Is COVID-19-associated cytokine storm distinct from non-COVID-19 secondary hemophagocytic lymphohistiocytosis?

Exp Biol Med (Maywood). 2022 Feb;247(4):330-337. doi: 10.1177/15353702211068840. Epub 2022 Jan 22.


Cytokine storm is an umbrella term that describes an inflammatory syndrome characterized by elevated levels of circulating cytokines and hyperactivation of innate and/or adaptive immune cells. One type of cytokine storm is hemophagocytic lymphohistiocytosis (HLH), which can be either primary or secondary. Severe COVID-19-associated pneumonia and acute respiratory distress syndrome (ARDS) can also lead to cytokine storm/cytokine release syndrome (CS/CRS) and, more rarely, meet criteria for the diagnosis of secondary HLH. Here, we review the immunobiology of primary and secondary HLH and examine whether COVID-19-associated CS/CRS can be discriminated from non-COVID-19 secondary HLH. Finally, we review differences in immunobiology between these different entities, which may inform both clinical diagnosis and treatment of patients.

Keywords: COVID-19; Cytokines; hemophagocytic lymphohistiocytosis; immunobiology; immunology/microbiology/virology; inflammation.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Neutralizing / therapeutic use
  • COVID-19 / complications*
  • Cytokine Release Syndrome / etiology*
  • Cytokine Release Syndrome / therapy*
  • Cytokine Release Syndrome / virology
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use
  • Lymphohistiocytosis, Hemophagocytic / diagnosis*
  • Lymphohistiocytosis, Hemophagocytic / etiology*
  • Lymphohistiocytosis, Hemophagocytic / immunology
  • Lymphohistiocytosis, Hemophagocytic / therapy


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Emapalumab
  • Interleukin 1 Receptor Antagonist Protein