Fever of Unknown Origin (FUO)

DR. JUAN CARLOS BECERRA MARTÍNEZ
CÁTEDRA DE MEDICINA INTERNA-MC3087
TECNOLÓGICO DE MONTERREY, CAMPUS GUADALAJARA

Definition and Classification
 Fever of unknown origin (FUO):
 Was defined by Petersdorf and Beeson in 1961 as:
○ 1.- Temperatures of >38.3°C
○ 2.- A duration of fever of >3 weeks
○ 3.- Failure to reach a diagnosis despite 1 week of inpatient
investigation.
 Durack and Street have proposed a revised
classification:
 1.- Classic FUO
 2.- Nosocomial FUO
 3.- Neutropenic FUO
 4.- FUO associated with HIV infection.
Harrison’s 18th Ed.

 Classic FUO:
 This newer definition is broader, stipulating
three outpatient visits or 3 days in the hospital
without elucidation of a cause or 1 week of
"intelligent and invasive" ambulatory
investigation.

 Nosocomial FUO:
 Fever >38.3°C develops on several occasions in
a hospitalized patient who is receiving acute care
and in whom infection was not manifest on
admission.
 3 days of investigation and including at least 2
days’ incubation of cultures.

 Neutropenic FUO:
 Temperature >38.3°C
 Neutrophil count <500/ml
 3 days of investigation
 2 days’ incubation of cultures

 HIV-associated FUO:
 Fever >38.3°C
 >4 weeks for outpatients or >3 days for
hospitalized patients
 HIV infection
 Appropriate investigation over 3 days, including 2
days’ incubation of cultures.

Classic FUO in Adults

 Infections:
 Is the #1 cause of Classic FUO
 Tuberculosis, typhoid fever and malaria remain a leading diagnosable cause
of FUO.
 Others:
○ CMV, EBV, HIV
○ Intraabdominal abscesses
○ Osteomyelitis
○ Endocarditis
○ Prostatitis, dental abscesses, sinusitis, and cholangitis
○ Fungal diseases: histoplasmosis, paracoccidioidomycosis and
coccidioidomycosis
○ Chikungunya virus
○ Cryptococcus neoformans
○ Plasmodium
○ Babesiosis

 Neoplasms:
 Are the next most common cause of FUO after
infections
 Noninfectious inflammatory diseases:
 Systemic rheumatologic or vasculitic diseases:
○ Polymyalgia rheumatica, lupus, and adult Still's disease
 Granulomatous diseases:
○ Sarcoidosis, Crohn's disease, and granulomatous
hepatitis.

 Classic FUO in the elderly (>50 years):
 Giant-cell arteritis is the leading etiologic entity in this
category (15–20% of FUO cases)
 Tuberculosis is the most common infection causing
FUO in the elderly
 Colon cancer is an important cause of FUO with
malignancy in this age group.

 Miscellaneous causes:
 Drug fever
 Pulmonary embolism
 Factitious fever
 The hereditary periodic fever síndromes:
○ Familial Mediterranean fever
○ Hyper-IgD syndrome,
○ TNF receptor–associated periodic syndrome (also known as
TRAPS or familial Hibernian fever)
○ Familial cold urticaria
○ Muckle-Wells síndrome
 Congenital lysosomal storage diseases:
○ Gaucher's and Fabry's disease.

 Drug-related etiology:
 Virtually all classes of drugs can cause fever:
○ Antimicrobial agents (b-lactam antibiotics)
○ Cardiovascular drugs (quinidine)
○ Antineoplastic drugs
○ Drugs acting on the central nervous system: phenytoin

 It is axiomatic that, as the duration of fever
increases, the likelihood of an infectious cause
decreases.

Approach to
the
patient with
classic FUOAbbreviations: ANA, antinuclear antibody;
CBC, complete blood count; CMV,
cytomegalovirus; CRP, C-reactive protein;
CT, computed tomography; Diff,
differential; EBV, Epstein-Barr virus; ESR,
erythrocyte sedimentation rate; FDG,
fluorodeoxyglucose F18; NSAIDs,
nonsteroidal anti-inflammatory drugs;
PET, positron emission tomography;
PMN, polymorphonuclear leukocyte;
PPD, purified protein derivative; RF,
rheumatoid factor; SPEP, serum protein
electrophoresis; TB, tuberculosis; TIBC,
total iron-binding capacity; VDRL,
Venereal Disease Research Laboratory
test.

Nosocomial FUO
 More than 50% of patients with nosocomial FUO are infected:
 Intravascular lines, septic phlebitis, and prostheses.
 The best approach is to focus on sites where occult infections may be
sequestered:
 The sinuses of intubated patients or a prostatic abscess in a man with a urinary
catheter.
 Clostridium difficile colitis.
 In <25% of patients the fever has a noninfectious cause:
 Acalculous cholecystitis, deep-vein thrombophlebitis, and pulmonary embolism.
 Others: Drug fever, transfusion reactions, alcohol/drug withdrawal,
adrenal insufficiency, thyroiditis, pancreatitis, gout.

Nosocomial FUO
 Multiple blood, wound, and fluid cultures are
mandatory.
 20% of cases of nosocomial FUO may go
undiagnosed.
 In many hospital settings, empirical antibiotic therapy
for nosocomial FUO now includes vancomycin for
coverage of S. Aureus as well as broad-spectrum
gram-negative coverage with piperacillin/tazobactam,
ticarcillin/clavulanate, imipenem, or meropenem.

Neutropenic FUO
 Neutropenic patients are susceptible to focal bacterial and fungal
infections:
 Bacteremic infections,
 Infections involving catheters
 Perianal infections.
 Candida and Aspergillus infections are common. Others: Herpes
simplex virus or CMV
 50–60% of febrile neutropenic patients are infected, and 20% are
bacteremic.
 The IDSA dictates the use of vancomycin plus ceftazidime,
cefepime, or a carbapenem with or without an aminoglycoside to
provide empirical coverage for bacterial sepsis

HIV-Associated FUO
 HIV infection alone may be a cause of fever.
 Mycobacterium avium or M. intracellulare, tuberculosis, toxoplasmosis,
CMV infection, Pneumocystis infection, salmonellosis, cryptococcosis,
histoplasmosis, strongyloidiasis
 Non-Hodgkin's lymphoma
 Of particular importance drug fever are all possible causes of FUO.
 Blood cultures and by liver, bone marrow, and lymph node biopsies.
Chest CT should be performed to identify enlarged mediastinal nodes.
 FUO has an infectious etiology in >80% of HIV-infected patients.

Fever of Unknown Origin (FUO)

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