Lessons Learned to Date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Hyperinflammation

Abstract

The first case of human transmission of SARS-CoV-2 was reported in China in December 2019. A few months later, this viral infection had spread worldwide and became a pandemic. The disease caused by SARS-CoV-2, termed COVID-19, is multifactorial and associated with both specific antiviral as well as inflammatory responses, the extent of which may determine why some individuals are asymptomatic while others develop serious complications. Here we review possible life-threating immune events that can occur during disease progression to uncover key factors behind COVID-19 severity and provide suggestions for interventions with repurposed drugs in wellcontrolled and randomized clinical trials. These drugs include therapeutics with potential to inhibit SARS-CoV-2 entry into host cells such as serine protease inhibitors of the cellular protease TMPS2 and drugs targeting the renin-angiotensin system; antivirals with potential to block SARS-CoV-2 replication or factors that could boost the antiviral response; monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response during COVID-19 progression toward the severe stage and therapeutics that could ameliorate the function of the lungs. Furthermore, in order to help make more informed decisions on the timing of the intervention with the drugs listed in this review, we have grouped these therapeutics according to the stage of COVID-19 progression that we considered most appropriate for their mechanism of action.

Obesity: A critical risk factor in the COVID‐19 pandemic

“…Obesity is associated with increased production of inflammatory cytokines such as TNF‐α, interleukins and interferons that characterize chronic low‐grade inflammation, which impair immune responses, both innate and adaptive. A hyperinflammatory response in which there are raised levels of interleukins and TNF‐α has been associated with increased mortality from COVID‐19 74 . The chronic inflammation in patients with obesity is speculated to be contributory to the observed increased mortality due to a potential enhancement of the inflammatory response to COVID‐19 infection and induced disturbances in T‐cell mediated immunity 75,76 .…”

The effect of tocilizumab on cytokine release syndrome in COVID-19 patients

“…In patients with COVID-19, especially those with a more severe pathology, there is a massive release of pro-inflammatory mediators and cytokines such as IL-1, IL-2, IL-6, IL-7, granulocyte colony-stimulating factor, macrophage inflammatory protein1-alpha, tumour necrosis factor α (TNFα), CRP, ferritin and d -dimer [ 15 – 19 ]. This cytokine storm, in addition to the patient’s aberrant immune response, is associated with viral replication and lung damage, with the formation of alveolar exudates that hinder gas exchange and favour the appearance of the ARDS, which can trigger multiorgan failure [ 17 , 19 , 20 ]. Based on these clinical parameters, it has been suggested that the immunological profile of the disease in severe COVID-19 patients resembles that of the CRS [ 21 , 23 ].…”

SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19

“…Infection can be asymptomatic or of varying degrees of severity. Severe COVID-19 that can result in death is characterized by pulmonary as well as multi-organ disease involving the heart, vascular system, kidneys as well as other organs and tissues (44)(45)(46)(47)(48). The cell receptor for SARS-CoV2 is angiotensin-converting enzyme 2 (ACE2), which is widely expressed on endothelial and smooth muscle cells in almost all organs (49).…”