HLH is characterized by an unremitting activation of CD8+ T lymphocytes and macrophages that leads to organ damage (notably in the liver, bone marrow, and central nervous system). This syndrome results from a broad set of inherited diseases, most of which impair T and NK lymphocyte cytotoxicity. The manifestations of HLH are often induced by a viral infection. EBV is the most frequent trigger. In severe forms of HLH, disease onset may start during the first year of life or even (in rare cases) at birth.
Diagnosis relies on the identification of the characteristic symptoms of HLH (fever, hepatosplenomegaly, edema, neurologic diseases, blood cytopenia, increased liver enzymes, hypofibrinogenemia, high triglyceride [hyperferritinemia] levels, elevated markers of T-cell activation, and hemophagocytic features in the bone marrow or cerebrospinal fluid). Functional assays of postactivation cytotoxic granule exocytosis (CD107 fluorescence at the cell membrane) can suggest genetically determined HLH. The conditions can be classified into three subsets:
1. Familial HLH with autosomal recessive inheritance, including perforin deficiency (30% of cases) that can be recognized by assessing intracellular perforin expression; Munc13-4 deficiency (30% of cases); syntaxin 11 deficiency (10% of cases); Munc18-2 deficiency (20% of cases); rare deficiencies in FAAP24 and RHOG; and a few residual cases that lack a known molecular defect.
2. HLH with partial albinism. Three conditions combine HLH and abnormal pigmentation, where hair examination can help in the diagnosis: Chédiak-Higashi syndrome, Griscelli syndrome, and Hermansky-Pudlak syndrome type II. Chédiak-Higashi syndrome is also characterized by the presence of giant lysosomes within leukocytes, in addition to a primary neurologic disorder with slow progression of symptoms over time.
3. XLP is characterized in most patients by the induction of HLH following EBV infection, while other patients develop progressive hypogammaglobulinemia similar to what is observed in CVID and/ or certain lymphomas. XLP is caused by a mutation in the SH2DIA gene that encodes the adaptor protein SAP (associated with a SLAM family receptor). Several immunologic abnormalities have been described, including low 2B4-mediated NK cell cytotoxicity, impaired differentiation of NKT cells, defective antigen-induced T-cell death, and defective T-cell helper activity for B cells. A related disorder (XLP2) has recently been described. It is also X-linked and induces HLH (frequently after EBV infection), although the clinical manifestation may be less pronounced. The condition is associated with a deficiency of the antiapoptotic molecule XIAP. The pathophysiology of XLP2 remains unclear; however, it may be related to control of inflammation in macrophages as there is a functional link between XIAP and NLRC4, an inflammasome component, in which gain of function can also induce HLH. XLP2 is also frequently associated with colitis.
HLH is a life-threatening complication. The treatment of this condition requires aggressive immunosuppression with either the cytotoxic agent etoposide or anti–T-cell antibodies; specific therapy targeting the IFN-γ pathway (JAK1), which is critical in causing HLH, is an additional option to consider. Once remission has been achieved, HSCT should be performed, since it provides the only curative form of therapy. Of note, acquired forms of HLH are more commonly observed in adults as a complication of infection, malignancies, or autoimmune diseases or sometimes on its own.
