Approach to the adult patient with fever of unknown origin

Author: Alan R. Roth, Gina M. Basello
Date: Dec 1, 2003

Adult patients frequently present to the physician's office with a fever (temperature higher than 38.3[degrees]C [100.9[degrees]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[degrees]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 (Table 1). (5)


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 antibiotics to 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, noninfectious causes of FUO are less common and include lymphomas, Kaposi's sarcoma, and drug-induced fever. (9,10)

Differential Diagnosis

The differential diagnosis of FUO generally is broken into four major subgroups: infections, malignancies, autoimmune conditions, and miscellaneous (Table 2). Several factors may limit the applicability of research literature on FUO to everyday medical practice. These factors include the geographic location of cases, the type of institution reporting results (e.g., community hospital, university hospital, ambulatory clinic), and the specific subpopulations of patients with FUO who were studied. Despite these limiting factors, infection remains the most common cause of FUO in study reports. (3,11,12)


Of the many infectious diseases that are associated with FUO, tuberculosis (especially in extrapulmonary sites) and abdominal or pelvic abscesses are the most common. (13) Intra-abdominal abscesses are associated with perforated hollow viscera (as occurs in appendicitis), diverticulitis, malignancy, and trauma. Other common infections that should be considered as the source of FUO include subacute bacterial endocarditis, sinusitis, osteomyelitis, and dental abscess. (11,13) As the duration of fever increases, the likelihood of an infectious etiology decreases. Malignancy and factitious fever are more common diagnostic considerations in patients with prolonged FUO. (14)


Because of a substantial increase in the elderly population, as well as advances in the diagnosis and treatment of diseases common in this population, malignancy has become a common etiologic consideration in elderly patients. Malignancies that sometimes are difficult to diagnose, such as chronic leukemias, lymphomas, renal cell carcinomas, and metastatic cancers, often are found in patients with FUO. (12)


Rheumatoid arthritis and rheumatic fever are inflammatory diseases that used to be commonly associated with FUO, but with advances in serologic testing, these conditions usually are diagnosed more promptly. At this time, adult Still's disease and temporal arteritis have become the most common autoimmune sources of FUO because they remain difficult to diagnose even with the help of laboratory testing.

Multisystem inflammatory diseases such as temporal arteritis and polymyalgia rheumatica have emerged as the autoimmune conditions most frequently associated with FUO in patients older than 65 years. (15) Elderly patients who present with symptoms consistent with temporal arteritis associated with an elevation of the erythrocyte sedimentation rate should be referred for temporal artery biopsy. (16)


Many unrelated pathologic conditions can present as FUO, with drug-induced fever being the most common. (11,14) This condition is part of a hypersensitivity reaction to specific drugs such as diuretics, pain medications, antiarrhythmic agents, antiseizure drugs, sedatives, certain antibiotics, antihistamines, barbiturates, cephalosporins, salicylates, and sulfonamides (Table 3).

Complications from cirrhosis and hepatitis (alcoholic, granulomatous, or lupoid) are also potential causes of FUO. (12,13) Deep venous thrombosis, although a rare cause of FUO, must be considered in relevant patients, and venous Doppler studies should be obtained. (17) Factitious fever has been associated with patients who have some medical training or experience and a fever persisting longer than six months. (18) Failure to reach a definitive diagnosis in patients presenting with FUO is not uncommon; 20 percent of cases remain undiagnosed. Even if an extensive investigation does not identify a cause for FUO, these patients generally have a favorable outcome. (19)

Evaluation of the Patient with FUO

The initial approach to the patient presenting with fever should include a comprehensive history, physical examination, and appropriate laboratory testing. As the underlying process develops, the history and physical assessment should be repeated. The first step should be to confirm a history of fever and document the fever pattern. Classic fever patterns such as intermittent, relapsing sustained, and temperature-pulse disparity may prove to be useful but rarely are diagnostic. (20)

(12.) Knockaert DC, Vanneste LJ, Bobbaers HJ. Recurrent or episodic fever of unknown origin. Review of 45 cases and survey of the literature. Medicine [Baltimore] 1993;72:184-96.

(13.) Kazanjian PH. Fever of unknown origin: review of 86 patients treated in community hospitals. Clin Infect Dis 1992;15:968-73.

(14.) Aduan RP, Fauci AS, Dale DC, Wolff SM. Prolonged fever of unknown origin (FUO): a prospective study of 347 patients. Clin Res 1978;26:558.

(15.) Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993;41:1187-92.

(16.) Epperly TD, Moore KE, Harrover JD. Polymyalgia rheumatica and temporal arteritis. Am Fam Physician 2000;62:789-96.

(17.) Mourad O, Palda V, Detsky A. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003; 163:545-51.

(18.) Mackowiak P, Durack D. Fever of unknown origin. In: Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:623-31.

(19.) Arnow PM, Flaherty JP. Fever of unknown origin. Lancet 1997; 350:575-80.

(20.) Mackowiak PA. Commentary. Fever patterns. Infectious Disease Clinical Practice 1997;6:308-9.

(21.) Kupferwasser LI, Darius H, Muller AM, Martin C, Mohr-Kahaly S, Erbel R, et al. Diagnosis of culture-negative endocarditis: the role of the Duke criteria and the impact of transesophageal echocardiography. Am Heart J 2001;142:146-52.

(22.) Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994;96:200-9.

(23.) Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis 1997;24:291-300.

(24.) Suga K, Nakagi K, Kuramitsu T, Itou K, Tanaka N, Uchisato H, et al. The role of gallium-67 imaging in the detection of foci in recent cases of fever of unknown origin. Ann Nucl Med 1991;5:35-40.

(25.) Lorenzen J, Buchert R, Bohuslavizki KH. Value of FDG PET in patients with fever of unknown origin. Nucl Med Commun 2001;22:779-83.

(26.) Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med 2003;253:263-75.

ALAN R. ROTH, D.O., is chairman and program director of the Jamaica Hospital Medical Center, Mount Sinai School of Medicine Family Practice Residency Program, Jamaica, N.Y. He is also associate professor of community and preventive medicine at Mount Sinai School of Medicine. Dr. Roth received his medical degree from the New York College of Osteopathic Medicine, Old Westbury, N.Y., and completed a family medicine residency at the Jamaica Hospital Medical Center.

GINA M. BASELLO, D.O., is assistant director of the Jamaica Hospital Medical Center, Mount Sinai School of Medicine Family Practice Residency Program, and clinical instructor of community and preventive medicine at the Mount Sinai School of Medicine. She received her medical degree from the New York College of Osteopathic Medicine and completed a family medicine residency at Jamaica Hospital Medical Center.

Address correspondence to Alan R. Roth, D.O., Jamaica Hospital Medical Center, Family Practice Residency Program, 89-06 135th Street, Suite 3C, Jamaica, NY 11418 (e-mail: Reprints are not available from the authors.

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