Risk Factors Associated with the Clinical Outcomes of COVID-19 and Its Variants in the Context of Cytokine Storm and Therapeutics/Vaccine Development Challenges

The recent appearance of SARS-CoV-2 is responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic and has brought to light the importance of understanding this highly pathogenic agent to prevent future pandemics. This virus is from the same single-stranded positive-sense RNA family, Coronaviridae, as two other epidemic-causing viruses, SARS-CoV-1 and MERS-CoV. During this pandemic, one crucial focus highlighted by WHO has been to understand the risk factors that may contribute to disease severity and predict COVID-19 outcomes. In doing so, it is imperative to understand the virology of SARS-CoV-2 and the immunological response eliciting the clinical manifestation and progression of COVID-19. In this review, we provide clinical data-based analyses of how multiple risk factors (such as sex, race, HLA genotypes, blood groups, vitamin D deficiency, obesity, smoking, and asthma) contribute to the inflammatory overactivation and cytokine storm (frequently seen in COVID-19 patients) with a focus on the IL-6 pathway. We also draw comparisons to the virulence and pathophysiology of SARS and MERS to establish parallels in immune response and discuss the potential for therapeutic approaches that may limit disease progression in patients with higher risk profiles than others. Moreover, we cover the latest information on approved or upcoming COVID-19 vaccines. This paper also provides perspective on emerging variants and associated opportunistic infections such as black molds and fungus that have added to mortality in some parts of the world, such as India. This compilation of existing COVID-19 studies and data will provide an excellent referencing tool for the research, clinical, and public health communities.