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Approach to the Adult Patient with Fever of Unknown Origin ALAN R

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Approach to the Adult Patient with Fever of Unknown Origin ALAN R Approach to the Adult Patient with Fever of Unknown Origin ALAN R. ROTH, D.O., and GINA M. BASELLO, D.O., Jamaica Hospital Medical Center, Mount Sinai School of Medicine Family Practice Residency Program, Jamaica, New York 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, autoim- mune 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. (Am Fam Physician 2003;68:2223-8. Copyright© 2003 American Academy of Family Physicians.) dult patients frequently pre- and changes in disease states, such as the emer- sent to the physician’s office gence of human immunodeficiency virus with a fever (temperature (HIV) infection and an increasing number of higher than 38.3°C [100.9°F]).1 patients with neutropenia. Others contend that Most febrile conditions are altering the definition would not benefit the Areadily diagnosed on the basis of presenting evaluation and care of patients with FUO.4 symptoms and a problem-focused physical The four categories of potential etiology of examination. Occasionally, simple testing FUO are centered on patient subtype—clas- such as a complete blood count or urine cul- sic, nosocomial, immune deficient, and HIV- ture is required to make a definitive diagnosis. associated. Each group has a unique differen- Viral illnesses (e.g., upper respiratory infec- tial diagnosis based on characteristics and tions) account for most of these self-limiting vulnerabilities and, therefore, a different cases and usually resolve within two weeks.2 process of evaluation (Table 1).5 When fever persists, a more extensive diagnos- tic investigation should be conducted. CLASSIC Although some persistent fevers are manifes- The classic category includes patients who tations of serious illnesses, most can be readily meet the original criteria of FUO, with a new diagnosed and treated. emphasis on the ambulatory evaluation of these previously healthy patients.6 The revised Definitions and Classifications criteria require an evaluation of at least three The definition of fever of unknown origin days in the hospital, three outpatient visits, or (FUO), as based on a case series of 100 pa- one week of logical and intensive outpatient tients,3 calls for a temperature higher than testing without clarification of the fever’s 38.3°C on several occasions; a fever lasting cause.5 The most common causes of classic more than three weeks; and a failure to reach a FUO are infection, malignancy, and collagen diagnosis despite one week of inpatient investi- vascular disease. gation. This strict definition prevents common and self-limiting medical conditions from NOSOCOMIAL See page 2113 for being included as FUO. Some experts have Nosocomial FUO is defined as fever occur- definitions of strength- argued for a more comprehensive definition of ring on several occasions in a patient who has of-evidence levels. FUO that takes into account medical advances been hospitalized for at least 24 hours and has Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2003 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. TABLE 1 Classification of Fever of Unknown Origin (FUO) Category of FUO Definition Common etiologies Classic Temperature >38.3°C (100.9°F) Infection, malignancy, collagen vascular disease Duration of >3 weeks Evaluation of at least 3 outpatient visits or 3 days in hospital Nosocomial Temperature >38.3°C Clostridium difficile enterocolitis, drug-induced, Patient hospitalized ≥ 24 hours but no fever or pulmonary embolism, septic thrombophlebitis, incubating on admission sinusitis Evaluation of at least 3 days Immune deficient Temperature >38.3°C Opportunistic bacterial infections, aspergillosis, (neutropenic) Neutrophil count ≤ 500 per mm3 candidiasis, herpes virus Evaluation of at least 3 days HIV-associated Temperature >38.3°C Cytomegalovirus, Mycobacterium avium-intracellulare Duration of >4 weeks for outpatients, >3 days complex, Pneumocystis carinii pneumonia, for inpatients drug-induced,Kaposi’s sarcoma, lymphoma HIV infection confirmed HIV = human immunodeficiency virus. Adapted with permission from Durack DT, Street AC. Fever of unknown origin—reexamined and redefined. Curr Clin Top Infect Dis 1991;11:37. not manifested an obvious source of infection that could assessed for three days without establishing an etiology for have been present before