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Am Fam Physician. 2022;105(2):137-143

Patient information: See related handout on fever of unknown origin in adults, written by the authors of this article.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Fever of unknown origin is defined as a clinically documented temperature of 101°F or higher on several occasions, coupled with an unrevealing diagnostic workup. The differential diagnosis is broad but is typically categorized as infection, malignancy, noninfectious inflammatory disease, or miscellaneous. Most cases in adults occur because of uncommon presentations of common diseases, and up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis. In the absence of localizing signs and symptoms, the workup should begin with a comprehensive history and physical examination to help narrow potential etiologies. Initial testing should include an evaluation for infectious etiologies, malignancies, inflammatory diseases, and miscellaneous causes such as venous thromboembolism and thyroiditis. If erythrocyte sedimentation rate or C-reactive protein levels are elevated and a diagnosis has not been made after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. Depending on clinical indications, this may include liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy. Empiric antimicrobial therapy has not been shown to be effective in the treatment of fever of unknown origin and therefore should be avoided except in patients who are neutropenic, immunocompromised, or critically ill.

Fever of unknown origin (FUO) in adults poses one of the greatest diagnostic challenges in medicine. For a large proportion of patients presenting with FUO in higher-income countries, a cause is never identified, and many cases are due to atypical presentations of common illnesses rather than rare disorders.1,2 The lack of a standard diagnostic workup leads to frustration for physicians and patients, and numerous noninvasive and invasive procedures are often performed without arriving at a definitive diagnosis.1,3 Currently, the most widely accepted definition of FUO requires only a clinically documented temperature of 101°F (38.3°C) or higher on several occasions and an unrevealing diagnostic workup.2,4 Previous definitions have provided suggested minimal time frames for investigation; however, these were acknowledged to be arbitrary and are not included in the current consensus definition.2,4

Clinical recommendationEvidence ratingComments
A comprehensive history and physical examination should be completed if no localizing signs and symptoms occur in patients with a prolonged febrile illness.79 CExpert opinion and consensus guidelines in the absence of clinical trials
In patients with a prolonged febrile illness, a minimum diagnostic workup should be performed before classifying the disease process as a fever of unknown origin.8 CExpert opinion and consensus guidelines in the absence of clinical trials
Erythrocyte sedimentation rate and C-reactive protein level should be measured in the initial workup of a patient who has a prolonged febrile illness without a clear source.1,14 CExpert opinion and consensus guidelines in the absence of clinical trials
In patients who have a fever of unknown origin with elevated inflammatory markers who have not received a diagnosis after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis.29 BMeta-analysis of one prospective study and 15 retrospective studies
If noninvasive diagnostic tests are unrevealing, tissue biopsy should be ordered because of the relatively high diagnostic yield; depending on clinical clues, this may include liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy.3134 BInconsistent cohort studies
Empiric antimicrobial therapy should be avoided except in neutropenic, immunocompromised, and/or critically ill patients.38,39 CExpert opinion and consensus guidelines in the absence of clinical trials

Differential Diagnosis

Common causes of FUO include infections, malignancies, noninfectious inflammatory disease (e.g., vasculitides, granulomatous disease, connective tissue diseases), miscellaneous, and undiagnosed2,4,5 (Table 16). Lower-income countries typically have higher rates of infection and malignancy as causes of FUO. Noninfectious inflammatory diseases and undiagnosed cases typically predominate in higher-income countries, most likely because of access to advanced imaging that can enable tumor detection.1,2,5

SubgroupCauses
Infection (20% to 40%)Bacterial
 Abdominal or pelvic abscesses
 Dental abscesses
 Endocarditis
 Sinusitis
 Tuberculosis (especially extrapulmonary/disseminated)
 Urinary tract infection
Viral
 Cytomegalovirus
 Epstein-Barr virus
Malignancy (20% to 30%)Colorectal cancer
Leukemia
Lymphoma (Hodgkin and non-Hodgkin)
Noninfectious inflammatory disease (10% to 30%)Connective tissue diseases
 Adult Still disease
 Rheumatoid arthritis
 Systemic lupus erythematosus
Granulomatous disease
 Crohn disease
 Sarcoidosis
Vasculitis syndromes
 Giant cell arteritis
 Polymyalgia rheumatica
 Temporal arteritis
Miscellaneous (10% to 20%)Drug induced
Factitious fever
Thromboembolic disease
Thyroiditis

Evaluation

INITIAL EVALUATION

Early identification and precise localization of the cause are key because diagnostic delay worsens outcomes and contributes to deaths2; however, there are no evidence-based guidelines for the evaluation of FUO. As a result, recommended approaches are largely based on expert opinion. Figure 1 outlines a suggested approach to the evaluation of FUO, beginning with a comprehensive history and physical examination.6 The initial history should include a complete accounting of the patient's symptoms and history of travel; work history; housing and home environment; recent medication use; tobacco, alcohol, and recreational drug use; contact with animals or sick people; and family history of cancers and inflammatory disorders.7,8 At a minimum, physical examination should include evaluation of the skin, oropharynx (with particular attention to dentition), heart, abdomen, lymph nodes, and genitalia.8,9

It is important to rule out factitious fever, which has been reported in up to 9% of cases.10 It should be suspected in cases of fever lasting longer than six months and in medical personnel. Signs such as high temperatures without tachycardia or skin warmth or unusual fever patterns (e.g., brief spikes, loss of evening peak, absence of fever when an observer is present) should also bring the diagnosis of factitious fever to mind.1,2,8,10 It is important to confirm the presence of fever and any temporal pattern it may exhibit. Several infectious etiologies, including malaria and tuberculosis, follow classic fever patterns.8,10 Table 2 summarizes physical examination findings that may help in narrowing the potential etiology of the FUO.8 If one or more of these signs are present, associated conditions should be ruled out before initiating a more general evaluation. Although these signs are found in as many as 97% of patients, they lead to a diagnosis in only 62% of patients with FUO.4,11,12

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