Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents

Abstract

Background Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. Discussion We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. Conclusion Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.

Potential COVID‐19 Therapeutic Agents and Vaccines: An Evidence‐Based Review

“…Moreover, IL‐6 also plays a pivotal role in the recruitment of macrophages, progression of inflammation, CRS, and ARDS. This excessive inflammatory response enhances vascular permeability and lung epithelial and endothelial cell apoptosis, which leads to ARDS and ventilation requirement 17 . Furthermore, this hyperinflammatory situation associates with coagulopathy, disseminated intravascular coagulation, and thromboembolisms in a small fraction of patients with critical COVID‐19.…”

Ultrarapid On-Site Detection of SARS-CoV-2 Infection Using Simple ATR-FTIR Spectroscopy and an Analysis Algorithm: High Sensitivity and Specificity

“… 3 SARS-CoV-2 exhibits a high propensity for infectious spread throughout populations. 2 Every COVID-19 positive case, if not contained, can readily spread to two or more people giving a virulent R number. 4 Some countries, such as South Korea, initially successfully fought the COVID-19 outbreak.…”

Activin A correlates with the worst outcomes in COVID-19 patients, and can be induced by cytokines via the IKK/NF-kappa B pathway

“…Initial viral load does correlate with disease severity (Fajnzylber et al, 2020). However, the cytokine storm often comes later in the disease, indicating the cytokine storm is part of the immune response to the virus (Khadke et al, 2020). The impression, therefore, is that these severely affected patients are not suffering directly from the viral load, but instead from an over-reaction of the immune system -the later occurring cytokine response, which in some patients over-induces Activin A.…”