FEVER OF UNKNOWN

ORIGIN
Outline
Introduction
Revised definition
Aetiology
Epidemiology
History and physical examination
Investigations
Treatment/management
Prognosis
Introduction
First described by Dr. Petersdorf and Dr. Beesom in 1961
Defined as a temperature of 38.3 degrees Centigrade or higher with a
minimum duration of three weeks without an established diagnosis
despite at least one week’s investigation in the hospital
Newer concept?
Definition was later changed
- accommodate technological advances allowing for sophisticated
outpatient evaluations
- increasing numbers of immunocompromised individuals including
those with human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (AIDS)
- complex treatment options becoming available
Revised definition
Proposed by Durack and Street in 1991
Divided cases into four distinct subclasses:
1. classic FUO
2. nosocomial FUO
3. neutropenic FUO
4. HIV-related FUO
Aetiology
The causes of fever of unknown origin (FUO) are often common
conditions presenting atypically
The list of causes is extensive and it is broken down into broader
categories, such as infection, noninfectious inflammatory conditions,
malignancies, and miscellaneous
Noninfectious Inflammatory Causes
of FUO
Giant cell (temporal) arteritis
Adult Still disease (juvenile rheumatoid arthritis)
Systemic lupus erythematosus (SLE)
Periarteritis nodosa/microscopic polyangiitis (PAN/MPA)
Rheumatoid arthritis (RA)
Antiphospholipid syndrome (APS)
Gout
Pseudogout
Behçet disease
Sarcoidosis
Felty syndrome
Takayasu arteritis
Kikuchi disease
Periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome
Infectious Causes of FUO
Tuberculosis (TB)
Q fever
Brucellosis
HIV infection
Abdominopelvic abscesses
Cat scratch disease (CSD)
Epstein-Barr virus (EBV) infection
Cytomegalovirus (CMV) infection
Enteric (typhoid) fever
Toxoplasmosis
Extrapulmonary TB
Organ-based infectious causes of
FUO
Subacute bacterial endocarditis (SBE)
Chronic sinusitis/mastoiditis
Chronic prostatitis
Discitis
Vascular graft infections
Whipple disease
Multicentric Castleman disease (MCD)
Cholecystitis
Lymphogranuloma venereum (LGV)
Tickborne infections: Babesiosis, Ehrlichiosis
Anaplasmosis
Tickborne relapsing fever
Histoplasmosis
Coccidioidomycosis
Leptospirosis
Visceral leishmaniasis
Rat-bite fever
Louse-borne relapsing fever
Malignant and Neoplastic Causes of
FUO
Lymphoma
Renal cell carcinoma
Myeloproliferative disorder
Acute myelogenous leukemia
Multiple myeloma
Breast/liver/pancreatic/colon cancer
Atrial myxoma
Metastases to brain/liver
Malignant histiocytosis
Miscellaneous Causes of FUO
Cirrhosis (due to portal endotoxins)
Drug fever
Thyroiditis
Crohn disease
Pulmonary emboli
Hypothalamic syndrome
Familial periodic fever syndromes
Cyclic neutropenia
Factitious fever
Common Causes of Fever in the
Different Subclasses
• Classic FUO: endocarditis, complicated urinary tract infections,
abscesses, and tuberculosis; In patients over the age of 65, connective
tissue diseases are determined to be the cause of fever more
frequently; Fever in travelers is more likely to be secondary to
infections such as malaria, typhoid fever, and acute HIV

• Nosocomial FUO: drug fever, complications post-operatively, venous

thromboembolic disease, malignancy, transfusion-related reactions,
or Clostridium difficile infection
• Neutropenic FUO: Fevers are common in this subclass and are
frequently due to infection

• HIV-related FUO: Fevers can be present during acute illness, but are
also common in the setting of untreated infection signifying additional
infection with opportunistic organisms
Epidemiology
Varies based on etiology of fever, age group, geography, environmental
exposure, and immune/HIV status
In developing countries, an infectious etiology of FUO is most prevalent
In developed countries, FUO is likely due to non-infectious
inflammatory disease
History and Physical Examination
There is no clear-cut diagnostic approach to fever of unknown origin
Thorough history with a focus on the most probable etiology based on
the patient’s symptoms is the key to pinpoint the origin of FUO
Information about previous illnesses, localizing symptoms, alcohol
intake, home medications, occupational exposures, pets, travel, and
familial disorders should not be overlooked
Important Aspects of History
Family history
Immunization history
Dental history
Occupational history
Travel history
Nutrition and weight history
Drug history (over-the-counter medications, illicit substances)
Sexual history
Recreational habits
Animal contacts
Surgery, trauma, or procedures
Fever Patterns
Tertian or quartan fever in prolonged malaria (occurring every third or fourth
day)
Undulant fever in brucellosis (fevers and sweats in the evening, resolving by
morning)
Tick-borne relapsing fever in borreliosis (week-long fevers with week-long
remissions)
Pel-Ebstein fever in Hodgkin disease (week-long high fevers with week-long
remissions)
Periodic fevers in cyclic neutropenia
Double quotidian fever (two fever spikes a day) in adult Still disease, malaria,
and typhoid
Historical Clues and Physical
Examination in Infectious Causes of
FUO
History of presenting illness should include prior invasive
procedures/surgeries, dentition, TB exposure, pet contacts,
mosquito/tick bites, rodent exposure, history of blood transfusions, and
immunosuppressive drugs

