Fever of unknown origin

Last updated: September 15, 2023

Summarytoggle arrow icon

Fever of unknown origin (FUO) is defined as a temperature of > 38.3°C (100.9°F) lasting for > 3 weeks with no clear etiology despite appropriate diagnostics. Infections, malignancy, and inflammatory or rheumatic conditions are the most frequent etiologies of FUO. The initial diagnostic approach to FUO should focus on a comprehensive history and physical examination with minimal initial diagnostics to identify diagnostic clues that can guide targeted diagnostics. If the diagnosis remains unknown, additional laboratory studies (e.g., serology, electrophoresis) and advanced diagnostics (e.g., PET-CT, tissue biopsy) should be considered. In a significant number of patients, the underlying etiology remains undiagnosed. Antipyretics and empiric therapy (e.g., antibiotics, glucocorticoids) should be avoided, if feasible, to prevent masking clinical findings and delaying the diagnosis even further. However, if a life-threatening or serious underlying condition (e.g., neutropenic fever, miliary tuberculosis, giant cell arteritis) is suspected, empiric therapy should be considered. The prognosis of FUO depends on the underlying cause and spontaneous remission can occur in up to 40% of patients.

Fever” and “Neutropenic fever” are covered in detail separately.

Definitiontoggle arrow icon

Definitions of FUO vary in literature. Some authors exclude immunocompromised patients from the FUO definition because the approach to diagnosis and treatment is markedly different from that for immunocompetent patients.

  • Classic FUO: temperature of > 38.3°C (100.9°F) recorded on multiple occasions that lasts for > 3 weeks with no clear etiology despite investigations on 3 outpatient visits, 3 days in the hospital, or 1 week of invasive ambulatory investigation
  • Nonclassic FUO is characterized by temperature > 38.3°C recorded on multiple occasions with no clear etiology after at least 2 days of culture incubation in addition the following specific features:
    • Neutropenic FUO (immunodeficient FUO): neutrophil count of < 500/mm3 or an anticipated fall in neutrophil count to < 500/mm3 within 1–2 days
    • HIV-associated FUO: fever that lasts for > 4 weeks (or > 3 days if hospitalized) in a patient with HIV
    • Nosocomial FUO: fever that lasts for > 3 days in a hospitalized patient who was afebrile on admission

References: [1][2]

Etiologytoggle arrow icon

Although there are hundreds of possible etiologies of FUO, an atypical presentation of a common condition is often accountable.

Classic FUO [1][3]

  • Most etiologies of classic FUO can be grouped into four major categories:
    • Infection
    • Inflammatory (e.g., rheumatic conditions, autoimmune conditions)
    • Malignancy
    • Miscellaneous
  • In 7–51% of cases, the underlying etiology remains undiagnosed.

In recent years, the frequency of infectious and miscellaneous causes of FUO has decreased in high-income countries, whereas the frequency of inflammatory diseases has increased. [1][4]

Healthcare-associated FUO [1]

In addition to the common causes of fever, consider the following in this group of patients:

Immunodeficiency-associated FUO [1]

In addition to the common causes of fever, consider the following in this group of patients:

Diagnosticstoggle arrow icon

Approach [1][4][7][8][9]

The evaluation of a patient with FUO should proceed in a stepwise fashion, guided by diagnostic clues obtained from the history and physical examination.

  • Perform a comprehensive clinical evaluation.
  • Order minimal initial diagnostics.
  • Identify hallmarks or diagnostic clues.
  • Diagnosis evident: Order appropriate diagnostic tests (see “Targeted testing based on diagnostic clues” below).
  • Etiology remains undiagnosed (FUO confirmed)
    • Consider the naproxen test to differentiate between an infectious etiology and an underlying malignancy.
      • Administer naproxen for 3 days.
      • Resolution of the fever with naproxen indicates that a malignant etiology is likely. [3]
    • Consider measuring procalcitonin levels to distinguish between a bacterial infection and a noninfectious inflammatory condition. [10]
  • Diagnosis remains unknown
    • Perform serial physical examinations and chart review
    • Order advanced tests (e.g., PET CT, biopsies) until a diagnostic endpoint is reached or the fever resolves. [11]

The majority of patients with FUO present with atypical symptoms of a common disease rather than common symptoms of a rare disease. [4]

Consider the possibility of factitious fever, especially in medical personnel. [3]

Initial diagnostics [1][2][3][7][12]

Minimum diagnostic workup

Additional diagnostics

The identification of diagnostic clues and/or hallmark features on initial clinical and diagnostic evaluation should guide a selective approach to diagnostic studies.

