Fever of Unknown Origin (FUO)



  • 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
  • In >50% of cases, no etiology is determined. The three most common underlying mechanisms for FUO are infection, malignancy, and systemic rheumatic or connective tissue diseases (2).


The exact incidence is not known.

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)
  • 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

  • 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.

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