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Chapter 191. Fever of Unknown Origin

David A. Oxman, MD

  1. What are the major categories of fever of unknown origin (FUO)?

  2. What basic tests should be done in evaluating patients with FUO?

  3. When is more specific laboratory testing or diagnostic imaging indicated?

  4. Which patients should receive empiric therapy?

  5. What is the prognosis of FUO?

The classic definition of fever of unknown origin (FUO) by Petersdorf and Beeson in 1961 was a fever greater than 38.3°C (101°F) on several occasions, persisting without diagnosis for at least 3 weeks, in spite of 1 week's investigation in hospital. In the 50 years since, medical practice has changed substantially, and much of the diagnostic evaluation for FUO can be accomplished on an outpatient basis. One proposed revision of the classic definition of FUO defines it as a febrile illness that has not been diagnosed after at least three outpatient visits or 3 days of hospitalization (Table 191-1). In practice, while an exact definition is difficult, FUO can be thought of as a persistent febrile illness that has eluded diagnosis despite a thorough history, physical examination, and routine diagnostic testing. Additionally, several specific categories of FUO have been proposed, including nosocomial FUO, HIV-related FUO, and FUO in the returning traveler. Over 200 different causes of FUO have been reported, but all etiologies fall into four broad groups: infectious, neoplastic, rheumatologic, and miscellaneous. The incidence of each etiology will vary with different patient populations and geographic locations.

Table 191-1 Contemporary Definitions of Fever of Unknown Origin (FUO)
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Table 191-1 Contemporary Definitions of Fever of Unknown Origin (FUO)
Type of FUODefinitionCommon Causes
Modified “classic” FUO
  • Fever ≥ 38.3°C (101°F) on several occasions for at least 3 weeks
  • No diagnosis after 3 days of hospitalization or three outpatient visits
  • Infection, malignancy, vasculitis and other rheumatological conditions, drug fever
  • In elderly patients in developed countries, often neoplastic; in young patients, often no diagnosis
Nosocomial FUO
  • Hospitalized patients with fever ≥ 38.3°C (101°F) on several occasions
  • Fever not present or incubating at admission
  • Diagnosis uncertain after 3 days of appropriate investigations, including 48 hours of incubating cultures
  • Clostridium difficile enterocolitis, pneumonia, infection of central line and other devices, candidemia, urosepsis, acalculous cholecystitis, drug fever, thromboembolism, sinusitis, gout, pseudogout, central fever, stroke, myocardial infarction
  • Dressler syndrome, malignant hyperthermia
Neutropenic FUO
  • Fever ≥ 38.3°C (101°F) on several occasions in a patient with an absolute neutrophil count of < 500/mm3
  • Diagnosis uncertain after 3 days of appropriate investigations, including 48 hours of incubating cultures
Pneumonia, central line sepsis, Clostridium difficile enterocolitis, mucositis, cellulitis, aspergillosis, candidiasis, fusariosis, herpes simplex virus, neutropenic enterocolitis (typhlitis)
HIV-related FUO
  • Patient with HIV infection and fever ≥ 38.3°C (101°F) on several occasions
  • Duration of at least 4 weeks in outpatients or 3 days in inpatients
  • Diagnosis uncertain after 3 days of appropriate investigations, including 48 hours of incubating cultures
  • Usually infectious, especially in patients not taking highly active antiretroviral therapy (HAART)
  • Most common cause worldwide is ...

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