Unexplained long-lasting fever/inflammatory syndrome

Unexplained long-lasting fever/inflammatory syndrome (Orphanet code 251332) is a clinical designation rather than a single defined genetic disease. It refers to cases of prolonged or recurrent fever accompanied by systemic inflammation that persist despite thorough diagnostic evaluation and for which no infectious, autoimmune, malignant, or other identifiable cause can be established. This category is sometimes referred to as fever of unknown origin (FUO) with an inflammatory component that remains undiagnosed after extensive workup. The condition primarily affects the immune and thermoregulatory systems, but the persistent inflammatory state can impact multiple organ systems including the musculoskeletal system (joint pain, myalgia), the skin (rashes), the gastrointestinal tract, and the hematologic system (elevated acute-phase reactants, anemia of chronic disease). Patients typically present with fevers lasting weeks to months, elevated inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), fatigue, weight loss, and general malaise. Some cases may eventually be reclassified into specific autoinflammatory or autoimmune conditions upon further investigation. Treatment is largely supportive and empirical, as no definitive targeted therapy exists for cases that remain truly unexplained. Management may include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or empirical trials of immunomodulatory agents such as interleukin-1 (IL-1) receptor antagonists or colchicine, depending on the clinical presentation. Close follow-up is essential, as some patients may develop features over time that allow reclassification into a specific diagnosis such as adult-onset Still disease, systemic lupus erythematosus, or a monogenic autoinflammatory syndrome.

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