Description

• Classic definition
  • Repeated fever >38.3°C
  • Fever duration at least 3 weeks
  • Diagnosis remains uncertain after 1 week of study in the hospital.
• The definition of fever of unknown origin (FUO) has evolved and is based on patient characteristics and presentation. The need for in-hospital evaluation has been eliminated in previously healthy people.
• Some expand the definition to include nosocomial, neutropenic (immunodeficient), and HIV-associated fevers.

Epidemiology

Incidence
The exact incidence is not known

Etiology and Pathophysiology

• >200 causes; each with prevalence of ≤5%
• Most commonly, FUO is an atypical presentation of a common condition.
• Spectrum of causes varies widely.
  • Noninfectious inflammatory diseases are the most frequent causes in high-income countries. Common causes include temporal arteritis, polymyalgia rheumatica, or rheumatoid arthritis.
• Infection
  • Abdominal or pelvic abscesses
  • Amebic hepatitis
  • Catheter infections
  • Cytomegalovirus
  • Dental abscesses
  • Endocarditis/pericarditis
  • HIV (advanced stage)
  • Mycobacterial infection (often with advanced HIV)
  • Osteomyelitis
  • Pyelonephritis or renal abscess
  • Sinusitis
  • Wound infections
  • Other miscellaneous infections
• Neoplasms
  • Atrial myxoma
  • Colorectal cancer and other GI malignancies
  • Hepatoma
  • Lymphoma
  • Leukemia
  • Solid tumors (renal cell carcinoma)
• Noninfectious inflammatory disease
  • Connective tissue diseases
    • Adult Still disease
    • Rheumatoid arthritis
    • Systemic lupus erythematosus
  • Granulomatous disease
    • Crohn disease
    • Sarcoidosis
  • Vasculitis syndromes
    • Giant cell arteritis
    • Polymyalgia rheumatica
• Other causes
  • Alcoholic hepatitis
  • Cerebrovascular accident
  • Cirrhosis
  • Medications
    • Allopurinol, captopril, carbamazepine, cephalosporins, cimetidine, clofibrate, erythromycin, heparin, hydralazine, hydrochlorothiazide, isoniazid, meperidine, methyldopa, nifedipine, nitrofurantoin, penicillin, phenytoin, procainamide, quinidine, sulfonamides
  • Endocrine disease
  • Factitious/fraudulent fever
  • Occupational causes
  • Periodic fever
  • Pulmonary emboli/deep vein thrombosis
  • Thermoregulatory disorders
• In up to 20–30% of cases, the cause of the fever is never identified despite a thorough workup.

Risk Factors

• Recent travel (malaria, enteric fevers)
• Exposure to biologic or chemical agents
• HIV infection (particularly in acute infection and advanced stages)
• Elderly
• Drug abuse
• Immigrants
• Young, (typically) female health care workers (factitious fever)

Geriatric Considerations
Common infectious causes of FUO in geriatric populations include intra-abdominal abscess, urinary tract infection, tuberculosis (TB), and endocarditis. Other common causes of FUO in patients >65 years include malignancies (particularly hematologic cancers) and drug-induced fever.

Pediatric Considerations

• ~50% of FUO in pediatric cases are infectious. Collagen vascular disease and malignancy are the next most common.
• Inflammatory bowel disease is a common cause of FUO in older children and adolescents.