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.
• Categories of fever of unknown origin (FUO): infection, neoplasia, inflammatory (rheumatologic or connective tissue disease), miscellaneous disease, and undiagnosed illness
• Often an atypical presentation of a common disease versus a rare disease; 75% of cases resolve without reaching a definitive diagnosis.

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 FUO 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.
  • Higher percentage of infectious causes in developing countries compared to developed countries
  • Although infection is the most common cause of FUO in developed countries, there is a higher incidence of noninfectious inflammatory disease when compared to developing countries.
• 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
    • Medication reactions include hypersensitivity, serotonin syndrome, adrenergic fever, neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic fever, DRESS syndrome, chemotherapy/infusion-related reaction, and mitochondrial uncoupling (pesticides/toxins) (1).
  • 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, tick-borne illness)
• 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
In geriatric populations aged >65 years, noninfectious multisystem diseases, such as polymyalgia rheumatica, giant cell arteritis, and other vasculitides have a higher incidence than infection. Common infectious causes in the elderly are intra-abdominal abscess, urinary tract infections, tuberculosis (TB), and endocarditis. Other common causes of FUO in patients aged >65 years include malignancies (particularly hematologic cancers) and drug-induced fever.

Pediatric Considerations

• 1/3 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.