In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.
Although most patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience mild to moderate symptoms that resolve after 6–10 days, almost 20% of patients develop severe illness characterized by atypical interstitial bilateral pneumonia and acute respiratory distress syndrome, with a high fatality rate.
Accumulating evidence suggests that an unbalanced and unrestrained innate immune response, which comes at the expense of effective adaptive immunity, underpins the progression of coronavirus disease 2019 (COVID-19).
In severe cases of COVID-19, massive endothelial dysfunction, widespread coagulopathy and complement-induced thrombosis can lead to the development of systemic microangiopathy and thromboembolism; these complications can be life-threatening and ultimately lead to multi-organ failure.
The kidney is one of the main targets of COVID-19 complications, and abnormal kidney function is associated with a significantly increased risk of death in severely ill patients.
Most repurposed anti-viral drugs have failed to improve clinical outcomes in COVID-19; by contrast, therapeutic interventions that target the host response, including the hyper-immune response, complement activation and systemic thrombosis, seem to be more promising approaches to the treatment of severe COVID-19
Available evidence demonstrates that SARS-CoV-2 infection induces immune dysfunction, widespread endothelial injury, complement-associated coagulopathy and systemic microangiopathy. The clinical outcome of COVID-19 seems to be profoundly dependent on the individual response of the host. Although the contribution of differences in viral loads to clinical outcome cannot be excluded271, it is possible that predisposing genetic or biological factors may modulate the degree of disease severity. Additionally, socioeconomic conditions and structural racism may contribute to poor disease outcomes in some regions, as demonstrated by disproportionately poor outcomes among minority ethnic groups, including Black, Asian and Pakistani populations272. Improved insights into the mechanisms underlying predisposition to adverse disease outcomes might aid the identification of new strategies and targets for therapy, as well as identify ways to improve outcomes for susceptible individuals and those from minority ethnic backgrounds. However, the development of new drugs is a long process and may not be useful for dealing with the immediate challenge posed by the current COVID-19 pandemic.
Currently, no vaccines or effective antiviral drugs are available for COVID-19, although many are in development and some may become available soon. The paucity of available specific therapies has stimulated the search for existing drugs that can be repurposed for COVID-19. So far, these drugs have included steroids, several anti-interleukin drugs, complement inhibitors and agents that target coagulation and endothelial dysfunction. However, some of these next-generation targeted therapies are not devoid of adverse effects, which can be serious and sometimes life-threatening. The identification of inexpensive and effective drugs — including low-dose steroids and LWMH — is of utmost importance to prevent exacerbation of inflammatory and thrombotic processes and halt disease progression. Given the spectrum of pathogenic mechanisms involved in the development of severe COVID-19, ranging from immune hyperactivation to thromboembolic complications, it is unlikely that a single individual treatment will be effective. Although corticosteroids may be able to target most of these pathogenic pathways, the multifactorial pathogenic nature of the disease indicates that multiple avenues of treatment might be required and major effort should therefore be invested to determine the optimal timing and combinations in which these drugs should be administered to maximize their efficacy in severely ill patients with COVID-19.
Reference & source information : https://www.nature.com/
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