When T cells and macrophages do not talk: the hemophagocytic syndromes

Hemophagocytic lymphohistiocytoses represent a rare but biologically and clinically important group of disorders. This review focuses on the clinical, pathophysiologic and genetic manifestations of these disorders along with critical aspects of timely and appropriate treatment.

Detailed laboratory investigations have led to significant advances in our understanding of the molecular and pathophysiologic features of hemophagocytic lymphohistiocytoses. These studies have provided new diagnostic tools and potential new therapeutic targets for future development. Parallel to these laboratory studies have been enormous advances in the treatment and improved clinical outcomes of patients with both primary and secondary hemophagocytic lymphohistiocytoses. The eventual merging of the improved understanding of the molecular pathway with novel gene therapy approaches may prove to be the final frontier in the optimal curative treatment of these disorders.

Several key molecular events have been defined which lead to a final common etiologic pathway of natural killer cell dysfunction leading to the hemophagocytic lymphohistiocytosis syndromes. In part through international clinical trials, effective curative therapies for about half of patients with severe forms of hemophagocytic lymphohistiocytosis have been developed. Although a significant advance, the fact that about 50% of patients are still not able to be cured with currently used approaches challenges physician-scientists to develop more innovative and effective diagnostic and therapeutic approaches.