If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. If erythrocyte sedimentation rate or C-reactive protein levels are elevated and a diagnosis has not been made after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis. Initial testing should include an evaluation for infectious etiologies, malignancies, inflammatory diseases, and miscellaneous causes such as venous thromboembolism and thyroiditis. In the absence of localizing signs and symptoms, the workup should begin with a comprehensive history and physical examination to help narrow potential etiologies. Most cases in adults occur because of uncommon presentations of common diseases, and up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis. The differential diagnosis is broad but is typically categorized as infection, malignancy, noninfectious inflammatory disease, or miscellaneous.
Fever of unknown origin is defined as a clinically documented temperature of 101☏ or higher on several occasions, coupled with an unrevealing diagnostic workup.