Targeted testing based on diagnostic clues [1][2][3][9]
Category Diagnostic clues Suggested testing
Inflammatory disease
Miscellaneous Subacute thyroiditis
Thromboembolic disease


Drug fever
  • Stop nonessential drugs.
  • Fever usually resolves within 72 hours of stopping the drug [12]
Familial Mediterranean fever [16]

Advanced diagnostics

If the underlying etiology remains undiagnosed despite initial diagnostics, advanced diagnostics to evaluate for less common causes of FUO should be performed.

Treatmenttoggle arrow icon

General principles [1][4][24]

  • Avoid antipyretics if feasible.
  • Avoid empiric therapy (e.g., antibiotics, glucocorticoids) unless there is rapid clinical deterioration or if a life-threatening etiology is suspected.
  • If the underlying etiology remains undiagnosed and FUO persists despite advanced diagnostics:
    • Specialist consultation (e.g., infectious diseases, rheumatology, oncology, and/or hematology) is advised.
    • Consider a trial of anakinra in patients with a suspected autoinflammatory condition and rapid clinical deterioration. [4][25]
  • Once a likely cause has been identified, manage accordingly (see dedicated articles for details).

An infectious etiology is less likely in FUO of prolonged duration.

Role of antipyretics and glucocorticoids [2][3]

Role of empiric antibiotic therapy [1][3][24]

Empiric therapy should only be considered in patients with rapid clinical deterioration, neutropenic fever, giant cell arteritis, or suspected life-threatening underlying etiology (e.g., miliary tuberculosis). [24]

Neutropenic fever is a medical emergency because of the impaired neutrophil-mediated inflammatory response to bacterial infections. Initiate empiric antibiotic therapy immediately after drawing blood and urine cultures.

Prognosistoggle arrow icon

Prognosis depends on the underlying cause.

