Final CAT:

Vitamin D is an immunomodulator that is known to protect from respiratory tract infections by enhancing innate immunity. Is there evidence that shows that this is true for COVID-19 as well?

Search Question: In patients who are COVID-19 positive does Vitamin D supplementation decrease mortality when compared to placebo?

Question Type: What kind of question is this? (boxes now checkable in Word)

☐ Prevalence         ☐ Screening           ☐ Diagnosis

☐ Prognosis          ☐ Treatment         ☐ Harms

PICO Search Terms: 

Google Scholar:

Vitamin D supplementation decrease mortality in patients with COVID-19 = 165,000 results

Vitamin D supplementation decrease mortality in patients with COVID-19 (Filters: 2020-2024, Sort by relevance, Review articles) = 14,200 results

– After applying the filters, I read the titles and abstracts of the articles from the first 5 pages and chose the ones the articles that were high level of evidence and were most relevant. I found that after the first 5 pages the articles didn’t really answer my search question.

Pub Med: 

Vitamin D supplementation for patients with COVID-19 = 353 results

Vitamin D supplementation for patients with COVID-19 (Filters: Within last 5 years, Meta-Analysis, Systematic Review, Full text) = 50 results

– After applying the filters, I skimmed the titles of all 31 results and read the abstracts of the articles that were relevant to answering my search and chose the articles based on that. I added the filter of Meta-Analysis and Systematic Review to get the highest level of evidence.

Science Direct:

Vitamin D supplementation decrease mortality in patients with COVID-19= 1,885 results

Vitamin D supplementation decrease mortality in patients with COVID-19 (Filters: 2021-2024, Review articles) = 590 results

– After applying the filters, I read the titles for the articles of the first 5 pages and read the abstracts for the most relevant ones to my search question. After the 5th page I noticed that the results weren’t as relevant to my question.

Articles Chosen:

Article 1: Shah, K. et al. (2022a) Does vitamin D supplementation reduce COVID-19 severity?: A systematic review, OUP Academic.  https://academic.oup.com/qjmed/article/115/10/665/6528876

Abstract:

The evidence regarding the efficacy of vitamin D supplementation in reducing severity of COVID-19 is still insufficient. This is partially due to the lack of primary robust trial-based data and heterogeneous study designs. This evidence summary, aims to study the effect of vitamin D supplementation on morbidity and mortality in hospitalized COVID-19 patients. Evidence summary of systematic reviews. For this study, systematic reviews and meta-analysis published from December 2019 to January 2022 presenting the impact of vitamin D supplementation on COVID-19 severity were screened and selected from PubMed and Google scholar. After initial screening, 10 eligible reviews were identified and quality of included reviews were assessed using AMSTAR and GRADE tools and overlapping among the primary studies used were also assessed. Results: The number of primary studies included in the systematic reviews ranged from 3 to 13. Meta-analysis of seven systematic reviews showed strong evidence that vitamin D supplementation reduces the risk of mortality (Odds ratio: 0.48, 95% CI: 0.346–0.664; P < 0.001) in COVID patients. It was also observed that supplementation reduces the need for intensive care (Odds ratio: 0.35; 95%CI: 0.28–0.44; P < 0.001) and mechanical ventilation (Odds ratio: 0.54; 95% CI: 0.411–0.708; P < 0.001) requirement. The findings were robust and reliable as level of heterogeneity was considerably low. However the included studies were of varied quality. Qualitative analysis showed that supplements (oral and IV) are well tolerated, safe and effective in COVID patients. Conclusion: The findings of this study show that vitamin D supplementation is effective in reducing the COVID-19 severity. Hence, vitamin D should be recommended as an adjuvant therapy for COVID-19.However, more robust and larger trials are required to substantiate it further.

Article 2: Nikniaz, L., Akbarzadeh, M. A., Hosseinifard, H., & Hosseini, M.-S. (2021, January 1). The impact of vitamin D supplementation on mortality rate and clinical outcomes of COVID-19 patients: A systematic review and meta-analysis. medRxiv. https://www.medrxiv.org/content/10.1101/2021.01.04.21249219v1

Abstract:

Several studies have suggested the positive impact of vitamin D on patients infected with SARS-CoV-2. This systematic review aims to evaluate the effects of vitamin D supplementation on clinical outcomes and mortality rate of COVID-19 patients. A comprehensive search was conducted through the databases of PubMed, Scopus, Web of Knowledge, Embase, Ovid, and The Cochrane Library with no limitation in time and language, until December 16, 2020. The results were screened based on their accordance with the subject. Two independent reviewers selected the eligible studies and the outcomes of interest were extracted. Using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for Randomized Controlled Trials (RCTs) and Quasi-Experimental Studies, the remaining results were appraised critically. Statistical analysis was performed using the Comprehensive Meta-Analysis (CMA) software version 2.0. Of the 2311 results, 1305 duplicated results were removed. After screening the titles, abstracts, and the full-text articles of the remaining records, four studies and 259 patients were enrolled, including 139 patients in vitamin D intervention groups. In three of the studies, the patients’ survival and mortality rate were evaluated. The pooled analysis of these studies showed a significantly lower mortality rate among the intervention groups (10.56%) compared with the control groups (23.88%) (OR = 0.264, 95% CI = 0.099–0.708, p-value = 0.008). Two of the studies reported the clinical outcomes based on the World Health Organization’s Ordinal Scale for Clinical Improvement (OSCI) score for COVID-19, where both of them showed a significant decrease in OSCI score in the vitamin D intervention groups. Additionally, One study reported a lower rate of intensive care unit (ICU) admission, and one study reported a significant decrease in serum levels of Fibrinogen. Prescribing vitamin D supplementation to patients with COVID-19 infection seems to decrease the mortality rate, the severity of the disease, and serum levels of the inflammatory markers. Further studies are needed to determine the ideal type, dosage and duration of supplementation.

