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

Differential Diagnosis

Common causes of FUO include infections, malignancies, noninfectious inflammatory disease (e.g., vasculitides, granulomatous disease, connective tissue diseases), miscellaneous, and undiagnosed^2,4,5 (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

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