Clinical Information

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder characterized by fever, cytopenias, coagulopathy, hepatosplenomegaly, neurologic symptoms, and hemophagocytosis in the bone marrow, spleen, lymph nodes, or liver. Patients often have elevated ferritin and soluble interleukin-2 receptor as well as low fibrinogen. The Histiocyte Society established criteria for HLH for the HLH-2004 clinical trial, and these criteria are often referred to by physicians considering a diagnosis of HLH. Primary HLH, also known as familial HLH (F-HLH), is attributed to disease-causing variants in several genes. Secondary, or acquired, HLH can be triggered by infection, malignancy, transplant, autoimmune disorders, or drugs. While the terms "primary" and "secondary” have been in use for some time, the North American Consortium for Histiocytosis recommended a new classification system that divides HLH into forms that respond to immunosuppressive treatment, which are referred to as “HLH disease,” and into forms that do not respond to immunosuppressive treatment, which are referred to as "HLH mimics."

In the pediatric population, the incidence of HLH is thought to range from 1 to 225 per 300,000 live births, be equally distributed between male and female infants, with the mean age of occurrence of 1.8 years. The epidemiology among adults is less well-studied; however, the incidence is estimated to be 1 of every 2000 adult admissions to tertiary medical centers, with a mean age at presentation of approximately 50 years.

Many genes have now been identified in association with F-HLH. In a pediatric population, genetic variants in PRF1 are account for approximately 25% of cases, while STXBP2 and UNC13D are each responsible for approximately 20% of cases, and XIAP accounts for 10% of cases. Disease-causing variants in PRF1, UNC13D, STX11, and STXBP2 prevent the release of cytotoxic granules into the immunological synapse, resulting in an inability to kill target cells. Pigment disorders, including Griscelli syndrome type 2, Chediak-Higashi syndrome, and Hermansky-Pudlak syndrome type 2 (due to variants in RAB27A, LYST, and AP3B1, respectively) also are associated with HLH. Due to significant granule trafficking defects, patients may also have bleeding tendencies, neutropenia, and neurological symptoms. X-linked lymphoproliferative disorders and Epstein-Barr virus susceptibility disorders are also associated with HLH. While most forms of F-HLH are inherited in an autosomal recessive pattern, there are autosomal dominant and X-linked forms.