What are key features of fever of unknown origin (FUO)?

Updated: May 17, 2021
  • Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD  more...
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Key features of fever of unknown origin (FUO), also known as pyrexia of unknown origin (PUO), are as follows:

  • Unexplained fevers are worrisome to patients and clinicians, but most persistent fevers are diagnosed, and often within one week of hospital evaluation or 3 outpatient visits.
  • Most fevers that persist beyond this period are caused by common conditions presenting uncommonly.
  • The upper limit of normal temperature in healthy outpatients and nonsurgical inpatients is 99.9º Fahrenheit (F) or 39º Celsius (C).
  • Hundreds of conditions may cause FUO. Although infections remain a significant cause, most FUOs in the developed world are caused by noninfectious inflammatory disorders, with malignancy a much smaller percentage. Infection is likely to evolve with increased global travel and the use of immunomodulating drugs.
  • The differential diagnoses of FUO depend on and continue to evolve based on regional factors, exposures, and available diagnostic tools.
  • A significant percentage of FUO cases are caused by miscellaneous conditions, and there is no standard algorithm for evaluating FUO. The approach to diagnostic study is best guided by ongoing assessment for historical, physical, and basic laboratory clues. Following clues, beginning with the least invasive evaluation, avoids unnecessary harm and cost to the patient.
  • Physical examination in FUO should pay special attention to skin, eyes, lymph nodes, liver, and spleen.
  • It is reassuring that most cases of FUO that remain undiagnosed despite intensive evaluations have good long-term prognoses and resolve within a year.
  • Historically, about 25-30% of cases remained undiagnosed despite extensive workup. A prospective multicenter study of cases from 2003 to 2005 in the Netherlands reported 51% of cases without a final diagnosis. [1]  A systematic review of 18 papers published from 2005 to 2015 from regions across the globe found a lack of diagnostic outcome in 23%. [2]  In light of considerable advances in diagnostics, this number seems surprisingly high and consistent. 

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