Hemophagocytic lymphohistiocytosis: when the immune system runs amok

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an exaggerated but ineffective immune response leads to severe hyperinflammation. Key players in HLH are activated lymphocytes and histiocytes which infiltrate all organs and secrete large amounts of cytokines. Cardinal symptoms are prolonged fever, hepatosplenomegaly, cytopenias, and hemophagocytosis. Biochemical markers include elevated ferritin, triglycerides, and low fibrinogen. HLH occurs on the basis of various inherited and acquired immune defects. Impaired function of natural killer cells and cytotoxic T cells is shared by all forms of HLH. Nearly all genetic defects identified in inherited cases of HLH are either mutations in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes which induce apoptosis upon entering the target cell. Additionally perforin is important for the down-regulation of the immune response. Acquired forms of HLH are found in association with infectious agents, in patients with autoimmune diseases, in malignant diseases, and in patients receiving immune suppression or after organ transplantation. - HLH is still difficult to diagnose and may be overlooked since initially it may masquerade as a normal infection. HLH should be considered when symptoms are more pronounced than usual and in case of progression. Suppression of the severe hyperinflammation can be achieved with immunosuppressive and immunomodulatory agents and cytostatic drugs. Patients with genetic HLH have to undergo stem cell transplantation for cure.