Fever of unknown origin (FUO) in adults is defined as a temperature higher than 38.3 C (100.9 F) that lasts for more than three weeks with no obvious source despite appropriate investigation. it refers to a condition in which the patient has an elevated temperature (fever) but despite investigations by a physician no explanation has been found.
If the cause is found it is usually a diagnosis of exclusion, that is, by eliminating all possibilities until only one explanation remains, and taking this as the correct one.

Causes:

Extrapulmonary tuberculosis is the most frequent cause of FUO. Drug-induced hyperthermia, as the sole symptom of an adverse drug reaction, should always be considered. Disseminated granulomatoses such as tuberculosis, histoplasmosis, coccidioidomycosis, blastomycosis and sarcoidosis are associated with FUO. Lymphomas are the most common cause of FUO in adults. Thromboembolic disease (i.e. pulmonary embolism, deep venous thrombosis) occasionally shows fever. Although infrequent, its potentially lethal consequences warrant evaluation of this cause. Endocarditis, although uncommon, is another important etiology to consider. Bartonella infections are also known to cause fever of unknown origin.

Diagnosis:

A comprehensive and meticulous history (i.e. illness of family members, recent visit to the tropics, medication), repeated physical examination (i.e. skin rash, eschar, lymphadenopathy, heart murmur) and myriad laboratory tests (serological, blood culture, immunological) are the cornerstone of finding the cause.
Other investigations may be needed. Ultrasound may show cholelithiasis, echocardiography may be needed in suspected endocarditis and a CT-scan may show infection or malignancy of internal organs. Another technique is Gallium-67 scanning which seems to visualize chronic infections more effectively. Invasive techniques (biopsy and laparotomy for pathological and bacteriological examination) may be required before a definite diagnosis is possible.
Positron emission tomography using radioactively labelled fluorodeoxyglucose (FDG) has been reported to have a sensitivity of 84% and a specificity of 86% for localizing the source of fever of unknown origin.
Despite all this, diagnosis may only be suggested by the therapy chosen. When a patient recovers after discontinuing medication it likely was drug fever, when antibiotics or antimycotics work it probably was infection. Empirical therapeutic trials should be used in those patients in which other techniques have failed.


Treatment:

Unless the patient is acutely ill, no therapy should be started before the cause has been found. This is because non-specific therapy is rarely effective and mostly delays diagnosis. An exception is made for neutropenic (low white blood cell count) patients in which delay could lead to serious complications. After blood cultures are taken this condition is aggressively treated with broad-spectrum antibiotics. Antibiotics are adjusted according to the results of the cultures taken.
HIV-infected persons with pyrexia and hypoxia will be started on medication for possible Pneumocystis jirovecii infection. Therapy is adjusted after a diagnosis is made.

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