Pediatric hemophagocytic lymphohistiocytosis

Blood. 2020 Apr 16;135(16):1332-1343. doi: 10.1182/blood.2019000936.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / genetics
  • Calcium-Binding Proteins / genetics
  • Child
  • Disease Management
  • Epstein-Barr Virus Infections / complications
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Lymphohistiocytosis, Hemophagocytic / diagnosis*
  • Lymphohistiocytosis, Hemophagocytic / genetics
  • Lymphohistiocytosis, Hemophagocytic / physiopathology
  • Lymphohistiocytosis, Hemophagocytic / therapy*
  • Signaling Lymphocytic Activation Molecule Associated Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / genetics

Substances

  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • NLRC4 protein, human
  • SH2D1A protein, human
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human