Pediatric hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multiorgan failure, and other manifestations. The syndrome has a high mortality rate. More and more, it is recognized that while HLH can be appropriately used as a broad summary diagnosis, many pediatric patients actually suffer from an expanding spectrum of genetic diseases that can be complicated by the syndrome of HLH. Classic genetic diseases in which HLH is a typical and common manifestation include pathogenic changes in familial HLH genes (PRF1, UNC13D, STXBP2, and STX11), several granule/pigment abnormality genes (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4, CDC42, and the Epstein-Barr virus susceptibility diseases. There are many other genetic diseases in which HLH is an infrequent complication of the disorder as opposed to a prominent manifestation of the disease caused directly by the genetic defect, including other primary immune deficiencies and inborn errors of metabolism. HLH can also occur in patients with underlying rheumatologic or autoinflammatory disorders and is usually designated macrophage activation syndrome in those settings. Additionally, HLH can develop in patients during infections or malignancies without a known (or as-yet-identified) genetic predisposition. This article will attempt to summarize current concepts in the pediatric HLH field as well as offer a practical diagnostic and treatment overview.

Graphical abstract

Figure 1.

Representative nonexhaustive flowchart of testing that can be considered during the evaluation of a pediatric patient with suspected HLH. No one algorithm is right for every patient. Clinicians should always consult with local multidisciplinary specialists regarding evaluations and consider consultation with physicians with expertise in HLH. Genetic testing should also be performed in many cases. CBC, complete blood count; CMV, cytomegalovirus; HSV, herpes simplex virus; PCR, polymerase chain reaction; PET-CT, positron emission tomography-computed tomography; TB, tuberculosis; TREC, T-cell receptor excision circle; VZV, varicella-zoster virus.

Figure 2.

Mechanisms of genetic HLH predisposition. HLH is thought to develop due to abnormal reciprocal activation of mononuclear phagocytes (MNPs; monocytes, macrophages, and dendritic cells) and type 1 lymphocytes (NK cells and Th1, CD8, and NKT cells). T cells with normal cytotoxic granules release them to induce MNP apoptosis and terminate the synapse, whereas impaired or perforin-deficient granules (gray) cannot terminate MNP activation. Immune synapse prolongation and excess IL-18 (from MNP and/or epithelial sources) both amplify production of lymphocyte cytokines like IFN-γ, which in turn further activates MNPs and promotes hemophagocytosis and release of HLH biomarkers like ferritin, CXCL9, and IL-18BP. Activated lymphocytes upregulate the IL-2 receptor, which is cleaved by proteases released by activated MNPs. The absence of XIAP may permit pathogenic inflammasome activation and lymphocyte apoptosis, while SAP deficiency impairs restimulation-induced cell death (RICD) and, like CD27 and CD70 deficiency, prevents normal killing of EBV-infected B cells.