Biology and Treatment of Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistocytosis (HLH) is a hyperinflammatory syndrome that occurs at all ages and is characterized by high levels of cytokines, secreted by activated T-lymphocytes and macrophages. All symptoms and laboratory changes can be explained by organ infiltration by these cells and hypercytokinemia. HLH occurs as an inherited form (genetic, primary HLH) with mutations primarily in the cytotoxic vesicle pathway, and an acquired form that, in children, is triggered mostly by infections, but also by autoinflammatory/autoimmune diseases, malignancies and metabolic diseases. The pathogenesis of genetic forms of HLH can be explained by the inability of cytotoxic cells to induce apoptosis in (infected) target cells and to terminate the immune response for which perforin is essential. The pathogenesis of acquired forms is multifactorial, and several factors may have to be present for the development of HLH: e.g. acquired immune defects; stimulation of the innate immune system via toll-like receptors or danger signals; interference of viruses and tumor cells with cytotoxicity and apoptosis; secretion of cytokines by tumor cells; mutations or single nucleotide polymorphisms in genes important for the immune response; heterozygous mutations in HLH-genes; environmental factors. Treatment of HLH is a balancing act between too little and too much therapy; cytokines have to be downregulated without destroying all immune defenses. Once HLH is controlled, therapy can be ended in acquired cases, whereas genetic cases need hematopoietic stem cell transplantation for cure. Therapy with corticosteroids and etoposide, as in the international HLH studies, is still the standard of care. New promising drugs are available; clinical trials have to confirm their efficacy.