Role of vitamin D deficiency and comorbidities in COVlD-19

Gabriela Gama Freire Alberca,Ricardo Wesley Alberca

Gabriela Gama Freire Alberca,Department of Microbiology,Institute of Biomedical Sciences-University of São Paulo,São Paulo 04307-100,Brazil

Ricardo Wesley Alberca,Laboratorio de Dermatologia e Imunodeficiencias(LIM-56),Departamento de Dermatologia,Faculdade de Medicina FMUSP,Universidade de São Paulo,São Paulo 04307-100,Brazil

Abstract Recent manuscripts described the incidence of vitamin D hypovitaminosis in coronavirus disease 2019(COVID-19)patients.Vitamin D deficiency is also common in patients with comorbidities that are associated with a poor COVID-19 prognosis.In this letter,we review the literature regarding the association of comorbidities,vitamin D deficiency,and COVID-19.

Key Words:COVID-19;SARS-CoV-2;Comorbidities;Vitamin D

TO THE EDlTOR

We read with great interest the article entitled “Association between population vitamin D status and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)related serious-critical illness and deaths:An ecological integrative approach” recently published by Papadimitriouet al[1]in theWorld Journal of Virology[1].This manuscript raised important questions and the authors performed an extensive analysis on vitamin D levels and COVID-19 incidence and severity in Europe,and the potential benefits of vitamin D supplementation to enhance the immune response to the SARSCoV-2[1].In the light of these results,we humbly want to state a few points for consideration.

Severe coronavirus disease 2019(COVID-19)patients present a systemic inflammatory response with a coagulation disorder,possibly evolving to death[2].Several comorbidities have been identified as risk factors for poor disease prognosis,such as old age[3],co-infections[4],obesity and diabetes mellitus[5],severe asthma,alcohol drinking[6],chronic obstructive pulmonary disease[7],chronic liver disease[8],and cancer[9].

Vitamin D deficiency is associated with poor response to respiratory infections[10],and few reports have identified vitamin D deficiency in moderate and severe COVID-19 patients with conflicting results[1,11,12].

Vitamin D receptor is expressed in many immune cells,including monocytes,macrophages,dendritic cells,neutrophils,and lymphocytes[13-15].Vitamin D increases the antimicrobial activity of monocytes and macrophages[16]and has antiinflammatory effects due to the induction of T regulatory cells and reduction in the T helper-17 immune response and pro-inflammatory cytokine production[15].

Papadimitriouet al[1]performed an important investigation on the association of vitamin D deficiency and COVID-19[1].Vitamin D levels can be influenced by many factors such as sun exposure,genetics,supplementation,and comorbidities[17-20].

Vitamin D hypovitaminosis is associated with several comorbidities that are also related to poor COVID-19 prognoses such as old age[21],co-infections[18],obesity[22],diabetes mellitus[23],alcohol drinking,and smoking[24-26],uncontrolled asthma,but not controlled asthma,chronic obstructive pulmonary disease[25-28],cancer[29],and solid organ transplant recipient patients[30].

Besides comorbidities,vitamin D hypovitaminosis is associated with poor glycemic control[23],which is also associated with poor COVID-19 outcomes in diabetic and non-diabetic patients[31].Cancer patients present low circulating levels of vitamin D[29]and experimental models have identified that vitamin D can modulate the disease development by regulating cell cycle and inflammatory response[32].

Vitamin D deficiency is a worldwide problem[33,34],and vitamin D supplementation has the potential to enhance the immune response to microorganisms[1].Vitamin D supplementation has been investigated for the treatment and prevention of severe COVID-19,indicating a potential reduction in COVID-19 severity[35].

A recent investigation found that prophylactic vitamin D supplementation in elderlies improved the SARS-CoV-2 immune response[36],and another investigation identified that the treatment with vitamin D reduces COVID-19 severity[37].Nevertheless,another report found no additional benefit in vitamin D supplementation during COVID-19[38].

Low vitamin D levels also modulate the Renin-Angiotensin-System,which could increase the susceptibility to COVID-19[39],since SARS-CoV-2 uses the angiotensinconverting enzyme 2 and Transmembrane Protease Serine 2(TMPRSS2)to invade the host’s cells[40].In addition,the lack of vitamin D is a risk factor for the development of autoimmune and neuropsychiatric disorders[41].

Lakkireddyet al[42]identified that increasing the serum levels of vitamin D to 80-100 ng/mL significantly reduced inflammatory biomarkers such as interleukin-6,C-reactive protein,and neutrophil-to-lymphocyte ratio during COVID-19,without side effects[42].

In addition,Papadimitriouet al[1]recommendation for vitamin D supplementation should also be considered in a broader context[1],outside the COVID-19 pandemic situation,due to the high incidence of vitamin D hypovitaminosis worldwide,the vast associations with other diseases,and the proposed doses do not require medical supervision[1].

COVID-19 vaccination is ongoing worldwide[43-45],since vitamin D can modulate the immune response to vaccines[46,47],investigations on the vaccines should consider evaluating vitamin D levels and the effects of supplementation on the immune response to vaccines.

In summary,vitamin D hypovitaminosis is associated with comorbidities that are known to affect COVID-19 severity and outcome.Further investigations should focus on patients with low vitamin D levels with and without comorbidities and supplementation trials to investigate the effects of vitamin D on the immune response to COVID-19 and COVID-19 vaccines.