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Fever of unknown origin

Last updated: October 19, 2021

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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.

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]

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:

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
Infection
Inflammatory disease
Malignancy
Miscellaneous Subacute thyroiditis
Thromboembolic disease

Cirrhosis

Sarcoidosis
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.

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.

Prognosis depends on the underlying cause.

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