Article 3:  Zhang, Y., Li, J., Yang, M., & Wang, Q. (2023, March 7). Effect of vitamin D supplementation on COVID-19 patients: A systematic review and meta-analysis. Frontiers in nutrition. https://pmc.ncbi.nlm.nih.gov/articles/PMC10027755/

Abstract:

To systematically evaluate the impact of vitamin D supplementation on mortality, ICU admission, and the rates of mechanical ventilation or intubation among COVID-19 patients. The PubMed, Embase, Cochrane Library, CBM, CNKI, VIP, and WanFang databases were searched from 1 December 2019 to 31 December 2022. The authors sought to identify randomized controlled trials and cohort studies that examined the relationship between vitamin D supplementation and mortality, ICU admission, and mechanical ventilation or intubation rates among COVID-19 patients. Two investigators independently searched the literature, extracted the data, and assessed the quality of the included studies. The Grading of Recommendation, Assessment, Development, and Evaluation approach was used to evaluate the quality of the evidence. Meta-analysis was conducted using RevMan 5.3, STATA 15.1, and R 4.1.3 software. Eight randomized controlled trials (RCTs) and eight cohort studies were included, involving 3359 COVID-19 patients. The pooled analysis of randomized controlled trials showed that vitamin D supplementation did not have a significant effect on reducing mortality (Relative Risk, RR = 0.94, 95% CI 0.69–1.29, P = 0.7), while the results of cohort studies indicated that vitamin D supplementation had a positive impact on reducing mortality among COVID-19 patients (RR = 0.33, 95% CI 0.23–0.47, P < 0.001). There was no statistically significant difference in the rates of ICU admission (RCTs: RR = 0.64, 95%CI 0.38–1.08, P = 0.10; cohort studies: RR = 0.32, 95% CI 0.08–1.29, P = 0.109) or rates of mechanical ventilation or intubation (RCTs: RR = 0.77, 95% CI 0.58–1.02, P = 0.07; cohort studies: RR = 0.93, 95% CI 0.55–1.58, P = 0.789). The results of this systematic review and meta-analysis suggest that vitamin D supplementation does not have a significant impact on reducing mortality, ICU admission, and the rates of mechanical ventilation or intubation among COVID-19 patients. However, due to the limited number and quality of the studies included, further high-quality studies are needed to confirm these findings.

Article 4: Sartini, M., Del Puente, F., Oliva, M., Carbone, A., Bobbio, N., Schinca, E., Giribone, L., & Cristina, M. L. (2024, February 28). Preventive vitamin D supplementation and risk for COVID-19 infection: A systematic review and meta-analysis. MDPI. https://www.mdpi.com/2072-6643/16/5/679

Abstract: Over the past few decades, vitamin D has been found to play a crucial role in bone homeostasis, muscle function, oncogenesis, immune response and metabolism. In the context of the COVID-19 pandemic, numerous researchers have tried to determine the role vitamin D might play in the immune response to the virus. The aim of this systematic review and meta-analysis is to demonstrate that preventive vitamin D supplementation can play a protective role in the incidence of COVID-19, mortality and admission to intensive care units (ICUs). A comprehensive search on the PubMed/MEDLINE, Scopus, Cochrane and Google Scholar databases was performed on 15 May 2023, and two of the authors independently screened the literature. As effect measures, we calculated the Odds Ratios with their corresponding 95% confidence intervals (ICs). The assessment of potential bias and the evaluation of study quality will be conducted independently by two researchers. Sixteen publications were selected for inclusion in the meta-analysis. Our findings indicate that vitamin D supplementation has a protective effect against the incidence of COVID-19 in RCT studies (OR 0.403, 95% IC 0.218, 0.747), in the incidence of COVID-19 in analytical studies (OR = 0.592, 95% IC 0.476–0.736) and in ICU admission (OR 0.317, 95% IC 0.147–0.680). Subsequent analyses were conducted by type of subject treated (patient/healthcare workers) and type of supplementation (vitamin D vs. placebo/no treatment or high dose vs. low dose). Our meta-analysis suggests a definitive and significant association between the protective role of vitamin D and COVID-19 incidence and ICU admission.

