Despite advances in diagnostic tools, FUO (fever of unknown origin) 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.

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) for more than 3 weeks and no established diagnosis despite appropriate investigation for 1 week.

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. However, the types of diseases that are noted in these categories have changed over the last 50 years. 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. Among persons with HIV infection, FUO is almost always due to an infectious cause. 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.

Infections remain the most common cause of FUO, constituting about a third of cases in various case series over the last five decades. The infections noted most often are abscesses, endocarditis, tuberculosis, and CMV infection. Abscesses are diminishing in importance, because they are discovered earlier in the workup for fever, before the definition of FUO is met. 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. Military 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.