ABSTRACT
Aim . Assess the association of plasma vitamin D levels or vitamin D supplementation with the outcomes of COVID- 19.Methods . PubMed, EMBASE, and Cochrane Library databases were searched. Studies with COVID-19 patients that reported an association between plasma vitamin D levels or vitamin D supplementation and mortality, need of hospitalization, ICU admission, or ventilation requirement published until December 8, 2020, were included. The risk ratio (RR) and confidence interval (CI) were pooled using a fixed-effects model. Results . A total of 16 studies were included in the meta-analysis, eleven cohorts, one case-control, one randomized clinical trial, and two quasi-experimental studies. Low plasma vitamin D levels in patients with COVID-19 were associated with mortality (RR=1.42, 95%CI 1.14 – 1.71), need for ICU admission (RR=1.76, 95%CI 1.03-2.49), and need for ventilation (RR=3.58, 95%CI 1.45-5.70). Regular vitamin D supplementation showed a decreased risk of death, and vitamin D treatment in patients with COVID-19 showed a decrease in the need for ICU admission. Conclusion . Sufficient vitamin D level is associated with better outcomes in patients with COVID-19. Vitamin D supplementation in patients with COVID-19 appears to reduce the risk of ICU admission and regular supplementation reduces mortality.
Keywords : 25-hydroxyvitamin D; Cholecalciferol; Ergocalciferols; Meta-analysis. SARS-Cov2.

INTROducTion

Since the first case registered in December 2019 in the city of Wuhan, Hubei Province, China, COVID-19 has spread rapidly throughout the world for presenting strong contagious and infectious characteristics1–3, which have caused 1,663,474 deaths until December 19th, 2020 in 198 countries4.
Worldwide data from the pandemic demonstrate a mortality rate of 0.9% in patients without comorbidities, which increases progressively based on the number of comorbidities and the age of the patients5. The existence of studies relating vitamin D levels to Acute respiratory infections6, led to the carrying out an ecological study wich showed that countries, where the plasma mean vitamin D population is low, had higher rates of infection and mortality from SARS-CoV27.
Isaia et al8 found a correlation between regions with higher levels of solar ultraviolet (UV) radiation and lower rates of morbidity and mortality related to COVID-19, the hypothesis discussed by the authors is that it may be related to vitamin D levels. Exposure to UV radiation determines the photo-conversion of the pro-vitamin D3 (7-dehydrocholesterol) in the skin to pre-vitamin D39.
In addition, many observational studies relating vitamin D level to COVID-19 outcomes have emerged with divergent results10–14 and in the absence of randomized clinical trials, we proposed conducting a systematic review to assess the association of plasma vitamin D levels or vitamin D supplementation in the mortality, and severity of COVID- 19.

METHODS

Data Search

Two investigators searched MEDLINE, EMBASE, and Cochrane Library. Studies published until December 8, 2020 were included. The following search strategy was used: (coronavirus OR “coronavirus infections” OR COVID-19 OR “severe acute respiratory syndrome coronavirus 2”) AND (“vitamin D” OR “ergocalciferol” OR “cholecalciferol” OR “vitamin D deficiency” OR calcitriol OR calcifediol OR alfacalcidol OR paricalcitol OR doxercalciferol). The language of the searches was limited to English, Spanish and Portuguese.

Study selection

The studies were screened by two independent authors. Disagreements were resolved through discussion among all authors. Summaries of retrieved articles were reviewed to exclude irrelevant studies, followed by reading full text for screening.
Studies were included if they met the following inclusion criteria: (1) enrolled COVID-19 patients with plasma vitamin D level (25-hydroxyvitamin D) or COVID-19 patients in vitamin D or analogs use. All studies used throat swab SARS-CoV-2 real-time reverse transcription-polymerase chain reaction (RT-PCR) nucleic acid to confirm COVID-19; (2) examined the association between vitamin D use or plasma vitamin D level with mortality or disease severity (death, hospitalization, intensive care unit - ICU admission and ventilation requirement); (3) observational or interventional studies. Ecological, cross-sectional, and studies that plasma vitamin D level was measured more than a year ago were excluded.