Exam findings: a new heart murmur which could be suggestive of

bacterial endocarditis, spinal tenderness indicating vertebral
osteomyelitis, splenomegaly- miliary TB, epstein-barr virus (EBV), and
cytomegalovirus (CMV) and epididymal nodule- extrapulmonary TB
Historical Clues and Physical
Examination in Malignant Causes of
FUO
Unintentional weight loss, age-appropriate cancer screening, family
history of cancer, smoking, and alcohol use are important in history
Physical exam: relative bradycardia suggestive of lymphoma/ central
nervous system (CNS) malignancy, a new heart murmur (atrial
myxoma), sternal tenderness (myeloproliferative disorder). Isolated
hepatomegaly and FUO (hepatoma or liver metastases)
Historical Clues and Physical
Examination in non Infectious
Causes of FUO
Autoimmune rheumatic diseases can manifest as FUO if the fever
precedes other, more specific manifestations such as arthritis,
pneumonitis, or renal involvement
Rheumatologic etiology of FUO is less likely if a patient reports symptoms
of rigors or chills
Physical exam: oral ulcers (Behcet disease, systemic lupus erythematosus
[SLE]), unequal pulses (Takayasu arteritis), lymphadenopathy (SLE, RA,
sarcoidosis), and rashes (sarcoidosis, SLE, adult Still disease). Epididymal
nodule (polyarteritis nodosa, SLE, and sarcoidosis); hepatomegaly
without splenomegaly argues against rheumatologic disorders
Historical Clues and Physical
Examination in Miscellaneous
Causes of FUO
Cirrhosis and Crohn disease are often overlooked as miscellaneous
causes of FUO
If suspected, it is important to inquire about past medical history,
history of alcohol intake, intravenous drug use, non-alcoholic
hepatosteatosis (NASH), and hepatitis
Physical examination: splenomegaly is an important diagnostic clue for
Crohn disease and liver cirrhosis
Investigation

NON-INVASIVE
VS
INVASIVE
 Non-invasive Tests
Complete blood count with differential
Complete metabolic panel
Urine analysis with microscopy and urine culture
Three sets of blood cultures (from different sites, several hours apart,
and prior to initiation of antibiotic therapy)
Chest radiograph
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Lactate dehydrogenase (LDH)
Creatinine phosphokinase
ANA
Rheumatoid factor
Cytomegalovirus IgM/PCR
Heterophile antibody test
Tuberculin skin test or interferon-gamma release assay
HIV immunoassay
CT scan of the abdomen
CT scan of the chest
Cardiac echocardiography can be helpful if culture-negative
endocarditis or atrial myxoma is suspected

To diagnose FUO, the non-invasive testing outlined above should have

been inconclusive. At this point, a clinician should exclude surreptitious
manipulation of the thermometer and analyze patients' medication lists
to evaluate for drug-induced fevers
Nuclear Medicine Tests
Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan
Highly sensitive
Helps in anatomic localization of infectious, inflammatory, or neoplastic
processes
Nonspecific, but can guide further definitive tests such as biopsy or
aspiration
If FDG-PET is not available, labeled leukocyte studies could be used as
an alternative
Have a lower diagnostic yield
Gallium and indium are used to label leukocytes
Invasive Tests
Biopsy: lymph nodes, liver, bone marrow, epididymal nodule, temporal
artery
Used to diagnose malignancy, certain infections, myeloproliferative
disorders, and inflammatory conditions

Endoscopy: upper and lower GIT, retrograde cholangiopancreatography

Helps in diagnosis of Crohn disease, biliary tract disease, and
gastrointestinal tumours
Crohn disease is the most common gastrointestinal cause of FUO; diarrhoea
and other abdominal symptoms are sometimes absent in young adults
Treatment / Management
No single standard FUO management protocol given the variety of
possible causes
Aim: investigate and rule out all possible diagnoses
Specific treatment should be started once a diagnosis is made
Empiric antibiotics are not indicated unless the patient with FUO is
neutropenic (antibiotics may delay the diagnosis of some occult
infections)
Empiric glucocorticoids are also not indicated unless there is strong
clinical suspicion for a specific rheumatologic diagnosis
For patients whose condition is deteriorating, empiric therapeutic trials
of antibiotics, steroids, or antituberculous agents may be considered
Prognosis
Varies based on the aetiology of the fever and nature of the underlying
disease
Poorer prognosis: elderly patients and those diagnosed with
malignancy
Children without a discernible cause do better than adults
51% of FUO cases remain undiagnosed
Prognosis for these patients is generally good
Highly probable that FUO will spontaneously resolve in weeks to
months
In stable patients without a diagnosis, non-steroidal anti-inflammatory
drugs can be used for symptomatic management
QUESTIONS?