Secondary hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (sHLH), also known as acquired or reactive hemophagocytic lymphohistiocytosis or macrophage activation syndrome (MAS) when occurring in the context of autoimmune diseases, is a severe hyperinflammatory syndrome characterized by uncontrolled and excessive activation of the immune system. Unlike primary (familial) HLH, which is caused by inherited genetic defects, secondary HLH is triggered by external factors including infections (particularly viral infections such as Epstein-Barr virus), malignancies (especially lymphomas), autoimmune or autoinflammatory conditions, and immunosuppressive therapies. The condition results from a cytokine storm driven by overactivated T lymphocytes and macrophages that infiltrate multiple organs. The disease affects multiple body systems, including the hematologic, hepatic, neurologic, and reticuloendothelial systems. Key clinical features include prolonged high fever, enlarged liver and spleen (hepatosplenomegaly), cytopenias (low blood cell counts affecting red blood cells, white blood cells, and platelets), markedly elevated serum ferritin, hypertriglyceridemia, hypofibrinogenemia, and evidence of hemophagocytosis (macrophages engulfing blood cells) in bone marrow, spleen, or lymph nodes. Liver dysfunction, coagulopathy, and neurological symptoms such as seizures or altered consciousness may also occur. Without prompt treatment, the condition can rapidly progress to multi-organ failure and death. Treatment of secondary HLH focuses on controlling the hyperinflammatory response and addressing the underlying trigger. Immunosuppressive therapy typically includes corticosteroids (such as dexamethasone), etoposide-based chemotherapy protocols (such as the HLH-94 or HLH-2004 regimens), cyclosporine A, and intravenous immunoglobulin. In cases associated with autoimmune disease (MAS), interleukin-1 receptor antagonists (anakinra) or other biologic agents may be used. Treatment of the underlying infection or malignancy is essential. In refractory cases, the anti-interferon-gamma antibody emapalumab or the JAK inhibitor ruxolitinib may be considered. Early recognition and aggressive treatment are critical for improving outcomes.

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