TO THE EDITOR
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 Papadimitriou et al in the World Journal of Virology. 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 SARS-CoV-2. 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. Several comorbidities have been identified as risk factors for poor disease prognosis, such as old age, co-infections, obesity and diabetes mellitus, severe asthma, alcohol drinking, chronic obstructive pulmonary disease, chronic liver disease, and cancer.
Vitamin D deficiency is associated with poor response to respiratory infections, 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 and has anti-inflammatory effects due to the induction of T regulatory cells and reduction in the T helper-17 immune response and pro-inflammatory cytokine production.
Papadimitriou et al performed an important investigation on the association of vitamin D deficiency and COVID-19. 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, co-infections, obesity, diabetes mellitus, alcohol drinking, and smoking[24-26], uncontrolled asthma, but not controlled asthma, chronic obstructive pulmonary disease[25-28], cancer, and solid organ transplant recipient patients.
Besides comorbidities, vitamin D hypovitaminosis is associated with poor glycemic control, which is also associated with poor COVID-19 outcomes in diabetic and non-diabetic patients. Cancer patients present low circulating levels of vitamin D and experimental models have identified that vitamin D can modulate the disease development by regulating cell cycle and inflammatory response.
Vitamin D deficiency is a worldwide problem[33,34], and vitamin D supplementation has the potential to enhance the immune response to microorganisms. Vitamin D supplementation has been investigated for the treatment and prevention of severe COVID-19, indicating a potential reduction in COVID-19 severity.
A recent investigation found that prophylactic vitamin D supplementation in elderlies improved the SARS-CoV-2 immune response, and another investigation identified that the treatment with vitamin D reduces COVID-19 severity. Nevertheless, another report found no additional benefit in vitamin D supplementation during COVID-19.
Low vitamin D levels also modulate the Renin-Angiotensin-System, which could increase the susceptibility to COVID-19, since SARS-CoV-2 uses the angiotensin-converting enzyme 2 and Transmembrane Protease Serine 2 (TMPRSS2) to invade the host’s cells. In addition, the lack of vitamin D is a risk factor for the development of autoimmune and neuropsychiatric disorders.
Lakkireddy et al 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.
In addition, Papadimitriou et al recommendation for vitamin D supplementation should also be considered in a broader context, 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.
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.