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Fever of unknown origin 

Fever of unknown origin

Fever of unknown origin

Steven Vanderschueren

and Daniël Knockaert


July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.


HIV serology should be a routine investigation.

Allergy testing sometimes used to confirm drug fever/reactions.

Minor editorial amendments.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 24 April 2017

Fever of unknown origin (FUO) refers to a prolonged febrile illness that persists without diagnosis after careful initial assessment. Although over 200 causes have been described, including rare diseases, most cases are due to familiar entities presenting in an atypical fashion.

Causes of FUO—The ‘big three’ are (1) infections—including tuberculosis, endocarditis, abdominal and hepatobiliary infections and abscesses, complicated genitourinary tract infections, pleuropulmonary infections, bone and joint infections, salmonellosis, cytomegalovirus, Epstein–Barr virus and HIV; (2) tumours—including lymphoma; and (3) multisystem inflammatory conditions—including connective tissue diseases, vasculitic syndromes and granulomatous disorders. A miscellaneous category including factitious fever, habitual hyperthermia, and drug fever deserves consideration early in a patient’s workup, since timely recognition may avert invasive and expensive procedures.

Clinical approach to the patient with FUO—The clinician must rely on a very careful and thorough clinical history and examination that does not neglect any part of the body, followed by appropriately targeted investigations directed by knowledge of the broad spectrum of diseases and local epidemiology. As advocated by Sutton’s law—‘go where the money is’—the approach should follow any possible diagnostic clues, which may sometimes be subtle. If clues are absent or prove misleading, then screening imaging techniques can focus further investigation, but a rigid algorithm and a blind pursuit of increasingly complex tests are ill-advised. Likewise, therapeutic trials without firm foundation are rarely diagnostically rewarding. If the diagnosis in a stable patient remains elusive despite vigorous effort, a watchful waiting approach is warranted as most patients with fever of persistently unknown origin do well.

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