admission. A minimum of three the fever.5 In most of these cases, the fever is caused by days of evaluation without establishing the cause of fever is opportunistic bacterial infections. These patients are usu- required to make this diagnosis.5 Conditions causing noso- ally treated with broad-spectrum antibiotics to cover the comial FUO include septic thrombophlebitis, pulmonary most likely pathogens. Occult infections caused by fungi, embolism, Clostridium difficile enterocolitis, and drug- such as hepatosplenic candidiasis and aspergillosis, must induced fever. In patients with nasogastric or nasotracheal be considered.9 Less commonly, herpes simplex virus may tubes, sinusitis also may be a cause.7,8 be the inciting organism, but this infection tends to present with characteristic skin findings. IMMUNE DEFICIENT Immune-deficient FUO, also known as neutropenic HIV-ASSOCIATED FUO, is defined as recurrent fever in a patient whose neu- HIV-associated FUO is defined as recurrent fevers over a trophil count is 500 per mm3 or less and who has been four-week period in an outpatient or for three days in a hos- pitalized patient with HIV infection.5 Although acute HIV infection remains an important cause of classic FUO, the virus also makes patients susceptible to opportunistic infec- The Authors tions. The differential diagnosis of FUO in patients who are ALAN R. ROTH, D.O., is chairman and program director of the Jamaica HIV positive includes infectious etiologies such as Mycobac- Hospital Medical Center, Mount Sinai School of Medicine Family Prac- terium avium-intracellulare complex, Pneumocystis carinii tice Residency Program, Jamaica, N.Y. He is also associate professor of community and preventive medicine at Mount Sinai School of Medi- pneumonia, and cytomegalovirus. Geographic considera- cine. Dr. Roth received his medical degree from the New York College tions are especially important in determining the etiology of of Osteopathic Medicine, Old Westbury, N.Y., and completed a family FUO in patients with HIV. For example, a patient with HIV medicine residency at the Jamaica Hospital Medical Center. who lives in the southwest United States is more susceptible GINA M. BASELLO, D.O., is assistant director of the Jamaica Hospital to coccidioidomycosis. In patients with HIV infection, non- Medical Center, Mount Sinai School of Medicine Family Practice Resi- dency Program, and clinical instructor of community and preventive med- infectious causes of FUO are less common and include lym- icine at the Mount Sinai School of Medicine. She received her medical phomas, Kaposi’s sarcoma, and drug-induced fever.9,10 degree from the New York College of Osteopathic Medicine and com- pleted a family medicine residency at Jamaica Hospital Medical Center. Differential Diagnosis Address correspondence to Alan R. Roth, D.O., Jamaica Hospital Med- The differential diagnosis of FUO generally is broken ical Center, Family Practice Residency Program, 89-06 135th Street, Suite 3C, Jamaica, NY 11418 (e-mail: [email protected]) Reprints into four major subgroups: infections, malignancies, are not available from the authors. autoimmune conditions, and miscellaneous (Table 2).Sev- 2224 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 11 / DECEMBER 1, 2003 Fever of Unknown Origin TABLE 2 Common Etiologies of Fever of Unknown Origin Infections Autoimmune conditions Tuberculosis (especially Adult Still’s disease extrapulmonary) Polymyalgia rheumatica Abdominal abscesses Temporal arteritis Pelvic abscesses Rheumatoid arthritis Dental abscesses Rheumatoid fever common in this population, malignancy has become a com- Endocarditis Inflammatory bowel disease mon etiologic consideration in elderly patients. Malignan- Osteomyelitis Reiter’s syndrome cies that sometimes are difficult to diagnose, such as chronic Sinusitis Systemic lupus erythematosus leukemias, lymphomas, renal cell carcinomas, and meta- Cytomegalovirus Vasculitides static cancers, often are found in patients with FUO.12 Epstein-Barr virus Miscellaneous Human immunodeficiency virus Drug-induced fever AUTOIMMUNE CONDITIONS Lyme disease Complications from cirrhosis Rheumatoid arthritis and rheumatic fever are inflam- Prostatitis Factitious fever matory diseases that used to be commonly associated with Sinusitis Hepatitis (alcoholic, Malignancies granulomatous, or lupoid) FUO, but with advances in serologic testing, these condi- Chronic leukemia Deep venous thrombosis tions usually are diagnosed
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