurrent meningitis mainly due to S. p n e u m o n ia e
Corticosteroid therapy Enterobacteriaceae; P . a e r u g in o s a ; anaerobic bac-
S ta p h y lo c o c c u s ;
teria; L i s t e r i a ; M y c o b a c t e r i a ; herpesvirus, varicella-zoster,
CMV . . . C a n d id a ; T o r u lo p s is ; A s p e r g illu s ; C r y p to c o c c u s ; P .
c a r im i; T o x o p la s m a g o n d ii; S tr o n g y lo id e s s te r c o r a lis ; G ia r d ia
la m b lia
358 U nex p la in ed F e ve r

TABLE 3
Major Infectious Agents Causing Diseases in Host Immune Deficiency1740

Host immune defense deficit Major infectious agents

Nonintegrity of the skin and mucosa S ta p h y lo c o c c u s e p id e r m id is ; S. a u r e u s ; C o r y n e b a c te r ia ; C a n d id a

sp.
Deficiency of phagocytosis Gram-positive cocci (mainly S ta p h y lo c o c c u s aureus)-, Enterobac-
teriaceae; P s e u d o m o n a s a e r u g in o s a ; N o c a r d ia ; A s p e r g illu s ; C a n -
d id a ; Z y g o m y c o s e s
Deficiency of humoral immunity (B-cell de- Gram-positive cocci; H a e m o p h ilu s in flu e n za e and less often other
fect) Gram-negative bacilli; enteroviruses, papovaviruses; P n e u m o c y s -
tis c a r in ii; G ia r d ia la m b lia
Deficiency of cellular immunity (T-cell de- S a lm o n e lla ; L is te r ia m o n o c y to g e n e s ; M y c o b a c te r ia ; L e g io n e lla ;
fect) N o c a r d ia ; C a n d id a ; C r y p to c o c c u s ; C o c c id io id e s ; H is to p la s m a .
All viruses, mainly those of the herpes group; P n e u m o c y s tis c a r -
in ii; T o x o p la s m a g o n d ii; S tr o n g y lo id e s s te r c o r a lis ; C r y p to s p o r i-
d iu m

As it is very rarely discovered in expectoration or in gastric juice, a bronchoalveolar

lavage is first done as it often gives positive results. In case of negativity, more aggressive
procedures may be proposed: distal bronchial brushing or transbronchial biopsy. Finally,
the ultimate procedure is surgical lung biopsy.
The organism will be optimally demonstrated by two stainings, for example, methe-
namine silver stain, Gram weigert, toluidine blue O . . . 1214 In the near future monoclonal
antibodies will be helpful.

VARIOUS CAUSES OF FEVER IN IMMUNODEPRESSED

PATIENTS
We have two distinct opposing situations: the granulocytopenic patients and the im-
munodepressed ones.110
Bacterial infection, septicemic or localized (mainly pneumonia) is the cause of the
majority of febrile episodes of neutropenic patients. As the median survival of inappropriately
treated patients is less than 3 days, an aggressive empirical antibiotic therapy must be
initiated.110 The management of a febrile neutropenic patient is a specific emergency situ-
ation.
In contrast, patients whose defenses are altered by other mechanisms require a different
approach for two main reasons: there is no therapeutic emergency, and the place of bacterial
infections is more limited. For example in one series of 194 episodes of fever in renal
transplanted patients a viral infection (mainly cytomegalovirus) was responsible for over
half of the febrile episodes, and bacterial infection for 14%6 or in a series of 6880 cancer
patients, a prolonged unexplained fever was present in 0.7%; half of the cases were due to
an infection, most often localized and due to Gram-negative organism.9

NONINFECTIOUS CAUSES OF U.F. IN IMMUNODEPRESSED PATIENTS

The fever may be linked to the cause of the immune depression. With cancer itself
(principally in the case of lymphoma9) the fever is due to tumor-related necrosis, pyrogens
or hemorrhage: fever then defervesces after the initiation of specific tumor therapy. With
rejection of the grafted viscera the diagnosis relies on biopsy.
The fever can be due to the chemotherapy: its timing is crucial for the diagnosis. It must
occur during or shortly after (no more than 12 h) the cure and usually spontaneously
disappears during the day following the end of treatment.
In one prospective study of 1001 febrile episodes, approximately 60% of the fevers
 359

occurring in nongranulocytopenic patients were not due to an infection, and the majority
occurred in association with chemotherapy administration.5
The most frequently involved drugs are methotrexate, L-asparaginase, cytosine-arabi-
noside, cyclophosphamide, Actinomycin D, and Busulfan as well as various drugs listed in
Chapter 18.
Fever can be due to an intratissular or intraluminal hemorrhage; this possibility is
discussed mainly in thrombopenic patients (see Chapter 25). Fever can follow a surgical
procedure or a blood product transfusion. Fever can reveal a secondary cancer complicating
the immunosuppressive therapy of the first one (mainly lymphoma) or of a transplanted
organ. Finally, fever can be the unique manifestation of venous thrombosis, not infrequent
in cancer patients (see Chapter 25).
Not only the above causes of U.F. are to be known by the physician, but also their
sequence in a given situation; as, for example, in a relatively frequent circumstance, the
renal transplanted patient.1819 In the first month following the surgical procedure, the in-
fections are mainly bacterial and do not differ from the postoperative complications seen in
nonimmunodepressed patients: wound infection, pneumonia. Then the infections are usually
due to opportunistic agents, mainly viruses: CMV, HBS, non-A, non-B hepatitis virus, EBV,
adenovirus, papovavirus . . . 1819
Rejection, sometimes associated with an infection (mainly due to CMV), can present
as an U.F. Renal biopsy often gives the diagnostic clue. When it does not, rejection may
be suspected and the diagnosis will be supported by the response to anti-rejection therapy
or even more to the removal of the graft.

ACQUIRED IMMUNE DEFICIENCY SYNDROME

This syndrome was first reported in some great cities of the U.S. in June 1981.20 Since
then it has become evident that it was worldwide, very frequent (more than 50,000 cases
were known by mid 1987) and due to a virus, now called HIV-1 (human immune deficiency
virus); a few cases contracted in West Africa are due to a related virus, HIV-2.21 HIV-1
infection is a great cause of U.F.23 25
The diagnostic criteria for AIDS were reviewed in 1987.22 AIDS is an illness charac-
terized by one or more of the following criteria. In the absence of laboratory evidence of
HIV infection, some diseases or treatments which are a cause of cellular immune depression
exclude the diagnosis of AIDS. These diseases or treatments are22

• High-dose or long-term systemic corticosteroid therapy or other immunosuppressive/

cytotoxic therapy months before the onset of the indicator disease
• Any of the following diseases diagnosed ^ 3 months after diagnosis of the indicator
disease: Hodgkin’s disease, non-Hodgkin’s lymphoma (other than primary brain lym-
phoma), lymphocytic leukemia, multiple myeloma, any other cancer of lymphoreticular
or histiocytic tissue, or angioimmunoblastic lymphadenopathy
• A genetic (congenital) immunodeficiency syndrome or an acquired immunodeficiency
syndrome atypical of HIV infection, such as one involving hypogammaglobulinemia

Even in the absence of laboratory confirmation, the following listed diseases can support
the diagnosis of AIDS:22

Candidiasis of the esophagus, trachea, bronchi, or lungs

Cryptococcosis, extrapulmonary cryptosporidiosis with diarrhea persisting >1 month
Cytomegalovirus disease of an organ other than liver, spleen, or lymph nodes in a
patient > 1 month of age
Herpes simplex virus infection causing a mucocutaneous ulcer that persists longer than
360 Unexplained Fever

1 month; or bronchitis, pneumonitis, or esophagitis of any duration affecting a patient

> 1 month of age
Kaposi’s sarcoma affecting a patient <60 years of age
Lyphoma of the brain (primary) affecting a patient < 60 years of age
Lymphoid interstitial pneumonia and/or pulmonary lymphoid hyperplasia (LIP/PLH
complex) affecting a child < 13 years of age
M yco b a c teriu m avium complex or Af. k a n sa sii disease, disseminated (at a site other
than or in addition to lungs, skin, or cervical or hilar lymph nodes)
P n eu m o cy stis ca rin ii pneumonia
Progressive multifocal leukoencephalopathy
Toxoplasmosis of the brain affecting a patient >1 month of age

When there is laboratory evidence of HIV infection (see below), the above listed disorders
also support the definite diagnosis of AIDS

• Bacterial infections, multiple or recurrent (any combination of at least two within a

2-year period), of the following types affecting a child <13 years of age:
Septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an
internal organ or body cavity (excluding otitis media or superficial skin or mu-
cosal abscesses), caused by H a e m o p h ilu s, S trep to co c cu s (including P n eu m o -
c o c c u s ), or other pyogenic bacteria
• Coccidioidomycosis, disseminated (at a site other than or in addition to lungs or cervical
or hilar lymph nodes)
• HIV encephalopathy (also called “ HIV dementia,” “ AIDS dementia,” or “ subacute
encephalitis due HIV” )
• Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical
or hilar lymph nodes)
• Isosporiasis with diarrhea persisting > 1 month
• Kaposi’s sarcoma at any age
• Lymphoma of the brain (primary) at any age
• Other non-Hodgkin’s lymphoma of B-cell or unknown immunologic phenotype and
the following histologic types:
Small noncleaved lymphoma (either Burkitt or non-Burkitt type)
Immunoblastic sarcoma (equivalent to any of the following, although not nec-
essarily all in combination: immunoblastic lymphoma, large cell lymphoma,
diffuse histiocytic lymphoma, diffuse undifferentiated lymphoma, or high-grade
lymphoma)
• Any mycobacterial disease caused by mycobacteria other than M. tuberculosis, dis-
seminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph
nodes)
• Disease caused by M . tu b ercu lo sis, extrapulmonary (involving at least one site outside
the lungs, regardless of whether there is concurrent pulmonary involvement)
• S a lm o n ella (nontyphoid) recurrent septicemia
• HIV wasting syndrome (emaciation, “ slim disease” )

WHO experts proposed other criteria for countries where diagnostic resources are limited.24
These criteria, listed below, are believed to be a sensitive definition, although not
formally evaluated; the diagnosis relies on these criteria and eventually on serological con-
firmation.

Adults
AIDS in an adult is defined by the existence of at least two major signs associated with
 361

at least one minor sign, in the absence of known causes of immunosuppression such as
cancer or severe malnutrition or other recognized etiologies.

Major signs:
• Weight loss 5*10% of body weight
• Chronic diarrhea for > 1 month
• Prolonged fever for > 1 month (intermittent or constant)

Minor signs:
• Persistent cough for > 1 month
• Generalized pruritic dermatitis
• Recurrent Herpes zoster
• Oropharyngeal candidiasis
• Chronic progressive and disseminated herpes simplex virus infection
• Generalized lymphadenopathy

The presence of generalized Kaposi’s sarcoma or cryptococcal meningitis is by itself suf-

ficient for a diagnosis of AIDS.

Children
Pediatric AIDS is suspected in an infant or child presenting with at least two of the
following major signs associated with at least two of the following minor signs, in the
absence of known causes of immunosuppression such as cancer or severe malnutrition or
other recognized etiologies.

Major signs:
• Weight loss or abnormally slow growth
• Chronic diarrhea for > 1 month
• Prolonged fever for > 1 month

Minor signs:
• Generalized lymphadenopathy
• Oropharyngeal candidiasis
• Common repeated infections (otitis, pharyngitis . . . )
• Persistent cough
• Generalized dermatitis
• Confirmed maternal LAV/HTLV-III infection24

We must emphasize that in adults as well as in children a prolonged fever is a major

sign of HIV infection.
The fever may be linked with an opportunistic infection, a lymphoma or Kaposi sarcoma,
or probably with the HIV-1 infection as it appears soon in the natural history of the infection,
many months before full-blown AIDS. We are not aware of U.F. due to HIV-2 infection,
but this absence probably reflects the scarcity of the published cases.
Minor manifestations of HIV infections may also present as U.F.

Minor Manifestations of HIV Infection

First, AIDS-related complex (ARC) may present as U.F. To satisfy the definition of
ARC, a person must have at least two signs or symptoms for at least 3 months and at least
two abnormal laboratory values.
362 U nex p la in ed F e ve r

TABLE 4
HIV Serology26

ELISA Western blot Radioimmunoprécipitation

Sensitivity +++ + + + +++

Specificity ++ + + + + + -I- +

Cost Low High High

Feasibility Everywhere Specialized lab. Specialized lab.

Note: Confirmation of the result of the ELISA test by one of the other two methods is
recommended.

Clinical signs/symptoms
• Fever, intermittent or continuous
• Lymphadenopathy of more than 1 cm in diameter, in two distinct areas, except inguinal
• Weight loss ^ 7 kg or ^10% of body weight
• Diarrhea
• Fatigue, malaise
• Night sweats

Laboratory studies
• Decreased number of T-helper cells
• Decreased ratio of T-helper/T-suppressor lymphocytes
• Anemia or leukopenia or thrombocytopenia or lymphopenia
• Increased serum globulin levels
• Decreased blastogénie response of lymphocytes to mitogens
• Cutaneous anergy to multiple skin test antigens
• Increased levels of circulating immune complex

Even milder manifestations of HIV infection may present as U.F.

• Isolated U.F. or fever associated with one of the following: persistent generalized
lymphadenopathy: a lymph node biopsy is mandatory24
• Clinical syndrome mimicking infectious mononucleosis, without heterophile antibod-
ies, which is one clinical manifestation of the primo-infection by HIV-1
• Cryptogenic neuropathy of the CNS and/or peripheric (neuritis)
• Lymphoid interstitial pneumonia
• Various carcinomas: B cell lymphomas; buccal or anal carcinoma . . .
• Angio-immunoblastic lymphadenopathy
• Angiofollicular lymph node hyperplasia
• Various digestive tract abnormalities
• Pseudo Whipple’s disease
• Hepatic peliosis
• Hepatic granulomas . . .

This list will probably be extended.

To confirm the diagnosis the physician will ask the virology department to isolate the
étiologie agents or its antigens from blood and/or other body fluids (CSF . . . ) or tissue
(lymph node . . . ); it is a complex and expensive technique. They will also be asked to
demonstrate the presence in the blood of antibodies which may appear as soon as 3 weeks
after the penetration of the virus within the body; this procedure is much easier because of
the existence of various kits.
The three techniques available in 1987 are summarized in Table 4.
 363

In conclusion, two opposing clinical situations may exist: in the neutropenic patient
fever is a priori of bacterial origin and its empiric therapy must be initiated as soon as
possible, just after the various bacterial samples are collected; if the fever persists after a
few days. The physician is faced with a difficult situation which lies beyond the scope of
this book. In contrast, when fever appears in a nongranulocytopenic immunodepressed patient
the managing physician has to discuss many causes, covered in various chapters of this
book. In all cases a good appreciation of the nature of the immune defect (Table 1) as well
as of the specific pathogens that may be involved (Table 2) is mandatory for better man-
agement of such a difficult problem.

REFERENCES
1. Grieco, M., Infections in the Abnormal Host, Yorke Medical Books, New York, 1980.
2. Levine, A., Graw, R., and Young, R., Management of infections in patients with leukemia and lymphoma.
Current concepts and experimental approaches, Semin. Hematol., 9, 141, 1972.
3. Levine, A., Schimpff, C., Graw, R., et al., Hematologic malignancies and other marrow-failure states:
progress in the management of complicating infections, Semin. Hematol., 11, 141, 1974.
4. Bode, F., Pare, P., and Fraser, R., Pulmonary disease in the compromised host, Medicine, 53, 255,
1974.
5. Young, R., Nosocomial infections in the immunocompromised adult, Am. J. Med., 70, 398, 1981.
6. Pizzo, P., Robichaud, K., Wesley, R., et al., Fever in the pediatric and young adult patient with cancer,
Medicine, 61, 153, 1982.
7. Bishop, J., Schimpff, S., Diggs, C., et al., Infections during intensive chemotherapy for non-Hodgkin’s
lymphoma, Ann. Intern. Med., 95, 549, 1981.
8. Atkinson, K., Kay, H., and McElwain, T., Fever in the neutropenic patient, Br. Med. J., 3, 160, 1974.
9. Klastersky, J., Weerts, D., Hensgens, D., et al., Fever of unexplained origin in patients with cancer,
Eur. J. Cancer, 9, 649, 1973.
10. Frottier, J., Kernbaum, S., Verliac, F., et al., Indications et choix des traitements antibacteriens chez
les malades soumis aux medications immunosuppressives et antimitotiques, Pathol. Biol. (Paris), 214, 141,
1976.
11. Gajdusek, C., Pneumocystis carinii — étiologie agent of interstitial plasma cell pneumonia of premature
and young infants, Pediatrics, 19, 543, 1957.
12. Hughes, W., Pneumocystis carinii pneumonia, N . Engl. J. Med., 297, 1381, 1977.
13. Kernbaum, S., Trinh Dinh, H., Bouton, C., et al., Epidemiologie de l’infection a Pneumocystis carinii,
Med. Hygiene, 36, 461, 1978.
14. Bee, P., Winn, W., and McKee, K., Pneumocystis carinii infection of the lung: radiologie and pathologie
correlation, Am. J. Radiol., 132, 741, 1979.
15. Friedman, B., Wenglin, B., Hyland, R., et al., Roentgenographically atypical Pneumocystis carinii
pneumonia, Am. Rev. Respir. Dis. Ill, 89, 1975.
16. Sirotzky, L., Memoli, V., Roberts, J., et al., Recurrent Pneumocystis pneumonia with normal chest
roentgenograms, JAMA, 240, 1513, 1978.
17. Maddison, S., Hayes, G., Slemenda, S., et al., Detection of specific antibody by enzyme-linked im-
munosorbent assay and antigenemia by counterimmunoelectrophoresis in humans infected with Pneumocystis
carinii, J. Clin. Microbiol., 15, 1036, 1982.
18. Peterson, P., Balfour, H., Fry, D., et al., Fever in renal transplant recipients: causes, prognostic sig-
nificance and changing patterns at the University of Minnesota Hospital, Am. J. Med., 71, 345, 1981.
19. Rubin, R., Wolfson, J., Cosimi, A., et al., Infection in the renal transplant recipient, Am. J. Med., 70,
405, 1981.
20. Center for Disease Control, Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men. New
York City and California, Morbid. Mortal. Weekly Rep., 306, 305, 1981.
21. Clavel, F. and Montagnier, L., L’etiologie virale du Sida, Rev. Prat., 36, 1163, 1986.
22. Centers for Disease Control, Revision of the CDC surveillance case definition for acquired immunodeficiency
syndrome, MMWR, 36 (Suppl. IS), 1, 1987.
23. Kernbaum, S., C availle-Cool, M., Klatzman, D., et al., Syndrome d’immuno-deficit acquis (Sida),
Encycl. Med. Chir. (Paris) Mal. Infect., 8002B, 10, 1, 1985.
364 Unexplained Fever

24. Second Meeting of the WHO Collaborating Centers on AIDS: Memorandum from a WHO meeting, Bull.
W.H.O., 64, 37, 1986.
25. Shiach, C., Burt, A., and Isles, C., Pyrexia of undetermined origin, diarrhoea, and primary cerebral
lymphoma associated with acquired immunodeficiency, Br. Med. J., 288, 449, 1984.
26. Rouzioux, C., Kernbaum, S., Rey, M.-A., et al., Indications, techniques, fiabilité de la sérologie LAV/
HTLV III en Janvier 1986, Med. Hyg., 44, 597, 1986.
 365

Chapter 22

UNEXPLAINED FEVER IN PATIENTS RETURNING FROM THE

TROPICS INCLUDING U.F. ASSOCIATED WITH
HYPEREOSINOPHILIA

G. Charmot and S. Kernbaum

INTRODUCTION
The great incidence of infectious diseases in tropical countries explains that persistent
unexplained pyrexia is a frequent diagnostic problem in patients coming back from these
areas. In addition to many conditions found in temperate areas, there are a number of viral
or parasitic infections which are found only in the tropics.
As the clinical presentations of the infections due to various microorganisms were
analyzed in Chapters 19 and 20, here we will mainly present guidelines useful to manage
the patient coming back from the tropics with an unexplained pyrexia.
Grossly, the risk of contracting a tropical infectious disease depends on the country
visited, the length of the stay, the way of life, and finally, on the preventive procedures
adopted, including vaccines, chemoprophylaxy, and hygiene precautions.
We will first present in two tables an overview of the various infectious tropical diseases
which may last many days according to the definition (Table 1). Thus, not appearing in
these tables are frequent diseases of short duration, such as those induced by arboviruses
(yellow fever, encephalitis, dandy fever . . . ).*3 Also excluded are diseases (infectious or
not) which have evolved for many weeks but are discovered after the trip in the tropics.
Many ubiquitous agents are peculiarly frequent in the tropics, such as hepatitis viruses,
Salmonella . . . The diseases they cause are presented in Table 2.

GUIDELINES TO DIAGNOSIS

MEDICAL HISTORY
The visited country is the first important point. Table 3 gives the necessary information
on this. As usual, it can be used to affirm a disease (ex. Lassa fever after a stay in Central
Africa) and to exclude another one (absence of Schistosomiasis in India).
The second clue is the time elapsed since the departure from the tropical country, which
indicates the minimum incubation time (Table 4). If the stay in the tropics was of short
duration, the date of arrival must be considered. Of course, as time elapses, the probability
that the U.F. is due to a tropical disease lowers.
The other clues are the mode of life (urban and/or rural) and the prophylaxy adopted.

PHYSICAL EXAMINATION
The conclusions of the physical examination allow the distinction between isolated
(“ nude” ) fever and fever associated with one prominent sign or symptom (listed in Table
7).
Isolated fever — Evocative, but not absolute clues are

1. Its mode of onset: a progressive onset pleads in favor of typhoid fever, an abrupt one
in favor of malaria.
2. The persistence of the fever as the unique manifestation of the disease after 2 weeks:
the most probable diseases are listed in Table 5. An invasive malaria is probably not
the cause of a high level persisting fever of more than 2 weeks duration because malaria
366 Unexplained Fever

TABLE 1
Main Specific Tropical Agents Which may Cause an Imported Unexplained Fever

Viruses — Ebola, Lassa (arbovirus, including yellow fever, give exceptionally a fever lasting more than 14 days)
Bacteria — B o r r e lia sp., B a r to n e lla b a c illifo r m is , Y e r sin ia p e s ti s , P s e u d o m o n a s p s e u d o m a lle i (agent of Melioidosis)
R ic k e tts ia sp.
Protozoa — P la s m o d iu m sp., L e is h m a n ia sp., E n ta m o e b a h is to ly tic a , T r y p a n o s o m ia sp.
Helminths — S c h is to s o m a sp., F a s c io la h e p a tic a , C lo n o r c h is s in e n s is , P a r a g o n im u s w e s te r m a n i, L o a lo a , W u ch -
e r e r ia b a n c r o fti, B r u g ia m a la y i

TABLE 2
Ubiquitous Febrile Diseases that are More Frequent in the Tropics

Due to viruses A, B, non-A, non-B hepatitis

Cytomegalovirus — Epstein-Barr virus (?)
Enterovirus
Due to bacteria All the agents of gastro-enteritis: S a lm o n e lla sp. (including S. ty p h i) ,
S h ig e lla sp., Y e r sin ia sp., S ta p h y lo c o c c u s , S tr e p to c o c c u s , Group A and
C M e n in g o c o c c u s , B r u c e lla sp. (around the Mediterranean Sea), Me-
lioidosis
Due to fungi Histoplasmosis
Due to helminths Schistosomiasis, capillariasis, trichinosis, fasciolasis, Clonorchiasis, intes-
tinal nematode infections, visceral larva migrans (due to T o x o c a r a c a n is ,
exceptionally to T. c a ti)

is usually diagnosed before that time; if not, either the patient died of malignant tertian
malaria or the fever has modified and adopted its typical recurring course.

Although it has been said that the fever pattern has little significance (Chapter 5), we have
listed in Table 6 some evocative patterns; of course, this table is also not absolute and must
be used with great caution.

Laboratory Investigations
The various examinations to be asked for are listed in Table 8. Routine examinations,
which are easy to perform and whose results are quickly available may be useful, such as:

• Search of malarial agents or other parasites on blood smears

• Direct examination of stools for the presence of erythrocytes and leukocytes
• As well as of pus after Gram staining
• Hematological routine examinations: peripheral blood cell count and erythrocyte sedi-
mentation rate (ESR) determination

In Table 9 are listed the main causes of U.F. associated with high ESR (^70 mm at 1 h),
according to the main clinical symptom. A normal ESR nearly excludes hepatic abscess,
visceral Leishmaniasis and Trypanosomiasis. In Table 10 are listed the diagnostic orientations
provided by the peripheral blood count.
The results of liver enzymes and of blood protides are rapidly obtained. The nature of
the inflammatory response may suggest the diagnosis, as is shown in Table 11.
If signs or symptoms of meningitis are present a CSF examination is mandatory. Its
diagnostic value is indicated in Table 12.

The Demonstration of the Causative Agent

Direct

• Culture of blood, stools, urine, lymph node juice . . .

 TABLE 3
Geographic Distribution of the Main Tropical Agents which Cause an Imported U.F,

Around West Other

Mediterranean Central Near Central Far Pacific Pacific
Sea Africa East Asia East Islands Islands America

Lassa, Ebola 0 + 0 0 0 0 0 0
Yellow Fever 0 + 0 0 0 0 0 +
Rickettsiosis + + + + + 0 0 +
Borreliosis + + + + 0 0 0 +
Bartonellosis 0 0 0 0 0 0 0 +
Malaria 0 + + + + 0 +
Visceral leishmaniasis + + (east) + + ± 0 0 +
Amebiasis + + + + + + 0 +
Chagas disease 0 0 0 0 0 0 0 +
Urinary schistosomiasis + (Egypt) + + 0 0 0 0 0
Digestive schistosomiasis + (Egypt) + + 0 0 0 0 +
Lymphatic filariasis 0 + 0 + + + + +
Eosinophilia meningitis 0 0 0 0 0 + + 0
367
368 Unexplained Fever

TABLE 4
Mean Incubation Time of the Main Tropical U.F.

3 to 8 days
Ebola and Lassa fevers
Gastroenteritis
Other Yersinia infections
Melioidosis
8 to 20 days
Ebola and Lassa fevers
Borreliosis
Rickettsiosis
Leptospirosis
Malaria
Hepatic amebiasis
20 days to 6 months
Malaria
Trypanosomiasis
Visceral leishmaniasis
Helminthiasis
Lymphatic filariasis
6 months to 3 years
P. vivax, P. malariae, P. ovale malaria
Hepatic amebiasis
Lymphatic filariasis
3 years to 20 years
P. malariae malaria
Hepatic amebiasis

Note: For bacterial infections (e.g., Salmonella) the incubation time de-
pends on the abundance and the invasiveness of the pathogen.

TABLE 5
Diagnostic Value of an Isolated Fever Persisting More
than 14 Days Without any Accompanying Sign or
Symptom

Possibly causal diseases

Typhoid fever
Hepatic amebiasis
Melioidosis
Visceral leishmaniasis
Trypanosomiasis
Borreliosis
Lepstospirosis
Helminthic infection

Diseases to be excluded

Malaria
Exanthematic rickettsiosis
Bartonellosis
Most viral diseases
Yersinia infections
 369

TABLE 6
Diseases Evoked (Not Affirmed) by the Fever Pattern

Fever pattern Probable disease(s)

Sustained fever Invasive malaria; typhoid fever

Relapsing fever Malaria
After a few days of apyrexia
After many days of apyrexia Borreliosis; leptospirosis
Hectic fever Hepatic amebiasis; bacterial hepatic abscess

TABLE 7
Diagnostic Value of the Clinical Abnormalities Associated with U.F.

Sign(s) or symptom(s) Probable disease(s)

Splenomegaly (often with hepa- Malaria; typhoid fever; borreliosis; visceral leishman-
tomegaly) iasis
Hepatic pain Any hepatic abscess (due to amebas or bacteria)
Skin inoculation lesion Rickettsiosis; trypanosomiasis
Exanthema Rickettsiosis; (not C. burnetii infection) Trypanosom-
iasis; typhoid fever; secondary syphilis
Enlarged lymph nodes Plague; African trypanosomiasis; filariasis
Severe muscle pain Borreliosis; leptospirosis; malaria
Jaundice Borreliosis, leptospirosis, malaria
Jaundice and pallor Malaria; bartonellosis
Hemorrhages Ebola or lassa fever
Dysenteric syndrome Amebiasis
Bloody stools Shigellosis, amebiasis, Campylobacter inf.
Hemoglobinuria Malaria
Lung suppuration Melioidosis, bacterial infection
Meningitis Bacterial infection; viral infection; borreliosis; eosino-
philic meningitis
Encephalitis Viral infection; cerebral malaria; African trypanosom-
iasis

TABLE 8
Examinations to be Performed in a Patient with U.F. Coming Back
From the Tropics

• Blood cell count

• Search for malaria agents
• ESR
• Blood cultures
• Liver enzyme tests
• Chest film
• Serodiagnosis orientated by clinical and main laboratory exam, such as amebiasis,
widal, wright, malaria, rickettsia, syphilis, CMV . . .
• Stool culture if stool abnormalities are present
• Search of a urinary infection if clinically suspected

• Animal inoculation: positive in 8 days in case of borreliosis

• Demonstration of the malaria agent in erythrocytes: it cannot remain undetected in a
good laboratory if its search is asked for; the test will have possibly to be repeated
two or three times twelve hourly in case of a negative result and of strong clinic
suspicion
• In contrast, trypanosomes or leishmanias may fail to be detected in blood, CSF, sternal
puncture, or lymph node juice, even in a good laboratory and after repeated exams
370 Unexplained Fever

TABLE 9
Main Causes of Tropical U.F . Associated with a High ESR

Main clinical symptom Diagnosis

Splenomegaly “ Chronic” or prolonged malaria

Visceral leishmaniasis
Superficial lymph nodes ± inconstant ex- African trypanosomiasis
anthemas
Inconstant exanthemas American trypanosomiasis
Liver pain Liver abscess

TABLE 10
Orientations Provided by Peripheral Blood Cell Examination in a Patient with U.F.

Main abnormality Suggested disease

Noninflammatory anemia Malaria, bartonellosis

Leukocytosis with neutrophilia Liver amebiasis, leptospirosis, borreliosis, a slight elevation is pres-
ent in P. falciparum malaria at the invasive phase
Leukocytosis with eosinophil elevation Fever due to the invasion by a helminth
Neutropenia with relative or absolute lym- Visceral leishmaniasis
phocytosis Malaria (after the invasive phase), viral infection
Thrombopenia Malaria, viral hemorrhagic fevers (Ebola, Lassa)

TABLE 11
Orientations Provided by Peripheral Blood Cell Examination and
Inflammatory Disorders in a Patient with U.F. and ESR >50 mm

Blood cell examination Inflammatory disorder Suggested disease

Leukocytosis with neutrophi- t fibrinemia Hepatic amebiasis

lia t a 2'globulin
Leukocytosis with eosino- t lgM, t IgG Helminth infection
philia
Neutropenia, anemia t IgG Visceral leishmaniasis
Variable t IgM, t IgG Malaria
Normal T IgM Trypanosomiasis

TABLE 12
C.S.F. Abnormalities in Febrile Tropical Meningitis

Microscope
demonstration
IgM >10% of causative
Neutrophils Eosinophils Lymphocytes Protides of protides agent Suggested disease

0 to ± 0 + + + 0 0 Viral infection
0 to ± 0 + + + + 0 + Borreliosis
0 0 ± ± 0 0 Cerebral malaria
0 0 + + + + African trypanosomiasis
0 + + 0 + 0 0 Helminthic infection

Indirect — The serodiagnosis of many of the suspected diseases is now available, but
it requires many days to be obtained (moreover, two samples are often necessary, see Chapter
32) and for some infections only highly specialized laboratories are able to perform it.
In Table 13 are listed the examinations which can affirm the suspected diseases. As
 371

TABLE 13
Specific Examination Necessary to Confirm a Suspected Diagnosis

Suspected diagnosis Examination to be performed

Viral infection Serodiagnosis ± isolation of the agent (cell culture; animal inoculation)
Rickettsial infection Serodiagnosis
Borreliosis Animal inoculation
Melioidosis Direct exam and culture of pus-serodiagnosis
Bartonellosis Blood smear exam, blood culture-serodiagnosis
Plague Direct exam and culture of pus, blood culture
Malaria Blood smear exam — serodiagnosis
Visceral leishmaniasis Search of intracellular agents in blood smears, bone marrow, lymph nodes,
or hepatocytes — serodiagnosis
African trypanosomiasis Search of the agents in blood, lymph, CSF — search of IgG in blood, CSF-
serodiagnosis
American trypanosomiasis Serodiagnosis
Schistosomiasis Serodiagnosis
Fasciolosis, Clonorchiasis Serodiagnosis
Visceral larva migrans Serodiagnosis ± liver punction
Trichinosis Serodiagnosis, muscle biopsy
Eosinophilic meningitis (angio- Eosinophilia of CSF — serodiagnosis
strongyloidosis)

TABLE 14
Therapeutic Trials

Disease Drug(s)

Malaria Quinine, Mefloquine, Chloroquine (possible resistances in S.E. Asia, South

America, and Africa)
Hepatic amebiasis Metronidazole (also active on anaerobic bacterial abscesses), Dehydroemetine
African trypanosomiasis Pentamidine in the first phase, Melarsoprol if CNS involved
Visceral leishmaniasis Pentavalent antimony compounds

Note: In each case: absence of response to antibiotics contrasting with a dramatic response to specific drugs only
(resistance excluded)

some of the suspected diseases respond quickly to a specific treatment, Table 14 lists the
therapeutic trials of diagnostic value.
After having presented these general guidelines it is necessary in the second part of this
chapter to describe briefly some basic features of the main tropical diseases which may
present as U.F.

MALARIA157
Plasmodium falciparum causes a severe infection which could be lethal in nonimmune
subjects, but without late relapses. P. vivax, P. ovale, and P. malariae are exceptional
causes of death but may relapse for 3 to 5 years (P. vivax, P. ovale) and even up to 25
years (P. malariae).
The incubation time, i.e., the delay between the anophele bites and the appearance of
the fever (which corresponds to the multiplication of the sporozoites in the hepatocytes) is
7 to 14 days for P. falciparum, 14 to 20 days for P. vivax and P. ovale, and 28 days for
P. malariae. In addition, some parasite strains of P. vivax and P. ovale may have a longer
incubation time, up to 6 months. P. malariae may give a very low parasitemia, which may
be asymptomatic, for up to 25 years; an intercurrent disease of any type may disrupt this
host-parasite equilibrium and lead to a clinical attack.
372 Unexplained Fever

In areas free of malaria, one must think of the disease in two types of patients: the
intravenous drug addicts (needle transmission) and the recipients of blood transfusions.
The primary attack (the most dangerous one) gives relatively slight symptoms in the
early stages. The fever (contemporary of the invasion of erythrocytes by asexual forms of
parasites) has no periodicity: it begins as a quotidian rise of temperature with malaise, chills,
sweats, headache, myalgias, and sometimes digestive (diarrhea, nausea . . . ) or even pul-
monary symptoms. Splenomegaly will appear after a few days.
P. falciparum may cause a pernicious attack with CNS symptoms (disorientation, de-
lirium, or coma . . . ), jaundice and renal insufficiency. Cerebral malaria presents mainly
as a febrile coma; the CSF exhibits an increase in lymphocytes and proteins. Death may
occur before the 10th day or later, when the typical tertian periodicity of fever has appeared.
Many other forms of P. falciparum malaria may be seen as it is a very variable disease,
mimicking many other conditions which may be misleading: it therefore must always be
suspected.
The other agents give a shorter primary attack, followed by tertian (P. vivax, P. ovale)
or quartian (P. malariae) periodicity of fever, which may last up to 20 to 30 days. Late
relapses are possible, more frequent in P. vivax infection.
The diagnosis is usually easy; it relies on the careful lecture of a Giemsa-stained blood
smear. The parasite species must be characterized and the percentage of parasitized red cells
must be determined.
False-positive results due to artefacts or Babesia infection (which shares the same treat-
ment) are rare.
False-negative results are more frequent and can be due to:

• A poorly trained laboratory technician

• The use of blood cell counting machines, not programmed for the search of malaria
• Low parasitemia
• Insufficient self-medication of the patient

These drawbacks can be obviated by the choice of a good laboratory asked to look for
malaria, by the repetition of blood samples twice a day for 48 h, and finally by the sero-
diagnosis: its positivity occurs at the 5th day of the fever and lasts many months after the
primary attack. But the serodiagnosis cannot affirm the relapse if the patient with known
antecedent of malaria has spontaneously taken antimalarial drugs.
In case of infection by a chloroquine-resistant P. falciparum strain (after a stay in
Southeast Asia, South America, or even Africa) if the patient had taken chloroquine pro-
phylaxy, fever will appear after its end, and the incubation is then prolonged by many weeks.
The most frequent infecting agents are P. falciparum and P. vivax, which may be
contracted in various areas:

Central Africa Asia America

P . fa lc ip a r u m + + +
P . v iv a x 0 1
-- +

The main differential diagnoses are the virus infections (influenza, arboviruses, viral
hepatitis . . . ) and typhoid fever.
If fever lasts more than 48 h after the disappearance of parasitemia, an associated infection
must be looked for.

HEPATIC AMEBIC ABSCESS14811

In contrast to intestinal amebiasis (which is the portal of entry, latent in 80% of cases),
 373

amebic liver abscess is febrile. Usually it is not a cause of U.F. because of the presence of
hepatic pain, hepatomegaly, leukocytosis, and elevated ESR. In spite of the frequent absence
of colic symptoms and Entamoeba histolytica in stools (present in no more than 20% of
cases), the diagnosis is easily suspected, and confirmed by echography (technique of choice)
and/or isotopic scanning and/or CAT scan (presence of liquid in a thick wall lacuna) and
by serodiagnosis (positive in at least 90% of cases the 4th and 5th day of fever) and/or the
puncture of the abscess bacteriologically sterile chocolate pus inconstantly containing the
amebas.
Diagnostic problems may however exist:9 Liver abscess may occur many years after a
stay in the tropics but also in any nontropical country. Chloroquine (which concentrates in
the liver), taken in abrupt onset cases simulating malaria, may induce a subacute delayed
course. “ Spontaneous” atypical onset is classical, presenting as an acute cholecystitis, a
febrile jaundice, an acute right base pleuropneumopathy and even more puzzling are cases
presenting without any pain, and with a normal liver size.8 One must evoke the diagnosis
mainly because of a stay in the tropics. Diagnostic help can be provided by leukocytosis
with neutrophilia (but it was absent in 1 of 20 cases in one series10) and frank elevation of
ESR (^50 mm) at the first hour; but in the same recent series in 15% of patients ESR was
below 50 mm: respectively, 14, 20, and 30 mm.10The diagnosis then relies on the systematic
use of liver imaging procedures and on the serodiagnosis, which may either become positive
at a late stage or even, in very few cases, never become positive.9 False positivity, in hepatic
cancer, is also exceptional.11
The main differential diagnoses includes bacterial liver abscesses (due to staphylococci,
anaerobes . . . ), cholecystitis, and hepatic cancers.

U.F. DUE TO HELMINTH INFECTIONS

Helminths infecting larvae migrate from their penetration site in human organisms (skin,
digestive tract mucosa) to their definitive place; during this passage in deep tissues, they
progressively become adult: this migration lasts 6 to 8 weeks.
The migration-maturation phase is accompanied by a host reaction, which may be latent
or not. Usually this reaction is more frequent and more severe when the larvae come from
an intermediate host (schistosomiasis, fasciolasis) or when the infecting helminths are par-
asites of lower mammals (trichinosis, visceral larva migrans). This host reaction is rare and
moderate in intestinal nematode infection (ascaridiasis, strongyloidosis, hookworm disease)
and is absent in filariasis.
Such a host-parasite reaction could be the expression of the antigenic incompatibility of
coexistence of larvae and host, and diminishes when larvae become adults. As this is never
the case with visceral larva migrans, such reaction persists.
When clinically patent, this host reaction to larvae is expressed by a mild, variable fever
lasting 3 weeks associated with general malaise, cough, epigastric pain, and arthralgias. The
examination may disclose skin rashes, periorbital edema (trichinosis), respiratory signs and
symptoms (mainly ascaridiasis), tender hepatomegaly (mainly in fasciolasis and in visceral
larva migrans), and splenomegaly (mainly in schistosomiasis). Peripheral blood eosinophilia
is helpful, but may appear a few days after the initiation of fever and may be overlooked
if its search is not repeated. In these febrile reactions, eosinophilia usually varies between
1000 and 3000/mm3.
It is accompanied by ESR elevation as well as polyclonal IgG elevation and total IgE
rise.
At this phase the precise parasite identification is difficult because the search for eggs
and larvae is negative. The orientation will be obtained by the notion of travel in endemic
areas and the possibility of contamination: ingestion of raw or poorly cooked pork or wild
374 Unexplained Fever

bear meat (trichinosis), skin contact with stagnant water (schistosomiasis), skin contact with
mud (strongyloidosis) . . . serodiagnosis (immunofluorescence, electrosyneresis, ELISA
tests . . . ) is often conclusive, mainly when seroconversion is demonstrated. In the near
future specific IgE or perhaps monoclonal antibodies will be of great help. In contrast,
cutaneous reactions are devoid of specificity. A few weeks later, when fever and eosinophilia
have subsided, eggs and larvae will be demonstrated in stools and/or urine.

SCHISTOSOMIASIS13
This very frequent tropical disease may present initially as a U.F.

Geographical Distribution

Far East
(Cambodia, South
North of of China, America, Brazil,
Africa, Egypt Central Africa Near East Philippines) West Indies

S. h a e m a to b iu m + + + 0 0
S. m a n s o n i + + + 0 +
S. ja p o n ic u m 0 0 0 + 0

In addition, S. intercalatum is present in Gabon and Cameroon and S. mekongi in Cambodia.

Sym ptom s an d Signs

These appear 15 to 20 days after the infecting bath. They are more severe in the case
of S. japonicum and 5. mansoni infection. Splenomegaly is frequent. Neurologic signs may
be present, mainly in S. japonicum and 5. mansoni infection (disorientation, delirium, even
epileptic attacks). In contrast, pulmonary signs are rare.

D iagnosis
The first positive reaction (positive around the 30th day of infection) is the circumovale
precipitin test followed by indirect fluorescence and ELISA tests. False-positive serologic
reactions may occur in trichinosis. Eggs will be found in urine (S. haematobium) and in
stools (other species) as soon as 70 to 80 days after the infection.

FILARIASIS13 25
A prolonged fever may be seen only in lymphatic filariasis (Wuchereria bancrofti, Brugia
malaya, Loa loa). Transmitted by various mosquitoes, it is present in most tropical areas,
including the Pacific islands. Fever accompanies the acute lymphangitic manifestations which
appear many months following inoculation: genital lymphangitis and acute adenitis with
centrifugal lymphangitis.
The recurrent episodes of fever, lymphadenitis, and lymphangitis are called paroxysmal
inflammatory filariasis, an enigmatic inflammatory entity which may be uneasy to diagnose
outside of filarial endemic areas. Two features are very helpful for diagnosis: first, the filarial
lymphangitis has a retrograde evolution contrasting with the bacterial infections; second, the
recurrent nature of the syndrome is evocative. Blood eosinophilia may be elevated between
the attacks, but is absent during them.25
Evoked in the case of a geographic filarial exposure, the diagnosis relies on the incon-
sistent demonstration of the diurnal or nocturnal microfilaremia; immunodiagnosis is of poor
value: false-negative and false-positive reactions are frequent.
Lymph node biopsy is of no value because the filariae are localized in the lymphatic
vessels and not in the nodes. A very low dose of diethylcarbamazine can help diagnosis if
it causes pruritus or the appearance of microfilariae in the blood.
 375

VISCERAL LARVA MIGRANS12

This disease is present worldwide and is the human infestation by larvae of T. canis, a
nematode which in its adult form is an intestinal parasite of dogs; it is very rarely due to
T. cati. It gives visceral and/or ocular manifestations; only the visceral localization can
present as U.F. It affects both sexes, mainly children, sometimes with a history of pica.
We have reviewed 350 detailed published cases:12 fever was present in about 70% of cases,
associated with hepatomegaly (75%), respiratory signs (66%), digestive signs (48%), malaise
(45%), nervous signs (36%), splenomegaly (always associated with hepatomegaly) (33%),
cutaneous signs (24%), lymphadenopathies (21%), cardiac symptoms (11%), and edemas
(11%). The eosinophilia is constant and sometimes very high.
The diagnosis relies on serologic test (IFI, ELISA tests) and/or the demonstration of the
parasites, by liver biopsy or exceptionally skin biopsy or autopsy.

CYSTICERCOSIS13
CNS cysticercosis may be a cause of U.F. It is due to the infection by the larval form
of the pork tapeworm, Taenia solium. The clinical manifestations depend on the number,
age, and location of the cysts in the neural tissues; it may cause a chronic meningitis
simulating tuberculosis, focal symptoms sometimes with intracranial hypertension, episodic
acute hydrocephalus, and spinal symptoms.
T. solium is worldwide in distribution but more prevalent in South Africa, Mexico, and
areas of South America, China, India, and Eastern Europe.
Blood eosinophilia is inconstant, as is the demonstration of calcified cysticerci in soft
tissue. The diagnosis relies on the detection of antibodies in blood and/or in CSF, usually
with the IHA technique.

TRYPANOSOMIASIS13
African Trypanosomiasis
Sleeping sickness is a disease contracted in rural areas or in forest galleries after the
bite of a glossina. T. gambiense infection is a purely human disease present in West and
Central Africa. T. rhodesiense infection is an anthropozoonosis, present in East Africa.
The parasites are flagellates; they are free in lymph and blood in the early stage, then
in the CSF at a later stage.
In sleeping sickness, fever is nearly constant; it appears 20 to 30 days after the infecting
bite, is moderate, variable, and long lasting. One must look for “ trypanosomal chancre,”
i.e., the local swelling, simulating a furuncle with its adenopathy, corresponding to the
infecting bite. Many enlarged lymph nodes (peculiarly supraclavicular) may be present, as
well as the patchy, fugitive annular erythemas. Blood cells are normal but two constant
abnormalities are present: an ESR above 50 mm and a polyclonal hyperimmunoglobulinemia
M.
Trypanosomes must be looked for either in blood on smears or after centrifugation and/
or after millipore filtration or in fresh lymph gland juice, and later in the CSF. Immuno-
diagnosis is less valuable (I.F., ELISA).
Without treatment, fever will subside; then, after a few months, the meningoencephalitis
will appear.
T. rhodesiense infection shares the same symptoms and signs but the disease runs a
much more rapid course, with a more frequent cardiac involvement than with T. gambiense.

American Trypanosomiasis
Chagas disease, due to T. cruzi, is also a rural disease, transmitted by Triatoma. It is
an anthropozoonosis, found in every country of South and Central America.
After an incubation of 15 days, a variable and long-lasting fever appears. The inoculation
chancre “ chagoma” may be seen as a skin swelling, sometimes necrotic or as a conjunctivitis
376 Unexplained Fever

with palpable edema and localized adenopathy. A transient rash may be seen on the chest
and the abdomen; hepatosplenomegaly, lymph node hypertrophy are frequent. Cardiac ar-
rhythmias and myocardial insufficiency are frequent, mainly in young children; areas of
myxedematous swelling may appear on certain parts of the body.
Trypanosomes may be found on direct examination of blood only in early cases; at a
later stage, they are scanty and can be found in blood culture on N N N medium or
demonstrated after animal (mouse) inoculation. Serodiagnosis (complement fixation test,
hemagglutination test, IFI test and ELISA reaction) is of great value.
Chronic manifestations of Chagas disease are afebrile (the trypanosomes are intracell-
ular).

VISCERAL LEISHMANIASIS
It is an anthropozoonosis, with an animal reservoir (dog). It is transmitted to man by
the bite of a phlebotoma, due to L. donovani (around the Mediterranean Sea), and to L.
infantum, and L. chagasi . . . in other tropical areas (America, Asia . . . ) The agent, an
obligate intracellular parasite, multiplies within the macrophages present in various tissues.
It is observed in the south of China, south of Russia, India, Near East, East Africa,
around the Mediterranean Sea, on the Atlantic coast of South America, and in the West
Indies.
Incubation varies from 1 to 6 months but may be more prolonged, up to 1 year. The
onset is insidious with a long-lasting and anarchic fever, sometimes with high peaks. It is
accompanied by pallor, asthenia, weight loss, sometimes by purpura, diarrhea, edemas, and
skin rashes. The spleen progressively enlarges and may become huge; it is accompanied by
hepatomegaly.
The diagnosis of this obscure fever with splenomegaly is helped by medical history
(travel in endemic areas and the presence of pancytopenia, and a polyclonal elevation of
IgG).
The diagnosis relies on the demonstration of the parasite within the macrophages, mainly
in the sternal medulla but false-negative results exist because leishmania are small and must
be sought by an expertly trained biologist. They become scantier as the disease evolves and
the sternal puncture must be repeated. The parasites are rarely present in blood monocytes.
They can then be looked for in lymph node or in hepatic biopsy. Splenic puncture is dangerous
and is contraindicated.
The serodiagnosis may be helpful, IFI is the best technique. Electrosyneresis and ELISA
reaction exist. False-positive results may be seen in malaria or trypanosomiasis.
Visceral leishmaniasis may be confused with malaria, septicemia, or hematologic ma-
lignancies. One must think of visceral leishmaniasis because it is a curable but life-threatening
disease. In case of doubt, a therapeutic trial with antimonial agents may be useful.

MELIOIDOSIS26
An infection due to P. pseudomallei must be considered in any patient who has lived
in endemic areas, mainly Southeast Asia. It may be latent for many years (up to 26 years)
and is frequently associated with a precipitating event. It presents as an acute, subacute, or
chronic process; the variable clinical pattern includes septicemia or localized infectious foci
in various tissues (lung, bone, brain . . . )

TROPICAL VIRAL DISEASES16 23 24

Viral infections are a very rare cause of U.F. because fever due to the frequent arbovirus
infections is of short duration.
Only two exceptional diseases, sometimes called African hemorrhagic fevers, may then
be present. The fever in these diseases may last 15 to 20 days, but is often of shorter duration.
 377

U.F. Due to Arenaviral Diseases: Lassa Fever

As fever of South American hemorrhagic fevers (due to Junin and Machupo viruses)
does not exceed 10 days, only Lassa fever may present as U.F. The virus is spread by the
urine of domestic rodents, probably all over central Africa.
After an incubation of 5 to 20 days, the initial illness is not characteristic: fever is
elevated and accompanied by prostration, pharyngitis, nausea, vomiting and/or diarrhea,
and myalgias. In the 2nd week, hemorrhages, central nervous system dysfunction, and
collapse may appear. Death occurs in half of hospitalized patients.

U.F. Due to Filivirus

Two filiviruses are pathogens of man, namely, Ebola and Marburg viruses. Outbreaks
of Ebola virus fever were described in the south of Sudan and northeast of Zaire and outbreaks
of Marburg virus fever in Central and South Africa, as well as in Europe, in laboratory
workers who had contact with the blood of monkeys captured in Uganda.
High fever is associated with prostration, diarrhea and/or vomiting and in severe cases
hemorrhage and collapse.

Guidelines to Management of Lassa and Ebola Fevers23,24

Filivirus fever simulates malaria, typhoid fever, and septicemia (mainly due to men-
ingococci). Diagnosis relies on serology and/or in the demonstration of the virus in blood
(available in few specialized laboratories, where all necessary precautions can be taken).
Affected patients are highly contagious and because of the severity of the disease, must
be isolated in specialized units. Hemorrhagic fever with renal syndrome is dealt with in
Chapter 27 as it is present worldwide.

U.F. with Hypereosinophilia

Pathologic eosinophilia is usually defined as a level ^500 mm3 in peripheral blood.
Because of the great variety of causes we will use tables with short comments to present
clearly this “ puzzle” . The function and control of the eosinophil, which are beyond the
scope of our chapter, will be found in References 14 and 15. Among the various diseases
listed in Table 15 we shall briefly describe the idiopathic hypereosinophilic syndrome.14
This syndrome, formerly called differently (eosinophilic leukemia . . . ), is character-
ized by the absence of any recognized cause, the persistence (for at least 6 months) of an
elevated (^=1500 eosinophils/mm3) eosinophilia, and the involvement of various organs.
Fifty cases were recently reviewed.14 Fever is the presenting symptom in only 12% of
cases. The other presenting symptoms are weakness and fatigue, 26%; cough, 24%; myalgia,
14%; angioedema, 14%; rash, 12% of cases.
The relative frequency of organ system involvement14 is

1. Neurologic involvement is present in 64% of cases. Three types can be distinguished:

symmetrical polyneuropathy; diffuse central nervous system alterations (altered be-
havior and cognitive function and sometimes ataxia), and focal central nervous system
deficit.14
2. Skin involvement is present in 56% of cases (dermographism, angioedema, rashes)
3. Cardiac disease, present in 54% of cases, is the major cause of death. It corresponds
to Loffler’s eosinophilic endocarditis,18 i.e., an obliterative and restrictive cardio-
myopathy with a thick fibrous endocarditis. It manifests as a progressive congestive
heart failure and/or mimics constrictive pericarditis. Multiple emboli were seen in 18%
of cases.
4. Splenomegaly is present in 46% of cases, and liver involvement in 32%.
5. Pulmonary disease, seen in 40% of cases, comprises various disorders, initially mim-
378 U nexplain ed F e ve r

TABLE 15
Main Disorders Associated with Eosinophilia12'22

Disorders Comments

Allergic or hypersensitivity diseases Commonest cause of eosinophilia in Europe and U.S.

Asthma seasonal rhinitis Exceptional cause of U.F.
Some drug reactions See Chapter 18
Infectious diseases
Parasitic infections
(Mainly tissue invasive helminths)
Schistosomiasis
Filariasis Only B r u g ia m a la y i, W u c h e re r ia b a n c r o fti, and L o a lo a
cause U.F.
Trichinosis
Strongyloidiasis
Visceral larva migrans
Ascaridiasis
Hookworm disease
Cysticercosis
Clonorchiasis
Fasciolasis
Paragonimosis
Hydatid disease Both E c h in o c o c c u s g r a n u lo s u s and E . m u ltilo c u la r is
Pneumocystosis Eosinophilia is very rare and low
Fungal infections See Chapter 19
Pulmonary aspergillosis
Coccidioidomycosis
Histoplasmosis
Bacterial (and related) infections) See Chapter 20
Tuberculosis Eosinophilia is exceptional
Brucellosis Eosinophilia is exceptional
Streptococcal infections Eosinophilia is exceptional
Chlamydia pneumonia in infants Eosinophilia is frequent
Connective tissue diseases
and related disorders
Systemic vasculitis (particularly allergic angiitis and See Chapter 18
granulomatosis)
Systemic lupus erythematosus Eosinophilia is rare
Scleroderma Eosinophilia is rare
Rheumatoid arthritis See Chapter 11 — eosinophilia is rare
Eosinophilia with fasciitis See Chapter 11
Neoplastic diseases
Lymphoma (Hodgkin’s disease, T cell lymphomas — See Chapter 13
including mycosis fungoides)
Certain leukemias — acute lymphoblastic, Sezary See Chapter 13
syndrome . . .
Solid tumors — mainly of two origins (digestive tract,
endocrine . . . ) often metastatic (liver . . . )
Cutaneous diseases See Chapter 16
Allergic: drug reaction, atopic dermatis Exceptional cause of U.F.
Duhring disease Exceptional cause of U.F.
Immunodeficiency states
Wiskott-Aldrich syndrome These disorders, usually discovered because of repeated
Hyper-IgE with infections infections, may present as U.F.
Selective IgA deficiency
Idiopathic hyperéosinophilie syndrome
 379

TABLE 16
Pulmonary Infiltrates with Peripheral Eosinophilia14’17,22

Diseases Comments
Allergic bronchopulmonary aspergillosis See Chapter 19
Drug reactions (Nitrofurantoin, betalactams . . . ) See Chapter 18
Vasculitis (mainly Churg and Strauss syndrome) See Chapter 18
Idiopathic hyperéosinophilie syndrome See supra
Parasitic infestation
Labile pulmonary eosinophilia
(Löffler’s syndrome) Usually asymptomatic but fever, cough . . . may be
seen; lung infiltration vanishes in 8— 15 days, due to
lung migration of larvae of ascaris, hookworm, stron-
gyloides trichina and visceral larva migrans
Tropical eosinophilia Chronic malaise, weight loss, fever, cough, asthma . . .
(Southeast Asia, India, Malaya) bronchus rales are frequent. Various chronic lung in-
filtrates. Due to microfilaremia, B . m a la y i, W . b a rt-
e r o f ti, B . p a h a n g i
Chronic eosinophilic pneumonia Predominant in females: chronic pneumonia, febrile,
life-threatening; the infiltrates are arranged in a pattern
of “ photographic negative” of pulmonary edema
Other illnesses characterized by pulmonary infiltrates
with infrequent peripheral eosinophilia
Bacterial and fungal infections
Lung cancer (metastatic more often than primary) Listed in Table 15
Autoimmune diseases, vasculitis excepted
Very rare cases without features of the aforementioned
groups

icking asthma or Löffler’s syndrome (see below). Then infiltration is constant and
associated with fibrosis.
6. Other involved organs are nose and sinuses in 26%, eyes in 18%, gastrointestinal
system in 14%, lymph nodes in 12%, and muscles in 12% of cases.

P ulm onary In volvem en t an d P eriph eral E o sin oph ilia1517 22

We shall only mention the eosinophilia associated with bronchial obstruction: asthma
is not a diagnostic challenge. But in some patients, a severe asthma with fever may be the
first manifestation of vasculitis (see Chapter 18).
In contrast, infiltrative pulmonary disease with eosinophilia may present as U.F. and
has many causes listed in Table 16.
In this chapter, various causes of U.F. in a patient coming back from the tropics have
been summarized with many tables. The most frequent are parasitic infections, whose
diagnosis will be greatly helped in the future by specific IgE use.

REFERENCES
1. Wilcocks, C. and Manson-Bahr, P., M a n s o n s T r o p ic a l D is e a s e s , 17th ed., Bailliere Tindall, London,
1976.
2. Woodruff, A., M e d ic in e in th e T r o p ic s , Churchill Livingstone, Edinburgh, 1974.
3. Gentilini, M. and Duflo, B., M e d e c in e T r o p ic a le , 3rd ed., Flammarion, Paris, 1982.
4. Hall, A., Imported fever including malaria, T h e P r a c titio n e r , 226, 1521, 1982.
5. Walker, E. and Williams, G., Infections on return from abroad, B r. M e d . J ., 286, 1197 and 1333, 1982.
6. Woodruff, A., Bowen, E., and Platt, G., Viral infections in travelers from tropical Africa, B r. M e d . J .,
1, 956, 1978.
380 Unexplained Fever

7. Cohen, S., Ed., Malaria, Br. Med. Bull., 38, 115, 1982.
8. Charmot, G., Frottier, J., Trinh, P., et al., Les formes febriles pures de l’amibiase hépatique, Ann.
Med. Intern., 127, 265, 1976.
9. Bastin, R. and Charmot, G., Les abcès amibiens du foie en France, Concours Med., 102, 4395, 1980.
10. Schwager, J. C. and Darsanesing, R., Abcès amibiens du foie. Elevation inconstante de la vitesse de
sedimentation, Nouv. Presse Med., 11, 3273, 1982.
11. Bonpart, J., Gendre, J.-P., Romano, P., et al., Reaction d’immunofluorescence amibienne positive au
cours d’un cancer secondaire du foie, Arch. Fr. Mal. Appl. Dig., 65, 235, 1976.
12. Erhard, T. and Kernbaum, S., Toxocara canis et toxocarose humaine, Bull. Inst. Pasteur, 77, 225, 1979.
13. Shanley, J. and Jordan, C., Clinical aspects of CNS cysticercosis, Arch. Intern. Med., 140, 1309, 1980.
14. Fauci, A., Harley, B., Roberts, W., et al., The idiopathic hyperéosinophilie syndrome: clinical, patho-
physiologic and therapeutic considerations, Ann. Intern. Med., 97, 78, 1982.
15. Schatz, M., Wasserman, S., and Patterson, R., The eosinophil and the lung, Arch. Intern. Med., 142,
1515, 1982.
16. Marland, P., Le poumon eosinophilique parasitaire, Rev. Fr. Mal. Respir., 3, 451, 1975.
17. Gentilini, M., Pinon, J., and Nosny, Y., Parasitoses a nematodes: le Poumon Eosinophile, Rev. Fr. Mal.
Resp., 3, 429, 1975.
18. Editorial, Löffler’s eosinophilic endocarditis, Lancet, II, 1028, 1981.
19. Flores, M., Merino-Angulo, J., Tanago, J., et al., Late generalized tuberculosis and eosinophilia, Arch.
Intern. Med., 143, 182, 1983.
20. Efstratopoulos, A., Spantideas, A., and Komninos, Z., Extreme eosinophilia due to common strepto-
coccal infection in an adult, Br. Med. J., 11, 588, 1980.
21. Fendler, J.-P., Tutin, M., and Pasquier, P., Les eosinophilies au cours des cancers, Presse Med., 40,
2239, 1965.
22. Carrington, C., Addington, W., Goff, A., et al., Chronic eosinophilic pneumonia, N. Engl. J. Med.,
280, 787, 1969.
23. Center for Disease Control, Viral Hemorrhagic Fever, Ann. Intern. Med., 101, 73, 1984.
24. Eyckmans, L. and Van der Graen, G., Viroses tropicales, Rev. Praticien, XXXIV, 1973, 1984.
25. Weller, P., Paroxysmal inflammatory filariasis, Arch. Intern. Med., 143, 1523, 1983.
26. Sanford, J., Melioidosis: another great imitator, in Infectious Diseases. Current Topics, Gilbert, D. and
Sanford, J., Eds., Grune and Stratton, New York, 1979, 147.
 381

Chapter 23

FEVER IN ONCOLOGY
Jacob Schächter

INTRODUCTION
Fever occurs frequently in cancer patients and most frequently is due to a complicating
infection. Although other noninfectious causes such as drug toxicity exist, certain tumors
are associated with fever per se. Petersdorf found in a study of 351 patients with cancer that
30% developed fever and 5% had fever that could be related only to their cancer without
superimposed infection.1
The differential diagnosis of fever in the cancer patient includes the following: (1) fever
as a paraneoplastic syndrome; (2) fever associated with infection; (3) fever related to therapy;
(4) tumor necrosis, hematoma, pulmonary embolism and thrombosis/phlebitis; and (5) ad-
renal insufficiency.

PARANEOPLASTIC FEVER
Tumor-associated fever is usually defined as unexplained fever that coincides with tumor
growth, disappears promptly on tumor removal or control, and reappears with tumor re-
growth. Alternatively, when the fever persists with uncontrolled tumor without any other
reasonable cause, the tumor is the likely etiology of the fever.2 There is no prognostic data
on the influence of fever associated with tumor, except for Hodgkin’s disease, in which
fever as a systemic symptom suggests a worse prognosis.3’4
Among the various neoplasms, fever is more likely to occur in lymphoreticular neo-
plasms, including Hodgkin’s disease and the non-Hodgkin lymphomas.5 Fever alone or with
other symptoms can be present in up to 25% of the patients with Hodgkin’s disease and
leukemia. In pre-leukemia, FUO can be present in up to 30% of the patients.6 In reviewing
the types of carcinoma frequently associated with fever, they include hepatoma and renal
cell carcinoma.7 8 Atrial myxoma, although rare, frequently presents also as FUO.9 It should
be pointed out that benign tumors such as leiomyomas of the uterus can cause FUO, especially
if they are necrotic (see Table 1).

FEVER DUE TO INFECTION

While the patient’s underlying malignancy can occasionally cause fever, in the advent
of cytotoxic chemotherapy, fever in the cancer patient has been closely linked with infection
(50 to 70%), especially when the patient is granulocytopenic (PMNs less than 500/mm3).
The detection and management of the febrile-granulocytopenic patient is complicated by the
fact that the granulocytopenia alters the host inflammatory response, making it difficult to
detect the infection (pyuria may be detected in only 10% of patients with urinary tract
infection). Moreover, the undetected and untreated infection can be rapidly fatal in the
granulocytopenic cancer patient. In general, two or three low-grade elevations above 38°C
(orally) or a single elevation above 38.5°C, together with a granulocyte count of less than
500/mm3 are sufficient criteria to begin therapy. The absence of physical findings suggestive
of infection do not exclude a potentially life-threatening bacteremia, since a great part of
the bacteremic patients lack any specific findings. An infectious etiology in the nongranu-
locytopenic patient is considered to be the cause of the fever whenever there is clinical and/
or microbiologic evidence of a localized or generalized infection.1213
382 U nexplain ed F e ve r

TABLE 1
Neoplasms Associated with Fever812

Frequent Rare

Hodgkin’s and non-Hodgkin lymphomas Lung cancer

Leukemia and pre-leukemia Atrial myxoma
Hepatoma Breast cancer — inflammatory
Renal cell carcinoma Brain (3rd ventricle) tumor
Hepatic métastasés Gastrointestinal tumor
Tumors associated with AIDS Pancreas carcinoma
Vascular tumor
Thyroid carcinoma
Retinoblastoma
Ovarian and uterine tumor
Seminoma
Prostate carcinoma
Osteosarcoma, Ewing sarcoma
Rhabdomyosarcoma
Neuroblastoma
Pheochromocytoma

TABLE 2
Chemotherapy Agents Known to Induce
Fever1516

Bleomycin Adriamycin
Dacarbazin (DTIC) 5-Fluoro-uracil (5-FU)
L-Asparaginase Mitomycin
Cytarabin Mithramycin
Cisplatin Procarbazine
Dactinomycin Thiotepa
Methotrexate

There are many predisposing factors to infection in patients with cancer, including the
following: (1) intravenous catheters and parenteral nutrition; (2) medication — steroids and
immunosuppressive medication; (3) diagnostic procedures including biopsies and operations;
(4) splenectomy in patients undergoing staging laparotomy; (5) defective Ab production as
in multiple myeloma; (6) defective cellular immunity as in Hodgkin’s disease; (7) granu-
locytopenia from bone marrow involvement with cancer or secondary to chemotherapy or
radiotherapy; and (8) various other factors leading to immunodeficiency.

FEVER RELATED TO THERAPY

Fever related to treatment in cancer patients is relatively common in patients receiving
Bleomycin. The fever is often observed in the first 48 h after drug administration.14 Drugs
that may cause unexplained fever in the oncologic patient are listed in Table 2.
Biological response modifiers that are in clinical use such as interferons and interleukin-
2 (IL-2) can also cause fever.
Fever occurring without evidence of hemolysis or infection is the single most common
type of reaction to blood product infusion. The reactions are usually mild, beginning about
an hour after the initiation of the transfusion with rigor and chills followed by a rise in
temperature. More severe reactions with hypotension, tachycardia and pulmonary infiltrates
rarely occur.17 The fever is most commonly a result of sensitization to granulocyte antigens,
but may also result from sensitization to lymphocyte antigen.
Fever as a result of radiation treatment is well documented, especially in the “ mantle
 383

field” of Hodgkin’s lymphoma. It depends very much on the volume of the lung irradiated
and the total dose given. The clinical picture of radiation pneumonitis includes shortness of
breath, cough, and occasionally, fever.18

MECHANISM OF FEVER

Microbial invasion, tissue injury, immunologic reactions, and inflammatory processes

induce a constellation of host responses in which fever is a prominent feature. The production
of a mediator called interleukin-1 (IL-1) is probably the most important event in the initiation
of the response. The primary sources of IL-1 are blood monocytes, tissue macrophages (such
as Kupffer cells in the liver), kératinocytes, corneal epithelial cells, renal mesangial cells,
and brain astrocytes. The fever is the result of the action of IL-1 on the thermoregulatory
center in the brain. IL-1 initiates fever by inducing an abrupt release in the synthesis of
prostaglandins in the anterior hypothalamus, which in turn raises the thermostatic set point,
and drives the mechanism of heat production until the blood temperature is elevated to match
the hypothalamic set point. The etiology of fever as a paraneoplastic syndrome could come
from the release of the pyrogen from the tumor cells or from the variety of normal cells that
have been demonstrated to have this pyrogen.219*20

DIAGNOSIS

In patients presenting with fever, emphasis has to be placed on a detailed history and
meticulous physical examination. There are two distinct possibilities present in these patients.
One possibility is that fever presents in patients without known diagnosis of a neoplasm. In
the search of a tumor, the presence of lymphadenopathy, hepatosplenomegaly, and skin
lesions should not be overlooked. Appropriate imaging techniques should be used, and any
suspicious findings may provide tissue for diagnosis or for the stimulus for further appropriate
studies.10 Baseline laboratory data are usually not specific enough to distinguish among
different causes of FUO — tumor markers such as alpha-fetoprotein in hepatoma or carcino-
embryonic antigen (CEA) for gastrointestinal tumors may be of some help. Elevated acid
phosphatase levels may suggest the diagnosis of advanced prostate carcinoma.21’23
A patient who has a known diagnosis of neoplasm who presents with fever should also
have a thorough examination. A few sites needing close examination are the oral cavity for
oropharyngeal lesions, and the perineum for perirectal abscess, which may not be painful
and manifest only as an asymmetric induration on rectal examination. Complete history and
physical examination, chest radiograph, urinalysis, and at least two blood cultures from
separate vein puncture sites for aerobic, anaerobic, and fungi are all mandatory. Further
evaluation is dictated by the patient’s clinical or laboratory findings. It should be pointed
out that the premature adoption of the diagnosis of fever due to the neoplasm itself, as in
a patient with liver métastasés, is dangerous and an extensive search for an infectious etiology
is important.12*24

TREATMENT

PARANEOPLASTIC FEVER
Treatment should be directed at the underlying tumor. The most dramatic remission of
paraneoplastic fever comes in successfully treated patients with Hodgkin’s lymphoma or
renal cell carcinoma. Palliation may be achieved by nonsteroidal anti-inflammatory agents
such as indomethacin or steroids.

