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.

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.

Table 2. Commonly used medications that can cause fever of unknown origin Antimicrobial agentsCarbapenemsCephalosporinsMinocycline HCl

Nitrofurantoin PenicillinsRifampinSulfonamides

AnticonvulsantsBarbiturates Carbamazepine Phenytoin

Antihistamines

Cardiovascular drugsHydralazine HCl Procainamide HClQuinidine

Histamine2 (H2) blockersCimetidine Ranitidine HCl

Iodides

Herbal remedies

Nonsteroidal anti-inflammatory drugsIbuprofenSulindac

Phenothiazines

Salicylates