Risk Factors Associated with the Clinical Outcomes of COVID-19 and Its Variants in the Context of Cytokine Storm and Therapeutics/Vaccine Development Challenges
Vaccines 2021, 9, 938. https://doi.org/10.3390/vaccines 9080938
John Hanna 1,+, Padmavathi Tipparaju 1,+, Tania Mulherkar1, Edward Lin 1, Victoria Mischley1, Ratuja Kulkarni1, Aliyah Bolton 1, Siddappa N. Byrareddy 2 and Pooja Jain *0
Department of Microbiology and Immunology, Drexel University College of Medicine Philadelphia,
2900 Queen Lane, Philadelphia, PA 19129, USA; jh3743 at drexel.edu (J.H.); pvt24 at drexel.edu (P.T.); thm35 at drexel.edu (T.M.); ewl35 at drexel.edu (E.L.); vmm75 at drexel.edu (V.M.); ratujak at gmail.com (R.K.); arb432 at drexel.edu (A.B.)
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; sid.byrareddy at unmc.edu * Correspondence: pj27 at drexel.edu + These authors contribute equally to this work.
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Abstract 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 positivesense 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.
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Fat-soluble vitamin D is obtained by humans either through diet or produced endogenously when UV rays from sunlight trigger synthesis in the skin , The vitamin D receptor is expressed on immune cells, including B cells, T cells, and antigen-presenting cells, allowing these immune cells to synthesize the active form of vitamin D , Vitamin D can reduce infections through the induction of cathelicidins and defensins, which lower viral replication rates and reduce the elevation of proinflammatory cytokines , A deficiency in vitamin D can lead to increased autoimmunity and susceptibility to infection, The European Calcified Tissue Society Working Group has defined severe vitamin D deficiency as having serum 25(OH)D levels of lower than 30 nmol/L . Several factors can lead to deficiency, such as the inability to sufficiently synthesize vitamin D . Although COVID- 19 can infect all age groups, most severe cases are typically seen in older populations with underlying conditions such as cardiovascular and pulmonary disease . These same older populations are also most susceptible to severe vitamin D deficiency, which may further exacerbate poor immune outcomes in these patients. It is also worth noting that geographical location may also affect vitamin D synthesis: for example, the aging population in Southern Europe has the most deficient vitamin D levels given that they typically spend less time outdoors, and skin pigmentation decreases vitamin D synthesis . Thus, an additional risk factor in poor SARS-CoV-2 outcomes may relate to geographical variation in relation to vitamin D deficiency.
Vitamin D has also been associated with hypertension and can impact the renin- angiotensin system. A randomized control study performed by McMullan et al. demonstrated that lower circulating 25-hydroxyvitamin D (25(OH)D) is associated with increased renin-angiotensin system (RAS) activity and thus increased blood pressure in humans . Given that hypertension is a crucial risk factor for COVID-19, this further suggests that vitamin D deficiency creates a critical risk factor for severe COVID-19 outcomes. Multiple cross-sectional analyses support these findings by showing that vitamin D deficiency was a common risk factor among two countries with the highest COVID-19 mortality rates, Italy and Spain . Thus, several studies have encouraged higher vitamin D3 doses as part of the treatment process for those infected by COVID-19 .
There have also been links between vitamin D and HLA-DR expression. In the past, vitamin D deficiency has been associated with a poorer prognosis in autoimmune conditions such as rheumatoid arthritis, lupus, and MS and an increased susceptibility toward infectious diseases such as respiratory tract infections and tuberculosis [78,79]. Recently, vitamin D has been postulated to increase susceptibility to SARS-CoV-2 due to both the outbreak occurring in the winter and the older population infected, both factors associated with vitamin D deficiency . Research has shown that calcitriol, a vitamin D derivative, upregulated CD14 expression and downregulated HLA-DR expression . Furthermore, vitamin D inhibited an increase in HLA-DR expression while limiting dendritic cell maturation . Vitamin D may be necessary for preventing the overactivation of the immune system seen in macrophage activation syndrome or the cytokine storm experienced by patients with severe COVID-19. Moreover, the other mechanisms of vitamin D's regulation on the immune system, such as downregulating the ACE2 receptor, could outweigh the harm done by downregulating HLA-DR and preventing DC maturation .
Deficiency in vitamin D has also been linked to an increase in IL-6, which is known to peak at the height of respiratory failure in COVID-19 cases. Vitamin D inhibits monocyte production of inflammatory cytokines, including IL-6, allowing healthy regulation. Therefore, vitamin D deficiency provides a risk factor for elevated IL-6 levels, and in turn, could be used as an indicator of potential severe respiratory symptoms in COVID-19 patients . Previous CoV pandemics such as SARS and MERS also show evidence of vitamin D deficiency-related complications. Vitamin D deficiency can contribute to complications such as cytokine storms, which were seen in many SARS and MERS cases. Due to observations of low vitamin D levels and high IL-6 expression in SARS, MERS, and COVID-19 patients, vitamin D supplementation may be considered as a useful measure to prevent dangerous symptoms from developing in viral respiratory infections .