Hemophagocytic lymphohistiocytosis and related disorders

The rate of diagnosis of hemophagocytic lymphohistiocytosis, a genetically heterogeneous and, frequently, rapidly fatal autosomal recessive disorder of immune regulation, is increasing worldwide. Awareness has grown through the Histiocyte Society and the publication of newly-recognized genetic causes. I summarize current knowledge regarding the pathophysiology, diagnosis and treatment of hemophagocytic lymphohistiocytosis.

Genetic defects leading to life-threatening hemophagocytic syndromes have recently been described. Two autosomal recessive gene defects underlie 40-50% of primary (familial) cases worldwide: perforin, the major immune cytotoxic protein, and MUNC 13-4, a protein involved in exocytosis of perforin-bearing cytotoxic granules during apoptosis. Related autosomal recessive defects of secretory cytotoxic lysosomes - LYST 1 (Chediak-Higashi syndrome), Rab27A (Griscelli syndrome), and X-linked lymphoproliferative disorder - also carry a very high risk of fatal hemophagocytic lymphohistiocytosis. Concurrently, treatment protocols involving multiagent immunomodulatory therapy followed by allogeneic hematopoeitic cell transplantation have been tested. With immunomodulatory treatment, 75% of children with hemophagocytic lymphohistiocytosis are symptomatically improved after 2 months of therapy. Disease-free survival after allogeneic hematopoeitic cell transplantation currently ranges from 50 to 70%.

Bench and clinical research have advanced understanding of the pathophysiology of hemophagocytic lymphohistiocytosis and related disorders, and significantly improved clinical outcomes during the past decade.