Description

• Classic definition
  • Repeated fever >38.3°C
  • Fever duration at least 3 weeks
  • Diagnosis remains uncertain (1) after 1 week of study in the hospital.
• In over 50% of cases, no etiology is determined. The three most common underlying mechanisms for fever of unknown origin (FUO) are infection, malignancy, and systemic rheumatic or connective tissue diseases (2).

Epidemiology

Incidence
The exact incidence is not known.

Prevalence
The definition of fever with unresolved cause (true FUO) is difficult, as it is a moving target, given the constant advancement of imaging and biomarker analysis. Therefore, the prevalence of fever of unknown origin is unknown.

Etiology and Pathophysiology

• True FUO are uncommon; most frequently, 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 systemic rheumatic diseases (polymyalgia rheumatica, giant cell arteritis), sarcoidosis, 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

• One-third are self-limited undefined viral syndromes. ~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.