An approach to fever of unknown Origin in adults

Fever of unknown origin (FUO) in adults is defined as a temperature higher than 38.3 C (100.9 F) that lasts for more than three weeks with no obvious source despite appropriate investigation. The four categories of potential etiology of FUO are classic, nosocomial, immune deficient, and human immunodeficiency virus–related. The four subgroups of the differential diagnosis of FUO are infections, malignancies, autoimmune conditions, and miscellaneous. A thorough history, physical examination, and standard laboratory testing remain the basis of the initial evaluation of the patient with FUO. Newer diagnostic modalities, including updated serology, viral cultures, computed tomography, and magnetic resonance imaging, have important roles in the assessment of these patients.

Adult patients frequently present to the physician’s office with a fever (temperature higher than 38.3°C [100.9°F]).1 Most febrile conditions are readily diagnosed on the basis of presenting symptoms and a problem-focused physical examination. Occasionally, simple testing such as a complete blood count or urine culture is required to make a definitive diagnosis. Viral illnesses (e.g., upper respiratory infections) account for most of these self-limiting cases and usually resolve within two weeks.2 When fever persists, a more extensive diagnostic investigation should be conducted. Although some persistent fevers are manifestations of serious illnesses, most can be readily diagnosed and treated.

Definitions and Classifications

The definition of fever of unknown origin (FUO), as based on a case series of 100 patients,3 calls for a temperature higher than 38.3°C on several occasions; a fever lasting more than three weeks; and a failure to reach a diagnosis despite one week of inpatient investigation. This strict definition prevents common and self-limiting medical conditions from being included as FUO. Some experts have argued for a more comprehensive definition of FUO that takes into account medical advances and changes in disease states, such as the emergence of human immunodeficiency virus (HIV) infection and an increasing number of patients with neutropenia. Others contend that altering the definition would not benefit the evaluation and care of patients with FUO.4
The four categories of potential etiology of FUO are centered on patient subtype—classic, nosocomial, immune deficient, and HIV-associated. Each group has a unique differential diagnosis based on characteristics and vulnerabilities and, therefore, a different process of evaluation


The classic category includes patients who meet the original criteria of FUO, with a new emphasis on the ambulatory evaluation of these previously healthy patients.6 The revised criteria require an evaluation of at least three days in the hospital, three outpatient visits, or one week of logical and intensive outpatient testing without clarification of the fever’s cause.5 The most common causes of classic FUO are infection, malignancy, and collagen vascular disease.


Nosocomial FUO is defined as fever occurring on several occasions in a patient who has been hospitalized for at least 24 hours and has not manifested an obvious source of infection that could have been present before admission. A minimum of three days of evaluation without establishing the cause of fever is required to make this diagnosis.5 Conditions causing nosocomial FUO include septic thrombophlebitis, pulmonary embolism, Clostridium difficile enterocolitis, and drug-induced fever. In patients with nasogastric or nasotracheal tubes, sinusitis also may be a cause.7,8

Immune-deficient FUO, also known as neutropenic FUO, is defined as recurrent fever in a patient whose neutrophil count is 500 per mm3 or less and who has been assessed for three days without establishing an etiology for the fever.5 In most of these cases, the fever is caused by opportunistic bacterial infections. These patients are usually treated with broad spectrum antibioticsto cover the most likely pathogens. Occult infections caused by fungi, such as hepatosplenic candidiasis and aspergillosis, must be considered.9 Less commonly, herpes simplex virus may be the inciting organism, but this infection tends to present with characteristic skin findings.

HIV-associated FUO is defined as recurrent fevers over a four-week period in an outpatient or for three days in a hospitalized patient with HIV infection.5 Although acute HIV infection remains an important cause of classic FUO, the virus also makes patients susceptible to opportunistic infections. The differential diagnosis of FUO in patients who are HIV positive includes infectious etiologies such as Mycobacterium avium-intracellulare complex, Pneumocystis carinii pneumonia, and cytomegalovirus. Geographic considerations are especially important in determining the etiology of FUO in patients with HIV. For example, a patient with HIV who lives in the southwest United States is more susceptible to coccidioidomycosis. In patients with HIV infection, non-infectious causes of FUO are less common and include lymphomas, Kaposi’s sarcoma, and drug-induced fever.
(To be continued)

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Obehi Cynthia