Prolonged Febrile Illness and Fever of Unknown Origin in Adults



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Am Fam Physician. 2014 Jul 15;90(2):91-96.

This clinical content conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions.

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

Fever of unknown origin has been described as a febrile illness (temperature of 101°F [38.3°C] or higher) for three weeks or longer without an etiology despite a one-week inpatient evaluation. A more recent qualitative definition requires only a reasonable diagnostic evaluation. Although there are more than 200 diseases in the differential diagnosis, most cases in adults are limited to several dozen possible causes. Fever of unknown origin is more often an atypical presentation of a common disease rather than an unusual disease. The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. Clinicians should perform a comprehensive history and examination to look for potentially diagnostic clues to guide the initial evaluation. If there are no potentially diagnostic clues, the patient should undergo a minimum diagnostic workup, including a complete blood count, chest radiography, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level testing. Further testing should include blood cultures, lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies. Human immunodeficiency virus and appropriate region-specific serologic testing (e.g., cytomegalovirus, Epstein-Barr virus, tuberculosis) and abdominal and pelvic ultrasonography or computed tomography are commonly performed. If the diagnosis remains elusive, 18F fluorodeoxyglucose positron emission tomography plus computed tomography may help guide the clinician toward tissue biopsy. Empiric antibiotics or steroids are generally discouraged in patients with fever of unknown origin.

Fever of unknown origin (FUO) in adults is one of the most vexing clinical conditions for clinicians and patients. There are no published guidelines, nor is there a recommended standard approach to the diagnosis. The definition of what constitutes FUO remains controversial.1,2 FUO was first described in a 1961 case series as prolonged febrile illness (temperature of 101°F [38.3°C] or higher) for three weeks or longer that did not have an established etiology despite a one-week inpatient evaluation.3,4 The arbitrarily defined three weeks allowed most acute, self-limited illnesses to resolve, as well as sufficient time to complete the initial investigation.5,6

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness.

C

15, 1721

Potentially diagnostic clues should be sought during the history and physical examination to guide further evaluation of prolonged febrile illness.

C

1517

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.

C

1, 2, 47, 1520, 27

Erythrocyte sedimentation rate and C-reactive protein levels should be measured in the initial workup of a patient who has prolonged febrile illness without a clear source.

C

5, 15, 28, 29

In patients who have a fever of unknown origin with an elevated erythrocyte sedimentation rate and/or C-reactive protein levels, and who have not received a diagnosis after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan with or without computed tomography may be useful in reaching a diagnosis.

C

15, 3740

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 clues, this may include liver, lymph node, temporal artery, or bone marrow biopsy.

C

2, 3, 5, 15, 19, 22, 27, 41


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness.

C

15, 1721

Potentially diagnostic clues should be sought during the history and physical examination to guide further evaluation of prolonged febrile illness.

C

1517

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.

C

1, 2, 47, 1520, 27

Erythrocyte sedimentation rate and C-reactive protein levels should be measured in the initial workup of a patient who has prolonged febrile illness without

The Authors

ELIZABETH C. HERSCH, COL, MC, USA, is the deputy commander for clinical services at General Leonard Wood Army Community Hospital in Fort Leonard Wood, Mo. At the time the article was written, Dr. Hersch was a staff family physician and geriatrician at the Tripler Army Medical Center Family Medicine Residency Program, Honolulu, Hawaii, and a clinical assistant professor of family medicine at the Uniformed Services University of the Health Sciences, Bethesda, Md.

ROBERT C. OH, LTC, MC, USA, is a sports medicine fellow at the National Capital Consortium in Bethesda, Md., and a clinical assistant professor of family medicine at the Uniformed Services University of the Health Sciences. At the time the article was written, Dr. Oh was the service chief for the Department of Family Medicine at Tripler Army Medical Center.

Author disclosure: No relevant financial affiliations.

The authors thank Diane Kunichika for her assistance with the manuscript.

Address correspondence to Elizabeth C. Hersch, COL, MC, USA, General Leonard Wood Army Community Hospital, 4430 Missouri Ave., Ft. Leonard Wood, MO 65473. Reprints are not available from the authors.


The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. government.

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