FEVER DUE TO INFECTION

All granulocytopenic cancer patients with fever deserve prompt empiric antibiotic man-
384 Unexplained Fever

agement. Since 85% of the initial pathogens are bacterial, it is essential that the antibiotics
cover the range of the potentially life-threatening organisms typical of the given institution.
This has usually necessitated two or three drug combinations. Whenever the initial antibiotic
therapy must take into account a bacterial pathogen, extended therapy should focus on
superinfection, particularly due to fungi. Infection in the non-neutropenic cancer patients
should focus on the suspected causative organism.25,26

FEVER DUE TO TREATMENT

Premedication with antipyretics or steroids may help to minimize the reactions due to
chemotherapeutic agents. Antihistamines are also frequently used but are of less certain
value. Fever due to blood products transfusion can be prevented by removal of the leukocytes
by filtration. Steroids are known to be active in the clinical picture of radiation pneumonitis.15

REFERENCES
1. Petersdorf, R. G., Fever and cancer, Hosp. Med., 1, 2, 1965.
2. Bodel, P., Tumors and fever, Ann. N.Y. Acad. Sci., 230, 6, 1974.
3. Carbone, P., Kaplan, H. S., and MusshofT, K., Report of the Committee on Hodgkin’s disease staging,
Cancer Res., 31, 1860, 1971.
4. Lobell, M., Boggs, D. R., and Wintrobe, M. M., The clinical significance of fever in Hodgkin’s Disease,
Arch. Intern. Med., 117, 335, 1966.
5. Reimann, H. A., Periodic fever of lymphomas, Ann. Clin. Lab. Sci., 7, 1, 1977.
6. Zanger, B. and Dorsey, A. N., Fever, manifestation of preleukemia, JAMA, 236, 1266, 1976.
7. Rawlins, M. D., Luff, R. H., and Granston, W. I., Pyrexia in renal carcinoma, Lancet, 1, 1371, 1970.
8. Rakatansky, H. and Heisner, J. B., The gastrointestinal tract. An often forgotten source of prolonged
fever, Arch. Med., 119, 321, 1967.
9. Godwin, J. F., Stanfield, C. A., and Steiner, R. E., Clinical features of left atrial myxoma, Thorax,
17, 91, 1962.
10. Wang, C., and Armstrong, D., FUO in neoplastic diseases, in Fever of Undetermined Origin, Murray,
H. W., Ed., Futura, Mount Kisco, NY, 1983.
11. Klastersky, J., Weerts, D., and Hensgen, C., FUO in patients with cancer, Eur. J. Cancer, 9 , 649,
1973.
12. Pizzo, P. A., Robichaud, K. J., and Commers, J. R., Fever in the pediatric and young adult patient
with cancer, Medicine, 61(3), 153, 1982.
13. Sickles, E. A., Green, M. H., and Wiernik, P. H., Clinical presentation of infection in granulocytopenic
patients, Arch. Intern. Med., 135, 715, 1975.
14. Blum, R. H., Carter, S. K. L., and Agre, K., A clinical review of bleomycin, Cancer, 31, 903, 1975.
15. Martindale, The Extra Pharmacopoeia, 28th ed., Wade, A., Ed.
16. Gerber, A. U., Approach to fever in the patient with cancer, Schweiz. Rundschau. Med., 72, 44, 1983.
17. Barton, J. C., Nonhemolytic transfusion reactions, Semin. Hematol., 18, 95, 1981.
18. Carmel, R. J. and Kaplan, H. S., Mantle irradiation in Hodgkin’s Disease, an analysis of technique,
tumor irradiation and complications, Cancer, 37, 2812, 1976.
19. Dinarello, C. A., Interleukin-1 and the pathogenesis of the acute phase response, N. Engl. J. Med., 311(22),
1413, 1984.
20. Gluckman, J. B. and Turner, M. D., Systemic manifestations of tumors of the small gut and liver, Ann.
N.Y. Acad. Sci., 230, 318, 1974.
21. Goldenberg, D. M., Neville, M., and Carter, A. C., CEA — its role as a marker in the management
of cancer, Cancer Res., 41, 2017, 1981.
22. McIntyre, K. R., Vogel, C. R., and Princler, G. P., Serum alpha FP as biochemical marker for
hepatocellular carcinoma, Cancer Res., 32, 1941, 1972.
23. Gittes, R. F., Serum acid phosphatase and screening for carcinoma of the prostate, N. Engl. J. Med., 309,
852, 1983.
24. Aderka, D., Kidron, D., Weinberger, A., and Pinkhas, J., Absence of correlation between liver me-
tastases and unexplained fever episodes, Cancer, 55(12), 2830, 1985.
25. Singer, C., Kaplan, M., and Armstrong, D., Bacteremia and fungemia complications in neoplastic
diseases, Am. J. Med., 62, 731, 1977.
26. Wenz, B., Microaggregate blood filtration and the febrile transfusion reaction, Transfusion, 23, 95, 1983.
 385

Chapter 24

FEVER OF UNEXPLAINED ORIGIN — PSYCHIATRIC ASPECTS

E. A. Bar-Natan

INTRODUCTION

Although fever has long been recognized as a symptom of disease, only recently has
modem medicine given us a better understanding of its significance. A wide variety of
defined diseases cause fever, such as infectious processes, neoplasms, autoimmune diseases,
and miscellaneous causes. Centuries ago it was believed that psychological factors affected
body temperature, Aristotle1 coined the phrase “ emotional pyrexia” , Lange2 in 1954 wrote
about “ love fever” and Tuke3 in 1872 wrote a definitive treatise on the influence of the
mind in the production of fever. However, it took a detailed physiological and anatomical
understanding of the hypothalamus and its functions to elucidate thermoregulatory mecha-
nisms.
Most febrile illnesses are due to common infections, are short-lived, and relatively easy
to diagnose. However, in certain cases the origin of fever is obscure and initially it is difficult
to arrive at a diagnosis. Most of these cases of fever of undetermined origin (FUO) are
eventually found to represent atypical manifestations of common diseases, rather than exotic
illnesses.4 A 1982 survey5 shows that in 13% of cases the diagnosis is never established.
There are four main aspects of fever associated with psychiatric features:

1. Psychiatric illness accompanied by underlying systemic disease

2. Psychiatric illness without underlying systemic disease, in which case there is no
conscious provocation of fever, the condition being known as psychogenic fever
3. Psychiatric illness associated with chronic fraudulent or factitious fever, in which case
the fever is consciously provoked
4. Neuroleptic Malignant Syndrome

SYSTEMIC DISEASES
Herpes simplex and acute inclusion-body encephalitis — Drachman and Adams39
reported six cases of herpes simplex with psychiatric symptoms at the beginning of the
disease. The disease is described in detail in Chapter 8.
Parasitic disorders — The psychiatric manifestations are due to severe metabolic changes
and/or localization of the parasite in the brain and meninges. The most important diseases
are (a) acquired toxoplasmosis complicated by and consequently characterized by distur-
bances of consciousness; (b) a paroxysmal malaria due to Plasmodium falciparum may be
manifested by altered intellectual function, behavioral changes, hallucinations, and even
coma (cerebral malaria). This condition should be suspected in the appropriate setting, such
as a patient residing in or returning from an endemic area; (c) African trypanosomiasis, in
the early febrile stage, may present with personality changes leading to frank psychosis and
even suicidal tendencies. When these features are associated with lymphadenopathy and
reversal of sleep pattern, the diagnosis should be considered.
Collagen-vascular diseases — In systemic lupus erythematosus (SLE), the psychiatric
features are variable and include anxiety, memory impairment, change of personality, hal-
lucinations, paranoia, and frank psychosis. Studies reported currently indicate that between
20 and 40% of SLE patients develop organic psychiatric diseases.40,41 Tishler and Abramov
reported a case of catatonic schizophrenia as the presenting and predominant feature in a
21-year-old woman, fulfilling the diagnostic criteria for SLE.42
386 U nex p la in ed F e ve r

PSYCHOGENIC FEVER
The concept of “ emotional pyrexia” has been a controversial subject since Aristotle’s
day.1 Psychiatric illness and emotional disturbance have been known to elevate body tem-
perature. Emotions such as apprehension and anxiety have been reported to raise body
temperature. Wynn10 found that 67% of 324 men reporting for the draft had a temperature
above 99°F, with 15% having a temperature above 100°F. Nikitopoulou and Crammer,11 in
a study of six manic-depressive patients, found that during depressive episodes the normal
circadian temperature cycle was disturbed. They support the hypothesis that manic-depression
is the manifestation of disordered circadian rhythms.
Psychogenic fever resulting from emotional stress is different from physiologic hyper-
thermia and habitual or constitutional hyperthermia. Vigorous muscular contraction during
exercise can raise rectal temperature to 104°F, and body temperature rises in the latter half
of the menstrual cycle. These rises produced as a result of normal physiological function
are known as physiologic hyperthermia. Habitual hyperthermia or constitutional hyperthermia
occurs for unknown reasons, when the temperature of an individual is chronically elevated
to a higher level (“ set point” ) temperature of a healthy reference population.12 Psychogenic
fever rarely exceeds 100°F, however, McNeil et al.13 describe the case of a 24-year-old
woman with borderline personality disorder and prolonged fever of unknown origin. This
patient was without fever for weeks at a time, at other times she had daily temperature
spikes from 100.2 to 103.5°F for a week or more. Extensive microbiologie and serologic
investigations were negative, except for positive ANA titers varying between 1:128 and
1:256. The LE cell preparation and ESR were normal. Thorough endocrine testing showed
normal thyroid and adrenal function, X-rays were all normal, and liver-spleen radionuclide
scan was negative. An echocardiogram showed mitral valve prolapse with no myxoma or
other abnormality. An EEG showed normal waking and sleep tracings. Biopsy of an inguinal
lymph node, and a rectum biopsy were normal.
The cause of this patient’s fever remained unknown until, by chance, it was observed
that pseudoseizures (characterized by semi-purposeful flailing of her arms and legs) lowered
her temperature on one occasion from 102.2 to 99.5°F. This led the medical team treating
the patient to consider a psychogenic cause and to administer a trial of sedation with
phénobarbital, which kept her afebrile for 4 days until she started to vomit the drug, after
which her fever gradually returned to 100.4°F. The positive response to phénobarbital
supports the diagnosis of psychogenic fever, as fever caused by infection or other inflam-
mation would not be expected to respond to barbiturates. However, McNeil et al. could not
account for her response to 30 mg/day prednisone which kept her afebrile for 11 days. They
maintained that this response was not consistent with their diagnosis of psychogenic fever
and proposed that this improvement corresponded to one of the afebrile periods in the natural
history of the illness.13 According to the above discussion of the pathogenesis of fever, it
is possible that prednisone, a corticosteroid, exerts an inhibitory effect in the release of
arachidonic acid and thus by blocking the formation of prostaglandins, interferes with the
production of fever.
The patient was diagnosed as suffering from hypothalamic dysfunction rendering her
extraordinarily sensitive to psychic stimuli. The rich neural connections between the limbic
cortex and hypothalamus make such an explanation possible. Similar neural pathways have
been implicated in order to explain changes in autonomic nervous activity in highly charged
emotional states.14
Many early studies have observed the association of chronic low-grade fever with psy-
choneurosis. Studies by Alt and Barker15 many years ago found that of all the patients with
FUO admitted to the Peter Bent Brigham Hospital in Boston 10% exhibited a “ tendency to
psychoneurosis or vasomotor disturbance” . The patients recovered spontaneously without
treatment.
Kintner and Rowntree16 attributed the low-grade FUO found in 25% of patients admitted
 387

to the Mayo Clinic between 1919 and 1930 to psychoneurosis, which they variously described
as “ chronic nervous exhaustion” , “ anxiety neurosis” , “ neurasthenia” , or “ functional
disease” .
More recently, an investigation by Hasan and White17 in 1979 attempted to verify the
presence of psychogenic fever by establishing its “ actual incidence” in a psychiatric pop-
ulation at a university hospital unit dealing mainly with patients suffering from psychoneu-
rosis. Although an increase in pulse rate was observed corresponding to the more stressful
periods of the day, that is, the period before ward rounds, no increase in temperature was
recorded. Of the 80 patients in the study, one case was diagnosed as factitious fever.
At present there seems to be a lack of interest in fever of psychogenic origin, evidenced
by a paucity of new research published. In a 1985 review of the last 60 years of study into
fever of unknown origin (FUO),18only a cursory diagrammatic reference is made to factitious
fever and none at all to psychogenic fever. Despite the observation that the patterns of FUO
have changed, in that there are less FUOs resulting from infectious processes and collagen/
autoimmune disease and more from neoplastic conditions and undiagnosed conditions, no
speculation or further study was mentioned regarding the latter psychogenic causes.18
Aduan19 describes a study by the National Institute of Allergy and Infectious Disease
(NIAID) and National Institutes of Health (NIH) between 1970 and 1976. The study evaluated
347 subjects with FUO, with a mean age of 35 years and mean fever duration of 4 years.
Despite extensive laboratory tests and prolonged, in-depth observation (up to 16 years), no
definitive diagnosis could be established in 65 subjects (29%). Ten subjects were thought
to have hypothalamic dysfunction causing their prolonged FUOs: seven of these subjects
had abnormal thermoregulatory responses to extremes of temperature in a metabolic chamber;20
another one had an episodic diencephalic syndrome associated with schizophrenia and normal
thermoregulatory responses, with the fever not responding to chlorpromazine; and one had
a borderline personality disorder with acute psychotic depression, whose fever was unre-
sponsive to antipsychotic medications. Another patient may have had psychogenic hyper-
thermia — unexplained low-grade fever associated with a hysterical personality disorder.
One subject without psychiatric illness had an FUO associated with neutropenia which
responded to lithium carbonate therapy. Four patients with idiopathic FUO were presumed
to have “ habitual hyperthermia” and/or exaggerated circadian temperature rhythms. Two
subjects were thought to have excessive physiologic hyperthermia, one associated with
exercise and another with ovulation. In the remaining 47 cases there was no diagnosis.
A definitive diagnosis could be made for 157 subjects in the study and of these there
were only 4 who exhibited a psychiatric syndrome, that is, depression with pseudodementia,
depressive reaction with hysterical features, reactive depression associated with corticosteroid
therapy, and chronic paranoid schizophrenia. Ninety-three subjects who had histories of
FUO but no fever during a 2-week hospitalization in the Clinical Center, NIH, or during
subsequent follow-up showed a comparatively high incidence of psychiatric diagnosis (22
out of 93). Four of these, all women with a mean age of 18 years, had highly suspected
but unverified factitious fever. One of the four suffered a borderline personality disorder
and another, a psychology student, had conversion reactions and dismissed herself from the
hospital against medical advice. A third patient had a hysterical personality disorder with
borderline features.
It is assumed that six subjects probably had exaggerated circadian temperature rhythms
(habitual hyperthermia) as the cause for their FUO, and four probably had excessive phys-
iologic temperature response to exercise (physiologic hyperthermia).19

FACTITIOUS OR FRAUDULENT FEVER

Factitious or fraudulent fever is diagnosed when the patient has induced his fever by
self-infection, by manipulation of the thermometer to produce a falsely high reading, or by
388 U nex p la in ed F e ve r

tampering with the hospital temperature chart. In all cases the patient practices deception,
often of a highly sophisticated and devious nature. Factitious fever has been largely ignored
in medical literature and it is not mentioned in recent reviews.518 Its diagnosis is often costly
and time-consuming; Ferguson and Maki1 estimate the total cost of one patient’s hospital-
izations in excess of $250,000. Factitious fever is most often diagnosed in retrospect and
is not accepted as a bona-fide psychiatric syndrome in its own right, but rather as a symptom
of underlying psychosis. Commonly, once the patient is confronted with evidence or sus-
picion of falsification and psychiatric help offered, the patient often proves uncooperative
and discharges himself from the hospital.21 Recently, much attention has been given to
Munchausen’s syndrome, a variation of chronic pathomimicry, and several cases of factitious
fever have been classified as a manifestation of this syndrome.21
Fraudulent fever has the following features:21

• Good general appearance, without weight loss

• Failure of fever to follow diurnal variation
• Absence of tachycardia with fever
• Rapid defervescence without diaphoresis
• Temperature exceeding 106°F
• Absence of fever when temperature measurements are closely monitored
• Urine temperature normal

The prognosis for adult patients with factitious fever is poor. Aduan19 cites their severe
underlying personality disorders as the primary reason for this. Ferguson et al.21 emphasize
that there is no effective treatment for adults who continue to feign or self-inflict illness;
some may eventually die from self-abuse or from iatrogenic causes. The few cases of children
and adolescents that have been recorded have had a more favorable prognosis. However,
Millard22 reports in a study of dermatological pathomimicry that a “ positive directive psy-
chotherapy” achieved an improvement in 11 out of 13 patients.
Of 111 cases of factitious fever investigated by Murray,23 most patients were young
(mean age 25 years) and female (79%). Fifty-two patients had medical or paramedical
training; most of these were nurses.
Most patients with FUO are not hospitalized for fever alone; in the majority of cases
they are admitted because of other complaints. Murray23 lists an array of presenting signs,
symptoms, and initial diagnoses in 99 cases of factitious fever.
Fever-related illnesses are one of the most commonly simulated illnesses; other examples
of pathomimicry include brain tumor or abscess; coma; cardiovascular or neurologic disease;
myocardial event; urinary tract infection; anemia; surgical wound infections; hemorrhage
(gastrointestinal, skin, vaginal); arthritis; and hypoglycemia.23

Methods Used to Produce Factitious Fever

In the report mentioned above by Murray23 in which 111 reported cases were studied,
it was found that most patients achieved fraudulent fever by manipulating the thermometer
(61%) and the next biggest group (28%) had self-induced infections, 5% had drug-induced
fever and 6% tampered with their hospital temperature charts. Hale and Evseichick24 report
a case in which the patient could produce a fraudulent thermometer reading by rapidly and
repeatedly contracting the anal sphincter muscles. Hasan and White17 report a patient who
wished to prolong her stay in hospital, so simulated a fever. This she did by substituting a
thermometer she had previously warmed for the one supplied in the normal ward round.
A similar case was reported by Aduan et al.25 An 18-year-old woman with a 4-year
history of fever underwent multiple diagnostic procedures until eventually it was discovered
that she had switched thermometers on at least 19 different occasions during the most recent
 389

period of “ fever” . After psychiatric consultation and psychological testing was obtained,
a diagnosis of borderline personality disorder was made. These patients exhibit defective
self-concepts and inadequate impulse control. They have a pattern of intense and unstable
interpersonal relationships and they cannot tolerate being alone. They suffer from intense
anger and hostility which may be expressed in episodic self-destructive acting-out, including
factitious illness, self-mutilation, or suicidal gestures. Sometimes borderline patients may
have superficially normal social functioning and their self-destructive behavior may be subtly
carried out or camouflaged by coexisting organic illness.19
Aduan et al.25 describe 13 cases where fever was produced by self-inflicted infections.
Twelve of these were women and ten were paramedical personnel. Pyrogenic substances
such as pure growths of bacterial culture, saliva, fecal, and other septic material were self-
administered. A typical case was that of a 25-year-old nurse hospitalized for fever and
abdominal pains of 10 months duration. Following multiple hospitalizations and laparotomies
and extensive diagnostic investigations, which were negative, a search of the patient’s room
revealed syringes, needles, and an open bottle of local anesthetic. The patient was confronted
with the evidence that she had been inoculating herself with contaminated materials. She
denied self-injection and possession of syringes and needles. Subsequently, she attempted
suicide four times. Some improvement was achieved using behavior modification. The final
diagnosis was severe hysterical personality, with depressive neurosis, or borderline state
with hysterical features.

Munchausen Syndrome
Munchausen Syndrome (M.S.) is a complex character disorder, many facets of which
might be displayed in patients exhibiting factitious fever. Unlike malingering, the patient
with M.S. has nothing to gain and is willing to undergo extensive and often painful diagnostic
procedures including repeated major operations.
Ferguson21 suggests the following for diagnosing suffers of M.S.:

• Prolonged history of symptomatic illness, often of many years

• Multiple hospitalizations, operations
• Historical medical details vague and difficult to confirm
• Often member of medical or paramedicalprofessions
• Demanding, manipulative behavior
• Demand for narcotics, not satisfied with minor analgesics
• Physical findings do not match history of prolonged illness
• Indifference, equanimity in face of invasive and hazardous diagnostic or therapeutic
procedures
• After confrontation with suspicion or evidence of fraud, patients typically become
truculent, indignant, and leave the hospital against medical advice.

M.S. is neither common, nor rare, and men suffer from it twice as much as women,
and the behavior pattern is established before the age of 20. It has been suggested that the
Munchausen patient develops a unique relationship with the physician, who assumes a
parental or authoritarian role. Illness becomes a way of gaining attention and fulfilling
dependency needs. The onset of this syndrome can often be traced to the discontinuation of
a significant relationship in the life of a patient.21
It can be seen that factitious and psychogenic fevers are complex syndromes, overlying
disorders of personality. They frequently baffle the diagnostician, who, in good faith, at-
tempts to uncover organic causes by embarking on extensive testing. The diagnosis requires
astute and time-consuming, prolonged observation. The prognosis is all too often unsatis-
factory. At present, these puzzling disorders remain unresolved.
390 U n ex p la in ed F e ve r

Finally, the differences in individual hypothalamic-sympathoadrenal response in adults

(which is significantly different in children) is worthy of investigation. Comparable to the
Dr. Fox effect;26 factitious fever is not yet easily identified or even established as a medical
entity in its own right.

NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic Malignant Syndrome (NMS) was first described and named by Delay and
Deniker in 1968.27 They thought that the syndrome appears due to phenothiazine therapy.
The syndrome affects both sexes in all ages, especially young men.28 The drugs associated
with this syndrome include all antipsychotic agents.28 31 The incidence of NMS is about 0.5
to 1% of patients receiving antipsychotic drugs.27,28 Some believe that rapid initiation with
high doses of neuroleptics increases the risk of NMS.29,34 Other predisposing factors are
dehydration, exhaustion, and use of long-acting neuroleptics.28,34 The onset of NMS is not
related to the duration of treatment with neuroleptics.30 Rechallenge with the same drug may
not cause recurrence of NMS.28 30 NMS develops over a period of 24 to 72 h.30The syndrome
occurs also in patients with neuropathology (Parkinson’s disease) after withdrawal of do-
paminergic agents.32,33
Mortality approaches 14% in patients taking oral neuroleptics and 38% in those receiving
long-acting depot agents. Clinical featues are hyperthermia, muscle rigidity, autonomic
instability and fluctuating consciousness.30,33 34 Autonomic dysfunctions include pallor, dia-
phoresis, fluctuating blood pressure, tachycardia, and cardiac arrhythmias. Hyperthermia is
a result of hypothalamic dysfunction and heat due to muscle rigidity; it may lead to death.
Muscle rigidity described as “ lead pipe” , may cause dyspnea, cyanosis and respiratory
insufficiency. Prolonged muscle rigidity may also lead to myoglobinuria and renal failure.
Laboratory abnormalities are nonspecific, they may result from dehydration29,35 in in-
creased BUN and serum sodium. Liver function tests show elevation of transaminases, LDH,
and alkaline phosphatase.34 Leukocytosis is often present, CSF is normal. The creatine
kinase level is often elevated28 34 probably due to myonecrosis as a result of muscle con-
tractions. Dialysis may help the renal failure but it does not remove neuroleptics which are
protein bound.28
Differential Diagnosis

(a) Phenothiazine heat stroke as a result of inhibiting sweating.30

(b) Idiopathic acute lethal catatonia is a very rare syndrome, with great similarity to NMS.
Stopping neuroleptics helps in the differential diagnosis of these syndromes.
(c) Drug interactions with monoamino-oxidase inhibitors.36
(d) Central anticholinergic syndrome — peripheral signs of atropine poisoning like dry
skin and mouth, dilated pupils, decreased bowel sounds, and urinary retention. The
temperature is elevated and confusion appears.

The treatment of NMS includes sodium dantrolene37 and bromocryptine mesylate.38 The
patient should be well cared, hydrated, urinary output should be monitored. Sodium dan-
trolene 0.25 mg/kg 3 times daily by intravenous infusion to relieve muscle rigidity and
hyperthermia and to enable the patient to swallow the bromocryptine. The treatment should
be continued for 10 days after initial positive response.
 391

REFERENCES
1. Aristotle, Parts of Animals, Peck, A. L. (translator), W. Heinemann, London, 1955.
2. Lange, J., Medicinalium Epistolarum Miscellaneae, T. Oporinus, Basel, 1554.
3. Tuke, D. H., Illustration o f the Influence o f the Mind Upon the Body in Health and Disease, Vol. 1, J. A.
Churchill, London, 1872.
4. Brophy, J. J., Current Medical Diagnosis and Treatment, Lange Medical Publications, California, 1986,
661.
5. Petersdorf, R. G., FUO — How it has changed in 20 years, Hosp. Pract., 841, 1985.
6. Dinarello, C. A. and Wolff, S. M., Molecular basis of fever in humans, Am. J. Med., 72, 799, 1982.
7. Greaves, M. W., Role of prostaglandins in inflammatory and proliferative skin disease, J. Dermatol., 7,
301, 1980.
8. Young, J. B., Brownjohn, A. M., Chapman, C., and Lee, M. R., Evidence for a hypothalamic
disturbance in cyclical oedema, Br. Med. J., 286, 1691, 1983.
9. Pelosi, A. J., Sykes, R. A., Lough, J. R. M., Muir, W. J., and Dunnigan, W. G., A psychiatric study
of idiopathic oedema, Lancet, II, 999, 1986.
10. Wynn, F. B., The psychic factors as an element in temperature disturbance shown by some observations
in the selective draft, JAMA, 73, 31, 1919.
11. Nikitopoulou, G. and Crammer, J. L., Change in diurnal rhythm in manic-depressive illness, Br. Med.
J., 1, 1311, 1976.
12. Remain, H. A., Habitual hyperthermia, JAMA, 99, 1860, 1932.
13. McNeil, G. N., Leighton, L. H., and Elkins, A. M., Possible psychogenic fever of 103.5°F in a patient
with borderline personality disorder, Am. J. Psychiatry, 141, 7, 1984.
14. Lown, B., De Silva, R. A., Reich, P., et al., Psychophysiologic factors in sudden cardiac death, Am. J.
Psychiatry, 137, 1325, 1980.
15. Alt, H. L. and Barker, M. H., Fever of unknown origin, JAMA, 94, 1457, 1930.
16. Kinter, A. R. and Rowntree, G., Long-continued, low-grade, idiopathic fever, JAMA, A102, 889, 1934.
17. Hasan, M. K. and White, A. C., Psychogenic fever, Postgrad. Med., 66, 152, 1979.
18. Welsby, P. D., Pyrexia of unknown origin sixty years on, Postgrad. Med. J., 61, 887, 1985.
19. Aduan, R. P., Psychiatric aspects of FUO, in FUO: Fever of Unknown Origin, Murray, H. W., Ed.,
Futura, Mt. Kisco, NY, 1983, 321.
20. Wolff, S. M., Adler, R. C., Buskirk, E. R., and Thompson, R. H., A syndrome of periodic hypothalamic
discharge, Am. J. Med., 36, 956, 1964.
21. Ferguson, E. E. and Maki, D. G., A baffling hyperpyrexia, Hosp. Pract., p. I l l , March 1978.
22. Millard, I. G., Dermatological pathomimicry: a form of patient maladjustment, Lancet, II, 969, 1984.
23. Murray, H. W., Factitious or fraudulent fever, in Fever of Unexplained Origin.
24. Hale, V. and Evseichick, O., Fraudulent fever, Am. J. Nurs., 43, 992, 1943.
25. Aduan, R. P., Fauci, A. S., Dale, D. C., Herzberg, J. H., and Wolff, S. M., Factitious fever and self-
induced infection, Ann. Intern. Med., 90, 230, 1979.
26. Editorial: The Doctor Fox effect, Lancet, 11, 1493, 1974.
27. Delay, J. and Deniker, P., Drug-induced extrapyrimidal syndromes, in Handbook of Clinical Neurology,
Vol. 6, Vinken, P. J. and Bruyn, G. W., Eds., North-Holland, Amsterdam, 1968, 248.
28. Caroff, S. N., The neuroleptic malignant syndrome, J. Clin. Psychiatry, 41, 79, 1980.
29. Henderson, V. W. and Wooten, G. F., Neuroleptic malignant syndrome: a pathogenic role for dopamine
receptor blockade?, Neurology (New York), 31, 132, 1981.
30. Smego, R. A., Jr. and Durack, D. T., The neuroleptic malignant syndrome, Arch. Intern. Med., 142,
1183, 1982.
31. McAllister, R. G., Jr., Fever tachycardia and hypertension with acute catatonic schizophrenia, Arch.
Intern. Med., 44(1), 37, 1978.
32. Toru, M., Matsuda, O., Makiguchi, K., and Sugano, K., Neuroleptic malignant syndrome-like state
following withdrawal of anti-parkinsonian drugs, J. Nerv. Ment. Dis., 169, 324, 1981.
33. Burke, R. E., Fahn, S., Majeux, R., Weinberg, H., Louis, K., and Willner, J. H., Neuroleptic
malignant syndrome caused by dopamine-depleting drugs in a patient with Huntington disease, Neurology
(New York), 31, 1022, 1981.
34. Lew, T.-Y. and Tellefsom, G., Chlorpromazine-induced malignant syndrome and its response to diazepam,
Biol. Psychiatry, 18, 1441, 1983.
35. Grunhaus, L., Sancovici, S., and Rimon, R., Neuroleptic Malignant Syndrome due to depot fluphenazine,
J. Clin. Psychiatry, 40, 99, 1979.
36. Goldberg, L. I., Monoaminooxidase inhibitors: adverse reactions and possible mechanisms, JAMA, 190,
456, 1964.
392 Unexplained Fever

37. Goulon, M., de Rohan-Chabot, P., Elkharrat, D., Gajdos, P., Bismuth, C., and Conso, F., Beneficial
effects of dantrolene in the treatment of neuroleptic malignant syndrome: a case report of two cases,
Neurology (New York), 33, 516, 1983.
38. Mueller, P. S., Vester, J. W., and Fermaglich, J., Neuroleptic Malignant Syndrome: successful treatment
with bromocryptine, JAMA, 249, 386, 1983.
39. Drachman, D. A. and Adams, R. D., Herpes simplex and inclusion body encephalitis, Arch. Neurol.,
7, 61, 1962.
40. Hall, R. C. and Stickney, S. K., Psychiatric symptoms in patients with systemic lupus erythematosus,
Psychosomatics, 22, 15, 1981.
41. MacNeill, A. et al., Psychiatric problems in systemic lupus erythematosus, Br. J. Psychiatry, 128, 442,
1976.
42. Tishler, M. and Abramov, A. L., Systemic lupus erythematosus presenting as katatonic schizophrenia,
Clin. Rheumatol., 3, 340, 1985.
 393

Chapter 25

MISCELLANEOUS CAUSES OF UNEXPLAINED FEVER

Serge Kernbaum

OCCULT INFECTIOUS FOCI (FOCAL SEPSIS)

A fever presenting as an U.F. may be the unique manifestation of occult abscesses.1'4
It usually is associated with various systemic signs and symptoms. Twenty-five hundred
years ago a king of Assyria was cured of his rheumatisms by the removal of infected teeth.
Since then a long, controversial, and sometimes acrimonious debate has taken place because
of the abuses of such diagnosis and the lack of satisfactory data. In the first few decades
of our century most authorities believed in the routine removal of “ diseased tonsils” and
of infected teeth, thought to be the first cause of most rheumatisms. After such excessive
procedures, for the past few decades, the inverse reaction took place and any relationship
was denied.
Our experience, as well as rigorous data from the literature, taught us that focal sepsis
does exist.
First, if the patient received an inaccurate antibiotic treatment, it is well known that the
signs and symptoms of the infectious focus may be masked. Such a previous treatment is
common: as, for example, in 14 out of 240 patients presenting with U.F.4 One useful clue
is the leukocyte count: in the same series 10 out of the 14 patients had more than 10,000
leukocytes per mm3 of blood.
Second, even in the absence of any prior antibiotic treatment, occult infectious foci,
presenting as U.F., are easily documented by various radiologic procedures. Intra-abdominal
abscesses which are located within the spleen, the liver, the kidney, or the female genital
tract, and may simulate cancer,6 are easily demonstrated by echography and/or CT scan.16
U.F. is also often due to dental infection.4,91216 It may be overshadowed by an aseptic
thrombophlebitis, often due to dental infection (as in 107 of 114 cases of cranio-facial
thrombophlebitis in a large series,10 but it may also be caused by other infections, as one
case of jugular thrombophlebitis due to infection of the parapharyngeal space.11
A purulent sinusitis, lasting up to 3 years,8 may also present as U.F.2'4,8,13 A latent
tonsil infection is a much rarer cause of U.F.,4 as well as the very rare retropharyngeal
abscess.25 The symptoms range from a slight discomfort to repeated patent infections, usually
treated by antibiotics with incomplete success. Tender enlarged lymph nodes are usually
present. The local swab is of no value, demonstrating only saprophytic flora, because the
pathogenic bacteria are deeply located in the tissue.14
In one series of 28 patients the infectious focus was located in tonsils (15), tonsils plus
sinus (1), tonsils plus kidney (1), teeth (6), sigmoid (1), and biliary tract ( l) .14
The occult infectious focus may present with systemic manifestations; the target organs
are the skin: various nonspecific rashes may exist: macula, erythema simulating scarlet fever,
urticaria, subcutaneous nodules . . . , on variable sites.
Two serous membranes can be affected: mainly synovitis: symptoms vary from joint
pain to true arthritis, sometimes associated with myalgia; the large joints are preferentially
involved (wrists, ankles, knees . . . ); as for cutaneous manifestations, they are asymmetric
and transient and follow a capricious course. Eight cases of recurrent pericarditis have been
reported.16 Pleurisy and peritonitis are rare.
The usual presentation in case of systemic manifestations will be summarized on the
basis of a series of 28 patients:14 both sexes were equally affected; the ages ranged from 2
to 62 years (mean age 31).
394 Unexplained Fever

There was no specific symptom or sign, but a variable association to the fever of skin
and articular symptoms, and sometimes of lesions of other target organs. The fever was
constant, of various types, often with wide nycthéméral variations, accompanied by chills
and sweat; it lasted for many weeks, with periods of apyrexia. It is to be noted that the
patients tolerated the fever well except during acute attacks of high fever with joint or other
visceral involvement, they were not acutely ill.
Laboratory examinations were nonspecific: hyperleukocytosis, often high (30,000 per
mm3) and with neutrophilia, was constant. ESR was usually high, often greater than 100
mm at the first hour, but was normal in one patient.1
All the bactériologie examinations were negative. Surgery alone allowed the discovery
of the causative bacteria: mainly Streptococcus sp., and a Proteus in one case.14
The disease evolves either with one unique attack of many weeks duration, or with
remission phases for many months.
Sometimes the fever is the unique manifestation of the infectious focus; more often it
is associated with at least one peripheral manifestation, usually skin or joint involvement.
The therapeutic response helped to define this entity. Antibiotics were valueless. In
contrast, corticosteroids could control the attacks, but had to be continued until the infected
focus was extracted.14 The key treatment is surgery.
A few cases will be reported briefly to illustrate this entity. One of the patients had nine
episodes of pharyngitis followed by fever, lasting 1 to 3 weeks, with arthralgia, myalgia,
24,000 leukocytes (91% polymorphs/mm3. He received penicillin once and in a few hours
fever rose to 40°C, pruritic morbilliform rash appeared, as well as aseptic pleurisy, peri-
carditis, and arthralgia. He was cured by tonsillectomy.14
Another patient experienced many episodes of fever during 10 years, associated with
arthritis, skin rashes on trunk, and splenomegaly, until a choledocolithiasis and a cholecystitis
were surgically cured.14 Eight patients had relapsing aseptic pericarditis, always preceded
by pharyngitis, and always responding to steroids. In seven of them, tonsillectomy was
performed and steroids could then be stopped in six. The eighth patient received bacterial
desensitization which led to a fatal thrombotic thrombocytopenic purpura.1416 A patient had
arthralgia, malaise, and fever of 6 weeks duration with hepatosplenomegaly, and was cured
by dental treatment, initially associated with a spiking fever.15
The pathophysiology of these events is unknown; we will just mention that an increased
size of tonsils is associated with a significant increase in the rate of streptococcal infections,17
and that the streptococcus has many weapons to induce human diseases.18
We do not know the exact nosologic situation of these cases. They could be linked with
the well-known various aspects of streptococcal allergies. For example, those presenting
like “ serum sickness“ ,19 cutaneous vasculitis,20 or, even more disturbing, polyarteritis no-
dosa.21 Clinically, they are not very different from adult Still’s disease (see Chapter 18).
They also have common features with the acute febrile neutrophilic dermatosis of Sweet.22
They are very close, if not identical, to subsepsis allergica of Wissler.23
But, although some clinical features evoke a collagen disorder,14 15 we do not agree with
the unifying hypothesis of Adams (who believes that these manifestations are a part of the
spectrum of auto-immune diseases24) as there is no reported patient (some of them have
been followed for more than 10 years) who experienced any autoimmune disease in the
largest French series.14
To conclude, the diagnosis of an occult focus relies on the resolution of all signs and
symptoms only after the surgical cure of the latent causal focus. Then the physician has to
think about such a focus and seek help from skillful specialists, namely, radiologists, oto-
rhinolarynologists, and/or stomatologists, who have acquired personal experience of such
silent infectious foci.
 395

CAT SCRATCH DISEASE (BENIGN LYMPHORETICULOSIS)

Cat scratch disease is characterized by an inflammatory lymphadenitis limited to one

region. Its etiological agent, a highly pleomorphic Gram-negative bacteria of the genus
Rothia, has recently been discovered.36 It can present as U.F. only when a rare complication
may overshadow the typical lymph node manifestations.
This worldwide disease usually occurs 1 to 8 weeks after a scratch or a bite from a cat.
Other animals (dogs, monkeys, birds) and even inanimate objects (thorns) were said to be
responsible for the disease. A primary local lesion at the site of inoculation is sometimes
present, as a papule or vesicopustule. It is followed by the regional inflammatory and usually
isolated, lymphadenopathy, sometimes associated with fever and mild malaise.26'27

Complications

Manifestations Comments

Encephalitis28 3137 and/or myelitis The most serious complication; more than 30 cases
known; usually occurs at the second or third week of
the disease; always self-limited in 1 to 6 months
Pneumonitis32 33 37 Atypical pneumonia with hilar enlargement
Genital ulcer and inguinal lymphadenopathy35 Exceptional, simulates venereal disease
Erythema nodosum26 27 The most frequent complication in our experience
Parotiditis34 Exceptional
Mesenteric lymphadenitis2627 37 May simulate appendicitis
Arthralgia or arthritis37 Exceptional
Digestive manifestation37: splenomegaly splenic ab- Exceptional
scess, enlarged nodes of the head of pancreas

DIAGNOSIS
Diagnosis relies first on medical history: close contact with animal, mainly cats, then
on the locoregional syndrome when it exists: inoculation lesion and lymphadenopathy.
The pathology of the lymph node is not pathognomonic, as it associates hyperplasia,
epithelioid cells, granuloma, and suppuration with or without central necrosis.26 The iden-
tification of the causative bacteria requires specific techniques.36
Finally, the diagnosis is confirmed by the skin test, prepared from the purulent material
aspirated from nodes of other patients. Injected intradermally, and read after 48 h: a positive
reaction consists of an induration of 5 mm or more and erythema of 10 mm or more; a
positive reaction lasting many days is of great diagnostic value.26 The skin test discards
tularemia and the pathology discards pyogenic adenitis.

EPIDEMIC NEUROMYASTHENIA (BENIGN MYALGIC

ENCEPHALOMYELITIS; ICELAND DISEASE)
We shall just briefly mention a disease whose existence is discussed38 although many
outbreaks were described always having the same contrast between the protean symptom-
atology and the minimal clinical findings.39 This puzzling entity may be characterized by a
low-grade fever, variable, and sometimes with diurnal swings.
Various outbreaks have been described worldwide, mostly in summer, affecting young
adults, mainly women, and more particularly, emotionally disturbed nurses, who usually
had frequented high schools. Sporadic cases exist but are even more difficult to diagnose.
Usually a young or middle-aged woman consults for the association of mild pharyngitis
with enlarged cervical lymph nodes followed by headache (sometimes the first symptom),
backache, pain in the limbs, and fatigability. Nausea, vomiting, and diarrhea may be present.
Fever is very rare; a variable, low-grade fever was present in 8.9% of 145 patients in one
396 Unexplained Fever

TABLE 1
Undiagnosed Fever Due to Vascular Thrombosis

Year of publi-
First author cation Incidence % Ref.

Petersdorf 1961 3/100 3 42

Rault 1973 8/240 3.3 43
Aubertin 1974 4/400 1 44
Gleckman 1977 3/34 9 45
Rouge 1981 6/120 5 46
Larson 1982 1/105 1 47

series.39 Clinical findings are minimal. There is a generalized tenderness and stiffness of
the muscles, which rapidly fatigate. Sometimes weakness progresses and paretic phenomena
are present.
With the exception of possible paresis of cranial nerves (mainly facial and oculomotor
ones) and possible bladder dysfunction, the neurologic examination is normal.
In contrast there are some behavioral manifestations: irritability, mood depression, etc.
The results of laboratory investigations are usually negative and as death never occurs, the
pathology is unknown. Relapses are frequent and usually, after a prolonged period of
disability, the patients recover after 1 or 2 months, but some enter a chronic relapsing course.
The etiology of this disease is unknown, its epidemic nature evokes a microbial agent,
possibly a virus: recently, Epstein-Barr virus was suspected.40
Moreover, McEvedy and Beard, after reviewing the reports of 15 recorded outbreaks,
have considered that it was a psychosocial phenomenon and suggested the name of “ myalgia
nervosa” on the analogy of “ anorexia nervosa” .38

UNDIAGNOSED FEVER ASSOCIATED WITH VASCULAR

THROMBOSIS
A thrombus is a solid phase or plug formed in the living heart or vessels from the
constituents of blood. Once formed, a thrombus may undergo three types of changes:
resolution, organization, and/or embolism. The major consequence of a thrombus or an
embolus is the ischemia generated in the local tissues: depending on its tissue localization,
the cells will be able or unable to survive until an adequate circulation is restored. The
necrotic areas, called infarcts, are associated with a definite inflammatory response that
seems to be a likely source of endogenous pyogen:41 fever is a well-known manifestation
of vascular thrombosis.
Thrombi may occur anywhere in the circulation: in the chambers of the heart, in the
arteries, in the veins, or in the capillaries. Vascular thrombosis associated with U.F. is
located mainly in the deep veins of the limbs, the pelvis, or the central nervous system,
and/or in the lung arteries.
The relative importance of vascular thrombosis among the various etiologies of U.F. is
shown in Table 1, where six U.S. and French series are summarized. It demonstrates that
their incidence is low (ranging from 1 to 5%) in the university hospitals and higher (9%)
in a community hospital,45 and grossly the same during 20 years.
The fever associated with vascular thrombosis is of various types;46 for example in
pulmonary thromboembolism, fever attributed solely to the thrombosis was found in 20 of
35 consecutive patients: temperature higher than 39°C may occur early; at the 6th day it
does not exceed 38.5°C, and then a low-grade fever may continue for 1 or even 2 weeks
in one patient in spite of 1 week of heparin therapy.48 Fever in cases presenting as U.F.
may have been present for many months.46
 397

TABLE 2
Thromboembolic Disorders46,49'54

• Increasing age
• Cancer
• Antecedent of venous thrombosis
• Antecedent of or concurrent cardiac disorder
• Recent surgical procedure or recent childbirth
• Prolonged bed rest (for any reason)
• Oral contraceptive drug
• Antithrombin III deficiency

It is well known that clinical recognition of venous thrombosis is very difficult. Then,
in patients with U.F., such thrombosis as well as pulmonary embolism must always be
looked for, particularly if the promoting factors listed in Table 2 are present, as venous
thrombosis occurs in most patients in the course of another illness.
The major factors responsible for in vivo thrombus formation are alterations in blood
flow, damage to the vessel wall, and changes in the coagulability of the blood. In patients
with malignancies, venous thrombosis can be associated with disseminated intravascular
coagulopathy and/or arterial emboli and/or nonbacterial thrombotic endocarditis.49

DIAGNOSIS OF VASCULAR THROMBOSIS

Clinical Signs and Symptoms
It is obvious that, in thrombosis presenting as U.F., the paucity of the signs and symptoms
is responsible for their unrecognition.
The calves of any patient with U.F. must be carefully examined and any unilateral pain
and/or swelling and/or tenderness is of great value. In the differential diagnosis, accident
of Baker’s cyst should be discussed.
Iliofemoral, axillary, or subclavian thrombophlebitis may be clinically latent or may be
confused with cellulitis, lymphangitis, or lymphedema.54
Pelvic thrombophlebitis may sometimes be septic. It occurs after childbirth or pelvic
surgery and is manifested by fever of various types (low grade and/or high, spiking tem-
perature). Physical examination often reveals nothing, or sometimes a localized tenderness
or a suggestive cordlike induration. Other symptoms are absent unless pulmonary embolism
occurs, or unless the thrombus extends to the common iliac vein. Blood cultures are positive
when the thrombosis is septic (the bacteria most often involved are Bacteroides sp., strep-
tococci, enterobacteriaceae . . . ).505154
Cerebral venous thrombosis may be aseptic or septic; it usually includes or is confined
to the superior sagittal sinus. It is associated with various conditions listed in Table 3. In
addition to the predisposing factors, physical examination may reveal findings of increased
intracranial pressure or focal deficit.52
The usual manifestation of pulmonary infarction is polypnea and/or tachycardia and/or
fever. The other symptoms, although less frequent, are pleuritic pain, cough, hemoptysis,
friction rub, and icterus; indeed minor degrees of embolism are frequent and can be com-
pletely unnoticed.53 Pulmonary infarction was more frequent (but not significantly) in the
small group of febrile patients with pulmonary embolism than in the apyretic ones studied
by Murray.48
The laboratory findings (leukocytosis and enzyme changes) are not useful diagnostic
tools;53 neither are the inconstant and nonspecific radiologic findings, nor the reflection of
hypoventilation, and hypoxemia with hypocapnia in the arterial blood gases.53 Then pul-
monary infarction may be easily confused with bronchitis, bronchopneumonia, neoplasm,
and pleurisy of other causes.53
398 U n ex p la in ed F e ve r

TABLE 3
Factors Predisposing to Cerebral Venous Sinus Thrombosis52

• Pregnancy (mainly the third trimester)

• Oral contraceptive agents
• Pyogenic infection (ENT; facial . . . )
• Local trauma
• Altered cerebral hemodynamics (shock, dehydration, congestive heart failure, throm-
bocytosis, sickle cell disease . . . )
• Antithrombin III deficiency

Special Diagnostic Techniques

D eep Throm bophlebitis
Doppler ultrasound detection is a quick, simple, and noninvasive method with many
limitations. It can detect complete venous occlusion of accessible veins; it is useful as a
screening procedure, and is valuable only when its conclusions are positive because many
errors may occur and a negative result does not rule out a thrombosis.53 54
The impedance plethysmography technique, which is also noninvasive, is promising
when used correctly; the changes in blood volume accompanying deep breathing are di-
minished in case of thrombosis.54 Combined with leg scanning it seems to be an excellent
diagnostic tool.55 The radioactive fibrinogen test is a very sensitive screening method which
depends on the preferential uptake of 125I-labeled human fibrinogen by a forming thrombus.
It has, however, some limitations.53 54
Phlebography is the single most accurate method, with few limitations; it is not a
screening procedure but is ideal for confirming the diagnosis of thrombophlebitis.53 54 It is
still too soon to assess the usefulness of gallium-67 scintigraphy in the detection of throm-
bophlebitis.56
Recently, the diagnostic accuracy of various techniques was prospectively evaluated.58
It was concluded that venoscanning may have a role as a screening procedure: it was equivocal
in 32% of patients but in the remaining ones its accuracy was 97%; in patients with equivocal
venoscan results the procedure with the greatest accuracy was X-ray veno-
graphy.58
In some patients with a strong suspicion of deep vein thrombosis, the use of heparin as
a diagnostic test is the last clue (see below).

P elvic T hrom bophlebitis

There is no accurate diagnostic aid except the anticoagulant regimen proposed about 20
years ago,57 which can be used in all cases of vascular thrombosis except those of cerebral
thrombosis; this excellent test is proned by many authorities in the field of fever of unknown
origin.43’45'46 50 51 It relies on the prescription of heparin (7500 to 10,000 U i.v. q-6 h) which
typically leads to apyrexia in 48 h; provided that there is no contraindication and that clotting
time is monitored. Some authors prone the concomitant administration of antibiotics, par-
ticularly those active against anaerobic bacteria.51 This test, though very valuable, is not
positive (i.e., apyrexia is not obtained in 48 h) in all cases of genuine vascular thrombosis.46 48

C erebral V enous Sinus Throm bosis

The demonstration of the thrombus in the venous sinus is best obtained by cerebral
angiography but the conjunction of two noninvasive methods, CT scan and radionuclide
scan or nuclear magnetic resonance seems to be of great value.52 The heparin test, potentially
harmful, cannot be recommended.
 399

Pulmonary Embolism
Two complementary procedures may be performed. Perfusion (131I-tagged human al-
bumin) and ventilation (inhalation of radioactive xenon) lung scanning may demonstrate the
characteristic multiple segmental perfusion defects with normal ventilation.53
Pulmonary angiography may be performed if the clinical suspicion is high and if the
above tests are of no diagnostic help.53
The heparin therapeutic test is also of great value, but also inconstantly positive.48
In conclusion, vascular thrombosis (in limbs, pelvic and cerebral veins and/or in pul-
monary arteries) is a rare but confirmed cause of U.F. It must always be suspected and if
predisposing factors are present (listed in Tables 2 and 3), every effort, with the help of
specialists (cardiovascular and radiologist consultants), must be made to establish that di-
agnosis. The heparin diagnostic test (not to be done if cerebral thrombosis is suspected),
which can give false-negative results, is sometimes the crucial diagnostic tool.

UNEXPLAINED FEVER ASSOCIATED WITH TISSUE

DESTRUCTION AND HEMORRHAGE

Tissue necrosis ranges from cytolysis of single cells to death of extensive parts of tissues.
The appearance of a necrotic area depends on the nature or the tissue, on the mechanism
of the necrosis and on which enzymes remain active in the tissues. Foci of necrosis are
usually associated with hemorrhage and/or vascular thrombosis. Necrotic areas are associated
with definite inflammatory responses that seem to be a likely source of endogenous pyrogen.59
Tissue necrosis is indeed accompanied by fever, but it lasts usually less than 1 week,
such as in myocardial infarction or acute pancreatitis; its persistence beyond 1 week may
indicate either a complication (septic or not) or an associated disorder.
The low-grade continuous fever present in about one third of the patients with advanced
cirrhosis60 is possibly due to cell necrosis. But it is definitely not a cause of U.F. since
diagnosis of liver disease is easy to establish.
It could be postulated that one tissue necrosis, for example, the sterile necrosis of a
uterine myofibroma, might be a cause of U.F., but we are not aware of any published case
and have never seen it in our practice.
In this chapter then, we shall only deal with occult tissue hemorrhages. Fever may result
from tissue destruction or may accompany the inflammatory reaction secondary to extra-
vascular sequestration of blood.61 Indeed in experimental62 as well as in human pathology,63
fever can be due to hemorrhage localized in the third cerebral ventricle but is accompanied
by CNS symptoms and intracerebral hematomas are exceptionally a cause of U.F. In fact,
it can be postulated that the common fever following neurosurgical procedures may be due
to a slow leakage of blood into the third ventricle, as well as it can also be postulated that
some cases of fever following cardiac surgery may be due to a slow leakage of blood into
the pericardial cavity. To conclude our hypothesis it can finally be postulated that the low-
grade fever sometimes seen in scurvy might be related to blood loss into the skin and deeper
tissues, including subperiostal hemorrhage.
Indeed, occult hematomas may be a very rare cause of U.F., as they were in the last
published sery, that of Larson et al.64 Three hematomas (intrahepatic subcapsular following
a trauma which occurred 5 months earlier; retroperitoneal, and hemopericardium) were
present among 105 cases of U.F., that is nearly 3% of all cases, the highest reported incidence
of such an etiology of U.F.
As anticoagulant therapy is often prescribed, future cases will certainly be observed.
The physician must be aware of their possibility, especially if a predisposing factor (listed
in Table 1) is present.
According to the literature61,64 67 and our own experience, we believe that only the
hematomas located in the tissues listed in Table 4 may be a cause of U.F.
400 Unexplained Fever

TABLE 4
Sites of Occult Hematomas Which may Present as an
U.F.61’64’66

• Pericardium
• Liver
• Retroperitoneal space
• Dissected aortic wall
• Adrenal gland ??

TABLE 5
Major Factors Predisposing to Occult Hematomas

• Spontaneous hemorrhagic disorders (thrombocytopenia, hypoproth-

rombinemia . . . )
• Anticoagulant therapy
• Recent trauma or surgical act
• Arteriosclerotic and/or hypertensive vascular disease
• Complicated pregnancy or postpartum state

Note: According to the literature61 64 67 and our experience we believe that

only the hematomas located in the tissues listed in Table 5 can be
a cause of U.F.

Pericardium and liver localizations are not a problem for the physician since cardiac
echography as well as hepatic echography or scintigraphy are basic exams in the management
of patients with U.F. Indeed, the bloody nature of the collection is not easy to assert but
punction or surgery will be successful.
Slow leakage of blood in the retroperitoneal space is not exceptional: it represented 6
of 93 major hemorrhagic complications of anticoagulant therapy in one large series.65 Spon-
taneous hematomas are more frequent, usually due to a local tumor, mainly of the kidney
(angiomyelipoma . . . ), which itself can be the cause of the fever. Their diagnosis is now
facilitated by the use of ultrasonography and/or CT scan. Murray et al.61 published four
fascinating cases of prolonged fever due to dissecting aneurysm of the aorta: in two of them
fever was prolonged for 5 and 11 weeks; the other two because of fever and a murmur of
aortic regurgitation were initially treated for bacterial endocarditis. These patients were
explored before the development of echocardiography and as the authors conclude, the early
use of this procedure confirmed by aortography will support the diagnosis; but in 1987 one
case of dissecting aneurysm still presented as U.F.67
Finally, the question remains whether subacute focal adrenal hemorrhage could be a
cause of U.F., although there is no published case and it can be due to an associated febrile
disease. Its frequency is high: between 0.14 and 0.60% of autopsied patients are reported
to have adrenal gland hemorrhage, and many patients do not show any features of adre-
nocortical insufficiency; moreover, fever was present in 59% of 39 published cases of
patients.66 It can only be postulated that some cases of U.F. could be due to focal adrenal
hemorrhage.
To conclude this short section, it can be said that occult hematomas, in contrast to tissue
necrosis, may be a cause of U.F. and that physicians must think about their possibility,
especially if one of the predisposing factors (listed in Table 5) is present.

UNDIAGNOSED FEVER DUE TO DISORDERS OF

THERMOREGULATION AND OF FLUID BALANCE

Various disorders of heat-regulating mechanisms, rare, heterogeneous and usually easy

to diagnose, may be the cause of fever of long duration.68
 401

The physiology and mechanisms of fever are reviewed in Chapter 2. We will discuss
here some pathological alterations of heat regulation.69'71

FEVER DUE TO CENTRAL NERVOUS SYSTEM DISEASES, HEAT

PRODUCTION DISORDERS
In the hypothalamus, the anterior and posterior nuclei are concerned with temperature
regulation, as well as with cardiovascular and endocrine control.69,70 They balance heat
production and peripheral heat loss.
Fever is due to their stimulation by leukocytic pyrogen via the synthesis of prostaglandin-
like molecules.71 Any lesion of these nuclei, whatever its nature, can lead to fever. These
fevers, called “ central” , are very rare. They are of various types, sometimes very high68
or cyclic.72
As the hypothalamus is very complex per se and has complex interrelationships with
the anterior and posterior pituitary, these central fevers are usually associated with two types
of disorders.
First, endocrine disorders:72 diabetes insipidus, inappropriate secretion of antidiuretic
hormone, hypopituitarism, premature puberty, obesity, sexual underdevelopment (sometimes
presenting as idiopathic adiposogenital dystrophy), excessive appetite, anorexia leading to
cachexia, or troubles of thirst73 (hypodipsia was the unique accompanying trouble in one
patient we have seen).
Second, neurologic disorders: headache, sleep, emotional and personality disorders, as
well as electroencephalographic abnormalities.72,77
The nature of the hypothalamic lesion is variable:

• Sequelae of birth trauma

• Tumors (arising in hypothalamus or close proximity and invading it): neuronal tumors
(astrocytoma, glioma . . . ); infundibuloma; teratoma (ectopic pinealoma); cranio-
pharyngioma . . .
• Basilar meningitis and granulomas: sarcoidosis; tuberculosis, eosinophilic granuloma,
sphenoid osteomyelitis . . .
• Sequelae of viral encephalitis: fever may appear during the acute phase or during
convalescence; poikilothermia may develop but is, as a rule, transient68

Sometimes, when etiologic treatment is impossible, some drugs can control fever:
chlorpromazine72 or valproate sodium.77
Fever due to disorders that alter fluid balance could be attributed to chronic congestive
cardiac failure which may be associated with a prolonged, low-grade fever.68 Young children
can be feverish when they are dehydrated: this is more often due to an error of their nutritional
regimen (ex. insufficiently diluted hyperosmolar powdered milk) than to heat stroke.

Fever Due to Disorders of Heat Loss

The major dermal mechanisms involved in the loss of heat by the skin (heat radiation,
facilitated by vasodilation and/or sweating) are altered. The fever associated with these
disorders is inconstant, variable, highest and most frequent during the warm season of the
year.68
It may have a neurologic cause, occurring sometimes in patients who have undergone
a dorsolumbar sympathectomy.68
Usually these fevers are due to various extensive skin disorders such as diffuse ichthyosis.
This congenital disorder affecting the skin of the entire body is easy to diagnose: the skin
is furrowed and scaly; the lesions are symmetrical, prominent on the faces of extension of
limbs.
402 U nex p la in ed F e ve r

Widespread and Severe Eczemas

Scleroderma: generalized cutaneous scleroderma may occur in childhood or adulthood
and is characterized by the hardness of the skin. The sclerosis may be either superficial
(bullous morphea) or dermal (typical morphea) with or without a lilac ring, or it may be in
panniculus or fascia. Subcutaneous or nodular scleroderma usually involves the trunk, hips,
or thighs.

Hereditary Anhidrotic (or Hypohidrotic) Ectodermal Dysplasia

This is a very rare congenital dysplasia, characterized by a partial or complete absence
of sweat glands. It has two types of inheritance: usually it is X-linked, sometimes it is
autosomal dominant, and males are predominantly affected. Partial and complete forms
exist, the latter being characterized by a similar facial appearance (prominence of the forehead
and depressed nasal bridge), abnormalities of hair (hypotrichosis) and of teeth (conical in
shape). The skin is thin, dry, white and soft.75,76 The diagnosis is confirmed by the study
of the sweat gland function, their absence on the skin biopsy, and dermatoglyphic analysis.76

REFERENCES
1. Dinarello, C. and Wolff, S., Fever of unknown origin, in Principles and Practice of Infectious Diseases,
Mandel, G., Douglas, G., and Bennett, J., Eds., John Wiley & Sons, New York, 1979, 407.
2. Weinstein, L. and Fields, B., Fever of obscure origin, in Seminars in Infectious Diseases, Vol. 1, Stratton
Intercontinental Medical Books, New York, 1978, 1.
3. Larson, E., Featherstone, H., and Petersdorf, R., Fever of undetermined origin: diagnosis and follow-
up of 105 cases 1970— 1980, Medicine, 61, 269, 1982.
4. Rault, Ph., Fievres inexpliquées, Medical thesis, Paris X, Bichat, 1973.
5. Stein, R., White blood cell count in fever of unknown origin, Am. J. Dis. Child., 124, 60, 1972.
6. Kirk, D., Silent pyonephrosis as a cause of chronic ill-health, Lancet, i, 705, 1982.
7. Dinarello, C. and Wolff, S., Approach to the patient with fever of unknown origin, in Infectious Diseases,
2nd ed., Mandell, G., Douglas, G., and Bennett, J., Eds., John Wiley & Sons, New York, 1985, 347.
8. Sohval, A. and Som, M., Masked sinusitis as cause of obscure fevere, Arch. Otolaryngol., 25, 37, 1937.
10. Cernea, P. and Laufer, J., Les thrombophlébites cranio-faciales d’origine bucco-dentaire, Rev. Stomatol.
(Paris), 54, 1017, 1953.
11. Boharas, S., Postanginal sepsis, Arch. Intern. Med., 71, 844, 1943.
12. Levinson, S. and Barondness, J., Occult dental infection as a cause of fever of obscure origin, Am. J.
Med., 66, 463, 1979.
13. Naschitz, J. and Yeshurun, D., Occult infection in the facial area presenting as fever of unknown origin,
Isr. J. Med. Sci., 21, 995, 1985.
14. Bastin, R., Verliac, F., Frottier, J., et al., Fovers infectieux et reactions inhabituelles de l’organisme,
in Les Infections Bactériennes d’Actualité, XL Congres Français de Medecine, Masson, Paris, 1977, 63.
15. Berry, E. and Silver, J., Pyorrhea as cause of pyrexia, Br. Med. J., 2, 1289, 1976.
16. Vilde, J. L., Dupont, B., Hincky, J. M., et al., Péricardites recidivantes et infections pharyngées, Ann.
Med. Intern. (Paris), 127, 745, 1976.
17. Feinstein, A. and Levitt, M., The role of tonsils in predisposing to streptococcal infections and recurrence
of rheumatic fever, N. Engl. J. Med., 282, 285, 1970.
18. Ginsburg, L, Mechanisms of cell and tissue injury induced by Group A Streptococci: relation to poststrep-
tococcal sequelae, J. Infect. Dis., 126, 294 and 419, 1972.
19. Henocq, E. and Alouf, J., “ Maladie serique’’ d’origine streptococcique, Nouv. Presse Med., 2, 2478,
1973.
20. Ky, N., Hazard, J., and Laroche, C., Allergies vasculaires cutanées d’origine streptococcique, Presse
Med., 76, 247, 1968.
21. Fordham, C., Epstein, F., Huffines, W., et al., Polyarteritis and acute post-streptococcal glomerulo-
nephritis, Ann. Intern. Med., 61, 89, 1964.
22. Sweet, R., Acute febrile neutrophilic dermatosis, Br. J. Dermatol., 100, 93, 1979.
23. Wissler, H., Subsepsis allergica, Helvetica Ped. Acta, 13, 405, 1958.
 403

24. Adams, D., A theory of the pathogenesis of rheumatic fever, glomerulonephritis and other auto immune
diseases triggered by infection, Clin. Exp. Immunol., 5, 105, 1969.
25. McCook, T. and Felman, A., Retropharyngeal masses in infants and young children, Am. J. Dis. Child.,
133, 41, 1979.
26. Mollaret, P., Reilly, J., Bastin, R., et al., Sur une adénopathie régionale subaiguë et spontanément
curable, avec intradermo-reaction et lesions ganglionnaires particulières, Bull. Soc. Med. Hosp. Paris, 66,
424, 1950.
27. Daniels, W. and McMurray, F., Cat scratch disease. Report of one hundred sixty cases, JAMA, 154,
1247, 1954.
28. Courtois, G., Saint Martin, M., and Gaba, E., Complications neurologiques de la maladies des griffes
du chat, Union Med. Canada, 94, 728, 1965.
29. Kaplan, M., Straus, P., and Devaux, J. P., Accidents encéphaliques de la maladie des griffes du chat,
Arch. Fr. Pediatr., 18, 1044, 1961.
30. Lyon, L., Neurologie manifestations of cat scratch disease, Arch. Neurol., 25, 23, 1971.
31. Steiner, M., Vuckovith, D., and Hadawi, S., Cat scratch disease with encephalopathy, J. Pediatr., 62,
514, 1963.
32. Turiaf, T. and Jeanjean, Y., La pneumonie atypique de la lymphoréticulose bénigne d’inoculation, J.
Fr. Med. Chir. Thor., 8, 141, 1954.
33. Marinesco, G., Banica, A., Steresco, P., et al., Pneumonie atypique chez l’enfant associée à la lym-
phoréticulose bénigne d’inoculation, Presse Med., 77, 861, 1969.
34. Laudenbach, P., Harar, E., Hallard, M., et al., Parotidite au cours d’une maladie des griffes du chat,
Nouv. Presse Med., 3, 1753, 1974.
35. Duperrat, B., Forme pseudovénérienne de la maladie des griffes du chat, Bull. Soc. Med. Hop. Paris,
67, 848, 1951.
36. Gerber, M., Sedgwick, A., MacAlister, T., et al., The aetiological agent of Cat Scratch Disease, Lancet,
1, 1236, 1985.
37. Margileth, A., Wear, D., and English, C., Systemic Cat Scratch Disease: report of 23 patients with
prolonged or recurrent severe bacterial infection, J. Infect. Dis., 155, 390, 1987.
38. McEvedy, C. and Beard, A., Concept of benign myalgic encephalomyelitis, Br. Med. J., 1, 11, 1970.
39. Dillon, M., Marshall, W., Dudgeon, J., et al., Epidemic neuromyasthenia: outbreak among nurses at
children’s hospital, Br. Med. J., 1, 301, 1974.
40. Holmes, G., Kaplan, J., Stewart, J., et al., A cluster of patients with a chronic mononucleosis-like
syndrome, JAMA, 257, 2297, 1987.
41. Atkins, E. and Bodel, P., Fever, N. Engl. J. Med., 286, 27, 1972.
42. Petersdorf, R. and Beeson, P., Fever of unexplained origin, Medicine, 40, 16, 1961.
43. Rault, P. H., Les fièvres prolongées de diagnostic difficile, Medical Thesis, Paris, 1973.
44. Aubertin, J., Leng, B., Lacut, J., et al., Les fièvres prolongées, Bord. Med., 9, 1291, 1974.
45. Gleckman, R., Crowley, M., and Esposito, A., Fever of unknown origin, Am. J. Med. Sei., 274, 21,
1977.
46. Rouge, P., Reboud, J., Franco, A., et al., Maladie thromboembolique revelee par une fièvre prolongée,
Angeiologie, XXXIII, 287, 1981.
47. Larson, E., Featherstone, H., and Petersdorf, R., Fever of undetermined origin: diagnosis and follow-
up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
48. Murray, H., Ellis, G., Blumenthal, D., et al., Fever and pulmonary thromboembolism, Am. J. Med.,
67, 232, 1979.
49. Sack, G., Levin, J., and Bell, W., Trousseau’s syndrome and other manifestations of chronic disseminated
coagulopathy in patients with neoplasms: clinical, pathophysiologic and therapeutic failures, Medicine, 56,
1, 1977.
50. Dunn, L. and Van Voorhis, L., Enigmatic fever and pelvic thrombophlebitis, N. Engl. J. Med., 276,
265, 1967.
51. Verscheiden, G., Les Thrombophlébites Pelviennes, Union Med. Canada, 106, 231, 1977.
52. Imai, W., Everhart, R., and Sanders, J., Cerebral venous sinus thrombosis: report of a case and review
of the literature, Pediatrics, 70, 965, 1982.
53. Dexter, L. and Dalen, J., Pulmonary embolism and acute corpulmonale, in The Heart, Arteries and Veins,
4th ed., Hurst, W., Logue, B., Schlant, T., et al., Eds., McGraw-Hill, New York, 1978, 1473.
54. Young, J. and De Wolfe, V., Diseases of the aorta, venoe cavoe and peripheral arteries and veins, in The
Heart, Arteries and Veins, 4th ed., Hurst, W., Logue, B., Schlant, T., et al., Eds., McGraw-Hill, New
York, 1978, 1878.
55. Hull, R., Hirsh, J., Sackett, D., et al., Combined use of leg scanning and impedance plethysmography
in suspected venous thrombosis: an alternative to venography, N. Engl. J. Med., 296, 1497, 1977.
56. Miller, J., Detection of deep venous thrombophlebitis by gallium 67 scintigraphy, Radiology, 140, 183,
1981.
404 U nex p la in ed F e ve r

57. Schulman, H. and Zatuchni, G., Pelvic thrombophlebitis in puerperal and postoperative gynecologic
patient: obscure fever as indication for anticoagulant therapy, Am. J. Obstet. Gynecol., 690, 1293, 1964.
58. Sandler, D., Martin, J., Duncan, J., et al., Diagnosis of deep-vein thrombosis: comparison of clinical
evaluation ultrasound, plethysmography and venoscan with X-ray venogram, Lancet, ii, 716, 1984.
59. Atkins, E. and Bodel, P., Fever, N. Engl. J. Med., 286, 27, 1972.
60. Tisdale, W. and Klatskin, G., The fever of Laennec’s cirrhosis of the liver, Yale J. Biol. Med., 33, 94,
1960.
61. Murray, H., Mann, J., Genecin, A., et al., Fever with dissecting aneurysm of the aorta, Am. J. Med.,
61, 140, 1976.
62. Rudy, T., Westergaard, J., and Yaksh, T., Hyperthermia produced by simulated intraventricular hem-
orrhage in the cat, Exp. Neurol., 58, 296, 1978.
63. Lausberg, G., Central temperature dysrégulation in increased intracranial pressure, new aspects, J. Neu-
rosurg. Sci., 21, 193, 1977.
64. Larson, E., Featherstone, H., and Petersdorf, R., Fever of undetermined origin: diagnosis and follow-
up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
65. Coon, W. and Willis, P., Hemorrhagic complications of anticoagulant therapy, Arch. Intern. Med., 133,
386, 1974.
66. Xarli, V., Steele, A., Davis, P., et al., Adrenal hemorrhage in the adult, Medicine, 57, 211, 1978.
67. Lesur, G., Le Bourgeois, P., Dorra, M., et al., Dissection aortique revelee par une fievre prolongée
inexpliquée, Presse Med., 16, 31, 1987.
68. Weinstein, L. and Fields, B., Fever of obscure origin, Semin. Infect. Dis., 1,1, 1978.
69. Atkins, E. and Bodel, P., Fever, N. Engl. J. Med., 286, 27, 1972.
69a. Berheim, H., Block, L., and Atkins, E., Fever: pathogenesis, pathophysiology and purpose, Ann. Intern.
Med., 91, 261, 1979.
70. Dinarello, C. and Wolff, S., Molecular basis of fever in humans, Am. J. Med., 72, 799, 1982.
71. Wolff, S., Adler, R., Buskird, E., et al., A syndrome of periodic hypothalamic discharge, Am. J. Med.,
36, 956, 1964.
72. Andersson, B. and Rundgren, M., Thirst and its disorders, Annu. Rev. Med., 33, 231, 1982.
73. Lopez-Morreno, J., Rodríguez-Portales, J., and Mahana, D., Fever of unknown origin. Biochemical
Cushing’s disease and cerebral dysrhythmia corrected by Valproate Sodium, J. Can. Med. Assoc., 132,
150, 1985.
74. Fog, M., General acquired anhydrosis: report of a case and investigation of the heat regulation and
circulation, JAMA, 107, 2040, 1936.
75. Richards, W. and Kaplan, J., Anhidrotic ectodermic dysplasia: an unusual cause of pyrexia in the newborn,
Am. J. Dis. Child., 117, 597, 1969.
76. Verbow, J., Hypohydrotic (or anhidrotic) ectodermal dysplasia. An appraisal of diagnostic methods, Br.
J. Dermatol., 83, 341, 1970.
77. Lopez-Morreno, J., Rodríguez-Portales, J., and Mahana, D., Fever of unknown origin. Biochemical
Cushing’s disease and cerebral dysrhythmia corrected by Valproate Sodium, J. Can. Med. Assoc., 132,
150, 1985.
Part IV
Unexplained Fever in Surgery
 407

Chapter 26

SURGICAL ASPECTS OF FEVER

J. Stadler, H. Stern, and J. Bohnen

INTRODUCTION
Despite the difficulties in interpretation of fever, the temperature chart is undoubtedly
the most commonly looked at recording on a surgical patient. Indeed, “ what is this patient’s
temperature?” is probably the most common question asked by any surgeon in any given
hospital. In the surgeon’s mind, fever equates with illness and defervescence with improve-
ment.
The implications of fever in surgical practice are quite different from that in nonsurgical
patients. These are alterations in physiologic and biochemical functions which often require
rather different management.1Therefore, emphasis will be placed on the placement of fever
as a sign within the decision making hierarchy in diagnosis and management of surgical
illnesses. In keeping with the thrust of this book, emphasis will also be placed on the
changing role of laparotomy in fever of unknown origin. “ Peripheral” aspects of fever,
such as T.P.N ., anorectal sepsis, and phlebitis in a general surgical practice will be discussed.
However, the authors feel the most practical contribution will be the algorithm developed
for use by the clinician in the everyday management of postoperative fever.

