Revised: May 9, 2014
Accepted: June 18, 2014
Published online: August 6, 2014
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that develops as a primary (familial/hereditary) or secondary (non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell (CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH (familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of (signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome (XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis (e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease (especially EBV-HLH).
Core tip: This review discusses the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), the algorithms used to identify the underlying immune defects at the molecular level, and the optimal therapeutic approaches. For any HLH cases, a screening for primary HLH should be made following the diagnostic algorithm. During the process, immunosuppressive therapy should be started to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is confirmed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be given. Supportive measures to control hemorrhage/organ dysfunction are also required. In cases of primary HLH or secondary/refractory HLH, timely allogeneic hematopoietic stem cell transplantation is recommended.