HLH

HLH, or hemophagocytic lymphohistiocytosis, is a life-threatening hyperinflammatory syndrome caused by excessive activation of macrophages and cytotoxic lymphocytes, leading to a cytokine storm. It can occur as a primary genetic disorder or as a secondary, acquired condition linked to infections, cancer, or autoimmune disease. Prompt recognition and treatment are essential.

Primary HLH is inherited and often presents in infancy or childhood. It results from defects in cytotoxic cell function (for example PRF1, UNC13D, STX11, STXBP2), which impairs the ability to halt immune activation. Secondary HLH can affect people of any age and is triggered by infections, malignancies, or autoimmune diseases.

Pathophysiology involves uncontrolled macrophage activation with excessive cytokine production (eg, IFN-γ, IL-6, IL-10, TNF-α). Clinically, patients typically have fever, hepatosplenomegaly, and cytopenias. Laboratory clues include hypertriglyceridemia, hypofibrinogenemia, markedly elevated ferritin, and elevated soluble CD25; CNS involvement may occur in some cases.

Diagnosis relies on HLH-2004 criteria, requiring five of eight features: fever, splenomegaly, cytopenias in at least two lineages, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low NK cell activity, ferritin elevation, and elevated soluble CD25. Genetic testing supports a primary HLH diagnosis; otherwise, HLH is considered secondary, with workup for triggers.

Treatment aims to suppress inflammation and treat triggers, typically with immunochemotherapy (etoposide and dexamethasone, with cyclosporine A) and supportive care. In genetic HLH, hematopoietic stem cell transplantation offers a potential cure. Newer therapies, such as anti–IFN-γ agents, are used in select patients. Prognosis improves with early diagnosis and response to therapy.