Less Can Be More When Targeting Interleukin-6-Mediated Cytokine Release Syndrome in Coronavirus Disease 2019

Coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome-coronavirus-2 is a worldwide public health emergency that will have a lasting generational impact in terms of mortality and economic devastation. Social distancing to prevent viral transmission and supportive care of infected patients are the main interventions now available. This global health crisis therefore merits innovative therapies. Cytokine release syndrome mediated by interleukin-6 is a critical driver of coronavirus disease 2019 mortality. Herein, we review and discuss key immunologic effects of direct interleukin-6 blockade, downstream nonselective Janus kinase inhibition, and selective Janus kinase 2 suppression to treat coronavirus disease 2019–related cytokine release syndrome. We provide evidence that selective targeting of interleukin-6 or Janus kinase 2 is well informed by existing data. This contrasts with broad, nonselective blockade of Janus kinase-mediated signaling, which would inhibit both deleterious and beneficial cytokines, as well as critical host antiviral immunity.