The expanding spectrum of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is more widely recognized by clinicians. No longer viewed as a disorder of young children, adult patients are now being identified and treated. In this review, I summarize clinical features of patients with recently identified genetic causes, discuss a new paradigm for understanding the clinical evolution of HLH, and update current results with hematopoietic cell transplantation.

The list of genetic defects underlying HLH continues to grow. Among the autosomal recessive defects underlying HLH, we add STX11 (Syntaxin 11) - a snare protein, and MUNC18-2 (also known as STXBP2 - Syntaxin-binding protein). These two proteins now join MUNC 13-4 as components of the degranulation machinery in cytotoxic lymphocytes, responsible for the delivery of Perforin and Granzyme B to selectively kill target cells. The mechanism of action in the newest X-linked disorder associated with HLH, XIAP deficiency (also termed XLP 2), is currently unknown. Treatment of HLH has also improved in recent years, at least in experienced centers where a significant number of patients are seen. Clinicians who are familiar with the dynamic evolution of the disease are learning how to modify treatment when initial or continuation therapy fails to achieve a stable clinical status, preferably clinical remission. Use of reduced intensity conditioning protocols pretransplant has resulted in superior short-term and long-term survival rates of greater than 85%.

Substantial progress continues to be made in exploring the complex cause and pathophysiology of HLH. Hand in hand, a greater recognition of the condition has led to improved treatments.