PRE-OPERATIVE FEVER: THE ROLE OF DIAGNOSTIC

LAPAROTOMY IN UNEXPLAINED FEVER
In this section we will establish some guidelines for the use of explorative laparotomy
in the resolution of the problem of unexplained fever.
In 1972, Howard and Hardin stated that, “ about 30 percent of all patients with FUO
will ultimately require explorative laparotomy” .2 About 10 years later, Kinney and Caldwell
confirmed that “ explorative laparotomy is a useful diagnostic approach” to the problem.1
However, in a review based on 10 years experience at Columbia Presbyterian Medical
Center, prior to 1968, a contrary conclusion suggested that “ explorative laparotomy for
FUO is disappointing from the point of the view of the relationship between operative
findings and fever.” Half of the patients had intra-abdominal abnormalities, and in 15% no
diagnosis could be made during the laparotomy.3
The two main types of diagnosis at laparotomy for FUO are infection and neoplasm.
Rothman reported 21 out of 24 positive findings at laparotomy for FUO. Thirteen patients
had inflammatory processes and seven had malignancies.4 Esposito and Gleckman reported
36% of patients with infection and 24% of patients with neoplasms in those investigated for
FUO.5 Bismuth reported 23 explorative laparotomies for FUO, in 18 (78%) of which the
results were positive. Ten patients had neoplasms and three had infectious diseases.6 Coon
reported that in 38 patients who underwent explorative laparotomy for FUO, 26% had
infection and 58% had neoplasms.7 He supported the role of laparotomy. However, regarding
laparotomy, Greenall et al., in 1983, concluded in their review that “ its overall value in
patients with FUO has not yet been proven” .8 Petersdorf compared two series of his that
underwent invasive diagnostic procedures; the first group prior to 1961 and the second from
1970 to 1980. He stated “ it was impressive, that the combination of tissue biopsy and
laparotomy was required to establish the final diagnosis” . The combination gave similar
results in the two groups.9
408 U nex p la in ed F e ve r

Esposito reported 15 to 20% peri-operative morbidity and mortality in patients subjected

to laparotomy for FUO.5 However, Geraci in 1959, Bismuth in 1976, Rothman in 1977,
and Coon in 1983 reported no mortality in more than 85 patients.4,6’710 These low mortality
figures have been used to support the concept of laparotomy in the patient with unexplained
fever.
As a result of newer diagnostic techniques that are continuously being added to the
practitioner’s armamentarium, the role of diagnostic laparotomy has decreased, but still
remains a decisive investigation in some difficult cases of unexplained fever.
New diagnostic tools, including ultrasound, CT, nuclear scans, and NMR are becoming
increasingly accurate in detecting intra-abdominal sources of infection. Thus, in the modem
medical center there has been an appreciable decline in the use of laparotomy.
Two cases illustrate the above. The first case is of fever and pain in a 66-year-old man.
Symptoms of fever persisted undiagnosed for 5 years. Following multiple investigations,
eventually a percutaneous liver biopsy revealed a diagnosis of hepatocellular carcinoma.
This patient did not require laparotomy.11 Witt described a patient with an intra-abdominal
leiomyoma whose main symptom was fever. The unusual tumor was diagnosed on ultrasound
examination and a directed (as against an exploratory) laparotomy performed.12
Certain other conditions that may produce postoperative fever, such as postcardiotomy
syndrome and drug fever,13 should not be subjected to invasive investigations.
Nevertheless, laparotomy may still play an important role in the diagnosis of unexplained
fever in the developing countries, where modem investigative techniques may be lacking.

INTRA-OPERATIVE FEVER: MALIGNANT HYPERTHERMIA

DEFINITION
Malignant hyperthermia (MH) is characterized by fever, frequently associated with
rigidity following administration of either a muscle relaxant or potent inhalational agent.14
It is inherited as an autosomal dominant trait, is potentially fatal, and is now regarded as a
myopathy of humans and swine. The syndrome requires a trigger, usually an anesthetic
agent, but can also be precipitated outside the operating room by high temperatures, infec-
tions, extreme anxiety, or muscle injury.15

CLINICAL FEATURES
Clinical features include tachycardia, unstable blood pressure, increase in ventilation
depth and rate, bright red flushing of the skin, rigidity of jaw muscles and generalized
skeletal stiffness and fulminant fever. Fever is a result of the various biochemical reactions
and not a cause. It is therefore a relatively late finding. However, generally the greater the
temperature, the greater the mortality rate.14

LABORATORY FEATURES
Early laboratory findings include elevations of lactic acid, pC02, serum glucose, phos-
phorus, Mg+ +, creatinine, myoglobin, K +, Ca + +. Late findings include decreased K+ and
Ca++ and massive elevations of CPK, LDH, and SGOT.1617 Late complications occur as
a result of alterations in clotting factors and release of massive amounts of myoglobin.
Mortality rates are approximately 58% during or post-anesthesia.15

PREVENTION
Recommendations for elective surgery include use of combinations of barbiturates,
narcotics, tranquilizers, or by ester type local anesthetics.15 However, the most effective
preventative measure is screening of relatives of suspected patients.15
 409

MANAGEMENT OF MH REACTIONS
The most important factor is to cease all potent inhalational agents and/or muscle re-
laxants, including changing of tubing and bags which may have absorbed vapors. Specific
measures then, include: increasing pH, cooling, buffering, replacement of K + , and admin-
istration of procaine and dantrolene sodium.1718 Lyopholized dantrolene (Dantreum IV) is
the most specific therapeutic agent available, and may be required in amounts as great as
10 mg/kg body weight.19 Calcium and catecholamine vasopressors are not indicated. Ap-
propriate monitoring and keeping the patient immobile are important.

POSTOPERATIVE FEVER
Traditional surgical teaching has always dictated that meticulous operative technique
will reduce postoperative septic febrile complications. This concept is now so universally
accepted that it is the fundamental principle of operative technique. However, there are
many other variables not entirely in the surgeons’ control which affect the postoperative
possibilities for development of fever. A systematic approach to postoperative fever is still
required and the principle of no benign fever is clearly applicable today.120
Fever following surgery can be due to infectious or noninfectious causes, as shown in
Table 1. One should approach the patient with postoperative fever by making the diagnosis
as quickly as possible, using history, physical examination and appropriate laboratory tests.
Indiscriminate use of antibiotics without a clear indication should be condemned because
(a) operative site infection requires mechanical drainage, not antibiotics, as primary treatment
and (b) antibiotics are inappropriate for noninfectious causes.
In Table 2, the time-table for postoperative fever is outlined. Fever in the first 24 to 48
h is generally caused by atelectasis and occasionally pneumonitis. Although traditionally it
was believed that there were no pathogenic bacteria involved at this stage, recent evidence
suggests that pathologic organisms can be grown from the sputum in many febrile patients
at this early stage. A high fever in the first day or two following operation may rarely be
due to life-threatening clostridial or streptococcal wound infection. If wound examination
reveals abnormal tenderness or color (red or brown), the wound should be opened and
debrided, and high-dose parenteral penicillin administered.
Thrombophlebitis may present initially as a fever in the postoperative period, frequently
around day 3. Morbidity can be high, particularly in high-risk groups such as bum patients.21
Wound infections usually present around day 5. If unrecognized and untreated they may
lead to unnecessary investigations of fever and serious wound complications. Urinary tract
infections causing fever are usually related to the placement of in-dwelling catheters and
may occur at any time, but most frequently after the fifth postoperative day.22
Subphrenic and other intra-abdominal abscesses usually occur late, more than one week
after abdominal surgery. Fevers are usually spiking in nature. In surgery for intra-abdominal
infection (e.g., perforated ulcer), the temperature is usually elevated before surgery, and
takes several days to return to normal following operation. It has been shown that recurrent
abdominal sepsis is extremely unlikely if the temperature and white blood cell count are
normal when antibiotics are discontinued.23 24 The mortality of untreated abdominal abscess
is high. Fortunately, newer scanning techniques, particularly CT and ultrasound, make not
only the diagnosis easier, but treatment via guided percutaneous needles much easier on the
patient.

OTHER POSTOPERATIVE CAUSES OF FEVER

Transfusion reactions and drug hypersensitivity are dealt with in other chapters in this
book. Fitting them into a set timetable of febrile sources is difficult since fever will clearly
relate to the timing of introduction of these agents.
Cardiac surgery has a list of febrile complications that can occur at varying intervals.
410 Unexplained Fever

TABLE 1
Causes of Postoperative Fever

Common Uncommon

Infectious

Surgical wound infection Bacteremia and/or endocarditis

Deep operative infection Pseudomembranous colitis (post antibiotic)
Intravascular catheter sepsis
Infected prosthesis Posttransfusion infection
Pneumonia Hepatitis, EBV, CMV, HIV (AIDS),
Urinary tract infection syphilis, toxoplasmosis, malaria
Nosocomial infection Parotitis
Maxillary sinusitis
Toxic shock syndrome
Systemic candidiasis
Retained surgical sponge

Noninfectious

Atelectasis Malignant hyperthermia

Aspiration pneumonia Myocardial infarction
Deep vein thrombosis Pancreatitis
Pulmonary embolism Acute cholecystitis (acalculous)
Drug fever Intravenous infusion pyrogenic reaction
Transfusion-related hemolytic reaction Thyroid storm
Allograft rejection Acute adrenocortical insufficiency (adrenal crisis)
Benign (physiologic) postoperative fever Reactivation of underlying disease (collagen disease,
malaria)
Hematoma
Dehydration
Factitious fever
Parenteral nutrition

Special Situations

Heart surgery Postpericardiotomy syndrome

Neurosurgery Aseptic meningitis
Gynecologic surgery Pelvic thrombophlebitis

TABLE 2
Modified Schedule for Postoperative Fever with Respect to
Time

Postoperative Causes of elevated temperature

day

1—2 Pulmonary problems leading to atelectasis and pneumonia,

streptococcal and clostridial infection
Phlebothrombosis — phlebitis, suppurative phlebitis — “ third
day sepsis”
5 Any wound or deep operative site infection, pulmonary em-
bolism, pneumonia
6—8 Deep operative site infection
After first week Subphrenic or intra-abdominal collection of pus, infected pros-
thesis or vascular graft, head injuries
Any time Transfusion reaction, allergic and drug fever, acalculous cho-
lecystitis, factitious fever, urinary tract infection
 411

Many are common to other forms of surgery, but some, like the post-pericardiotomy syn-
drome, are specific. The interested reader is referred to a review by Silber and Katz.25
Infections of prosthetic devices are particularly important causes of fever. First, as in
cases of vascular grafts and joint replacements, the results of infection can be catastrophic
for the patient. Second, the diagnosis can be frequently difficult to make. Intravenous cannula
infections can be frequently overlooked and according to Altemeier are the source of the
third day surgical fever.26
Quadriplegics may develop unusual periodic fever apparently of noninfectious causes.27 29
Factitious fever must always be bom in mind in establishing unusual diagnosis of fever.30

FEVER AND PERITONITIS

Any peritoneal irritation will cause fever, along with many other clinical manifestations.
The presence of fever supports the diagnosis of peritonitis but does not help to clarify the
etiology of the peritonitis. Fever is a sign in any of the following classifications of peritonitis:
septic vs. aseptic, bacterial vs. viral, primary vs. secondary.31
The mesothelium of the peritoneum is sensitive to damage and will reflect an inflam-
matory protective process with fever quite rapidly. A localized peritonitis can deteriorate
into a generalized one because of the unique fluid movement system of the peritoneum.32
The most common causes of peritonitis are secondary. Examples include acute appen-
dicitis, cholecystitis, and perforated ulcer and colon. The initial peritonitis and fever may
be caused by chemical irritation of the mesothelium as in perforated ulcer with late bacterial
contamination, or with an initial bacterial contamination as in a perforated appendix or colon.
Fever in these patients generally occurs immediately, is high and remains at an elevated
level until the insult is removed.
A different pattern of fever occurs in patients with intra-abdominal abscesses. Fevers
are spiking, generally with a peak at night. Examples include postoperative complications,
e.g., subphrenic or pelvic abscesses, missed or late presentations of acute processes such
as appendiceal abscesses, or tubo-ovarían abscesses. Rare examples include foreign bodies.
Peritoneovenous and CSF shunts have been shown to be very serious sources of intra-
abdominal infection and fever.33 34 In one series, 62% of reported patients with peritoneo-
venous shunts had fever related to the shunt.33 Of 300 children with CSF shunts, 15 developed
intra-abdominal complications, which presented with fever and other signs and symptoms.34
Fever in peritonitis is part of a complex response to irritated mesothelium. The pattern
of fever will depend on the timing of presentation and the presence or absence of bacterial
contamination. However, as outlined in other chapters of this book, fever as well as other
signs of peritonitis may not be present in the following group of patients: the elderly, immune-
compromised, and steroid-dependent.

PERIPHERAL ASPECTS OF FEVER

ANORECTAL SEPSIS
Anorectal infections generally present early with the classical signs of localized pain,
swelling, erythema, and low-grade fevers. They predominantly arise from infected crypts.
The diagnosis is not usually difficult to make. However, in a number of patients as follows,
anorectal infections may present predominantly as a fever of unknown origin.

1. Ischiorectal abscesses in general

2. Obese patients
3. Diabetics
4. Elderly
5. Para/quadriplegics
412 Unexplained Fever

Ischiorectal abscesses can cause extensive local necrosis and occasionally death. Treatment
is predominantly by incision and drainage. Antibiotics may be indicated in diabetics and in
patients with massive tissue destruction.

TOTAL PARENTERAL NUTRITION (TPN)

A number of papers have discussed the septic complications of TPN.35,36 The sepsis
may be related to the excellent culture medium that the solutions provide, but more commonly
are related to the in-dwelling catheter, whether peripheral or central.30 Maki and others have
stressed the prevention of sepsis is best managed by a team approach, with TPN specialty
nurses and effective aseptic protocols.37 Nevertheless, even with this approach, and reduced
septic complication rate, the in-dwelling catheter must always be suspected in the presence
of fever.
Current recommendations for fever, while on TPN, include removal of the catheter and
culturing of its tip, and blood.
In the absence of fever, most authors have recommended catheter change every 30 days,
since the incidence of catheter sepsis increases significantly beyond that.38 Frequently, TPN
is used to support patients who have multisystem disease, including fever prior to the initiation
of TPN. This makes catheter related sepsis more difficult to detect. Most catheter related
sepsis occurs following 48 h post-insertion. Frequent assessment, culturing, etc. following
this period is recommended.
Most common infections are staphylococcal, and are managed by catheter removal. In
severe infections, immunocompromised patients, and those with prosthetic vascular grafts,
one should add penicillinase-resistant antibiotics, such as Cloxacillin, and cephalosporins.
The most common pathogen, Staphylococcus epidermidis, is treated initially with Vanco-
mycin. If laboratory tests then show sensitivity to Cloxacillin, this should be used.

TRAUMA AND FEVER

Fever is so common in trauma patients that it is virtually accepted as the norm. In
general, the sources of fever are the same as in other surgical patients.
Nevertheless, a number of patients will develop unexplained “ idiopathic fever.” Straheli
reported 92% of post-traumatic children studied developed this type of elevation of body
temperature usually in the first week of hospitalization.39The etiology of this fever is unclear.
Proposed theories include hematoma formation, cell destruction with pyrogen, e.g., inter-
leukin-1 release.29 Pulmonary embolism may more frequently present as FUO in trauma
victims.40
The postoperative trauma patient may develop infections and febrile states as in any
other postoperative environment. A problem peculiar to trauma victims occurs in spinal cord
injuries. In a series of 70 prospectively studied patients, 67% developed fever ± infection.28
Post-splenectomy infections are so serious that we have dealt with them in a separate section.
Late septic complications include missed perforated viscera, hemothorax, and intra-abdom-
inal hematomas which can subsequently result in abscess formation.
The craniocerebral trauma patient may also develop noninfectious fever. A proposed
mechanism is direct mechanical disruption of the hypothalamic center.3 However, this theory
does not fully explain the observed fevers in quadriplegic patients with no head injury.27

POST-SPLENECTOMY FEVER

It has been calculated that the incidence of fatal bacterial infections in children who
have had splenectomies for trauma is 14 times greater than the expected in a normal pop-
ulation.41 In adults, the precise risk of overwhelming infection is difficult to determine, but
 413

is very uncommon.42 What is known is that post-splenectomy sepsis is rapidly progressive

and frequently fatal.43 The current recommendations are therefore generally directed at
prevention. Conservative approaches to splenic trauma, particularly in children, have been
shown to be possible.
Combinations of penicillin prophylaxis and pneumococcal vaccine are recommended as
preventive measures. Penicillin is particularly important for infants and for patients in whom
the indication for splenectomy was an underlying splenic or hematologic disorder.44 45

NECESSITY (OR LACK OF) FOR FEVER PROTOCOL

Yeung evaluated 256 postoperative children of whom 28.5% developed a temperature

greater than 38°C. Only 1.6% had a septic process. His conclusion was that a formal fever
protocol was not required in children.46 Similar data is difficult to find in adults.47 The
authors feel that a rigid protocol is probably not worthwhile but algorithms such as outlined
in Tables 1 and 2 are important to use as clinical guides.

REFERENCES
1. Kinney, J. M. and Caldwell, F. T., Fever. Etiology, physiologic and metabolic effects and management
in surgical patients, in Text Book of Surgery, Vol. 1, 12th ed., Davis-Christopher, Sabiston, D. C., Ed.,
W. B. Saunders, Philadelphia, 1981, 178.
2. Howard, P. H. and Hardin, W. J., The role of surgery in fever of unknown origin, Surg. Clin. North
Am., 52 (No. 2), 397, 1972.
3. Roe, C. F., Surgical aspects of fever, Curr. Prob. Surg., November 1968, 26.
4. Rothman, D. L., Schwartz, S. I., and Adams, J. T., Diagnostic laparotomy for fever or abdominal pain
of unknown origin, Am. J. Surg., 133, 273, 1977.
5. Esposito, A. L. and Gleckman, R. A., A diagnostic approach to the adult with fever of unknown origin,
Arch. Intern. Med., 139, 575, 1979.
6. Bismuth, H., Pujol, J. P., and Green, R. A., Apport De La Laparotomie Au Diagnostic Des Fievres
Inexpliquées, Chirurgie, 102, 573, 1976.
7. Coon, W. W., Diagnostic celiotomy for fever of undetermined origin, S.G.O., 157, 467, 1983.
8. Greenwall, M. J., Gough, M. H., and Kettlewell, M. G., Laparotomy in the investigation of patients
with pyrexia of unknown origin, Br. J. Surg., 70, 35, 1983.
9. Petersdorf, R. G., F.U.O., how it has changed in 20 years, Hosp. Prac., April 15, 1985, 84.
10. Geraci, J. E., Weed, L. A., and Nichols, D. R., Fever of obscure origin — The value of abdominal
exploration in diagnosis, JAMA, 169, 1306, 1959.
11. Ludmerer, K. M. and Kissane, J. M., Fever, abdominal pain and hepatomegaly in a 66-year-old man,
Am. J. Med., 78, 481, 1985.
12. Witt, J. H., Marks, M. I., Smith, E. I., Altshuler, G., Wilson, D. A., and Humphrey, G. B.,
Leiomyoma presenting as prolonged fever, anemia and thrombocytosis, Cancer, 52, 2359, 1983.
13. Murray, H. W., Ed., F.U.O. Fever of Undetermined Origin, Futura, Mt. Kisco, NY, 1983.
14. Britt, B. A. and Kalon, W., Malignant hyperthermia: a statistical review, Can. Anaes. Soc. J., 17, 293,
1970.
15. Britt, B. A., Malignant hyperthermia, Mod. Med. Can., 31, 511, 1976.
16. Britt, B. A., Malignant hyperthermia: a pharmacogenetic disease of skeletal and cardiac muscle, N. Engl.
J. Med., 74, 1140, 1974.
17. Nelson, T. E. and Flewellen, E. H., Current concepts: the malignant hyperthermia syndrome, N. Engl.
J. Med., 309, 416, 1983.
18. Britt, B. A., Recent advances in malignant hyperthermia, Anaes. Analg., 51, 891, 1972.
19. Nelson, T. E. and Flewellen, E. H., Rationale for Dantolene vs. Procainamide for treatment of malignant
hyperthermia, Anaesthesia, 50, 118, 1979.
20. Alexandre, J. H. and Germain, M., La Fievre Chez Les Opérés Et Les Accouchées, Rev. Prat., 21, 29,
4343, 1971.
21. Stadler, J., Karp, M. P., Steine, J. M., Stein, E., and Levenson, S. M., Suppurative thrombophlebitis
caused solely by Candida albicans, Burns, 4, 133, 1979.
414 Unexplained Fever

22. Bohnen, J. M. A. and Meakins, J. L., Postoperative infection in essentials of infectious diseases, Mandell,
L. and Ralph, E., Eds., Blackwell Scientific, 1985, 353.
23. Lennard, E. S., Dellinger, E. P., Wertz, M. J., and Minshew, B. H., Implications of leukocytosis and
fever at conclusion of antibiotic therapy for intra-abdominal sepsis, Ann. Surg., 195, 19, 1982.
24. Stone, H. H., Bourneuf, A. A., and Stinson, L. D., Reliability of criteria for predicting persistent or
recurrent sepsis, Arch. Surg., 120, 17, 1985.
25. Silber, E. N. and Katz, L. N., Heart Diseases, Macmillan, New York, 1975, 555.
26. Altemeier, W. A., McDonough, J. J., and Fullen, W. D., Third day surgical fever, Arch. Surg., 103,
158, 1971.
27. Sugarman, B., Fever in recently injured quadriplegic persons, Arch. Phys. Med. Rehabil., 63, 639, 1982.
28. Sugarman, B., Brown, D., and Musher, D., Fever and infection in spinal cord injury patient, JAMA,
248, 67, 1982.
29. Kirkeby, O. J. and Risoe, C., Influence of neural pathways on the pyrexial response to surgical trauma,
Acta Chir. Scand., 151, 7, 1985.
30. Murray, H. W., Factitious fever updated, Arch. Intern. Med., 139, 739, 1979.
31. Rohr, M. S. and MacDonald, C. J., Abdominal wall umbilicus, peritoneum mesenteries, omentum and
retroperitoneum, in Text Book of Surgery, Sabiston, D. C., Ed., W. B. Saunders, Philadelphia, 1986, 774.
32. Hau, T., Ahrenholz, H. D., and Simmons, L. R., Secondary bacterial peritonitis, the biological basis
of treatment, Curr. Prob. Surg., 16(10), October, 1979.
33. Prokesch, C. R. and Rimland, D., Infectious complications of the peritoneovenous shunt, Am. J. Gas-
troenterol., 78(4), 235, 1983.
34. Rush, S. D., Walsh, W. J., Belin, P. R., and Pulito, R. A., Ventricular sepsis and abdominal related
complication in children with cerebrospinal fluid shunts, Surgery, 97(4), 420, 1985.
35. Jernigan, W. R., Gardiner, W. C., Mahr, M. M., et al., Use of internal jugular vein for placement of
central venous catheter, S G O, 130, 520, 1970.
36. Filler, R. M. and Coran, A. G., Total parenteral nutrition in infants and children: central and peripheral
approaches, Surg. Clin. North Am., 56(2), 395, 1976.
37. Maki, D. G., Preventing infection in intravenous therapy, Hosp. Prac., 95, April, 1976.
38. Bentley, D. W. and Lepper, M. H., Septicemia related to the in-dwelling venous catheter, JAMA, 206,
985, 1972.
39. Straheli, L. T., Fever following trauma in childhood, JAMA, 199(7), 163, 1967.
40. Wilson, K. H. and Tuazon, C. V., Pulmonary embolus 5 days post injury presenting as fever of unknown
origin, J. Trauma, 20(37), 259, 1980.
41. Erahlis, A. J. and Filler, R. M., Splenectomy in childhood: a review of 1413 cases, J. Pediatr. Surg.,
7, 382, 1972.
42. Dickerman, J. D., Traumatic asplenia in adults: a defined hazard?, Arch. Surg., 116, 361, 1981.
43. Krivit, W., Giebink, G. S., and Leonard, A., Overwhelming post-splenectomy infection, Surg. Clin.
North Am., 59, 223, 1979.
44. Gates, G. F., Sepsis in children following splenectomy, J. Nucl. Med., 19, 113, 1978.
45. Hatch, J. P., Sibbald, W. J., and Austin, T. W., Overwhelming pneumococcal infection in a hyposplenic
adult, Can. Med. Assoc. J., 129, 851, 1983.
46. Yeung, R. S. W., Buck, J. R., and Filler, R. M., The significance of fever following operations in
children, J. Pediatr. Surg., 17, 347, 1982.
47. Freischlag, J. and Busuttil, R. W., The value of postoperative fever evaluation, Surgery, 94, 358, 1983.
 415

Chapter 27

UNEXPLAINED FEVER IN UROLOGY

E. Merimsky

INTRODUCTION
Patients with infections comprise the greatest percentage of any group with fever of un-
known origin (FUO). Urinary tract infection is by far the most common urologic disease, and
its manifestations result from bacteria producing either irritation of urethral and vesical mucosa
(fever being usually absent in bladder infections) or the classical clinical presentation of upper
urinary tract infection which includes fever, frequently accompanied by chills and flank
pains. It should be realized, however, that the clinical presentations may vary greatly.13
The clinical manifestations of chronic urinary tract infections are more difficult to define.
There may be flare-ups of acute symptoms or the disease may be silent. Tuberculosis remains
the most prominent cause of FUO. The diagnosis of tuberculosis, although suspected, might
be delayed till a positive culture is obtained or until enough proof is gathered by biopsy or
operation in order to start with a specific therapy.
Fever of unknown origin as published in 1961 by Petersdorf and Beeson4 and defined
by Dinarello and Wolf in 1979 (as a fever of 2 to 3 weeks duration with a temperature
exceeding 38.3°C and no diagnosis established after 1 week in hospital) is extremely rare
in urology. As soon as there are clinical manifestations localizing the disease in urinary tract
(localization of pain, disturbances on urinations, pathologic urinalysis), and with the advent
of sophisticated electronic methods of investigation as ultrasound, radionuclides, comput-
erized tomography, etc., diagnosis is generally feasible in a matter of days, and the diagnostic
yield is increased. A renal carbuncle or a perinephric abscess, for example, is not necessarily
associated with pyuria or bacteremia, yet by ultrasound or isotopes it can be easily diagnosed.
Malignancy may be associated with fever which may be the only presenting feature.
Hypernephromas are notoriously occult and one patient in ten presents with pyrexia.
Retrospective studies of groups of patients satisfying the criteria of FUO have shown
that the majority are found either to have illnesses which are notoriously difficult to diagnose
or to have unusual presentations of common diseases.
In general, a febrile patient with urological complaints will be put on antiboitics as soon
as samples of blood and urine are sent for culture. The response will be quick enough or
the antibiotic will have to be changed. Often enough fever will resolve even before diagnosis
is achieved. The longer a fever defies diagnosis, the less likely are infective causes present
and the more common are the granulomatous and miscellaneous group of diseases.
Persistent pyrexia does not always imply serious disease. Invasive diagnostic procedures
are indicated only when clinical deterioration is evident. If fever persists, the decision must
be made to either discharge the patient, perform an exploratory laparotomy or initiate a
therapeutic trial.
During the past 10 years a number of previously unknown infections have been rec-
ognized, some of which might have some correlation with the urogenital system, as for
example AIDS, herpes virus infections, growing virulence of S ta p h y lo co c cu s e p id e rm id is ,
the hemorrhagic fever with renal failure syndrome caused by Hantaan virus, urethritis, and
associated syndromes commonly caused by C h la m yd ia tra c h o m a tis , the toxic shock syn-
drome produced by S ta p h y lo co c cu s a u reu s strains colonizing the vagina, etc.5 The reader
is referred to specific publications on these subjects.
416 U n ex p la in ed F e ve r

RENAL INFECTIONS

Renal infections are generally acute and don’t play a role in the diagnosis of FUO. The
manifestations of acute urinary tract infections are usually easy to recognize. The classical
clinical presentation includes fever, frequently accompanied by chills and flank pain. In
general the febrile patient will be put on antibotics as soon as samples of blood and urine
are sent for culture. Fever might subside even before diagnosis is achieved. Yet, sometimes
the clinical picture will be prolonged and the differential diagnosis will be problematic. With
the advent of sophisticated electronic methods of investigation such as ultrasound, radio-
nuclides scans, computerized tomography, etc., the diagnosis yield is increased. Invasive
diagnostic procedures are indicated only when clinical deterioration is evident. If fever
persists, the decision must be made to either discharge the patient, perform an exploratory
laparotomy6 or initiate a therapeutic trial. The longer a fever defies diagnosis, the less likely
are infective causes present, and the more common are the granulomatous and miscellaneous
groups of diseases at stake.

GLOMERULONEPHRITIS
Glomerulonephritis is not in the domain of the urologist, unless the patient consults for
hematuria or at the end stage when renal transplantation is contemplated.
Diagnosis in the acute stage is based on the onset of hematuria, proteinuria, reduced
glomerular filtration rate, hypertension, edema (renal salt and water retention).7
Five major glomerulopathic syndromes are recognized: acute glomerulonephritis, rapidly
progressive glomerulonephritis, chronic glomerulonephritis, the nephrotic syndrome and
asymptomatic urinary abnormalities.7 9 The kidney is either the sole or predominant organ
involved or is involved as a complication of infection or drug exposure.7,10 11
Generally, there is no problem of FUO and differential diagnosis is based on renal
biopsies. Yet, there are cases where high temperature is a predominant feature and diagnosis
is quite a problem.11 15

PYELONEPHRITIS
Acute pyelonephritis is the pathological process following bacterial infection in the renal
parenchyma and pelvicalyceal system.16 17 The acute form just to mention it, will be char-
acterized by flank pain, flank tenderness, fever, dysuria, and frequency.4 17-22 In the absence
of destruction or congenital anomalies, the patient with acute pyelonephritis might dem-
onstrate a perfectly normal urogram.23 In other cases there will be enlargement of the involved
kidney, impaired excretion of the contrast material, the collecting system often appears
narrowed and elongated as a result of edema.20 The most difficult diagnosis will be with
renal carbuncle or perinephric abscess.21,24 27 CT or ultrasound is then indicated.24,28 31
Chronic pyelonephritis is a difficult term to define.1719 There is considerable doubt
whether many of the cases pathologically diagnosed as chronic pyelonephritis in patients
without obstructive uropathy result from infection. Perhaps interstitial nephritis rather than
chronic pyelonephritis should be used to describe the pathological entity, since pyelone-
phritis, implying inflammation of the kidney pelvis, is largely an autopsy diagnosis. Pye-
lonephritis is actually underdiagnosed, only 16 to 20% of what the classical pathologists
call pyelonephritis is diagnosed. Some patients will have no symptoms at all or only lower
urinary tract symptoms. In order to diagnose chronic pyelonephritis, there should be evidence
of past or present bacteremia, renal involvement by clinical means and chronicity.17,32 The
radiological diagnosis is made on the basis of scanning of the kidney or blunting and dilatation
of calyces. Urography will frequently provide information with regard to the extent of the
inflammatory disease, and will occasionally suggest an unusual type of infection such as
tuberculosis or xanthogranulomatous pyelonephritis.1729,31,32
 417

RENAL ABSCESS
Renal abscess may develop as a consequence of diffuse pyelonephritis or as a local
manifestation of bacteremia due to a suppurative focus elsewhere in the body, like upper
respiratory tract infection, tonsilitis, osteomyelitis, breast abscess, epididymo-orchitis, dental
extraction, or a wound infection. In some cases, multiple renal abscesses may exist. The
interval between the primary infection and the appearance of the renal carbuncle varies from
a few days to many months. Urinary symptoms are usually absent and urine culture is often
sterile. The main clinical picture consists of fever, chills, nausea, and unilateral flank pain.
Two thirds of the patients have an unilateral flank tenderness. Differential diagnosis will be
mainly with acute pyelonephritis or obstructed uropathy.19,3336
The radiographic findings will be that of a normal kidney, or show an image of any
renal mass. The plain film may show a poor visualization of both the psoas shadow and the
outline of the affected kidney with thoracolumbar scoliosis. Retrograde pyelography does
not help in the diagnosis unless to exclude an obstructive uropathy. Ultrasound findings of an
anechoic mass or a sonolucent mass with septa are suggestive of renal carbuncle, while the
finding of low level echoes is suggestive of acute focal nephritis, without liquefection.23,37 39
CT scans offer another noninvasive technique for investigating suspected renal or peri-
renal disease. Correct use of CT scan and ultrasound in conjunction with IVP has lessened
or eliminated the need for angiography.34,40 41
In spite of the above-mentioned methods, the correct diagnosis of acute renal carbuncle
is established preoperatively in only a sixth of the cases.27 In our experience of seven cases,
ultrasound gave the diagnosis. We believe that a renal carbuncle is by far more frequent
than suspected, and is usually treated as acute pyelonephritis. Diagnosis is missed unless
an ultrasound is done, whether the IVP is normal or not, and whether gallium scan show
an inflammatory sight.33,42
Renal abscesses have a predilection for the corticomedullary region. They may resolve
by antibiotic treatment or may drain spontaneously through the renal collecting system. On
the other hand, the extension of bacteria and suppuration through the renal capsule into the
perirenal space forms a perinephric abscess.43"46
Until 1960, S ta p h y lo co c cu s a u reu s was the common organism found in renal ab-
scesses.47,48 Nowadays, Gram-negative, most commonly E. c o li , is the most prevalent germ.
In our cases some were sterile and from others K le b s ie lla , E n te ro b a c te r , C o li , P seu d o m o n a s
a eru g in o sa , and P ro te u s m ira b ilis were isolated. Percutaneous drainage is one mode of
treatment.44,49,50 With the development of more effective antibiotics, a trend is developing
for a conservative treatment of the renal carbuncle.5153 The success of the conservative
treatment depends on several factors:

1. Diagnosis should be made early, when the inflammatory process is still localized in
the kidney.
2. The antibiotic treatment should be parenteral and intensive and should be continued
for at least 2 weeks.
3. There must be a close follow-up of the patients using repeated ultrasonographic studies
until the complete resolution of the process.51,54

PYONEPHROSIS
Pyonephrosis refers to the condition in which the pelvis and calyces are filled with pus.
The diagnosis of pyonephrosis is suspected when the clinical symptoms of fever anf flank
pain are combined with the radiologic evidence of obstruction to the urinary tract. This
condition, the result of long-standing obstruction and infection, presents a picture of marked
destruction of renal parenchyma, dilated calyces of thin walls, multiple cavities filled with
infected exudate, and minimal renal functioning units. The destruction and loss of function
are due to the combination of back-pressure and infection.19,55
418 Unexplained Fever

Obstruction of the kidney may result from a ureteral stone, ureteropelvic junction ste-
nosis, malignancy (colon, uterus, ovary, bladder), retroperitoneal fibrosis etc. The classic
form of pyonephrosis is still tuberculosis resulting in autonephrectomy. Intravenous pye-
lography will generally show a nonfunctioning kidney. Sonography and/or computerized
tomography gives a prompt diagnosis if dilatation of the collecting system, and needle
puncture of the kidney yields pus and establishes the presence of pyonephrosis.56 A per-
cutaneous nephrostomy catheter is then inserted and serves for initial drainage of infected
urine and for evaluation of residual kidney function before definitive surgery. Gallium-67
citrate has sometimes demonstrated a pyonephrosis, but it probably cannot distinguish py-
onephrosis from pyelonephritis, renal abscess, or even renal tumor. The nephrostomy tube
used for drainage can provide a direct evaluation of kidney function, diagnostic nephros-
togram, dissolution of stones and permanent kidney drainage. The most common organisms
cultured are Bac. Koch or Gram-negative bacteria.55,57
Rare forms of pyonephrosis are reported occasionally. Kirchner and Turner58 reported
a case of Bacteroides ruminicola pyonephrosis, probably secondary to tuberculosis. It would
appear that most suppurative infections of the male genito-urinary tract involve anaerobic
bacteria, the dominant organism isolated being Bacteroides fragilis.59 Lizza et al.,60 in a
clinicopathological conference, discussed a chronic fistula developing after nephrectomy for
pyonephrosis related with squamous cell carcinoma.

XANTHOGRANULOMATOUS PYELONEPHRITIS
Xanthogranulomatous pyelonephritis (X-G-P) was first described by Schlagenhaufer in
1916.61 Malek, in reviewing 18 cases in 197262 called it “ The Great Imitator” as it closely
mimics tumors, pyonephrosis, perinephric abscess, lipomatosis, and renal cysts. It is only
recently that preoperative diagnosis became feasible thanks to computerized tomography.63
Ultrasound examination is not without limitations. The presence of obstructing renal stones,
thickening of the perirenal fascia, and inability of the kidney to handle intravenously injected
contrast medium can be assessed with computerized tomography. Low density renal areas
may indicate lipid infiltration of the kidney or incorporation of the fat of the renal bed into
the tumefactive mass.63,64
X-G-P has several constant symptoms and signs: pain (abdominal or colicky), temper-
ature, long-standing infection, high sedimentation rate, and laboratory data indicating a
urinary tract infection. Sex and race do not influence the incidence. Age varies from 48
days to over 70 years.62,65,66
In retrospect, many authors have come to the conclusion that they should have diagnosed
X-G-P from the start.65,66 According to Friedenberg,67 a nonfunctioning kidney with dilatation
of the pyelocalyceal system and chronic urinary tract infection should suggest the diagnosis
of X-G-P, particularly when B. proteus is isolated on culture of urine.65,66 Salmon and
Koehler68 claim that the presence of a large stone in a nonfunctioning kidney is a characteristic
sign, though the same sign for Tsung and Lin69 is diagnostic for hypernephroma. Hooper’s
definition70 comprises a nonfunctioning kidney and infected urine.
Recently, Lizza et al.71 diagnosed X-G-P preoperatively by percutaneous fine needle
aspiration biopsy, and Tonelli and Gianotti72 conclude that X-G-P is not an autonomous
disease, but simply a stage in the development of subacute or chronic suppurative pyelo-
nephritis, usually due to a member of the Enterobacteriaceae, either Proteus species or
Escherichia coli. Other organisms were also reported, separately or polymicrobial infections:
Staphylococci (15% of the cases), Pseudomonas, Klebsiella. Urine is sterile in 26% of the
cases. The relatively high incidence of sterile cultures suggests a possible role of anaerobic
bacteria, the extent and role of which is unknown.73 Malek and Elder74 found bacteroides
and Peptostreptococcus species in the renal parenchyma of X-G-P.
Xanthogranulomatous pyelonephritis in children is rarely associated with nonfunctioning
 419

kidney or calcification. The pattern is predominantly localized or segmental, although the

diffuse form exists too, usually on the left side. Etiology may be attributed partially to
hyperosmolarity of serum and urine, and to leukocyte specific antinuclear antibodies. X-G-
P is a variant of local cellular response in renal parenchyma to bacterial invasion. In children
diagnosis is generally by histology after a nephrectomy performed because of a renal mass.75 76
Yazaki et al.77 compared X-G-P in childhood in Japan to that in English literature. The
majority of patients were girls in the English literature, whereas the opposite sex was seen
in Japan. The involved kidney was functioning on an excretory urogram in the majority of
cases reported in the English literature; however, in all cases from Japan, the involved kidney
was nonfunctioning. These findings further support the newer concept that X-G-P in child-
hood exists in focal as well as diffuse forms.

INFECTED RENAL CYSTS

Suppurative solitary renal cysts are uncommon.78,79 They may result from walling off
of a renal abscess, infection of a dilated calyceal cyst that has lost its connection with the
pelvis through inflammatory fibrosis, or infection of a pre-existing simple renal cyst by
extension from local pyelonephritis or by hematogenous spread.80
The course of the disease is long and insidious, and diagnosis may be delayed for weeks
or months. Differential diagnosis might be difficult with carbuncle of the kidney, tubercu-
losis, xanthogranulomatous pyelonephritis or even with a simple cyst.66,80 Ultrasound ex-
amination of an infected renal cyst may show a typical benign cyst pattern if the contents
are free of debris, but the presence of particulate matter will produce echoes which change
position with gravity.81,82 Computerized tomography is more accurate by showing the dif-
ferences in attenuation. Cyst aspiration under ultrasound guidance and bacteriological study
will pose the final diagnosis.83'85 Untreated, the cyst might perforate to form a perinephric
abscess.86

EM PHYSEMATOUS PYELONEPHRITIS
Emphysematous pyelonephritis is a rare, life-endangering suppurative infection of the
renal parenchyma and perirenal tissue.87 The disease is encountered mainly in patients with
diabetes mellitus and is characterized by the production of intrarenal and, occasionally,
perirenal gas. The first case was reported in 1898 by Kelly and MacCallum88 but the
designation is that of Schultz and Klorfein.89
The clinical presentation usually suggests severe acute pyelonephritis—chills, fever,
flank pain, lethargy and confusion are the clinical manifestations encountered most fre-
quently. In 18% of the cases, FUO was the sole presenting feature. It then has a more
indolent course, lasting for weeks and even months. The average duration of symptoms
before diagnosis is of 0.5 to 240 days.87,89
In the majority of patients, no local physical findings are present, while costovertebral
angle tenderness may be elicited in some and palpable abdominal mass and crepitus in tissues
overlying the affected kidney may exist in a few. The latter finding usually presages a dismal
outcome.
Prompt radiologic examination is the definitive modality to diagnose emphysematous
pyelonephritis. The most common radiographic patterns are gas collections in the renal
parenchyma and perirenal tissues as demonstrated by a plain abdominal film and excretory
urography.90 Sophisticated techniques, such as nuclear scanning, ultrasonography, and com-
puterized tomography may supersede an IVP.89,91'93
The main causative organisms are those found normally in the urinary and gastrointestinal
tracts. E sch eric h ia c o li is by far the most common organism (71%), followed by K le b sie lla
p n eu m o n ia e , A e ro b a c te r a re o g en es, and P ro te u s m ira b ilis. Anaerobic bacteria were isolated
in only one case. C a n d id a a lb ic a n s was reported by Johnson et al.94
420 U n ex p la in ed F e ve r

SYSTEMIC INFECTIONS

TUBERCULOSIS
Tuberculosis remains the most prominent cause of FUO in the genitourinary
tract.4 21’22’26’27 29 Symptoms are usually insidious, and only 30% of the patients will present
with constitutional symptoms of fever, weight loss, and night sweats. Symptoms may be
overlooked completely until the appearance of cystitis or epididymitis. Gross or microscopic
hematuria and pyuria with a sterile urine on culture for bacteria should always call tuberculosis
to mind. Any prolonged healing process after an operation, or any complication especially
with long standing suppuration should focus the attention on the possibility of tuberculo-
s j s 24,27-28,95-96

A positive tuberculin skin test, caseating granuloma on biopsy, characteristic changes

on the excretory urogram, bladder lesions on cytoscopy, and the presence of sterile pyuria
or microscopic hematuria will help the diagnosis. Positive urine cultures are obtained from
80% of the patients. Hypertension will be found in 4% of patients with renal tuberculosis.
Genitourinary disease may follow by 20 or more years the primary pulmonary infection. A
normal excretory urogram does not rule out tuberculosis. Since poor visualization of the
kidney on the urogram is a common feature of urinary tuberculosis, high dose urographin
should be used in suspected cases. On the scout film of the abdomen one may see calcifi-
cations which are found in 16% of the cases. They may be granular punctate, single or
scattered throughout the kidney, occasionally one sees putty-like calcifications, and less
frequently mottled calcification within the ureter. The earliest urographic findings consist
of slight dilatation and frayed appearance of calyces. As the disease progresses, erosion of
the pyramid and cortical necrosis develop, leading to irregular cavities extending into the
cortex, and they may or may not connect with the calyx. As strictures occur at the site of
physiological narrowing, one sees a totally pinched off calyx or autonephrectomy. Not all
nonvisualization results from total autoamputation and it is not rare to see return of visu-
alization after adequate chemotherapy.23’24’28 95
The chemotherapeutic regimen for treating tuberculosis can readily eradicate the bac-
terium from the urine, but in many instances, the sequelae of healing (fibrosis) will cause
progressive renal destruction. The appearance of a relatively normal renal architecture at
sonography, and the presence of nonvisualization at urography, should raise the suspicion
of renal tuberculosis. It would be impossible at sonography to differentiate caliectasis with
extensive debris from caseous necrosis with nonobstructed calyces and adjacent granu-
lomas.97 The only imaging technique that may be of value in this situation would be retrograde
pyelography where contrast medium may gain access to a dilated collecting system. It is
important to remember that other granulomatous diseases can simulate the renal tuberculosis
sonographic pattern.
In patients undergoing renal tuberculosis, follow-up urograms or radionuclide studies
are extremely important to evaluate healing and demonstrate the formation of strictures at
an early stage.
Isolated tuberculous epididymo-orchitis is a rare entity. In practically all cases, this is
secondary to a prostatic lesion which, in turn, is secondary to a renal lesion, the latter being
bloodbome from a pulmonary focus. Tuberculosis should be considered in the differential
diagnosis of a scrotal swelling even in the absence of a history of previous tuberculosis.98 99
Therapeutic trials are indicated only in specific instances. If tuberculosis is the cause of
the fever of unknown origin, a decrease in the magnitude or total subsidence of fever will
occur within 2 or 3 weeks.

BILHARZIOSIS
Fever of unknown origin might be of parasitic origin, especially in endemic areas,
namely, during the phase of invasion of the bilharziosis.29 Widespread bilharziosis with
 421

accompanying damage to the urinary tract undoubtedly predisposes to bacterial infection.100

Domart et al.101 draw attention to the frequency of “ tropical” fever and the often misleading
symptoms which accompany the invasive stage of schistosomiasis.
There is a latent period of 2 to 10 weeks, then high fever of 39 to 40°C, irregular and
undulante, accompanied by headache, muscular pain, and chills, urticaria eruption, gas-
trointestinal troubles, hepatosplenomegaly, leukocytosis of more than 20,000 and eosino-
philia of 50% or more, Vogel-Minning Test and immunoelectrophoresis of the serum are
helpful. Recuperation of eggs from stool or urine is late in the disease, from 8 to 18 weeks.

SALMONELLOSIS
In endemic areas, localization of typhoid bacilli in an obstructed urinary tract can lead
to intermittent bacteremic episodes. Focal contamination may lead to retrograde urinary tract
involvement, or hematogenous dissemination with focal localization in the genitourinary
system may lead to pyelonephritis. Salmonella organisms can produce abscesses in almost
any anatomic site. There is a strong tendency for Salmonella to localize in tissues that are
the site of pre-existing disease — different tumors (including hypernephroma), schistosom-
iasis,100 tuberculosis, and nephrolithiasis.102,103 A case of isolated prostatic abscess by Sal-
monella typhimurium was reported by Melzer et al. in P.M .104
Leukopenia of 3000 to 4000 cells/mm3 is characteristic. Urine is usually normal. Or-
ganisms can be recovered by culture from blood (70 to 90%), stool cultures (10 to 15%)
and urine cultures (10 to 15%).

FEVER AND MALIGNANT DISEASE

Fever in neoplasia is controversial. It is commonly accepted that malignant disease is
associated with fever and occasionally fever may be the only presenting feature as, for
instance, in renal carcinoma.18,105,106
The incidence of fever in renal carcinoma is variable:21,29,107,108 11 to 12% according to
Molavi and Weinstein, but only 2.5% according to Berger and Simkoff.27 About 20% of
children with Wilms’ tumor may demonstrate fever at an early stage.
Renal cell carcinoma is called also “ the great imitator” because it may mimic a great
number of diseases with systemic manifestations. Occasionally, fever may be the only
presenting feature. Clinical clues which may suggest the diagnosis include: hematuria (micro-
or macroscopic), weight loss, flank pain and fullness, anemia, and the sudden appearance
of a varicocele associated with lower extremity edema. Sometimes the presenting clinical
manifestations are those of a metastasis (lung, bone, liver, or CNS).
The ESR is always very high. The diagnostic work-up involves the following imaging
procedures: IVP with nephrotomography, ultrasonography, and computerized tomography
(CT).171
It is probable that the tumor itself produces endogenous pyrogen.105 The old idea that
necrosis, ulceration, or infarction in the tumor is a sufficient explanation for fever in ma-
lignant disease has little to support it. Localized abscess or infection,28 obstruction,107 post-
operative complications, sometimes masked by the tumor and not discovered until necropsy,
are common.21,109 110 Neither the character nor the severity of the fever are of any help when
it comes to deciding whether the cause is the malignancy itself or an associated infection.
Development of metastases may be heralded by return of fever.26,111
Cancer patients are susceptible to all the infections that may cause fever in other people.
Fever is an extremely common manifestation of malignant disease.106,107 One should distin-
guish between:

1. Fever related to cancer

2. Fever indirectly related to cancer
3. Fever unrelated to cancer
422 U n ex p la in ed F e ve r

Fever due to cancer per se is exceedingly rare, according to Browder et al.107 only in
5.4% of the cases. Infiltration of the tumor by leukocytes may be important in the patho-
genesis of fever in cancer. Urinary tract infections are responsible most often for fever in
patients with pelvic neoplasms. Other examples of fever indirectly related to cancer are
febrile episodes following transurethral resections or after insertion of catheters. Fever un-
related to cancer is manifested by respiratory infections or parasitization of carcinomas by
Salmonella. Other causes for fever include cerebral, pulmonary and myocardial infarcts,
thrombophlebitis, etc.
Sporadic rare cases of carcinoma manifesting with fever as the main symptom are met
occasionally.106 Nakamura and colleagues112 for instance, published a case of metastatic
prostatic carcinoma whose initial symptoms were fever and back pain. Dawson and Harding113
reported a case of pheochromocytoma presenting as pyrexia of undetermined origin.
Opportunistic fungal infections have become important causes of sickness and death in
immunosuppressed patients. They pose difficult problems of diagnosis and treatment. In-
vasive candidiasis, aspergillosis, and mucomycosis are common autopsy findings. About
half of the patients with invasive candidiasis are leukopenic.114
Herpes viruses are also troublesome opportunistic pathogens infecting patients with
neoplastic diseases especially those receiving chemotherapy. They include herpes simplex,
types 1 and 2, Epstein-Barr virus, varicella zoster virus, and cytomegalovirus. Several of
these pathogens may themselves be oncogenic. Generally, primary or first infections with
these agents tend to be more severe than recrudescent disease. Diagnosis is based on the
search of antibodies. Immunofluorescent staining of vesicle scrapings or tissue specimens
is a rapid and sensitive technique for viral identification. Recently, monoclonal antibodies
with type specificity have been developed. The virus can sometimes be visualized by electron
microscopy of tissue specimens or vesicle fluid.

THE RETROPERITONEUM

PERINEPHRIC ABSCESS
Perinephric abscess is more common than thought of, in spite, or perhaps because of
the widespread use of various antibiotics. The correct diagnosis is still the main problem,
although it becomes much easier since the advent of radionuclide studies, ultrasound and
computerized tomography, each of these having its indication and usefulness.
The first drainage of a perinephric abscess was realized by Germain Colot in 1474 (cited
by Thorley)46 and hundreds of cases were reported since. Nevertheless, only four large series
on this subject have been published. In 1942, Pelvin et al. published 11 cases, in 1967
Salvatierra et al. reported 71 cases, Thorley et al., 46 cases in 1974, and we had 29 patients
in 15 years (1967 to 1982).115117 Mortality is generally high, up to 50% of the cases. In
our series, mortality was limited to 6.8%. Only in one case was the diagnosis made after
death (P.M).
Stones are present in a high percentage of cases (20 out of 29 in our series), and diabetes
is also frequent (42% in our cases). Staphylococcus and Gram-negative bacilli are isolated
with equal frequency.118 High temperature is present in most cases, but some will have only
a subfebrile state. Differential diagnosis is difficult especially with renal malignancy. Female
prevalence is striking. Age varies from 20 to 80. Diagnosis is done in V5 of the cases,
recognized at operation in V4 and only at autopsy in V3. Two percent are bilateral.
Radiological signs are nonspecific and are largely debated by different authors: existence
of a perirenal mass, obliteration of the psoas margin, obliteration of the renal shadow
(Alexander’s sign), displacement of the colon, limitation of diaphragmatic movements,
presence of gas in the excretory system or the retroperitoneum, displacement of the kidney
or a nonfunctioning kidney.23119
 423

The inflammatory reaction around the kidney causes it to lose its normal mobility. This
can be shown by exposing the same X-ray film during both inspiration and expiration. The
abnormal kidney will move either not at all or considerably less than its mate. Films taken
in both the supine and erect positions will demonstrate the renal fixation effect. In our last
nine cases diagnosis was made by computerized tomography and was confirmed by drain-
age.23
Sometimes diagnosis is difficult because of a combination of different pathologies, like
perinephric abscess and xanthogranulomatous pyelonephritis, or perinephric abscess and
carcinoma of the kidney, or like the case reported by Cowley et a l.,120 staghorn calculus in
a renal cell carcinoma combined with xanthogranulomatous pyelonephritis of the same kidney
and a perinephric abscess. This case is important since all these three entities are frequently
confused with each other.
Dysuria, frequency, fever, flank pain, anorexia, weight loss, palpable mass, hematuria,
pyuria, anemia, accelerated sedimentation rate, diabetes, and renal stones can all be found
in any of the three pathologies mentioned above.
Location of the perinephric abscess can be unusual and add to the difficulty of the
diagnosis. One of our cases had a pelvic abscess, retrovesical, due to a pelvic kidney
obstructed by a stone. Sometimes the location is anterior, irritating the peritoneum and
simulating an abdominal process, such as described by Loup.121 Bilateral cases were ob-
served.122
Ultrasound is effective not only in diagnosing the abscess but also in localizing the site
for percutaneous drainage as reported by Elyaderani.123Gallium citrate scans might be helpful
sometimes but are of limited value. The main objection is the need to wait 48 to 72 h after
intravenous injection to obtain maximal target-to-background ratios. In septic patients this
delay is often unacceptable. Also focal activity along a postoperative suture line should not
be ignored. A positive gallium scan provides specific information, whereas a negative scan
does not rule out an abdominal abscess.25 124 Confirmation should always be obtained by
ultrasound or computerized tomography.30117125127

RETROPERITONEAL FIBROSIS
Retroperitoneal fibrosis was first described by Albarran in 1905. Ormond in 1948 es-
tablished idiopathic retroperitoneal fibrosis as a clinical entity. Since then, more than 600
cases were reported. Retroperitoneal fibrosis is a hard fibrous plaque that is often centered
about the sacral promontory and may envelop the ureters, aorta, vena cava, and nerves. It
consists of a deposition of collagen with areas of cellular inflammation representing the
maturation of nonspecific, nonsuppurative inflammation.128129
The process may be idiopathic or secondary. Causes of secondary retroperitoneal fibrosis
include malignancy, injury, infection, drugs and auto-immune process such as vasculitis.130-132
When these are excluded, it may be considered idiopathic.128129
Pain, the most common presenting complaint, is referred to the abdomen or back, testicle,
thigh, or pelvis. It is noncolicky and dull in character. Other complaints include weight loss,
gastrointestinal complaints, fever, and occasionally anuria.133 Laboratory findings include
anemia, elevated blood urea nitrogen and an elevated sedimentation rate.128 Fever in ret-
roperitoneal fibrosis might present as a symptom as reported by Persky and Huus134 and
discussed by Henry et al.130
The intravenous pyelogram remains the most useful screening tool to evaluate the ret-
roperitoneal space.131 It permits the estimation of renal size, position, function, and internal
anatomy. Displacement of the kidney or ureters or bladder deformities are clues to retro-
peritoneal pathology. Tomographic cuts enhance these details. The classical finding on IVP
is bilateral narrowing of the ureters at the level of L5 with medial deviation. Even the most
severely narrowed ureter usually admits a ureteral catheter.132 CT is highly effective because
424 Unexplained Fever

of the abundance of fat present. It generally demonstrates a mass effect with a density in
the range of muscle or solid organs. Ultrasound is less expensive and is more available but
requires skilled personnel for its performance. Retroperitoneal pneumography has essentially
been replaced by the diagnostic techniques discussed above. The diagnosis is ultimately
established by surgical exploration with deep tissue biopsies. Early diagnosis is critically
important to prevent death or permanent damage to organs.129

RETROPERITONEAL TUMORS
Primary retroperitoneal tumors are rare. Eighty-five percent of primary retroperitoneal
tumors are malignant, with lymphomatous tumors being the most common. Most lesions
are unresectable at initial exploration.
Most patients present late in their disease course with large extensive tumors. Many
have had symptoms for 6 months or more prior to soliciting medical care. Pain is the most
common complaint. Other symptoms include weight loss, nausea, constipation, anorexia,
edema, anuria, fever, and varicocele.129
Lymphography is the most accurate single method of detecting retroperitoneal metas-
tases. However, CT provides better definition of the extent of the tumor mass. The use of
both modalities is preferable. Each test is equally effective in diagnosing retroperitoneal
metastases, but neither is accurate enough definitely to differentiate retroperitoneal metastases
from nonseminomatous testicular tumors.129 135 136

THE ADRENAL AS A CAUSE OF FUO

Adrenal cysts are rare pathologic lesions with a reported incidence of about 0.06%.
They are more common in females. They remain asymptomatic until reaching a large size
when vague abdominal or respiratory manifestations are present or they might be infected
and produce a pyogenic cyst associated with a severe febrile illness. There might be also
an adrenal abscess associated with suppurative pyelonephritis and perinephric extension.
Four such cases were published in the literature.137,138
An intravenous urogram will show a normal kidney or a slight distortion of the calyces.
Diagnosis will be made by CT scan or ultrasound which will show the mass arising from
the adrenal gland and demonstrate the cystic (or not cystic) nature of the mass. Selective
renal and adrenal angiography may be helpful in distinguishing a vascular adrenal tumor
from a cyst.138

THE URETERS
Ureteric Malformations
The ureter is seldom a cause of fever, and even less so, a reason for FUO. Yet, some
rare malformations might get infected and cause fever such as a blind-ending bifid ureter,
ureteral diverticula, retrocaval ureter, etc. In these entities, the clinical picture will be of a
recurrent urinary tract infection or a FUO.139141
Culp in 1947140 classified ureteric outpouches into distinct entities. Ureteric diverticula
are frequently incidental findings and do not require treatment. Those which do present
symptoms are usually associated with urinary tract infections or with calculi. Diagnosis
might be delayed. Ultrasound or computerized tomography would help with the diagnosis,
and sometimes a retrograde pyelography will give the clue.

Ureteral Stumps
Diseases of the ureteral stump have received increasing recognition of late. Involvement
of the ureteric stump subsequent to primary renal pelvic and ureteral neoplastic operations
has been reported in ever increasing numbers. Pyogenic ureteral stump, a result of leaving
behind a distal obstructed end of the ureter has also been noted (pyonephrosis, tuberculosis,
low ureteral calculus, or stricture).
 425

The symptoms of an involved ureteral stump may be those of the original condition
requiring the nephrectomy. Pain in the lower abdomen, gait disturbances (psoic irritation),
elevated temperature, pyuria, urinary symptoms, or hematuria will be some of the symptoms.
In a patient with a history of a previous nephrectomy and persistent temperature accompanied
by other symptoms as well, it is important to think of stump involvement. The diagnosis is
made by cytoscopy, ureteral retrograde catheterization, cystography to rule out reflux in the
stump, ultrasound, and computerized tomography.142145

THE GENITAL TRACT

EPIDIDYMO-ORCHITIS
The genital tract is seldom the site of FUO since the symptoms help to localize the
source and because of the exposure of the affected parts to inspection and palpation. Yet,
there are rare cases in which diagnosis is deferred for a long time. The most important cause
is tuberculosis, especially when the clinical picture is of a mild and long-standing or recurrent
epididymitis, whether it is in a teenager or an elderly patient. Sometimes a long standing
epididymitis not responding to conventional therapy will masquerade as a tumor of the testis.
The search for beta subunits and alpha-fetoproteins will give the clue. Sometimes an ex-
ploration is necessary to determine the diagnosis.32 146' 149

NONSPECIFIC URETHRITIS
A chronic urethritis or nonspecific urethritis is generally without fever. Yet, in some
cases of Mycoplasma and Chlamydial infection there will be fever accompanying swelling
and tenderness of the epididymis or testis, as well as that of the prostate (as reported by
Bruce et al.).32,146'148

PROSTATIC ABSCESS
In the majority of cases, prostatic abscesses arise from an acute prostatitis resulting from
an infection of the posterior urethra. However, metastatic abscesses do arise from a wide
number of infectious processes that are staphylococcal in origin. Predisposing factors are
bladder neck outlet obstruction, diabetes mellitus and instrumentation. Symptomatology is
variable, ranging from mild fever and general malaise to a full-blown picture of lower urinary
tract disease, suprapubic or perineal pain and varying degrees of prostatism and urinary
retention associated with fever, chills, sweating, and leukocytosis. The early symptoms,
however, may be entirely constitutional and have little relation to the urinary tract. The
process may be prolonged for weeks before localization is possible.
It is difficult to distinguish acute prostatitis with sepsis from prostatic abscess. The
symptoms are similar and the local findings are ambiguous or nonspecific: the gland is hot,
enlarged, tender, edematous, fluctuating, or indurated. Low-grade fever often suggests the
presence of an abscess. Percutaneous perineal biopsy and aspiration, and cultural material
may afford an early diagnosis and may even result in a resolution of the abscess. Ultrasound
and CT are very helpful.32 150 151

GRANULOMATOUS PROSTATITIS
Granulomatous prostatitis is usually detected as a hard lobe or area of the prostate which
always follows an urinary tract infection. Autoimmune or allergic phenomena have been
implicated in causation of granulomatous prostatitis. Biopsy provides the only accurate means
of diagnosis. There will be a chronic inflammatory process with destruction of normal
glandular architecture by eosinophilic infiltration and central fibroid necrosis with nearby
histiocytes, giant cells and active fibroblasts; small blood vessels show intimal swelling.
The nonspecific granulomatous prostatitis is associated with an allergic history; some insist
426 U n ex p la in ed F e ve r

it is in asthmatic patients. In our experience, there were cases of granulomatous prostatitis

in which no relation could be proven with allergic or asthmatic conditions.32151' 155

PROSTATIC CARCINOMA
Prostatic carcinoma is a common malignancy in the elderly male. Fever as the initial
manifestation of prostatic carcinoma is a very rare occurrence.112,151

FUO DUE TO POSTOPERATIVE COMPLICATIONS

Persistent postoperative temperature, whether immediate or arising later in the course
of the convalescence, when all acute reasons were eliminated, might be perplexing.26 28,96,153
The most common reasons are presented here.

URINOMA OR HEMATOMA
This is a deeply situated collection of urine or infected hematoma, especially after a
renal operation. It is amazing how sometimes big collections will persist without pain,
redness or edema of the skin in the wound area. A good sign is to pass the finger along the
scar and feel for a dimple — this would be the site for drainage. Ultrasound, computed
tomography, and gallium-67 imaging will help the diagnosis.60,156

REMOTE ABSCESSES
Remote abscesses, especially after sepsis and dissemination of germs, should be looked
for. An abdominal abscess usually causes severe distress with fever, leukocytosis, pain, and
toxicity. However, a small but significant proportion of patients with abdominal abscesses
may appear entirely well with no elevated temperature or white blood cell count. Here again,
plain films, computed tomography, ultrasound and gallium-67 will be the clue for diagno-
s j s 60,124,156

FOREIGN BODIES
Foreign bodies, whether forgotten inadvertently during the operation, or placed purposely
like stents, catheters, prosthesis, etc., should be considered as a cause of prolonged fever.

FLARE-UP OF PREVIOUS DISEASE

Sometimes an operation will flare up a previous dormant disease which will be the cause
of the fever, as for example tuberculosis. Cultures and biopsies will solve the diagnostic
problem. Sometimes, a urinary tract tuberculosis might develop after an operation on a
patient with a previously so-called tuberculosis of the spine.96

DRUG INDUCED
A persistent temperature might be drug induced. Sulfonamides, iodides, barbiturates,
nitrofurantoin, and phenolphthalein, as well as many antibiotics are well known to produce
fever. It is advisable in such cases to change the drug or even to stop medication altogether
for 24 to 48 h .106

PELVIC THROMBOPHLEBITIS
Pelvic thrombophlebitis might be the reason for persistent temperature in patients after
pelvic operations. Schulman and Zatuchmi proposed the administration of heparin as a
diagnostic test.157

SPINAL OSTEOMYELITIS
The association between genitourinary surgery and the subsequent development of spinal
osteomyelitis is well documented. The frequency of vertebral involvement in urinary tract
 427

infection varies from 10 to 70%. Prostatectomy or pyelolithotomy, and especially operations

on pyonephrotic kidneys might result in vertebral osteomyelitis some months after operation.
Spinal osteomyelitis affects the vascular metaphyseal region beneath the anterior longitudinal
ligament, and then spreads across the disc via the nutrient vessels to involve adjacent vertebral
bodies. Unlike malignant deposits, infective lesions destroy the disc space. Lumbar vertebrae
are most often involved; T8_9 to L34 lesions have been reported. It occurs mainly in adults
with a mean age between 60 and 70 years. Fever, back pain, and stiffness are the major
findings in vertebral osteomyelitis. The first modifications seen by radiology do not appear
before 2 to 8 weeks of evolution of the disease. Early technetium-99m bone scans are of
great diagnostic help.158162

FUO IN HEMODIALYSIS AND TRANSPLANT RECIPIENTS

Infectious diseases remain a major cause of morbidity and mortality in renal transplant
recipients. Fever is frequently the only early clinical sign of allograft rejection. Etiologies
of fever in these patients are however both diverse and often obscure at the onset.
Geographic considerations are important. Coccidioidomycosis, histoplasmosis, tuber-
culosis, and parasitic infections will be relatively more important as causes of fever in areas
in which these diseases are endemic. Not only are differences to be expected among transplant
centers, but also differences may occur over time in the same center.
Etiologies of fever in the hemodialysis patients are as follows: infections (endogenous),
septic pulmonary emboli, bacterial endocarditis, post transfusion, pyrogenic reaction, re-
jection (if transplanted) or other undetermined causes. In 12% of cases, the patient is unaware
of the temperature. Only in rare cases there are chills and high temperature. The clinical
picture will be different in postoperative dialysis or postransplantation dialysis, in patients
possessing their kidneys or in anephric patients. Postoperative patients are more sensitive
to pyrogenic substances, especially those after transplantation.163166
A new aspect has emerged lately with the change in mode of treatment. Staphylococcus
epidermidis became an important cause of peritonitis in patients undergoing chronic am-
bulatory peritoneal dialysis.5167
The advanced states of uremia associated with both acute and chronic renal failure can
be accompanied by an inability to develop fever. When this state is at least partially corrected
by dialysis, the febrile response to infection returns toward normal.
The operative wound of a renal transplant recipient is usually vulnerable to infection.168
Patients are frequently anemic and hypoalbuminemic. Host defenses have been severely
compromised by chronic renal failure and are further impaired during the postoperative
period by the administration of immunosuppressive drugs.
Hamburger and colleagues169 stress the fact that there exists an unexplained fever, well
tolerated, irregular or en plateau, moderate or high, sometimes with daily spikes of 3 to 4
h duration, always with the same patient. It appears generally in the first months post
transplantation in patients who received high doses of corticosteroids and in whom there
was a reduction in the daily doses. The fever disappears if the doses of prednisone are
augmented.
Peterson et al.170 stress that the most important cause of fever in the first 4 months after
transplantation is a viral infection, CMV (cytomegalovirus) being the most common agent.
On the other hand, fever developing more than one year after transplantation is due to
bacterial and fungal infections. Febrile episodes associated with CMV infection alone or in
conjunction with rejection are rarely fatal. This is in marked contrast to CMV infections
complicated by other systemic infections in which a rate of death of 83% is reported.
Since serologic and culture confirmation of the diagnosis of overt CMV disease may
take several weeks, the clinician must early on rely on a clinical diagnosis. Complete blood
428 U nex p la in ed F e ve r

count, platelet count and serum creatinine are determined daily. Chest roentgenogram and
urine specimens for bacterial and fungal cultures are taken every other day. Glutamic-
oxaloacetic transaminase, alkaline phosphatase, bilirubin, and amylase levels are determined
twice a week, as well as electrocardiogram, urine for viral culture and serum for cytomeg-
alovirus complement-fixing and indirect immunofluorescence antibody tests. Blood cultures
for bacteria, fungi, and viruses are obtained twice in 24 h. Other diagnostic tests such as
allograft, bone marrow or liver biopsy, lumbar puncture, and bronchoscopy are performed
as clinically indicated.

