Cytokine Storm

Cytokine StormTo the Editor: In their review article on cytokine storm, Fajgenbaum and June (Dec.3 issue) 1 include a discussion of signaling by mitogenactivated protein kinase (MAPK), nuclear factor κB, and mammalian target of rapamycin.We feel compelled to point out one major omission that has a clear therapeutic effect for cytokine storm in general and for therapies for coronavirus disease 2019 (Covid-19) in particular: the p38 MAPK-MAPKAPK2 pathway.This pathway is a master regulator that controls the expression of many proinflammatory cytokines in myeloid and lymphoid cells, including interleukin-6, interleukin-1β, interferon-γ, and tumor necrosis factor α, through both transcriptional and post-transcriptional mechanisms after tissue damage or exposure to pathogen-associated molecular patterns or other stimuli.[2][3][4] Covid-19 infection has been shown to lead to phosphorylation and activation of p38 MAPK. 5 Therefore, small-molecule inhibitors of p38 MAPK (e.g., losmapimod) and of the p38 MAPK-MAPKAPK2 signaling complex (e.g., ATI-450) are currently in clinical trials as anti-Covid-19 therapeutics (ClinicalTrials.govnumbers, NCT04511819 and NCT04481685, respectively).These two drugs are expected to show efficacy that extends beyond that seen with single monotherapies directed at individual cytokines alone.