A Cytokine Circus with a Viral Ringleader: SARS-CoV-2-Associated Cytokine Storm Syndromes

Abstract

An unbridled host immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to underlie severe cases of the disease and has been labeled a 'cytokine storm syndrome' (CSS). Here, we emphasize that categorization of syndromes triggered by a completely novel pathogen based on other seemingly similar, but potentially distinct, known entities is an inherently risky endeavor.

Keywords: COVID-19;cytokine storm syndrome; inflammation; multisystem inflammatory syndrome in children; severe acute respiratory syndrome coronavirus 2; virology.

Figure 1

Schematic Overview of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Associated Cytokine Storm Syndrome (S-CSS) and Multisystem Inflammatory Syndrome in Children (MIS-C). (A) SARS-CoV-2 infects Type II pneumocytes initially in airways and alveoli, resulting in activation of alveolar macrophages, cytokine production, and additional inflammatory infiltration. (B) Simplified SARS-CoV-2 viral lifecycle indicating production of non-structural proteins (NSPs) that suppress an initial interferon (IFN) response in infected cells that ordinarily restricts viral replication. This virulence mechanism may contribute proximally to a dysregulated inflammatory response. (C) S-CSS occurs primarily in adults and involves multiple organ systems, most prominently the lung, heart, liver, gastrointestinal, renal, vasculature, coagulation, and lymphoid populations. Lung injury and multiorgan dysfunction may also contribute to each other in a feed-forward manner (double-headed arrow). Proposed mechanisms of S-CSS include: (i) cytokine hyperproduction; (ii) cellular injury to directly infected cells; (iii) coagulopathy due to endothelial injury; and/or (iv) depletion of lymphocyte populations. (D) MIS-C occurs primarily in children with distinct findings, including prominent cardiac and gastrointestinal involvement, and more infrequent or less severe involvement of other systems. It remains to be determined whether MIS-C is a direct consequence of cytokines produced by acute or persistent infection (i); direct infection of involved tissues (ii); or (iii) represents a delayed para-infectious autoinflammatory complication of SARS-CoV-2 exposure (indicated by hourglass symbol). ≈, reflects the uncertainty over whether MIS-C is a distinct syndrome or exists along the spectrum of disease seen in S-CSS. In (C) and (D), more severe or frequently involved systems are indicated by red outlines, less severe or more infrequent involvement by orange outlines.