Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy

Best Pract Res Clin Rheumatol. 2020 Aug;34(4):101515. doi: 10.1016/j.berh.2020.101515. Epub 2020 May 7.


Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic triggers. Sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.

Keywords: Hemophagocytic lymphohistiocytosis (HLH); Macrophage activation syndrome (MAS).

Publication types

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

MeSH terms

  • CD8-Positive T-Lymphocytes
  • Cytokines
  • Glucocorticoids
  • Humans
  • Lymphohistiocytosis, Hemophagocytic* / diagnosis
  • Lymphohistiocytosis, Hemophagocytic* / etiology
  • Lymphohistiocytosis, Hemophagocytic* / therapy
  • Macrophage Activation Syndrome* / diagnosis
  • Macrophage Activation Syndrome* / etiology
  • Macrophage Activation Syndrome* / therapy


  • Cytokines
  • Glucocorticoids