Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by extreme immune activation, resulting in pathologic inflammation. The diagnosis includes a spectrum of inherited or acquired defects in cytotoxic lymphocyte function, often with uncontrolled infections. HLH may also arise as the result of persistent antigen stimulation due to autoimmune disease or malignancy. HLH is often described in binary terms as "primary," indicating Mendelian inheritance of gene mutations resulting in cytotoxic lymphocyte dysfunction, or "secondary" indicating an acquired reactive disorder. Increasing evidence describes HLH as more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Early recognition of HLH and evaluation of potential causes is critically important, as survival generally requires urgent treatment with immune suppression and resolution of the activating antigen. However, the diagnosis of HLH is challenged by the myriad of pathways that lead to pathologic inflammation and the clinical overlap with other conditions. Further improvements in therapy will require prospective trials to define optimal strategies for each patient based on the individual paths that lead to pathologic inflammation.