REFERENCES
1. Bryan, C. S. and Reynolds, K. L., Community acquired bacteremic UTI: epidemiology and outcome, J.
Urol, 132, 490, 1984.
2. Bryan, C. S. and Reynolds, K. L., Hospital acquired bacteremic UTI: epidemiology and outcome, J.
Urol, 132, 494, 1984.
3. Busch, R. and Huland, H., Correlation of symptoms and results of direct bacterial localization in patients
with urinary tract infections, J. Urol, 132, 282, 1984.
4. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report of 100 cases, Medicine, 40, 1,
1961.
5. Geddes, A. M., Recently recognized infections, Med. Int., 2, 130, 1985.
6. Howard, P. H., Jr. and Hardin, W. J., The role of surgery in fever of U.O., Surg. Clin. North Am.,
52, 397, 1972.
7. Glassock, R. J. and Brenner, B. M., The major glomerulopathies, in Principles of Internal Medicine,
9th ed., Harrison, T. R., Ed., McGraw-Hill, New York, 1980, 1311.
8. Lagrue, G. and Laurent, J., Epidemiologie des nephropathies glomérulaires primitives, Presse Med., 13,
255, 1984.
9. Simon, P., Ang, K. S., Bavay, P., Cloup, C., Mignard, J. P., and Ramee, M. P., Glomérulonéphrite
à immunoglobulines A, Presse Med., 13, 257, 1984.
10. Markovic, B., Néphropathie endémique des Balkans, Nouv. Presse Med., 9, 3263, 1980.
11. Riou, B., Richard, Ch., Rimailho, A., Bottineau, G., Trincard, M. D., and Auzepy, Ph., Néphrite
interstitielle aiguë immunoallérgique à la noramidopyrine, Presse Med., 13, 1377, 1984.
12. Scully, R. E., Mark, E. J., and McNeely, B. U., Weekly clinicopathological exercises, N. Engl. J.
Med., 305, 1334, 1981.
13. Scully, R. E., Mark, E. J., and McNeely, B. U., Weekly clinicopathological exercises, N. Engl. J.
Med., 306, 975, 1982.
14. Scully, R. E., Mark, E. J., and McNeely, B. U., Weekly clinicopathological exercises, N. Engl. J.
Med., 308, 1343, 1983.
15. Scully, R. E., Mark, E. J., and McNeely, B. U., Weekly clinocopathological exercises, N. Engl. J.
Med., 309, 970, 1983.
16. Asbach, H. W. and Melekos, M., Fieber in der Urologie, Z. Allg. Med., 57, 2035, 1981.
17. Kass, E. H., Progress in Pyelonephritis, F. A. David, Philadelphia, 1965.
18. Dufour, A., Les fièvres urinaires, Rev. Prat., 21, 4359, 1971.
19. Flocks, R. H., Urinary tract infection, Med. Clin. North Am., 54, 397, 1979.
20. Klein, L. A., Koyle, M., and Berg, S., The emergency management of patients with ureteral calculi and
fever, J. Urol, 129, 938, 1983.
21. Larson, E. B., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow-up of 105 cases 1970— 1980, Medicine, 61, 269, 1982.
22. Petersdorf, R. G., Chills and fever, in Principles of Internal Medicine, 9th ed., Harrison, T. R., Ed.,
McGraw-Hill, New York, 1980, 59.
23. Popky, G. L. and Pollack, H. M., Radiological evaluation of patients with urinary tract infection, in
Urinary Tract Infection and Its Management, Kaye, D., Ed., C. V. Mosby, St. Louis, 1972.
24. Esposito, A. L. and Gleckman, R. A., A diagnostic approach to the adult with fever of unknown origin,
Arch. Intern. Med., 139, 575, 1979.
25. Forgacs, P., Wahner, H. W ., Keys, T. F., and Van Scoy, R. E., Gallium scanning for the detection
of abdominal abscesses, Am. J. Med., 65, 949, 1978.
26. Jacoby, G. A. and Swartz, M. N., Fever of undetermined origin, N. Engl. J. Med., 289, 1407, 1973.
 429

27. Molavi, A. and Weinstein, L., Persistent perplexing pyrexia: some comments on etiology and diagnosis,
Med. Clin. North Am., 54, 379, 1970.
28. Cross, A. S. and Tramont, E. C., Fevers of unknown origin, Military Med., 141, 761, 1976.
29. Isaac, B. and Kernbaum, S., Fièvres prolongées inexpliquées, Nouv. Presse Med., 10, 3311, 1981.
30. McNeil, B. J., Sanders, R., Alderson, P. O., Hessel, S. J., Finberg, H., Siegelman, S. S., Adams,
D. F., and Abrams, H. L., A prospective study of computed tomography, ultrasound and Gallium imaging
in patients with fever, Radiology, 139, 647, 1981.
31. Morehouse, H. T., Weiner, S. N., and Hoffman, J. C., Imaging in inflammatory disease of the kidney,
A. J. R., 143, 135, 1984.
32. Stamey, T. A., Pathogenesis and Treatment of U. T. I., Williams & Wilkins, Baltimore, 1980.
33. Anderson, K. A. and McAninch, J. W., Renal abscesses: classification and review of 40 cases, Urology,
16, 334, 1980.
34. Goldman, S. M., Minkin, S. D., Naraval, D. C., Diamond, A .. B., Pion, S. J., Meringoff, B. N.,
Sidh, S. M., Sanders, R. C., and Cohen, S. P., Renal carbuncle: the use of ultrasound in its diagnosis
and treatment, J. Urol., 118, 525, 1977.
35. Hoverman, I. V., Gentry, L. O., Jones, D. W ., and Guerriero, W. G., Internal abscess: report of 14
cases, Arch. Intern. Med., 140, 914, 1980.
36. Rosenfield, A. T., Glickman, M. E., Taylor, K. J. W., Crade, M., and Hodson, J., Acute focal
bacterial nephritis (acute lobar nephritis), Radiology, 132, 553, 1979.
37. Funston, M. R., Fisher, K. S., Van Blerk, P. J. P., and Bortz, J. H., Acute focal bacterial nephritis
or renal abscess? A sonographic diagnosis, Br. J. Urol., 54, 461, 1982.
38. Himmelfarb, E. H., Rabinowitz, J. G., Kinkhabwala, M. N., and Becker, J. A., The roentgen features
of renal carbuncle, J. Urol., 108, 846, 1972.
39. Rao, M. M., Vaska, P. H., Albertyn, L. A., and Mathew, T. H., Intrarenal abscess in a transplant
organ, J. Urol., 130, 971, 1983.
40. Mendez, G., Isikoff, M. B., and Morillo, G., The role of computed tomography in the diagnosis of renal
and perirenal abscesses, J. Urol., 122, 582, 1979.
41. Rabinowitz, J. G., Kinkhabwala, M. N., and Robinson, T., Acute renal carbuncle, Am. J. Roentgenol.,
116, 740, 1972.
42. Brugh, R., Gooneratne, N. S., Rittenberg, G. M., and Rous, S. N., Gallium-67 scanning and con-
servative treatment in acute inflammatory lesions of the renal cortex, J. Urol., 121, 232, 1979.
43. Carson, C. C., Ill, Renal carbuncle and perinephric abscess, in Urologie Surgery, 3rd ed., Glenn, J. F.,
Ed., Lippincott, Philadelphia, 1983, 207.
44. Costello, A., Blandy, J., and Hateky, W., Percutaneous aspiration of renal cortical abscess, Urology,
21, 201, 1983.
45. Salvatierra, O., Jr., Bucklew, W. B., and Morrow, J. W., Peripheral abscess: a report of 71 cases, J.
Urol., 98, 296, 1967.
46. Thorley, J. D., Jones, S. R., and Sanford, J. P., Perinephric abscess, Medicine, 53, 441, 1974.
47. Nesbit, R. N. and Dick, V. S., Acute Staphylococcal infection of the kidney, J. Urol., 43, 623, 1940.
48. Welch, N. M. and Prather, G. C., Renal carbuncle (Staphylococcal abscess of the kidney), J. Urol., 62,
646, 1949.
49. Finn, D. J., Palestrant, A. M., and De Wolf, W. C., Successful percutaneous management of renal
abscess, J. Urol., 127, 425, 1982.
50. Pedersen, J. F., Hancke, S., and Kristensen, J. K., Renal carbuncle: antibiotic therapy governed by
ultrasonically guided aspiration, J. Urol., 109, 111, 1973.
51. Kaver, I., Merimsky, E., Shilo, R., and Braf, Z. F., Conservative approach in treating acute renal
carbuncle, Isr. J. Med. Sci., 21, 157, 1985.
52. Schiff, M., Glickman, M., Weiss, R. M., Ahren, M. J., Touloukian, R. J., Lytton, B., and Andriole,
V. T., Antibiotic treatment of renal carbuncle, Ann. Intern. Med., 87, 305, 1977.
53. Timmons, J. W. and Perlmutter, A. D., Renal abscess: a changing concept, J. Urol., 115, 299, 1976.
54. Konetschnik,F., Goldin, A. R., and Marshall, V. R., Management of acute renal carbuncle, Br. J.
Urol., 54, 467, 1982.
55. Dairiki Shortliffe, L. M. and Stamey, T. A., Infections of the Urinary Tract: Introduction and General
Principles in Urology, 5th ed., Campbell, M. F., Ed., W. B. Saunders, Philadelphia, 1986, 764.
56. Coleman, B. G., Arger, P. H., Mulhern, C. B., Jr., Pollack, H. M., and Banner, M. P., Pyonephrosis:
sonography in the diagnosis and management, A. J. R., 137, 939, 1981.
57. Yoder, I. C., Pftster, R. C., Lindfors, K. K., and Newhouse, J. H., Pyonephrosis: imaging and
intervention, A. J. R., 141, 735, 1983.
58. Kirchner, F. K. and Turner, B. I., Bacteroides ruminicola pyonephrosis, Br. J. Urol., 54, 432, 1982.
59. Bartelet, J. G. and Gorbach, S. L., Anaerobic bacteria in suppurative infections of the male genito-
urinary system, J. Urol., 125, 376, 1981.
430 Unexplained Fever

60. Lizza, E. F., Elyaderani, M. K., Foshag, L. J., Boyd, C. B., and Belis, J. A., Chronic fistula developing
2 years after nephrectomy for pyonephrosis, J. Urol., 129, 792, 1983.
61. Schlagenhaufer, F., Uber eigentuemliche Staphylomykosen der Nieren und des pararenalen Bindegewebes,
Frankfurt Ztsch. Pathol., 19, 139, 1916.
62. Malek, R. S., Greene, L. F., De Weerd, J. H., and Farrow, G. M., Xanthogranulomatous pyelonephritis,
Br. J. Urol., 44, 296, 1972.
63. Solomon, A., Braf, Z., Papo, J., and Merimsky, E., Computerized tomography in xanthogranulomatous
pyelonephritis,/. Urol., 130, 323, 1983.
64. Subramanyam, B.R., Megibow, A. J., Raghavendra, B. N., and Bosniak, M. A., Diffuse xantho-
granulomatous pyelonephritis: analysis by computed tomography and sonography, Urol. Rad., 4, 5, 1982.
65. Merimsky, E., Canetti, R., and Firstater, M., Xanthogranulomatous pyelonephritis, Harefuah, 96, 231,
1979.
66. Merimsky, E., Papo, J., and Firstater, M., Xanthogranulomatous pyelonephritis mimicking infected
renal cysts, Int. Surg., 66, 273, 1981.
67. Friedenberg, M. J. and Spjut, H. J., Xanthogranulomatous pyelonephritis, Am. J. Roentgent. Rad. Ther.,
90, 97, 1963.
68. Salmon, R. B. and Koehler, P. R., Angiography in renal and perirenal inflammatory masses, Radiology,
88, 9, 1967.
69. Tsung, S. H. and Lin, J. I., Stone like calcification of hypernephroma, Urology, 22, 278, 1983.
70. Hooper, R. G., Kempson, R. L., and Schlegel, J. U., Xanthogranulomatous pyelonephritis, /. Urol.,
88, 585, 1962.
71. Lizza, E. F., Elyaderani, M. K., and Belis, J. A., Atypical presentation of xanthogranulomatous pye-
lonephritis: diagnosis by ultrasonography and fine needle aspiration biopsy, /. Urol., 132, 95, 1984.
72. Tonelli, S. and Gianotti, P., On the nature of xanthogranulomatous pyelonephritis, Urol. Int., 24, 330,
1969.
73. Winn, R. E. and Hartstein, A. I., Anaerobic bacterial infection and xanthogranulomatous pyelonephritis,
a case report, J. Urol., 128, 567, 1982.
74. Malek, R. S. and Elder, J. S., Xanthogranulomatous pyelonephritis: a critical analysis of 26 cases and
of the literature, J. Urol., 119, 589, 1978.
75. Danielli, L., Zaidel, L., Raviv, U., and Beyar, H., Xanthogranulomatous pyelonephritis in an infant, J.
Urol., 127, 304, 1982.
76. Klugo, R. C., Anderson, J. A., Reid, R., Powell, I., and Cerney, J. C., Xanthogranulomatous pye-
lonephritis in children, /. Urol., 117, 350, 1976.
77. Yazaki, T., Ishikawa, S., Ogawa, Y., Takahashi, S., Nemoto, S., Rinsho, K., Kanoh, S., and
Kitagawa, R., Xanthogranulomatous pyelonephritis in childhood: case report and review of English and
Japanese literature, J. Urol., 127, 80, 1982.
78. Deliveliotis, A., Zoros, S., and Varkarakis, M., Suppuration of a solitary cyst of the kidney, Br. J.
Urol., 39, 472, 1967.
79. Mogowan, A. J. and Ippolito, J. J., Infected solitary renal cyst, J. Urol., 93, 559, 1965.
80. Limjoco, U. R. and Strauch, A. E., Infected solitary cyst of the kidney: report of a case and review of
the literature, J. Urol., 96, 625, 1966.
81. Green, M. G., King, D. L., and Casarella, W. J., A reappraisal of sonolucent renal masses, Radiology,
12, 163, 1976.
82. Rosenfeld, A. J., Genito-urinary Ultrasound, Churchill Livingstone, London, 1979.
83. Mindell, H. J., Percutaneous renal cyst puncture: unusual results, J. Urol., 114, 332, 1975.
84. Morris, A. D. P. and Evans, A. F., Percutaneous aspiration and drainage of an infected renal cyst, Br.
J. Urol., 56, 227, 1984.
85. Stables, D. P. and Jackson, R. S., Management of an infected simple renal cyst by percutaneous aspiration,
Br. J. Rad., 47, 290, 1974.
86. Finlay, D. B. L., Lowe, J. S., and Kaur, K., Perforation of a suppurative solitary renal cyst, Br. J.
Urol., 68, 585, 1981.
87. Michaeli, J., Mogle, P., Perlberg, S., Heiman, S., and Caine, M., Emphysematous pyelonephritis, J.
Urol., 131, 203, 1984.
88. Kelly, H. A. and MacCallum, W. G., Pneumaturia, JAMA, 31, 375, 1898.
89. Schultz, E. H. and Klorfein, E. H., Emphysematous pyelonephritis, 87, 762, 1962.
90. Lowe, F. C. and Walther, J. M., Case profile: emphysematous pyelonephritis, Urology, 28, 532, 1986.
91. Kim, D. S., Woesner, M. E., Howard, T. F. and Olson, L. K., Emphysematous pyelonephritis dem-
onstrated by computed tomography, A. J. R., 132, 287, 1979.
92. Lautin, E. M., Gordon, P. M., Friedman, A. C., Dourmashkin, L., and Fromowitz, F., Emphyse-
matous pyelonephritis: optimal diagnosis and treatment, Urol. Radiol., 1, 93, 1979.
93. Graham, J. N., Case profile: tomography in emphysematous pyelonephritis, Urology, 27, 277, 1986.
 431

94. Johnson, J. R., Ireton, R. C., and Lipsky, B. A., Emphysematous pyelonephritis caused by Candida
albicans, J. Urol., 136, 80, 1986.
95. Christensen, W. I., Genitourinary tuberculosis: review of 102 cases, Medicine, 53, 377, 1974.
96. Laudet, J., Hiesse, C., Lucsko, M., Le Duc, A., Beaufils, H., Barbagelatta, M., and Morin, M.,
Néphropathie granulomateuse d’origine tuberculeuse révélée par une fièvre au long cours, Nouv. Presse
Med., 9, 3259, 1980.
97. Schaffer, R., Becker, J. A. and Goodman, J., Sonography of tuberculous kidney, Urology, 22, 209,
1983.
98. Ferrie, B. G. and Rundle, J. S. H,, Tuberculous epididymo-orchitis: a review of 20 cases, Br. J. Urol.,
55, 437, 1983.
99. Stein, A. L. and Miller, D. B., Tuberculous epididymo-orchitis: a case report, J. Urol., 129, 613, 1983.
100. Miller, W. S. and Floyed, T. M., Chronic urinary Salmonella carriers, Lancet, 1, 343, 1954.
101. Domart, A., Gentilini, M., and Gaxotte, Ph., Fièvres de Safari — a propos de 18 observations d’invasion
bilharzienne, Sem. Hop. Paris, 45, 627, 1969.
102. Hook, E. W. and Guerrant, R. L., Salmonella infections, Principles of Internal Medicine, 8th ed.,
Harrison, T. R., Ed., McGraw-Hill, New York, 1977, 842.
103. Scott, M. B. and Cosgrove, M. D., Salmonella infection and the genito-urinary system, J. Urol., 118,
64, 1977.
104. Melzer, M., Altmann, G., and Rakowszcyk, M., Urinary tract infection due to Salmonella, Harefuah,
65, 395, 1965.
105. Cronin, R.E., Kaehny, W. D., Miller, P. D., Stables, D. P., Gabow, P. A., Ostroy, P. R., and
Schrier, R. W., Renal cell carcinoma: unusual systemic manifestations, Medicine, 55, 291, 1976.
106. Rodriguez, V., Burgess, M., and Bodey, G. P., Management of fever of unknown origin in patients
with neoplasm and neutropenia, Cancer, 32, 1007, 1973.
107. Browder, A. A., Huff, J. W., and Petersdorf, R. G., The significance of fever in neoplastic disease,
Ann. Intern. Med., 55, 932, 1961.
108. Wood, M. J., (Editorial) Symptoms in Medicine: Fever, Medicine, 1, 24, 1981.
109. Editorial, Fever in malignant disease, Br. Med. J., 1, 591, 1974.
110. Scully, R. E., Galdabini, J. J., and McNeely, B. U., Weekly clinicopathological exercises, N. Engl. J.
Med., 304, 657, 1981.
111. Strum, W. B., Remote recurrence of renal cell carcinoma, Urology, 23, 68, 1984.
112. Nakamura, J., Papac, R., and Ward, R., Fever as initial manifestation of prostatic carcinoma, Urology,
19, 72, 1982.
113. Dawson, J. and Harding, L. K., Pheochromocytoma presenting as pyrexia of undetermined origin:
diagnosis using Gallium 67, Br. Med. J., 284, 1164, 1982.
114. Gold, J. W. M., Opportunistic fungal infections in patients with neoplastic disease, Am. J. Med., 76,
458, 1984.
115. Merimsky, E. and Feldman, C., Perinephric abscess: report of 19 cases, Int. Surg. 66, 79, 1981.
116. Merimsky, E., Ashner, M., and Feldman, C., Formation rétropéritonéale de gaz, signe révélateur de
l’abcès périnéphrétique, J. d'Urol., 88, 171, 1982.
117. Merinsky, E., Kaver, L, Papo, J., and Ben Arzi, F., Apport de la tomodensitométrie dans le diagnostic
des phlegmons périnéphrétiques, J. d'Urol., 89, 21, 1983.
118. Khauli, B. B., Kalash, S., and Young, J. D., Jr., Torulopsis glabrata perinephric abscess, J. Urol.,
130, 968, 1983.
119. Parks, R. E., The radiographic diagnosis of perinephric abscess, J. Urol., 64, 555, 1950.
120. Cowley, J. P., Connolly, C. E., Hehir, M., and O’Beirn, S. F., Renal carcinoma with staghorn calculus,
perinephric abscess and xanthogranulomatous pyelonephritis in same kidney. Subcutaneous abscess of thigh
as initial presentation, Urology, 21, 635, 1983.
121. Loup, J., Phlegmon périnéphritique antérieur, Ann Urol., 13, 39, 1979.
122. Pastor, E. G., Bilateral perinephric abscess, Urol. Cutan. Rev., 47, 20, 1943.
123. Elyaderani, M. K., Subramanian, V. P., and Burgess, J. E., Diagnosis and percutaneous drainage of
perinephric abscess by ultrasound and fluoroscopy, J. Urol., 125, 405, 1981.
124. Habibian, M. R., Staab, E. V., and Matthews, H. A., Gallium citrate Ga 67 scans in febrile patients,
JAMA, 233, 1073, 1975.
125. Haaga, J. R., Alfidi, R. J., Havrilla, T. R., Cooperman, A. M., Seidelmann, F.E., Reich, N. E.,
Weinstein, A. J., and Meaney, T. F., CT detection and aspiration of abdominal abscesses, Am. J.
Roentgenol., 128, 465, 1977.
126. Miossec, J. C., Guerin, J., and Morin, P. P., Intérêt de l’échotomographie dans l’exploration des
collections liquidiennes rénales, Ann. Radiol., 23, 573, 1980.
127. Quinn, M. J., Sheedy, P. F., II, Stephens, D. H., and Hattery, R. R., Computed tomography of the
abdomen in evaluation of patients with fever of unknown origin, Radiology, 136, 407, 1980.
128. Ormond, J. K., Idiopathic retroperitoneal fibrosis: an established clinical entity, JAMA, 174, 1561, 1960.
432 Unexplained Fever

129. Wheatley, J. K., Retroperitoneal fibrosis, tumors and cysts, in Urologie Surgery, 3rd ed., Glenn, J. F.,
Ed., Lippincott, Philadelphia, 1983.
130. Henry, L. G., Doust, B., Korns, M. E., and Bernhand, V. M., Abdominal aortic aneurysm and
retroperitoneal fibrosis: ultrasonographic diagnosis and treatment, Arch. Surg., 113, 1456, 1978.
131. Mitchinson, M. J., Some clinical aspects of idiopathic retroperitoneal fibrosis, Br. J. Surg., 59, 58, 1972.
132. Simon, H. B. and Nygaard, K. K., Ureteral obstruction due to idiopathic retroperitoneal fibrosis, JAMA,
174, 1569, 1969.
133. Byrd, W. E., Hunt, R. E., and Burgess, R., Retroperitoneal fibrosis as a cause of fever of undetermined
origin, West. J. Med., 134, 357, 1981.
134. Persky, L. and Huus, J. C., Atypical manifestation of retroperitoneal fibrosis, J. Urol., I l l , 340, 1974.
135. Ehrlichman, R. J., Kaufman, S. L., Siegelman, S. S., Trump, D. L., and Walsh, P. C., Computerized
tomography and lymphangiography in staging testis tumors, J. Urol., 126, 179, 1981.
136. Thomas, J. L., Bernardino, M. E., and Bracken, R. B., Staging of testicular carcinoma: comparison
of CT and lymphangiography, A. J. R., 137, 991, 1981.
137. Okafo, B. A., Nickel, C., and Morales, A., Pyogenic cyst of adrenal gland, Urology, 21, 619, 1983.
138. Suri, S., Agra walla, M. L., Mitra, S. K., and Bhagwat, A. G., Adrenal abscess in a neonate presenting
as a renal neoplasm, Br. J. Urol., 54, 565, 1982.
139. Barrett, D. M. and Malek, R. S., Ureteral diverticulum, J. Urol., 114, 33, 1975.
140. Culp, O. S., Ureteral diverticulum: classification of the literature and report of an authentic case, J. Urol.,
58, 309, 1947.
141. Wespes, E., De Sy, W., Thiry, A. J., and Schulman, C. C., Blind ending bifid and double ureter,
Urology, 21, 586, 1983.
142. Amar, A. D., Surgical alternatives to excision of refluxing ureteral stump, Br. J. Urol., 43, 297, 1971.
143. Bergman, H. and Hotchkiss, R. S., The ureteral stump, in The Ureter, 2nd ed., Bergman, H., Ed.,
Springer-Verlag, New York, 1981.
144. Ljunggren, E., Complication caused by the stump of the ureter after nephrectomy, J. Urol., 59, 179,
1948.
145. Rieser, C., A consideration of the ureteral stump subsequent to nephrectomy, J. Urol., 64, 275, 1950.
146. Bonissol, Ch., Pathogenie des mycoplasmes et des chlamydies, J. d'Urol., 88, 231, 1982.
147. Bruce, A. W., Chadwick, P., Willett, W. S. and O’Shaughnessy, M., The role of chlamydiae in
genitourinary disease, J. Urol., 126, 625, 1981.
148. Schächter, J., Chlamydial infections, N. Engl. J. Med., 298, 428, 1978.
149. Scheibel, J. H., Andersen, J. T., Brandenhoff, P., Geerdsen, J. P., Bay-Nielsen, A., Schultz, B. A.,
and Walter, S., Chlamydia trachomatis in acute epididymitis, Scand. J. Urol. Nephrol., 17, 47, 1983.
150. Couch, A. D., Prostatic Abscess in Urologie Surgery, 3rd ed., Glenn, J. F., Ed., Lippincott, Philadelphia,
1983, 991.
151. Tannenbaum, M., Urologie Pathology: The Prostate, Lea and Febiger, Philadelphia, 1977.
152. Green, L. F., Granulomatous prostatis, in Current Urologie Therapy, Kaufman, J. J., Ed., W. B. Saunders,
Philadelphia, 1980, 290.
153. Thompson, I. M. and Montie, J. E., Complications of transabdominal prostatectomy, in Complications
of Urologie Surgery, Smith, R. B. and Skinner, D. G., Eds., W. B. Saunders, Philadelphia, 1976, 272.
154. Hedelin, H., Johansson, S., and Nilsson, S., Focal prostatic granulomas, Scand. Urol. Nephrol., 15,
193, 1981.
155. Towfighi, J., Sadeghee, S., Wheeler, J. E., and Enterline, H. T., Granulomatous prostatis with emphasis
on the eosinophilic variety, A. J. C. P., 58, 630, 1972.
156. Littenberg, R. L., Taketa, R. M., Alazraki, N. P., Halpern, S. E., and Ashburn, W. L., Gallium 67
for localization of septic lesions, Ann. Intern. Med., 79, 403, 1973.
157. Schulman, H. and Zatuchni, G., Pelvic thrombophlebitis in puerperal and postoperative gynecologic
patient. Obscure fever as an indication for anticoagulant therapy, Am. J. Obstet. Gynecol., 90, 1293, 1964.
158. Dolfin, D., Barkin, J., Arenson, A. M., and Herschorn, S., Psoas abscess after operation on lumbar
spine, Urology, 21, 544, 1983.
159. Finsterbusch, A. and Fluman, J., Osteomyelitis of the vertebrae in infection of the urinary tract, Harefuah,
87, 60, 1974.
160. Hale, J. E. and Aichroth, P., Vertebral osteomyelitis: a complication of urological surgery, Br. J. Surg.,
61, 867, 1974.
161. Leigh, T. F., Kelly, R. P., and Weens, S., Spinal osteomyelitis associated with urinary tract infections,
Radiology, 1955, 65, 334, 1955.
162. Shmueli, G., Herold, Z., and Fano, M., Osteomyelitis of the vertebrae, Harefuah, 83, 281, 1970.
163. Dobkin, J. F., Miller, M. H., and Steigbigel, N. H., Septicemia in patients on chronic hemodialysis,
Ann. Intern. Med., 88, 28, 1978.
164. Dutz, W., Fabian, R., and Hiller, R., Febrile Reaktionen wahrend der hamodialyse, Z. Urol., 66, 683,
1973.
 433

165. Lees, J. A., Falk, R. M., Stone, W. J., and McDougal, W. S., Pyocystis, pyonephrosis and perinephric
abscess in end stage renal disease, J. Urol., 134, 716, 1985.
166. Rault, R., Symptomatic urinary tract infections in patients on maintenance hemodialysis, Nephron, 37,
82, 1984.
167. Brahm, M., A simple diagnostic method of peritonitis in patients on CAPD, Scand. J. Urol. Nephrol.,
18, 223, 1984.
168. Banowsky, L. H. W., Surgical complications of renal transplantation, in Urologie Surgery, 3rd ed., Glenn,
J.F., Ed., Lippincott, Philadelphia, 1983, 375.
169. Hamburger, J., Crosnier, J., Dormont, J., and Bach, J. F., La transplantation renale — Theorie et
pratique, Flammarion Medecine-Sciences, Paris, 1971.
170. Peterson, P. K., Balfour, H. H., Fryd, D. S., Ferguson, R. M., and Simmons, R. L., Fever in renal
transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota
Hospital, Am. J. Med., 71, 345, 1981.
171. Rawlins, M. D., Luff, R. H., and Cranston, W. L, Pyrexia in renal carcinoma, Lancet, 1, 1371, 1970.
 435

Chapter 28

UNEXPLAINED FEVER IN GYNECOLOGY

J. R. Cohen, M. Burke, and A. Ber

INTRODUCTION
Febrile diseases of the female genital tract are a frequent clinical problem which may
be associated with significant morbidity. In general, fever usually accompanies typical
gynecological symptoms such as pain, discharge, and bleeding, and the diagnosis is straight-
forward. However, in unusual situations, fever may be a major or prominent manifestation
and the patient may present with unexplained fever. Fever in obstetric and gynecologic
patients may be due to infection but, not infrequently, the cause is noninfectious and obscure.1
In this and the following chapters we will review the important clinical entities that may
result in unexplained fever in the pregnant and nonpregnant female.

OVULATION FEVER
Some women have a low-grade unexplained fever which persists for 2 weeks each month
prior to menstruation and is related to ovulation. In these cases, the only investigation
required is to record the temperature chart for a period of 3 months.2

LOWER GENITAL TRACT INFECTION

The major causes of infection of the vulva, cervix, vagina, and urinary tract in women
may have overlapping symptoms, such as vulvar irritation, dysuria, and dyspareunia. Fever
is the less frequent symptom in these infections. However, fever as a prominent symptom
can occur occasionally in cases of acute herpes simplex genital infections.

GENITAL HERPES SIMPLEX3 5

Following a short incubation period, the patient usually presents with fever, malaise,
and inguinal lymphadenopathy. The clinical presentation differs, depending upon the location
of the lesions. Itching, tension, and pain may antedate the development of vesicles that
rapidly appear on an erythematous base containing clear exudate. On examination, the lesion
consists of groups of three to ten vesicles and can be seen on the vulva, vagina, cervix, and
perineal region. The vesicles usually heal without scarring after 2 weeks.
In recurrent exacerbations, the symptoms are milder and are of shorter duration. In many
cases, the patient herself may notice the lesions. Diagnosis may be confirmed by isolation
of the tissue culture. The specimens of choice are the vesicular fluid and scrapings collected
from the base of the lesion with a swab. Complement fixing and neutralizing antibodies
appear within 1 week of onset of infection.6 Failure to identify antibodies within 3 weeks
is evidence against herpes virus infection.

PELVIC INFLAMMATORY DISEASE AND RELATED

DISORDERS
Pelvic inflammatory disease (PID) refers to a variety of acute and chronic infections of
the female pelvis. It may be caused by diverse organisms and not infrequently is polymi-
436 U n ex p la in ed F e ve r

crobial.7 8 The disease may be acquired in a number of ways, such as sexual contact, blood-
borne, and nocosomially following surgery. PID has a wide clinical spectrum, ranging from
an almost asymptomatic condition to severe pelvic pain and fever, and on to peritonitis.
Although fever is not usually the most prominent symptom, some patients may present with
unexplained fever.9 Laparoscopically confirmed cases of PID indicate that only about 40%
of patients have fever.10 Symptoms and signs are variable and relatively nonspecific. Patients
with serious infections may present with minimal manifestations.
Diagnosis may be elusive and the physician should search for the following features:

1. Abdominal pain — acute onset of lower abdominal or pelvic pain, usually bilateral
but occasionally unilateral; sometimes a feeling of pelvic pressure with low back pain
radiating to the legs; pain usually appearing after menstruation
2. Vaginal discharge — often purulent and four-smelling
3. Nausea, sometimes with vomiting
4. Fever, usually exceeding 38.5°C, frequently accompanied by chills and tachycardia
5. Headache and malaise
6. Dysuria
7. Abdominal tenderness — usually in both lower quadrants
8. Adnexal tenderness

The laboratory and imaging work-up may include:

1. Gram stain of endocervical smear looking for Gram-negative intracellular diplococci

2. Leukocyte count, which is usually elevated, with a left shift
3. ESR — elevated
4. Culture and antibiotic sensitivity testing of vaginal discharge and endocervical fluid
5. Ultrasonography may define adnexal masses, especially in the case of tuboovarian
abscess
6. Culdocentesis may be necessary to obtain material for microbiologic analysis
7. Laparoscopy — when the diagnosis is not clear, this is the ultimate method for
establishing it and also provides peritoneal fluid for analysis

ETIOLOGY
A number of organisms may produce the clinical picture of PID. The leading agents
are Neisseria gonorrhoeae, Chlamydia trachomatis, anaerobic bacteria, and Mycoplasma
hominis. Chlamydia and N. gonorrhoeae are more commonly found in the young sexually
active female, whereas anaerobes occur more frequently in association with I.U.D. or older
women. N. gonorrhoeae12,13 accounts for approximately 50% of cases of PID and may be
manifested clinically (apart from PID) as urethritis, lower genital infections, pharyngitis,
proctitis, arthritis-dermatitis syndrome, and perihepatitis.
Chlamydia1415 usually has a milder clinical course than other forms, but low-grade fever
is not uncommon. In addition to lower genital infection and urethritis, it may cause the
Hugh-Fitz-Curtis syndrome.1617 Diagnosis requires culture and monoclonal antibody testing.
Every attempt should be made to reach an etiological diagnosis in order to prevent infertility.
Anaerobic bacteria play an important role on the causation of PID. Bacteroides fragilis,
Clostridium, and Peptostreptococcus are most frequently isolated. As mentioned above,
polymicrobial growth is common.
The differential diagnosis11 includes both gynecologic and nongynecologic disorders:

Gynecologic:
Ectopic pregnancy
Complicated ovarian cyst or tumor
 437

Endometriosis
Degenerating fibroids
Spontaneous abortion
Nongynecologic:
Acute appendicitis
Inflammatory bowel disease
Diverticulitis
Urinary tract infection

PID may develop complications which also present problems in diagnosis of the febrile
patient. These include pelvic abscess, perihepatitis (mentioned above) and peritonitis. These
entities are discussed elsewhere.

CHRONIC PID
Chronic PID may be manifested by recurrent pelvic pain, infertility, low-grade fever,
leukocytosis, and elevated ESR. Physical examination may be indefinite and fail to disclose
an extensive inflammatory process. Definitive diagnosis may be made by laparoscopy.

TUBERCULOSIS1821
Genital tuberculosis affects women mainly in their reproductive years, about 80 to 90%
being diagnosed in this age group. The average incidence of genital TB among infertile
women22 varies from 5 to 10% in different series. Recently, an increased incidence has been
found in postmenopausal women in whom the condition presents with bleeding. Symptoms
and physical findings are variable. The most common symptom is low-grade pelvic pain
that may persist for months. Usually the pain is mild to moderate, but with progression of
the disease, it can become severe. Other symptoms include weight loss, fatigue, prolonged
low-grade fever with evening elevation of temperature, mild anemia, and tachycardia. Men-
strual disorders are found in 10 to 40% of the patients and include menorrhagia, metrorrhagia,
and amenorrhea.
Physical examination may reveal adnexal masses which vary from a slight thickening
of the fallopian tube to a large tuboovarian mass which is usually less tender than a pyogenic
abscess. The diagnosis should be suspected in patients with the above symptoms and signs,
and a family or personal history of tuberculosis. Salpingitis not responding to conventional
antibiotic therapy should raise a suspicion of tuberculosis. The finding of an adnexal mass
and fever in a virgin is suggestive of tuberculous salpingitis. The diagnosis is confirmed by
the following laboratory tests:

1. Chest X-ray.
2. Tuberculin test.
3. Endometrial curettage or biopsy with histologic examination. About half the patients
will show tuberculous endometritis.
4. Bactériologie examination includes a direct smear, culture, and guinea pig inoculation.
They should be performed on endometrium removed at curettage, as well as menstrual
blood.
5. Hysterosalpingography is performed with the relatively innocuous water-soluble me-
dium, and may demonstrate characteristic lesions. The tubal lining may be irregular
with areas of dilation. Saccular diverticole extending from the tube, may give the
picture of a cluster of currants.
6. Laparoscopy. Serosal tubercles may be found. However, the procedure should be
performed with great care to avoid perforation.
7. Laparotomy. Final diagnosis is made by laparotomy and careful pathologic study of
the tissue.
438 Unexplained Fever

ACTINOMYCOSIS2325
Pelvic actinomycosis is a rare disease caused mainly by the Gram-positive anaerobic
bacterium Actinomyces israelii. The disease is more prevalent in the age range from 20 to
40 years. The main predisposing factors are surgery, I.U.D.26 and ruptured appendix. The
clinical presentation is not specific. In the absence of fistulae and chronic sinuses, there are
few typical features of actinomycosis. Early symptoms are low-grade fever or flu-like syn-
drome.23 The onset is often insidious. Patients may complain of low-grade fever,23 weight
loss, and lower abdominal pain.
These vague symptoms are clinically indistinguishable from malignant or other pelvic
inflammatory diseases. A localized pelvic mass may be palpated, more prevalent on the
right side. A diagnosis is usually delayed and sometimes is made only after several surgical
procedures.

PELVIC COCCIDIOIDOMYCOSIS
Pelvic coccidioidomycosis27 is a rare disease caused by Coccidioides immitis which is
found in the soil of parts of South America, southwestern U.S., and northern Mexico. There
are two different pathologic and clinical presentations of pelvic coccidioidomycosis: the
pelvic inflammatory disease, in which the ovaries, the fallopian tubes, and peritoneum are
affected, is a more benign form of the disease. The endometritis and endocervicitis form
are fatal and described in disseminated diseases. Manifestation of the former type includes
fever, pelvic pain, and pelvic masses (i.e., abscesses). The diagnosis is usually made
following laparotomy and removing the tubo-ovarian abscess. Elevated C. immitis comple-
ment fixation titer is found when there is dissemination of the disease. The diagnosis of the
other form was made, according to the few reports, by curettage or hysterectomy.
Methods for confirming the diagnosis include wet preparation, fungal cultures, and
histologic examination.

PELVIC ABSCESS28 29
An important cause of unexplained fever in the female following pelvic infections, or
gynecologic procedures, is pelvic abscess. This condition may occur as a complication in
the puerperium or following abortion, pelvic surgery, and PID. In addition, it may occur
after rupture of appendix or intestinal diverticulum. FUO has been described following
rupture of ovarian cyst,30 appendicitis,31 and PID.32 The abscess formation is frequently
associated with mixed bacterial infection: N. gonorrhea (usually not isolated), C. tracho-
matis, anaerobic bacteria (Bacteroides species and Gram-positive cocci), Gram-negative
rods (E. coli), Actinomyces israelii, and M. hominis.
The clinical presentation is variable. Lower abdominal pain is frequently present and
may be accompanied by fever, chills, nausea, vomiting, diarrhea, pain on defecation, dysuria,
and dyspareunia. Physical examination may reveal abdominal distention and rebound ten-
derness. White blood cell count and ESR are usually elevated. Anemia is frequently found,
especially in patients with a chronic abscess. Ultrasonography may be helpful in demon-
strating pelvic abscess.33
Certain clinical entities will now be discussed:

1. Rupture of pelvic abscess34 may give rise to acute surgical abdomen which may be
life-threatening.
2. Isolated ovarian abscess35 is usually iatrogenic in origin. Pelvic discomfort and fever
persist beyond 4th postoperative day and a mass is usually not felt at this stage.

Late postoperative ovarian abscess develops after a variable time interval.

 439

ENDOMETRIOSIS
Endometriosis is not usually associated with fever, although rarely an infected endo-
metrial cyst36 may occur. This condition generally presents in a nulliparous woman com-
plaining of lower abdominal pain and fever. There may also be a history of infertility,
dysmenorrhea, and irregular menses. On examination, a temperature in the range of 37.2
to 39.5°C, as well as lower abdominal and adnexal tenderness are found.

INFECTED ABORTION37 38
Pelvic infection and febrile morbidity following abortions is less frequent nowadays
because of liberalization of abortion legislation, leading to a decreased number of criminal
abortions, and advances in the methods of pregnancy termination.
Diagnosis may be troublesome, particularly if the pregnancy had been illegally terminated
and the patient fails to describe this to the physician. Further symptoms may appear a short
time following the abortion, or after a long interval. Risk factors include retained products
of conception, advanced gestational age, concomitant maternal illness, presence of I.U.D.,
uterine bleeding, and prolonged injection-abortion interval with instillation technique.
Clinical presentation varies from a mild disease to severe septic shock. Symptoms and
signs include fever (occasionally with chills), vaginal bleeding, foul-smelling discharge,
lower abdominal pain with nausea, vomiting, and diarrhea. All forms of abortions (complete,
incomplete, inevitable, and threatened) may be accompanied by fever. Clinical evaluation
should include the following:

1. Vital signs.
2. Abdominal examination may reveal localized lower abdominal tenderness, ileus or
even generalized peritonitis.
3. Pelvic examination.
4. Laboratory evaluation.
a. CBC, electrolytes, BUN, creatinine. Hyperkalemia may be found due to myonecrosis,
hemolysis, and renal failure.
b. Gram-stained smears from the cervix.
c. Aerobic and anaerobic cultures of endocervix, blood, and products of conception.
d. Urine culture.
e. Coagulation studies (DIC39 may occur).
f. Abdominal X-ray: (i) free air may suggest bowel or uterine perforation, (ii) gas in the
uterine wall (Clostridium welchi infection40), (iii) abscess formation.

Late complications include bleeding, anemia, tissue retention, infection, and fever of
unknown origin.41

TOXIC SHOCK SYNDROME

Toxic shock syndrome (TSS) has undergone an epidemiologic morphosis since the first
description by Todd in 1976. The first patients were seven children who presented with an
unusual multisystemic syndrome, characterized by fever, hypotension, headache, confusion,
rash, vomiting, diarrhea, and oliguria.42
TSS then assumed the role of a menstrual-related disease, associated with tampon use.
Nowadays the condition may be associated with a variety of surgical procedures43 including
tubal ligation, total abdominal hysterectomy, laparotomy, mastectomy, hemiorraphy, vaginal
delivery, Caesarean section, and in some cases of septic abortion.
The condition should be suspected in the appropriate clinical setting. The diagnosis
should be established early to avoid life-threatening complications.
According to the CDC definition,44 a patient must exhibit the following four major signs:
440 Unexplained Fever

(1) fever >38.9°C; (2) rash; (3) hypotension; and (4) desquamation. In addition, at least
three organ systems must be involved, such as gastrointestinal (vomiting, diarrhea), muscular
(myalgia, elevated CK); mucous membranes (hyperemia); renal (elevated BUN or creatinine
levels); hepatic (icterus, enzyme abnormalities); hematologic (thrombocytopenia) and CNS
(disorientation, coma).
The differential diagnosis includes other infectious disorders such as meningococcemia,
streptococcal infection with scarlet fever, leptospirosis, and measles, as well as Kawasaki’s
disease.

INFLAMMATORY DISORDERS
Crohn’s disease may occasionally present with fever accompanied by manifestations
attributed to the female reproductive tract, including pelvic abscesses, dyspareunia, and
vulvovaginitis. Often the clinical features suggest an acute abdomen. A tender, lower ab-
dominal or pelvic mass may be palpated. The condition is frequently misdiagnosed as
appendicitis, pelvic inflammatory disease, or a complication of an ovarian cyst. This is
unfortunate because in most cases surgery is not indicated. In fact, appendectomy in these
cases may predispose to pelvic abscess formation.45
Giant cell arteritis of the female genital tract may rarely occur as an isolated finding or
as a part of a systemic disorder. The condition is often asymptomatic and discovered inci-
dentally after histologic examination of resected specimens. Recently, a case of a 57-year-
old woman with 4 months fever, chills, anorexia, and weight loss was described.46 Previous
history disclosed total abdominal hysterectomy for leiomyomas, and excision of incidentally
discovered retroperitoneal pheochromocytoma. Pelvic examination revealed a nontender
mass posterior to the bladder. Explorative laparotomy was performed and followed by ovarian
cystectomy and bilateral salpingo-oophorectomy. Microscopic examination of the cyst dem-
onstrated mucinous cystadenoma. The small- to medium-sized arteries of the cyst wall, the
other ovary, the fallopian tubes, and the mesosalpinx displayed widespread giant cell arteritis.
A rare condition which may present with lower abdominal pain, fever and a tender
palpable mass is pelvic inflammatory pseudotumor, a xanthogranulomatous reaction of ob-
scure etiology occurring within the female genital tract.47 As the name implies, the condition
mimics clear cell carcinoma histologically.

PELVIC THROMBOPHLEBITIS48 51
Septic thrombophlebitis following pelvic surgery or childbirth may present with unex-
plained fever with limited or absent physical findings on pelvic examination.48 Patients may
have low-grade or spiking fever. Abdominal pain and tenderness may or may not be present.
When pelvic tenderness is discovered, the patient is considered to have pelvic inflammatory
disease, but there is no response to several serially prescribed antibiotics. The administration
of anticoagulants results in prompt defervescence, and their use has been proposed as a
diagnostic test for the condition.49
Blood cultures should be sent for both aerobic and anaerobic organisms: a positive result
is suggestive, although a negative result does not rule out the possibility. Imaging procedures
such as impedence plethysmography, venography, intravenous pyelography, pelvic and
abdominal sonography, and CT scanning should establish the diagnosis. As pelvic throm-
bophlebitis may be complicated by pulmonary embolism, a perfusion-ventilation scan should
be performed in order to establish or rule out this complication.
A distinct clinical variant is ovarian vein thrombophlebitis,52,53 which invariably occurs
 441

on the right side, although in a few cases, is bilateral. It is an infrequent complication of

the puerperium, characterized by the triad of lower abdominal or flank pain, fever and a
mass adjacent to the uterus. Occasionally, fever is the major manifestation.52 Like pelvic
thrombophlebitis, it may cause pulmonary embolism, which may even be fatal. Ovarian
thrombophlebitis may be mistaken for an appendicular abscess, tuboovarian abscess, or
torsion of an ovarian cyst. The condition is usually diagnosed only at laparotomy. Presurgical
diagnosis may be made by using noninvasive imaging techniques and laparoscopy, which
allow conservative management.

FEVER IN TUMORS OF THE FEMALE REPRODUCTIVE

SYSTEM
OVARIAN TUMORS
Early ovarian cancer is usually clinically silent, unless there is a complication such as
torsion or rupture. An unusual presentation of ovarian tumors is with prolonged unexplained
fever.2 54 57 The fever may occur in the absence of secondary infection or métastasés, and
usually resolves swiftly after the removal of the tumor.
Complications such as infection of the tumor or torsion of the pedicle, leading to
infarction and peritonitis, may be accompanied by fever, in addition to abdominal or pelvic
pain, nausea and vomiting.58

UTERINE TUMORS
Leiomyoma (fibroid) is the most common tumor found in women, occurring at any age,
but especially between 32 and 48 years. Rarely, it may be the cause of unexplained fever,
usually as the result of necrosis or hemorrhagic lesions2 or secondary infection and sup-
puration. A pedunculated submucous tumor may protrude into the cervix or vagina and is
subject to ulceration and infection, which may be accompanied by fever and pain.59 An
uncommon febrile complication of a degenerating uterine leiomyoma is Clostridium per-
fringens septicemia.60
Leiomyosarcoma may complicate a uterine fibroid or may develop de novo. The disease
is usually manifested by vaginal bleeding, pain, or a pelvic mass. A small number of cases
present with prolonged fever and weight loss.61 An unusual case of a 54-year-old woman
with fever of 5 months duration has been described.62 On examination, the uterus was
enlarged and nodular. Following hysterectomy, the fever subsided. Histologic examination
revealed a myométrial tumor exhibiting necrosis, hemorrhage, and sarcomatous features.
Commenting on a paper about sarcoma of the uterus,63 Campbell reported a case of long-
standing fever and malaise in this condition.
Cancer of the cervix will not usually be manifested by fever. However, the disease may
very rarely be complicated by infection and present with fever of unknown origin.64 Fever
may occur as a result of an inflammatory complication of radiotherapy for carcinoma of the
cervix.65
Adenocarcinoma of the endometrium may sometimes be complicated by infection, and
present with a febrile course.66

BREAST TUMORS
Although such a presentation is rare, unexplained fever may occur in breast cancer under
certain circumstances: (a) as an initial manifestation, usually in the presence of métastasés,67
especially hepatic, but also in their absence;68 (b) as a sign of disease progression, recurrence
or a new site of metastasis.69 The origin of fever is either from the tumor itself or as a result
of secondary infection, including breast abscess.64
442 U nex p la in ed F e ve r

TABLE 1
Fever Following Gynecologic Surgery

Infection
Pulmonary
Urinary
Pelvic
Wound
Thromboembolism
Thrombophlebitis of the lower extremity
Pelvic thrombophlebitis
Pulmonary embolism
Drug fever
Activation of underlying disorder
Collagen-vascular disease (systemic lupus erythematosus, dermatomyositis)
Sickle-cell crisis
Localized collections of serum (seroma) or blood (hematoma)

POSTOPERATIVE FEVER IN GYNECOLOGY

Postoperative fever following gynecologic surgery is common. The major causes are
infectious, but several other conditions should be considered (see Table 1).

REFERENCES
1. Klimek, J. J., Ajemian, E. R., Gracewski, J., Klemas, B., and Quintiliani, R., A prospective analysis
of hospital-acquired fever in obstetric and gynecologic patients, JAMA, 247, 3340, 1982.
2. Weinstein, L. and Fields, B., Fever of obscure origin, Semin. Infect. Dis., 1,1, 1978.
3. Nahmias, A. J. and Roizman, B., Infection with herpes simplex viruses 1 and 2, N. Engl. J. Med., 289,
667, 719, 1973.
4. Person, D. A., Kaufman, R. H., Gardner, H. L., et al., Herpes virus type 2 in genitourinary infection,
Am. J. Obstet. Gynecol., 116, 993, 1973.
5. Becker, T. M. and Nahmias, A. J., Genital herpes—yesterday, today, tomorrow, Annu. Rev., 36, 185,
1985.
6. Leinikki, P. and Salo, O. P., Genital herpes: virological diagnosis and antibody response, Acta Dermatol.
Venerol. (Stockholm), 53, 65, 1973.
7. Eschenbach, D. A., Buchanan, T. M., and Pollock, H. M., Polymicrobial etiology of acute pelvic
inflammatory disease, N. Engl. J. Med., 293, 166, 1975.
8. Cunningham, F. G., Hanin, J. C., Gilstrap, L. C., et al., The bacterial pathogenesis of acute pelvic
inflammatory disease, Obstet. Gynecol., 52, 161, 1978.
9. Petersdorf, R. G. and Root, R. K., Chills and fever, in Harrison’s Principles of Internal Medicine, 11th
ed., Braunwald, E., Ed. McGraw-Hill, New York, 1987, 50.
10. Ledger, W. J., Laparoscopy in the diagnosis and management of patients with suspected salingo-oophoritis,
Am. J. Obstet. Gynecol., 138, 1012, 1980.
11. Jacobson, L., Differential diagnosis of acute pelvic inflammatory disease, Am. J. Obstet. Gynecol., 136,
1006, 1980.
12. Mardh, P. A., An overview of infectious agents of salpingitis, their biology and recent advances in methods
of detection, Am. J. Obstet. Gynecol., 138, 933, 1980.
13. Bowie, W. R. and Jones, H., Acute pelvic inflammatory disease in outpatients: association with Chlamydia
trachomatis and Neisseria gonorrhoeae, Ann. Intern. Med., 95, 685, 1981.
14. Mardh, P. A., Chlamydia trachomatis infection in patients with acute salpingitis, N. Engl. J. Med., 296,
1377, 1977.
15. Gjonnaess, H., Dalaker, K., and Anestad, G., Pelvic inflammatory disease: étiologie studies with
emphasis on chlamydial infection, Obstet. Gynecol., 59, 550, 1982.
16. Kornfeld, S. J. and Worthington, M. G., Culture-proved Fitz-Hugh-Curtis syndrome, Am. J. Obstet.
Gynecol., 139, 106, 1984.
 443

17. Wang, S.-P., Eschenbach, D. A., Holmes, K. K., et al., Chlamydia trachomatis infection in Fitz-Hugh-
Curtis Syndrome, Am. J. Obstet. Gynecol., 138, 1034, 1980.
18. Schaefer, G., Female genital tuberculosis, Clin. Obstet. Gynecol., 19, 223, 1976.
19. Sutherland, A. M., Pelvic tuberculosis, Br. J. Obstet. Gynecol., 84, 881, 1977.
20. Henderson, D. N., Harkins, J. L., and Stitt, J. F., Pelvic tuberculosis, Am. J. Obstet. Gynecol., 94,
630, 1966.
21. Hutchins, C. J., Tuberculosis of the female genital tract — a changing picture, Br. J. Obstet. Gynecol.,
84, 534, 1977.
22. Morris, C. A., Boxall, F. N., and Cayton, H. R., Genital tract tuberculosis in subfertile women, J. Med.
Microbiol., 3, 85, 1970.
23. Lomax, C. W., Harbert, G. M., Jr., and Thornton, W. N., Jr., Actinomycosis of the female genital
tract, Obstet. Gynecol., 48, 343, 1976.
24. Burkman, R., Schlesselman, S., and McCaffrey, L., The relationship of genital actinomyces and the
development of pelvic inflammatory disease, Am. J. Obstet. Gynecol., 143, 585, 1982.
25. Drew, N. C., Genital and pelvic actinomycosis: case report, Br. J. Obstet. Gynecol., 88, 776, 1981.
26. Yoonessi, M. et al., Association of Actinomyces and intrauterine contraceptive devices, J. Reprod. Med.,
30, 48, 1985.
27. Parker, P. and Adcock, L., Pelvic coccidioidomycosis, Obstet. Gynecol. Surv., 36, 225, 1981.
28. McNamara, M. T. and Mead, P. B., Diagnosis and management of the pelvic abscess, J. Reprod. Med.,
17, 299, 1976.
29. Ginsburg, D. S., Stern, J. G., and Hamod, K. A., Tubo-ovarian abscess. A retrospective review, Am.
J. Obstet. Gynecol., 138, 1055, 1980.
30. Dinarello, C. A. and Wolff, S. M., Fever of unknown origin, in Principles and Practices of Infectious
Diseases, 2nd ed., Mandell, G. L., Douglas, R. G., and Bennett, J. E., John Wiley & Sons, New York,
1985, 339.
31. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report on 100 cases, Medicine, 40,
1, 1961.
32. Larson, E. B., Featherstone, H. J., and Petersdorf, R. C., Fever of undetermined origin: diagnosis and
follow-up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
33. Ulrich, P. C. and Sanders, R. C., Ultrasonic characteristic of pelvic inflammatory masses, J. Clin.
Ultrasound, 4, 199, 1976.
34. Pedowitz, P. and Bloomfield, R., Ruptured adnexal abscess (tubo-ovarian) with generalized peritonitis,
Am. J. Obstet. Gynecol., 88, 721, 1964.
35. Willson, J. R. and Black, J. R., Ill, Ovarian abscess, Am. J. Obstet. Gynecol., 90, 34, 1964.
36. Schmidt, C. L., Demopoulos, R. L, and Weiss, G., Infected endometrial cysts: clinical characterization
and pathogenesis, Fertil. Steril., 36, 27, 1981.
37. Wentz, A. C., Burnett, L. S., and King, T. M., Techniques of pregnancy termination. I, Obstet. Gynecol.
Surv., 28, 3, 1973.
38. Burnhill, M. S., Reducing complication of first trimester abortion, Contemp. Obstet. Gynecol., 13, 145,
1979.
39. Kafrissen, M. E., Barbe, M. W., Workman, P., Schultz, K. F., and Grimes, D. A., Coagulopathy
and induced abortion methods: rates and relative risks, Am. J. Obstet. Gynecol., 147, 344, 1983.
40. O’Neill, R. T. and Schwarz, R. H., Clostridial organisms in septic abortions — report of 7 cases, Obstet.
Gynecol., 35, 458, 1970.
41. Castadot, R. G., Pregnancy termination techniques, risks, and complications and their management, Fertil.
Steril., 45, 5, 1986.
42. Todd, J., Fishault, M., Karpal, F., and Welch, T., Toxic shock syndrome associated with phage —
group 1 — staphylococci, Lancet, 2, 1116, 1978.
43. Friedel, S. and Mercer, L. J., Non-menstrual toxic shock syndrome, Obstet. Gynecol. Surv., 41, 336,
1986.
44. Centers for Disease Control, Update: Toxic shock syndrome — United States, MMWR, 32, 398, 1983.
45. Donaldson, L. B., Crohn’s Disease: “ its gynecologic aspect’’, Am. J. Obstet. Gynecol., 131, 196, 1978.
46. Bell, D. A., Mondschein, M., and Scully, R. E., Giant cell arteritis of the female genital tract: a report
of three cases, Am. J. Surg. Pathol., 10, 696, 1986.
47. McEntee, G. P., Coughlan, M., Corrigan, T., and Dervan, P., Pelvic inflammatory pseudotumour:
problems in clinical and histological diagnosis, Br. J. Obstet. Gynaecol., 92, 1067, 1985.
48. Dunn, L. J. and Vanvoorhis, L. W., Enigmatic fever and pelvic thrombophlebitis: response to antico-
agulants, N. Engl. J. Med., 276, 265, 1967.
49. Schulman, H. and Zatuchni, G., Pelvic thrombophlebitis in puerperal and postoperative gynecologic
patient: obscure fever as an indication for anticoagulant therapy, Am. J. Obstet. Gynecol., 90, 1293, 1964.
50. Duff, P. and Gibbs, Pelvic vein thrombophlebitis: diagnostic dilemma and therapeutic challenges, Obstet.
Gynecol. Surv., 38, 365, 1983.
444 Unexplained Fever

51. Cohen, M. B., Pernoll, M. L., Gerwitz, C. M., et al., Septic pelvic thrombophlebitis: an update, Obstet.
Gynecol., 62, 83, 1983.
52. Munsick, R. A. and Gillanders, L. A., A review of the syndrome of puerperal ovarian vein thrombo-
phlebitis, Obstet. Gynecol. Surv., 36, 57, 1981.
53. Hughey, M., McElin, T. W., and Caprini, J. A., Nonsurgical diagnosis and management of puerperal
ovarian vein thrombophlebitis, Am. J. Obstet. Gynecol., 133, 461, 1979.
54. Fransen, H. and Bottiger, L. E., Fever of more than two weeks’ duration, Acta Med. Scand., 179, 147,
1966.
55. Maestu, R. P., Buzon, L. M., Fraile, L., et al., Carcinoma de ovario como causa de fiebre de origen
desconocido: a proposito de un caso, Rev. Clin. Esp., 153, 65, 1979.
56. Schofield, P. M., Kirtsop, B. A., Reginald, P. and Harington, M., Ovarian carcinoma presenting as
pyrexia of unknown origin, Postgrad. Med. J., 61, 177, 1985.
57. Bedrine, H., Les fievres prolongées en gynécologie, Assis. Med., 23, 282, 1965.
58. Ehren, I. M., Mahour, G. H., and Isaacs, H., Jr., Benign and malignant ovarian tumors in children
and adolescents: a review of 63 cases, Obstet. Gynecol. Surv., 39, 599, 1984.
59. Buttram, V. C., Jr. and Reiter, R. C., Uterine leiomyomata: etiology, symptomatology, and management,
Fertil. Steril., 36, 433, 1981.
60. Kaufmann, B. M., Cooper, J. M., and Cookson, P., Clostridium perfringens septicemia complicating
a degenerating uterine leiomyoma, Am. J. Obstet. Gynecol., 118, 877, 1974.
61. Gallup, D. G. and Cordraya, D. R., Leiomyosarcoma of the uterus: case reports and a review, Obstet.
Gynecol. Surv., 34, 300, 1979.
62. Hosang, R., Bain, B. C. and Denbow, C. E., Pyrexia of unknown origin: a case of uterine leiomyosarcoma,
Br. J. Obstet. Gynaecol., 89, 864, 1982.
63. McFarlane, K. Y., Sarcoma of the uterus: an analysis of 42 cases, Am. J. Obstet. Gynecol., 59, 1304,
1950.
64. Klastersky, J., Weerts, D., Hensgens, C. and Debusscher, L., Fever of unexplained origin in patients
with cancer, Eur. J. Cancer, 9, 649, 1973.
65. Van Herik, Fever as a complication of radiation therapy for carcinoma of the cervix, Am. J. Roentgenol.
Radiat. Ther. Nucl. Med., 93, 104, 1965.
66. Braverman, S., Adachi, A., Lev Gur, M., et al., Spontaneous gas gangrene of the uterus associated
with endometrial malignancy, Am. J. Obstet. Gynecol., 156, 1205, 1987.
67. Pettersson, T., Fever of obscure origin: a follow-up investigation of 88 cases, Acta Med. Scand., 171,
575, 1962.
68. Sheon, R. P. and van Ommen, R. A., Fever of obscure origin: diagnosis and treatment based on a series
of sixty cases, Am. J. Med., 34, 486, 1963.
69. Chawla, S. P., Buzdar, A. U., Hortobagyi, G. N., and Blumenschein, G. R., Tumor-associated fever
in breast cancer, Cancer, 53, 1596, 1984.
 445

Chapter 29

UNEXPLAINED FEVER IN OBSTETRICS

A. Ber, A. Golan, and J. R. Cohen

INTRODUCTION

Fever during pregnancy has a special significance since the physician is dealing with
two patients at the same time (mother and child). The search for the cause should be carried
out as in any other patient, although certain points deserve special attention. Irrespective of
the cause, fever may have a harmful effect on the pregnancy and can lead to its premature
termination. On the other hand, certain diseases should be more thoroughly sought, either
because of a known association with pregnancy or because of a higher risk for the mother
or the fetus in terms of premature delivery or possible malformations. One should bear in
mind that infections which have a serious effect on the fetus, such as toxoplasmosis, cy-
tomegalovirus infection, or rubella may occur in the absence of prominent signs, including
fever. The specific relation and course of various diseases in pregnancy will be discussed
below.

PHYSIOLOGICAL CHANGES DURING PREGNANCY IN

RELATION TO DIAGNOSIS OF INFECTION
CARDIOVASCULAR SYSTEM
Heart rate — Rises during pregnancy reaching 90 beats per minute near term.
Cardiac output — Rises as early as the end of the first trimester reaching a peak which
exceeds the nonpregnant level by 1.5 1/min.
Blood pressure — In the supine and left lateral position both systolic and diastolic
arterial pressures decrease reaching a nadir between 28 and 32 weeks of gestation. Both
return to nonpregnant values near term.1,2

HEMATOLOGIC CHANGES
Hemoglobin concentration — Blood volume and the total red cell mass increase to 45
and 30% above nonpregnant values, respectively. As the increase in plasma volume is
relatively greater, the net result is the “ physiologic anemia of pregnancy” .
White blood cell count — The increase in white cell count is a very important change:
9500/mm3 in the first trimester (range 3150— 15300/mm3) and 10500/mm3 in the second
and third trimester (range 5000 to 16000/mm3). An elevation during pregnancy over 16000/
mm3 is considered to be pathologic. However, during delivery and in immediate postpartum
phase, the leukocyte count may reach 25000/mm3; this rise may be accompanied by a slight
shift to the left.
Clotting factors — An increase in several clotting factors may be noted during preg-
nancy. The most prominent changes are increased fibrinogen level which can reach 250 to
600 mg/dl and factor VIII which increases from 50 to 200% to 100 to 300%.
The erythrocyte sedimentation rate (ESR) — Elevated during gestation and may reach
60 mm in the first hour. This correlates mainly with the increase in fibrinogen and alpha-
2 and beta globulins in the plasma. Hence, this test is of little value during pregnancy.1,2

RENAL CHANGES
Glomerular filtration rate — Increases and reaches 40% over nonpregnant values by
the 20th week of gestation. Normal values range from 110 ml to 150 ml/min.
446 Unexplained Fever

Serum uric acid, urea, and creatinine — All decrease significantly during pregnancy
and return to nonpregnant values near term.13

HEPATIC CHANGES
The levels of liver enzymes serum glutamic oxaloacetic transaminase (SGOT) and serum
glutamic pyruvic transaminase (SGOT) are unaltered during pregnancy. Alkaline phosphatase
levels increase due to the production of a heat stable isoenzyme by the placenta. Total serum
protein concentration, mainly albumin, decreases by 20%.1,4

TEMPERATURE
The body temperature during pregnancy may be slightly elevated, but it does not usually
exceed 38°C (100.4°F).2

IMMUNE SYSTEM
The pregnant woman has an attenuated cell-mediated immune system manifesting itself
by impaired responsiveness of T-lymphocytes. This change leads to a decreased resistance
to infections. This is important as the fetus, who lacks an immune system until 20 weeks
of gestation, is suceptible and may be affected by viremia or bacteremia in the mother.2
It should be kept in mind that a pregnant patient may present at the emergency room
with apparent abdominal distension, low blood pressure, tachycardia, and low-grade fever.
An increased leukocyte count and ESR may also be found. Yet all these features may well
be normal during pregnancy.2

VIRAL INFECTIONS57
The decreased resistance in the pregnant mother which predisposes to infection may
lead to fetal demise, mainly in the first trimester when the fetus has no immunological
response. In other cases the fetus may survive such an infection with severe congenital
malformations and chronic perinatal infection. The commonest viruses involved are rubella,
cytomegalovirus, and herpes simplex.

RUBELLA
Rubella is the best known of the viral infections which may be hazardous to the fetus.
The disease has no particular features in the pregnant state but one must remember that up
to 50% of the infections are subclinical. Early infection can induce abortion. When viremia
occurs during the first 8 weeks the fetus usually becomes infected. The surviving fetus will
be chronically infected even in the neonatal period. The risk of malformations is greater
during this 8-week period but the possibility of a malformed fetus persists until 20 weeks
of gestation. The well-known rubella syndrome consists of cardiac lesions, cataracts, and
low birth weight. Other defects include retinopathy, hearing loss, and psychomotor retar-
dation which may progress postnatally or become apparent years later. Virtually any organ
system may be affected. Diagnosis is based on the presence of rubella IgM antibody, or the
demonstration of rising titers of IgG antibody in repeated serum samples.

CYTOMEGALOVIRUS
Cytomegalovirus usually develops after a primary maternal infection during the first two
trimesters of pregnancy. The viremia may occur with minimal symptomatology. The risk
of congenital infection is 30% and includes cardiovascular and CNS defects and less fre-
quently, abnormalities of the musculoskeletal or gastrointestinal systems. Mental retardation
and hearing loss will be apparent after a few years. Early infection can induce abortion.
Diagnosis can be confirmed by IgM antibodies.
 447

HERPES SIMPLEX TYPES I AND II

Herpes simplex types I and II5 8 viruses may be transmitted transplacentally. Herpes
type II (genital herpes) has a tendency to be reactivated by pregnancy and symptomatic
infections of this virus are three times as common as in the nonpregnant state. Neither virus
is teratogenic but can cause viremia and intrauterine fetal death. The main risk of contam-
ination is during the birth process where a passage through a contaminated birth canal can
cause herpes encephalitis and death in 90% of newborns. Whenever a history of a genital
herpes infection in the patient or her partner exists, thorough follow-up during pregnancy
is indicated. Weekly cervical cultures are obtained regardless of whether genital lesions are
present. A patient with clinical disease or a positive culture within 2 weeks prior to delivery
should undergo a Caesarean section before membranes are ruptured. In the event of spon-
taneous rupture of membranes a Caesarean section should be performed if it is feasible
within 6 h, according to some authors5 7,8 (or within 24 h, according to others6).

VARICELLA
Varicella during pregnancy has no teratogenic effect on the fetus. When contracted by
the mother in the last 4 days prior to delivery, the neonate should be given hyperimmune
serum because as many as 17% of those infants may show signs of chickenpox and a 30%
mortality rate has been reported. This occurs because the maternal varicella antibodies do
not have sufficient time to develop and be transferred to the fetus.

HEPATITIS A AND B
Hepatitis A4 has no teratogenic effect, and transplacental transmission is rare. There is
an increased risk of prematurity and abortions. Pregnant women, as any adult, tend to have
a more serious disease than children. Immunoglobulin should be given to the exposed mother
as soon as possible and to her offspring immediately after birth. Hepatitis B is a much more
serious disease during pregnancy and newborns of carrier mothers, positive for “ e” and
surface antigens have an 80 to 90% chance of becoming infected. Ninety percent of these
infants become chronic carriers and 25% of them will eventually die of chronic liver disease.
As in hepatitis A, the disease has a more severe course during pregnancy and can cause an
increased rate of abortions and prematurity. As only 5% of the newborns are infected by
the transplacental route, the disease in the infant can theoretically be prevented. The infant
is given hepatitis B immune globulin and hepatitis B vaccine. This combination is effective
in preventing the disease in 90% of cases.9

OTHER VIRUSES
Other viruses, measles and polio are rare nowadays during pregnancy as a result of
vaccination. Mumps virus may induce early abortion but no known fetal defects resulting
from mumps were reported. A few cases of fetal endocardial fibroelastosis have been reported
but no definite relationship was established.6 Influenza has no teratogenic effect, although
it may increase the risk of abortion.6

ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS)1013

The importance of AIDS, a relatively new but frightening disease in obstetrics, lies in
the fact that the virus can be transmitted transplacentally, even when the mother does not
have any symptoms of the disease. There is one report of a child who contracted the disease
from breast milk.11 By the end of 1986 more than 300 cases of pediatric AIDS were reported.
The estimated risk of an antibody positive mother to transmit the disease to her offspring
may reach 88%. The Centers for Disease Control (CDC) figure is 65% based on a group
of women who already had a child with AIDS and subsequently became pregnant again.
AIDS manifests itself in the child usually at about 6 months of age, but sometimes as early
as a few weeks. About one third of affected children are premature. The majority of the
448 U n ex p la in ed F e ve r

mothers were not ill at the time of the delivery. An important yet unresolved question is
whether an antibody positive woman should be advised against having a child.

BACTERIAL INFECTION
Urinary tract infection (UTI)2,3,14-16 is probably the most common infection during
pregnancy. Certain physiological changes occur in the urinary tract during pregnancy. The
ureteral peristalsis is reduced from the 3rd month of gestation due to progestagenic effect.
Hydroureter of pregnancy is well known: the ureters are dilated above the pelvic brim. These
changes are more prominent on the right side due to the physiological dextroversion of the
uterus and to anatomical differences between the ureters. Due to uterine compression of the
bladder during the first and third trimester, the pregnant women may complain of urgency
and frequency, which can be wrongly interpreted as symptoms of infection. Urinary tract
infection can cause severe maternal and fetal morbidity especially when it progresses to
acute pyelonephritis. The latter may lead to bacteremia; 3% of these patients may even
develop endotoxic shock with multiple organ failure. Premature labor may be a grave fetal
consequence. Contributing factors to symptomatic UTI are low socioeconomic group, a
previous history of UTI or nephrolithiasis, asymptomatic bacteruria, and sickle-cell hemo-
globin. In untreated asymptomatic bacteruria, 25 to 40% of the pregnant women will develop
acute pyelonephritis. The key points of management during pregnancy are prevention and
early identification of the high-risk patient. The causative agents are the same as in the
nonpregnant state, E. c o li being the most frequent organism. Women having symptomatic
UTI during pregnancy are prone to develop the same infection in the puerperium and should
be given prophylactic treatment.

LISTERIOSIS
Listeriosis,214,15 caused by L iste ria m o n o c y to g e n e s , occurs particularly during the third
trimester but may occur at any stage of pregnancy. The infection has no specific clinical
manifestations and often mimics influenza or pyelonephritis. The patient presents with fever,
myalgia, headache, diarrhea and flank pain. L iste ria m o n o cy to g en es can cause abortion. In
Western Europe, 1 to 6% of abortions are attributed to this agent, which can also cause
premature delivery and intrauterine fetal death. “ Early” and “ late” neonatal infections have
been described. In the former, the organism is transmitted transplacentally, in the latter the
infection is acquired during delivery or postnatally or as a result of low level maternal
bacteremia in the third trimester. Penicillin or ampicillin are both effective therapeutic agents.

CAMPYLOBACTER21415
C a m p ylo b a c te r has been recognized since 1947 as a cause of septic abortions accom-
panied by respiratory manifestations, premature deliveries, and neonatal meningoencephal-
itis. The maternal manifestations resemble bronchopneumonia but are inconstant.

SYPHILIS214 15
S yph ilis is mentioned in detail elsewhere in this book. Treatment does not differ from
that for the nonpregnant state, except that tetracyclines should not be used. The Jarish
Herxheimer reaction manifested by fever, tachycardia, myalgia, and less frequently hypo-
tension is common in the pregnant state. The reaction is caused by massive and sudden
destruction of spirochetes by antibiotics.

APPENDICITIS
The incidence of a cu te a p p e n d ic itis15 19 is not increased during pregnancy and there is
an equal distribution during the three trimesters. Symptoms, mainly in the third trimester
 449

when the appendix is displaced by the gravid uterus, are atypical and the diagnosis is often
delayed. The mortality from acute appendicitis in the general population is 0.1%, whereas
in pregnancy it is 2% and reaches 7% in the third trimester. The incidence of appendiceal
rupture is increased in the pregnant state. Perforation with generalized peritonitis is associated
with increased incidence of preterm delivery, maternal, and fetal death. The right lower
abdominal pain is often situated above its classical location. Nausea, vomiting, and anorexia
are present in 50 to 70% of cases.
Laboratory tests are of little value because of the physiological leukocytosis of pregnancy.
Differential diagnosis should include cholecystitis, pancreatitis, small bowel obstruction,
pyelonephritis, acute red degeneration of uterine myoma, and torsion of an adnexal mass.

