Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.

Figure 1

Pathogenesis of hemophagocytic lymphohistiocytosis. The function of LYST, probably important for correct size and function of lytic granules, is not entirely understood. Note the empty granula in perforin deficiency. Adapted from [8,47,88]. CHS, Chédiak Higashi syndrome; CTL, CD8+ cytotoxic T lymphocyte; FHL, familial hemophagocytic lymphohistiocytosis; GSII, Griscelli syndrome type II; HPSII, Hermansky-Pudlak syndrome type II; NK, natural killer.

Figure 2

Natural killer (NK) cell degranulation assay. X-axis, CD107a; y-axis, CD56. Note that the patient only shows 0.17% degranulation, the control 31.17%. Degranulation >15% is considered normal, 5 to 15% abnormal and possibly pathological, requiring additional testing, and <5% deficient.

Figure 3

Diagnostic work-up based on degranulation assays in suspected hemophagocytic lymphohistiocytosis. 2B4, surface molecule on NK cells; AICD, activation-induced cell death; CHS, Chédiak Higashi syndrome; CTL, CD8+ cytotoxic T lymphocyte; FHL, familial hemophagocytic lymphohistiocytosis; GS2, Griscelli syndrome type II; HLH, hemophagocytic lymphohistiocytosis; NK, natural killer; SAP, signaling lymphocytic activation molecule-associated protein; XIAP, X-linked inhibitor of apoptosis. This research was originally published in Blood. Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, Chiang SC, Marcenaro S, Meazza R, Bondzio I, Walshe D, Janka G, Lehmberg K, Beutel K, zur Stadt U, Binder N, Arico M, Moretta L, Henter JI, Ehl S: A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 2012, 119:2754-63. © The American Society of Hematology [51].

Figure 4

Microscopic findings in hemophagocytic lymphohistiocytosis and conditions predisposing to it. (a) Macrophage phagocytosing erythrocytes and erythroblast (bone marrow). (b,c) Giant granule in monocyte (bone marrow) (b) and small granules in neutrophil (peripheral blood) (c) in Chédiak Higashi syndrome (CHS). (d) Extracellular amastigotes in visceral leishmaniasis (bone marrow). (e) Pigment clumps in a hair shaft in a patient with Griscelli syndrome type II. (f) Evenly distributed melanin granules, larger as in normal hairs, in a patient with CHS. Smears are shown at 600× magnification, hair at 100×.