Lymphohistiocytosis

Lymphohistiocytosis refers to a hyperinflammatory syndrome in which lymphocytes and histiocytes (macrophages) become inappropriately activated, producing a sustained cytokine storm. The term is often used to describe hemophagocytic lymphohistiocytosis (HLH), a life-threatening condition that can be familial (genetic) or acquired. HLH represents an umbrella for disorders characterized by excessive immune activation that damages multiple organs.

Pathophysiology typically involves defective cytotoxic function of natural killer cells and CD8+ T cells, allowing persistent activation of macrophages. This leads to widespread inflammation, hemophagocytosis in the bone marrow and other tissues, and abnormalities in liver function, coagulation, and metabolism. Triggers include infections (notably Epstein-Barr virus), malignancies, autoimmune diseases, and genetic mutations affecting cellular cytotoxicity.

Clinical features commonly include prolonged fever, splenomegaly, cytopenias affecting one or more blood cell lines, elevated ferritin, hypertriglyceridemia or low fibrinogen, and liver dysfunction. Central nervous system involvement and coagulopathy may occur. Laboratory testing aids diagnosis, which is based on established criteria requiring multiple findings: fever, splenomegaly, cytopenias, high triglycerides or low fibrinogen, hemophagocytosis in tissue, low or absent natural killer cell activity, high ferritin, and elevated soluble CD25 (sIL-2 receptor). Genetic testing helps distinguish primary from secondary forms.

Treatment aims to suppress hyperinflammation and treat the underlying trigger. Standard regimens include corticosteroids, etoposide, and cyclosporine; intrathecal therapy is used for central nervous system involvement. Hematopoietic stem cell transplantation is considered for genetic forms. Newer therapies targeting specific inflammatory pathways, such as monoclonal antibodies against interferon-gamma, are being used in select cases. Prognosis depends on the form, timeliness of diagnosis, and response to therapy.