Hemophagocytic lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) is a condition in which the body makes too many activated immune cells (macrophages and lymphocytes).[1] People with HLH usually develop symptoms within the first months or years of life. Symptoms may include fever, enlarged liver or spleen, cytopenia (decreased number of blood cells), and neurological abnormalities.[2][3] HLH may be inherited in an autosomal recessive manner or it can have non-genetic causes in which case it is called acquired HLH. There are five subtypes of inherited HLH which are designated as familial HLH, types 1-5. Each subtype is caused by a change (mutation) in a different gene. The genetic cause of type 1 is currently unknown. Types 2-5 are caused by mutations in the PRF1 gene, the UNC13D gene, the STX11 gene and the STXBP2 gene, respectively.[4] Treatment depends on a number of factors, including the severity of symptoms, the age of onset, and the underlying cause of the condition.[4][5]

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.[6]

CLINICAL FEATURES

Initial presentation — HLH presents as a febrile illness associated with multiple organ involvement. Thus, initial signs and symptoms of HLH can mimic common infections, fever of unknown origin, hepatitis, or encephalitis. With few exceptions, the clinical features are similar regardless of whether an underlying genetic defect has been identified. (See 'Genotype-phenotype correlations' above.)

The HLH-2004 study, which included 369 patients, reported the following clinical findings [77]:

●Fever – 95 percent

●Splenomegaly – 89 percent

●Bicytopenia – 92 percent

●Hypertriglyceridemia or hypofibrinogenemia – 90 percent

●Hemophagocytosis – 82 percent

●Ferritin >500 mcg/L – 94 percent

●Low/absent NK cell activity – 71 percent

●Soluble CD25 elevation – 97 percent

In addition to the typical presenting signs and symptoms, some HLH gene mutations are associated with distinct clinical features. As an example, a review of 37 patients with STXBP2 mutations reported hypogammaglobulinemia, severe diarrhea, bleeding, and sensorineural hearing loss in 59, 38, 22, and 16 percent, respectively [58]. Defective granule mobilization by neutrophils has also been identified in these patients [78]. This leads to inadequate bacterial killing, especially of gram negative bacteria, and is hypothesized to lead to the association of chronic diarrhea in this subset of HLH patients.

Some clinical findings are observed less frequently in affected patients from different ethnic groups. This was illustrated in a case series of 20 neonates from Japan, in which the incidence of fever was extremely low in the eight preterm infants (12 percent); hypertriglyceridemia and neutropenia were uncommon; and familial mutations were undetectable in most patients (65 percent) [79].