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Prolonged Febrile Illness and Fever of Unknown Origin in Adults ELIZABETH C

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Prolonged Febrile Illness and Fever of Unknown Origin in Adults ELIZABETH C Prolonged Febrile Illness and Fever of Unknown Origin in Adults ELIZABETH C. HERSCH, COL, MC, USA, General Leonard Wood Army Community Hospital, Fort Leonard Wood, Missouri ROBERT C. OH, LTC, MC, USA, Fort Belvoir Community Hospital, Fort Belvoir, Virginia 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 diag- nosis, 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 differ- ential 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 com- plete blood count, chest radiography, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimenta- tion 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 fluoro- deoxyglucose 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. (Am Fam Physician. 2014;90(2):91-96. Copyright © 2014 American Academy of Family Physicians.) CME This clinical content ever of unknown origin (FUO) from initial visit for fever through the end conforms to AAFP criteria in adults is one of the most vexing of hospitalization. There was no difference for continuing medical education (CME). See clinical conditions for clinicians in types of diagnoses for those who met the CME Quiz Questions on and patients. There are no published strict 1991 definition compared with those page 74. Fguidelines, nor is there a recommended who received a diagnosis in less than three Author disclosure: No rel- standard approach to the diagnosis. The weeks.10 Therefore, FUO may be assumed evant financial affiliations. definition of what constitutes FUO remains when no reasonable diagnosis is reached ▲ 1,2 Patient information: controversial. FUO was first described in a after an appropriate inpatient or outpatient A handout on this topic, 1961 case series as prolonged febrile illness investigation.2,6,10-17 Table 1 compares the written by the authors of (temperature of 101°F [38.3°C] or higher) for evolution of the definition of FUO.2,3,6,7,10-17 this article, is available at http://www.aafp.org/ three weeks or longer that did not have an Other subtypes of FUO are nosocomial, afp/2014/0715/p91-s1. established etiology despite a one-week inpa- neutropenic, and human immunodeficiency html. tient evaluation.3,4 The arbitrarily defined virus–associated.7 These subtypes have dif- three weeks allowed most acute, self-limited ferent approaches to evaluation and are illnesses to resolve, as well as sufficient time beyond the scope of this article.17 to complete the initial investigation.5,6 FUO was further defined in 1991, suggest- Differential Diagnosis ing that the minimum evaluation be changed The etiologies of FUO have changed over to at least three outpatient visits or three time because of shifting disease patterns and days in inpatient care.7 Others have proposed new diagnostic techniques.14 There are more shorter lengths of time (e.g., two weeks, than 200 diseases in the differential diagno- because today’s patients present earlier and sis.4,15,17 In multiple case series, however, the receive a diagnosis more quickly).8,9 A ret- etiology of FUO is limited to several dozen rospective review of 226 hospitalized febrile causes, and patients often have an atypical patients examined the timing of diagnosis presentation of a common disease.2,6,18 JulyDownloaded 15, 2014 from ◆ Volume the American 90, Number Family Physician 2 website at www.aafp.org/afp.www.aafp.org/afp Copyright © 2014 American Academy of FamilyAmerican Physicians. Family For the private,Physician noncom 91- mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Fever of Unknown Origin SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References A comprehensive history and physical examination should be performed if there are no C 15, 17-21 localizing signs and symptoms in patients with prolonged febrile illness. Potentially diagnostic clues should be sought during the history and physical examination to C 15-17 guide further evaluation of prolonged febrile illness. In patients with a prolonged febrile illness, a minimum diagnostic workup should be C 1, 2, 4-7, 15-20, 27 performed before classifying the disease process as a fever of unknown origin. Erythrocyte sedimentation rate and C-reactive protein levels should be measured in the initial C 5, 15, 28, 29 workup of a patient who has prolonged febrile illness without a clear source. In patients who have a fever of unknown origin with an elevated erythrocyte sedimentation C 15, 37-40 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. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue C 2, 3, 5, 15, 19, 22, biopsy because of the relatively high diagnostic yield. Depending on clinical clues, this may 27, 41 include liver, lymph node, temporal artery, or bone marrow biopsy. 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. Common causes of FUO are listed in Table 2.6,15-23 Typ- Figure 1 outlines a diagnostic approach to patients with ical subgroups used in the differential for classical FUO prolonged febrile illness and FUO.1,2,4-7,15-20,23,27 are infection (20% to 40%), malignancy (20% to 30%), Hospitalization may be considered at any time during noninfectious inflammatory diseases (10% to 30%), the evaluation, especially if the patient exhibits signs of miscellaneous (10% to 20%), and undiagnosed (up to a critical illness. Approximately 12% to 35% of patients 50%).1,4-6,14-18,22-24 Noninfectious inflammatory diseases die from an FUO-related cause (generally infection commonly include connective tissue diseases, vascu- or malignancy), yet of those whose conditions remain litides, and granulomatous diseases.16,17 In developed undiagnosed, most recover or have a benign course with countries, the noninfectious inflammatory diseases and a good prognosis.5,22 undiagnosed groups comprise a higher proportion of FUO cases.5,10,15,17 Underdeveloped countries have higher COMMON INFECTIONS rates of infection and neoplasm.6,24 Drug fever is impli- At the initial encounter, testing for common infections cated in 1% to 3% of FUO cases16 (Table 3 20,21,25,26). should include a complete blood count with differential, electrolyte panel, liver enzymes, urinalysis with culture, From Prolonged Febrile Illness to FUO Because there are no guidelines to the approach of the febrile patient, most evaluation recommendations are Table 1. Definitions of Fever of Unknown Origin based on expert opinion.17 On initial presentation, most clinicians perform a history and physical examination in Original (1961)3 Temperature ≥ 101ºF (38.3ºC) on several pursuit of an infection. When there are no clear localiz- separate occasions ing signs or symptoms, clinicians should expand on the Fever lasting longer than three weeks patient’s symptoms and historical information, looking Evaluation of at least one week in the hospital for potentially diagnostic clues to guide the evaluation Revised (1991)7 Temperature ≥ 101ºF on several separate 17-20,25,27 (Table 4). This is a continuous, iterative pro- occasions 19-21 cess. Potentially diagnostic clues lead to a diagnosis Fever lasting longer than three weeks in 62% of patients, although clues can be misleading Evaluation of at least three outpatient visits because they are found in 97% of patients.15-17 or three days in inpatient care If no potentially diagnostic clues are found, a mini- Qualitative2,6,10-17 Temperature ≥ 101ºF documented clinically mum diagnostic workup should be performed. Infec- on several separate occasions tions predominate early in FUO diagnoses, and the Appropriate initial diagnostic workup (inpatient or outpatient) does not reveal longer FUO remains undiagnosed, the less likely it is etiology of fever caused by an infection.27 After infections, the etiology of FUO transitions to noninfectious inflammatory diseases Information
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