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.

Keywords: Acute respiratory distress syndrome; Angiotensin converting enzyme 2; Antiviral; COVID-19; Chloroquine; Cytokine release syndrome; Immunotherapy; Pathophysiology; SARS-CoV-2; Tocilizumab.

Fig. 1

Viral replication pathway of Covid-19. The virus first attaches to the ACE2 receptor and internalizes into the respiratory epithelial cell and causes the release of its genome. The S protein (spikes on the viral surface responsible for attachment to host cell receptors), M protein (shapes the virion, promotes membrane curvature and binds to the nucleocapsid), E protein (helps with viral assembly and release)

Fig. 2

Alveolar micro-environment showing pathophysiology of acute respiratory distress syndrome (ARDS). The Th response causes the release of IL-17 which activates TNF alpha which enhances epithelial injury and activates neutrophils to cause degranulation. IL-6 is produced by alveolar macrophages which also stimulates neutrophils. Once the epithelial integrity of alveolus is breached epithelial sodium channel (Enac) channels and Na/K channels fail to maintain homeostasis eventually leading to an increase in permeability of capillaries causing exudation of fluids. T reg cells also trigger TGF beta which causes fibrosis to the damaged epithelial membrane. Most of the COVID-19 patients present with ground-glass opacities and fibrosis of their lungs

Fig. 3

Immune dysregulation in cytokine release syndrome. The involvement of the immune system in COVID-19 is in 3 phases: initial inflammation which is characterized by delayed interferon response and robust viral replication, the pulmonary inflammation phase which is characterized by sub-optimal T-cell and antibody response, leading to increased vascular leakage and permeability and impaired viral clearance, and the hyperinflammation phase which is characterized by very severe infiltration of monocytes, macrophages and neutrophils—this leads to progressive lung injury and ARDS as well as hemodynamic instability and shock