Fever of

Unknown
Origin
IMMUNOCOMPROMISED
Objectives

 Definitionand
pathophysiology of fever
 FUO: classifications and
etiology
 Diagnostic workup of FUO
 Prognosis
Fever versus Hyperthermia

 Fever: resetting of the thermostatic set-point in the

anterior hypothalamus and the resultant initiation
of heat-conserving mechanisms until the internal
temperature reaches the new level.
 Hyperthermia: an elevation in body temperature
that occurs in the absence of resetting of the
hypothalamic thermoregulatory center
Mechanisms of
Hyperthermia and
Associated Conditions
1. Excessive heat production: exertional hyperthermia,
thyrotoxicosis, pheochromocytoma, cocaine, delerium
tremens, malignant hyperthermia
2. Disorders of heat dissipation: heat stroke, autonomic
dysfunction
3. Disorders of hypothalamic function: neuroleptic malignant
syndrome, CVA, trauma
Wunderlich’s Maxim

 After analyzing >1 million axillary temperatures

from ~25,000 patients, Wunderlich identified 37.0°
C (36.2-37.5) as the mean temperature in healthy
adults.
 Temperature readings >38.0° C were deemed as
“suspicious/probably febrile.”
Normal Body Temperature

 For healthy individuals 18 to 40 years of

age, the mean oral temperature is 36.8° ±
0.4°C (98.2° ± 0.7°F)
 Low levels occur at 6 A.M. and higher
levels at 4 to 6 P.M.
 The maximum normal oral temperature is
37.2°C (98.9°F) at 6 A.M. and 37.7°C
(99.9°F) at 4 P.M.
 These values define the 99th percentile
for healthy individuals.
Normal Body Temperature
Caveats
 Rectal temperatures are generally 0.4°C (0.7°F) higher than
oral readings.
 Tympanic membrane (TM) values are 0.8°C (1.6°F) lower than
rectal temperatures when thermometer is in the unadjusted-
mode.
Hypothetical Model for the Febrile Response

Interleukin-1 β and TNF-α play prominent roles

in fever production by stimulating the release of
cyclic AMP from the glial cells and activating
neuronal endings from the thermoregulatory
center that extend into the area.
Bacterial Pyrogens
 Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is
transferred to CD14 on macrophages, which
stimulates the release of TNFα.
 Staphylococcus aureus enterotoxins
 Staphylococcus aureus toxic shock
syndrome toxin (TSST)
Both Staphylococcus toxins are superantigens and
activate T cells leading to the release of interleukin
(IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-
gamma in large amounts
 Group A and B streptococcal toxins
Exotoxins induce human mononuclear cells to
synthesize not only TNFα but also IL1 and IL-6
Fever of Unknown Origin
 Fever of at least 3 weeks’ duration
 Temperature of 101° F (38.3° C) or
greater on several occasions
 Remains undiagnosed after 3 days
of in-hospital testing or during two
or more outpatient visits.
FUC IN
IMMUNOCOMPROMISED
 Marked by fever of more than 38°C for 3 days, as
well as by negative cultures at 48 hours
 The cause is most often an infection
 Although aetiology is only established in about
half the cases
 Categories of FUO
Feature Nosocomial Neutropenic HIV-associated Classic

Patient’s Hospitalized, Neutrophil count Confirmed HIV- All others with

situation acute care, no either <500/µL or positive fevers for ≥3
infection when expected to weeks
admitted reach that level in
1-2 days
Duration of 3 daysb 3 daysb 3 daysb (or 4 3 daysb or 3+
illness while weeks as outpatient
investigated outpatient) visits

Examples Septic Perianal infection, MAIc infection, Infections,

thrombophlebitis, aspergillosis, TB, non- malignancy,
sinusitis, C. candidemia Hodgkin’s inflammatory
difficile colitis, lymphoma, drug diseases, drug
drug fever fever fever
aAllrequire temperatures of ≥38.3°C (101°F) on several occasions.
bIncludes at least 2 days’ incubation of microbiology cultures.
cM. avium/M. intracellulare.
Etiology of FUO Over a 40
Year Period
Infectious Causes of FUO
 Intraabdominal abscess (liver, splenic,
psoas, etc)
 Appendicitis, cholecystitis, tubo-ovarian
abscess, pyometra
 Intracranial abscess, sinusitis, dental abscess
 Chronic pharyngitis, tracheobronchitis, lung
abscess
 Septic jugular phlebitis, mycotic aneurysm,
endocarditis, intravenous catheter infection,
vascular graft infection
 Wound infection, osteomyelitis, infected
joint prosthesis, pyelonephritis, prostatitis
Infectious Causes of FUO

