Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts

Abstract

Clinical evidence indicates that the fatal outcome observed with severe acute respiratory syndrome-coronavirus-2 infection often results from alveolar injury that impedes airway capacity and multi-organ failure-both of which are associated with the hyperproduction of cytokines, also known as a cytokine storm or cytokine release syndrome. Clinical reports show that both mild and severe forms of disease result in changes in circulating leukocyte subsets and cytokine secretion, particularly IL-6, IL-1β, IL-10, TNF, GM-CSF, IP-10 (IFN-induced protein 10), IL-17, MCP-3, and IL-1ra. Not surprising, therapies that target the immune response and curtail the cytokine storm in coronavirus 2019 (COVID-19) patients have become a focus of recent clinical trials. Here we review reports on leukocyte and cytokine data associated with COVID-19 disease in 3939 patients in China and describe emerging data on immunopathology. With an emphasis on immune modulation, we also look at ongoing clinical studies aimed at blocking proinflammatory cytokines; transfer of immunosuppressive mesenchymal stem cells; use of convalescent plasma transfusion; as well as immunoregulatory therapy and traditional Chinese medicine regimes. In examining leukocyte and cytokine activity in COVID-19, we focus in particular on how these levels are altered as the disease progresses (neutrophil NETosis, macrophage, T cell response, etc.) and proposed consequences to organ pathology (coagulopathy, etc.). Viral and host interactions are described to gain further insight into leukocyte biology and how dysregulated cytokine responses lead to disease and/or organ damage. By better understanding the mechanisms that drive the intensity of a cytokine storm, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; immunotherapy; leukocyte.

Graphical abstract

FIGURE 1

Major blood leukocyte, cytokine changes, and therapy strategies in mild vs. severe SARS-CoV-2 infection. Conceptual model of the interplay between immune activation and clinical pathology from patients with mild vs. severe infection, as well as current therapeutic strategies and possible outcome. Figure is made with BioRender (https://app.biorender.com/)

FIGURE 2

Severe SARS-CoV-2 infection: summary of aberrant activation of leukocytes and cytokine production contributing to a cytokine storm and pathology. Conceptual model of observations associated with severe SARS-CoV-2 infection. The activation of monocytes/macrophages and lymphocyte subsets in blood are likely to be major sources of cytokine release, together with the infiltration of leukocytes into lung tissue. Alveolar injury is shown to be associated with cell infiltrates, the release of neutrophil extracellular traps (NETs), hyperplasia of type II pneumocytes, among others, all of which could result in ARDS, lung insufficiency and a cytokine storm (exacerbated if combined with a superimposed bacterial infection). COVID-19/bacterial pneumonia image provided by: Dr. Ana S. Kolansky, University of Pennsylvania. Figure is made with BioRender (https://app.biorender.com/)