Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury

Abstract

Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies. Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies. Within the 10 months following notification by the World Health Organization's (WHO) China Country Office of a pneumonia of unknown cause detected in the city of Wuhan (Hubei province, China) (January 2020), the COVID-19 pandemic, now known to be caused by Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2), has fundamentally altered global health and economies and changed our country, community and families.1Garg S Kim L Whitaker M et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 - COVID-NET, 14 States, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464Crossref PubMed Scopus (0) Google Scholar To date (November 2020), the pandemic has resulted in more than 55 million infected individuals worldwide and ∼1.3 million deaths.2Sokouti M Sadeghi R Pashazadeh S et al.Comparative Global epidemiological investigation of SARS-CoV-2 and SARS-CoV diseases using meta-MUMS tool through incidence, mortality, and recovery rates.Arch Med Res. 2020; 51: 458-463Crossref PubMed Scopus (14) Google Scholar Whereas the majority (80%) of patients with confirmed SARS-CoV-2 infection exhibit mildly symptomatic, self-limited coronavirus disease (COVID-19), approximately 15% of infected subjects progress to severe pneumonia requiring supplemental oxygen and 5% further progress to develop acute respiratory distress syndrome (ARDS), and/or multiorgan failure (MOF)3Wu Z McGoogan JM Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242Crossref PubMed Scopus (11871) Google Scholar (Fig 1) which drives mortality rates that surpass 40%. The unprecedented nature of the SARS-CoV-2/COVID-19 pandemic has highlighted multiple unmet medical needs including the glaring absence of effective FDA–approved targeted pharmacotherapies.5Bohn MK Hall A Sepiashvili L Jung B Steele S Adeli K Pathophysiology of COVID-19: mechanisms underlying disease severity and progression.Physiology. 2020; 35: 288-301Crossref PubMed Scopus (144) Google Scholar This has created urgency within basic science, translational, and clinical research communities, particularly as immunity-derived protection against the novel coronaviruses such as SARS (severe acute respiratory syndrome, 2002-2004), and MERS (Middle East respiratory syndrome, 2012-2015) proved to be inefficient and unpredictable.6Li CK-f Xu X Host immune responses to SARS coronavirus in humans.Mol Biol SARS-Coronavirus. 2009; : 259-278https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123234/pdf/978-3-642-03683-5_Chapter_16.pdfGoogle Scholar,7Kumar S Nyodu R Maurya VK Saxena SK Host Immune Response and Immunobiology of Human SARS-CoV-2 Infection.Coronavirus Dis 2019 (COVID-19). 2020; : 43-53https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189399/pdf/978-981-15-4814-7_Chapter_5.pdfCrossref Google Scholar The availability of effective SARS-CoV-2 vaccines and anti-SARS-CoV-2 drugs are imminent and of obvious utility, however, neither therapeutic strategy addresses the pathobiology of COVID-19-ARDS, that is, the unremitting activation of innate immunity inflammatory pathways with unchecked lung and systemic inflammation. The activation of evolutionarily-conserved inflammatory cascades by SARS-CoV-2, as well as significant amplification of these pathways by exposure to excessive levels of ventilator-induced mechanical stress,8Wu J Yan Z Schwartz DE Yu J Malik AB Hu G Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury.J Immunol. 2013; 190: 3590-3599Crossref PubMed Scopus (191) Google Scholar results in massive increases in circulating levels of inflammatory cytokines producing vascular leak, edema of multiple critical organ (lung, kidneys, heart, brain, liver, gastrointestinal tract), and dysregulated activation of the coagulation cascade, ultimately leading to multiorgan dysfunction and death.9Brower RG Matthay MA et al.Acute Respiratory Distress Syndrome NVentilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.N Engl J Med. 2000; 342: 1301-1308Crossref PubMed Scopus (10443) Google Scholar, 10Hong SB Huang Y Moreno-Vinasco L et al.Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury.Am J Respir Crit Care Med. 2008; 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