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.

Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

“…Comorbidities such as hypertension, diabetes, obesity, and atherosclerosis are related to the severe form of the disease, being more prevalent among hospitalized individuals with a higher average-case lethality [ [6] , [7] , [8] , [9] , [10] , [11] , [12] ]. The disease severity is characterized by the overactivation of the immune system causing a cytokine storm responsible for cytokine release syndrome (CRS) [ 13 , 14 ]. The inflammatory response starts with a local release of cytokines, such as interleukin-6 (IL-6) and tumoral necrosis factor-alpha (TNF-α), that may spread systemically, leading to acute respiratory distress syndrome (ARDS) and multiple organ failure, the final result being death, at least in the most severe cases of COVID-19 [ 15 , 16 ].…”

JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

“…As JAK inhibitors attenuate JAK signaling and subsequent cytokine release, their administration may best be suited for patients with progressing COVID-19 who have not yet experienced a cytokine storm. [40] By contrast, as Type I interferons induce cellular antiviral states via the JAK/STAT pathway, its administration may be most efficacious early on in disease progression where the virus is still replicating. While the literature surrounding this is sparse, one study included in this meta-analysis concluded that early administration of interferon-alpha-2b could induce positive outcomes in COVID-19 patients compared to standard treatment, while its late administration was associated with slower recovery.…”

Monoclonal Antibodies Capable of Binding SARS-CoV-2 Spike Protein Receptor Binding Motif Specifically Prevent GM-CSF Induction

“…Furthermore, we have found two RBM-cross-reactive monoclonal antibodies that competitively and MCP-1). It has also been suggested as a "driver" of the disease progression particularly in a subset (~ 20%) of COVID-19 patients with more severe pneumonia that often escalates to respiratory failure and death [26][27][28][29] . Furthermore, GM-CSF might also be a key mediator of the cytokine storm in COVID-19 and other inflammatory diseases 30,31 .…”