CHOLECYSTITIS220
During pregnancy, fasting and residual gallbladder volumes are twice the nonpregnant
values. The rate of emptying is markedly reduced as progesterone impairs gallbladder con-
tractions. Under estrogenic influence alterations in bile salt composition occur and the amount
of cholesterol reaching the gallbladder is increased. These factors account for the increased
proneness of the pregnant woman to gallbladder disease. Nevertheless, cholecystitis is not
common and there is no general agreement that there is an increased risk during pregnancy.
The treatment is exactly as in the nonpregnant state.

TUBOOVARIAN ABSCESS
Tuboovarian abscess21 is usually a late sequel of pelvic inflammatory disease or septic
abortion; a few cases have occurred during pregnancy.

OTHER INFECTIONS
Even though they may have no increased prevalence in pregnancy, pulmonary infections,
brucellosis217 (that can cause abortion), salmonellosis, infectious mononucleosis, leptospi-
rosis, and tuberculosis22 23 can appear together with fever. Pulmonary tuberculosis and tu-
berculous peritonitis may complicate pregnancy. Congenital tuberculosis has been reported
in the offspring of infected mothers.

CHORIOAMNIONITIS15 24 27
In modem obstetric preterm delivery, this remains the single most important factor in
neonatal mortality. Chorioamnionitis must be looked for in any women with premature
rupture of membranes (PROM) even though it may occur in patients with intact membranes.
In the latter, occult genital tract infection is the cause, predisposing to preterm delivery
with many pathogens being responsible. Studies have shown the close relationship of vaginal
colonization by Streptococcus B hemolyticus and chorioamnionitis, with subsequent severe
neonatal disease. The classical signs of amnionitis are maternal and fetal tachycardia, ma-
ternal fever, purulent or foul-smelling vaginal discharge, and leukocytosis. When all of
these are present, we are already dealing with a severe disease. The infection may be fatal
to the fetus and a source of severe morbidity to the mother, without previous warning. In
a recent study only 27 of 333 cases of histopathologic chorioamnionitis of 8.1% had maternal
fever. The authors estimated that approximately 25% of the preterm deliveries were statis-
tically attributable to chroioamnionitis. A high suspicion of amnionitis should be entertained
in any woman with PROM presenting with fever without any apparent cause.

PROTOZOAN INFECTIONS
TOXOPLASMOSIS628
The infected pregnant woman is usually asymptomatic. When symptomatology exists,
it consists of malaise, myalgia, and fever. Severe cases can present with a picture of
450 Unexplained Fever

pneumonia, myocarditis, and chorioretinitis. The infection can cause abortion, premature
delivery, and the newborn may have manifestations of the disease including meningitis,
encephalitis, convulsions, hydrocephalus or microcephaly, hepatosplenomegaly, lymphad-
enopathy, jaundice, and thrombocytopenia. The infant either dies or is severely mentally
retarded. Diagnosis is made by finding IgM specific antibodies. Pyrimethamine and sulfa-
diazine should be used even though they are fetotoxic, because of the severe consequences
of an untreated infection on the fetus.

OTHER INFECTIONS
One should remember the possibility of malaria and schistosomiasis especially if the
patient has returned from tropical countries. Amebiasis can present either as dysentery or as
an amebic abcess.6,17,28

INFLAMMATORY CAUSES OF FEVER

As we are dealing with a young group of patients one should not forget to look for
autoimmune disease such as SLE or Hashimoto’s thyroiditis. Familial Mediterranean fever
(FMF) should be looked for in cases of recurrent peritonitis, fever, or pleuritis and arthritis,
mainly in a patient of Sephardic Jewish, Armenian, or Arabic ancestry.17

PANCREATITIS29
This is a serious disease at any time and especially during pregnancy, where the mortality
rate may reach 20%. The incidence is 1 in 4000 to 12,000 deliveries. The diagnosis follows
the same lines as in the nonpregnant patient, since levels of amylase and lipase are unchanged
by pregnancy.

INFLAMMATORY BOWEL DISEASE (IBD)30

Both ulcerative colitis and Crohn’s disease affect young individuals and may be en-
countered during pregnancy. The long-held belief that IBD worsens during pregnancy is
known to be incorrect. IBD has probably very little effect on the course of pregnancy and
similarly pregnancy has no adverse effect on the course of the disease.

TUMORS IN PREGNANCY
MYOMA UTERI IN PREGNANCY31
Cameous or red degeneration of myomas occurs in 8% of tumors discovered in preg-
nancy. The myoma undergoes aseptic necrosis with hemorrhage within the tumor and sub-
sequent hemolysis. Clinical features include pain, tenderness, and occasionally low-grade
fever. Pedunculated subserous myomas are prone to torsion and infection. Torsion of such
a myoma during pregnancy, with subsequent gangrene, is an indication for surgical inter-
vention, which usually has no deleterious effect on the pregnancy.

OVARIAN TUMORS32
Ovarian cysts may undergo torsion mainly in the first trimester; subsequent peritonitis
necessitates surgical intervention. These cysts are usually 6 cm or larger in size, although
cases of torsion of a small Morganni cyst during pregnancy have been reported as well.
Similar features occur in cases of a ruptured corpus luteum cyst. Torsion occurs also in
early puerperium due to changes of organ anatomic relations.
Taking into account the age distribution of leukemia and Hodgkin’s disease, one must
not overlook the possibility of these diseases manifesting themselves initially during preg-
nancy.
 451

POSTPARTUM FEVER

Febrile morbidity was defined by the Joint Committee on Maternal Welfare as “ a

temperature of 100.4°F (38°C) or higher, ocurring on any 2 of the first 10 days postpartum,
exclusive of the first 24 h and measured orally by a standard technique at least four times
daily.” Infections of extragenital origin such as pyelonephritis and pneumonia should be
excluded.
This definition is not completely accurate since today we know that fever in the first
24 h, previously considered not to be connected to the delivery process, may be caused by
genital infection, particularly in cases of prolonged PROM and protracted labor with repeated
vaginal examinations,33 35 internal intrapartum monitoring36 or postpartum uterine cavity
revision. The infection may present as en d o m etritis or p a ra m e tritis. Signs vary from mild
malaise to fulminating sepsis. Significant uterine tenderness is not invariably present. Re-
tained secundines may cause fever, uterine bleeding, or passage of placental tissue. Curettage
is indicated to remove these placental fragments. Treatment of metritis is by antibiotics for
10 days.13 Lack of response within 48 h requires réévaluation including a search for evidence
of pelvic thrombophlebitis. T u boovarian a b sc e ss discussed in the previous chapter may be
a late sequel of metritis.15 21
T h rom bo p h leb itis and th ro m b o e m b o lic d ise a se occur more frequently in the puerperium
and should be investigated as in the nonpregnant state. Thrombophlebitis in the ovarian
veins termed the rig h t o va ria n vein sy n d ro m e , is characterized by fever and a sausage-
shaped tender mass palpated on vaginal examination; anticoagulant therapy is mandatory in
such cases.37
Another cause of infection is p e r in e a l infection arising in a repaired episiotomy or perineal
laceration38 or following pudendal block anesthesia, which may even lead to abscess for-
mation.39 Rarely it may progress to n ecro tizin g fa s c iitis which carries a high mortality rate.40
When the patient who fails to respond to conservative treatment complains of persistent pain
at the site of an incision, the wound should be inspected for color change from red to blue-
grey. A wide incision of all necrotic tissue is a life-saving procedure in these cases.41
An infected isc h io -re c ta l h em atom a can be a serious complication: infection is usually
due to staphylococci; treatment should include drainage and removal of sutures, in addition
to antibiotic treatment.42
M a stitis is another postpartum infection usually caused by S ta p h y lo co c cu s au reu s. It
usually develops 3 to 4 weeks postpartum although it may become apparent at any time
during lactation.43 B re a st en g o rg em en t itself may cause fever; in one study bromocriptine
meslate given within 18 h postpartum to women who did not wish to breast-feed prevented
this physiological puerperal fever.44
U rin ary tra c t infection is very common in the puerperium (as stated before) mainly in
women who had UTI during pregnancy. Post-Caesarean section infections are very common
and up to 40% of these patients have postpartum fever due to infection in various sites.1245,46
Less frequent causes of puerperal fever include tu b e rc u lo sis ,47 to x ic sh o ck sy n d ro m e ,48
m y co p la sm a ,49 and ch la m y d ia l in fections. As is the case during pregnancy, virtually any
febrile disease may appear during the puerperium. The main task of the clinician is to be
aware of this fact and to differentiate the features of any of these diseases from the phys-
iological events that may take place during the postpartum period.
452 U n ex p la in ed F e ve r

REFERENCES
1. Key, T. C. and Resnik, R., Maternal changes in pregnancy, in Obstetrics and Gynecology, 5th ed.,
Danforth, D. N. and Scott, J. R., Eds., Lippincot, Philadelphia, 1986, 327.
2. Vilde, J. L., Colau, J. C., and Sureau, C., Etats fébriles au cours de la grossesse diagnostic et conduite
a tenir. Maladies infectieuses, Rev. Prat., 27, 29, 1977.
3. Cruiksbank, D. P., Urinary tract disease, in Obstetrics and Gynecology, 5th ed., Danforth, D. N. and
Scott, J. R., Eds., Lippincot, Philadelphia, 1986, 505.
4. Fallon, J. H., Liver disease in pregnancy, in Medical Complications During Pregnancy, 2nd ed., Burrow,
G. and Ferris, T. F., Eds., W. B. Saunders, Philadelphia, 1982.
5. Horstmann, D. M., Viral infections, in Medical Complications During Pregnancy, 2nd ed., Burrow, G.
and Ferris, T. F., Eds., W. B. Saunders, Philadelphia, 1982, 333.
6. South, M. A. and Sever, J. L., Viral and protozoan disease, in Obstetrics and Gynecology, 5th ed.,
Danforth, D. N. and Scott, J. R., Eds., Lippincot, Philadelphia, 1986, 551.
7. Taina, E., Hanninen, P., and Gronroos, M., Viral infections in pregnancy, Acta Obstet. Gynecol. Scand.,
64, 35, 1985.
8. Whilley, R. J. et al., The natural history of herpes simplex virus infection of the mother and newborn,
Pediatrics, 66, 489, 1980.
9. Wong, V. C. W., Ip, H. M. H., Reesink, H. W., et al., Prevention of the HBsAg carrier state in newborn
infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine
and hepatitis B immunoglobulin, Lancet, 1, 921, 1984.
10. CDC. Recommendations for assisting in the prevention of perinatal transmission of HTLV-III/LAV and
AIDS, MMWR, 1985, 34.
11. Ziegler, J. B., Cooper, D. A., and Johnson, R. O., Postnatal transmission of AIDS-associated retrovirus
from mother to infant, Lancet, 1, 896, 1985.
12. Rutherford, G. W., Oliva, G., Grossman, M., et al., Guidelines for control of perinatally transmitted
T-lymphotropic virus type III/lymphadenopathy-associated virus infection and care of infected mothers,
infants and children, San Francisco AIDS Foundation, 1986, 18.
13. Pinching, A. J. and Jeffries, D. J., AIDS and HTLV-III/LAV Infection: consequences for obstetrics and
perinatal medicine, Br. J. Obstet. Gynaecol., 92, 1211, 1985.
14. Andriole, V. T., Bacterial infection, in Medical Complications During Pregnancy, 2nd ed., Burrow, G.
and Ferris, T. F., Eds., W. B. Saunders, Philadelphia, 1982, 302.
15. Monif, G. R. G., Infectious Diseases in Obstetrics and Gynecology, 2nd ed., Hagerston, M. D., Ed.,
Harper and Row, New York, 1982.
16. Pedler, S. J. and Bint, A. J., Management of bacteriuria in pregnancy, Drugs, 33, 413, 1987.
17. Isaac, B. and Kernbaum, S., Fievres prolongées inexpliquées, Nouv. Presse Med., 10, 3311, 1981.
18. Brant, H. A., Acute appendicitis in pregnancy, Obstet. Gynecol., 29, 130, 1967.
19. Partington, C. K., Studley, J. G. N., and Menzies-Gow, N., Abdominal pregnancy complicated by
appendicitis: case report. Br. J. Obstet. Gynaecol., 93, 1011, 1986.
20. Hiatt, J. R., Carol, J., Hiatt, G., et al., Biliary disease in pregnancy. Strategy for surgical management,
Am. J. Surg., 151, 263, 1986.
21. Jafari, K. et al., Tubo-ovarian abscess in pregnancy, Acta Obstet. Gynecol. Scand., 56, 1, 1977.
22. Snider, D., Pregnancy and tuberculosis, Chest, 86 (Suppl. 3), 10s, 1984.
23. Brooks, J. H. and Stirrat, G. M., Tuberculous peritonitis in pregnancy, Br. J. Obstet. Gynaecol., 93,
1009, 1986.
24. Guzick, D. S. and Winn, K., The association of chorioamnionitis with preterm delivery, Obstet Gynecol.,
65(1), 6, 1985.
25. Minkoff, H., Prematurity: infection as an étiologie factor, Obstet. Gynecol., 62, 137, 1983.
26. Ledger, W. J., Hospital infections: gynecologic, obstetric and perinatal infections, Ann. Intern. Med.,
89(Part 2), 774, 1978.
27. Naeye, R. L. and Peters, E. C., Amniotic fluid infections with intact membranes leading to perinatal
deaths: a prospective study, Pediatrics, 61, 171, 1978.
28. Lee, V. R., Parasitic infections, in Medical Complications During Pregnancy, 2nd ed., Burrow, G. and
Ferris, T. F., Eds., W. B. Saunders, Philadelphia, 1982, 386.
29. Willoughby, C. P. and Truelove, S. C., Acute pancreatitis in pregnancy. A review of 98 cases and a
report of 8 new cases, Obstet. Gynecol. Surv., 28, 469, 1980.
30. Sorokin, J. J. and Levine, S. M., Pregnancy and inflammatory bowel disease. A review of the literature,
Obstet. Gynecol., 62, 247, 1983.
31. Winer-Muram, H. T., Muram, D., Gillieson, M. S., et al., Uterine myomas in pregnancy, Can. Med.
Assoc. J., 128, 949, 1983.
32. Merrill, J. A., Zaloudek, C., Tavassoli, A., and Kurman, R. J., Lesions of the ovary, in Obstetrics
and Gynecology, 5th ed., Danforth, D. N. and Scott, J. R., Eds., Lippincot, Philadelphia, 1986, 1106.
 453

33. Gibbs, R. S. and Weinstein, A. J., Puerperal infection in the antibiotic era, Am. J. Obstet. Gynecol.,
124, 769, 1976.
34. Eschenbach, D. A., Acute postpartum infection, Emerg. Med. Clin. North Am., 3, 87, 1985.
35. Humphrey, M. D., Postpartum infection: a survey, Med. J. Aust., 2, 657, 1972.
36. Wagner, M. M. et al., Septic dermatitis of the maternal endomyometritis with intrapartum fetal monitoring,
Pediatrics, 74, 81, 1984.
37. Munsick, R. A. and Gillanders, L. A., A review of puerperal ovarian vein thrombophlebitis, Obstet.
Gynecol. Surv., 36, 57, 1981.
38. Shy, K. K. and Eschenbach, D. A., Fatal perineal cellulitis from an episiotomy site, Obstet. Gynecol.,
54, 292, 1979.
39. Wegner, D. R. and Gitchell, R. G., Severe infections following pudendal block anesthesia; need for
orthopedic awareness, J. Bone Jt. Surg., 55, 202, 1973.
40. Lawthian, J. T. and Gillard, L. J., Postpartum necrotizing fasciitis, Obstet. Gynecol., 56, 661, 1980.
41. Ammari, N. N., Hasweh, Y. G., Hassan, A. A., and Karyoute, S., Postpartum necrotizing fasciitis:
case report, Br. J. Obstet. Gynaecol., 93, 82, 1986.
42. Hibbard, L. T., Snyder, E. N., and McVann, R. M., Subgluteal and retropsoal infection in obstetric
practice, Obstet. Gynecol., 39, 137, 1972.
43. Thomsen, A. C., Espersen, T., and Maigaard, S., Course and treatment of milk stasis noninfectious
inflamation of the breast and infectious mastitis in nursing women, Am. J. Obstet. Gynecol., 149, 492,
1984.
44. Almeida, O . D. and Kitay, D., Lactation suppression and puerperal fever, Am. J. Obstet. Gynecol., 154,
940, 1986.
45. Gibbs, R. S., Infection after cesarean section, Clin. Obstet. Gynecol., 28, 697, 1985.
46. Rehu, M. and Gustof, N., Risk factors for febrile morbidity associated with cesarean section, Obstet.
Gynecol., 54, 269, 1980.
47. Bra, H. S., Golde, S. H., and Egan, J. E., Tuberculosis presenting as puerperal fever, Obstet. Gynecol.,
70, 488, 1987.
48. Friedeil, S. and Mercer, L. J., Nonmenstrual toxic shock syndrome. A review, Obstet. Gynecol. Sur.,
41(6), 325, 1986.
49. Brown, M. B., Cassell, G. H., McCormack, W. M., et al., Measurement of antibody to Mycoplasma
hominis by an enzyme-linked immunoassay and detection of class-specific antibody response in women
with postpartum fever, Am. J. Obstet. Gynecol., 156, 701, 1987.
Part V
Unexplained Fever at Different Ages
 457

Chapter 30

UNEXPLAINED FEVER IN THE PEDIATRIC AGE GROUP

Theodore C. Iancu

INTRODUCTION

The concept considering the child as a ‘small adult’ has disappeared with the advent of
modem pediatrics as an important and independent specialty. In a similar manner, neona-
tology has gained an important place within pediatrics, since premature and newly bom
babies are no longer considered to be just ‘smaller infants’ but a large group of patients
with very special, age-related problems. Moreover, the infants with very low birth weights
(500 to 1250 g) are now recognized as a group with its own specific problems, whereas at
the other end of the spectrum, adolescent medicine deals with the problems of this age
group.
The problem of unexplained fever in pediatrics has to be therefore approached by taking
into account the physiological, developmental, environmental, and pathological conditions
active in each and every pediatric subgroup. Only such an endeavor can provide an answer
to the particular patient who presents with fever, the origin of which is not self-evident or
disclosed by physical examination and routine laboratory examinations.
We will consider ‘unexplained fever’ in a rather broad manner, and not according to
the strict, time-linked defmtion of the classical ‘fever of unknown origin’ (FUO). The causes
of the latter are not essentially dissimilar to those found in adults and have been described
in detail.13 On the other hand, the fever will frequently remain ‘unexplained’ if the necessary
clinical and laboratory investigations, dictated by a carefully taken history and the use of
common sense, have not been performed. The present chapter should provide the reader
with some clinical clues and directions to be followed in order to establish a diagnosis as
soon as possible and with the help of minimal diagnostic procedures. Notwithstanding the
cost of extensive investigations, the physical and emotional trauma inflicted upon the child
and his family are all too frequently forgotten.

FEVER IN THE FULL-TERM NEONATE, PREMATURE INFANT,

AND VERY LOW BIRTH WEIGHT INFANT
PHYSIOPATHOLOGICAL PARTICULARITIES OF THE NEONATAL PERIOD
(0 TO 30 DAYS)
The apparent incapacity of the newborn, and especially of the premature infant, to adapt
to the cold environment, has generated the concept that these babies behave as poikylotherms
rather than homeotherms. Since 195 84 evidence has been available showing that newborns
possess, in fact, all the mechanisms operative later for the maintenance of temperature
homeostasis. However, the capacity to adapt to important changes in the environment is
limited, and when exceeded, the shift towards hypo- or hyperthermia is swift and deleterious.
A description of the conditions leading to heat loss in the normal or prematurely bom infant
is beyond the scope of this review. Since it has been recognized that a warm ambience
increases the chances of survival of prematures5’6 and reduces both mortality and morbidity
of prematures and full-term newborns, efforts have been directed toward the establishment
of the ‘neutral thermal environment’, at which the newborn expends the least amount of
calories to keep a constant temperature. The question ‘how warm is warm?’ has no single
answer. Gestational age, intrauterine nutrition, concomitant hypoxia, acidosis, anemia, and
458 Unexplained Fever

many other infant-related factors combine with external conditions of heat administration
and loss to produce an individual requirement for each patient. Most cases of fever in the
small premature infant, as well as many such cases in the full-term baby, are the result of
an exaggerated effort to avoid hypothermia. Because of the many factors operative in neonatal
thermoregulation the distinction between the environmentally overheated infant from one
with disease-related fever can occasionally be difficult.
As early as 1965, Oliver6 suggested that the best way to distinguish between a febrile
premature infant with an infection and one in whom the increased temperature is due to
overheating is to examine the skin temperature distribution: if the foot is as warm to the
touch as the abdomen, it is most likely that the environment is too warm; on the other hand,
if foot temperature is distinctly cool, an explanation for the infant’s fever such as infection
must be sought, because the fever of infection is usually associated with reduced heat loss
(vasoconstriction, hence cool extremities), plus hypermetabolism. This observation has been
further emphasized by Segal7 who used a thermobaric diagram to depict Oliver’s concept.
More recently, Pomerance et al.8 have demonstrated the value of measuring the rectal
temperature-leg temperature difference as an objective guideline for evaluation of temperature
elevation in the full-term neonate. The rectal-leg temperature difference was markedly higher
in infants in whom the temperature was elevated as part of a disease than in those babies
in whom the temperature was elevated by manipulation of the environment.

FEVER DUE TO INFECTIONS (BACTERIAL, VIRAL, AND OTHERS)

Most prematures, and especially those with very low birth weight, will react to infections
with hypothermia rather than hyperthermia. However, an important percentage of newborn
full-term babies will display significant temperature elevations as an early sign of life-
endangering infections. Fever occurring on the third day of postnatal life was found to have
a significantly higher chance of being associated with bacterial disease than fever occurring
at any other time in the first 4 days of life. Newborns with temperatures higher than 39°C
had a significantly higher incidence of bacterial disease than newborns with lower temper-
atures.9 While the approach towards febrile newborns may vary among different centers,
there is unanimous agreement concerning the need of their further evaluation once overheating
and dehydration have been excluded as the cause of temperature elevation. In the neonatal
period (0 to 30 days postnatal life), fever is currently defined as rectal or axillary temperature
of 37.8°C or above.9 Table 1 lists the conditions most frequently associated with abnormally
high temperatures.
Neonatal septicemia (sepsis neonatorum) due to etiological agents which cannot be
identified remains the most important cause of ‘unexplained’ fever and thermic instability
in the newborn period. However, when signs and symptoms other than fever are present,
vigorous antibiotic treatment is mandatory in this age group where morbidity and mortality
due to bacterial infections are extremely high. The early use of antibiotics occasionally
precludes bacteriological diagnosis after initial therapy. The reasons for the high percentage
of negative culture results, even when adequate specimens were obtained before antibiotics
were initiated, are unknown. The small size of the inoculum, the small amount of blood
obtained for culture, and the omission of special culture-growth media needed for the growth
of rare and especially ‘demanding’ bacteria have all been suggested, but not been proven
to be responsible for the low rate of identification.
Neonatal septicemia is frequently discussed together with meningitis1011 because of the
possible invasion of the meninges during systemic bacterial disease in this vulnerable age
group. Although in most febrile newborns with septicemia and/or meningitis the diagnosis
is obvious and reached without delay, this life-endangering condition may occasionally be
less self-evident. In some babies, especially those given antibiotics, the course of the disease
may be prolonged and the alarming signs absent.
 459

TABLE 1
Fever in the Neonatal Period

Infections
Otitis media
‘Respiratory distress syndrome’ (due to group B strep.)
Sepsis, meningitis, including partially treated
Superficial infections
Viral diseases, mainly herpes, CMV, ECHO 11
Birth trauma
Adrenal hemorrhage
Asphyxia, brain edema
Intraventricular hemorrhage
Subdural hematoma, subdural effusion
Malformations
Aspiration pneumonia, secondary to gastroesophageal reflux
Aspiration pneumonia, secondary to tracheoesophageal malformations
CNS malformations
Gastrointestinal malformations with bacterial overgrowth
Urinary tract malformations with infection
Miscellaneous
Anhydrotic ectodermal dysplasia
Congenital adrenal hyperplasia
Congenital ichthyosis
Cow’s milk fever, mainly whole milk powder
Cystic fibrosis
Dehydration (especially in small for gestational age newborns)
Diabetes insipidus
Familial dysautonomia
High environmental temperature
High protein content of diet, including parenteral feeding
Hyperthyroidism
Jaundice (kemicterus; obstructive cholangiopathy)

During the last 50 years, marked changes in nursery pathogens have been noted. At
present, significant differences can be found among various continents, countries, cities,
and hospitals. Nevertheless, general trends can be recognized. In the U.S. and some Western
European countries, group B streptococci (GBS) may account for as many as V3 of all cases
of neonatal sepsis, being the most common bacterial agent causing bacteremia and/or men-
ingitis in prematures and infants younger than 6 weeks of age.12 In a recent study from
Israel, Weintraub et al. have shown a much lower maternal colonization and even rarer
neonatal colonization with GBS than in other countries. The reasons for these differences
are poorly understood.13 Other pathogens have been isolated from the blood or cerebrospinal
fluid (CSF) of newborn and premature infants including E. co li, Group D Streptococci,
S ta p h ylo co ccu s a u re u s , the K leb sie lla -E n te ro b a c te r group, L iste ria m o n o c y to g e n e s , and
P seu d o m o n a s a eru g in o sa . The group of bacteria usually found in infants and children beyond
the neonatal period which can be occasionally isolated in sick newborns comprises H a e -
m oph ilu s in flu en za e , S tre p to c o c c u s p n e u m o n ia e , N e isse ria m e n in g itid is , S a lm o n ella typhi-
m u riu m , and S h ig ella species. The role of anaerobes has not been fully clarified. High
mortality and substantial morbidity have been associated with infections caused by B a c te r -
o id e s and C lo strid iu m species.10
The factors determining the transformation of asymptomatic bacteremia into symptomatic
sepsis or meningitis have not been clearly identified. Host as well as maternal and environ-
mental factors may influence contamination and development of disease in exposed new-
borns. For the pediatrician faced with a febrile newborn, it is of major importance to recognize
as early as possible the other signs of sepsis which are mostly not specific: alternating hyper-
460 Unexplained Fever

and hypothermia despite no change in the ambient temperature; apnea, respiratory distress,
and, in artificially ventilated infants, hypoxia with increased Fi02 requirements; pallor, cold
extremities, jaundice, petechiae; feeding difficulties — poor suck, regurgitations and vom-
iting, abdominal distension and reduced peristalsis, diarrhea or constipation; irritability,
lethargy, jitteriness, or seizures. The presence of one or more of these signs and symptoms,
in addition to fever, indicate clinical follow-up and laboratory investigations. The general
condition of the newborn is, nevertheless, of major importance in the decision-making process
as related to the timing and extent of these diagnostic procedures.
McCracken and Feij10 have described a number of clinical syndromes encountered in
newborns with bacterial infections, all of which may present as fever of unexplained origin.
In as many as 50% of all cases, the search for the etiological agent will fail. In the ‘Early-
Onset Syndrome’, GBS an&Listeria monocytogenes will cause an acute, sometimes fulminant
disease mainly with a respiratory distress syndrome similar to that of the hyaline membrane
disease. When Listeria monocytogenes is the causative organism, fever, a flu-like disease,
occasionally with gastrointestinal symptoms, and positive blood cultures can be found in
the mother. In the infant, a maculopapular skin rash, petechiae, purulent conjunctivitis,
granulomatous posterior pharyngitis, hepatosplenomegaly, and a miliary type of broncho-
pneumonia are considered typical findings. The ‘Late-Onset Syndrome’ due to these same
agents begins usually insiduously between 2 to 4 weeks of age, but sometimes as late as 3
months. Fever is prolonged in most patients, and some may have meningeal involvement
without overt signs of meningitis. In patients with Listeria meningitis, the CSF contains
mainly mononuclear cells, in contrast to other bacterial infections. Bacteria detected in
newborns with both systemic and localized disease include again GBS, E. coli, and rarely
H. influenzae. More frequently, Staphylococcus aureus is found in purulent secretions on
the umbilical stump, on the glandular area after circumcision, in eye secretions, and within
the pustular or bullous lesions of pemphigus neonatorum. More recently, phage II coagulase-
positive staphylococci have been isolated in various neonatal skin infections, including
bullous impetigo, toxic epidermal necrolysis and nonstreptococcal scarlet fever. Some new-
borns with Staphylococcus aureus infection will develop fever and more deeply located skin
or breast abscesses, purulent arthritis, osteomyelitis, and rarely, pulmonary involvement or
meningitis.
While the above-mentioned clinical picture is rather typical for Staphylococcus aureus,
it is important to realize that other bacteria like GBS and H. influenzae can also cause such
manifestations. Salmonella strains can produce osteomyelitis and E. coli accounts for 70%
of all cases of meningitis caused by enteric bacilli, which can be complicated by brain
abscesses. This latter complication is found in 50% of newborns surviving Citrohacter
diversus meningitis. Urinary tract infections are mostly due to E. coli, even in the neonatal
period, and are very frequently associated with fever, with or without other signs of sepsis.
Feeding problems and prolonged jaundice are among the nonspecific manifestations of
urinary tract infection often found in the newborn baby.

OTHER CAUSES OF FEVER IN THE NEONATAL PERIOD

Dehydration fever is especially frequent in hot areas, but not only in infants suffering
from acute gastroenteritis with diarrhea and excessive fluid loss. Even normal, full-term
healthy newborns will develop an increased temperature if ample water supplements are not
provided on especially hot and dry days. Typically, the temperature, which may reach 39°C,
is higher during the early hours of the morning, if no supplementary water has been given
during the night. This type of fever is similar, to some extent, to the hyperthermia of
newborns in overheated incubators or under radiant heaters. Undressing the infant, and
providing a cooler ambient temperature and large amounts of water, will result in a drop in
the temperature within 6 to 24 h. Feeding the newborn infant with cow’s milk, mostly if
 461

prepared from whole-milk powder, will frequently contribute to the elevation of the tem-
perature. It has been suggested that these infants will have a discrete hypertonic dehydration,
as a consequence of the high content of NaCl and protein in whole cow’s milk powder and
temperature elevation is a consequence of both the dehydration and of the specific dynamic
activity of the proteins.
C o n g en ita l a d re n a l h yp erp la sia when accompanied by dehydration, as in the 21-hy-
droxylase deficiency, can present with fever as well, which is frequently ‘unexplained’,
because signs, symptoms and laboratory abnormalities may be initially subtle.
In tra ven tric u la r h em o rrh a g e and a d re n a l h em o rrh a g e have been described as producing
long-standing fever in neonates. In the former, both the accompanying brain damage and
the hemorrhage itself may contribute to the unstable temperature, whereas in the latter, it
is mainly the resorption of the blood itself which has been incriminated, as it has been
noticed in other systemic hemorrhagic diseases when bleeding occurs into viscera or other
body tissues.14That hemolysis per se can produce fever is suggested by its appearance during
hemolytic crises of various origins, including those seen in the neonatal period, and occa-
sionally after blood transfusions.
Brain damage at any age, including the neonatal period, can be associated with prolonged
periods of fever, and k ern icteru s and su b d u ra l h em atom a or su b d u ra l effusion can produce
fever even in their early stages. A n h y d ro tic ec to d e rm a l d y sp la sia has been reported to be
an unusual cause of pyrexia in the newborn,15 and in fa m ilia l d ysa u to n o m ia (Riley-Day
syndrome) both hypo- and hyperthermia can be frequently noticed. The dysfunction of
thermoregulation persists later in life and is considered to be part of the general imbalance
of the nervous system or of centrencephalic origin.

FEVER IN INFANCY (1 TO 24 MONTHS) AND CHILDHOOD (2

TO 16 YEARS)

Some of the causes of unexplained fever occurring in neonates will persist, especially
in the second month of life. These are temperature elevations related to a hot environment,
dehydration of various causes, milk fever, as well as CNS pathology, bleeding disorders,
and some of the genetic conditions, like familial dysautonomia. Even when hospital facilities
are available, the cause of the fever may remain unidentified in as many as 52.6% of febrile
infants less than 8 weeks of age.16 The classification frequently used for ‘fever of unknown
origin’ can be applied to both infants and children. It includes in fectiou s d is e a s e s , co lla g en -
va scu la r d is e a s e s , m a lig n a n cie s , and m iscella n eo u s c a u se s .3 Table 2 lists the conditions
associated with unexplained fever in infancy and childhood.13’17,18 The detailed discussion
of the subject is beyond the scope of this chapter, but several aspects deserve further comment.

INFECTIOUS CAUSES OF UNEXPLAINED FEVER

Beyond 2 months of age there is a striking rise in the number of patients seeking medical
advice and having fever. Since fever is such a frequent complaint (present in up to 20% of
the visits of a pediatric population in urban or suburban clinics)19 and can either be benign,
or the first sign of a life-threatening infection, many attempts have been made to identify
infants and children at high risk for bacteremia and septicemia. Fever without localizing
signs (FWLS) is present in 5 to 10% of febrile children younger than 24 months.18 The
degree of fever plays an important role in any such attempt: the majority of infants have
mild elevations and no diagnosable illness.19 Fever above 38.3°C is relatively uncommon
in very young infants, but progressively increases in frequency with each month of age.
Fever above 40°C has a greater probability of being due to a serious underlying infection,
and more infants with meningitis are found in this group. However, in all groups investigated,
more than half of the patients had negative bacteriological studies. Among 175 infants less
462 U n ex p la in ed F e ve r

TABLE 2
Prolonged Fever in Infancy and Childhood

Infections
Bacterial hepatitis and cholangitis
Cat-scratch disease
Chlamydia trachomatis infections
Chronic otitis media, oto-antritis, mastoiditis, adenoiditis
Deep abscesses
Dental infections
Endocarditis (including subacute), myocarditis, pericarditis
Mycoplasma pneumoniae infections
Osteomyelitis
Partially treated meningitis, meningoencephalitis
Rickettsial infections, including Q fever
Septicemia, including pneumococcal, meningococcal, streptococcal and FWLS
Tuberculosis, brucellosis, leptospirosis, spirochetal infections
Tularemia
Typhoid fever; other salmonella infections (‘enteric fever’)
Upper respiratory tract infections with lymphadenopathy
Urinary tract infections
Yersinia enterocolitica, Y. pseudotuberculosis infection
Acute infectious lymphocytosis
Cytomegalovirus infection
Drug-induced hepatitis
Hepatitis, autoimmune
Hepatitis, viral, icteric and anicteric
Infectious mononucleosis
Coccidiomycosis
Cryptococcosis
Leishmaniasis, visceral
Malaria
Schistosomiasis
Toxoplasma infections
Trichinosis
Visceral larva migrans
Blastomycosis
Candidiasis, systemic
Histoplasmosis
Collagen-vascular disease
Erythema multiforme
Familial Mediterranean fever
Hemolytic-uremic syndrome
Inflammatory bowel disease
Mucocutaneous lymph node syndrome
Periarteritis nodosa
Periodic fever
Rheumatic fever
Rheumatoid arthritis
Serum sickness
Systemic lupus erythematosus
Malignancies
Brain tumors
Ewing’s sarcoma
Hepatoma
Leiomyoma
Leukemia
Lymphoma (Hodgkin and non-Hodgkin)
Neuroblastoma
Osteosarcoma
Wilms’ tumor
 463

TABLE 2 (continued)
Prolonged Fever in Infancy and Childhood

Miscellaneous
Adrenal insufficiency
Atropine poisoning
Cow’s milk aspiration — Heiner’s pneumonia
Cow’s milk intolerance and powder-milk fever
Degenerative brain diseases
Diabetes insipidus
Drug fever
Ectodermal dysplasia
Factitious fever
Familial dysautonomia
Heat stroke
Histiocytosis X
Immunologic deficiencies
Inadequate fluid intake
Infantile cortical hyperostosis
Low-grade fever in overweight and/or active children
Postpericardiotomy syndrome
Sarcoidosis
Sickle-cell anemia and other hemolytic anemias
Subdural effusion or hematoma
Thyroiditis
Thyrotoxicosis

than 8 weeks of age, Crain16 found only 11 infants (6.2%) with positive bacterial cultures
from CSF, blood, stool, or urine. Only six infants (3.4%) had bacteremia. The bacteria
identified in this study were S a lm o n ella strains, S trep to co c cu s p n e u m o n ia e , H . in flu en zae ,
E. c o lif GBS, and S h ig ella species. As for infants with GBS bacteremia and/or meningitis,
it was considered that this condition is limited to prematures and infants below 60 days of
age. Recently, Strauss reported its occurrence in two infants aged 90 and 115 days, re-
spectively.20 Thus, GBS should be added to the list of agents causing unsuspected bacteremia
in infants older than 60 days.
The fact that many small infants present with FWLS makes the diagnosis of unexplained
fever even more difficult. A white blood cell count (WBC) of 15,000/mm3 or higher and
an erythrocyte sedimentation rate (ESR) greater than 30 mm/h will identify about 2/3 of
children with serious bacterial illness.19 However, about 60% of children with a high WBC
and ESR will not have serious underlying infection. Thus, the decision of performing or
not performing a lumbar puncture must frequently rely on clinical judgment.21
Anderson and colleagues22 studied the clinical features and natural history of unsuspected
H aem oph ilu s in fluenzae (Hib) type b bacteremia. Their patients were typically under 2 years
of age, had high fevers, and frequently had otitis media at presentation. These children were
found to be at high risk for developing serious focal infections, particularly meningitis
(32%), despite empiric antibiotic therapy. Those developing focal complications had a
significantly higher mean fever of 40.3°C compared to 39.7°C. Even though 66% of the
children were discharged from the emergency department at the time of the initial visit with
the diagnosis of otitis media, we quote this report since 12% were diagnosed as ‘fever
without source’, another 12% as ‘viral syndrome’ and 10% were diagnosed as febrile seizures,
gastroenteritis, and pharyngitis. Because of the high risk of developing serious focal infec-
tions, notably meningitis, children with documented or suspected Hib bacteremia should be
promptly and carefully re-evaluated, even if oral antibiotics were instituted at the time of
the initial visit. Parenteral antibiotic therapy is the treatment of choice for most of these
patients.
464 U nex p la in ed F e ve r

Notwithstanding the above-described cases of occult bacteremia progressing to menin-

gitis, most infants with se p tic e m ia and m enin gitis will present with acute symptoms so that
few infants with these conditions will fall into the group of ‘unexplained fever’. A less acute
evolution can raise diagnostic difficulties such as in b a c te ria l e n d o c a r d itis , and in some
u rinary tra c t in fection (UTI) with intermittent urinary findings. Nine centers collaborated
to determine the rate of UTI in infants with unexplained fever.23 Among 193 febrile infants
aged 0 to 2 years, there was a rate of 4.1% confirmed urinary tract infections. All infections
were in girls, with a rate of 7.4%. These data support the advisability of culturing the urine
of infant girls with unexplained fever.
A multitude of a b sc e sse s which can remain undiagnosed for variable periods of time
(pararectal, pelvic, perinephric, intra-abdominal, subdiaphragmatic, and liver abscesses).
O ste o m ye litis can occasionally present as a low-grade infection without localizing signs,
such as in infections of the pelvis, spine, scapula. S a lm o n ella in fections of bone and joints,
mainly with salmonella typhi, are not as rare as previously considered and can produce fever
without localizing signs. C h ro n ic m a sto id itis can be at the origin of prolonged fever in
infants with im m une d efic ien cies and ch ro n ic o to rrh ea . Infants and small children up to 3
years of age, who have repeated bouts of acute otitis media during the winter season, may
present with temperature elevations in the morning, which have been attributed to in fection s
o f h yp ertro p h ic a d en o id s. There are no controlled studies documenting the relationship
between upper respiratory infections (URTI) and unexplained fever. Their presence in a
certain group of infants with frequent URTI during the cold season, and the improvement
noted after aggressive antibiotic treatment, strengthens the supposition that these are bacterial
infections of the upper respiratory lymphatic tissue.
Among infections of the central nervous system, p a r tia lly tre a te d m en in gitis, su b d u ra l
effusions, and bra in a b sc e sse s in a n tib io tic -tre a te d ch ildren can be at the origin of prolonged,
unexplained fever. Among systemic infections without localization, ‘stre p to c o c c o sis' and
‘p n e u m o c o c c o sis ’ have been diagnosed with increased frequency.
In recent years, g a stro in te stin a l in fection s with C a m p y lo b a c te r je ju n i and Y ersinia en-
te ro co litic a have been responsible for endemic and epidemic diarrhea, which can be accom-
panied by a multitude of extra-intestinal manifestations. C a m p y lo b a c te r je ju n i can cause
fever, occasionally up to 40°C, and seizures, in a proportion exceeding that expected in
infants and children with fever of other etiologies.24 Y ersinia e n te ro co litic a gastroenteritis
and Yersinia p se u d o tu b e rc u lo sis can be preceded or followed by episodes of unexplained
fever and arthritis or arthralgia, but prolonged fever may be the only sign.25
V iral in fection s accompanied by unexplained fever in infancy include cy to m e g a lo v iru s
infection, the in fectiou s m o n o n u cleo sis syn d ro m e (not necessarily due to the Epstein-Barr
virus) and the h ep a titid es. The latter are usually hepatitis B virus (HBV)-related and can be
diagnosed by the presence of serological markers. These viral infections are frequently
acquired through blood transfusions and may present with fever and extra-hepatic manifes-
tations long before a diagnosis of hepatitis is made. Chronic active hepatitis (CAH) of the
autoimmune type can be either HB V-related or of unknown origin. A rare type of autoimmune
hepatitis which has been found in children from age 4 years is characterized by anti-liver-
kidney microsomal antibodies.26 All types of autoimmune and HB V-related chronic active
heptitis, as well as drug-induced hepatitis, can present with prolonged and undiagnosed
periods of fever. Serological markers for HBV infection or autoimmune processes may take
time to become positive. Liver biopsy and extensive serological investigation are often
required for the establishment of the correct diagnosis.27
In addition to hepatitis, transfusion-associated infections include those with the human
immunodeficiency virus (HIV). Approximately 95% of patients with hemophilia A and
extensive use of non-heat-treated factor VIII concentrate were found to have HIV antibodies.
As of January 1986, there have been 53 reported cases of transfusion-associated acquired
 465

immunodeficiency syndrome (AIDS).28 An additional case has been recently reported29 in

a 44-month-old girl with prolonged fever and bleeding per rectum. Many of these patients
have associated infections with cytomegalovirus, P n e u m o cy stis ca rin ii and/or other oppor-
tunistic infections.
In otherwise healthy children, most rickettsial, fungal, and parasitic diseases are quite
rare and present with some feature which enables diagnosis in a relatively short time.
However, Q fever, a rickettsial disease due to C o x iella bu rnetii, was diagnosed in 18 children
younger than 3 years of age in The Netherlands during a 16-month period.30 Four children
had relapsing episodes of fever during several months. The diagnosis of Q fever was con-
firmed serologically by means of a complement-fixation test and immunofluorescence for
IgM. Toxoplasmosis may cause problems since an elevated antibody titer is not necessarily
equivalent to active infection.

COLLAGEN-VASCULAR DISEASES
J u ven ile rh eu m a to id a rth ritis, the systemic form or Still’s disease, is characterized by
a febrile onset, which can precede the arthritis by as much as 6 months. Daily spiking
temperature elevation may reach 39°C or more, often with 2 peaks daily. Other manifestations
include a salmon-colored morbilliform rash, often with central clearing and occurring any-
where on the body. The rash occurs mainly when the temperature is elevated. The presence
of hepatosplenomegaly and generalized lymphadenopathy and laboratory examinations, which
are negative for bacterial or other infection, will point towards the correct diagnosis in most
cases. Regretfully, because of the ‘septic’ fever, marked leukocytosis, and positive acute
phase reactants, patients are frequently treated with antibiotics, even though bacteriological
studies are negative. The other forms of rheumatoid arthritis usually present with joint
involvement in parallel with the presence of temperature elevations. Systemic lupus erythe-
matosus (SLE) has been reported in all age groups, from infancy to adulthood, but fever is
associated with the typical butterfly rash and arthritis. R h eu m atic fe v e r , H enoch -S ch on lein
p u rp u ra , and the h em o lytic-u rem ic syn d ro m e are other examples of vasculitis, but they
seldom present with fever without other symptoms which enable diagnosis.
M u cocu ta n eo u s lym ph n o d e syn d ro m e (MLNS-Kawasaki disease)31 originally described
in Japan, is now known to have a worldwide distribution and a peak incidence at 18 months
of age. Its inclusion in the group of collagen-vascular diseases is justified by the failure as
yet to identify a bacterial or viral agent and by the fact that some patients have coronary
thrombosis and other features of infantile polyarteritis. In its first stage, which lasts 1 to 14
days, the infants present with an acute febrile illness, during which 90% of the patients
develop bilateral conjunctival infection, truncal erythematous maculopapular rash, palmar
and plantar erythema, erythema of mucous membranes, and cervical lymphadenopathy.
During this stage, aseptic meningitis, diarrhea, and liver involvement, including hydrops of
the gallbladder, can also be found. During the subacute stage, lasting from day 10 to 25,
desquamation of the extremities takes place, progressing centrally from palms and soles.
Although the fever may have subsided, the infants continue to be anorexic and irritable.
Laboratory examinations are noncontributory, with the exception of marked thrombocytosis.
This justifies treatment with low aspirin doses, in an attempt to prevent cardiac infarction
secondary to coronary arteries involvement with aneurysms and thrombosis, reported in some
cases of MLNS. More recently, intravenous gamma glubulin (400 mg/kg/day for 5 days)
has been found to be beneficial, along with aspirin. The chronic stage of the disease lasts
for another 1 to 2 months, during which the clinical manifestations fade away. Because of
the coronary involvement, death can occur even several months after clinical remission.

M ALIGNANCIES
The neoplasms which can present with fever in infancy and childhood are mainly acute
lymphocytic leukemia (ALL), neuroblastoma, Hodgkin’s and non-Hodgkin lymphoma, sar-
466 U n ex p la in ed F e ve r

coma, and hepatoblastoma. An incidence varying between 2 and 13% has been reported for
malignancies as final diagnoses among pediatric patients with FUO.18 Rarer tumors, such
as leiomyoma of the large bowel, can present as prolonged fever, anemia, and thrombo-
cytosis.32 In the pre-chemotherapy era, fever was frequently attributed to tumor-related
necrosis, hemorrhage, or pyrogens.33 In the patient on chemotherapy, fever has been linked
with infection, especially in the granulocytopenic patient. However, since an infectious
etiology can be established in no more than 50 to 70%, it appears that in some patients the
fever must be tumor-related (25% in nongranulocytopenic and 48.2% in granulocytopenic
patients).33 Wood and Corbitt34 studied the incidence of viral infections in leukemic children
with acute pyrexia of unknown origin. Among 150 children receiving therapy for leukemia
these investigators identified 105 viral infections, with herpes simplex virus and varicella-
zoster virus being the most common agents. Adenoviruses, parainfluenza viruses, rhinovi-
ruses, and enteroviruses were other important causes of morbidity. This information is
especially important in view of the newer antiviral agents available. The attitude towards
infants with diagnosed malignancies who are immunosuppressed and who have fever is
practically identical to that toward older children but requires empiric antibiotic therapy,
regardless of their underlying malignancy or clinical presentation.

MISCELLANEOUS
From this group, we will discuss in some detail only a few conditions of special interest
in pediatrics.
Infantile c o r tic a l h y p e ro sto sis — C offey d ise a se affects infants usually in the first 3
months of age. Days or weeks of unexplained fever are followed by swelling of soft tissues
over the jaws. The mandible and occasionally long and flat bones will show progressive
cortical thickening, and the level of serum alkaline phosphatase is moderately elevated. The
fever subsides after a few weeks, but may return during episodes of re-exacerbation which
sometimes continue during infancy.
F e ve r in the a b u se d infant a n d ch ild is quite frequent. The smaller the patient, the higher
the chances of fever in a battered child. The exact mechanism of temperature elevation is
not clear. Since many infants have multiple fractures roentgenographically similar to sub-
periostal bleeding, resorption of hematoma can be implicated. Some battered children have
suffered brain concussions, with or without retinal bleeding, but whether the fever is of
cerebral origin is not known. In some abused infants the presence of fever, leukocytosis,
local signs of bone inflammation, and radiological findings will erroneously guide the
diagnosis towards low-grade osteomyelitis. S u b d u ra l h em atom a or su b d u ra l effusion may
not only follow traumatic delivery, but also concussion during the first months of life, and
may appear long before head enlargement or neurological signs are found. A few infants
with c e re b ra l p a ls y or d e g e n e ra tiv e bra in d ise a se s can also present with prolonged low-
grade fever and failure to thrive.
With regard to m e ta b o lic cau ses, fever following fe e d in g w ith co n ce n tra te d w h o le c o w ’s
m ilk fo rm u la is encountered not only in the neonatal period, but in infancy as well, especially
during the first 6 months of life, when the water intake is limited. Hyperosmolality and
relative or absolute water deprivation are also found during a cu te g a stro e n te ritis w ith d e -
h ydration , but in this condition the fever is seldom ‘unexplained’. In various forms of
d ia b e te s in sipidu s, fever is the only symptom for a long time. Frequently, a typical inversion
of the normal diurnal temperature variation can be observed, with higher readings in the
morning than in the afternoon, apparently because of the reduced fluid intake at night.35
D ru g f e v e r can be produced by most of the currently used therapeutic agents, but those
frequently involved are penicillin, sulfonamides, amphotericin B, antihistamines, phenytoin,
barbiturates, and salicylates. The cephalosporins, rifampicin, nitrofurantoin, streptomycin,
hydralazine, atropine, epinephrine,and immunosuppressive agents such as azothioprine and
 467

cyclosporin cause fever less frequently. Drugs account for 1 to 2% of prolonged fevers of
unknown origin in children.36 There are several mechanisms by which drugs can produce
fever, but prolonged fever is usually the result of a hypersensitivity reaction to the drug,
immunological in nature and involving IgG and IgE antibodies. Allergic symptoms such as
rash, urticaria, pruritus, and eosinophilia may be present. Their absence does not exclude
the diagnosis of drug fever. The general condition of the patient is usually good and the
fever is out of proportion to the general condition. Following the withdrawal of the drug,
the fever disappears rapidly. P seu d o m em b ra n o u s co litis (PMC) and a n tib io tic -a sso c ia te d
co litis (AAC) are frequently associated with prolonged fever, the nature of which is over-
looked. Although all broad-spectrum antibiotics have been implicated, ampicillin, amoxi-
cillin, and clindamycin are the most prominent, corresponding to the extent of their use.
The heat-labile cytotoxin of C lo strid iu m d ifficile is present in the stools of 95% of patients
with PMC and more than 50% of those with AAC. The discontinuation of the antibiotic
will suffice in some patients, but oral vancomycin therapy, which has dramatic effects on
all manifestations including fever and diarrhea, is required in PMC. Metronidazole and
bacitracin have also been found to be effective in PMC, while AAC has usually a benign,
self-limited course that subsides spontaneously when antibioitics are discontinued. Fever
has been sometimes noted in ‘a lle r g ic ' co n d itio n s such as u rtic a ria , c o w 's m ilk in to lera n ce,
H e in e r'sp n e u m o n ia (cow’s milk aspiration), p u lm o n a ry h em o sid ero sis, and seru m sic k n e ss .
In both u lce ra tiv e c o litis and C ro h n 's d is e a s e , fever may precede any other symptom
by weeks and even months. In ulcerative colitis, a low-grade fever peaking in the evening
can be documented for prolonged periods of time, occasionally associated with chills,
leukocytosis and an elevated erythrocyte sedimentation rate (ESR). E ryth em a n odosum , in
the past usually preceding or accompanying tuberculous secondary spread, is now more
frequently found in children with prolonged low-grade fever who will subsequently be
diagnosed as having inflammatory bowel disease. In Crohn’s disease, fever is found in up
to 70% of the patients, is usually intermittent and rarely exceeds 39°C. Both ulcerative
colitis and Crohn’s disease exist from early infancy into adulthood.
P e rio d ic d iso r d e rs such as fa m ilia l M e d ite rra n e a n f e v e r (F M F ), p e r io d ic fe v e r , and
etio ch o la n o lo n e f e v e r have in common the appearance of fever for a few days, followed by
long periods of normal temperature (weeks or months in FMF, and 7 to 21 days in periodic
fever). Etiocholanolone fever has been described in patients with recurrent fever and elevated
level of this unconjugated steroid in the serum. More recently, the existence of this entity
has been questioned.37 In contrast, FMF affects a relatively large number of children and
adolescents. High fever lasting for a few days can be the only symptom, but most children
will complain of colicky abdominal pain which will frequently be diagnosed as acute ap-
pendicitis. Serum fibrinogen levels will rise during the attack, and may remain permanently
increased, similarly to the ESR. Arthralgia or arthritis is occasionally encountered and
amyloidosis and renal failure are later complications. A positive family history and Jewish-
Sephardic, Armenian, or Arab origin will increase the index of suspicion. In 1984, Van der
Meer and colleagues reported on six patients of Dutch ancestry with a clinical picture similar
to FMF.38 All patients had recurrent attacks of fever of unknown cause, beginning in infancy
or childhood. In addition to FMF-typical signs and symptoms, generalized lymphadenopathy
was found. Also present were high serum IgD levels and a large number of plasma cells
with cytoplasmic IgD in the bone marrow. Similarly to FMF, colchicine therapy induced
remissions in these patients. In the ‘periodic fever syndrome’ described initially by Rei-
mann,39 the afebrile interval appeared to be quite regular and short, and the patients were
neutropenic.
B enign lo w -g ra d e f e v e r has been repeatedly noted in infants and small children, without
any physical or laboratory findings of disease. Frequently, a variable degree of obesity is
present and a temperature of 38 to 38.2°C can be measured, especially after physical activity,
even of short duration, or after meals. Maternal anxiety increases the number of temperature
468 Unexplained Fever

measurements in otherwise healthy children. Admission to hospital and subsequent noso-

comial infection will end in several episodes of intercurrent infections, only increasing the
family’s certitude that the child is ill. Simple routine investigation should suffice to exclude
organic disease in a healthy-appearing and normal-behaving child.
Several variants have been described under the heading of factitious fever.40 Some
neurotic parents or older children (including those with school phobia), have been found
rubbing the thermometer or dipping it into hot water in order to convince the entourage of
the existence of a ‘real’ disease. Frequently parents and child collaborate in creating the
psychoneurotic setting focused on the symptom ‘fever’. The measurement of urinary tem-
perature is useful in differentiating true from factitious fever due to manipulation of the
thermometer.41 The ensuing secondary gain may not be obvious and psychiatric advice and
family therapy are mandatory. Other parents are extremely anxious and disturbed by the
slightest temperature elevation or even by the normal-high temperature of the late afternoon.
To justify their repeated demands for investigations and examinations, they purposefully
exaggerate the temperature readings and try to convince the physician by providing tem-
perature charts. Many parents, without any neurotic or frank emotional disturbance, are
unduly worried about low-grade fever, with temperature of 38.9°C or less. Their overconcem
has been designated ‘fever phobia’.42 These parents are convinced that even moderate fever
can cause serious neurological side-effects. Health education, clear explanation with regard
to the significance of fever and the few indications for antipyretic therapy, are required in
order to reduce fever phobia and the use of superfluous, potentially harmful antithermic
procedures.

UNEXPLAINED FEVER IN THE ADOLESCENT

In this age group, there are few conditions preceded by, or associated with, prolonged
fever of unclear etiology. Among infectious diseases, special attention should be directed
towards the various forms of chronic hepatitis, including autoimmune HBV-associated CAH,
non-HBV-associated autoimmune (‘lupoid’) hepatitis, anicteric non-A, non-B hepatitis, and
infectious mononucleosis. Bacterial infections frequently diagnosed late include endocarditis,
deeply located abscesses, urinary tract infections, and tuberculosis. Special attention should
be directed towards infections transmitted during sexual activities. Typically, patients with
urethritis have no systemic symptoms. However, should the terminal vesicles, prostate, or
kidneys be involved with the infective process, fever is usually a feature. The causative
factors which must be considered are bacterial infections (including gonorrhea), chlamydial
and monilial infections, trichomoniasis, and the presence of trauma or foreign bodies.
Gonococcal salpingitis can occur not only in an acute but also in a subacute or chronic form.
Perihepatitis has been reported as a complication occurring in as much as 27% of adolescents
with salpingitis, which is a higher rate than is reported in adults. In some cases of perihepatitis,
and in Reiter’s syndrome, Chlamydia trachomatis has been identified as the causative agent.
Similarly to the gonococcal infections, chlamydial infections can be asymptomatic, uncom-
plicated, or complicated and disseminated, and associated with febrile episodes of variable
duration.43
A number of noninfectious diseases are found more frequently beyond puberty, such as
inflammatory bowel disease, hepatic cirrhosis, SLE, Hodgkin and non-Hodgkin lymphomas,
hepatoma, Behcet’s syndrome, and some of the brain tumors.

THE APPROACH TO THE INFANT AND CHILD WITH

UNEXPLAINED FEVER

The approach to the pediatric patients with unexplained and/or prolonged fever is usually
a ‘staged’ program. We will only stress the age-specific aspects of the problem.
 469

1. Is the temperature elevation ‘genuine’ and the result of disease? The importance of
the ambient thermal environment cannot be overemphasized, especially in countries
with a hot climate and when the child is overdressed. On a warm day, a child who
has a temperature of 38 to 38.5°C should have his temperature taken again after a half
hour to cool off, before concluding that he has fever. This applies not only to single
episodes, but also to children with prolonged fever, who are submitted to numerous
investigations, although no objective signs of disease are present.
2. Once the fever has been established as real, its pattern is important and should be
recorded. No antipyretics should be given before temperature measurements. This
symptomatic therapy is preferably given only to patients with a fever higher than
39.0°C or if the child is uncomfortable or has a history of febrile convulsions. As
early as 1897, Holt wrote: “ The routine practice of ordering full doses of antipyretic
drugs whenever on the first visit an elevation of three or four degrees is discovered
cannot be too strongly deprecated. In many cases it is very important to know whether
the temperature uninfluenced by drugs is remittent, intermittent, or steadily high, and
hence the advantage of waiting until a diagnosis has been made before disturbing the
temperature curve, always provided, of course, that the child is in no danger from the
high temprature — a condition which is certainly not common.” The importance of
this statement, which is difficult to improve, is even greater in the antibiotic era.
Regretfully, pediatricians are still prescribing antibiotics without a diagnosis, even for
conditions which do not require a blind ‘therapia magna sterilisans’.
3. The investigations to be performed in a child with prolonged, unexplained fever may
vary in different settings. Geographical, cultural, and epidemiological factors are
important. Whether the child is investigated by a pediatrician, a family physician, in
a private clinic, or in a teaching hospital will also influence the extent of investigations.
The degree of previous experience of the examiner is of paramount importance in the
process of decision-making, especially in small infants and children. In such cases the
specter of the missed meningitis or septicemia may generate frequent useless, traumatic
and potentially dangerous diagnostic procedures. Observing the patient with prolonged
fever in hospital is quite convenient for the pediatrician, but less so for the patient,
his family and the health insurance budget. A frequently adopted strategy is the
performance of examinations and investigations which may detect life-endangering
illness and avoid hospitalization, if the general condition of the child is satisfactory
and the parents are reliable. The ‘Day-Hospital’ is a most useful framework for such
patients. If the first line routine examinations are negative, the investigations are
directed towards the finding of rare infective agents (venous, arterial, and bone marrow
cultures for aerobic and anaerobic bacteria); the possibility of tumors, deeply located
abscesses or malformations is investigated with the help of bone scans, ultrasonographic
studies, CT scan, and possibly magnetic resonance imaging. Focal infectious processes
(one dental and four abdominal infections) were correctly identified in five patients
with at least 3 weeks of unexplained fever using indium-111-granulocyte scintigraphy.44
Thanks to these modem modalities, previously used invasive methods such as lym-
phography, arteriography, and laparotomy are only rarely needed.

CONCLUSIONS
With the pediatric age group ranging from prematurity into adolescence, the multitude
and heterogeneity of factors responsible for unexplained fever is larger than that of any other
class of patients. If the initial examinations are not rewarding, a teamwork approach including
subspeciality studies and extensive laboratory investigations, may become necessary. Be-
cause of the continuous expansion of investigative methods, a staged method (? computer-
470 U n ex p la in ed F e ve r

assisted) may be the best way to avoid the gathering of noncontributory information. Ret-
rospective studies have shown, however, that a carefully taken history, a complete physical
examination, and the performance of routine laboratory investigations can solve most cases
of unclear fever. With all the progress in investigative methods, an empathic attitude, backed
by sound clinical judgment and common sense, is still most rewarding when facing the
problematic pediatric patient with unexplained fever.

ACKNOWLEDGMENTS

The author is grateful to the Milman Fund for Pediatric Research for supporting in part
this work and to Dr. M. Efrat for his comments and suggestions.

REFERENCES
1. McClung, J. H., Prolonged fever of unknown origin in children, Am. J. Dis. Child, 124, 544, 1972.
2. Pizzo, P. A., Lovejoy, F. H., and Smith, D. H., Prolonged fever in children: review of 100 cases,
Pediatrics, 55, 468, 1975.
3. Feigin, R. D. and Shearer, W. T., Fever of unknown origin in children, Curr. Probl. Pediatr., 6, 2,
1976.
4. Silverman, W. A., Fertig, J. W., and Berger, A. P., The influence of the thermal environment upon
the survival of newly bom premature infants, Pediatrics, 22, 876, 1958.
5. Jolly, H., Molyneux, P., and Newell, D. J., A controlled study of the effect of temperature on premature
babies, J. Pediatr., 60, 889, 1962.
6. Oliver, T. K., Temperature regulation and heat production in the newborn, Pediatr. Clin. North Am., 12,
765, 1965.
7. Segal, S., Neonatal intensive care, Pediatr. Clin. North Am., 13, 1149, 1966.
8. Pomerance, J. J., Brand, R. J., and Meredith, J. N., Differentiating environmental from disease-related
fevers in the term newborn, Pediatrics, 67, 485, 1981.
9. Voora, S., Srinivasan, G., Lilien, L. D., et al., Fever in full-term newborns in the first four days of life,
Pediatrics, 69, 40, 1982.
10. McCracken, G. H., Jr. and Freij, B. J., Neonatal septicemia and meningitis, in Pediatrics, 18th ed.,
Rudolph, A. M., Ed., Appleton and Lange, 1987, 479.
11. Klein, J. O., Feigin, R. D., and McCracken, G. H., Jr., Report of the task force on diagnosis and
management of meningitis, Pediatrics, 78 (Suppl.), 959, 1986.
12. Backer, C. J. and Edwards, M. S., Group B streptococcal infections, in Infectious Diseases of the Fetus
and Newborn Infant, Remington, J.S. and Klein, J. O., Eds., W. B. Saunders, Philadelphia, 1983, 820.
13. Weintraub, Z., Regev, R., Iancu, T. C., et al., Perinatal group B streptococcal infections, Isr. J. Med.
Sci., 191, 900, 1983.
14. Green, M., Pediatric Diagnosis, 3rd ed., W. B. Saunders, Philadelphia, 1980, 273.
15. Richards, W. and Kaplan, M., Anhydrotic ectodermal dysplasia, Am. J. Dis. Child, 117, 597, 1969.
16. Crain, E. F. and Shelov, S. P., Febrile infants: predictors of bacteremia, J. Pediatr., 101, 686, 1982.
17. Pawlowski, N. A. and Lopez, R. I., Children and adolescents, in FUO: Fever of Undetermined Origin,
Murray, H. W., Ed., Futura, New York, 1983, 235.
18. Lorin, M. I., The Febrile Child, John Wiley & Sons, New York, 1982.
19. Pantell, R. H., Naber, M., Lamar, R., et al., Fever in the first six months of life, Clin. Pediatr., 19,
77, 1980.
20. Strauss, R. H., Fever without localizing signs and Group B Streptococcus bacteremia in two patients 90
days of age and older, Am. J. Dis. Child., 141, 940, 1987.
21. McCarthy, P. L. and Dolan, T. F., The serious implications of high fever in infants during their first
three months, Clin. Pediatr., 15, 794, 1976.
22. Anderson, A. B., Ambrosino, D. M., and Siber, G. R., Haemophilus influenzae type b unsuspected
bacteremia, Pediatr. Emerg. Care, 3, 82, 1987.
23. Roberts, K. B., Charney, E., Sweren, R. J., et al., Urinary tract infection in infants with unexplained
fever: a collaborative study, J. Pediatr., 103, 864, 1983.
24. Lerner, A., Iancu, T. C., Landoy, Z., et al., Seizures associated with Campylobacter jejuni enteritis,
Pediatr. Infect. Dis., 3, 281, 1984.
 471

25. Bliddal, J. and Kaliszan, S., Prolonged monosymptomatic fever due to Yersinia enterocolitica, Acta Med.
Scand., 201, 387, 1977.
26. Smith, M. G. M., Williams, R., Walker, G., et al., Hepatic disorders associated with liver/kidney
microsomal antibodies, Br. Med. J., 2, 80, 1974.
27. Chandra, R. K., Immunology of liver disease, in Chandra, R. K., Ed., The Liver and Biliary Systems in
Infants and Children, Churchill Livingstone, Edinburgh, 1979, 264.
28. Groopman, J., Joffe, H., and Sullivan, J., Acquired immunodeficiency syndrome (AIDS), presented at
the educational seminars of the American Society of Hematology, New Orleans, LA, December 7 to 10,
1985.
29. Case records of the Massachusetts General Hospital, (Case 8-1987), N. Engl. J. Med., 316, 466, 1987.
30. Richardus, J. H., Dumas, A. M., Huisman, J., et al., Q fever in infancy: a review of 18 cases, Pediatr.
Infect. Dis., 4, 369, 1985.
31. Yanagihara, R. and Todd, J. K., Acute febrile mucocutaneous lymph node syndrome, Am. J. Dis. Child,
134, 603, 1980.
32. Witt, J. H., Marks, M. I., Smith, E. I., Altshuler, G., et al., Leiomyoma presenting as prolonged
fever, anemia, and thrombocytosis, Cancer, 52, 2359, 1983.
33. Pizzo, P. A., Robichaud, K. J., Wesley, R., et al., Fever in the pediatric and young adult patient with
cancer, Medicine, 61, 153, 1982.
34. Wood, D. J., and Corbitt, G., Viral infections in childhood leukemia, J. Infect. Dis., 152, 266, 1985.
35. Godard, C., Fever in childhood: a practicing pediatrician’s point of view, Ann. Nestle, 42, 11, 1984.
36. Lohr, J. A. and Hendley, J. O., Prolonged fever of unknown origin, Clin. Pediatr., 16, 768, 1977.
37. Wolff, S. M., Fauci, A. S., and Dale, D. C., Unusual etiologies of fever and their evaluation, Ann. Rev.
Med., 26, 277, 1975.
38. Van der Meer, J. W. M., Radi, J., Meyer, C. J. L. M., et al., Hyperimmunoglobulinaemia D and
periodic fever: a new syndrome, Lancet, i, 1087, 1984.
39. Reimann, H. A., Periodic disease: a probable syndrome including periodic fever, benign paroxismal
peritonitis, cyclic neutropenia and intermittent arthralgia, JAMA, 136, 239, 1948.
40. Murray, H. W., Factitious fever updated, Arch. Intern. Med., 139, 739, 1979.
41. Murray, H. W., Tuazon, C. U., Guerrero, I. C., et al., Urinary temperature, N. Engl. J. Med., 296,
23, 1977.
42. Schmidt, B. D., Fever phobia, Am. J. Dis. Child, 134, 176, 1980.
43. Klein, J. R., Update: adolescent gynecology, Pediatr. Clin. North Am., 27, 141, 1980.
44. Schmidt, K. G., Rasmussen, J. W., Sorensen, P. G., et al., Indium-111-granulocyte scintigraphy in
the evaluation of patients with fever of undetermined origin, Scand. J. Infect. Dis., 19, 339, 1987.
 473

Chapter 31

UNEXPLAINED FEVER IN GERIATRICS

M. Burke, C. Merdler, and D. Goldrey

INTRODUCTION
As life expectancy increases, the elderly are becoming a larger proportion of the patient
population presenting with unexplained fever. In many ways fever in the elderly resembles
that in younger adults, but there are several important distinctions. Elderly persons tend to
have less financial security and an inferior nutritional status than their younger counterparts,
even in the so-called developed countries. They tend to lead a rather solitary existence and
their health care is frequently deficient. Since their perception of illness is often vague and
lacking in details, the medical history may be meager and unsatisfactory. Moreover, the
physician is likely to find that the examination of the aged is very time-consuming due to
slowness of response and a diminished tolerance on the part of the patient, and this may
result in an inadequate physical examination. The physician who is investigating the elderly
febrile patient must keep the above in mind, and must act patiently and painstakingly when
attempting to unravel the source of the fever.
When dealing with fever in elderly patients the physician encounters problems both in
diagnosis and management. First, fever may be missed as a symptom for the following
reasons:

1. Impaired febrile response in the elderly. Since the time of Hippocrates, who noted
that “ the fevers of old men are less acute than others, for the body is cold” , it is
known that the febrile response is diminished in old age. There is an overall impairment
of this response, as a result of multiple factors: underlying chronic diseases, immune
senescence, poor nutritional status,1 decreased sensitivity of the hypothalamus to leu-
kocyte pyrogen (LP), aging peripheral vascular system resulting in decreased vaso-
constriction, sweating, and shivering.2 The elderly may have a low basal temperature,
with significant fever being manifest only in the evening. Further, the febrile response
may be delayed in the elderly, yet it is detectable with effective monitoring of the
temperature.3
2. Failure of the elderly to appreciate fever as a symptom. The elderly patient may not
perceive an increased temperature. Self-reporting of illness is notoriously unreliable
in the aged. The patient may present with vague complaints or neuropsychiatric symp-
toms, such as confusion or somnolence. Occasionally, the onset of the disease will
be manifested by dehydration, resulting from an inapparent febrile state.
3. Concomitant disease. Elderly patients are prone to suffer from more than one condition4
at the same time. The coexistence of another disease is likely to have two main effects.
First, a common disorder, e.g., infection of the respiratory or urinary tract may “ mask’’
an underlying, potentially serious condition, such as infective endocarditis, giant cell
arteritis, or malignancy. Second, the accompanying disease may lead to a diminished
febrile response, e.g., renal failure or hypothyroidism.
4. Drug therapy. The elderly are frequently receiving several forms of medication. Drugs
such as corticosteroids, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), phe-
nothiazine, and antibiotics may modify the febrile response. In addition, therapeutic
agents may themselves be responsible for unexplained fever in the elderly.
474 U n ex p la in ed F e ve r

Second, the clinician’s handling of the elderly febrile patient is troublesome owing to
the possible severity of the underlying disease and the technical complexity in performing
diagnostic investigations. Older patients presenting with fever are more inclined to have a
serious disorder with a greater likelihood of grave complications.5 Extensive invasive in-
vestigations are not as well tolerated by the aged patient. Preparation of the patient for
certain procedures such as colonoscopy and barium enema are more difficult. Elderly patients
are often unable to remain still during long imaging procedures because of agitation or
physical reasons, such as arthritis or low back pain. There is a greater disinclination by the
patient to undergo operative procedures such as laparotomy and biopsy, which even the
surgeon may be reluctant to perform on the elderly and infirm.

