Primary hemophagocytic lymphohistiocytosis

Primary hemophagocytic lymphohistiocytosis (HLH), also known as familial hemophagocytic lymphohistiocytosis (FHL) or familial erythrophagocytic lymphohistiocytosis, is a group of rare, life-threatening inherited immune disorders characterized by uncontrolled activation and proliferation of T lymphocytes and macrophages. These overactivated immune cells infiltrate multiple organs, causing severe tissue damage and a dangerous hyperinflammatory state. The disease primarily affects the hematologic, hepatic, neurological, and immune systems. Primary HLH is caused by genetic defects in proteins essential for the cytotoxic function of natural killer (NK) cells and cytotoxic T lymphocytes, impairing their ability to eliminate infected or abnormal cells and properly regulate immune responses. Key clinical features include prolonged high fever, enlarged liver and spleen (hepatosplenomegaly), cytopenias (low blood cell counts affecting red cells, white cells, and platelets), hypertriglyceridemia, hypofibrinogenemia, elevated ferritin levels, and the hallmark finding of hemophagocytosis — the engulfment of blood cells by activated macrophages — observed in bone marrow, spleen, or lymph nodes. Neurological involvement, including seizures, irritability, and altered consciousness, occurs in a significant proportion of patients and can lead to long-term complications. Without treatment, primary HLH is rapidly fatal. Several genetic subtypes have been identified, including FHL types 1 through 5, caused by mutations in genes such as PRF1 (perforin), UNC13D (Munc13-4), STX11 (syntaxin 11), and STXBP2 (Munc18-2). Primary HLH can also occur as part of broader immunodeficiency syndromes such as Griscelli syndrome type 2, Chédiak-Higashi syndrome, and X-linked lymphoproliferative disease. Treatment typically follows the HLH-94 or HLH-2004 protocols, which include immunosuppressive and chemotherapeutic agents such as dexamethasone, etoposide, and cyclosporine A to control the hyperinflammatory response. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for primary HLH. More recently, emapalumab, an anti-interferon-gamma monoclonal antibody, has been approved for refractory or recurrent primary HLH.

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