Description

• Classic definition
  • Repeated fever >38.3°C (>100.9°F)
  • Fever duration >3 weeks in adults or ≥8 days among children.
  • Diagnosis remains uncertain despite thorough inpatient or outpatient evaluation (1).
• Categories of fever of unknown origin (FUO): infection, malignancy, noninfectious inflammatory diseases (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

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-associated infections
  • Dental abscesses
  • Endocarditis/pericarditis
  • HIV (acute and/or advanced stage)
  • Mycobacterial infection (often with advanced HIV)
  • Osteomyelitis
  • Prostatitis
  • Pyelonephritis or renal abscess
  • Sinusitis
  • Tuberculosis
  • Other pathogens (brucellosis, cytomegalovirus, disseminated fungal infections, enteric fever, Epstein-Barr virus, malaria, toxoplasmosis)
  • Wound infections
  • Other miscellaneous infections
• Neoplasms
  • Atrial myxoma
  • Colorectal cancer and other GI malignancies
  • Hepatoma
  • Lymphoproliferative diseases (e.g., lymphoma; leukemia)
  • Myelodysplastic syndromes
  • Multiple myeloma
  • Solid tumors (e.g., renal cell carcinoma, neuroblastoma, sarcomas)
• Noninfectious inflammatory disease
  • Autoimmune/connective tissue diseases
    • Adult still disease
    • Juvenile idiopathic arthritis (JIA)
    • Rheumatoid arthritis
    • Systemic lupus erythematosus
  • Granulomatous disease
    • Crohn disease
    • Granulomatosis with polyangiitis (GPA)
    • Sarcoidosis
  • Vasculitis syndromes
    • Antiphospholipid syndrome
    • Giant cell arteritis
    • Kawasaki disease
    • Panarteritis nodosa (PAN)
    • Polymyalgia rheumatica
• Other causes
  • Alcoholic hepatitis
  • Castleman syndrome
  • 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, mitochondrial uncoupling (pesticides/toxins) (1).
  • Endocrine disease
  • Familial Mediterranean fever
  • Factitious/fraudulent fever
  • Occupational causes
  • Periodic fever
  • Pulmonary emboli/deep vein thrombosis
  • Sarcoidosis
  • Thermoregulatory disorders
  • Thyroid disease
• In up to 20–30% of cases, the cause of the fever is never identified despite a thorough workup.

Risk Factors

• Travel (e.g., malaria, enteric fevers, tick-borne illness) and immigration
• Exposure to biologic or chemical agents
• HIV infection (particularly in acute infection and advanced stages)
• Elderly
• History of substance use,

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, 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. 1/2 of FUO in pediatric cases are infectious. Collagen vascular disease and malignancy are the next most common. Inflammatory bowel disease is a more common cause of FUO in older children and adolescents.
• If the child is well-appearing, outpatient observation with serial evaluations and monitoring is reasonable.
• In ill-appearing children, admission in indicated for closer monitoring, expedited evaluation, and supportive therapies.