Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous hyperinflammatory syndrome with different pathways of pathogenesis resulting in similar clinical presentations. It is best defined and understood if presenting in the context of genetic immunodeficiencies associated with defects of lymphocyte cytotoxicity. In these “primary” forms of HLH, cellular and soluble immune effectors are relatively well characterized. While etoposide-based broad cell-directed therapies remain standard of care, more specific therapies targeting these effectors individually are increasingly available. Anti-CD52 as a cell-directed therapy and anti-IFN-gamma, IL-18BP, and JAK-inhibition as cytokine-directed therapies are expected to broaden the therapeutic options, but the precise role of these drugs in first-line and rescue treatment indications remains to be defined. A number of additional inborn errors of immunity are associated with episodes of immune activation fulfilling the clinical criteria of HLH. Impaired pathogen control is a key driver of hyperinflammation in some conditions, while others are characterized by a strong autoinflammatory component. This heterogeneity of disease-driving factors and the variable severity in disease progression in these conditions do not allow a simple adaptation of protocols established for “primary” HLH to HLH in the context of other inborn errors of immunity. Cytokine-directed therapies hold significant promise in these increasingly recognized disorders.
Highlights
Reviewed by: Anna Shcherbina, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Russia
Poor T/natural killer cell (NK)-cell mediated control of Epstein-Barr virus (EBV)-infected B cells, in part linked to impaired activation of 2B4 mediated cytotoxic function, is the basis of hemophagocytic lymphohistiocytosis (HLH), that develops in about 30% of XLP1 patients [23]
In a retrospective single-center analysis of 38 patients with familial hemophagocytosis, a protocol consisting of steroids, cyclosporine A (CSA) and first-line Antithymocyte Globulin (ATG) resulted in a higher initial remission rate compared to the HLH-94 protocol but was associated with a higher percentage of relapses before Hematopoietic Stem Cell Transplantation (HSCT) (32% versus 13%) [54]
Summary
Hemophagocytic lymphohistiocytosis (HLH) is a highly inflammatory syndrome with uncontrolled, excessive immune activation. Clinical manifestations of HLH are mainly a result of tissue infiltration by T cells and macrophages and the accompanying excessive cytokine storm This model of “primary” HLH pathophysiology has mainly been established in key studies in cytotoxicity deficient mice that develop all clinical features used for the diagnosis of HLH in patients upon persistent wide-spread systemic infection with lymphocytic choriomeningitis virus [19]. In a group of additional inborn errors of immunity, HLH occurs less frequently, it can still be the presenting clinical manifestation In these diseases, HLH pathogenesis is variable and mostly different from that of “primary” disease (Table 1). Poor T/NK-cell mediated control of EBV-infected B cells, in part linked to impaired activation of 2B4 (a SLAM receptor) mediated cytotoxic function, is the basis of HLH, that develops in about 30% of XLP1 patients [23].
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