Referencestoggle arrow icon

  1. Wright WF, Auwaerter PG. Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma. Open Forum Infect Dis. 2020; 7 (5).doi: 10.1093/ofid/ofaa132 . | Open in Read by QxMD
  2. Hersch EC, Oh RC. Prolonged febrile illness and fever of unknown origin in adults. Am Fam Physician. 2014; 90 (2): p.91-6.
  3. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, et al. A Prospective Multicenter Study on Fever of Unknown Origin. Medicine. 2007; 86 (1): p.26-38.doi: 10.1097/md.0b013e31802fe858 . | Open in Read by QxMD
  4. Mulders-Manders C, Simon A, Bleeker-Rovers C. Fever of unknown origin. Clin Med. 2015; 15 (3): p.280-4.doi: 10.7861/clinmedicine.15-3-280 . | Open in Read by QxMD
  5. Roth AR, Basello GM. Approach to the Adult Patient with Fever of Unknown Origin. Am Fam Physician. 2003; 68 (11): p.2223-2229.
  6. Cunha BA, Lortholary O, Cunha CB. Fever of Unknown Origin: A Clinical Approach. Am J Med. 2015; 128 (10): p.1138.e1-1138.e15.doi: 10.1016/j.amjmed.2015.06.001 . | Open in Read by QxMD
  7. Schüttrumpf S, Binder L, Hagemann T, Berkovic D, Trümper L, Binder C. Procalcitonin: a useful discriminator between febrile conditions of different origin in hemato-oncological patients?. Ann Hematol. 2003; 82 (2): p.98-103.doi: 10.1007/s00277-002-0584-y . | Open in Read by QxMD
  8. Mulders-Manders CM, Engwerda C, Simon A, van der Meer JWM, Bleeker-Rovers CP. Long-term prognosis, treatment, and outcome of patients with fever of unknown origin in whom no diagnosis was made despite extensive investigation. Medicine. 2018; 97 (25): p.e11241.doi: 10.1097/md.0000000000011241 . | Open in Read by QxMD
  9. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  10. Mourad O, Palda V, Detsky AS. A Comprehensive Evidence-Based Approach to Fever of Unknown Origin. Arch Intern Med. 2003; 163 (5): p.545.doi: 10.1001/archinte.163.5.545 . | Open in Read by QxMD
  11. Ziaj S, Mitchell C, Roufosse C, Dubrey S. Occult microscopic polyangiitis presenting as pyrexia of unknown origin. Br J Hosp Med. 2014; 75 (3): p.172-173.doi: 10.12968/hmed.2014.75.3.172 . | Open in Read by QxMD
  12. Yosipovitch G. Chronic pruritus: a paraneoplastic sign. Dermatol Ther. 2010; 23 (6): p.590-596.doi: 10.1111/j.1529-8019.2010.01366.x . | Open in Read by QxMD
  13. Schwartz RA, Nervi SJ. Erythema nodosum: A sign of systemic disease. Am Fam Physician. 2007; 75 (5): p.695-700.
  14. Zadeh N, Getzug T, Grody WW. Diagnosis and management of familial Mediterranean fever: Integrating medical genetics in a dedicated interdisciplinary clinic. Genetics in Medicine. 2011; 13 (3): p.263-269.doi: 10.1097/gim.0b013e31820e27b1 . | Open in Read by QxMD
  15. Kim SE, Kim UJ, Jang MO, et al. Diagnostic Use of Serum Ferritin Levels to Differentiate Infectious and Noninfectious Diseases in Patients with Fever of Unknown Origin. Dis Markers. 2013; 34 (3): p.211-218.doi: 10.1155/2013/915389 . | Open in Read by QxMD
  16. Takeuchi M, Dahabreh IJ, Nihashi T, Iwata M, Varghese GM, Terasawa T. Nuclear Imaging for Classic Fever of Unknown Origin: Meta-Analysis. J Nucl Med. 2016; 57 (12): p.1913-1919.doi: 10.2967/jnumed.116.174391 . | Open in Read by QxMD
  17. Kotsiri I, Panotopoulos C, Magiorkinis E. The Role of PET/CT in the Investigation of Fever of Unknown Origin. J Adv Med Med Res. 2020: p.71-82.doi: 10.9734/jammr/2020/v32i530417 . | Open in Read by QxMD
  18. Kaya A, Ergul N, Kaya SY et al. The management and the diagnosis of fever of unknown origin. Expert Rev Anti Infect Ther. 2014; 11 (8): p.805-815.doi: 10.1586/14787210.2013.814436 . | Open in Read by QxMD
  19. Sekar P, Johnson JR, Thurn JR, et al. Comparative Sensitivity of Transthoracic and Transesophageal Echocardiography in Diagnosis of Infective Endocarditis Among Veterans With Staphylococcus aureus Bacteremia. Open Forum Infect Dis. 2017; 4 (2).doi: 10.1093/ofid/ofx035 . | Open in Read by QxMD
  20. Reynolds HR, Jagen MA, Tunick PA, Kronzon I. Sensitivity of transthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era. Journal of the American Society of Echocardiography. 2003; 16 (1): p.67-70.doi: 10.1067/mje.2003.43 . | Open in Read by QxMD
  21. De Kleijn EMHA, van Lier HJJ, van der Meer JWM. Fever of unknown origin (FUO): II. Diagnostic procedures in a prospective multicenter study of 167 patients. Medicine. 1997; 76 (6): p.401-414.doi: 10.1097/00005792-199711000-00003 . | Open in Read by QxMD
  22. Sipahi OR, Senol S, Arsu G, et al. Pooled analysis of 857 published adult fever of unknown origin cases in Turkey between 1990-2006. Med Sci Monit. 2007; 13 (7): p.CR318-22.
  23. Foggo V, Cavenagh J. Malignant causes of fever of unknown origin. Clin Med. 2015; 15 (3): p.292-4.doi: 10.7861/clinmedicine.15-3-292 . | Open in Read by QxMD
  24. Bryan CS, Ahuja D. Fever of Unknown Origin: Is There a Role for Empiric Therapy?. Infect Dis Clin North Am. 2007; 21 (4): p.1213-1220.doi: 10.1016/j.idc.2007.08.007 . | Open in Read by QxMD
  25. Harrison SR, McGonagle D, Nizam S, et al. Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology. JCI insight. 2016; 1 (6): p.e86336.doi: 10.1172/jci.insight.86336 . | Open in Read by QxMD
  26. Vanderschueren S, Eyckmans T, De Munter P, Knockaert D. Mortality in patients presenting with fever of unknown origin. Acta Clin Belg. 2014; 69 (1): p.12-16.doi: 10.1179/0001551213z.0000000005 . | Open in Read by QxMD

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