APPROACH TO THE ELDERLY FEBRILE PATIENT

The approach to the elderly patient presenting with fever is essentially similar to the
younger one and with the increased proportion of population in their sedentary age, great
efforts should be made to prevent disease, correctly diagnose and treat them.
The stepwise procedure of making a diagnosis is most important and although tiresome,
should be rigidly followed.
Comprehensive history should be taken from the patient, keeping in mind that the
complaints can be far related from the underlying disease causing fever. Therefore, a careful
medical history for previous diseases, including chronic ones as diabetes, parkinsonism, or
heart diseases should be taken. Also, inquiries about previous surgical interventions are
important, as acute abdomen can appear due to residual stones after cholecystectomy or
adhesions. This task is sometimes difficult, as the elderly patient with fever is confused and
unable to report his complaints.
It should be remembered that any case of disorientation, confusion and decreased alert-
ness, can precede an infectious disease as a forerunner of fever. Therefore inquiries should
be made in his close surrounding — family members or staff members — in order to gather
all relevant information. The physician should also obtain an accurate list of all medications
including sleeping pills, vitamins and “ over-the-counter” drugs.
In the elderly patient, it is important to establish whether we are dealing with an infectious
disease or other disorders causing fever.
The full physical examination of the aged patient should be undertaken in every case
and particular attention should be paid to all possible ways of entry for infections. These
include a search for skin infections as infected boils, diabetic foot ulcers, and bed sores.
The rectal examination can add valuable information about prostatic gland size consistency
and discharges. The bimanual vaginal examination should also be undertaken as forgotten
pessaries can lead to macerations and secondary infections, and may disclose a gynecologic
tumor.
In-dwelling urethral catheters or the condom-type catheter are frequently a source of
infection, although the frequent occurrence of anatomic disorders in the elderly male, such
as urethral strictures or prostatic hypertrophy, may predispose the patient to urinary tract
infection with fever.
The functional status of the patient should be carefully evaluated, because a debilitated
person has a greater risk of developing infections.
In order to establish the diagnosis in the elderly patient, it is mandatory to evaluate his
temperature twice daily and the respiratory rate, for 48 h. The recommended procedure of
temperature measurement is the rectal, and this should be taken for a full 5 min. An accurate
measurement can discover fever not established by other methods.
Surveillance for infection on first examination includes culturing any infected site,
including skin lesions, urine culture in person with in-dwelling catheter, and routine blood
and urine analysis. All bladder irrigations in patients with in-dwelling catheters should be
 475

discontinued. Also, segregation of suspected or identified infected patient until the pathogen
is defined is recommended. When a serious infection is excluded, the elderly ill patient
should remain in the community, under close care, but repeated medical examination should
initially be planned and treating policy changed according to the clinical condition of the
patient.
Whenever an infection is diagnosed, a careful investigation should be performed in
search of the cause.
Septic fever, for instance, which has many possible causes in the group, should arouse
suspicion of hidden pus accumulation in the elderly. In any case of confusion with fever,
blood cultures should be taken.
Septicemia as proven by blood cultures is not infrequent in the elderly and 50% of all
cases are diagnosed in patients over 65 years, half of them having a severe underlying
disease. The elderly also have an enhanced tendency to develop endocarditis, which may
occur on apparently normal heart valves in 30% of the cases.
Among the underlying diseases, the physician has to take into consideration cancer and
rheumatic disorders, and concomitant investigation is frequently necessary in the elderly
patient.

CLINICAL MANIFESTATIONS OF FEVER IN THE ELDERLY

Fever is rarely higher than 39.5° in the elderly and rigors are quite exceptional. The
rectal temperature appears to reflect the presence of fever more accurately than either oral
or axillary readings.6 Symptoms and signs of febrile diseases of the elderly tend to be diffuse
and nonspecific: malaise, confusion, restlessness, headache, lethargy, anorexia, weight loss,
tachypnea, tachycardia, and dehydration. Localizing features are less frequently observed,
e.g., absence of neck stiffness in meningitis, paucity of abdominal symptoms and signs in
intra-abdominal infections.

ETIOLOGIC ASPECTS OF FEVER IN THE ELDERLY710

Certain conditions are more commonly encountered in cases of the elderly presenting
with unexplained fever. As in the general population, the three large categories of infection,
neoplasia, and collagen-vascular disease are the principal causes of unexplained fever. The
most common of these is infection, the main types encountered being intra-abdominal and
hepatobiliary infection, infective endocarditis, and tuberculosis. Certain well-recognized
causes of unexplained fever in the young are rarely (but not never!) seen in the elderly,
e.g., factitious fever, sarcoidosis, and FMF. Other conditions are uncommonly observed:
inflammatory bowel disease, adult Still’s disease, systemic lupus erythematosus, and rheu-
matic fever.

Infection11
Intra-abdominal infection12 is often a very difficult problem in the elderly. In the acute
abdomen due to a silent perforation of a peptic ulcer, intestinal diverticulum, appendix or
gallbladder, the older patient may fail to demonstrate typical features of peritoneal irritation.
Instead, after peritoneal spilling and abscess formation, the presentation may be that of
FUO.8 The clinical picture of acute cholecystitis may be uncharacteristic. Diagnostic delay
occurs in approximately one third of patients,13 principally due to the mildness of abdominal
pain and minimal findings on physical examination. Some patients present with fever, mental
disorientation, and jaundice without substantial abdominal features. Acute appendicitis has
476 U n ex p la in ed F e ve r

to be considered in the differential diagnosis of unexplained abdominal pain, confusion or

fever and leukocytosis in the elderly patient who has not undergone appendectomy. There
is an enhanced tendency to rupture and abscess formation in this age group.14 Pyogenic liver
and other intra-abdominal abscesses frequently present with unexplained fever. A previous
history of abdominal surgery may be remote or absent. Localizing features such as abdominal
pain and tenderness as well as hepatomegaly are often absent. Confusion, anorexia, and
weight loss may be the presenting features. The sonogram is a valuable tool in the evaluation
of unexplained fever in the elderly. Several clinical problems are associated with infective
endocarditis in old age.15 The disease appears to be on the rise in the elderly, although an
increased awareness has maintained its relatively low incidence as a cause of unexplained
fever. The condition is more often acquired nocosomially than in younger patients. Errors
in diagnosis are frequent and mortality is higher. The elderly are less likely to report fever
and chills. Anorexia, weight loss, confusion, and focal neurologic manifestations are more
common. A murmur in the elderly is frequently incorrectly labeled “ innocent” . Fever is
very often attributed to a (more common) respiratory or urinary tract infection. The inability
to make the diagnosis and improper use of antibiotics may contribute to increased mortality
in the elderly.
Despite a decline in the incidence of tuberculosis in most Western countries, the disease
appears to be increasing in the elderly. Another factor is that the tuberculin test is more
likely to be negative in the elderly. Further, they tend to present with advanced disease and
to be diagnosed late.

Tumors
Neoplasia is more frequent in the elderly and may make its appearance as a febrile
disorder, either because of tumor necrosis, tumor embolism, or secondary infection. The
principal neoplastic conditions causing unexplained fever in the elderly are lymphoma (Hodg-
kin’s and non-Hodgkin’s), leukemia, primary solid tumors of the kidney, colon, pancreas,
and prostate and secondaries to the liver.

Collagen-Vascular Diseases
Giant cell arteritis is a relatively common collagen disorder and a very important cause
of unexplained fever in the elderly.7 The classic presentation of headache, tender temporal
artery, visual disturbances, myalgia, and arthralgia may be absent or inconspicuous. The
patient may present with fever, which may even be hectic in nature, together with anemia,
raised ESR, and liver dysfunction.16 The diagnosis is confirmed by temporal artery biopsy.
Vasculitis, including polyarteritis nodosa, is not uncommon as a cause of unexplained fever.
Still’s disease, rheumatic fever, and SLE17 are occasional causes. The differential diagnosis
of fever and rheumatic pains or arthralgia in the elderly includes, in additon: gout, pseu-
dogout, infective endocarditis, suppurative arthritis, thyrotoxic acropathy, and polychon-
dritis.

Miscellaneous Causes
Drug fever appears to occur more commonly in the elderly,18 but this has been disputed
recently.19 We observed that 4 out of 5 cases of prolonged unexplained fever due to drugs
occurred in patients aged over 65. In general, the elderly have a higher incidence of side
effects of drugs than their younger counterparts for several reasons. Since they are more
likely to suffer from multiple illnesses, they usually receive more than one therapeutic agent.
“ Age-related” changes in organs and tissues will effect pharmacokinetics via alterations in
excretory or metabolic functions, resulting in relatively higher concentration of the drug in
the body. Quinidine hypersensitivity with fever and hepatosplenomegaly has been recently
described in an elderly patient.20 Tuberculin-positive elderly patients appear to be more
 477

susceptible to isoniazid-induced hepatitis,21 which occasionally is manifested by fever. De-

viations in compliance may cause the elderly patient to take either the inappropriate drug
or the incorrect dosage. Social conditons such as loneliness, bereavement and financial
insecurity in the elderly lead to discontent. The physician is usually unable to offer any
assistance other than to prescribe (yet another!) medication for depression.
A very important, yet frequently overlooked, cause of unexplained fever in the older
patient is recurrent pulmonary embolism.
The appearance of inflammatory bowel disease in the elderly may be overlooked; the
condition may be manifested as diarrhea, abdominal pain, fever, and weight loss. A recent
case draws attention to the fact that the geriatric physician must be aware of unusual causes
of fever in the elderly. A 75-year-old female presented with fever, polyarthralgia, dry cough,
and hypercalcemia, which was subsequently found to be due to sarcoidosis.22

REFERENCES
1. Keenan, R. A., Moldawer, L. L., Yang, R. D., Kawamura, I., Blackburn, G. L., and Bistrian, B.,
An altered response by peripheral leukocytes to synthesize or release leukocyte endogenous mediator in
critically ill, protein-malnourished patients, J. Lab. Clin. Med., 100, 844, 1982.
2. Jones, P. G., Kauffman, C. A., Bergman, A. G., Hayes, C. M., Kluger, M. J., and Cannon, J. G.,
Fever in the elderly: production of leukocytic pyrogen by monocytes from elderly persons, Gerontology,
30, 182, 1984.
3. McAlpine, C. H., Martin, B. J., Lennox, I. M., and Roberts, M. A., Pyrexia in infection in the elderly,
Age Ageing, 15, 230, 1986.
4. Wilson, L. A., Lawson, I. R., and Brass, W., Multiple disorders in the elderly: a clinical and statistical
study, Lancet, 2, 841, 1962.
5. Keating, H. J., Ill, Klimek, J. J., Levine, D. S., and Kiernan, F. J., Effect of aging on the clinical
significance of fever in ambulatory adult patients, J. Am. Geriatr. Soc., 32, 282, 1984.
6. Downtown, J. H., Andrews, K., and Puxty, J. A. H., ‘Silent’ pyrexia in the elderly, Age Ageing, 16,
41, 1987.
7. Esposito, A. L. and Gleckman, R. A., Fever of unknown origin in the elderly, J. Am. Geriatr. Soc.,
26, 498, 1978.
8. Cunha, B. A., Fever of unknown origin in the elderly, Geriatrics, 37(6), 30, 1982.
9. Kauffman, C. A. and Jones, P. G., Diagnosing fever of unknown origin in older patients, Geriatrics,
39(2), 46, 1984.
10. Gleckman, R. A. and Esposito, A. L., Fever of unknown origin in the elderly: diagnosis and treatment,
Geriatrics, 41(3), 45, 1986.
11. Meyers, B. R., Serious infections in the elderly, Mt. Sinai J. Med., 54, 18, 1987.
12. Norman, D. C. and Yoshikawa, T. T., Intraabdominal infections in the elderly, J. Am. Geriatr. Soc.,
31, 677, 1983.
13. Morrow, D. J., Thompson, J., and Wilson, S. E., Acute cholecystitis in the elderly: a surgical emergency,
Arch. Surg., 13, 1149, 1983.
14. Hirsch, S. B. and Wilder, J. R., Acute appendicitis in the elderly, Mt. Sinai J. Med., 54, 28, 1987.
15. Terpenning, M.S., Buggy, B. P., and Kauffman, C. A., Infective endocarditis: clinical features in young
and elderly patients, Am. J. Med., 83, 626, 1987.
16. Ghose, M. K., Shensa, S., and Lerner, P. I., Arteritis of the aged (giant cell arteritis) and fever of
unexplained origin, Am. J. Med., 60, 429, 1976.
17. Baer, A. N. and Pincus, T., Occult systemic lupus erythematosus in elderly men, JAMA, 249, 3350,
1983.
18. Lipsky, B. A. and Hirschmann, J. V., Drug fever, JAMA, 245, 851, 1981.
19. Mackowiak, P. A. and LeMaistre, C. F., Drug fever: a critical appraisal of conventional concepts: an
analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature, Ann.
Intern. Med., 106, 728, 1987.
478 Unexplained Fever

20. Rosin, A. J., Van DJjk, Y. M., Graftstein, I., and Herbert, J., Hepatosplenomegaly as a manifestation
of quinidine hypersensitivity, Age Ageing, 9, 253, 1980.
21. Kopanoff, D. E., Snider, D. E., Jr., and Caras, G. J., Isoniazid-related hepatitis: a U.S. Public Health
Service cooperative study, Am. Rev. Respir. Dis., 117, 991, 1978.
22. Tsai, J-S., Davis, C. S., and Freedman, M. L., A seventy-eight-year-old woman with fever, cough,
joint pains, and hypercalcemia, J. Am. Geriatr. Soc., 36, 73, 1988.
Part VI
Diagnostic Procedures and Management
of Unexplained Fever
 481

Chapter 32

LABORATORY DIAGNOSTIC TESTS IN THE EVALUATION OF

FEVER

Stephen A. Berger

INTRODUCTION

Although a wide variety of laboratory tests are helpful in the diagnosis of febrile illness,
the clinician should realize that such procedures are primarily designed to support or confirm
specific diagnoses. Often, the laboratory is confronted with a barrage of patient specimens
whose quantity grows in proportion to the frustration and uncertainty of the clinical staff.
In a classic examination of the subject, Larson et al. summarized the often chaotic approach
to laboratory diagnosis as follows: ‘4A virtually uncountable number and variety of diagnostic
blood tests were performed in these patients . . . hematology, chemistry and immunology
tests did not result in the definitive diagnosis in a single instance.” 1
Needless to say, a patient specimen should never be submitted without a thorough
understanding of the required laboratory test. Bactériologie cultures, microscopic exami-
nation, serology, and other procedures useful in the diagnosis of unexplained fever are
subject to a wide range of sensitivity, specificity, and cross reactions. The laboratory should
be informed of prior immunizations and ongoing antimicrobial therapy; diagnostic suspicions
should be noted, particularly if rare or fastidious microorganisms are to be identified.
Infectious causes of fever vary widely with respect to geographic location, patient age,
and associated disease. “ Exotic” pathogens may be sought in cases of recent travel or
contact with suspect foods, animals, etc. Malaria and a number of other parasitic infestations
are likely to become apparent or reactivate many years after acquisition.

MICROSCOPY

The identification of any infectious disease pathogen must begin with direct examination
of a clinical specimen. The microbiologie smear is among the least expensive and most
rapid tests in medicine. Techniques used in staining and interpretation have changed little
in the past 100 years.
Microscopic examination should be interpreted with caution. Identification of pathogens
among normal flora can be difficult; and the value of the specimen itself (i.e., sputum vs.
saliva) should be taken into consideration. Some pathogens require specialized stains or
lighting techniques such as dark field or fluorescence microscopy. Table 1 summarizes the
microscopic features of several pathogens found in patients with unexplained fever.

THE MICROBIOLOGIC CULTURE (SEE TABLE 1)

In recent years, several rapid and automated systems have been marketed for the iden-
tification and susceptibility testing of infectious agents. It is often possible to generate a
final report within a few hours from receipt of specimen. Computerization of the microbiology
laboratory has permitted the clinician to follow trends in hospital epidemiology and antibiotic
sensitivity.
The term “ unexplained fever” implies that routine culture of a number of specimens
has been unrevealing. Before proceeding to further cultures, the clinician should ascertain
that preliminary specimens were properly collected and were not submitted under the ‘‘cover’’
of antimicrobial therapy. Specific cultures should be approached as follows.
482 U nexplain ed F ever

TABLE 1
Microscopy and Culture in the Evaluation of Unexplained Fever

Organism/disease Direct smear Culture

Bacteria

Borrelia spp. (See text) in vitro culture not available rou-

tinely
Brucella spp. DFA staining of clinical material (See text)
Francisella tularensis Difficult to identify with ordinary
stains, DFA stain used
Legionella spp. DFA staining of clinical material Highest yield with culture of biopsy
specimens
Leptospira spp. Dark field (See text)
Mycobacterium spp. UV microscopy using fluorochrome Specialized media — laboratory
stains — increased sensitivity over should be consulted when these
standard acid-fast stains organisms are suspected
Mycoplasma pneumoniae Culture into enriched media
Nocardia asteroides Acid-fast with 2% H2S04 Consult laboratory if suspected
Rickettsia spp. Occasionally identified on direct (See text)
smear of infected tissue — Gime-
nez, Giemsa, FA stains
Spirilum minor Blood/exudate; dark field & phase in vitro culture not available
microscopy, in vitro culture not
available
Staphylococci (See text, “ endocarditis” )
Streptobacillus moniliformis Stain wound exudates/joint fluid Specialized culture in enriched me-
dia
Treponema pallidum Dark field in vitro culture not possible
Yersinia spp. Stool culture requires enrichment
techniques
Fungi

The identification of fungi by smear and culture is similar for most species. It is important to consult the laboratory
regarding clinical diagnosis and optimal acquisition of specimens

Parasites

Amebiasis (extraintestinal) Fresh abscess material for wet Culture of abscess material can be
mount performed in many laboratories
Babesia spp. Giemsa-stained thin blood smears
Filiariasis Stained and wet thick/thin blood
films + concentrates — obtain
blood between 10 pm and 2 am
Leishmania donovani Stained tissue (see text) Biopsy material can be cultured on
specialized (e.g., NNN medium)
Malaria Multiple thick and thin smears at
different points in the febrile cycle
Toxoplasmosis Biopsy imprints may reveal the or-
ganism
Trichinosis Biopsy rarely indicated
Trypanosomiasis Smear of blood, CSF, tissue aspi- Culture in specialized media occa-
rates sionally positive

Viruses

Cytomegalovirus Examine specimens by light micros- Culture urine and throat secretions
copy, IF
Epstein-Barr virus Throat secretions have been cul-
tured on fetal B lymphocytes
Hepatitis viruses Not cultured in vitro
 483

BLOOD
Most systemic bacterial infections are characterized by intermittent bacteremia. The
recovery rate varies with severity of infection, infected target organ and microbial species.
In general, acquisition of three culture specimens during a 24-h period is sufficient for
recovery of any bacteremic pathogen. A large number of patients in the series of Larson et
al. had over 20 blood cultures taken, notwithstanding his impression that four to six are
sufficient for the investigation of FUO.1
Blood specimens are taken at the peak of fever if possible. If anaerobic infection is
considered, appropriate liquid media should be inoculated. Currently available media are
adequate for the recovery of fungi; however, specialized technique is necessary for identi-
fication of mycobacteria.

Endocarditis
Intravascular infections such as endocarditis and infected dialysis shunts are characterized
by continuous bacteremia. Organisms are recoverable from the first blood specimen in up
to 96% of culture-positive endocarditis patients.2 Acquisition of three blood specimens
increases the yield slightly and serves to discount the possibility of transient bacteremia or
external contaminant. In ca. 60% of cases, a ll blood culture bottles will be positive. Positivity
rates are highest in cases of “ acute” type infective endocarditis.
Culture-negative endocarditis may represent the following: (1) prior treatment with an
antimicrobial agent; (2) infection due to nutritionally fastidious streptococci or other organ-
isms; (3) infection due to organisms which do not grow in routine media (C o x iella b u rn e tii ,
mycobacteria); (4) infection due to certain fungi which do not “ shed” into the blood stream
CA sp erg illu s ); (5) a small percentage of tricuspid valve infections (with presumed trapping
of infected material in the pulmonary microcirculation); and (6) noninfectious endocarditis,
such as seen in lupus erythematosus and terminal carcinoma.
In most instances, three specimens taken during a single 24-h period are sufficient for
diagnosis. Additional blood cultures are recommended when the patient has received an
antimicrobial agent during the preceding 2 weeks. The value of hypertonic media for recovery
of cell wall-deficient (L-form) bacteria is controversial. In some cases, supplement of blood
culture media with L-cysteine or pyridoxal phosphate has increased the recovery rate of
nutritionally deficient streptococci.
Routine blood cultures are negative in over 50% of fungal endocarditis episodes.3 Some
have found that arterial blood specimens are more often positive than venous blood in cases
of C a n d id a endocarditis. Recent data suggest that detection of circulating mannan (a yeast
wall constituent) using gas-liquid chromatography or ELISA can aid diagnosis. Other studies
have found that precipitating and agglutinating antibody directed against C a n d id a or A s -
p e r g illu s is present in cases of endocarditis.
Antibodies to ribitol teichoic acid (a cell wall constituent of Gram-positive cocci) have
been demonstrated in over 95% of patients with endocarditis due to S ta p h y lo co c cu s a u re u s .4
The test, which employs counterimmune electrophoresis, has a high rate of false positives;
a negative assay does not reliably rule out the diagnosis. High titers are also encountered
in patients with multiple extravascular staphylococcal abscesses and acute osteomyelitis. It
may be argued, therefore, that the test is valuable in the detection of major staphylococcal
infection requiring prolonged intravenous antibiotic therapy — regardless of the precise
anatomic diagnosis.
Ancillary tests for infective endocarditis include quantitation of circulating rheumatoid
factor and immune complexes. A positive latex fixation or similar test is found in 50 to 60%
of endocarditis patients, with highest incidence after the fifth week of illness. Circulating
immune complexes are nonspecific, and can be detected in normal individuals and various
extravascular infections. High concentrations (>100 |xg aggregated human gamma globulin
equivalent per 100 ml) are somewhat more suggestive of endocarditis. The titer of both
484 U nexplain ed F ever

rheumatoid factor and immune complexes may be followed as a parameter of successful

therapy.
In previous years, blood obtained from a small needle puncture of the ear lobe was
smeared and examined for characteristic large histocytes. Such cells are not specific for
endocarditis, and are also found in malaria, typhoid, epidemic typhus, and tuberculosis.
Depressed levels of serum complement activity can accompany azotemia and abnormal
urine sediment, and suggest a diagnosis of acute glomerulonephritis. False-positive reaginic
tests for syphilis (e.g., VDRL) are found in approximately 0.2% of endocarditis patients.

Slowly Growing or Fastidious Pathogens

Most clinical laboratories process blood cultures for one week before discarding. B ru cella
species are often evident only after 2 or more weeks using routine liquid media. In some
cases of endocarditis, streptococci also require more than 1 week’s incubation. The laboratory
should be consulted if such infections are possible in a given patient.
Fungi will grow adequately in currently used blood culture media, and do not require
specialized culture techniques in most cases. Mycobacteria have been successfully recovered
from blood culture by first concentrating the specimen and plating to appropriate solid media.
Spirochetes and other rare causes of bacteremia are discussed below.

“ Contaminants”
Recovery of B a c illu s species, “ diptheroids” or S ta p h y lo co c cu s ep id erm id is from a single
blood specimen can generally be considered as “ contaminant.” Such species may, however,
be significant if recovered repeatedly or in the setting of immune suppression or an intra-
vascular prosthesis. On occasion, L iste ria m o n o cyto g en es is misidentified as a “ diphtheroid”
by the laboratory.

URINE
As a rule, routine urine cultures are typified by a high rate of false positives due to
growth of contaminants to “ significant” numbers. The clinician should realize that the
concentration of bacteria generally considered as indicative of infection (100,000 per ml)
applies only to facultative Gram-negative bacilli in adults without anatomic or functional
urinary tract disease. Lower concentrations are diagnostic in instances of fungal infection
or specimens submitted from nephrostomy or bladder aspirates.
Sterile pyuria in the febrile patient often suggests the presence of a prostatic or renal
abscess or noninfectious inflammation of the urinary tract. Fifty percent of patients with
urinary tract tuberculosis have pyuria. A fresh morning specimen in its entirety should be
submitted for mycobacterial culture in such cases (24-h collections are no longer necessary).
Acid-fast smears of urinary concentrates are not helpful.
The routine urinalysis is useful in recognizing infectious and noninfectious causes of
renal disease. Urinary sediment may be examined for erythrocytes, inflammatory cells, and
casts, as well as desquamated cells indicative of local carcinomata. Characteristic “ owl’s
eye” epithelia are found during infection with cytomegalovirus.
Capsular antigens from H a em o p h ilu s influenzae, S trep to co c cu s pn eu m o n ia e, and C r y p -
to co ccu s n eoform an s are concentrated in urine during systemic infection; a variety of in-
expensive kits based on coagglutination and latex agglutination are available for detection
of these substances.

STOOL
The diagnostic value of stool examination is related to the nature and timing of the
specimen itself. Relatively few stool pathogens are implicated in cases of unexplained fever,
and obscure fever is not a common feature during the course of intestinal parasitoses. Indeed,
only 10% of patients with hepatic amebic abscess shed amebas into the stool.
 485

Although diarrhea is rare in typhoid fever, stool examination may reveal large numbers
of mononuclear cells on direct smear. The stool culture in typhoid is generally negative until
the 10th to 14th day of illness. Unusual infections of the ileocecal region such as yersiniosis
and intestinal tuberculosis may be diagnosed through culture of stool on specialized media.

SPUTUM
The value of sputum culture is directly related to the adequacy of the specimen itself.
Saliva is inhabited by a number of interesting bacterial and fungal pathogens which will
confuse the clinican if identified. When significant, such organisms are generally encountered
in the setting of clinically overt pulmonary disease.
Some pulmonary pathogens are rarely identified in expectorated sputa, and require
bronchoscopy or biopsy for recovery. Specimens obtained by fiberoptic bronchoscopy are
appropriate for identification of P n eu m o cystis ca rin ii and L eg io n ella . Lung biopsy may be
necessary in instances of invasive aspergillosis or phycomycosis. In contrast, such organisms
as C ryp io c o c c su s n eoform an s and N o ca rd ia a ste ro id e s are often found in sputum. The
laboratory should be advised if fungal or mycobacterial culture is required.
In the past, identification of M y co b a c teriu m tu b ercu lo sis and other mycobacteria has
required 4 to 6 or more weeks. A radiometric culture system available in many laboratories
now permits identification of these organisms within 7 days.

BIOPSY SPECIMENS
The liver biopsy has long been considered a crucial test in the diagnosis of obscure
fever. Indeed, the most common cause of FUO in many series has been extrapulmonary
tuberculosis with hepatic involvement. When examination of such specimens for mycobac-
teria is anticipated, the laboratory should be consulted in advance. Liver biopsy may also
be helpful in the evaluation of other granulomatous infections such as brucellosis, crypto-
coccosis and histoplasmosis.
Brucellosis, histoplasmosis, and infective endocarditis have occasionally been diagnosed
through culture of bone marrow specimens. Microscopic examination of bone marrow smears
is useful in the identification of L eish m a n ia , P la sm o d iu m , and T ryp a n o so m a . Specimens
rich in reticulendothelial tissue (e.g., lymph node, spleen) may also be cultured for B a rto n e lla
and L isteria . Histological examination of bone marrow may be diagnostic of lymphoma,
metastatic carcinoma, and granulomatous diseases.
Biopsy is occasionally useful in the diagnosis of parasitic diseases such as trichinosis
and toxoplasmosis; however, the diagnosis in these conditions is generally based on serologic
examination nowadays.

HEMATOLOGIC PARAMETERS

THE HEMOGRAM
A wide variety of hematologic abnormalities may accompany fever. Changes in the
concentration of formed elements are, for the most part, nonspecific.11 For example, nor-
mocytic anemia is a common feature of malignancy, malaria, tuberculosis, endocarditis,
and collagen-vascular disease.
Infection may produce either elevation or reduction in the total white blood cell count
as well as the relative percentage of each of the leukocyte subsets. The concentration of
polymorphonuclear leukocytes is increased by stress, hemorrhage, corticosteroids and other
drugs, uremia, gout, rheumatic fever, and myeloproliferative diseases. Neutropenia accom-
panies infiltrative diseases of the bone marrow, viral infection, tuberculosis, endotoxemia,
brucellosis, typhoid, tularemia, lupus erythematosus, and ingestion of various drugs.
Lymphocytosis may point to a diagnosis of brucellosis, typhoid, viral hepatitis, tuber-
486 Unexplained Fever

culosis, or primary lymphatic disease. Lymphocytosis with an increased percentage of atyp-

ical forms is characteristic of infectious mononucleosis, toxoplasmosis, and cytomegalovirus
infection. Atypical forms are also encountered in serum sickness and some cases of toxo-
plasmosis and syphilis.
Eosinophilia is found in allergic disorders as well as collagen-vascular disease, ovarian
carcinoma, inflammatory bowel disease, scarlet fever, tuberculosis, and chronic myelogen-
ous leukemia. Of the parasites, only helminths (e.g., worms) are consistently associated
with eosinophilia. During recovery from bacterial infection, one may encounter eosinophilia
as well as increased concentrations of lymphocytes and monocytes. Eosinopenia is seen in
severe infection due to a variety of pathogens, including helminths.
The concentration of basophilic leukocytes is increased in chronic myelogenous leu-
kemia, Hodgkin’s disease, and chronic sinusitis. Circulating monocytes increase in brucel-
losis, tuberculosis, malaria, kala-azar, trypanosomiasis, endocarditis, inflammatory bowel
disease, rickettsial infection, and lymphoma. Either thrombocytopenia or thrombocytosis
may accompany leukemia, carcinomatosis, and a variety of inflammatory diseases. Platelet
counts diminish in many bacterial, viral, rickettsial, and rheumatic diseases; and may herald
disseminated intravascular coagulation.

THE ERYTHROCYTE SEDIMENTATION RATE (ESR)

The ESR has been used by clinicians since 1918 for the diagnosis of and follow-up of
systemic disease. The technical aspects and significance of this test have been reviewed by
Davey and Nelson.12
The ESR is decreased in trichinosis, chronic lymphatic leukemia, and disseminated
intravascular coagulation. A variety of anti-inflammatory drugs may decrease the ESR in
conditions which are normally associated with elevated values.
Elevated ESR is found in infection, malignancy, and collagen-vascular disease, as well
as pregnancy, myocardial infarction, and thyroid disease. Values exceeding 100 mm/h
usually herald infection,12 although cancer and rheumatic disease may also produce such
elevations. Extreme elevations in patients with malignancy may signal the presence of
métastasés.

SEROLOGIC TESTS (SEE TABLE 2)

With few exceptions, the serologic demonstration of acute infection requires examination
of acute and convalescent specimens for a significant change in antibody titer. Occasionally
a later fall in titer may be useful. In some diseases (e.g., legionellosis) antibody activity is
delayed for a number of weeks. In others, demonstration of specific IgM in a single specimen
is sufficient.
In recent years, serologic testing has been revolutionized by the advent of monoclonal
antibodies, enzyme-linked immunosorbent (ELISA) techniques, and simple commercial kits
based on coagglutination and latex agglutination and nucleic acid probe technology.

FEBRILE AGGLUTININS
All too often the laboratory receives a request for “ viral serology’’, “ serology screen,’’
or “ febrile agglutinins.’’ In most laboratories, “ febrile agglutinins’’ include a screening test
for the following: brucellosis, salmonellosis, and rickettsioses.
Antibody against Brucella is detected through a simple tube agglutination test which
employs a standard antigen from Brucella abortus. The test is sufficient for detection of
antibody to other Brucella species, with the exception of Brucella canis. False-positive titers
have been described in tularemia, typhoid fever, and yersiniosis.
 487

TABLE 2
Serologic Studies Useful in the Evaluation of Unexplained Fever

Test used (minimum

Organism/disease positive titer) Comments

Bacteria

Borrelia spp. IFA

Brucella spp. Ag (160) Rising titer diagnostic
Coxiella (Q fever) CF Phase 2 antigen suggests acute disease. Phase
1 more typical of chronic infection
Francisella tularensis Ag (40) Becomes positive during second week of ill-
ness
Legionella spp. IFA (2? 256 suggestive) 90% sensitive if two titers taken
ELISA Experimental
Detection of antigens in urine under
study
Leptospira Micro Ag Difficult to perform
Macro Ag (600) ELISA Sensitive, specific, not yet marketed
Mycobacterium spp. ELISA, GLC, mass spectrometry
and other systems have shown
some success in detecting myco-
bacterial cell products in clinical
material
Mycoplasma pneu- CF (256) 58% sensitive in pneumonia
moniae Immune adherence HA test Under development — 90% sensitive
Nocardia asteroides CF, ID Experimental
Rickettsia spp. (See text)
Salmonella typhi (See text)
Spirilum minor CF Not generally available
staphylococci (see
text, “ endocardi-
tis” )
Streptobacillus moni- tube Ag (80) Not generally available
liformis
group A Streptococ- (See text)
cus
Treponema pallidum (See text)
Yersinia spp. Floe (160)

Fungi

Aspergillosis ID, CIE Positive test = aspergilloma or invasive dis-

ease
CF Erratic results
RIA (For serum antigen-experimental)
Blastomyces CF (8) 50% sensitive
dermatitidis ID 80% sensitive
Candida albicans LA (8) May be positive in heavy contamination with-
out disease
ID Cross reaction with Torulopsis for detection of
EIA mannan antigen, 70% sensitive (experimen-
tal), serum arabinotol (experimental)
Coccidioides immitis CF (2) Higher titer with invasive disease
TP 80% sensitive — confirm with CF
Cryptococcus neofor- LA (4) For detection of antigen in urine, CSF, or
mans serum
IFA, TA Not widely used
EIA For antigen and antibody-under study
488 U nexplain ed F ever

TABLE 2 (continued)
Serologic Studies Useful in the Evaluation of Unexplained Fever

Test used (minimum

Organism/disease positive titer) Comments
Fungi
Histoplasma capsula- CF (8) 90% sensitive
tum
ID, CIE 70% sensitive
LA (16) Should confirm with one of above
Zygomycosis (mucor- No reliable serologic test
mycosis)

Parasites

Amebiasis (extrain- IHA (256) 95% sensitivity

testinal)
ELISA Not widely used, serum for antigens by El A
(experimental)
Babesia spp. IFA Per CDC
Filiariasis Serum for antigens by CIE (experi-
mental)
Leishmania donovani IFA (16) Commerical kits
CF (8) not available
Malaria3 IFA (64) 100% sensitivity, not species specific
ELISA (32) 100% sensitivity
Toxocariasis ELISA (32) 78% sensitivity
Toxoplasmosis IFA-IgG (256) 100% sensitivity
IFA-IgM (64 in adults and any titer 70% sensitivity
in newborns)
ELISA-IgG 100% sensitivity
ELISA-IgM 90% sensitivity
LA-IgG (100) 80% sensitivity, serum and CSF for antigens-
experimental
Trichinosis BFT (5) 75% sensitivity, urine for antigens-experimen-
tal
Trypanosomiasis CF ^V8 titer in acute
IHA ^ 1/128 in chronic

Viruses

Cytomegalovirus CF As in other serologic tests, demonstration of

IHA IgM or a ^4-fold rise in titer is diagnostic of
EIA ongoing disease

Epstein-Barr virus (See text)

Hepatitis A (See text)
Hepatitis B (See text)

Note: Abbreviations:
I = indirect
D = direct
FA = fluorescent antibody
Ag = agglutination
CF = complement fixation
Micro = microscopic
Macro = macroscopic
ELISA = enzyme-linked immunosorbent assay
GLC = gas-liquid chromatography
 489

TABLE 2 (continued)
Serologic Studies Useful in the Evaluation of Unexplained Fever

Test used (minimum

Organism/disease positive titer) Comments

ID = immunodiffusion
Floe = flocculation
CIE = counterimmune electrophoresis
LA = latex agglutination
TP = tube precipitin
TA = tube agglutination
HA = hemagglutination

a Serologic tests for malaria may require 3 weeks to positivity.

The Weil-Felix test is included among “ febrile agglutinins” for historical reasons, and
is rarely helpful in evaluation of patients with obscure fever. The test becomes positive
toward the end of the second week of typhus and spotted fever rickettsioses, and is negative
in Q-fever, trench fever, and rickettsialpox. False-positive reactions may be encountered in
leptospirosis, borreliosis, and Proteus infections.
Acute infection with Salmonella species is characterized by elevation in serum titers
toward the H- and O- antigens of these bacteria. High titers toward the O- antigen alone
may persist for years and reflect prior infection or immunization.
Unexplained fever with multisystem manifestations is encountered during the secondary
stage of syphilis. At this point, both the reaginic (e.g., VDRL) and antitreponemal (FTA)
tests are positive. Reaginic tests are sensitive, but notoriously nonspecific, and should not
be relied upon for diagnosis without confirmation.

NONINFECTIOUS DISEASES
Demonstration of antibodies directed against bacterial cell products has been a mainstay
in the diagnosis of acute rheumatic fever for decades. Quantitation of antistreptolysin O
(ASO) has a diagnostic sensitivity of only 80% in such patients. The positive level, expressed
in Todd units, varies with patient age and geographic area. False positive ASO determinations
are found in patients with chronic liver disease; false negatives following prompt abortion
of streptococcal infection with antibiotics.
Assays for Anti-DNAse-B are more sensitive and specific in the diagnosis of rheumatic
fever than are ASO. A recently introduced latex screening test shows great promise as a
rapid and inexpensive screen for the disease.

LUPUS ERYTHEMATOSUS AND OTHER RHEUMATIC DISEASES

Larson et al. found that antinuclear antibody tests are of little value, except in excluding
certain diagnoses. Paradoxically, the ease of obtaining ANA and rheumatoid factor tests
allows identification of collagen disease in patients before it evolves into unexplained fever
or FUO.1
The “ rheumatic” or “ collagen-vascular” diseases are characterized by a wide range of
circulating antibodies directed against autologous antigens. Antinuclear (ANA) antibodies
react with DNA, histones, nonhistone proteins (NHP), or NHP bound to RNA and nucleoli.5
Anti-double-stranded DNA is found in 40 to 60% of patients with systemic lupus ery-
thematosus (SLE), and is highly specific (antibody to single-stranded DNA is less specific).
Individual patterns of antibody to histone, NHP, and NHP-RNA are specific to other rheu-
matic diseases. The highest range of differing antibodies (polyspecificity) is encountered in
490 Unexplained Fever

SLE; drug-induced SLE is more limited. Quantitation of these antibodies can be used to
follow disease and therapy.
With rare exceptions, a negative ANA by immunofluorescence rules out the diagnosis
of SLE. A negative test for ANA does not discount the possibility of Sjogren’s syndrome,
polymyositis, rheumatoid arthritis, or scleroderma.
Rheumatoid factor (RF) is an antibody directed against antigenic determinants on the
Fc fragment of IgC. It is nonspecific, and found in old age, most rheumatic diseases, sarcoid,
liver disease, and several forms of neoplasia, viral infection, and parasitic infestation.
Circulating immune complexes; antimitochondrial, anti-smooth muscle, and other autoanti-
bodies are found in a variety of rheumatic disorders.6,7

SKIN TESTS
A wide variety of skin tests are available for the diagnosis of viral, bacterial, fungal,
and parasitic infection. Such tests may also be used in epidemiologic surveys, allergy testing,
confirmation of prior vaccination, and the evaluation of the anergic patient. Many of the
skin tests used in the diagnosis of unexplained fever are nonspecific and subject to cross
reactions. Most tests are only indicators of current or past experience with a given antigen.
Some tests will, themselves, elevate serum titers or even promote subsequent skin reactivity
to repeated tests.
Skin test reactivity is decreased in malignancy, malnutrition, chronic liver disease,
measles, infectious mononucleosis, leprosy, uremia, systemic mycosis, tuberculosis, and
during therapy with corticosteroids or cytotoxic agents.8

TUBERCULOSIS
The Mantoux test should be carefully administered, with attention to use of proper
antigens, injected wiradermally. The extent of induration (not erythema) is determined 48
h after injection of 0.1 ml of purified protein derivative (5 tuberculin units). Reactivity of
^10 mm is positive; 5 to 9 mm is “ doubtful.” The tine test is useful for large scale testing,
but is imprecise, expensive, and subject to false-positive reactions. All positive tine tests
should be verified by Mantoux testing.
False-positive tuberculin tests may follow frequent repeated testing. Prior inoculation
with BCG may result in a low-grade positive reaction. Evaluation of infection by “ atypical”
mycobacteria is best performed with species-specific antigens (PPD-Y, G, B, F, S, T).9

OTHER BACTERIA
Skin tests for lymphogranuloma venereum (Frei test) and brucellosis are no longer used.
The intradermal test for cat-scratch disease (presumably a bacterial infection) is positive in
90%, but may only become reactive after 3 to 4 weeks of illness. False positives are
encountered among patient contacts and veterinarians.

FUNGI
Intradermal tests are available for coccidioidomycosis, histoplasmosis, North American
blastomycosis, candidiasis, cryptococcosis, and paracoccidioidomycosis. In most instances,
0.1 ml of antigen is injected intradermally to the volar surface. Such tests are subject to all
of the shortcomings described above, and are generally reserved for epidemiologic surveys.

PARASITES
Intradermal tests have been used for the diagnosis of schistosomiasis, fascioliasis, fi-
lariasis, ascariasis, and leishmaniasis. The Casoni test for echinococcosis is characterized
by low sensitivity and lifelong positivity. In general, serologic tests are preferred for such
diseases.
 491

BIOCHEMICAL EXAMINATIONS

A number of chemical assays of serum, urine, and other specimens may reveal organ
dysfunction due to inflammatory or infiltrative disease. Thus, evaluation of the febrile patient
should include studies of pancreatic, thyroid, renal, and hepatic products. Immune “ secre-
tions” such as leukocytes and immunoglobulins reflect reaction to inflammatory insult as
well as intrinsic disease of the spleen, bone marrow, lymph tissues, etc.

SERUM PROTEIN ELECTROPHORESIS

Over 100 serum proteins have been identified in human serum; the ability to separate
them in an electric field reflects the amphoteric properties of individual molecules. The
response of serum protein patterns is not sufficiently specific to be diagnostic in cases of
unexplained fever; however, important clues may occasionally be apparent.10
Alpha-2 globulin is elevated in infection, collagen-vascular disease, and malignancy;
whereas certain complement components migrate in the beta range, and are decreased with
complement consumption.
Elevation of IgA is seen in chronic liver disease, collagen-vascular disease, and gran-
ulomatoses. A “ beta-gamma bridge” may be seen on routine protein electrophoresis. IgG
is elevated in chronic infection, lupus erythematosus, Sjogren’s syndrome, lymphoma, and
rheumatoid arthritis. Monoclonal elevations may reflect plasma cell dyscrasias, solid tumors
or, rarely, tuberculosis.

ENZYME ASSAYS
The most valuable enzymatic test in evaluation of obscure fever is the serum alkaline
phosphatase. Elevated levels of hepatic alkaline phosphatase may reflect liver abscess,
hepatoma, hypernephroma, lymphoma, cirrhosis, marked hyperthyroidism, splenic infarc-
tion, the typhoidal form of infectious mononucleosis and CMV infection, metastatic car-
cinoma (especially hepatic and prostatic), sarcoidosis, and tuberculosis. Indeed, high enzyme
levels should prompt liver biopsy when noninvasive tests have been exhausted. Elevation
of other hepatic enzymes, such as oxaloacetic transaminase and aminotransferase, are en-
countered in hepatitis, Q-fever, typhoid, secondary syphilis, and toxoplasmosis.

SPECIFIC INFECTIOUS DISEASES

BACTERIA
By definition, bacteria responsible for “ unexplained fever” are either localized to poorly
accessable anatomic sites or difficult to identify. Such difficulty may be intrinsic to the
species involved, or may reflect prior antibiotic administration, inadequate technique, failure
to consider the possibility of a given species, etc.

Borreliosis
The species of Borrelia responsible for relapsing fever are generally identified on ex-
amination of thick smears of peripheral blood. A small drop of blood is applied to a clean
glass slide and spread in a circular manner to a diameter of approximately 1 cm. Giemsa,
Wright, Leishman, or other routine stains are adequate. Inoculation of clinical material into
chick embryo or suckling rodents is a sensitive test, but rarely performed nowadays.
Borrelia bergdorferi, the etiologic agent of Lyme disease, is not culturable by routine
laboratory methods. A number of immunologic tests (indirect fluorescent antibody; ELISA)
show great promise in the detection of specific serum antibody.

Leptospirosis
Leptospira species are recoverable from peripheral blood during the first week of illness
492 Unexplained Fever

only. The specialized media necessary (Fletchers; Ellinghausen-McCullough-Johnson-Har-

ris) are not routinely available in many laboratories. Positive cultures are often delayed for
up to 4 weeks, and may therefore be of limited value to the physician.
Following the first week of leptospirosis, spirochetes may be demonstrable on dark field
examination of urine for several months. Fresh urine should be brought to a neutral pH with
NaHC03 and transported promptly to the laboratory. Dark field preparations of cerebrospinal
fluid may also be positive.
The most commonly used serologic test for leptospirosis, microscopic agglutination, is
serovar-specific and tedious to perform. Recently, macro-agglutination and ELISA tests have
become available.

Chlamydia
Of the chlamydial infections, only psittacosis is mentioned as a cause of unexplained
fever. The disease is best diagnosed by demonstration of a rising complement fixing (CF)
antibody titer. Lymphogranuloma venereum is usually overt clinically, and rarely presents
as fever alone. The CF titer is also diagnostic here; the Frei intradermal test is no longer
performed.

Rat Bite Fever

Spirillum minor is not cultureable on artificial media. Although mouse inoculation is a
sensitive test, results may take 2 to 4 weeks. Occasionally, dark field examination of blood
or lymph node aspirates reveals the spirochete.
Streptobacillus moniliformis is cultured in highly supplemented media using specialized
techniques. Direct examination of joint fluid and other exudates is occasionally helpful; and
agglutinating antibodies may be demonstrated in the sera of patients.

FUNGI
Relatively few fungal species are implicated in unexplained fever. All too often, visu-
alization of fungi in direct smears and cultures is discounted as “ contaminant.” Available
diagnostic procedures are outlined in Table 2.

PARASITES
The majority of parasitic infestations are either clinically overt or unassociated with
persistent fever. The following may occasionally produce prolonged febrile illness.

Toxoplasmosis
Since infection by Toxoplasma gondii is extremely widespread and encountered early
in life, a large segment of the population is found to be seropositive. High 1/1000) levels
of specific IgG antibody may persist for life. The serodiagnosis of toxoplasmosis is best
made, therefore, by demonstration of IgM antibody and significant changes in titer (see
Table 2).

Malaria
The mainstay of laboratory malariology remains the carefully prepared and interpreted
blood smear. This author favors a Giemsa-stained thin film obtained during an afebrile
interval in the malarial cycle. Multiple examinations and thick films (see Borrelia) are often
necessary as well. The serodiagnosis of malaria is still in its infancy, but holds great promise
for the future (see Table 2).

Visceral Leishmaniasis: see Table 2

Trichinosis
Sensitive serologic techniques have obviated the need for biopsy diagnosis in recent
 493

years. The high prevalence of asymptomatic trichinosis in many populations suggests caution
in the interpretation of a single serologic titer.

Amebic Abscess
Intestinal amebiasis is unlikely to produce obscure fever. Tissue invasion is associated
with elevation in specific antibody titer (see Table 2).

VIRUSES
In general, viral disease is clinically overt and/or self limited. Therefore, relatively few
viruses are implicated in prolonged fever and FUO. Most such episodes occur in pediatric
practice. Common causes of prolonged and unexplained fever include viral hepatitis, Epstein-
Barr virus infection, and cytomegalovirus disease.

Epstein-Barr Virus
The heterophile antibody test (Paul-Bunnell) is positive in approximately 85% of patients
with infectious mononucleosis, with most false-negative studies occurring among children.
In such cases, specific antiviral antibody can still be demonstrated.
Both IgG and IgM antibody directed against viral capsid antigen (VCA) are demonstrable
during acute EBV infection. IgM activity disappears after ca. 4 weeks; IgG may persist for
many years. Antibody directed at viral “ early antigen” (EA) is also indicative of concurrent
or recent infection. During convalescence, anti EBV-associated nuclear antigen (EBNA)
appears, and high levels may persist for life.
Burkitf s lymphoma is associated with high levels of IgG-VCA, IgG-EA (restricted
component) and anti-EBNA. Nasopharyngeal carcinoma is associated with IgG-VCA, anti-
EBNA, and IgG-EA (diffuse component).

Cytomegalovirus
Cytomegalovirus infection can be diagnosed by identification of characteristic inclusion-
bearing cells in urine, sputum, and other material. Serologic studies (Table 2) should be
interpreted with caution in view of the high incidence of asymptomatic past infection.

Viral Hepatitis
Liver disease due to hepatitis A and B viruses is rarely responsible for unexplained
fever. An extensive discussion of the wide spectrum of antigen and antibody tests is beyond
the scope of this text, and the reader is referred to one of several recent publications on this
subject.13 At this writing, hepatitis A infection is confirmed with demonstration of either
IgG or IgM antibody. Infection by hepatitis B is best demonstrated by detection of circulating
surface antigen (HbsAg). The latter appears weeks prior to clinical illness, and may persist
for years in “ carriers” and individuals with chronic hepatitis.

REFERENCES
1. Larson, E. B., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow-up of 105 cases, 1970— 1980, Medicine (Baltimore), 61, 269, 1982.
2. Warner, A. S., Cobbs, C. G., Kaye, D., and Hook, E. W., Studies on the bacteremia of bacterial
endocarditis, JAMA, 202, 199, 1967.
3. Rubinstein, E., Noreiga, E. R., Simberkoff, M. S., Holzman, R., and Rabat, J. J., Jr., Fungal
endocarditis: analysis of 24 cases and review of the literature, Medicine (Baltimore), 54, 331, 1975.
4. Tuazon, C. V. and Sheagren, J. W., Teichoic acid antibodies in the diagnosis of serious infections with
Staphylococcus aureus, Ann. Intern. Med., 64, 543, 1976.
494 Unexplained Fever

5. Nakamura, R. M. and Tan, E. M., Recent advances in laboratory tests and the significance of auto-
antibodies to nuclear antigens in systemic rheumatic diseases, Clin. Lab. Med., 6, 41, 1986.
6. Dresner, E. and Trombley, P., The latex-fixation reaction in nonrheumatic diseases, N. Engl. J. Med.,
261, 981, 1959.
7. Shur, P. H., Immune-complex assays: the state of the art, N. Engl. J. Med., 289, 161, 1978.
8. Betts, R. F., Skin testing, in Principles and Practice of Infectious Diseases, 2nd ed., Mandell, G. L.,
Douglas, R. G., Jr., and Bennett, J. E., Eds., John Wiley & Sons, New York, 1985, 149.
9. Lefford, M. J .,. Immune response to mycobacteria, in Manual of Clinical Immunology, 3rd ed., Rose,
N. R., Friedman, H., and Fahey, J. L., Eds., American Society for Microbiology, Washington, D.C.,
1986, 415.
10. Wolf, P. L., Interpretation of electrophoretic patterns of serum proteins, Clin. Lab. Med., 6, 441, 1986.
11. Davey, F. R. and Nelson, D. A., Leucocytic disorders, in Clinical Diagnosis and Management by Lab-
oratory Methods, 17th ed., W. B. Saunders, Philadelphia, 1985, 704.
12. Bedell, S. E. and Bush, B. T., Erythrocyte sedimentation rate. From folklore to facts, Am. J. Med., 78,
1001, 1985.
13. Hollinger, F. B. and Dienstag, J. L., Hepatitis virusess, in Manual of Clinical Microbiology, 4th ed.,
Lennette, E. H., Balows, A., Hausler, W. J., Jr., and Shadomy, H. J., Eds., American Society for
Microbiology, Washington, D.C., 1985, 813.
 495

Chapter 33

SYSTEM IMAGING IN UNEXPLAINED FEVER

Albert Solomon and Jack Baron

NUCLEAR MEDICINE IMAGING

Nuclear medicine imaging procedures (radionuclide scans) can provide valuable diag-
nostic information, are noninvasive and safe with minimal radiation dose to the patient.
They are relatively cost-effective and should always be considered as a possible initial
imaging procedure in the investigation of fevers of unknown origin or for the detection and
localization of pyogenic foci. The information provided includes early detection and local-
ization, differential diagnosis (e.g., metastatic vs. inflammatory lesion), the extent and degree
of severity of the lesion and the assessment of response to treatment with follow-up scans.
Nuclear medicine procedures have an advantage over ultrasound and computerized to-
mography in that the demonstration of lesions is based on functional or metabolic changes
in an organ or focal area within it, whereas the other imaging modalities are based more on
tissue density changes which may show up at a later stage than the functional alterations.
This emphasizes the value of nuclear medicine imaging in the early detection of disease
and, in the case of fevers of unknown origin, as an initial imaging procedure.
The nuclear medicine procedures may be divided into three groups:

1. Individual organ imaging for the detection of focal or diffuse lesions such as liver,
bone, kidney, and brain imaging (Table 1). In addition to abscesses or other inflam-
matory processes, these organ scans may reveal the presence of other disease processes
or malignant lesions such as lymphoma. The presence of an enlarged liver or spleen
may also help in directing the line of investigation.
2. Blood flow and blood pool imaging for the visualization of hyperemic (inflammatory)
areas or a localized abscess (avascular area, usually surrounded by a vascular rim).
3. Imaging with specific radiopharmaceuticals that are preferentially taken up in inflam-
matory or infectious lesions (Table 2). Gallium citrate (67Ga), and more recently, “ ‘In-
labeled leukocytes have been used successfully for this purpose.12

Imaging with 11‘In-leukocytes has proven highly sensitive and specific for the visual-
ization of localized and diffuse lesions with less false-positive results compared to 67Ga
imaging, and sensitivity of labeled leukocytes for the detection of lesions is consistently
quoted as above 90%.12 Both 67Ga and 11‘In-leukocytes are, however, relatively expensive,
and this could explain why they have not gained wider use.
Recently, a number of reports have appeared describing the successful labeling of
granulocytes with " mTc.3 If the clinical evaluation proves successful, this could result in a
major breakthrough, since 99mTc is used routinely in all nuclear medicine departments. The
cost of the procedure should thus fall dramatically, making it a widely available cost-effective
procedure. Other advantages of " mTc over imaging with 67Ga or “ ‘In are

1. The " mTc gamma rays are better suited to gamma camera imaging, enabling better
image quality per dose administered.
2. " mTc has a half-life of 6 h compared to 67Ga and “ ‘In with half lives of about 3 days
resulting in a considerable reduction in radiation dose to the patient.
3. A special collimator is required for the higher energy gamma rays from 67Ga and ‘“ In.
496 U nex p la in ed F e ve r

TABLE 1
Nuclear Medicine Imaging: Individual Organ
Scans for the Investigation of
Unexplained Fevers

Organ Radiopharmaceutical

Liver and spleen " mTc colloid

Liver and biliary tract " mTc HIDA
Bone " mTc methylene disphosphonate
Brain " mTc pertechnetate or WmTc DTPA
Kidney (dynamic) " mTc DTPA
Blood flow Any ""Tc label3
Blood pool " mTc red blood cells

3 The first pass of any of the above WmTc compounds through

the organ or area of interest following an i.v. bolus injection
enables imaging of the arterial supply and venous drainage
in that area.

TABLE 2
Nuclear Medicine Imaging with Labeled Leukocytes — Some Clinical Applications
(Detection, Localization, and Follow-Up)5

• Bone inflammatory process

• Liver abscess
• Brain abscess, meningitis, encephalitis
• Kidney or perinephric abscess
• Infected cyst
• Inflammatory bowel disease
• Abdominal abscess
• Chest and lung inflammatory lesions
• Pancreatitis
• Rheumatoid arthritis

" mTc leukocyte scans make use of collimators already available routinely in all nuclear
medicine departments.

It must be remembered, however, that the labeling of the leukocytes requires some
expertise and the appropriate laboratory facilities for the separation of granulocytes, and
then labeling with 99mTc.4 The withdrawal, separation, labeling and reinjection should not
take longer than 1 h, and imaging can be performed 4 h post-injection. Occasionally, a 24-
h image may be necessary.
A particularly promising radiopharmaceutical appears to be " mTc hexamethylpropyle-
neamine oxime ( " mTc-HMPAO), which is now used successfully as a brain blood flow
imaging agent due to its rapid transfer through the blood to brain barrier. This lipid soluble
radiopharmaceutical has been shown to successfully label granulocytes after simple mixing
with the separated cells. This may turn out to be the procedure of choice, due to its simplicity
and suitability for routine use. In addition, tomographic gamma camera imaging using
emission computerized tomography (ECT), a relatively inexpensive accessory to conven-
tional gamma cameras, results in a vast improvement in image resolution and lesion de-
tectability, and will no doubt become more widely available in the future.
 497

ULTRASOUND, COMPUTERIZED TOMOGRAPHY, AND

MAGNETIC RESONANCE IMAGING

Technological advances have placed the diagnostic radiologist at the forefront of modem
investigative procedures. Standard radiographic techniques use tissue absorption factors in
the production of the final image of the organ or anatomical site being investigated. However,
the advent and application of computer assisted instrumentation has broadened the radiol-
ogist’s ability to examine the body. Additionally, tissue attentuation qualities have become
measurable. Tissues of different structures within the body being of varying elemental
composition exhibit dissimilar attenuation qualities. In the generation of computerized to-
mographic (CT) cross sectional images of the X-ray attenuation coefficients, an image is
formed that delineates within the body, showing relative anatomic relationships. The digital
output displayed on a cathode ray tube (CRT) is a measure of the attenuation coefficients
in transverse body sections. The computer data acquisition is relayed to a reconstructive
system, and the digitalized image is viewed on the CRT viewing screen. The equipment
provides the means of adjusting attenuation levels (window setting) in order to best view
the different tissues or organs.
Magnetic resonance imaging (MRI) makes use of the property and characteristics of
tissue protons (H+ nuclei) when the body is exposed to the influence of a strong magnetic
field. The phased resonance signals (energy) emitted by tissues when influenced by the
magnetic field, can be recorded and viewed by digitalized computer reconstruction of the
signals on a CRT viewing screen. The different signal sequence and the recovery phases
recorded when the tissues are subject to the strong magnetic field are referred to as the Tj
biased and T2 biased relaxation times. The physical guide lines and concepts are complex.
The production of high quality clinical magnetic resonance images requires a combination
of many sophisticated electronic components, together with the powerful magnet: MRI is
still evolving rapidly. Although many aspects and applications are still to be studied, chemical
shift imaging remains promising as a method of adding specificity to MRI diagnosis.6 MRI
is still in its infancy, with many exciting profiles still to be explored. However, with the
present state of the art, imaging of body systems is still governed by cost effectiveness and
availability of instruments. CT, ultrasonography, nuclear medicine, and routine radiographic
procedures all retain their place in patient assessments. Basic problems are still regularly
and satisfactorily resolved by routine radiological investigations.
Ultrasound imaging is accomplished by a pulse-echo technique. The pulses of ultrasound,
generated by a transducer, are transmitted into the patient, where they produce echoes at
organ boundaries and from within the tissues. The returning echoes are detected by the same
transducer. The information is then processed and digitalized to form the image viewed on
the CRT screen. Technical factors govern the output of the apparatus and its use. Dynamic
(real time) imaging, capable of producing many images (frames) per second, is accomplished
by rapid automated scanning, by either mechanical or automated electronic means. The
latter machines allow a dynamic and persistent image to be observed, permitting observation
of physiologic movement. The advent of real time scanning procedures has reduced the need
of exceptional operator skill; however, the art of scanning requires practice.
Nuclear medicine imaging and real time ultrasonography are freely available in most
modem institutions. Preliminary surveys in patients often resort to the procedures which are
usually available, relatively inexpensive, and require minimal time outlay or effort in their
use. Computerized tomographic examinations, in more recent years, are generally available
in the larger medical institutions. However, MR imaging is not within the scope of everyday
use, except in the more fortunate establishments. Proffering guide lines and indications for
procedures and investigations will be tempered by availability. The fact, however, remains
that basic procedures should be carried out first. Where the clinical index of suspicion is
498 U nex p la in ed F e ve r

high, e.g., suspect respiratory disease, a simple radiograph of the chest is the obvious initial
investigation.
In the case of questionable involvement of an organ, a radionuclide scan or ultrasound
investigation on the basis of cost-effectiveness should be the initial test, following clinical
appraisal and assessment.
Inflammatory changes and abscess formation, neoplasms, lymphomatous diseases, para-
sitic invasion leading to localizing organ reaction, and pathological invasion of organs or
regions, that allow the identification of significant tissue changes in their various physical
manifestations, are within the diagnostic scope of the imaging procedures. Occult liver,
pancreas, splenic, renal, pelvic, and retroperitoneal growth or abscesses may often be iden-
tified by nuclear medicine, ultrasonography, CT, or MR scans.
A pragmatic approach to the initial choice of imaging is to be found in the clinical and
laboratory investigations. Hepatosplenomegaly or the presence of enlarged lymph glands
suggests diffuse reticuloendothelial diasese. A CT scan in this situation might confirm the
presence of hepatosplenomegaly and/or thoracic or abdominal lymphadenopathy. Fine needle
CT guided gland or liver aspiration would then logically follow. Hematological changes
indicative of an infective process, e.g., a high white blood cell count, could initiate the use
of a nuclear imaging procedure in an attempt to localize an infective source.

THE CHEST AS A SOURCE OF UNEXPLAINED FEVER

Tantamount to the understanding of modem system and organ imaging is the fact that
although the procedures are able to demonstrate unsuspected pathology, absolute diagnostic
reliability requires tissue histology, and in the case of infections, organismal isolation and
identification, i.e., specific diagnostic proof. The routine chest radiograph may reveal a
tumor mass or mediastinal lymphadenopathy, however, the more subtle unsuspected lesions
are undoubtedly more easily revealed by CT or MRI. In the diagnosis of chest diseases, CT
at present offers greater spatial resolution than does MR, the latter perhaps being superior
to CT in identifying a mediastinal mass and distinguishing it from normal structures.7 CT
is better able to evaluate small lymph nodes or bronchi, permitting the detection of bronchial
abnormalities, as well as hilar masses.7 The detection of an abnormal bronchus can serve
as a guide to transbronchoscopic biopsy procedures.
Alveolar infiltrates may be so subtle as to be undetected on the plain chest radiograph.
In tuberculosis, the presence of an unsuspected cavity indicating reactivity of disease may
be defined by CT; additionally, early nondiscemable miliary nodules on the plain chest X-
ray are relatively easy to find with CT.8
Mediastinal tumors and infective processes, as well as small parenchymal, peripheral
lung or pleural lesions are often not visible on a chest radiograph, but displayed by CT,
thus revealing the source of unexplained fever.
Cardiac imaging has been in the forefront of the new advances; in addition to nuclear
imaging and echocardiography, gated CT and MRI cardiac evaluation has already found
favor in some of the larger institutions. Many of the investigations are mainly directed at
the evaluation of anatomical defects, flow states, and cardiac performance. However, these
modem imaging procedures are able to demonstrate valvular vegetations, and intracardiac
tumor masses, which may well be the cause of a fever of unknown source.9
Nuclear medicine imaging procedures, e.g., the labeled leukocyte scans, are extremely
sensitive in the detection and localization of local or diffuse inflammatory changes in the
lungs and mediastinum. In many cases, this investigation should be the initial imaging
procedure.

THE ABDOMEN
Intra-abdominal abscesses remain a common diagnostic problem. Reports suggest that
70% of patients with abdominal abscess have extraneous intraperitoneal gas demonstrated
 499

on routine abdominal films. However, this may necessitate total opacification of the bowel
with barium to demonstrate the extraneous air.10 Ultrasound11 and CT12 are highly sensitive
modalities for locating and outlining abnormal fluid collections. Abscesses on ultrasound
appear as round or oval fluid collections with increased echogenicity internally. Gas within
the fluid collection is highly suggestive of abscess formation.13 There may be considerable
overlap in the appearances, on ultrasonography, between abscesses, hematomas, lympho-
cèles, bilomas, or seromas.14 In all of these situations the only means of a definitive diagnosis
is by percutaneous needle aspiration and bactériologie examination, which could be done
under guided ultrasonography direction.
Computed tomography (CT) is considered more accurate than ultrasound in detecting
abdominal abscesses.12 Criteria for CT identification of an abscess are well defined; this
includes identification of a region of low attenutation values in an extraluminal location or
within the parenchyma of solid abdominal organs, e.g., liver, spleen, pancreas.15 Intracav-
itary gas is a helpful additional finding and has been reported in 40 to 50% of intra-abdominal
abscesses.16
In the evaluation of retroperitoneal and psoas abscesses, neither ultrasound nor nuclear
medicine is as efficient as computed tomography.17 CT imaging of the pancreas remains
invaluable both in the diagnosis and treatment of pancreatic disease.18 It is apparent that CT
can aid in the diagnosis and treatment of retro- and intraperitoneal inflammatory fluid
collections, but percutaneous needle aspiration of the fluid is necessary to separate infected
from noninfected collections.
Certain pitfalls are inherent in the appraisal of inflammatory masses for, e.g., necrotic
tumors and tissues may occasionally have intracavitary air and not be infected. Pus collections
may appear solid. This occurs often in pelvic and pancreatic masses. In the final assessment
the necessity for tissue diagnosis and organism identification remains mandatory. This basic
tenet is essential in planning treatment for pyrexia of undetermined etiology. It is in this
regard that CT or ultrasound guided needle aspiration of the pathology is most helpful.
Nuclear medicine scans with labeled leukocytes have been shown to be more than 90%
accurate in the detection and localization of intra-abdominal inflammatory lesions, and may
be the initial imaging procedure preferred.

THE LIVER AND SPLEEN AS SOURCES OF UNEXPLAINED FEVER

Reference has already been made to the diagnostic ability of radionuclide scans, ultra-
sound, and CT in the detection of inflammatory lesions and abscesses. The assessment of
hepatic abnormalities, i.e., primary focal lesions or metastatic hepatic neoplasms is usually
beyond routine radiography. Magnetic resonance imaging of the liver holds great promise
in evaluating benign from malignant lesions. However, in the imaging of the spleen, MRI
has not been of value in diagnostic splenic métastasés or lymphoma on a routine basis.19
CT is the all round best modality for lesion detection in the liver.20 If nuclear medicine is
chosen as the basic hepatic screening examination, other modalities such as ultrasound and
CT will have to be used frequently to add specificity to suspected abnormalities.21
Significant organomegaly, particularly the enlarged spleen, is reliably assessed by nuclear
medicine, ultrasound, and CT. The recently introduced faster and more sophisticated CT
scanners, in combination with intravenous bolus contrast enhanced dynamic liver and splenic
scans, may disclose diffuse infiltrative organ pathology. The combination of hepatosple-
nomegaly and retroperitoneal lymphadenopathy revealed by ultrasound or CT should alert
the clinician to the diagnosis of a lymphoma as the cause of fever in the patient.
Some specific diagnostic characteristics permit accurate comment to be made on nuclear
medicine, ultrasound, and CT investigation of the liver or spleen. The calcified rim of a
septate cystic lesion, which additionally shows daughter cyst inclusion in the fluid mass is
diagnostically specific of an hydatid cyst, best demonstrated on ultrasound. Pyogenic or
amebic abscesses are rarely able to be differentiated merely on CT or US characteristics.
500 U nex p la in ed F e ve r

Hepatic angiography is seldom performed for diagnostic reasons in more recent years,
having been replaced by the newer imaging modalities.21 A liver or spleen focal defect on
the conventional " mTc colloid scan, combined with increased uptake on the 67Ga or labeled
leukocyte scan (usually uptake higher than the surrounding tissue), can be diagnostic of an
abscess. Follow-up 67Ga or leukocyte scans will reflect the response of the lesion to therapy.

THE PANCREAS
In evaluating the patient with suspected abnormality, the use of imaging modalities may
vary from one institution to the next. In most cases, CT offers the most information regarding
pancreatic lesions. If the image findings remain equivocal after CT or ultrasound, endoscopic
retrograde cholangiopancreatography (ERCP) may be the diagnostic test which would yield
information regarding significant ductal abnormalities.22 The pancreas is one of the most
difficult organs to image by NMR.23
Pancreatitis may be associated with carcinoma of the gland and possibly accounts for
the occasional patient presenting with an accompanying low grade fever. Differentiation of
carcinoma from pancreatitis may pose a great problem. Secondary changes of carcinoma
would include hepatic metastases. Peripancreatic adenopathy and direct spread surrounding
the inferior vena cava, superior mesenteric artery, or celiac axis may be seen on CT.24
Cancer and pancreatitis may co-exist in 6 to 10% of patients.22
Although ultrasound may be used as a preliminary screening procedure for the pancreas,
CT generally offers the most information. In an equivocal case, ERCP may be of help.25
Pancreatitis and its complications including abscess formation, infected pseudocysts,
and phlegmons of the pancreas, may be identified both by CT and ultrasound. The definitive
information in doubtful cases may be obtained by thin needle aspiration, or aspiration biopsy
under ultrasound or CT direction.
Nuclear medicine imaging with labeled leukocytes can differentiate mild from severe
pancreatitis.

THE KIDNEY AS A SOURCE OF UNEXPLAINED FEVER

As in most imaging modalities, ultrasound is unable to provide a tissue-specific diagnosis.
However, renal sonography is particularly well suited in determining the characterization of
renal masses. Lesions in excess of 2 cm in diameter will usually be detected by their
sonographic appearance in the kidney.26 Ultrasonography is able to detect simple renal cysts
more accurately.27 Less commonly, an abscess will be indistinguishable from a simple cyst
on ultrasonography.28 Other cystic lesions of the kidney, detectable by ultrasonography as
a cause of fever, include cystic and necrotic tumors, pyonephrosis, abscesses, tuberculous
cavities, and infected cysts. Needle aspiration aided by organismal or cytological identifi-
cation is usually required to finalize the diagnosis. Renal cell carcinoma, apart from being
a solid lesion, may develop a cystic component by virtue of extensive necrosis, or develop
in the wall of a pre-existing renal cyst. Solid renal masses that may masquerade as possible
malignancies include metastases, acute focal bacterial nephritis, lymphoma, sarcoma, and
focal xanthogranulomatous inflammation.29 Ultrasonography is a mandatory investigation
for the detection of renal pathology as a cause of fever.
The ease of renal assessment and the ability to demonstrate mass lesions such as ab-
scesses, infected cysts, and tumor-invasion of the kidney is additionally reinforced by both
CT and MRI examination. Sonography and CT are both capable of detecting acute focal
bacterial nephritis:30 Xanthogranulomatous pyelonephritis produces characteristic changes
that are recognizable on CT examination.31 Although CT is not used as a screening exam-
ination for renal malignancy, it allows recognition of kidney tumors, particularly when used
in combination with contrast enhanced CT scans. Lymphoma of the kidney occurs in several
forms: diffuse infiltration, a solitary mass, or discrete multiple nodules.32Lymphoma includes
the kidney secondarily, but is frequently silent. Renal involvement is much easier to detect
 501

by CT after contrast enhancement, which, while enhancing the renal tissue, only slightly
enhances the lymphoma tissue.33 Early experience with MR examination of the kidney offers
an increased ability to detect tissue changes. There is the strongest possibility emerging that
MR may be the means of differentiating aspects of disease processes that have hitherto not
been possible.

