Immunomodulation as Treatment for Severe Coronavirus Disease 2019: A Systematic Review of Current Modalities and Future Directions

Clin Infect Dis. 2021 Jun 15;72(12):e1130-e1143. doi: 10.1093/cid/ciaa1759.


In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; hyperinflammatory; immunomodulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Systematic Review

MeSH terms

  • Antiviral Agents / therapeutic use
  • COVID-19*
  • Humans
  • Immunity, Humoral
  • Immunomodulation
  • Randomized Controlled Trials as Topic
  • SARS-CoV-2


  • Antiviral Agents