Fever of unknown origin
A strategic approach to this diagnostic dilemma
Kamal Amin, MD; Carol A. Kauffman, MD
Vol 114 / no 3 / september 2003 / postgraduate medicine
CME learning objectives
To recognize the potential causes of fever of unknown origin
To become familiar with an approach to initial diagnostic workup for fever of unknown origin
To understand the further targeted diagnostic evaluation sometimes needed with fever of unknown origin
The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.
Second in a series of articles on problem infections in primary care, coordinated by Larry J. Strausbaugh, MD, hospital epidemiologist and staff physician, Veterans Affairs Medical Center, Portland, Oregon, and professor of medicine, Oregon Health & Science University School of Medicine, Portland.
Preview: Fever of unknown origin (FUO) remains a challenging clinical problem despite recent advances in diagnostic tools and techniques. Because primary care physicians are often the first ones to encounter a case of FUO, it is important that they be familiar with the best strategy and steps for confronting this problem intially. Here, Drs Amin and Kauffman review the major causes of FUO in adults and describe an in-depth approach to laboratory and radiologic tests that help establish a diagnosis. Amin K, Kauffman CA. Fever of unknown origin: a strategic approach to this diagnostic dilemma. Postgrad Med 2003;114(3):69-75
Despite advances in diagnostic tools, FUO remains a challenging clinical problem. The primary care physician is often the first to confront this condition. Frequently, a specialist in infectious diseases, rheumatology, or hematology is consulted. Nevertheless, the initial approach to this diagnostic dilemma should be one with which the primary care physician is familiar. A series of standard tests can often establish a specific diagnosis or at least the broad category into which the diagnosis falls. In most cases, the cause of FUO is a familiar disease with an uncommon presentation, rather than a rare disorder.
Definition
Before embarking on an extensive workup, it is important to be certain that a patient's problem meets the definition of FUO: documented fever (temperature, >38.3°C [101°F]) for more than 3 weeks and no established diagnosis despite appropriate investigation for 1 week.
Causes of fuo
The three major categories of causes of FUO--infections, collagen vascular and granulomatous diseases, and tumors--remain unchanged from the classic studies of Petersdorf and Beeson (1) (table 1). However, the types of diseases that are noted in these categories have changed over the last 50 years (2-8). For example, systemic lupus erythematosus, a common cause of FUO in the past, is now more easily diagnosed by serologic tests and rarely qualifies as an FUO. Diseases that were unknown or not well described several decades ago, such as HIV and cytomegalovirus (CMV) infections, are causes of FUO today. In contrast, rheumatic fever has all but disappeared. Many diseases that previously caused FUO no longer attain this status because of dramatic improvements in diagnostic imaging in the last several decades.
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Table 1. Documented causes of fever of unknown origin over last 50 years | ||||||
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Investigator (survey yr) |
No. of patients |
Infections (%) |
Tumors (%) |
Collagen vascular and granulomatous diseases (%) |
Miscellaneous (%) |
No diagnosis (%) |
|
Petersdorf (1952-1957) |
100 |
36 |
19 |
19 |
19 |
7 |
|
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Larson (1970-1980) |
105 |
30 |
31 |
17 |
9 |
12 |
|
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Knockaert et al* (1980-1989) |
199 |
25 |
7 |
26 |
21 |
20 |
|
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Kazanjian (1984-1990) |
86 |
33 |
24 |
26 |
8 |
9 |
|
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DeKleijn (1992-1994) |
167 |
26 |
13 |
24 |
7 |
30 |
|
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*Data from Knockaert et al (7) and Knockaert et al (19). | ||||||
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The causes of FUO differ among various patient groups. For example, self-limited viral syndromes are an uncommon cause of FUO in older adults, but temporal arteritis, tumors, and tuberculosis are more likely in older persons than younger ones (9,10). Among persons with HIV infection, FUO is almost always due to an infectious cause (11). In addition, travelers may be exposed to unusual infectious agents that they carry with them when they return home, thus expanding the differential diagnosis for FUO (12).
InfectionsInfections remain the most common cause of FUO, constituting about a third of cases in various case series over the last five decades (4). The infections noted most often are abscesses, endocarditis, tuberculosis, and CMV infection (3-7). Abscesses are diminishing in importance, because they are discovered earlier in the workup for fever, before the definition of FUO is met (6,7). Most cases of typical staphylococcal or streptococcal endocarditis are easily diagnosed. FUO is more likely to be encountered in patients who have culture-negative endocarditis due to inappropriate prior antibiotic use or difficult-to-culture organisms.
Tuberculosis, although less common now than half a century ago, must always be considered as a cause of FUO. Miliary and extrapulmonary tuberculosis are the most likely forms to present as FUO. Several viral infections can produce prolonged fevers and present as FUO; of these, CMV infection is the most common, but Epstein-Barr virus (EBV) and HIV infections are also causes of FUO.
TumorsTumors have classically been the second most common cause of FUO in adults (4). However, in recent reports, they have accounted for only 7% to 13% of FUO cases (6,7). The routine use of computed tomography (CT) has led to earlier diagnosis of many tumors, and they are not as common a cause of FUO as they once were.
Tumors that present most often as FUO are hematologic malignancies, especially Hodgkin's disease and other lymphomas. Pel-Ebstein fevers--those that occur daily for days to weeks then disappear, only to reappear later in the same pattern--are now rarely seen. Other hematologic malignancies, such as multiple myeloma and leukemias, are less common causes of FUO.
Among solid tumors, renal cell carcinoma is most often noted to cause FUO; much less commonly, hepatomas and cancer of the colon and gastrointestinal tract, lung, and breast can cause FUO. Atrial myxomas are mentioned less frequently as enigmatic causes of fever, probably because of the earlier use of transesophageal echocardiography than in the past.
Collagen vascular diseases, granulomatous diseases Recent reviews of FUO that have grouped collagen vascular diseases and granulomatous diseases together have found this category to be a more common cause of FUO than tumors (6,7). Still's disease is the most frequent diagnosis in adults younger than 50 years (3,5-7); in older adults with FUO, temporal arteritis is the most common diagnosis (8,9). Other causes of FUO include polyarteritis nodosa, cryoglobulinemia, polymyositis, Wegener's granulomatosis, and sarcoidosis. Inflammatory bowel disease may present as FUO with few abdominal or gastrointestinal complaints.
Other causes of FUO Common entities, such as pulmonary emboli and hematomas, can manifest as FUO primarily. Many different drugs can cause fever (table 2), and hyperthyroidism and thyroiditis can also present as FUO. Periodic fevers, such as familial Mediterranean fever, are rare and occur in select populations. Factitious and fraudulent fevers--interesting diagnostic dilemmas that appear in every series of FUO--are uncommon; they occur almost entirely in young women linked to the healthcare profession.
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Table 2. Commonly used medications that can cause fever of unknown origin |
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Antimicrobial agentsCarbapenems Cephalosporins Minocycline HCl Nitrofurantoin Penicillins Rifampin Sulfonamides AnticonvulsantsBarbiturates Carbamazepine Phenytoin Antihistamines Cardiovascular drugsHydralazine HCl Procainamide HCl Quinidine Histamine2 (H2) blockers Cimetidine Ranitidine HCl Iodides Herbal remedies Nonsteroidal anti-inflammatory drugsIbuprofen Sulindac Phenothiazines Salicylates
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