THE PELVIS
Occasionally the clinician suspects pelvic disease, i.e., tumor, an occult inflammatory
mass, or reticuloendothelial pathology, e.g., lymphoma, as the source of an unexplained
fever. Prostatic carcinomas are generally latent and unusually present themselves as a source
of unexplained pyrexia, except perhaps by causing significant residual bladder urine. In this
event, secondary infection of the residue may result in urinary sepsis and pyrexia. It is
generally agreed that no modality, with the exception of ultrasound, is capable of detecting
intraglandular disease.34 At present, CT36 and MR35 are both better used for staging prostatic
carcinoma than making the primary diagnosis.
In the rare event of a bladder carcinoma presenting with pyrexia, both CT and MR are
equally able to demonstrate the lesion.34
Ultrasonography is the initial investigation used in examining a patient with a pelvic
mass. Ultrasound may have difficulty in detecting isolated pockets of ascites or pus, sep-
arating bowel loops, or lymph node metastases. Despite these limitations, its ability to
localize a lesion and suggest an etiology may help the clinician understand the magnitude
of the mass and what approach is necessary.36 CT is able to demonstrate ovarian carcinoma
spread to areas difficult to detect at surgery.37

THE RETROPERITONEAL LYMPH GLANDS, SOFT TISSUE AND

VASCULAR STRUCTURES
A major contribution of ultrasound and CT has been the noninvasive imaging of ab-
dominal and pelvic lymph nodes. These modalities, while not evaluating intranodal archi-
tecture, are capable of directly imaging lymph nodes in regions not routinely demonstrated
by lymphangiography. Very few clinicians have not been confronted by the patient with a
pyrexia of unknown source, that has finally been verified as a Hodgkin’s or non-Hodgkin
lymphoma presentation. The demonstration of pathologically enlarged retroperitoneal or
pelvic lymph nodes, particularly when cytologic confirmation has been obtained after fine
needle aspiration, obviates the need for more invasive procedures. Lymphangiography,
because of its ability to display intranodal detail, still finds favor in certain situations, having
an accuracy of 91%.38 CT detection of retrocrural mesenteric and peri-pancreatic lymph
node enlargement is perhaps superior to ultrasound detection of these nodes. Lymph glands
in excess of 1.0 cm to 1.5 cm in size are regarded as pathological.
Vascular changes, such as thrombus formation of the inferior vena cava, are demonstrable
by all three scanning modalities, i.e., ultrasound, CT, and MR. A specific diagnosis of
septic thrombus can be made by identifying multiple gas bubbles within a low attenuation
intraluminal caval filling defect by CT.39
CT has been useful in detecting infected aortic grafts. CT usually demonstrates a peri-
aortic fluid or gas collection.40 A CT guided needle aspiration of the fluid is required to
obtain specimens for culture.
CT is the imaging method of choice in the evaluation of retroperitoneal abscesses and
primary retroperitoneal neoplasms, such as liposarcomas, leiomyosarcomas, fibrosarcomas,
and malignant teratomas. Metastatic retroperitoneal tumors are usually lymphomas or lymph
node metastases from pelvic testicular, lung, or gastrointestinal neoplasms. MR imaging is
at present in its infancy, but offers great potential for the investigation of retroperitoneal
pathology.
502 U nex p la in ed F e ve r

THE CENTRAL NERVOUS SYSTEM, SPINAL COLUMN, AND HEAD AND

NECK STRUCTURES
Intracranial infections have been identified as mass lesions on both CT and MR. Rim
enhancement after intravenous contrast or central liquefaction of the abscess are features of
a nonspecific nature that offer clues to the diagnosis in the correct clinical setting. Similarly,
granulomatous diseases, e.g., tuberculosis involving the brain, present nonspecific features
on CT. Demyelinating diseases of the brain, other than multiple sclerosis, include demye-
linating changes following acute disseminated encephalomyelitis. These changes have been
studied by MR and diagnostic criteria have now been devised.41 Cerebral tumors are par-
ticularly well demonstrated by both CT and MR. Magnetic resonance imaging permits
detailed study of the sub-tentorial components of the skull, i.e., cerebellum and brain stem
structures, which previously were less easily defined by CT investigation.
The diagnostic impact of CT in the evaluation of the spine has steadily increased as
high resolution technique has provided improved bony detail and soft tissue assessment.
Adjacent soft tissue and bony involvement of the vertebrae in inflammatory conditions,
pyogenic or tuberculous, are readily demonstable by both CT and MR. MR appears more
sensitive than plain film radiography or CT and more specific than nuclear medicine studies
in the diagnosis of disk space infection and vertebral osteomyelitis.42
MR has the ability to image the spinal cord in its entirety and facilitate the identification
of intramedullary masses, including abscesses.
Facial and neck structures may harbor infection or tumor masses; both CT and MR are
particularly suitable for the investigation of these areas. CT retains the ability to demonstrate
bony structural details; destructive lesions of bone due to inflammatory or tumor invasion
are at present particularly well suited to CT investigation.
Nuclear medicine imaging with labeled leukocytes may resolve the problem of an equiv-
ocal CT scan, where the uptake of the leukocytes is indicative of an inflammatory change.

REFERENCES
1. Sfaniakis, G. N., Al-Sheikh, W., and Heal, A., Comparisons of scintigraphy with In111 leukocytes and
Ga67 in the diagnosis of occult sepsis, J. Nucl. Med., 23, 618, 1982.
2. Schauwecker, D. S., Hee-myung Park, Mock, B. H., Burt, R. W., Kernick, C. B., Ruoff, A. C.,
Ill, Sinn, H. J., and Wellman, H. N., Evaluation of complicating osteomyelitis with T c"m MDP, In111
granulocytes, and Ga67 citrate, J. Nucl. Med., 25, 349, 1984.
3. Sundrehagen, E., Bengtsson, A. M., Bremer, P. D., Jacobson, H., von Krusenstierna, S., Larsson,
S. A., Schnell, P. O., Svenberg, T., Svenberg, P., and Appelgren, A., A new method for granulocyte
labelling with Tc"m— preliminary results in abscess detection, J. Nucl. Med., 27, 555, 1986.
4. Mortelman, L., Verbruggen, A., Bogaerts, M., de Bakker, C., and de Roo, M., In vitro evaluation
of granulocyte labelling with In111 chelated to three different agents, J. Nucl. Med., 27, 1014, 1986.
5. Datz, F. L. and Thorne, D. A., Effect of antibiotic therapy on the sensitivity of In111 labelled leucocytes
scans, J. Nucl. Med., 27, 1849, 1986.
6 Bydder, G. H., Nuclear magnetic resonance of the brain, Cardiovasc. Intervent. Radiol., 8, 264, 1986.
7. Webb, W. R., Magnetic resonance imaging of the hila and mediastinum, Cardiovasc. Intervent. Radiol.,
8, 306, 1986.
8. Naidich, D. P., McCanley, D. I., Leitman, B. S., Genieser, N. B., and Hulnick, D. H., CT of pulmonary
tuberculosis, in Computed Tomography of the Chest, Siegelman, S. S., Ed., Churchill Livingstone, New
York, 1984, 175.
9. Kisslo, J., The cardiac diagnostic unit. A new approach to patient care, Radiol. Clin. North Am., 21(4),
623, 1983.
10. ConneI,T., Stephens, D. H., Carlson, H. C., and Brown, M. L., Upper abdominal abscesses: a continuing
and deadly problem, AJR, 134, 759, 1980.
11. Doust, D. B. and Thompson, R., Ultrasonography of abdominal fluid collections, Gastrointest. Radiol.,
3, 273, 1978.
 503

12. Koehler, P. R. and Moss, A. A., Diagnosis of intra-abdominal and pelvic abscesses by computed to-
mography, JAMA, 244, 49, 1980.
13. Kressel, H. Y. and Filly, R. A., Ultrasonographic appearance of gas containing abscesses in the abdomen,
AJR, 130, 71, 1978.
14. Mueller, P. R., Ferruci, J. I., Jr., Simeone, J. F., Cronan, J. J., Wittenberg, J., Neff, C. C., and
van Sonnenberg, E., Bilomas: special considerations in detection and drainage, AJR, 140, 715, 1983.
15. Ferruci, J. I., Jr. and van Sonnenberg, E., Intra-abdominal abscess. Radiological diagnosis and treatment,
JAMA, 246, 2728, 1981.
16. Haaga, J. R., Alfidi, R. J., Havrilla, T. R., Cooperman, A. M., Seidelmann, F. E., Reich, N. E.,
Weinstein, A. G., and Meaney, T., CT detection and aspiration of abdominal abscesses, AJR, 123, 465,
1977.
17. Jeffrey, R. B., Callen, P. W., and Federle, M. P., Computed tomography of psoas abscesses, 7. Comp.
Assist. Tomogr., 4, 639, 1980.
18. Karlson, K. B., Martin, E. C., Fankuchen, E. I., Mattern, R. F., Schultz, R. W., and Casarella,
W. J., Percutaneous drainage of pancreatic pseudocysts and abscesses, Radiology, 142, 619, 1982.
19. Stark, D. D., Moss, A. A., and Goldberg, H. I., Nuclear magnetic resonance of the liver, spleen, and
pancreas, Cardiovasc. Intervent. Radiol., 8, 329, 1986.
20. Zeman, R. K., Panshter, D. M., Schiebler, M. L., Choyke, P. L., Jaffe, M. H., and Clark, L. R.,
Hepatic imaging: current status, Radiol. Clin. North Am., 23(3), 473, 1985.
21. Djang, W. T., Young, S. W., Castellino, R. A., and Lantieri, R., Computed tomography of the liver:
evaluating focal defects on radionuclide liver-spleen scans, AJR, 142, 937, 1984.
22 Clark, L. R., Jaffe, M. H., Choyke, P. L., Grant, E. G., and Xeman, R. K., Pancreatic imaging,
Radiol. Clin. North Am., 23(3), 489, 1985.
23 Stark, D. D., Moss, A. A., Goldberg, H. I., Davis, P. L., and Federle, M. P., Nuclear magnetic
resonance imaging of the pancreas. Normal and pathological findings, Radiology, 159, 153, 1984.
24. Fishman, E. K. and Siegelman, S. S., Computed tomography of pancreatic carcinoma, in Computed
Tomography of the Pancreas, Siegelman, S. S., Ed., Churchill Livingstone, New York, 1983, 123.
25. Moss, A. A., Federle, M., Shapiro, H. A., Ohio, M., Goldberg, H. I., Korobkin, M., and Clemett,
A. R., The combined use of computed tomography and endoscopic retrograde cholangiopancreatography
in the assessment of suspected pancreatic neoplasm. A blind clinical evaluation, Radiology, 134, 159, 1980.
26. Sanders, R. C., Renal ultrasound, Radiol. Clin. North Am., 13, 417, 1975.
27 Pollack, H. M., Banner, M. P., Arger, P. H., Peters, J. C., Mulhern, C. B., Jr., and Coleman,
B. G., The accuracy of grey scale renal ultrasonography in differentiating cystic neoplasms from benign
cysts, Radiology, 143, 741, 1982.
28. Gerzof, S. G. and Gale, M. E., Computed tomography and ultrasonography for diagnosis and treatment
of renal and retroperitoneal abscesses, Urol. Clin. North Am., 9, 185, 1982.
29. Amis, E. G. and Hartman, D. S., Renal ultrasonography: a practical overview, Radiol. Clin. North Am.,
22, 315, 1984.
30. Morehouse, H. T., Weiner, G. N., and Hoffman, J. C., Imaging in inflammatory disease of the kidney,
AJR, 143, 135, 1984.
31. Solomon, A., Braf, Z., Papo, J., Merimsky, E., Computerised tomography in xanthogranulomatous
pyelonephritis,/. Urol., 130, 323, 1983.
32. Chilcote, W. A. and Borkowski, G. P., Computed tomography in renal lymphoma, J. Comp. Assist.
Tomogr., 7, 439, 1983.
33. Dunnick, N. R. and Korobkin, M., Computed tomography of the kidney, Radiol. Clin. North Am., 22,
297, 1984.
34. Choyke, D. L., Thickman, D., Kresser, H. Y., Lynch, J. H., Jaffe, M. H., Clark, L. R., and Zeman,
E. K., Controversies in the radiologic diagnosis of pelvic malignancies, Radiol. Clin. North Am., 23, 531,
1985.
35. Bryan, P. J., Butter, H. E., and Puma, J. P., Magnetic resonance imaging of the pelvis, Radiol. Clin.
North Am., 22, 897, 1984.
36. Lurain, J. R., Newer diagnostic approaches to the evaluation of gynecologic malignancies, Obstet. Gynecol.
Surg., 37, 437, 1982.
37. Solomon, A., Brenner, H. J., Rubinstein, Z. J., Chaitchuk, S., and Morag, B., Computed tomography
in ovarian cancer, J. Gynecol. Oncol., 15(1), 48, 1983.
38. Marglin, G. and Castellino, R., Lymphographic accuracy in 632 consecutive previously untreated cases
of Hodgkin’s disease and non-Hodgkin’s lymphoma, Radiology, 140, 351, 1981.
39. Schmitz, L., Jeffrey, R. B., Palubinskas, A. J., and Moss, A. A., CT demonstration of septic thrombosis
of the inferior vena cava, J. Comp. Assist. Tomogr., 5, 259, 1981.
504 U nex p la in ed F e ve r

40. Mark, A., Moss, A. A., Lusby, R., and Kaiser, J. A., CT evaluation of the complications of abdominal
aortic surgery, Radiology, 145, 409, 1982.
41. Bydder, G. R., Magnetic resonance imaging of the brain, Radiol. Clin. North Am., 22(4), 779, 1984.
42. Pauschter, D. M., Modic, M. T., and Masaryk, T. J., Magnetic resonance imaging of the spine:
applications and limitations, Radiol. Clin. North Am., 23(3), 551, 1985.
 505

Chapter 34

TREATMENT

Yardena Siegmann-Igra

INTRODUCTION
The therapeutic approach to a febrile disease should, as far as possible, be directed
towards the cause of fever (causative therapy), i.e., the use of specific antimicrobials active
against the causative microorganism, or other effective therapeutic agent.
Ideally, each time a physician is faced with a febrile patient, he should make a pre-
sumptive or definitive diagnosis, check whether a specific therapy for the situation exists,
and decide whether it should be given to the patient. Practically, even a presumptive diagnosis
is often difficult to postulate (unexplained fever), and the question whether to treat and in
what manner, is a very difficult one.
It is not the intention of this chapter to list therapeutic regimens for specific disease
entities. Conventional textbooks exist for this purpose. Our aim is to try to aid the perplexed
physician confronted with undiagnosed fever, with the decision whether to treat when there
is no specific diagnosis, and what to prescribe for various clinical situations.

MANAGEMENT OF FEVER AS SUCH

SHOULD FEVER BE REDUCED?

Fever was already recognized in the ancient world (Bible, Hippocrates) as a sign of
disease. However even today, its role in the pathophysiology of febrile diseases is not
completely understood, although significant progress has been made.12 The important ques-
tion of whether fever is detrimental to the human body, or has any beneficial effect in the
defense against disease, has not yet been fully ascertained.
Moderate fevers are probably harmless, except in those individuals with compromised
cardiovascular function. However, the deleterious effects of high fever on the central nervous
system are well known: febrile convulsions in children, delirium and unconsciousness in
adults, (especially elderly persons), and fatal effects of temperature over 43°C.3
On the other hand, although common sense argues for a beneficial role of fever, and
many years ago induction of fever was even considered therapeutic in certain infections,
there is no sound evidence to this effect.
Recently, however, some scattered information has emerged demonstrating the beneficial
effect of fever on the survival of infected lizards,4 on the function of the immune system,56
on viral titers and clearance,7 and on the activity of several antimicrobials on certain bacteria.8
Also, the failure to raise temperature in the presence of infection occurs in the most debilitated
and is a bad prognostic sign.
Thus far, there is no unequivocal evidence as to whether common fevers should merely
be carefully watched, or fought against. There is a “ natural” tendency among physicians
to “ routinely” reduce fever in febrile patients. The arguments for this aptitude are usually
as follows:

1. To reduce the risk of febrile convulsions especially in children under 3 or 4 years of

age
2. To avoid the risk of mental changes, particularly in the elderly
3. To prevent cardiac insufficiency in patients with limited cardiac reserves
506 U nex p la in ed F e ve r

4. To reduce hyperventilation, sweating and loss of fluids, and to prevent the hyperca-
tabolic states characteristic of high or prolonged fevers
5. To relieve patients’ discomfort, improve appetite, etc.
6. To avoid recrudescence of herpes simplex infection (“ fever blisters’’)
7. In addition, the proponents for therapy claim that there is no significant risk from
properly used antipyretics, or environmental methods for fever reduction.

The arguments against routine reduction of fever are as follows:

1. The vast majority of fevers do not exceed 40°C and are of short duration
2. Generally, fever is harmless except in extreme conditions
3. Fever is a useful sign of disease, in observing the natural course of the disease and
helping judge the response to specific therapies. Its suppression may obscure an im-
portant guide to the true situation. This is especially true when the diganosis has not
yet been established
4. The waves of fever and sweating caused by intermittent antipyretic doses may be more
uncomfortable for the patient, than the sustained fever
5. There are potential adverse effects of antipyretic drugs or methods
6. The belief that fever plays some beneficial role in the defense against disease, as
mentioned above.

Accordingly, the decision of whether or not to reduce fever must always take into
account the following data: the patient’s age, the degree of fever; its duration; the patient’s
general condition, and to what extent it is influenced by the fever; and the presumptive
etiology and pathophysiology of fever in the individual patient. In most cases, the decision
will also be influenced by the subjective need of the patient and by the individual approach
of the physician.
In general, our policy is not to reduce fever unless at least one of the following exists:

1. Convulsions or mental changes attributed to the fever

2. Extreme temperature, specifically over 40°C at any age, and especially with patho-
genesis such as heat stroke, or malignant hyperthermia. Temperature exceeding 41°C
should be regarded as a medical emergency
3. Extreme age, either very young or very old, and especially with a history of previous
adverse reaction to fever
4. Marked subjective discomfort pronounced by the patient, especially when including
myalgia and headache, which are also relieved by antipyretic drugs
5. Prolonged high fever causing significant hypercatabolic state
6. Reduced cardiac or pulmonary function to the extent that further tachycardia or tach-
ypnea might be harmful.

By What Means?
Fever may be reduced by pharmacologic measures, i.e., the use of antipyretic drugs,
or by environmental measures, such as external cooling.

A n tipyretic D rugs
In fever (as distinguished from hyperthermia), the increased body temperature is the
result of an elevation of the set point of the temperature regulatory region in the hypo-
thalamus.9 Antipyretic drugs reduce fever by lowering the hypothalamic set point towards
normal;9 therefore, this is the most rational and physiologic approach to fever reduction.
(Antipyretics do not reduce normal temperature when given in recommended doses.)
 507

As to the choice of drug: many compounds have demonstrated antipyretic activity,

however, two drugs remain the most useful and most widely employed: aspirin and acet-
aminophen. Nonsteroidal anti-inflammatory agents and phenylbutazone have more toxic
reaction than aspirin and acetaminophen and are more specifically used than merely for fever
reduction. Aminopyrine and dipyrone are effective antipyretics widely used in many coun-
tries, but have been withdrawn in others because of the risk of side effects. Thus, the actual
choice is between the time-honored, familiar aspirin and the relatively new acetaminophen.
A detailed pharmacologic description of these drugs is beyond the scope of this chapter;
however, some hints as to their differential use and characteristics are presented here.
The mechanisms of action of aspirin and acetaminophen are similar, and both are equally
effective in reducing fever; acetaminophen has a slightly stronger effect on temperature
change, and aspirin has a somewhat longer duration of effect.10With regard to safety, aspirin
seems to be more toxic, having been proven responsible for many cases of both nonfatal
and fatal poisoning, especially in children. Even in the recommended doses, it has undesirable
effects on the hemostatic mechanism and on gastric mucosa11 and has been implicated in
Reye’s syndrome. Acetaminophen is quite safe and undesirable effects are rare when given
in therapeutic dosage. It has a potential of serious hepatic toxicity in cases of massive
overdosage; however fatalities are practically unheard of.11
Thus, acetaminophen is generally preferred in young infants, where the risk of aspirin
toxicity is more substantial. It is also specifically preferred in patients with clotting abnor-
malities, peptic ulcer, gouty arthritis, and asthma, and should also be used in cases of allergy
or intolerance to aspirin. On the other hand, aspirin has a general anti-inflammatory action
which acetaminophen does not; it is therefore preferred in cases of acute rheumatic fever or
juvenile rheumatoid arthritis. On balance, with the exceptions cited above, there appears to
be no advantage or disadvantage for using either drug for the purpose of lowering elevated
temperature.

E xtern al C ooling
Environmental measures do not affect the set point of the thermoregulatory region in
the hypothalamus, and thus constitute an “ unphysiologic” approach to fever reduction.9
They are based on loss of body heat through the principles of conduction, convection,
radiation, and evaporation at the body surface. There are various physical methods, such as
sponging with tepid water, cold water, or water-alcohol mixture, air conditioning, and the
use of fans or cooling blankets. The cooler the environment, the more effective the method.
However, the discomfort of the patient is also greater, and the risk of “ overshooting” is
substantial. When these methods are not used in conjunction with antipyretic drugs, shivering
and vasoconstriction occur, and the body works harder to maintain the elevated temperature.9
Therefore, the method of choice for fever reduction when indicated is the use of anti-
pyretics and, if necessary, a physical method may be combined to facilitate and enhance
heat dissipation. However, it should be noted that in extremely high fever, especially due
to heat stroke or malignant hyperpyrexia when antipyretics are practically ineffective (the
set point remains normal), the physical methods are most important. They constitute the
only effective way to lower temperature, which may be the principal life-saving procedure.

O th er S u pportive M easures
Other ancillary methods are recommended to prevent excessive heat production and
maintain the febrile patient as comfortable as possible. These include encouraging bed rest
to avoid physical exertion, ensuring adequate hydration, keeping patient lightly clothed in
a comfortable environmental temperature, and avoiding excessive caloric intake. In prolonged
fever, the supplementation of iron and vitamins should also be considered. In most common
febrile illnesses these measures may constitute the only “ therapy” recommended for the
patient.
508 Unexplained Fever

TREATMENT OF PRESUMPTIVE DISEASE

“ Causative therapy” for an undiagnosed disease sounds like an anachronism. However,

there are many situations in which patients may benefit from empiric therapy. Such therapy
should always be given with a specific diagnosis in mind, and be suited to the particular
complex of symptoms and signs presented by the individual patient. Since the clinical
variations are endless, it is very difficult to construct a general guideline for therapeutic
trials in unexplained fever (U.F.).
In the following discussion we shall try to present the various considerations associated
with the decision of whether to treat, and when and what to prescribe in the many clinical
variations of U.F. Since etiologies of U.F. are infectious, neoplastic, collagenous, granu-
lomatous, and miscellaneous diseases, the discussion will follow this order, but from the
point of view of types of empiric therapy; i.e., antimicrobial (against bacteria, mycobacteria,
parasites, fungi, viruses, etc.), anticancer and anti-inflammatory therapy.
In any case, empiric therapy should never be started before a careful clinical evaluation
is made and appropriate cultures, thick smears, serologies, etc. are obtained (including
necessary punctures if relevant).

EMPIRIC ANTIBACTERIAL THERAPY

Among the many illnesses presenting as U.F., those caused by bacteria are probably
the most rapidly fatal on the one hand, and relatively amenable to therapy on the other.
Therefore, whenever a patient with U.F. is severely ill or rapidly deteriorating within hours
or days, septicemia should promptly be considered and antibiotic therapy should not be
withheld. Likewise, the febrile granulocytopenic (or otherwise immunocompromised) pa-
tient, even without deterioration, is also a candidate for immediate empiric antibacterial
therapy, since the probability for bacterial infection is high, the absence of an evident focus
of infection is common,12 and the risk for mortality substantial. With regard to the choice
of drugs, this should always be accomplished with specific organisms in mind, based on an
educated guess according to the clinical situation. Our first line drugs for the granulocytopenic
patient are mezlocillin + gentamicin. This is directed against the three most common
infecting organisms: E. coli, Pseudomonas, and Klebsiella,13 A combination of two drugs
is recommended since it was shown (in granulocytopenic patients) that the results are better
when therapy includes two drugs to which the organisms are sensitive.14 Any combination
of an acylureido penicillin (or a third generation cephalosporin) with an aminoglycoside is
acceptable.15 Since the fourth most common organism is the Staphylococcus, which usually
originates from skin, we recommend the addition of an antistaphylococcal agent (cloxacillin,
nafcillin, vancomycin) as a third drug, in the presence of even a subtle evidence for the
skin or soft tissue serving as the focus of infection or portal of entry.
The same initial combination may also be appropriate for the nongranulocytopenic
clinically ill patient with U.F., since the expected infecting organisms are mostly Gram-
negative bacilli followed by streptococci, orginiating most commonly from an unidentified
focus in the urinary or biliary tract. All these species are well covered by the combination
of mezlocillin and gentamicin; however, since Pseudomonas is less likely to infect the
nonimmune compromised patient, other combinations such as ampicillin plus gentamicin or
cefazolin plus gentamicin are also acceptable. Again, it should be borne in mind that (1)
combinations such as mezlocillin + gentamicin or ampicillin + gentamicin are not effective
against staphylococci, and if there is anything to suggest this organism (such as previous
boils or carbuncles, tooth abscess, or skin abrasions), an antistaphylococcal agent should
be included; (2) if the disease occurs in a person who has been hospitalized for some time,
especially if he is already on antibiotics for a previous problem, the consideration for the
choice of antibiotics should take into account the possibility of resistant, hospital-acquired
organisms and should preferably include a third generation cephalosporin, possibly in com-
 509

bination with amikacin; and in case of suspected staphylococcal infection — vancomycin

— if methicillin-resistant organisms are prevalent in this institution.
T yph oid f e v e r may present in a very similar way to other septicemias. However, the
“ routine” therapy for sepsis is mostly ineffective against S a lm o n ella typhi. Therefore, when
a “ septic” patient has relative bradycardia, decreased white count and normal sedimentation
rate, and there is a history of living in or traveling to an area where typhoid fever is endemic,
rose spots should be searched for carefully, and chloramphenicol included in the empiric
therapy.
A localized collection of pus is a frequent cause of U.F. and the most common sites
are intra-abdominal.16 The following clinical situations justify starting empiric therapy for
a presumptive a b sc e ss (even in the absence of positive radionuclide scans or other imaging
techniques): lower lobe abnormalities on chest X-rays, decrease in the normal diaphragmatic
movements, tenderness over the liver, spleen, or by rectal or pelvic examination, a previous
abdominal surgery, gynecological intervention or a diagnostic procedure such as colonoscopy
of sigmoidoscopy, the presence of an intestinal disease such as diverticulitis, ulcerative
colitis, or terminal ileitis and the occurrence of an unexplained bacteremia before or during
the course of the U.F. Any one, or especially a combination of the above, may be highly
suggestive of an abscess. Various imaging techniques should be repeated periodically during
therapy, since they often become positive later, especially in granulocytopenic patients when
the white count increases. In contrast to the old idea that an abscess cannot be cured unless
it is drained, there is increasing evidence today that intrahepatic17 and perinephric18 abscesses
may be successfully treated conservatively. Therefore, it is worthwhile starting antibiotic
therapy for suspected abscesses. As to the choice of antimicrobials, those should be directed
against aerobic Gram-negative bacilli, anaerobes, and staphylococci which constitute the
common pathogens in most types of abscesses. An effective drug combination for this purpose
is clindamycin and gentamicin. When there is also a history of living in or traveling to
countries where amebiasis is endemic (particularly where standards of personal and envi-
ronmental sanitation are low, and especially in tropical and subtropical climates) and the
suspected abscess may be intrahepatic, or intestinal, an antiamebic drug should be included.
In such situations, we use metronidazole with gentamicin. The possibility of localized pus
in extra-abdominal sites such as lung, brain, pharynx, sinuses, or teeth should not be ignored,
although they are less likely to present without localizing signs.
O steo m ye litis may be considered as a special type of abscess, the localization of which
is sometimes difficult to assess. In a child, fever and limb tenderness a few days after trauma
(which may be mild and unimpressive), should immediately be treated with high dose
intravenous antistaphylococcal agent, even without positive blood cultures, before the bone
scan turns positive on the third or fourth day.
The need for empiric therapy for e n d o ca rd itis is obvious, in the presence of UF and
valvular heart disease (rheumatic, congenital, mitral valve prolapse, or other), and especially
in the presence of a prosthetic valve. As a matter of fact, this is one of the very few situations
in U.F. where withholding therapy is considered as mismanagement.
However, in the absence of valvular pathology, the decision is more difficult and depends
on such clues as: illicit drug abuse, unexplained congestive heart failure, renal failure of
unclear etiology, embolic phenomena, or peripheral manifestations of infectious endocarditis.
Increased sedimentation rate is a very important supportive sign since endocarditis with
normal sedimentation rate is almost unheard of. Blood cultures, M mode and two-dimensional
echocardiogram, and serology for Q fever and brucella should always be carefully performed.
The optimal therapy for culture negative endocarditis is controversial. We support the
view of penicillin + gentamicin therapy,19 whereas others recommend a vancomycin +
gentamicin combination to cover also the possibility of S ta p h y lo c o c c u s .20
Additional bacterial diseases for which empiric therapy may be sensible are leptospirosis
and brucellosis. Certain forms of leptospirosis (particularly due to L. ic tero h a e m o rrh a g ica )
510 Unexplained Fever

may be rapidly fatal and early therapy is crucial. Therefore, whenever a person with typical
occupational background (farmers, veterinarians, abattoir workers) or with recreational ex-
posure presents with U.F. and is severely ill, penicillin (or tetracycline) should be given,
especially in the presence of pneumonia, meningitis, renal failure, vascular collapse, hepatic
impairment, hemorrhages, or any combination of the above.
In contrast, brucellosis is usually a subacute disease which is seldom fatal; therefore,
there is no need to start empiric therapy before a careful evaluation is accomplished. However,
occupational exposure, similar to that for leptospirosis, as well as a history of ingestion of
unpasteurized milk, or milk products, together with some of the following symptoms: weak-
ness, anorexia, weight loss, arthralgia, splenomegaly, and lymphadenopathy, may be highly
suggestive for brucellosis and warrant therapeutic trial with tetracycline plus streptomycin
even when serology is pending or equivocal.
Rickettsial, chlamydial or mycoplasma infections are uncommon causes of U.F.2122 In
the vast majority of cases there are some clinical clues as to the possible etiology, such as
history of appropriate exposure, rash, cough, pulmonary infiltrates, etc. and the course is
mostly benign. However, the need for acute and convalescent sera for serologic diagnosis
is common to all three types of infection meaning that therapy is often given on clinical
grounds before definitive diagnosis is established. Since certain rickettsial diseases may
actually lead to a fatal outcome, it is particularly important to start tetracycline therapy in
suspected cases, especially with the knowledge that the most important clue for diagnosis,
namely, the rash, may be missing.23

EMPIRIC ANTITUBERCULOUS THERAPY

Tuberculosis was the single most common disease entity responsible for U.F. in Pe-
tersdorf s first series in 196121 and is still a commonly overlooked diagnosis.24 Every patient
with U.F. should receive very careful consideration, in this respect, even in the absence of
the slightest sign. Negative PPD skin test (as well as other negative skin tests: Candida,
SKSD) and normal chest X-ray are not only compatible with, but also characteristic of,
disseminated miliary tuberculosis in the immunocompromised host. Therefore, empiric ther-
apy with isoniazid + rifampin is a common therapeutic trial in U.F.. Additional circum-
stances for which this therapy is advisable in U.F. are positive PPD skin test and a rapidly
progressive illness in an elderly patient, granulomatous hepatitis or other granulomatous
disease of unclear etiology, subacute meningitis with predominant lymphocytes and pul-
monary infiltrates especially of a miliary pattern. A “ reversed” fever pattern with morning
spikes, night sweats, and weight loss may serve as possible hints for the diagnosis of
tuberculosis.

EMPIRIC ANTIPARASITIC THERAPY

Malaria is frequently missed merely because it is not considered. However, when thought
of, the diagnosis can easily be confirmed, once properly prepared blood smears are carefully
examined. Thus the need for empiric antimalarial therapy is uncommon. However, since
the most important clue to this diagnosis in nonendemic countries (with or without chem-
oprophylaxis) is travel to an endemic area, patients with such history, should receive empiric
antimalarial therapy, even before repeated thick smears are examined, especially if the patient
is anemic, azotemic, mentally impaired, or hypotensive. The typical fever pattern in malaria
may also serve as a clue for empiric therapeutic trial. Chloroquine is the drug of choice for
disease acquired in areas where no chloroquine-resistant strains were reported. Otherwise,
quinine combined with doxycycline or with Fansidar (a fixed dose combination of sulfadoxine
and pyrimethamine) is recommended.
Another parasitic disease which was already mentioned in association with liver abscess
is amebic disease. In treating presumptive liver or intestinal abscess our usual choice is
 511

metronidazole + gentamicin. In the presence of diarrhea and colitis, it is usually possible

to demonstrate the amebic trophozoites in the stool and the need for empiric antiamebic
therapy for colitis seldom occurs. However, in prolonged gastroenteritis due to Giardia
lamblia, the chance to recover the parasite from stool is lower and therefore, the use of
empiric therapy may be reasonable (with or without examination of duodenal contents).
Again, the use of metronidazole is appropriate for this purpose.
Visceral leishmaniasis is a very rare cause of U.F.;25 however, the diagnosis (when
entertained) can readily be made from bone marrow smear, lymph node, or liver biopsy.
However, in the event of possible exposure, even in an area of low endemicity, and in the
presence of splenomegaly and hyperglobulinemia, this diagnosis should be considered and
the possibility of empiric therapy with sodium stibogluconate may be employed.
Nowadays in AIDS patients, a common occurrence is the need to treat interstitial pneu-
monia in the absence of evidence for Pneumocystis carinii. This is usually accomplished
by high dose trimethoprim-sulfamethoxasole, but cryptococcal etiology should not be ig-
nored, and additional empiric antifungal therapy may be needed.

EMPIRIC ANTIFUNGAL THERAPY

Since fungi are less easily grown from body fluids than from bacteria, empiric therapy
may be justified in certain clinical situations. However, the therapy for most systemic fungal
infections is amphotericin B, which is quite a toxic drug. Therefore, the number of such
clinical situations is limited; for example: interstitial pneumonia or lymphocytic meningitis
in a patient with AIDS (suspecting disseminated cryptococcosis), or pulmonary infiltrate in
a person residing in an endemic area for histoplasmosis.
Occult fungal infection has been shown to be a major cause of death in cancer patients
with protracted granulocytopenia. Therefore, it was recently recommended that such patients
receive amphotericin B if fever persists beyond 7 days of empiric antibacterial therapy.26
We feel that this is particularly advisable in the presence of clinical clues, such as the growth
of Candida from urine, the presence of esophagitis or mucositis, or an in-dwelling intravenous
catheter.
The same is also true for the severely ill nongranulocytopenic patient (particularly in
the intensive care unit) who requires empiric antifungal therapy, when not responding to
various other antimicrobials.

EMPIRIC ANTIVIRAL THERAPY

The number of viral infections for which a specific and effective antiviral drug is
available, is very limited. The only situation which is worthwhile mentioning here is acyclovir
therapy for suspected herpes simplex encephalitis, a disease which does not usually present
as U.F. However, when a patient presents with fever and acute encephalopathy with seizures
or other signs of focal brain involvement, such therapy should be considered. Generally,
empiric antiviral therapy has no place in U.F. in spite of the relatively frequent viral etiology
in U.F.

EMPIRIC ANTICANCER THERAPY

Hematologic and other malignancies are common etiologies in U.F. However, anticancer
chemotherapy should never be given without specific diagnosis. The relatively high toxicities
of such drugs and the specificity of most agents against limited types of cancer, render such
empiric therapy unreasonable and risky. On the other hand, when other etiologies have been
ruled out and fever is suspected to be a nonspecific sign of malignant dissease, naproxen
has been advised as a symptomatic and diagnostic aid.27 Corticosteroids should not be blindly
utilized in such situations, since in certain malignant diseases, (particularly lymphoma and
lymphatic leukemia) clinical response may occur, giving a false security of controlling the
disease, thus preventing a more effective therapeutic approach.
512 U nex p la in ed F e ve r

EMPIRIC ANTI-INFLAMMATORY THERAPY

In some collagen diseases such as rheumatoid arthritis, Still’s disease, rheumatic fever,
etc., some patients may significantly benefit from nonsteroidal anti-inflammatory agents.
Drugs such as aspirin, acetaminophen, indomethacin, or ibuprofen are worthwhile trying in
patients with U.F., especially if associated with arthralgia, or myalgia. Some authors re-
commend such nonspecific therapy in any patient who continues to be sick without diagnosis,
and if this regimen fails, adrenal corticosteroid therapy is advised.16 The issue of cortico-
steroid therapy in U.F. is quite complicated. It is very tempting to use corticosteroids in
U.F. since many patients respond to this therapy, but the response is often nonspecific and
temporary. Therefore, such therapy should be given with great caution and never without
serious consideration.
First, infection should be ruled out before employing such treatment, particularly pre-
vious or active tuberculosis. Second, the patient should be carefully followed-up to justify
continuation and dose adjustment (and perhaps alternate day regimen) and monitor side
effects of therapy. Our approach is to use corticosteroids only when specific disease entities,
benefitting from such therapy, are considered, for example: UF with headache and high
sedimentation rate in an elderly patient, when temporal artery biopsy is negative or the result
is pending. Suspicion of other forms of vasculitis in the presence of pulmonary infiltrates,
atypical skin lesions and equivocal biopsy results may also be reasonable indication for
empiric corticosteroid therapy.

OVERVIEW
In general, the use of medication in the absence of a definitive diagnosis is discouraged.
There are very few situations, such as endocarditis or tuberculosis, that when suspected,
must be empirically treated even without substantial proof. It should be kept in mind that
most cases which remain undiagnosed eventually recover21 and that the potential untoward
effects of therapy should never outweigh the risk of the disease.
Therefore, the therapeutic approach should distinguish between the acutely febrile pa-
tient, for whom aggressive therapeutic approach is required (as delineated in part of this
chapter), vs. the relatively well patient evaluated for prolonged continuous or intermittent
unexplained fever, for whom empiric trial is seldom indicated. In the seriously ill patient,
when more than one diagnosis warrants therapeutic trial, it may be reasonable to employ
more than one empiric regimen concomitantly for the sake of the patient, rather than for
the sake of diagnostic conclusion. The contrary is true for nonemergency situations; when
indicated, therapeutic trials should be performed one by one in logical order, starting either
with the most likely diagnosis, or better still, with the disease of the graver ourcome, or
with the least harmful empiric therapy. A common difficulty is the hesitancy as to how long
to continue therapeutic trial before deciding whether it is successful or not. For most anti-
bacterial and antifungal regimens, it is possible to judge the results within 5 to 7 days,
whereas antituberculous therapy requires at least two weeks before a conclusion can be
reached. The effect of corticosteroids is frequently dramatic and recognizable within hours
or up to 2 days. When a therapeutic trial is successful it should be continued for the appropriate
period for this diagnosis; when unsuccessful, it should be discontinued. Each patient with
U.F., whether treated or not, should receive periodic réévaluation at reasonable intervals,
since new findings may be crucial for diagnosis and for the decision in favor of empiric
therapy.
 513

REFERENCES
1. Bernheim, H. A., Block, L. H., and Atkins, E., Fever: pathogenesis, pathophysiology and purpose, Ann.
Intern. Med., 91, 261, 1979.
2. Atkins, E., Fever: new perspectives in an old phenomenon, N. Engl. J. Med., 308, 958, 1983.
3. Murphy, P. A., Temperature regulation and the pathogenesis of fever, in Principles and Practice of
Infectious Diseases, 2nd ed., Mandell, G. L., Douglas, R. G., and Bennett, J. E., Eds., John Wiley &
Sons, New York, 1985, 334.
4. Kluger, M. J., Ringler, D. H., and Anver, M. R., Fever and survival, Science, 188, 166, 1975.
5. Roberts, N. J., Jr. and Steigbigel, R. T., Hyperthermia and human leukocyte functions: effects on
response of lymphocytes to mitogen and antigen and bactericidal capacity of monocytes and neutrophils,
Infect. Immun., 18, 673, 1977.
6. Roberts, N. J., Jr., Temperature and host defence, Microbial. Rev., 43, 241, 1979.
7. Husseini, R. H., Sweet, C., Collie, M. H., and Smith, H., Elevation of nasal viral levels by suppression
of fever in ferrets infected with Influenza viruses of differing virulence, J. Infect. Dis., 145, 520, 1982.
8. Mackowiak, P. A., Marling-Cason, M., and Cohen, R. L., Effects of temperature on antimicrobial
susceptibility of bacteriak J. Infect. Dis., 145, 550, 1982.
9. Lorin, M. I., Rational Symptomatic Therapy of Fever and other Elevations o f Body Temperature in the
Febrile Child, John Wiley & Sons, New York, 1982, 199.
10. Levejoy, F. H., Jr., Aspirin and acetaminophene: a comparative view of their antipyretic and analgesic
activity, Pediatrics, (Suppl) 62, 904, 1978.
11. Jaffe, S. J., Management of fever in infants and children, in Fever, Lipton, J. M., Ed., Raven Press, New
York, 1980, 225.
12. Keating, M. J., Lawson, R., Grose, W., and Bodey, G. P., Combination therapy with ticarcillin and
sulfamethoxazole-trimethoprim for infections in patients with cancer, Arch. Intern. Med., 141, 926, 1981.
13. Singer, C., Kaplan, M. H., and Armstrong, D., Bacteremia and fungemia complicating neoplastic disease:
a study of 364 cases, Am. J. Med., 62, 731, 1977.
14. Young, L. S., Combination or single drug therapy for gram negative sepsis, in Current Clinical Topics in
Infectious Diseases, Vol. 3, Remington, J. S. and Swartz, M. V., Eds., McGraw-Hill, New-York, 1982,
77 .
15. Pizzo, P. A., Empiric therapy and prevention of infection in the immunocompromised host, in Principles
and Practice of Infectious Diseases, 2nd ed., Mandell, G. L., Douglas, R. G., and Bennett, J. E., Eds.,
John Wiley & Sons, New York, 1985, 1680.
16. Dinarello, C. A. and Wolff, S. M., Fever of unknown origin, in Principles and Practice of Infectious
Diseases, 2nd ed., Mandell, G. L., Douglas, R. G., and Bennett, J. E., Eds., John Wiley & Sons, New
York, 1985, 339.
17. Reynolds, T. B., Medical treatment of pyogenic liver abscess, Ann. Intern. Med., 96, 373, 1982.
18. Kaver, I., Merimsky, E., Shilo, R., and Braf, Z. F., Conservative approach in treating acute renal
carbuncle, Isr. J. Med. Sci., 21, 157, 1985.
19. Cannady, M. P. B. and Sanford, J. P., Negative blood cultures in infective endocarditis: a review, South
Med. J., 69, 1420, 1976.
20. Ravidin, J. I. and Mandell, G. R., Outcome and management of patients with FUO, in FUO: Fever of
Undetermined Origin, Murray, H. W., Ed., Futura, Mount Kisco, NY, 1983, chap. 20.
21. Petersdorf, R. G. and Beeson, P. B., Fever of unexplained origin: report on 100 cases, Medicine, 40,
1, 1961.
22. Larson, E. B., Featherstone, H. J., and Petersdorf, R. G., Fever of undetermined origin: diagnosis and
follow-up of 105 cases, 1970— 1980, Medicine, 61, 269, 1982.
23. Westerman, E. L., Rocky mountain spotless fever, a dilemma for the clinician, Arch. Intern. Med., 142,
1106, 1982.
24. Rosenthal, T., Pitlik, S., and Michaeli, D., Fatal undiagnosed tuberculosis in hospitalized patients, J.
Infect. Dis., 131 (Suppl), S51, 1975.
25. Siegman-Igra, Y., Waizbard, E., Rubinstein, A., Shabi, J., and Cabili, S., Visceral leishmaniasis
presenting as fever of unknown origin, Trop. Geogr. Med., 39, 70, 1987.
26. Pizzo, P. A., Robichaud, K. J., Gill, F. A., and Witebsky, F. G., Empiric antibiotic and antifungal
therapy for cancer patients with prolonged fever and granulocytopenia, Am. J. Med., 72, 101, 1982.
27. Chang, J. C. and Gross, H. M., Utility of naproxen in the differential diagnosis of fever of undetermined
origin in patients with cancer, Am. J. Med., 76, 597, 1984.
Index
 517

INDEX

A cryptococcosis and, 317

diarrhea and, 109, 110
AAC, see Antibiotic-associated colitis hepatitis and, 290
Abdomen, 49— 50 hepatobiliary diseases in, 136
abscesses in, 409, 426, 498—499 leukopenia and, 198
pain in, see Abdominal pain in pediatrics, 361, 465
Abdominal pain, 102— 103, 109— 113, 116, see Pneumocystis carinii and, 355
also Gastrointestinal tract diseases in pregnancy, 447—448
in geriatrics, 476, 477 pulmonary infections and, 93
in pediatrics, 467 sporotrichosis and, 320
PID and, 436 urological infections and, 415
in retroperitoneal fibrosis, 118 Acrodermatitis of childhood, 304
Abscesses, 421, see also specific types
Actinomyces
abdominal, 409, 426, 498—499
bovis, 309
adrenal, 424
israelii, 309, 313
amebic, 372— 373, 493, 499
naeslandii, 309
brain, 159— 160, 343, 460, 464
formation of, 498 propiomicus, 309
intra-abdominal, see Intra-abdominal abscesses spp., 125, 336, see also Actinomycosis
intrahepatic, 509 Actinomycosis, 104, 116, 133, 309— 313, 438, see
ischio-rectal, 411, 412 also Actinomyces
kidney, 417 Acute arthritis, 235, 239
liver, 131 — 132, 338, 372— 373, 510 Acute fever, 41
lung, 104 Acute intermittent porphyria, 237
pancreatic, 146 Acute leukemia, 215— 217, see also specific types
in pediatrics, 464 Acute lymphoblastic leukemia (ALL), 215, 465
pelvic, 411, 438 Acute myeloblastic leukemia (AML), 215
perinephric, 422—423, 509 Acute pancreatitis, 238
prostatic, 425 Acute thyroiditis, 229
pyrogenic, 131 Acyclovir, 511
remote, 426 Addison’s disease, 110
retroperitoneal, 117— 118, 501 Adenitis, 116, 117, 339
retropharyngeal, 393 Adenocarcinomas, 99, 114, 441, see also Cancer;
spinal epidural, 167 specific types
splenic, 193
colonic, 120
subphrenic, 116— 117, 125
pancreatic, 120
surgery and, 409, 411, 412
Adenomas, 99, see also Cancer; specific types
tuboovarian, 449, 451
colonic, 115
Abused children, 466
liver cell, 141
ACCR, see Amylase creatinine clearance ratio
Acetaminophen, 507, 512 Adenopathies, 342
N- Acetylglucosamine, 18 Adenosine triphosphatase (ATPase), 225
N-Acetylmuramic acid, 18 Adenoviruses, 228, 265, 304, see also specific
Acne types
conglobata, 181, 248 leukemia and, 215
fulminans, 248 in pediatrics, 466
vulgaris, 248 Admission fever, 166
Acquired hypertriglyceridemia, 239 Adolescents, 468
Acquired immune deficiency syndrome (AIDS), 4, Adrenal gland, 26
43, 91, 164, 264, 359— 363, 511 abscesses in, 424
in adults, 360— 361 atrophy of, 231
benign hematologic disorders and, 190 cysts in, 424
Candida and, 316 diseases of, 230— 231, see also specific types
in children, 361 hyperplasia of, 231
cholecystitis and, 143 insufficiency of, 231, 335
CMV and, 144 Adrenolytic drugs, 231
518 Unexplained Fever

Aerobacter spp., 201 microcytic, 205

African trypanosomiasis (sleeping sickness), 247, normocytic, 202— 203
375, 385 refractory, 217
Agglutinins, 486—489 sickle cell, 192— 193, 204
Agranulocytosis, 194, 195, 198 sideroblastic, 218
AIDS, see Acquired immune deficiency syndrome Aneurysms, 78, 283, 400
AIDS-related complex (ARC), 110, 191, 361 Angiography, 11, 424, 500
Air-thermoscope, 2 Angioimmunoblastic lymphoadenopathy, 4, 190,
AL, see Acute leukemia 212
ALA, see gamma-Aminolevulinic acid Angiitis, 98, 284— 285
Alcoholic hepatitis, 4, 55, 74, 125, 137 Anhidrotic ectodermal dysplasia, 402
Alcoholism, 105, 206, 320, 346 Ankylosing spondylitis, 293
Alimentary tract, 101, see also Gastrointestinal tract Anorectal sepsis, 411—412
ALL, see Acute lymphoblastic leukemia Anosomia, 162
Allergic alveolitis, 271, 272 Antibiotic-associated colitis (AAC), 109, 467
Allergic angiitis, 98 Antibiotics, 198, 231, 345, 384, 508, see also spe-
Allergic bronchopulmonary aspergillosis (ABPA), cific types
97, 318 fever caused by, 261
Allergic diathesis, 284 inaccurate treatment with, 393
Allergic granulomatosis, 98, 284 in infants, 458
Allergies, 7, 41, 261, see also specific types in pediatrics, 458
drug, 278, 290, 291 prophylactic, 412, 413
streptococcal, 394
Antibodies, 199, 204, see also specific types
Allopurinol, 210
anti-DNA, 277, 278
Alveolitis, 271, 272
antigens and, 17
Amebiasis, 109, 115, 134— 135, 450, 509
anti-heart, 68
Amebic abscess, 372—373, 493, 499
anti-HIV, 191
Amebic colitis, 109
anti-native DNA, 275
Amebic disease, see also specific types
antinuclear, 277, 489
treatment of, 510
auto-, 214
American histoplasmosis, 318— 319
American trypanosomiasis, 375— 376 heterophil, 199, 493
Amikacin, 509 HSV, 130
Aminoglycosides, 198 IgM, 309
gamma-Aminolevulinic acid (ALA), 237 monoclonal, 11, 374, 491
Aminopyrine, 507 to nuclear antigens (ANA), 277
p-Aminosalicylic acid, 204 streptococcal, 334
AML, see Acute myeloblastic leukemia teichoic acid, 333
Amnionitis, 449 Anticoagulants, 231, 398, see also specific types
Amphetamines, 263 Anti-DNA antibodies, 277, 278
Amphotericin B, 216, 217, 263, 511 Antifungal therapy, 511
Ampicillin, 261, 508 Antigen-antibody complexes, 17
Amylase creatinine clearance ratio (ACCR), 146 Anti-heart antibodies, 68
Amyloidosis, 231, 236, 237 Antihistamines, 384
ANA, see Antibodies to nuclear antigens Anti-inflammatory agents, 383, 473, 507, 512, see
Anaerobic bacteria, 89, 92, 180, 336— 337, 436, also specific types
509 Antimalarials, 204, 510, see also specific types
Analgesics, 263, see also specific types Antimonial agents, 376, see also specific types
Anatomic nosology, 279— 280 Anti-native DNA antibodies, 275
Androgens, 17, 198, 231, see also specific types Antinuclear antibodies, 277, 489
Anemia, 101, 111, 118, see also specific types Antiparasitic therapy, 510— 511, see also specific
aplastic, 195, 198, 204 types
Cooley’s, 204 Antipyretics, 20, 42, 384, 469, 506— 507, see also
extracorpuscular hemolytic, 204— 205 specific types
Fanconi’s, 195, 199 Antitreponemal tests, 489
fever associated with, 202— 206 Antistreptolysin O, 489
hemolytic, see Hemolytic anemias Antistreptolysin titer, 52
intracorpuscular hemolytic, 203— 204 Antithrombin III deficiency, 120
iron deficiency, 205 Antithymocytic globulin (ATG), 198
macrocytic, 206 Antituberculous therapy, 510
megaloblastic, 196 Antiviral therapy, 511, see also specific types
 519

Aortic arch syndrome (Takayasu’s arteries), 77, Atypical measles syndrome, 304
280—281 Atypyical mycobacteria, 91— 92
Aortic dissection, 76, 103 Autoantibodies, 214, 490
Aplasia, 196 Autoimmune diseases, 275—294, see also specific
Aplastic anemia, 195, 198, 204 types
Appendicitis, 103, 109, 113— 116, 411 Autoimmune hemolysis, 204
in geriatrics, 475—476 Autoimmune hemolytic anemia, 214
in pediatrics, 467 Autoimmune neutropenia, 196
in pregnancy, 448—449 Autonomic dysautonomia, 168
Appendicular tumors, 115 Autonomic dysreflexia, 166
Arboviruses, 365, see also specific types Axillary temperature, 35
ARC, see AIDS-related complex 5-Azacytidine, 209
Arenaviruses, 162, 377, see also specific types
Arachidonic acid, 20 B
Arizona spp., 338
Arterial diseases, 76—78, see also specific types Babesia, 264
Arterial infection, 78 Babesiosis, 350— 351
Arterial tumors, 78 Back pain, 47, 76, 118
Arteriography, 132 Bacteremia, 43, 327— 331, 381, 483, see also spe-
Arteriosclerotic aneurysm, 78 cific types
Arteritis, 45, 63, 77, 107 break-through, 331
giant cell, 118, 473, 476 defined, 327
temporal, 281— 282 etiologic factors in, 328
Arthralgia, 101, 501, 512 occult, 330
Arthritis, 63, 336, 346, see also specific types in pediatrics, 461, 463
acute, 235, 239 persistent, 331— 346
bacterial, 179— 180 polymicrobial, 329
fungal, 179 Bacteria, see also Bacterial infections; specific types
hip, 180 cell wall-deficient, 314
infectious, 179— 181 cultures of, 482
Lyme, 4, 181, 246, 346, 491 EP and, 18
in pregnancy, 450 Gram-negative, see Gram-negative bacteria
reactive, 181— 182 Gram-positive, 18
rheumatoid, see Rheumatoid arthritis laboratory tests and, 490, 491—492
septic, 341, 342 leukemia and, 215
serositis and, 235 microscopy and, 482
spetic, 340 serologic studies of, 487
suppurative, 476 Bacterial arthritis, 179— 180
Arthritis-dermatitis syndrome, 436 Bacterial endocarditis, 343, 464
Ascariasis, 144, 490 Bacterial infections, 67, 327, see also Bacteria; spe-
Aseptic meningitis, 344, 465 cific types
Aseptic thrombophlebitis, 393 in adolescents, 468
ASPA, see Allergic bomchopulmonary aspergillosis anaerobic, 89, 92, 180, 336— 337, 436, 509
L-Asparaginase, 209 in immunocompromised patients, 93
Aspergillosis, 97, 317— 318 in infants, 458—460
Aspergillus liver involvement in, 131— 133
fumigatus, 97, 318 in pediatrics, 458—460
spp., 216, 247, 483 in pregnancy, 448—449
Aspiration, 89—90, 105, 190 of skin, 243— 245, 250
Aspirin, 20, 473, 507, 512 thrombocytopenic purpura and, 201
Asplenia, 334 treatment of, 263
Astrocytes, 383 Bacterial meningitis, 158— 159
Astrocytoma, 164 Bacteroides
Atelectasis, 409 fragilis, 115, 336, 436
ATG, see Antithymocytic globulin melanogenicus, 92
Atherosclerotic aneurysms, 78 spp., 115, 116
Atherosclerotic heart disease, 63 BAL, see Bomchoalveolar lavage
ATPase, see Adenosine triphosphatase Barbiturates, 426
Atrial myxoma, 381 Barium enema, 110, 111
Atropine, 23, 263 Bartonella
Atypical lymphoid hyperplasia, 190 baciliformis, 344
520 Unexplained Fever

spp., 485 menstrual cycle and, 33, 52

Bartonellosis, 344 normal, 15— 19, 33
Basilar meningitis, 165 oral, 35
BBB, see Blood brain barrier during pregnancy, 446
Behcet’s disease, 165, 178, 249, 287, 468 range of, 15
Benefits of fever, 23— 29 rectal, 35
Benign hematologic disorders, 189— 206, see also seasonal variation in, 33
specific types skin, 36
Benign lymphadenopathy, 189— 193 tympanic, 35
Benign lymphoreticulosis (cat scratch disease), 163, urinary, 35— 36, 468
246, 395, 490 urinary bladder, 36
Benign myalgic encephalomyelitis (epidemic neuro- Boerhaave syndrome, 104
myasthenia), 395—396 Bone cancer, 186
Benign splenomegaly, 189— 193 Bone demineralization, 229
Benign white blood cell disorders, 194— 199, see Bone infarction, 238
also specific types Bone lesions, 238
Beta-hemolytic streptococci, 334 Bone marrow, 485
Bile acids, 17 Bone marrow aspiration, 190
Bile duct carcinoma, 145 Bone marrow transplantation (BMT), 198
Bilharziosis, 420—421 Bone pain, 218, 345
Biliary cirrhosis, 290, 291 Bone scans, 469
Biliary tract disease, 116, 142— 146, see also spe- Borrelia
cific types burgdorferi, 346, 491
Biliary tract infection, 144 recurrentis, 245
Biliary tract obstruction, 128 spp., 18, 133, 264, 345, 491, see also Borreliosis
Biliary tract tumors, 142, 145 Borreliosis, 489, 491, see also Borrelia
Bilomas, 499 Boutonneuse fever, 131
Biochemical studies, 29 Bradycardia, 43
Biochemical tests, 491 Brain abscess, 159— 160, 343, 460, 464
Biopsy, 55, 89, 111, see also specific types Brain astrocytes, 383
bone marrow, 190 Brain diseases, 502, see also specific types
kidney, 416 Brain tumors, 468, 502
liver, 128— 129, 131, 137, 138, 140, 290, 291 Break-through bacteremia, 331
muscular, 283, 351 Breast carcinoma, 75
lymph node, 190 Breast engorgement, 451
specimens for, 485 Breast tumors, 441
synovial, 174, 183 Bronchial adenoma, 99
temporal artery, 281 Bronchiolitis obliterans organizing pneumonia, 98
Bi-phasic (camel-back) pattern, 42 Bronchoalveolar lavage (BAL), 88, 290
Birth trauma, 459 Bronchopneumonia, 341, 343
Bladder carcinoma, 501 Bronchopulmonary aspergillosis, 318
Blastomycosis, 92, 247, 320— 321, 490 Bronchoscopy, 264
Bleeding, see Hemorrhage Brucella spp., 125, 245, 486, see also Brucellosis
Bleomycin, 209, 263, 382 hepatitis and, 133
Blood, 25, see also entries under Hematologic Brucellosis, 42, 45, 245, 263, see also Brucella
Blood brain barrier, 16, 20 laboratory tests and, 485, 486, 490
in laboratory workers, 265
Blood forming organs, 25
liver involvement in, 132— 133
Blood infusions, 264, 265
persistent, 341— 343
Blood product infusion, 382
in pregnancy, 449
Blood tests, 483—484
treatment of, 509, 510
Blood transfusion reactions, 409
Brugia malaya, 374
BMT, see Bone marrow transplantation
BT, see Body temperature
Body temperature Buerger’s disease (thromboangiitis obliterans), 79,
axillary, 35 282
cardiac, 35 Bullous eruptions, 249, 254
circadian rhythm and, 33, 166 Burkitt’s lymphoma, 301, 493
clinical sites for measurement of, 34— 36
core, 35 c
esophageal, 35
impairment of central regulation of, 164— 167 Caesarean section infections, 451
impairment of peripheral regulation of, 167— 168 Caffeine, 167
 521

Caffey disease (infantile cortical hyperostosis), 466 differential diagnosis of fever and, 70
CAH, see Chronic active hepatitis Cardiac murmurs, 64, 65, 76, 77
Camel-back (bi-phasic) pattern, 42 Cardiac temperature, 35
Campylobacter Cardiac tumors, 75— 76
fetus, 79, 108, 136, 143, 337 Cardiovascular disorders, 50, 55, 63— 79, see also
jejuni, 464 specific types
spp., 107, 109, 111, 118, 182, 448 approach to patients with, 63— 64
Cancer, 3, 9, 23, 91, 381— 384, see also Malig- differential diagnosis of fever in, 64
nancy; specific types Cardiovascular endocarditis, 342
bone, 186 Cardiovascular system, 25, see also entries under
cervical, 441 Cardiac
coccidioidomycosis and, 319 disorders in, see Cardiovascular disorders
cryptococcosis and, 317 Carditis, 69—70, 339
in immunocompromised patients, 358 Caroli’s disease, 142, 144
liver, 101, 373 Carrion’s disease (bartonellosis), 344
lung, 88 Casoni test, 490
musculoskeletal, 186 Castleman’s disease, 212—213
ovarian, 441 Catatonia, 165
sporotrichosis and, 320 Cathectin, 3
treatment of, 511 Cat scratch disease (benign lymphoreticulosis), 163,
Candida 246, 395, 490
albicans, 315 Causative therapy, 508
fungal arthritis and, 179 CEA, see Carcinoembryonic antigen
laboratory tests and, 483 Celiac disease, 291
leukemia and, 216 Cell-mediated immunity, 209
meningitis and, 316 Cellular inflammatory pseudotumor, 118
parapsilosis, 316 Cell wall-deficient bacteria, 314
skin manifestations of, 247 Centigrade thermometers, 3
spp., 67, 110, 179, 315, 316, see also Candidi- Central fever, 225
asis endocarditis and, 316 Central nervous system, 27, 502
treatment of, 511 Central nervous system disorders, 42, 158— 160,
tropicalis, 316 401—402, see also specific types
Candidiasis, 105, 110, 134, 490, see also Candida chronic inflammatory (slow virus), 163— 164
systemic, 314— 316 in pediatrics, 461
Canicola fever, 344 primary, 164— 169
Carcinoembryonic antigen (CEA), 140, 383 Central temperature regulation impairment, 164—
Carcinoid syndrome, 107, 110, 114 167
Carcinomas, 125, 144, see also Cancer; specific Cephalosporins, 198, 412, 508
types Cephalosporium, 321
bile duct, 145 Cerebral malaria, 372, 385
bladder, 501 Cerebral palsy, 466
breast, 75 Cerebral tumors, 468, 502
colonic, 110, 115 Cerebral venous sinus thrombosis, 398
epidermoid, 99 Cervical cancer, 441
esophageal, 105 CGD, see Chronic granulomatous disease
gallbladder, 145 Charcot-Leyden crystals, 98
hepatocellular, 141 Chédiak Higashi syndrome, 197
intestinal, 114 Chest radiography, 85, 498
kidney, 421 Child abuse, 466
kidney cell, 128, 381, 421, 500 Chills, 40
laboratory tests and, 485 Chlamydia
large cell, 99 burnetii, 309
lung, 75 pneumoniae, 305
nasopharyngeal, 493 psittaci, 305, 306
prostatic, 383, 426, 501 spp., 264, 425, see also Chlamydial infections
small cell, 99 trachomatis, 109, 305, 415, 436, 468
Carcinomatous meningitis, 165 Chlamydial endocarditis, 306
Cardiac catheterization, 68 Chlamydial infections, 305— 307, 492, see also
Cardiac failure, 72—73 Chlamydia’, specific types
chronic congestive, 401 in adolescents, 468
congestive, 71, 120, 401 in obstetrics, 451
522 Unexplained Fever

treatment of, 510 CNS, see Central nervous system

Chloramphenicol, 204, 509 Cocaine, 263
Chloroquine, 510 Coccidioides immitis, 179, 438
Chlorpromazine, 401 Coccidioidomycosis, 92, 134, 247, 265, 319, 438,
Cholangiocarcinoma, 141, 142 490
Cholangitis, 125, 143— 144 Cocksackie virus, 246
Cholecystitis, 103, 116, 134, 143, 338, 342, 373 Cogan’s syndrome, 286— 287
AIDS and, 136 Cold, 16
in geriatrics, 475 Colistin, 216
peritonitis and, 411 Colitis, 42, 109
in pregnancy, 449 antibiotic-associated (AAC), 109, 467
Choledocholithiasis, 142 pseudomembranous, 467
Cholelithiasis, 101, 128, 142
treatment of, 511
Cholestasis, 137
ulcerative, 42, 109, 111 — 112, 140, 450, 467
Chondritis, 294
Collagen diseases, 126, 275, see also Collagen-vas-
Chonorchiasis, 144
cular diseases; Connective tissue diseases;
Chorioamnionitis, 449
specific types
Choriomeningitis, 162
treatment of, 512
Chorioretinitis, 450
Collagen-vascular diseases, 23, 41, 45, 46, 58, 76,
Chronic active hepatitis (CAH), 140
Chronic congestive cardiac failure, 401 107, see also Collagen diseases; Rheumatic
diseases; specific types
Chronic eosinophilic pneumonia, 97— 98
Chronic granulomatous disease (CGD), 197 benign hematologic disorders and, 192
Chronic inflammatory (slow virus) CNS diseases, biliary tract in, 142
163— 164 in geriatrics, 475, 476
Chronic lymphocytic leukemia (CLL), 214, 486 hemorrhagic disorders and, 119
Chronic myelogenous leukemia (CML), 217 hepatomegaly and, 125
Chronic necrotizing pulmonary aspergillosis, 318 laboratory tests and, 485, 486, 489
Chronic obstructive lung disease, 90 in pediatrics, 461, 465
Churg-Strauss syndrome, 98, 284 psychiatric symptoms and, 385
CIE, see Counterimmunoelectrophoresis Colon
Cimetidine, 263 adenocarcinoma of, 120
Circadian rhythm, 33, 166 carcinoma of, 110
Circulating immune complexes, 277, 283, 285 diverticulitis of, 116
Circulatory compromise, 72— 73 tumors in, 114— 115
Cirrhosis, 3, 55, 125, 133, 137— 138, 140 Colorado-tick fever, 42, 45, 345
in adolescents, 468 Complement assays, 278
advanced, 399 Complement components, 17, 491
cryptococcosis and, 317 Computerized tomography (CT), 11, 52, 55, 58,
hepatitis and, 290, 291 76, 497—502
macrocytic anemia and, 206 abscesses and, 426
Citrobacter adrenal and, 424
diversus, 460
benign hematologic disorders and, 189
spp., 338
diarrhea and, 110
Classification of fever, 4, 7— 10, see also specific
emission (ECT), 496
types
herpes and, 162
Clindamycin, 109
intracranial infections and, 502
Clinical features of fever, 36, 39—41, see also spe-
cific types kidney infections and, 416
Clinical measurement sites, 34— 36 liver abscess and, 132
Clinical thermometers, 23, 33— 34 pancreatic disorders and, 146, 147
CLL, see Chronic lymphocytic leukemia in pediatrics, 469
Clostridium prostatic abscess and, 425
difficile, 109, 467 in pulmonary disease, 85
perfringens, 109, 441 retroperitoneal tumors and, 424
spp., 115, 336 retroperitoneum and, 422
welchii, 204 spinal epidural abscess and, 167
Cloxacillin, 412, 508 urological infections and, 421
Clubbing, 50, 107, 114 Confusion, 41
CML, see Chronic myelogenous leukemia Congestive cardiac failure, 71, 120, 401
CMV, see Cytomegalovirus Conjunctival suffusion, 344
 523

