Fever of unknown origin

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:

• Drug fever
• Intravascular catheter-related infection
• Venous thromboembolism (DVT, pulmonary embolism)
• Clostridioides difficile colitis
• Inflammatory response to major surgery
• Occult abscess
• Transfusion reactions
• Sinusitis
• Candidemia (if critically ill)

Immunodeficiency-associated FUO ^[1]

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

• Opportunistic infections (e.g., candidiasis, aspergillosis, CMV infection)
• Drug fever (more common in neutropenic patients) ^[1]
• Malignancy
• In people living with HIV, also consider HIV-associated conditions (e.g., Pneumocystis pneumonia, MAC infection, Kaposi sarcoma) and immune reconstitution inflammatory syndrome.

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.
  • Document contact with animals, travel history, diet history, immunosuppression, family history, social and sexual history, occupational history, drugs and medications, implants, catheters, and grafts (see “Focused history” in “Fever”).
  • Conduct serial physical examinations (see “Focused examination” in “Fever” and “Differential diagnosis of fever by course”).
  • Consider discontinuing nonessential drugs to exclude drug fever.
• Order minimal initial diagnostics.
• Identify hallmarks or diagnostic clues.
  • See “Differential diagnoses of fever by risk factors.”
  • See “Differential diagnoses of fever by associated finding.”
  • Consult ophthalmology for fundoscopic evaluation. ^[3]
• 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

• Laboratory studies
  • CBC with differential (see “Differential diagnoses of fever by associated finding” and “Overview of WBC parameters”)
  • Acute phase reactants : erythrocyte sedimentation rate; (ESR) and C-reactive protein (CRP)
  • Liver chemistries
  • Serum electrolytes
  • LDH
  • Creatine kinase
  • Urinalysis and urine culture
  • Blood culture (three sets) if bacteremia is suspected ^[3][8]
• Imaging
  • X-ray or CT chest
  • Ultrasound or CT abdomen and pelvis

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.

Advanced diagnostics

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

• Additional nonspecific laboratory studies
  • Serum ferritin: Highly elevated levels are suggestive of a noninfectious etiology. ^[7][17]
  • Cryoglobulins: may be positive in patients with neoplastic disease, inflammatory disease, or viral infection
  • Cold agglutinins: elevated in certain infections (e.g., mycoplasma pneumonia, EBV, viral hepatitis), malignancy (e.g., lymphoma), or inflammatory disease
  • Uric acid: elevated levels are suggestive of malignancy
• Further serologic testing, e.g., for EBV infection, CMV infection, brucellosis, bartonellosis
• Serum protein electrophoresis ^[3]
  • Monoclonal gammopathy: e.g., multiple myeloma, Waldenstrom macroglobulinemia
  • Polyclonal gammopathy: e.g., HIV, malaria, SLE
• Advanced imaging studies
  • FDG-PET scan ^[18][19]
    • Consider for all patients without a diagnosis after initial diagnostics, especially those with elevated CRP and/or ESR. ^[7]
    • FDG uptake identifies tissues with high metabolic activity, indicating areas that warrant further investigation.
  • CT or MRI chest and abdomen: Consider if not already obtained, FDG-PET is unavailable, or FDG-PET indicates an intrathoracic or intraabdominal abnormality. ^[3][20]
  • Transesophageal echocardiogram (TEE): Consider for suspected bacterial endocarditis. ^[21][22]
• Invasive tests ^[2][23]
  • Lymph node biopsy ^[3]
    • Consider for patients with lymphadenopathy.
    • Posterior cervical, supra/infraclavicular, and epitrochlear nodes have the highest diagnostic yield.
    • Avoid anterior cervical, axillary, and inguinal node biopsies, as histological results are usually nondiagnostic.
  • Temporal artery biopsy: Consider in patients ≥ 55 years of age. ^[7][8]
  • Liver biopsy: Consider in patients with suspected hepatic involvement (e.g., those with altered liver enzymes or liver abnormalities on imaging studies). ^[7]
  • Bone marrow studies
    • Consider bone marrow biopsy if diagnostic clues for myeloproliferative or myelodysplastic disease are present (e.g., pancytopenia, atypical cells on peripheral blood smear). ^[7]
    • Consider bone marrow culture for suspected culture-negative bacterial endocarditis, miliary tuberculosis, or typhoid fever if it would alter the management. ^[3][12]
  • Diagnostic laparoscopy or laparotomy: rarely indicated unless a biopsy cannot be obtained using another modality ^[1][3]

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]

• Antipyretics and glucocorticoids can alter or mask specific features of certain conditions and should be largely avoided unless:
  • An infectious etiology and lymphoma have been ruled out
  • A potentially debilitating inflammatory etiology (e.g., giant cell arteritis) is suspected
  • The patient has significant cardiovascular comorbidities
• If antipyretics are needed, acetaminophen is preferred (see “Antipyretics” for dosages). ^[2]
• Empiric glucocorticoids should be initiated immediately if temporal arteritis is suspected.

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

• Avoid empiric antibiotic therapy in clinically stable and immunocompetent patients.
• Consider empiric antibiotics in the following special populations to prevent rapid deterioration:
  • Suspected miliary tuberculosis (e.g., FUO in immunosuppressed individuals): See “Treatment of tuberculosis.”
  • Suspected culture-negative infective endocarditis (e.g., prosthetic valve endocarditis): See “Empiric antibiotic therapy for infective endocarditis.”
  • Neutropenic FUO: See “Empiric antibiotic therapy for neutropenic fever.”
  • Nosocomial FUO: See “Postoperative fever” and “Nosocomial infections.”
  • HIV-associated FUO: See “HIV-associated conditions” and “HIV.”

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.

• Spontaneous remission of fever occurs in ∼ 40% of patients. ^[11]
• Mortality rate is ∼ 7% at 5 years (mostly due to malignancy, primarily non-Hodgkin lymphoma) ^[11][26]