Hemophagocytic lymphohistiocytosis: updates and evolving concepts

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulatory syndrome that is associated with underlying defects of perforin-dependent cytotoxic function. This review seeks to update readers on new scientific insights and evolving clinical concepts related to this rare but fatal disorder.

Clinically, HLH is defined by severe inflammation and potentially fatal damage to a variety of organ systems including the bone marrow, liver, or brain. Recent preclinical studies have increasingly defined HLH as a syndrome of abnormal and excessive T-cell activation, which leads to toxic activation of macrophages and other innate immune cells. Although macrophages have long been suspected to be important for disease development, recent studies have for the first time demonstrated their central role in the development of inflammation-associated cytopenias. In addition to defining new therapeutic targets, these scientific insights suggest significant overlap between HLH and severe inflammation in a variety of clinical contexts. Recent clinical observations are also changing how HLH is conceptualized. Increased recognition of HLH in older children and adults, sometimes in association with classic disease-associated mutations, is challenging the traditional view of HLH as either a distinctly familial or a sporadic disorder.

Recent scientific and clinical insights are expanding understanding and recognition of HLH, driving an evolution in how it is defined, and suggesting future directions for improving therapy of this disorder.