Connective tissue diseases, 192, 275— 291, see also in pregnancy, 446
Collagen diseases; specific types transplants and, 427
skin manifestations of, 248— 249 Cytosine arabinoside, 210
Contrast venography, 79 Cytotoxic agents, 490, see also specific types
Convulsions, 40—41, 505
Cooley’s anemia (thalassemia major), 192, 204 D
Core temperature, 35
Corneal epithelial cells, 383 Dacarbazine (DTIC), 210
Coronary artery vasculitis, 283 Dandy fever, 365
Corticosteroids, 198, 265, 317, 319, 473, 490, 512, Dantrolene sodium, 167
see also specific types Deafness, 237
Counterimmunoelectrophoresis (CIE), 54, 159, 333, Deep mycoses, 314, 321
334, 335, 340 Deep vein thrombosis, 79
Coxiella burnetti, 131 Degenerative brain diseases, 466
Coxsackie virus, 74, 228 Dehydration, 230, 460, 461, 466, 473
CPK, see Creatine kinase Delirium, 41
Cranial neuropathies, 237 Demyelinating diseases of brain, 502, see also spe-
Craniopharyngioma, 164 cific types
C reactive protein, 278 Dental infection, 393
Creatine kinase (CPK), 168 Dermatomycosis, 265
Crithidia luciliae, 278 Dermatomyositis, 176— 177, 248
Crohn’s disease, 42, 106, 107, 109, 111, 140, 440 Dermatopolymyositis, 279
hepatitis and, 290 Dermatosis, 394
microcytic anemia and, 205 Diabetes, 179, 317, 411, 466
in pediatrics, 467 Diabetic hyperosmolar coma, 240
in pregnancy, 450 Diagnosis, 51— 57, 383
Cryoglobulinemia, 277, 286 of infective endocarditis, 64—65
Cryptococcosis, 109, 134, 317, 485, 490, 511 procedures for, 68
Cryptococcus neoformans, 134, 179, 484, 485
of pulmonary infections, 89— 90
Cryptosporidium spp., 110, 143, 144
of respiratory diseases, 96
CT, see Computerized tomography
Diagnostic laparotomy, 407—408
Curtis-Fitz-Hugh syndrome (perihepatitis), 136,
Dialysis, 427—429
306, 335, 436
Diarrhea, 106— 111, 112, 319
Cutaneous manifestations, see Skin
DIC, see Disseminated intravascular coagulation
Cyclic fever, 236
Diethylcarbamazine, 374
Cyclic neutropenia, 42, 55, 194, 237
Diffuse fasciitis with eosinophilia (Schulman’s syn-
Cyclophosphamide, 212
drome), 178— 179
Cyclosporin, 198
Cysticercosis, 375 Digitalis, 261
Cystitis, 420 Dilantin, 212
Cysts, see also specific types Diphtheria, 160
adrenal, 424 Diphyllobothrium latum, 206
hydatid, 499 Dipyrone, 507
kidney, 418, 419 Dissecting aneurysm, 76
liver, 142 Disseminated gonococcal infection, 335
Cytomegalovirus (CMV), 103— 105, 125, 264, Disseminated intravascular coagulation (DIC), 201,
265, 302— 304 331, 486
AIDS and, 136 Disseminated lupus erythematosus, 202
benign hematologic disorders and, 190 Diverticula, 104— 105, 106, 113
complications of, 303 Diverticular disease, 113— 114
diagnosis of, 303— 304 Diverticulitis, 115, 116, 120
diarrhea and, 109 DNA viruses, 299, see also specific types
drug fever and, 261 Dohle bodies, 196
hemolytic anemias and, 204 Doppler ultrasonography, 79
in immunocompromised patients, 355, 359 Doxycycline, 345, 510
laboratory tests and, 484, 486, 493 Dranculosis, 247
latent, 299, 301 Dranculus medinensis, 179, 247
leukemia and, 215 Drug eruption, 248
liver and, 130 Drug fever, 1, 7, 42, 68, 209—210, 261, 408
malignant hematologic disorders and, 210, 211 agents responsible for, 262
in pediatrics, 464, 465 in geriatrics, 476
524 Unexplained Fever

in pediatrics, 466 bacterial, 343, 464

Drug-induced hepatitis, 125, 464, 477 candida, 316
Drug-induced liver injury, 138— 140 cardiovascular, 342
Drug-induced lymphadenopathy, 192 culture-negative, 67
Drug-induced neutropenia, 195 infective, see Infective endocarditis
Drugs, see also specific drugs, types laboratory tests and, 483—484, 485
allergies to, 278, 290, 291 in pediatrics, 464
hypersensitivity to, 261, 409 subacute bacterial (SBE), 160
intoxication from, 23, 41 subacute chlamydial, 306
reactions to, 41, 98 treatment of, 509, 512
toxicity of, 137, 261 Endocrine system, 26— 27
DTIC, see Dacarbazine Endocrinological disorders, 225— 232, see also spe-
Dumb-rabies, 162 cific types
Duodenal diseases, 105— 107, see also Gastrointes- Endogenous pyrogens (EP), 3, 17—20, 209, see
tinal tract diseases; specific types also specific types
Duodenal diverticulum, 106 Endometriosis, 439
Duration of fever, 1 Endometritis, 451
Dysautonomia, 168 Endoscopy, 111, 264
Dysgenesis, 195 Endotoxin, 18
Dysglobulinemia, 286 Endotrachial intubation, 264
Dysplasia, 402 Enigmatic fever, 79
Enpyrema, 92
E Enteric fever, 2, 340
Enteritis, 109, 110, 111
Ebola virus, 377 Enterobacteriaceae, 331, 338
EBV, see Epstein-Barr virus Enterobacter spp., 109, 116, 330, 338, 417
Echinococciasis, 145 Enterococcus spp., 215, 333
Echinococcosis, 490 Enterocolitis, 109
Echocardiography, 68, 74, 76 Enteroviruses, 466, see also specific types
ECT, see Emission computerized tomography Enzyme assays, 491, see also specific types
Eczemas, 402 Enzyme-linked immunosorbent assays (ELISA), 54,
Electrolytes, 52 130, 333, 351, 374, 483, 486
Electromyography, 283 Eosinopenia, 486
Electronic thermometers, 33— 34 Eosinophilia, 97—98, 144, 200, 351
Electrophoresis, see also specific types diffuse fasciitis with (Schulman’s syndrome),
serum protein, 491 178— 179
Electrosyneresis, 374 disorders associated with, 378
ELISA, see Enzyme-linked immunosorbent assays laboratory tests and, 486
Embolism, see also specific types peripheral, 97—98, 379
pulmonary, see Pulmonary embolism Eosinophilic granuloma of lung, 97
systemic, 75 Eosinophilic leukemia, 200
thrombo-, 71— 72 Eosinophilic pneumonia, 97— 98
Emission computerized tomography (ECT), 496 Eosinophils, 200
Emphysematous pyelonephritis, 419 EP, see Endogenous pyrogen
Empiric antibacterial therapy, 508— 510 Epidemic neuromyasthenia (benign myalgic enceph-
Empiric anticancer therapy, 511 alomyelitis, Iceland disease), 395—396
Empiric antifungal therapy, 511 Epidemic typhus, 245, 309
Empiric anti-inflammatory therapy, 512 Epidermal necrolysis, 249
Empiric antiparasitic therapy, 510—511 Epidermoid carcinomas, 99
Empiric antituberculous therapy, 510 Epididymis, 425
Empiric antiviral therapy, 511 Epididymo-orchitis, 425
Empyema, 143, 341, 342 Epidural abscess, 167
Encephalitis, 41, 158, 342, 365, see also specific Epidymitis, 420
types Epiglottitis, 340
herpes, 447, 511 Epilepsy, 157, 169
psychiatric symptoms and, 385 Epinephrine, 230, 263
Venezuelan equine, 265 Epithelial cells, 383
Encephalomyelitis, 161, 395— 396, 502 Epstein-Barr virus (EBV), 57, 125, 190, 199, 246,
Encephalopathy, 165 261, 264, 299— 301
Endocarditis, 41, 321, 336, 341 diagnosis of, 301
in adolescents, 468 in immunocompromised patients, 359
 525

laboratory tests and, 493 Family history, 44—45

liver and, 130 Fanconi’s anemia, 195, 199
lymphomas induced by, 301 Fasciola hepatica, 144
subacute thyroiditis and, 228 Fascioliasis, 144— 145, 490
Equine encephalitis, 265 Fasciitis, 178— 179
Erysipelas, 244 Fatal catatonia, 165
Erysipeloid of Rosenbach, 244, 336 Fava beans, 204
Erysipelothrix rhusiopathiae, 336 Felty syndrome, 192
Erythema, 319 Female reproductive system tumors, 441—442
Erythema chronicum migrans, see Lyme arthritis a-Fetoprotein, 383
Erythema multiforme, 248 Fever blisters, 41, 506
Erythema nodosum, 248, 286, 339, 348, 467 Fever phobia, 468
Erythropoiesis, 204 Fever protocol, 413
Escherichia coli, 107, 115, 116, 330 Fibariasis, 490
detection of, 159 Fiberoptic bronchoscopy (FOB), 87— 88
enterotoxigenic, 109 Fibrinogen, 79
hemolytic anemias and, 204 Fibrosarcomas, 501
in infants, 460 Fibrosis, 118, 423— 424
invasive forms of, 108 Fielder’s myocarditis, 74
kidney abscess and, 417 Filaria, 264
leukemia and, 215 Filariasis, 247, 374
malignant hematologic disorders and, 215 Filivirus, 377
in pediatrics, 460, 463 Fitz-Hugh-Curtis syndrome (perihepatitis), 136,
persistent, 336, 338 306, 335, 436
skin manifestations of, 247 Florentine thermometers, 2
thrombocytopenic purpura and, 201 Fluid balance disorders, see also specific types,
treatment of, 508 400—402
Esophageal disorders, 104— 105, see also specific FMF, see Familial Mediterranean fever
types FOB, see Fiberoptic bronchoscopy
Esophageal temperature, 35 Focal sepsis (occult infectious foci), 393— 394
Esophagitis, 104, 511 Food poisoning, 341
Essential mixed cryoglobulinemia, 286 Foreign bodies, 426, 468
Essential thrombocythemia, 218 Fort Bragg fever, 344
Etiocholanolone, 19, 231, 467 Francisella tularensis, 340
Etoposide, 210 Fraudulent fever, see Factitious fever
Exogenous pyrogens, 17 Fulminant meningococcemia (Waterhouse-Frideri-
External cooling, 507 chsen syndrome), 201, 334
Extracorpuscular hemolytic anemias, 204— 205 Fungal arthritis, 179
Extrahepatic biliary tract diseases, 142— 146, see Fungi, 4, 92—93, 384, see also specific types
also specific types cultures of, 482
Extraheptatobiliary conditions, 128 EP and, 18
Extreme pyrexia, 43, 53 in immunocompromised patients, 93
Extrinsic allergic alveolitis, 271, 272 laboratory tests and, 490, 492
leukemia and, 216, 217
of liver, 134
F
microscopy of, 482
neutropenia and, 198
in pediatrics, 465
Fabry’s disease, 168, 237— 238
serologic studies of, 487—488
Factitious fever, 36, 42, 385, 387— 390
of skin, 252— 253
in geriatrics, 475
skin manifestations of, 247
methods for producing, 388— 389
treatment of, 511
in pediatrics, 468
Furunculosis, 243— 244
surgery and, 411 Fusarium spp., 216
Fahrenheit thermometers, 2 Fusobacterium
False aneurysm, 78 nercorphorum, 337
Familial dysautonomia (Riley-Day syndrome), 168 nucleatum, 92
Familial Mediterranean fever (FMF), 1, 146, 235—
237 G
in geriatrics, 475
in pediatrics, 467
in pregnancy, 450 Gallbladder, 143, 145, 146
526 Unexplained Fever

Gallium scanning, 68, 96 extreme pyrexia and, 43

Gangrene, 244, 338 persistent, 338
Gastric infarction, 106 thrombocytopenic purpura and, 201
Gastric tumors, 106 treatment of, 509
Gastrintestinal disorders, 55, see also specific types Gram-positive bacteria, 18, see also specific types
Gastritis, 105 Granulocyte antigens, 382
Gastroenteritis, 102, 340, 464, 466 Granulocytes, 194, 495
Gastrointestinal bleeding, 120 Granulocytopenia, 214, 215, 217, 358, 381, 508,
Gastrointestinal endoscopy, 264 511
Gastrointestinal infections, 464 Granulocytosis, 218
Gastrointestinal tract, 27 Granuloma-forming disorders, 95— 97, 288—289,
Gastrointestinal tract diseases, 101 — 120, see also see also specific types
specific types Granulomas, 288, see also specific types
abdominal pain and, 102— 103 defined, 288
approach to patient with, 102— 103 lethal midline, 284, 285
bleeding disorders and, 119— 120 Granulomata, 131
esophageal, 104— 105 Granulomatosis, 96, 98
malabsorptive, 118— 119 allergic, 284
vascular disorders and, 119— 120 lymphomatoid, 213, 285
Gastroscopy, 105
Wegener’s, 96, 284, 285
Gaucher’s disease, 193, 238
Granulomatous angiitis, 284—285
GBS, see Guillain-Barre syndrome
Granulomatous diseases, 288, see also specific types
Generalized pastular psoriasis, 249
Granulomatous hepatitis, 4, 125, 130, 133, 134,
Genetic patterns, 44—45
138, 140, 290—291
Genital herpes, 435
polyarthritis and, 339
Genital tract, 425—426
septic metastases and, 342
Genital tract infections, 305— 306, 435, 451, see
Granulomatous prostatitis, 425—426
also specific types
Graves’ disease, 226
Genital turberculosis, 437
Guillain-Barre syndrome (GBS), 162
Genitourinary disease, 116
Genitourinary exam, 50 Gynecology, 435—442, see also specific conditions
Gentamicin, 508, 509, 511
Geriatrics, 473—477, 505 H
approach in, 474—475
clinical manifestations of fever in, 475
etiologic aspects of fever in, 475—476 Habitual hyperthermia, 43—44
staphylococcal infections in, 332 Haemophilus influenzae, 180, 215, 244, 340, 460,
Giant angiofollicular lymph node hyperplasia, 463
212— 213 Hafnia spp., 338
Giant cell arteritis, 63, 118, 473, 476 Hairy cell leukemia (HCL), 214— 215
Giant cells, 281, 282 Halothane anesthesia, 167
Giardia Iambiia, 109, 119, 511 Hamartoma, 99, 165
Giardiasis, 109, 136 Hand-Schuller-Christian disease, 97
Glomerulonephritis, 339, 342, 416 Hand thermometry, 2
Glucose-6-phosphate dehydrogenase, 126, 204 Hantaan virus, 415
Glycolipid storage diseases, 237— 238 Hashimoto’s thyroiditis, 450
Glycoproteins, 196 Haverhill fever, 343
Glycosphingolipid metabolism disorders, 237— 238 HCC, see Hepatocellular carcinoma
Goiter, 107 HCL, see Hairy cell leukemia
Gonococcal infections, 244, 335, see also specific HD, see Hodgkin’s disease
types Head, 502
Gonococcal septicemia, 334 Heart failure, see Cardiac failure
Gonorrhea, 109, 115, 468, see also Neisseria gon- Heat loss, 15, 263
orrhoeae central regulation of, 16— 17
Goodpasture’s syndrome, 294 disorders in, 401
Gout, 239, 476 Heat production, 15
Gram-negative bacteria, 115, 265, see also specific central regulation of, 16— 17
types disorders in, 401—402
arterial infection and, 78 Helminths, 144— 145, 373— 379, see also specific
arthritis and, 180 types
EP and, 18 laboratory tests and, 486
 527

Hematologic disorders, 55, see also specific types Hepatobiliary diseases, 125— 147, see also Liver;
benign, see Benign hematologic disorders specific types
malignant, see Malignant hematologic disorders in AIDS, 136
Hematologic studies, 67, 485—486 approach to patients with, 126— 128
Hematomas, 426, 499, see also specific types in geriatrics, 475
formation of, 412 helminthic, 144— 145
intra-abdominal, 412 IBD and, 140— 141
ischio-rectal, 451 jaundice and, 126— 128
occult, 399, 400 liver biopsy and, 128— 129
subdural, 466 Hepatoblastoma, 466
Hematuria, 342, 420, 421 Hepatoma, 381, 468
Hemochromatosis, 231 Hepatomegaly, 125— 126, 131, 144, 476
Hemodialysis, 427—429 Hepatosplenomegaly, 107, 200, 212, 238, 383, 498
Hemoglobinopathies, 126, 204, see also specific Hereditary anhidrotic ectodermal dysplasia, 402
types Hereditary hypertriglyceridemia, 238— 239
Hemograms, 485—486 Herpangina, 246
Hemolysis, 126, 204, 345, 461 Herpes, 1, 4, 104, 125, 130, 162, 304— 305, see
Hemolytic anemias, 203— 204, 210, see also spe- also Cytomegalovirus (CMV); Epstein-Barr
cific types virus (EBV); specific types
autoimmune, 214 diarrhea and, 109
extracorpuscular, 204— 205 genital, 435
leukemia and, 215
intracorpuscular, 203— 204
liver and, 130
Hemolytic diseases, 55, 192— 193, see also specific
malignant hematologic disorders and, 210
types
in pediatrics, 466
Hemophagocytic syndrome, 302
in pregnancy, 446, 447
Hemophilus cellulitis, 244
psychiatric symptoms and, 385
Hemopoietic system, 25
skin manifestations of, 245, 249
Hemorrhage, 25, 162, 305, 399—400
treatment of, 511
treatment of, 510 urological infections and, 415
Hemorrhagic disorders, 200— 202, see also specific
Herpes encephalitis, 447
types Herpes simplex encephalitis, 511
in gastrointestinal tract, 119— 120 Herpes zoster, 45, 211
in pediatrics, 461 Herxheimer reaction, 245
Henoch-Schonlein purpura, 248, 286 Heterophil agglutinin test, 52
Heparin, 398 Heterophil antibodies, 199, 493
Hepatic, see Liver Hexheimer reaction, 263
Hepatitis, 101, 125, 129— 130, 264, 304 Hibernian fever, 237
in adolescents, 468 Hip arthritis, 180
AIDS and, 136 Histiocytoses, 218— 219
alcoholic, 4, 55, 74, 125, 137 Histocytosis, 88, 97
brucella, 133 Histologic examination, 55
Candida, 134 Histoplasmosis, 92, 104, 105, 318— 319, 485, 490,
chronic, 137 511
chronic active (CAH), 140 History of fever, 2— 3, 5—6
complications of, 129 HIV, see Human immunodeficiency virus
drug-induced, 125, 464, 477 Hodgkin’s disease, 41, 42, 47, 128, 210— 211
in geriatrics, 477 in adolescents, 468
granulomatous, see Granulomatous hepatitis chemotherapy for, 340
hypersensitivity vasculitis and, 286 in geriatrics, 476
in immunocompromised patients, 359 laboratory tests and, 486
isoniazid-induced, 477 paraneoplastic fever and, 381
laboratory tests and, 485, 491, 493 in pediatrics, 465
in laboratory workers, 265 system imaging and, 501
neonatal, 130 Hormones, 198, 225, see also specific types
in pediatrics, 464 sex, 226
peliosis, 142 steroid, see Steroids
peri-, 136, 306, 335, 436 thyroid, 263
in pregnancy, 447 Hospital employees, 266— 269
in tropics, 365 Hospitalization, 53, 57— 58
types of, 129 Host defenses, 23
528 Unexplained Fever

HTLV, see Human T-cell leukamia virus Idiopathic fever, 412

Hugh-Fitz-Curtis syndrome (perihepatitis), 136, Idiopathic hypereosinophilic syndrome, 377
306, 335, 436 Idiopathic infarction of lymph nodes, 193
Human immunodeficiency virus (HIV), 130, 164, IL, see Interleukin
190, 299, 355, 359, 360, see also Acquired Ileitis, 339
immune deficiency syndrome (AIDS) Immune complexes, 277, 283, 285, 483, 490
antibodies to, 191 Immune diseases, 9, see also Immunocompromised
in children, 361 patients; specific types
clinical signs of, 362 in pediatrics, 464
minor manifestations of, 361— 363 Immune neutropenia, 195— 196
in pediatrics, 361, 464 Immune thrombocytopenia, 214
symptoms of, 362 Immunity, 18— 19
Human T-cell leukemia virus (HTLV), 214 cell-mediated, 209
Hydatid cyst, 499 in pregnancy, 446
Hydradenitis suppurativa, 181 Immunization, 192
Hydrocortisone, 226 Immunocompromised patients, 89, 91, 355— 363,
5-Hydroxytryptamine, 20 see also Immune diseases; specific types
Hypercalcemia, 214, 229 candidiasis and, 134
Hyperecsinophilia, 98, 377— 379 causes of fever in, 358— 359
Hyperlipidemia, 238— 239 cryptococcosis in, 134, 317
Hypernatremia, 240 diarrhea in, 110
Hyperéosinophilie syndrome, 200 etiologic factors and, 356
Hyperparathyroidism, 229 infectious agents causing disease in, 358
Hyperplasia, 190, 212— 213, 231 noninfectious causes of fever in, 358— 359
Hypersensitivity, 275— 294, 334, 409 pulmonary infections in, 93
Hypersensitivity diseases, see also specific types TPN in, 412
Hypersensitivity pneomonitis, 271, 272 treatment in, 508
Hypersensitivity vasculitis, 285— 286 Immunofluorescence, 346, 374
Hypersplenism, 196 Immunoglobulin A, 491
Hypertension, 120, 230 Immunoglobulin G, 491, 493
Hyperthermia, 7, 28, 43 Immunoglobulin M, 493
habitual, 43—44 Immunoglobulin M antibodies, 309
malignant, 17, 167, 408—411 Immunoproliferative small intestinal disease
prolonged muscle contractions as cause of, 167 (IPSID), 114
Hyperthyroidism, 110 Immunosuppressed patients, see Immunocompro-
Hypertriglyceridemia, 238— 239 mised patients
Hypocomplementemia, 276 Immunosuppressive drugs, 198, 427, see also spe-
Hypogammaglobulinemia, 214 cific types
Hypoglycemia, 229— 230, 240 Impetigo, 243, 249
Hypoglycorrhachia, 161 Indomethacin, 211, 512
Hypohidrotic ectodermal dysplasia, 402 Infantile cortical hyperostosis (Caffey disease), 466
Hypophysis, 26 Infants, 461—468, see also Pediatrics
Hypopituitarism, 226 newborn, 457—461
Hypotension, 73 premature, 457—461
Hypothalamic damage, 164— 166 very low birth weight, 457—461
Hypothalamic dysfunction, 387, 390 Infarction, 115, 141, see also specific types
Hypothalamus, 20, 225—226, 383, 401 bone, 238
Hypothermia, 16, 240 gastric, 106
Hysteric fever, 166 of lymph nodes, 193
myocardial, 71, 72, 103, 104
splenic, 218
I Infected abortion, 439
Infected atherosclerotic aneurysms, 78
Infections, 1, 23, 41, 381— 382, 383— 384, see
Iatrogenic fever, 7, 261— 272, see also specific also specific types
types fungal, see Fungi
IBD, see Inflammatory bowel disease in geriatrics, 475—476
Ibuprofen, 512 hospital-acquired, 57
Iceland disease (epidemic neuromyasthenia), 395— malignant hematologic disorders and, 210
396 neutropenia due to, 195
Ichthyosis, 401 opportunistic, 210, 211, 338, 465
Icteric leptospirosis (Weil’s disease), 344 parasitic, see Parasites
 529

pregnancy and, 445—446 Intra-abdominal abscesses, 116— 117, 409, 411,

prevention of, 216— 217 476, 498—499
protozoal, 134— 136, 449—450 treatment of, 509
thrombocytopenic purpura associated with, 201 Intra-abdominal hematomas, 412
Infectious arthritis, 179— 181 Intra-abdominal infections, 115— 117, 475
Infectious diseases, 8, see also Bacterial infections; Intracorpuscular hemolytic anemias, 203—204
Fungi; Viruses; specific types Intracranial infections, 502
in adolescents, 468 Intrahepatic abscesses, 509
hospital employees and, 266— 269 Intra-operative fever, 408—411
laboratory tests and, 491—493 Iodides, 426
in pediatrics, 461—465 Iodine, 7, 227
Infectious endocarditis, 509 Iodine-labeled fibrinogen, 79
Infectious mononucleosis, 130, 199— 200, 204, IPSID, see Immunoproliferative small intestinal dis-
246, 261, 299 ease
complications of, 300 Iron deficiency anemia, 205
differential diagnosis of, 301 Iron malabsorption, 205
laboratory tests and, 486, 490, 493 Irregular pattern, 42
in pediatrics, 464 Ischio-rectal abscesses, 411, 412
Ischio-rectal hematoma, 451
in pregnancy, 449
Isoimmune neonatal neutropenia, 196
Infective endocarditis, 11, 41, 64— 69, 75, 76, 118,
Isoniazid-induced hepatitis, 477
334
ls o s p o r a b e lli, 110
clinical features of, 65— 66
diagnosis of, 64— 65
differential diagnosis for, 68— 69
j
in geriatrics, 473, 475, 476
Jacob-Creutzfeldt disease, 265
laboratory tests and, 67—68, 485
Japanese 7-day fever, 344
persistent fever in, 68
Jaundice, 126— 128, 131, 475
special forms of, 66—67
Joints, 28, 111
Inflammation, 128, see also specific types Jones’ Criteria, 70
gynecological, 440 Junin virus, 162
of liver, 137— 141 Juvenile rheumatoid arthritis, 23, 279, 465, 507
in pregnancy, 450
treatment of, 512 K
vertebrae in, 502
Inflammatory bowel disease (IBD), 101, 107, Kala-azar, 42, 486
109— 112, 115, 120 Kaposi’s sarcoma, 136, 191, 360
in adolescents, 468 Kaposi’s varicelliform eruption, 246
in geriatrics, 475, 477 Kawasaki’s disease, 77, 246, 283— 284, 345
hepatobiliary complications of, 140— 141 Keratinization disorders, 249, 254— 255
in pregnancy, 450 Kératinocytes, 383
Influenza, 180, 215, 265, 340, 466, see also spe- Kétoconazole, 217
cific types Kidney, 26, 500— 501
Infrared thermometry, 34 abscesses in, 417
Inherited disorders, 235—240, see also specific biopsies of, 416
types carcinoma of, 421
Insidious fever, 41 cysts in, 418, 419
Insulin, 261 failure of, 74, 510
Interferon, 3, 209, 382 lyphoma of, 500
Interleukin-1, 3, 17— 18, 209, 225, 383 in pregnancy, 445—446
Interleukin-2, 382 pyonephrotic, 427
Interleukins, 17, see also specific types transplants of, 427
Intermittent fever, 42 Kidney cell carcinoma, 128, 381, 421, 500
Interstitial lung disease, 88 Kidney infections, 416—419, see also Urological
Intestinal diseases, 106— 116, see also specific infections; specific types
types Kidney stones, 422
approach to patient with, 106— 111 K le b s ie lla spp., 109, 115, 116, 330
Intestinal lymphoma, 119 kidney abscess and, 417
Intestinal obstruction, 103 leukemia and, 215
Intestinal tuberculosis, 112— 113 neutropenia and, 195
Intestinal tumors, 114— 115 persistent, 338
530 U n ex p la in ed F e ve r

thrombocytopenic purpura and, 201 candidiasis and, 134

treatment of, 508 chronic lymphatic, 486
Koplik’s spots, 246 chronic lymphocytic (CLL), 214
Kostmann’s infantile agranulocytosis, 195 chronic myelogenous (CML), 217
Kupffer cells, 383 diarrhea and, 110
eosinophilic, 200
L in geriatrics, 476
hairy cell (HCL), 214— 215
Laboratory tests, 52, 67—68, 481—493, see also laboratory tests and, 486
specific types in pediatrics, 465
biochemical, 491 prevention of infection and, 216— 217
blood, 483—484 prolymphocytic, 214
culture type, 481—485 Leukenoid reaction, 194
of hematologic parameters, 485—486 Leukocytes, 109
serologic, 486—490 Leukocytoclastic angiitis, 179
skin, 490 Leukocytoclastic vasculitis, 285
sputum, 485 Leukocytosis, 25, 114, 449
stool, 484—485 Leukopenia, 198, 276, 341, 421
urine, 484 Limulus lysate, 159
Laboratory workers, 265 Lip disorders, 249
Laparoscopy, 79 Liposarcomas, 501
Laparotomy, 407—408 Liquid crystal temperature strips, 34
Large cell carcinomas, 99 Liquid-n-glass thermometers, 2
Large intestine, 106— 115 L is te r ia
Lassa fever, 162, 377 244, 335— 336
m o n o c y to g e n e s ,
Latex agglutination test, 173, 333, 335 spp., 264, 460, 485, see also Listeriosis
L e g io n e lla Listeriosis, 244, 448, see also L is te r ia
p n e u m o p h ila ,
89, 90, 264, see also Legionnaires’ Liver, 25— 26, 499—500
disease abscesses in, 131 — 132, 338, 510
spp., 42, 485 actinomycosis of, 133
Legionellosis, see Legionnaire’s disease amebiasis of, 134— 135
Legionnaires’ disease, 4, 42, 90, 265, 486, see also amebic abscess of, 372— 373
L e g io n e lla arteriography of, 132
Leigh’s encephalopathy, 165 bacterial infections and, 131 — 133
Leiomyomas, 99, 381, 441 cancer of, 101, 373
Leiomyosarcoma, 79, 106, 441 cirrhosis of, see Cirrhosis
L e is h m a n ia d o n o v a n i, 247 cystic conditions of, 142
Leishmaniasis, 247, 376, 485, 490, 492—493, 511 direct infection of, 125
Leiomyosarcomas, 501 drug-induced injury to, 138— 140
Leiomyoma, 106 fungi and, 134
Lemierre’s post anginal septicemia, 337 herpes and, 130
Leprosy, 183, 246, 490 infections involving, 129— 130
L e p to s p ir a inflammation involving, 137— 141
a u s tr a lis ,
344 nodularity of, 125
344
a u tu m n a l is , in pregnancy, 446
c o n ic o la , 344 protozoal diseases of, 134— 136
h e b d o m a lis , 344 in salmonella infections, 133
p o m o n a , 344 scintography of, 132
spp., 125, 133, 245, 344, 491—492, see also spirochetes in, 133— 134
Leptospirosis tuberculosis of, 132
Leptospirosis, 133, 160, 244, 245, 344— 345, 449, tumors in, 125, 128, 141 — 142
489, see also L e p to s p ir a Liver biopsy, 128— 129, 131, 137, 138, 140, 290,
laboratory tests and, 491—492 291
treatment of, 509, 510 in pediatrics, 464
Lethal effects of fever, 24 specimens for, 485
Lethal midline granuloma, 284 Liver cell adenoma, 141
Leukemia, 3, 23, 41, 75, see also specific types Liver cell carcinoma, 141
acute, 215— 217 Liver cell damage, 126
acute lymphoblastic (ALL), 215, 465 Liver disease, 493, see also specific types
acute myeloblastic (AML), 215 Liver function tests, 52
alimentary tract and, 101 Liver portal thrombosis, 218
 531

LMG, see Lethal midline granuloma T-cell, 212

Loa loa, 374 Lymphomatoid granulomatosis, 213, 285
Loffler’s syndrome, 200 Lymphomatous diseases, 498, see also specific
Lower genital tract infection, 435 types
Low-grade fever, 42, 43—44, 347, 467 Lymphomatous tumors, 424
Lumbar puncture, 158 Lymphopenia, 25
Lungs, 27 Lymphoproliferative disorders, 202
abscesses in, 104 Lymphoreticulosis, 163, 246, 395, 490
cancer of, 88
carcinoma of, 75 M
granuloma of, 97
scanning of, 96 Machupo virus, 162
tumors of, 99 Macrocytic anemia, 206
Lupus, see Systemic lupus erythematosus (SLE) Macroglobulinemia, 213—214
Lyme arthritis, 4, 181, 246, 346, 491 Macrophages, 17, 19, 383
Lymphadenitis, 132, 190 Magnetic resonance imaging (MRI), 11, 76, 132,
Lymphadenopathy, 126, 212, 383, 510 162, 497—502
angioimmunoblastic, 212 bone cancers and, 186
benign, 189— 193 intracranial infections and, 502
drug-induced, 192 osteomyelitis and, 186
generalized, 190— 191 in pediatrics, 469
local, 190— 191 spinal epidural abscess and, 167
Lymphadenopathy, 107 Malabsorptive disorders, 118— 119, see also spe-
Lymphangiography, 501 cific types
Lymphoid hyperplasia, 190 Malaria, 2, 41, 42, 43, 135, 161, 334, see also
Lymph nodes, 48 Plasmodium malariae
biopsy of, 190 cerebral, 372, 385
enlarged, 498, 501 laboratory tests and, 485, 492
idiopathic infarction of, 193
in pregnancy, 450
retroperitoneal, 501
psychiatric symptoms and, 385
Lymphocedes, 499
relapsing fever and, 345
Lymphocyte antigen, 382
risks of, 371—372
Lymphocytes, 199— 200
skin manifestations of, 248
Lymphocytic choriomeningitis, 162
splenomegaly and, 191
Lymphocytic leukemia, 214
treatment of, 510
Lymphocytic meningitis, 511
Lymphocytic products, 17 Malignancy, 23, 74, 91, 286, see also Cancer; spe-
Lymphocytosis, 25, 130, 199 cific types
Lymphogranulomatous disease, 290 acquired hypertriglyceridemia of, 239
Lymphogranuloma venereum, 490, 492 in geriatrics, 473
Lymphokines, 225 laboratory tests and, 486
Lymphoma-mimicking disorders, 212— 213, see in pediatrics, 461, 465—466
also specific types secondary, 101
Lymphomas, 75, 99, 101, 107, 110, 125, see also urological, 421—422
Cancer; specific types Malignant hematologic disorders, 209— 219, see
AIDS and, 360 also specific types
Burkitfs, 301, 493 drug fever and, 209— 210
candidiasis and, 134 lymphoma-mimicking, 212— 213
EBV-induced, 301 tumors and, 209
gastric, 106 Malignant hyperthermia, 17, 167, 408—411
in geriatrics, 476 Malignant lymphoma, 210— 212
in immunocompromised patients, 358 Malignant neuroleptic syndrome, 166
intestinal, 114, 119 Mannitol, 230
IPSID-associated, 114 Mantoux test, 490
kidney, 500 MAO inhibitors, 263
laboratory tests and, 485, 486, 491 Marburg virus, 377
malignant, 210— 212 Mastitis, 451
Mediterranean abdominal, 114 Mastoiditis, 464
non-Hodgkin’s, see Non-Hodgkin’s lymphoma May-Heggelin anomaly, 196
pelvic, 501 McDuffie syndrome, 286
splenic, 212 MDS, see Myelodysplastic syndromes
532 U nex p la in ed F e ve r

Measles, 228, 245, 246, 446, 447, 490 Miliary tuberculosis, 91, 132, 348, 510
Mechanism of fever, 383 Milk fever, 461
Meckel’s diverticulitis, 116 Mixed connective tissue diseases, 192, 279, 291,
Medical history, 44—58, 365 see also specific types
diagnosis and, 51— 57 Mixed cryoglobulinemia, 286
epidemiologic data in, 45 Molecular biology, 198
family history and, 44—45 Monoamines, 20
physical examination and, 47— 51 Monoclonal antibodies, 11, 374, 491
problem list and, 51— 57 Monocytes, 17, 200, 383
specialists and, 50— 51 Monocytopenia, 25, 212, 214
Mediterranean abdominal lymphoma, 114 Monocytosis, 25
Mediterranean fever, see Familial Mediterranean fe- Mononucleosis, see Infectious mononucleosis
ver (FMF) Mortality, 58
Megaloblastic anemia, 196 Moschkowitz’s syndrome (TTP), 201— 202
Melanomas, 99, see also specific types MRI, see Magnetic resonance imaging
Melioidosis, 376 Mucocutaneous lymph node syndrome (Kawasaki
Melkerson-Rosenthal syndrome, 249 syndrome), 77, 246, 283— 284, 345
Meningeal tuberculosis, 247 Mucormycosis, 320
Meningitis, 41, 43, 45, 336, 340— 342 M u c o r spp., 216, 247, 320
aseptic, 344 Mucositis, 511
bacterial, 158— 159 Multiple myeloma, 99, 202, 213— 214
basilar, 165 Multiple sclerosis, 502
candida, 316 Mumps, 161, 162, 228, 447
carcinomatous, 165 Munchausen’s syndrome, 388— 390
in infants, 458, 460 Muscles, 27— 28
lymphocytic, 511 biopsy of, 283, 351
neonatal, 159 contractions of, 167
in pediatrics, 458, 460, 461, 463—465 Musculoskeletal cancers, 186
serosal, 160 Musculoskeletal disorders, 173— 186, see also spe-
sterile, 261 cific types
treatment of, 510 Myalgia, 512
Meningococcal infections, 158, 231, 264, 334— Mycobacteria, 18, 91—92, see also M yc o b a c te riu m ',
335, see also M e n in g o c o c c a l, specific types specific types
of skin, 244 M y c o b a c te r iu m
M e n in g o c o c c a l s e p tic e m a , 244, see also Meningo- a v iu m - in tr a c e llu la r e ,
91, 109, 136
coccal infections fo r tu itu m , 91, 183, 264
Meningoencephalitis, 161, 321, 336, 346 in tr a c e llu la r e , 183
Meningoencephalomyelitis, 161 k a n s a s ii, 91, 183
Menstrual cycle, 33, 52 m a r in u m , 183
6-Mercaptopurine, 210 s c r o fu la c e u m , 91
Mercury-in-glass thermometers, 33 tu b e r c u lo s is , 89, 90, 115, 125, 183, see also Tu-
Mesangial cells, 383 berculosis laboratory tests and, 485
Mesenteric adenitis, 116, 117 Mycoplasma infections, 307, 308, see also specific
Mesenteric arteritis, 107 types
Mesenteric disorders, 117— 118, see also specific in obstetrics, 451
types PID and, 436
Mesenteric thrombosis, 218 treatment of, 510
Mesenteric vein thrombosis, 103 urethritis and, 425
Mesenteritis, 118 Mycoses, 314, 321
Metabolic changes, 28 Mycotic aneurysms, 78
Metabolic disorders, 10, 41, 235— 240, see also Myelodysplastic syndromes (MDS), 217, see also
specific types specific types
in pediatrics, 466 Myelomas, 99, 202, 213—214
Methicillin, 509 Myeloperoxidase deficiency, 197
Methotrexate, 210 Myeloproliferative syndromes, 218, see also specific
Metronidazole, 509, 511 types
Mezlocillin, 508 Myobacterial skeletal infections, 182— 183, see also
Microbial arteritis, 78 specific types
Microbiologic cultures, 481—485 Myocardial infarction, 71, 72, 103, 104
Microcytic anemia, 205 Myocarditis, 73— 74, 76, 346, 450
Microscopy, 481 Myoma uteri, 450
 533

Myositis, 178 paraneoplastic fever and, 381

system imaging and, 501
N Noninfectious diseases, 1, 41, 57— 58, 125, see
also specific types
Nafcillin, 508
in immunocompromised patients, 358—359
Nalidixic acid, 204, 216
Naproxen, 210, 211, 511 laboratory tests and, 489
Nasopharyngeal carcinoma, 493 of skin, 248, 253— 254
Neck, 502 Nonpathologic hyperthermia, 7
Necrotizing fasciitis, 451 Nonspecific urethritis, 425
Necrotizing pulmonary aspergillosis, 318 Nonsteroidal anti-inflammatory agents, 383, 473,
N e is s e r ia 507, 512, see also specific types
115, 436, see also Gonorrhea
g o n o rrh o ea e,
Nonthrombocytopenic purpura, 202
m e n in g itid e s ,
335
Norepinephrine, 20
m e n in g itis , 244
Neomycin, 216 Normal body temperature, 15— 19, 33
Neonatal fever, 457—461 Normal thermoregulation, 15— 20
Neonatal neutropenia, 196 Normocytic anemia, 202— 203
Neoplasia, 9, 41, 475, see also Tumors North American blastomycosis, 490
Neoplastic diseases, see specific types; Tumors Norwalk virus, 107, 109
Nephritis, 500
Nosocomial infection, 264, see also Iatrogenic fe-
Nephrolithiasis, 229
ver; specific types
Nephrotic syndrome, 115
Neuritis, 342, 346 Nuclear fluorescence, 277
Neuroblastomas, 465 Nuclear medicine, 11, 495—496, see also specific
Neurogenic tumors, 99 methods
Neuroleptic drugs, 166, see also specific types
Neuroleptic syndrome, 166, 385, 390 o
Neurological disorders, 41, 157— 169, 336, see also
specific types
Obesity, 411, 467
parasitic, 161
O b s id ia spp., 320
rickettsial, 161— 163
viral, 161 — 163 Obstetrics, 445—451, see also Pregnancy; specific
Neurological exam, 50 conditions
Neurological impairment due to fever, 157— 158 Occult bacteremia, 330
Neuromyasthemia, 163, 395— 396 Occult hematomas, 399, 400
Neutropenia, 42, 55, 194— 196, 355 Occult infectious foci (focal sepsis), 393— 394
autoimmune, 196 Occupational fevers, 7— 8, 261— 272, see also spe-
cyclic, 194, 237
cific types
drug-induced, 195
O n c h o c e r c a v o lv u lu s , 247
evaluation of patients with, 197— 198
immune, 195— 196 Onchocerrcasis, 247
infection as cause of, 195 Oncology, see Cancer
isoimmune neonatal, 196 Open lung biopsy, 89
management of patients with, 198— 199 Opportunistic infections, 210, 211, 338, 465, see
Neutrophilia, 194 also specific types
Neutrophilic dermatosis, 394
Ophthalmological exam, 50—51
Neutrophils, 196— 199
NHL, see Non-Hodgkin’s lymphoma Oral cavity disorders, 249, 383
Niemann-Pick disease, 193 Oral contraceptives, 120
Nitrofurantoin, 204, 426 Oral temperature, 35
Nitrogen mustard, 210 Orchi-epididymitis, 342
NMS, see Neuroleptic malignant syndrome Organic disease, 44, see also specific types
N o c a r d ia
Organ vasculosum laminae terminalis (OVLT), 17,
313
a s te r o id e s ,
20
spp., 264, 485
Omithodorus, 345
Nocardiosis, 247, 313— 314
Non-Hodgkin’s lymphoma, 210— 212, 360, 381, Oroya fever, 344
465, 468 Osteomyelitis, 183— 186, 336, 341, 464, 483
in adolescents, 468 spinal, 426—427
in geriatrics, 476 treatment of, 509
534 U n ex p la in ed F e ve r

vertebral, 502 Peliosis hepatitis, 142

Otitis media, 463 Pelvic abscess, 411, 438
Ovarian cancer, 441 Pelvic coccidioidomycosis, 438
Ovarian tumors, 441, 450 Pelvic exam, 50
OVLT, see Organ vasculosum laminae terminalis Pelvic inflammatory disease, 103, 116, 435—440
Ovulation fever, 435 Pelvic lymphoma, 501
Oxidant drugs, 204, 263, see also specific types Pelvic pain, 436, 437
Pelvic thrombophlebitis, 79, 398, 426, 440—441,
P 451
Pelvis, 501
Pain, 47, see also specific types Penicillin, 198, 263, 413, 508, 509
abdominal, see Abdominal pain P n e u m o c y s tis c a r in ii , 215
back, 118 Peptic ulcers, 101, 105, 115, 116
bone, 218, 345 P e p to s tr e p to c o c c u s spp., 92
joint, 111 Percutaneous fine needle aspiration, 89— 90
pelvic, 436, 437 Perforated ulcer, 411
Panarteritis, 281, 282 Perforating tumors, 116
Pancreas, 27, 500 Pericardial friction rub, 75
Pancreatic adenocarcinoma, 120 Pericardiotomy, 411
Pancreatic disorders, 116, 146— 147, see also spe- Pericarditis, 73— 74, 101, 235, 336, 340, 343
cific types recurrent, 393
Pancreatitis, 103, 104, 116, 146, 238, 450, 500 Perihepatitis, 136, 306, 335, 436
Pancytopenia, 204, 205 Perineal infection, 451
Pan-dysautonomia, 166, 168
Perinephric abscess, 422—423, 509
Papillomas, 99
Periodic fever, 235, 236— 238, 411, 467
Papular acrodermatitis of childhood, 304
Peripheral aspects of fever, 411—412
Paracoccidioidomycosis, 247, 490
Peripheral eosinophilia, 97—98, 379
Para-infective turberculous poly arthropathy, 182
Peripheral nervous system disorders, 164— 169, see
Parainfluenza, 215, 466
also specific types
Parametritis, 451
Peripheral neuritis, 346
Paraneoplastic fever, 381, 383
Peripheral neuropathies, 237
Paraplegics, 411
Peripheral temperature regulation impairment,
Parasites, 45, 98, 161, 498, see also specific types
167— 168
cultures of, 482
Peritoneovemous shunts, 511
laboratory tests and, 486, 490, 492—493
microscopy of, 482 Peritonitis, 115— 116, 120, 235, 336, 411
in pediatrics, 465 recurrent, 450
persistent, 349— 351 tuberculous, 449
serologic studies of, 488 Persistent bacteremia, 331— 346
of skin, 247— 248, 252 Peyronie’s disease, 144
treatment of, 510— 511 PGE, see Prostaglandin E
Parasitic rheumatism, 179 Phaelohyphomycosis, 247
Parathyroid, 26 Pharyngitis, 436
Parkinson’s disease, 157, 167 Phenacetin, 204
Parotitis, 342, 343 Phenolphthalein, 426
Paroxysmal hypertension, 230 Phenothiazines, 263
Paroxysmal nocturnal hemoglobinuria (PNH), 203 Phenylbutazone, 507
P a s te u r e lla m u lto c id a , 339 Phenytoin sodium (Dilantin), 212
Pathophysiology of fever, 17, 23— 29 Pheochromocytoma, 230—231
Patterns of fever, 1, 41—44 Phlebothrombosis, 218
PBG, see Porphobilinogen Phlebotomus, 344
PCP, see P n e u m o c y s tis c a r in ii pneumonia Phlegmonous gastritis, 105
Pediatrics, 457—470, 505 Phobia of fever, 468
acrodermatitis in, 304 Physical exam, 47— 51, 365— 371
AIDS in, 361, 465 PID, see Pelvic inflammatory disease
approach to patients in, 468—469 PIE, see Pulmonary infiltrates with eosinophilia
HIV in, 361, 464 Pituitary gland, 225—226
infectious diseases in, 461—465 Plague, 339
P e d ic u lu s h u m a n u s , 345 Plasmacytoma, 99
Pel-Ebstein curve, see Hodgkin’s disease P la s m o d iu m
Pel-Ebstein fever, 42, 210 f a lc ip a r u m , 42, 161, 371, 385
 535

m a la r ia e , 42, see also Malaria protozoan infections in, 449—450

o v a le ,372 tumors in, 450
spp., 485 viral infections in, 446—448
v iv a x , 42, 371, 372 Premature infants, 457— 461
Plethysmography, 79 Pre-operative fever, 407—408
Pleuritis, 101, 235, 450 Primary pulmonary histiocytosis-X, 97
Pleuro-pulmonary diseases, 50
Primary sclerosing cholangitis, 144
PMC, see Pseudomembranous colitis
Probenecid, 204
P n e u m o c o c c u s , see S tr e p to c o c c u s p n e u m o n ia e
Problem list, 51— 57
P n e u m o c y s tis
4, 89, 93— 95, 355
c a r in ii,
Procarbazine, 209, 210
laboratory tests and, 485 Proctitis, 436
in pediatrics, 465 Progesterone, 225, 232
treatment and, 511 Prognosis, 58
spp., 264 Progressive fever, 41
Pneumonia, 2, 41, 42, 43, 90, 92, 104, 215, see Prolonged fever, 1, 157, 467
also Pneumonitis; specific types Prolymphocytic leukemia, 214
aspiration, 105 Prostaglandin E, 209, 218
bronchiolitis obliterans organizing, 98
Prostaglandins, 20, 225, 383, see also specific types
broncho-, 341, 343
Prostatectomy, 427
chronic eosinophilic, 97—98
cytotoxic drugs and, 265 Prostatic abscess, 425
interstitial, 511 Prostatic carcinoma, p383, 426, 501
Pneumonitis, 92, 248, see also Pneumonia Prostatic epididymis, 425
hypersensitivity, 271, 272 Prostatitis, 425, 425—426
irradiation-induced, 265 Prosthetic devices, 264— 265, 411, 412
radiation, 384 Prostaglandin E, 20
surgery and, 409 Protein electrophoresis, 52
PNH, see Paroxysmal nocturnal hemoglobinuria Proteinuria, 41
Polio, 42, 447
P r o te u s
Polyarteritis, 476
m ir a b ilis , 417
Polyarteritis nodosa, 98, 110, 118, 125, 248, 282—
283 spp., 115, 201, 330, 338, 489
Polyarthritis, 248, 339 Protozoal infections, 134— 136, 449—450, see also
Polyarthropathy, 182 specific types
Polychondritis, 294, 476 P r o v id e n c ia spp., 388
Polycythemia vera, 218 PSC, see Primary sclerosing cholangitis
Polymicrobial infections, 115, 329, see also specific Pseudocysts, 500
types Pseudomembranous colitis (PMC), 109, 467
Polymyalgia rheumatica, 281 P seu dom on as
Polymyositis, 176— 177, 490 a e r u g in o s a ,
215, 244, 247, 330, 338, 417
Pontiac fever, 90
338
b a c te r e m ia ,
Porphobilinogen (PGB) deaminase, 237
Porphyria, 116, 165 spp., 115, 201, 215, 331, 508
Porphyrin metabolism disorders, 237 Pseudotumors, 118
Portal thrombosis, 218 Psittacosis, 265, 492
Post anginal septicemia, 337 Psoriasis, 249
Post-Caesarean section infections, 451 Psychiatric aspects of fever, 385— 390
Postcardiotomy syndrome, 63, 408 Psychic hyperthermia, 7
Postoperative fever, 7, 408—411, 426—427, 442 Psychogenic fever, 43, 385, 386— 387, 389
Postpartum fever, 451 Psychosis, 165— 166
Postperfusion syndrome, 130
Pubic symphysitis, 180
Post-pericardiotomy syndrome, 411
Pulmonary aspergillosis, 318
Post-splenectomy fever, 412—413
Post-transfusion fever, 63 Pulmonary disease, see also Respiratory diseases;
PPD, see Purified protein derivative specific types
Pregnancy, see also Obstetrics diagnostic techniques in, 85— 89
AIDS and, 447—448 Pulmonary embolism, 4, 55, 75, 98— 99, 103, 218
bacterial infection in, 448—449 diagnosis and, 399
coccidioidomycosis and, 319 in geriatrics, 477
physiological changes during, 445—446 trauma and, 412
536 U nex p la in ed F e ve r

Pulmonary histiocytosis-X, 97 Regional enteritis, 111

Pulmonary infections, 88, 90— 95, 105, see also Reiter’s syndrome, 181, 468
specific types Relapsing fever, 1, 42, 245, 345, 465
diagnsosi of, 89— 90 Relapsing polychondritis, 294
in immunocompromised patients, 93 Remittent fever, 42
in pregnancy, 449 Remote abscesses, 426
Pulmonary infiltrates with eosinophilia (PIE), 97— Renal syndrome, 305, see also Kidney
98 Replacement therapy, 198, 201
Pulmonary thromboembolism, 71— 72 Reproductive system tumors, 441—442
Pulmonary tuberculosis, 449 Respiratory diseases, 85—99, see also Pulmonary
Pulseless disease (Takayasu’s arteritis), 280—281 disease; specific types
Pure white cell aplasia, 196 diagnosis of, 85—90, 96
Purified protein derivative (PPD), 18 granuloma-forming, 95—97
Pyelolithotomy, 427 Respiratory infections, 265, see also specific types
Pyelonephritis, 103, 341, 416, 418—419, 424, 500 in pediatrics, 464
Pylephlebitis, 338 Reticular dysgenesis, 195
Pyoderma gangrenosum, 248 Retractile mesenteritis, 118
Pyogenic abscess, 131 Retroperitoneal abscess, 117— 118, 501
Pyomyositis, 178 Retroperitoneal disorders, 117— 118, see also spe-
Pyonephrosis, 417— 418 cific types
Pyonephrotic kidneys, 427 Retroperitoneal fibrosis, 118, 423—424
Pyrexia, 209 Retroperitoneal lymph glands, 501
Pyrexin, 3
Retroperitoneal tumors, 424
Pyrimethamine, 510
Retroperitoneum, 422—425
Retropharyngeal abscess, 393
Q Reye’s syndrome, 507
Rhematic fever, 334
Q-fevet, 131, 309, 345
Rheumatic diseases, see also Collagen-vascular dis-
laboratory tests and, 489, 491
eases; specific types
in laboratory workers, 265
laboratory tests and, 489—490
in pediatrics, 465
Rheumatic fever, 23, 41, 63, 69—70, 76
treatment of, 509
atypical presentations of, 291
Quadriplegics, 411
description of, 291— 292
Qualitative disorders of neutrophils, 196— 197
Quindine, 204, 476 in geriatrics, 475
Quinine, 204, 510 laboratory tests and, 489
Quinolones, 198, 216 treatment of, 507, 512
Rheumatic heart disease, 63, 71
R Rheumatism, 179, 181
Rheumatoid arthritis, 173— 176, 202, 279
RA, see Rheumatoid arthritis benign hematologic disorders and, 192
Rabies, 162— 163 juvenile, 23, 465, 507
Radiation, 15— 16, 265, 382 laboratory tests and, 490, 491
Radiation pneumonitis, 384 treatment of, 512
Radioimmunoassays, 11 Rheumatoid factor, 68, 173, 276, 283, 483
Radioimmunological Farr test, 278 Rhinocerebral syndrome, 320
Radiological patterns, 86— 87 Rhinoviruses, 215, 265, 466, see also specific types
Radiology, 110 Rhizopus spp., 320
Radionuclide studies, 79, 416, 422, 495 Richter’s syndrome, 214
RARS, see Refractory anemia with ringed sidero- Rickettsia
blasts acari, 245
Rashes, 107 conorii, 245
Rat-bite fever, 245, 343, 345, 492 quintana, 307
Raynaud’s phenomenon, 179 rickettsi, 163, 245, see also Rickettsial diseases
Reactive arthritis, 181 — 182 Rickettsial diseases, 41, 42, 131, 245, 307— 309,
Reaginic tests, 489 see also Rickettsia; specific types
Rectal temperature, 35 acute, 161 — 163
Recurrent fever, 42, 236, 237 laboratory tests and, 486, 489
Red cell enzyme defects, 204, see also specific major features of, 310—311
types complications of, 312
Refractory anemia, 217 in pediatrics, 465
 537

of skin, 245, 250— 251 focal (occult infectious foci), 393— 394
thrombocytopenic purpura and, 201 Septic arthritis, 340— 342
treatment of, 510 Septicemia, 101, 115, 327— 331, see also specific
Rickettsial pox, 245, 489 types
Riedels’ thyroiditis, 144 defined, 327
Right ovarian vein syndrome, 451 neonatal, 458
Riley-Day syndrome (familial dysautonomia), 168 in pediatrics, 461, 464
Rocky-Mountain spotted fever, 42, 131, 163, 245 treatment of, 508, 509
Roseola infantum, 246 Septicopyremia, 327
Rotavirus, 109
Septic shock, 73, 331, 439
Rubella, 246, 446
Septic thrombus, 501
Rubeola, 264
Serologic tests, 52, 54, 486— 490, see also specific
s Seromas, 499
types

SACE, see Serum angiotensin converting enzyme Serositis, 235

S e r r a tia spp., 215, 330, 338
Sacroiliitis, 180, 342
S a lm o n e lla Serum angiotensin converting enzyme (SACE), 96
c h o le r a e s u is ,
340 Serum chemistries, 52
d u b lin , 341 Serum creatine kinase, 168
e a s tb o u r n e , 341 Serum protein electrophoresis, 491
e n te r itid is , 340 Serum sickness, 261, 285, 486
hemolytic anemias and, 204 Sex hormones, 226, see also specific types
in infants, 460 Sheehan syndrome, 226
m a n c h e n , 341 Sheep erythrocyte agglutination test, 173
n e w b r u n s w ic k , 341 S h ig e lla spp., 108, 109, 182, 338, 463
n e w p o r t, 341 Shivering, 16
in pediatrics, 460, 463 Shock
persistent, 338 septic, 73, 331, 439
spp., 78, 108, 182, see also Salmonella infections spinal, 166
Group D, 340
Shunts, 411
ty p h i , 125, 341, 509
Sicca syndrome (Sjogren’s syndrome), 192, 202,
Salmonella infections, 102, 264, 340— 341, 345,
291, 294, 490, 491
421, see also S a lm o n e lla
Sickle cell anemia, 192— 193, 204
laboratory tests and, 486, 489
Sickle cell crisis, 41
liver in, 133
in pregnancy, 449 Sickle cell disease, 334, 340, 341
in tropics, 365 Sickle cell hemoglobinopathy, 126
Sarcoidosis, 96, 118, 165, 192, 202, 231, 289— Sideroblastic anemia, 218
290 Sinuitis, 486
in geriatrics, 475 Sinus thrombosis, 398
sporotrichosis and, 320 Sjogren’s syndrome, 179, 192, 202, 291, 294, 490,
Sarcomas, 76, 141, see also Cancer; specific types 491
Kaposi’s, 136, 191, 360 Skeletal infections, 182— 183, see also specific
in pediatrics, 465—466 types
SBE, see Subacute bacterial endocarditis Skeletal tuberculosis, 182
Schistosomiasis, 341, 450, 490 Skin, 27, 243—255
Schonlein-Henoch purpura, 334 bacterial infections of, 243— 245, 250
Schulman’s syndrome (diffuse fasciitis with eosino- examination of, 48
philia), 178— 179
fungi and, 247, 252— 253
Scintigraphy, 289
noninfectious diseases of, 248, 253— 254
Scleroderma (systemic sclerosis), 110, 278— 279,
402, 490 parasitic diseases of, 247—248, 252
Sclerosing cholangitis, 144 rashes on, 107
Sclerosis, 110, 278— 279, 402, 490 rickettsial infections of, 245, 250— 251
Sea-blue histiocyte syndrome, 193 spirochetes in, 245, 251
Seasonal variation in body temperture, 33 temperature of, 36
Sepsis, 3, 41, 327— 331, see also specific types viral infections of, 245— 247, 251— 252
anorectal, 411—412 Skin tests, 490
clinical features of, 329 SLE, see Systemic lupus erythematosus
defined, 327 Sleeping sickness, 247, 375— 376, 385
538 U n ex p la in ed F e ve r

Slow virus (chronic inflammatory) CNS diseases, spp., 109, 331— 331, 508, see also Staphylococ-
163— 164 cal infections
Small cell carcinomas, 99 s te r c o r a li s , 181
Small intestine, 106— 115, 113, 114 Stem cell disorders, 194— 195, see also specific
Sodium stibogluconate, 511 types
Soft tissue structures, 501 Steroids, 19, 58, 231— 232, 383, 384
Spanish toxic epidemic syndrome, 287— 288 androgenic, 17, 198, 231
Specific granule deficiency, 197 withdrawal from, 231
Spinal column, 502 Still’s disease, 42, 58, 118, 292— 293, 394
Spinal cord trauma, 166— 167 in geriatrics, 475, 476
Spinal epidural abscess, 167 treatment of, 512
Spinal osteomyelitis, 426—427 Stomach diseases, 105— 107, see also Gastrointes-
Spinal shock, 166 tinal tract diseases; specific types
S p ir illu m m in o r , 245, 343, 492 Stones, 422
Spirochetes, 18, 45 Stool tests, 484—485
of liver, 133— 134 Storage diseases, 193, see also specific types
persistent, 344— 346 glycolipid, 237— 238
of skin, 245, 251 S tr e p to b a c illu s m o n ilifo r m is , 245, 343, 492
treatment of, 263 Streptococcal allergies, 394
Spleen, 499— 500 Streptococcal antibodies, 334
abscesses in, 193 Streptococcal gangrene, 244
infarction of, 218 Streptococcal infections, 41, 116, see also specific
lymphoma of, 212 types; S tr e p to c o c c u s
vein thrombosis of, 218 in infants, 459
Splenectomy, 412—413 in pediatrics, 459
Splenomegaly, 111, 125, 342, 510, 511 of skin, 244
benign conditions associated with, 189— 193 treatment of, 508
workup for, 193 S tr e p to c o c c u s
Spondylitis, 183 b o v is , 115, 334
Spondylodiscitis, 342 e p id e r m id is , 331
Sporotrichosis, 319— 320 f e c a l i s , 115
S p o r o tr ic h u m s c h e n c k ii, 319 p n e u m o n ia e , 204, 211, 213, 334, 463
Spotted fever, 1, 309, 489 spp., 115, 180, 331, 333—334, 394, see also
Spotted fever without spots, 1,11 Streptococcal infections
Sprue, 119 v ir id a n s , 215
Septicemia, see also specific types Streptococcus B, 449
SSPE, see Subacute sclerosing panencephalitis Streptozyme, 334
Staphylococcal infections, 204, 212, see also spe- Stress, 227
cific types; S ta p h y lo c o c c u s Stroke, 169
in geriatrics, 332 S tr o n g y I o id e s s te r c o r a li s , 93
in obstetrics, 451 Subacute bacterial endocarditis (SBE), 160
of skin, 243— 244 Subacute chlamydial endocarditis, 306
treatment of, 509 Subacute sclerosing panencephalitis (SSPE), 163
Staphylococcal pyomyositis, 178 Subacute thyroiditis, 228
Staphylococcal toxic epidermolysis, 244 Subarachnoid hemorrhage, 157
S ta p h y lo c o c c u s Subdural hematoma, 466
au reu s, 79, 109, 116, 330 Subphrenic abscess, 116— 117, 125
arthritis and, 180 Subsepsis allerica of Wissler, 394
in infants, 460 Subtraction angiography, 11
kidney abscess and, 417 Succinylcholine, 167
leukemia and, 215 Sulfadoxine, 510
in obstetrics, 451 Sulfamethoxazole, 216, 511
in pediatrics, 460 Sulfonamides, 204, 426
persistent, 332 Superinfection, 264, 384
TSS and, 415 Suppurative arthritis, 476
e p id e r m id is , 180, 181, 329, 412, 415 Suppurative pyelonephritis, 424
hemodialysis and, 427 Supra-infection, 264, 384
persistent, 332 Surgery, 74, 120, 394
transplants and, 427 anorectal sepsis and ,411 —412
s a p r o p y tic u s , 332 intra-operative fever and, 408—411
 539

post-operative fever and, 408, 409—411 clinical measurement sites and, 34— 36
pre-operative fever and, 407—408 Thermoregulation
Sustained fever, 42 change in, 263
Sweating, 15, 16, 40 defined, 15
Sweet’s syndrome, 248 disorders of, 7, 400—402, see also specific types
Swineherd’s disease, 344 normal, 15— 20
Sympathectomy, 401 Thermoregulation center, 383
Symphysitis, 180 Thoracic tumors, 99
Synovial biopsy, 174, 183
Thoracoscopy-guided biopsy, 89
Synovitis, 393
Thorax, 49
Syphilis, 3, 104, 105, 134, 245, 263, 264, 484
Thromboangiitis obliterans (Buerger’s disease), 79,
diarrhea and, 109
282
laboratory tests and, 486, 489, 491
Thrombocythemia, 218
persistent, 345— 346
in pregnancy, 448 Thrombocytopenia, 25, 67, 201, 204, 214, 486
secondary, 334, 345 Thrombocytopenic purpura, 201— 202
Systemic candidosis, 314— 316 Thrombocytosis, 465, 486
Systemic diseases, 385, see also specific types Thromboembolic disorders, 397, see also specific
Systemic embolism, 75 types
Systemic infections, 190— 191, 420—422, 464, see Thromboembolism, 71— 72, 338
also specific types Thrombophlebitis, 78— 79, 286, 330, 342
Systemic lupus erythematosus (SLE), 23, 41, 48, aseptic, 393
51, 74, 102, 110, 118, 275— 278 pelvic, 398, 426, 440—441, 451
in adolescents, 468 surgery and, 409
benign hematologic disorders and, 192 Thrombosis, 79, 218
clinical manifestations of, 276 cerebral venous sinus, 398
criteria for, 277 liver portal, 218
in geriatrics, 475, 476 mesenteric, 103, 218
laboratory tests and, 485, 489—490, 491 splenic, 103, 218
in pregnancy, 450 vascular, 103, 218, 396— 399
psychiatric symptoms and, 385
venous, 103, 120, 218, 398
skin manifestations of, 248, 276
Thrombotic thrombocytopenic purpura (TTP),
Systemic sclerosis (scleroderma), 110, 278— 279,
201—202
402, 490
Thrombus, 501
System imaging, 495—502
Thrombophlebitis, 218
T Thyroid, 26
Thyroid crisis, 227
T. saginata, 181 Thyroid disease, 63
Takayasu’s arteritis (aortic arch syndrome), 77, Thyroid gland, 226
280—281 Thyroid hormone, 263
TB, see Tuberculosis Thyroiditis, 144, 228, 229, 450
T-cell lymphomas, 212 Thyrotoxic crisis, 227
Teichoic acid antibodies, 333 Thyrotoxicosis, 118, 226— 227
Temperature scales, 33, see also Thermometers Thyroxine, 225, 226
Temporal arteritis, 45, 281— 282 Tick typhus, 245
Temporal artery biopsy, 281 Tissue destruction, 399—400
Teratoma, 99 TNF, see Tumor necrosis factor
Testicular epididymis, 425
Torulopsis, spp., 316
Testicular tumors, 425
Total parenteral nutrition (TPN), 412
Tetracyclines, 261, 510
Toxic epidemic syndrome, 287— 288
Thalassemia major (Cooley’s anemia), 192, 204
Thalassemia syndromes, 204, see also specific types Toxic erythema, 319
Therapy, see Treatment Toxic granulation, 196
Thermistors, 34 Toxic shock syndrome (TSS), 73, 332, 415, 439—
Thermometers, 2, 3, see also Thermometry 440, 451
as cause of fever, 36 Toxocariasis, 145
clinical, 23, 33— 34 Toxoplasma, 264
faulty, 36 Toxoplasma gondii, 93, 125, 349, 492
types of, 33— 34 Toxoplasmoids, 349— 350
Thermometry, 3, 33— 36, see alto Thermometers Toxoplasmosis, 136, 449—450, 465, 486, 491, 492
540 U n ex p la in ed F e ve r

TPN, see Total parenteral nutrition in obstetrics, 451

Tracheobronchitis, 104 persistent, 346— 351
Transformed cells, 19 post-operative flare-up of, 426
Transfusion-associated infections, 464 in pregnancy, 449
Transfusion reactions, 409 retroperitoneal fibrosis and, 118
Transfusions, 63, 105 skeletal, 182
Transplantations, 198, 265, 427—429 of skin, see Leprosy
Transthoracic needle aspiration, 88 sporotrichosis and, 320
Transtracheal aspiration, 89 treatment of, 501, 512
Trauma, 105, 120, 166— 167, 412, 459, 468 urinary tract, 484
Traumatic hemorrhage, 165 urological infections and, 420
Traveler’s diarrhea, 109 Tuberculous myositis, 178
Treatment, 505— 512, see also specific types Tuberculous peritonitis, 449
Trench fever, 489 Tuboovarian abscess, 449, 451
T reponem a Tularemia, 42, 244, 340, 485, 486
c a r a te u m , 245 Tumor cells, 19
p a llid u m , 125, 133, 345 Tumor necrosis factor (TNF), 3, 209
p e r te n u a , 245 Tumors, 99, 120, 164, 209, 421, see also specific
spp., 245 types
T r ic h in e lla s p ir a li s , 247, 351 appendicular, 115
Trichinosis, 3, 161, 247, 351, 486, 492—493 arterial, 78
Trichomoniasis, 468 benign, 141
Triiodothyronine, 225, 226 biliary tract, 142, 145
Trimethoprim, 216, 511 brain, 468
Tropical diseases, 365—379, see also specific types breast, 441
diagnosis of, 365— 371 cardiac, 75— 76
geographic distribution of, 367 cerebral, 502
helminthic, 373— 379 of colon, 114— 115
incubation time of, 368 female reproductive system, 441—442
laboratory investigations of, 366— 371 formation of, see Neoplasia
viral, 376— 379 gastric, 106
Tropical myositis, 178 in geriatrics, 476
Tropical sprue, 119 intestinal, 114— 115
T r y p a n o s o m a spp., 264, 485 liver, 125, 128, 141 — 142
Trypanosomiasis (sleeping sickness), 247, 375— lung, 99
376, 385 lymphomatous, 424
TSS, see Toxic shock syndrome neurogenic, 99
TTP, see Thrombotic thrombocytopenic purpura ovarian, 441, 450
Tuberculin test, 91, 182, 347, 476 in pediatrics, 469
Tuberculosis, 3, 41, 42, 43, 104, 105, 115, see also perforating, 116
M y c o b a c te r iu m tu b e r c u lo s is in pregnancy, 450
in adolescents, 468 retroperitoneal, 424
adrenal insufficiency and, 231 small intestine, 114
airborne spread of, 264 testicular, 425
defined, 346 thoracic, 99
description of, 91—91 uterine, 441
of duodenum, 106 venous, 79
epididymo-orchitis and, 425 Wilms’, 421
extrapulmonary, 347 Turberculous poly arthropathy, 182
genital, 437 Tympanic temperature, 35
in geriatrics, 475, 476 Typhoid fever, 3, 41, 42, 45, 115, 340, 341, 365
hepatitis and, 290 changing pattern of, 341
importance of, 291 laboratory tests and, 485, 486, 491
intestinal, 112— 113 in laboratory workers, 265
laboratory tests and, 485, 490, 491 treatment of, 509
in laboratory workers, 265 Typhus, 245, 309, 489
liver, 132
malignant hematologic disorders and, 211 u
meningeal, 247
miliary, 91, 132, 348, 510 Ulcerative colitis, 42, 109, 111 — 112, 140, 450,
of myocardium, 74 467
 541

Ulcers, 101, see also specific types leukocytoclastic, 285

peptic, 105, 115, 116 skin manifestations of, 248
perforated, 411 treatment of, 512
Ultrasonography, 11, 79, 110, 132, 143, 146, VCA, see Virus capsid antigen
497— 502 Vein thrombosis, 218
abscesses and, 426 Venezuelan equine encephalitis, 265
adrenal and, 424 Venography, 79
benign hematologic disorders and, 189 Venous diseases, 77— 79, see also specific types
kidney infections and, 416
Venous sinus thrombosis, 398
in pediatrics, 469
Venous thrombosis, 103, 120, 218, 398
prostatic abscess and, 425
Venous tumors, 79
retroperitoneum and, 422
Verruga peruana, 344
urological infections and, 421
Undulant fever, 1, 42 Vertebral osteomyelitis, 502
Unexplained fever, defined, 1 Very low birth weight infants, 457—461
Upper respiratory infections, 464 Vibrio
Ureteral stumps, 424—425 fetus, see Campylobacter fetus
Ureters, 424—425 parahemolyticus, 108
Urethritis, 415, 425, 436 Viral hepatitis, see Hepatitis
Urinary bladder temperature, 36 Virus-associated hemophagocytic syndrome, 302
Urinary temperature, 35— 36, 468 Virus capsid antigen (VCA), 199
Urinary tract infections, 103, 409, 415, 451, see Viruses, 8, 45, 304— 305, see also specific types
also Urological infections; specific types acute, 161 — 163
in infants, 460 ofCNS, 161
in pediatrics, 460, 464 cultures of, 482
in pregnancy, 448 DNA, 299
Urinary tract tuberculosis, 484 EP and, 18
Urine tests, 484 in infants, 458—460
Urinoma, 426 laboratory tests and, 490, 493
Urological infections, 415—428, see also Genital
leukemia and, 215
tract infections; Kidney infections; specific
liver involvement in, 129— 130
types
microscopy of, 482
retroperitoneal, 422—425
neutropenia and, 198
systemic, 420—422
Urticaria, 237, 285 Norwalk, 107, 109
Uterine leiomyomas, 381 in pediatrics, 458—460, 464, 466
Uterine tumors, 441 in pregnancy, 446—448
UTI, see Urinary tract infections respiratory, 265
serologic studies of, 488—489
V of skin, 245— 247, 251— 252
slow, 163— 164
Vaccination, 192 subacute thyroiditis caused by, 228
Vaccinia, 245 thrombocytopenic purpura and, 201
Valproate sodium, 401 treatment of, 511
Vancomycin, 263, 412, 508 tropical, 376— 379, see also specific types
Varicella, 130, 211, 245, 246, 264 Visceral larva migrans, 375
leukemia and, 215 Visceral leishmaniasis, 247, 376, 492—493, 511
in pediatrics, 466
Visceral thrombophlebitis, 79
in pregnancy, 447
Vitamin K derivatives, 204
Variola, 245
Vogt-Koyanagi Harada (VKH) syndrome, 165
Vascomycin, 509
Vascular disorders, 10, 41, 76— 79, see also Colla-
gen-vascular diseases; specific types w
Vascular injury, 23
Vascular structures, 501 Warmth receptors, 16
Vascular thrombosis, 396—399 Waterhouse-Friderichsen syndrome (fulminant men-
Vasculitides, 279— 280 ingococcemia), 201, 334
Vasculitis, 101, 145, 165, 279, 280, 282 Weber-Christian disease, 118, 286
coronary artery, 283 Wegener’s granulomatosis, 96, 284, 285
in geriatrics, 476 Weil-Felix test, 489
hypersensitivity, 285— 286 Weil’s disease (icteric leptospirosis), 344
542 U n ex p la in ed F e ve r

Wernicke’s encephalopathy, 165 Y

Whipple’s disease, 107, 110, 119, 160, 289
White blood cell disorders, see also specific types Yaws, 245
White cell aplasia, 196 Yeast infections, 316, see also specific types
White cell disorders, 194— 199 Yellow fever, 130, 345, 365
Y e r sin ia
Wilms’ tumor, 421
e n te r o c o litic a ,108, 338, 339, 464
Wilson’s disease, 137 p e stis, 338, 339
Wound infection, 409 p s e u d o tu b e r c u lo s is , 338— 339, 464
W u sc h e r e r ia b a n c r o fti, 247, 374 spp., 107, 109, 111, 181, 182, 336, 338, see
also Yersiniosis
X Yersiniosis, 486, see also specific types; Y e r sin ia

Xanthogranulomatous pyelonephritis, 418—419,

z
500 Zygomycosis, 320
Xanthomata, 239 Zygomycotes, 320
X-linked lymphoproliférative syndrome (XLP), 301