 Tuberculosis, Mycobacterium avium complex,

syphilis, Q fever, legionellosis
 Salmonellosis (including typhoid fever), listeriosis,
ehrlichiosis,
 Actinomycosis, nocardiosis, Whipple’s disease
 Fungal (candidaemia, cryptococcosis,
sporotrichosis, aspergillosis, mucormycosis,
Malassezia furfur)
 Malaria, babesiosis, toxoplasmosis,
schistosomiasis, fascioliasis, toxocariasis,
amoebiasis, infected hydatid cyst, trichinosis,
trypanosomiasis
 Cytomegalovirus, HIV, Herpes simplex, Epstein-
Barr virus, parvovirus B19
Collagen Vascular
Diseases
 Adult Still’s disease, SLE
 Giant cell arteritis/polymyalgia rheumatica,
ankylosing spondylitis
 Wegener’s granulomatosis
 Rheumatic fever
 Polymyositis, rheumatoid arthritis
 Felty’s syndrome, eosinophilic fasciitis
Malignancies
 Lymphoma
 Renal cell carcinoma
 Hepatocellular carcinoma
Miscellaneous Causes of
FUO
 Complex partial status epilepticus,
cerebrovascular accident, brain
tumour, encephalitis
 Drug fever, Sweet’s syndrome, familial
Mediterranean fever
 Gout, pseudogout
 Kawasaki’s syndrome, Kikuchi’s
syndrome
 Crohn’s disease, ulcerative colitis,
sarcoidosis, granulomatous hepatitis
 Deep vein thrombosis
 Atelectasis?
 Drug Fever
 Common in hospitalized patients and is very difficult to diagnose
 Maximum temperatures range from 38°C to 43°C
 “It is a diagnosis of exclusion” clues include that the patient look
less sick than you would expect, has a fever of around 38.9°C to
40°C with relative bradycardia.
 Patient presents with maculopapular rash in 5%-10% of cases.
Making drug induced the obvious diagnosis.
 Common drugs that trigger fever are antibiotics, especially beta-
lactams and sulphonamides. Alpha methyldopa and quinidine are
most commonly implicated.
 Laboratory findings that indicate fever is drug induced include;
elevated white blood cell count with left shift; mildly elevated liver
function tests; very high erythrocyte sedimentation rate (ESR) and
low-grade eosinophilia.
Minimal Initial Diagnostic
Workup

For FUO
Comprehensive history
 Physical examination
 CBC + differential
 Blood film reviewed by hematopathologist
 Routine blood chemistry
 UA and microscopy
 Blood (x 3) and urine cultures
 Antinuclear antibodies, rheumatoid factor
 HIV antibody
 CMV IgM antibodies; heterophile antibody test (if c/w mono-like
syndrome)
 Q-fever serology (if risk factors)
 Chest radiography
 Hepatitis serology (if abnormal LFTs)
Liver Biopsy and Bone
Marrow Biopsy
 Diagnostic yield of  The diagnostic yield
liver biopsy has of bone marrow
ranged from 14% to cultures in
17%. immunocompetent
 Physical exam
individuals has been
finding of found to be 0% to
hepatomegaly or 2%1,2
abnormal liver
profile are not
helpful in predicting
abnormal biopsy
result.
 Complication rate is
0.06% to 0.32%
 Diagnostic Value of
Naproxen
 77 patients
presenting with FUO
were treated with
naproxen.
 Overall temperature
decreased from
39.1°C to 37.4°C.
 The sensitivity of the
naproxen test for
neoplastive fever
was 55% and the
specificity was 62%.
Proposed Approach to FUO

Mourad, O. et al. Arch Intern Med 2003;163:545-551.

Approach to Fever in the ICU
Prognosis

 Prognosis is determined primarily by the

underlying disease.
 Outcome is worst for neoplasms.
 FUO patients who remain undiagnosed after
extensive evaluation generally have a favorable
outcome and the fever usually resolves after 4-5
weeks.
Summary

 FUO is often a diagnostic dilemma

 Infections comprise ~30% of cases
 Bone marrow biopsies are of low diagnostic yield
 Diagnostic approach should occur in a step-wise
fashion based on the H&P
 Patient’s that remain undiagnosed generally have
a good prognosis