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Approach to Fever of Unknown Origin

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Authors: Patrick Tierney, MD and Trushar Dungarani, DO

The approach to a patient presenting with fever of unknown origin (FUO) should include a comprehensive history, physical examination, and appropriate diagnostic testing.


A comprehensive history should include questions about:

  1. The fever itself (e.g. route of measurement, peak temperature, patterns, time of day, etc.)
  2. Systemic symptoms (e.g. weight loss, decreased appetite, rash, myalgias, arthralgias, etc.)
  3. Localized symptoms (e.g. cough, urinary symptoms, headache, abdominal pain, bone pain, etc.)
  4. Travel history, sick contacts, animal contacts, family history, and sexual history
  5. Potential causes of drug-induced fever: diuretics, pain relievers, salicylates, anti-arrhythmic agents, anti-seizure drugs, sedatives, antihistamines, barbiturates, cephalosporins, penicillins, sulfonamides

Physical Examination:

Laboratory Testing:

If the above laboratory work-up is negative, obtain a CT of chest, abdomen and pelvis with po/iv contrast. 

Further diagnostic testing:

A. If an infectious disease is suspected...

Second-Line Tests: TTE, sputum culture for AFB, HIV test, Hepatitis A, B, and C serologies, RPR, ASO titer, serology for CMV, EBV

Third-Line Tests: TEE, LP, Sinus CT, Gallium scan

B. If a non-hematologic malignancy is suspected...

Second-Line Tests: Mammography, Chest CT with contrast, Endoscopy, Bone Scan, Gallium Scan

Third-Line Tests: MRI of the brain, Lymph node biopsy, Skin lesion biopsy, Liver biopsy, Ex-Lap

C. If a hematologic malignancy is suspected...

Second-Line Tests: Peripheral smear, SPEP

Third-Line Tests: Bone marrow biopsy

D. If a rheumatologic disease is suspected...

Second-Line Tests: RF, ANA, cryoglobulin, ferritin

Third-Line Tests: Temporal artery biopsy, Lymph node biopsy

E. Venous Doppler studies should be obtained in relevant patients.

Keep in mind for some of these tests the false positive rate (which can lead to unnecessary investigations) can be similar to the rate of a helpful result.  One study± of 73 patients from the Netherlands seen between December 2003 and July 2005 found:

  • CXR: performed in 73 patients; helpful in 6 (8%) and false-positive in 8 (11%)
  • Chest CT: performed in 46 patients; helpful in 9 (20%) and false-positive in 8 (17%)
  • Abdominal CT: performed in 60 patients; helpful in 12 (20%) and false-positive in 17 (28%)
  • PET scan: performed in 70 patients; helpful in 23 (33%) and false-positive in 10 (14%)

Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore) 2007; 86:26.

Final Points:

  • Factitious fever should be considered in patients who have some medical training or experience and a fever persisting longer than six months
  • Failure to reach a definitive diagnosis of FUO occurs in up to 30% of cases
  • Patients for whom no definitive diagnosis is reached generally have a favorable outcome


Adapted from Roth (2003) Am Fam Physician 68:2223-8