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Fever of Unknown Origin (FUO)
1. DR. JUAN CARLOS BECERRA MARTÍNEZ
CÁTEDRA DE MEDICINA INTERNA-MC3087
TECNOLÓGICO DE MONTERREY, CAMPUS GUADALAJARA
2. 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.
3. Definition and Classification
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.
Harrison’s 18th Ed.
4. Definition and Classification
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.
Harrison’s 18th Ed.
5. Definition and Classification
Neutropenic FUO:
Temperature >38.3°C
Neutrophil count <500/ml
3 days of investigation
2 days’ incubation of cultures
Harrison’s 18th Ed.
6. Definition and Classification
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.
Harrison’s 18th Ed.
8. 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
Harrison’s 18th Ed.
9. Classic FUO in Adults
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.
Harrison’s 18th Ed.
12. Classic FUO in Adults
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.
Harrison’s 18th Ed.
13. Classic FUO in Adults
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.
Harrison’s 18th Ed.
17. Classic FUO in Adults
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
Harrison’s 18th Ed.
18. Classic FUO in Adults
It is axiomatic that, as the duration of fever
increases, the likelihood of an infectious cause
decreases.
Harrison’s 18th Ed.
20. 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.
Harrison’s 18th Ed.
21. 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.
Harrison’s 18th Ed.
22. 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
Harrison’s 18th Ed.
23. 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.
Harrison’s 18th Ed.