Article 5: Yang, Y., Sun, W., Yang, F., Zhang, G., Li, X., Sun, S., & Xing, Y. (2024, May 7). Therapeutic effects of vitamin D supplementation on COVID-19 aggravation: A systematic review and meta-analysis of randomized controlled trials. Frontiers. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1367686/full

Abstract: 

The therapeutic effects of vitamin D supplementation on Coronavirus disease 2019 (COVID-19) aggravation remain controversial and inconclusive. To probe into this contentious issue, we performed the present meta-analysis of randomized controlled trials (RCTs). Literature published up to June 2023 was retrieved from Cochrane Library, PubMed, Web of Science and Embase. RCTs assessing mortality, intensive care unit (ICU) admission, mechanical ventilation (MV), length of hospitalization (LOH), and inflammatory markers containing C-reactive protein (CRP), D-dimer, interleukin-6 (IL-6), lactate dehydrogenase (LDH) were included. 19 RCTs were involved in the analysis and were conducted subgroup analyses on the baseline COVID-19 severity and vitamin D administration. In the severity subgroup, statistically significant effects in moderate to severe group were observed in ICU admission (OR 0.43, 95% CI 0.23, 0.80; p = 0.008), MV (OR 0.44, 95% CI 0.27, 0.72; p = 0.001) and LOH (SMD –0.49, 95% CI –0.92, −0.06; p = 0.027). In the administration subgroup, effects of ICU admission (OR 0.39, 95% CI 0.16, 0.97; p = 0.044), MV (OR 0.18, 95% CI 0.07, 0.46; p = 0.000) and LOH (SMD –0.50, 95% CI –0.96, −0.04; p = 0.034) were more pronounced in patients supplied with multiple-dose vitamin D than single-dose. Although the result of mortality showed no statistically significant effect, it indicated a reduced trend (OR 0.87, 95% CI 0.63, 1.12; p > 0.05). The results of inflammatory markers reached no statistical differences. This meta-analysis revealed that moderate to severe COVID-19 patients supplied with multiple doses of vitamin D were less apt to need ICU admission, mechanical ventilation and have shorter hospital stays.

Article 6: Feiner Solís, Á., Avedillo Salas, A., Luesma Bartolomé, M. J., & Santander Ballestín, S. (2022, October 17). The effects of vitamin D supplementation in COVID-19 patients: A systematic review. MDPI. https://www.mdpi.com/1422-0067/23/20/12424

Abstract: Vitamin D has an immune-modulating effect on respiratory tract infections. For this reason, it has been proposed as part of the treatment in COVID-19. Furthermore, vitamin D deficiency has been associated with worse clinical outcomes of this disease. The aim of this systematic review was to determine whether vitamin D supplementation modifies the disease course. Therefore, eleven studies involving randomised clinical trials are analysed, in which groups of COVID-19 patients with or without vitamin D supplementation as part of the treatment are compared. A control group was treated with best available therapy, and in some of the clinical trials, also with a placebo. According to the outcomes, it seems that patients benefit from receiving a daily or maintained in time vitamin D dose regardless of vitamin D serum levels at the beginning of the trial. The administration of a single vitamin D dose does not seem to have any effect on the health status of these patients. However, the outcomes are heterogeneous and larger clinical trials are necessary.

Summary of the Evidence:

 

 

Conclusions: 

Article 1: 

– Overall, the evidence of this article suggests that vitamin D has a huge role in lowering COVID-19 – related mortality, ICU hospitalizations, and ventilation.

Article 2: 

– In patients with COVID-19, vitamin D supplementation lowers the rate of mortality, severity of disease, and serum levels of inflammatory markers.

Article 3:

– Results of the article suggest that vitamin D supplementation does not have a significant impact on reducing mortality, ICU admission, and the rates of mechanical ventilation or intubation among COVID-19 patients. However, the article emphasized the need to confirm these findings with higher quality studies due to limited number and quality of studies in this article.

Article 4: 

– The findings of this Meta-Analysis show a strong association between the protective role of Vitamin D and COVID-19 incidence and ICU admission.

Article 5: 

– Findings of this article showed that moderate to severe COVID-19 patients given multiple doses of vitamin D had shorter hospital stays and were less likely to need ICU admission or mechanical ventilation.

Article 6: 

– The articles findings showed that supplementation of Vitamin D on a daily or sustained basis is safe and could provide clinical benefit in disease progression in patients with COVID-19.

Overarching Conclusion:

– Based on the data from majority of the articles, Vitamin D supplementation has shown to reduce mortality in patients with COVID-19 as well as reduce rates of ICU admission and and ventilation/intubation.

Clinical Bottom Line:

Weight of Evidence: 

Article 2: I ranked this as the best on my weight of evidence because it is a Systematic Review and Meta-Analysis article that explores the mortality rates and ICU admission rates when patients with COVID-19 are given Vitamin D supplementation. 259 patients were enrolled including 139 patients in Vitamin D intervention group.

Article 4: I would rank this article as second on my weight of evidence as it is a Systemic Review and Meta-Analysis article. This article discusses the protective role Vitamin D supplementation has in patients with COVID-10. The article includes 16 publications for inclusion in the meta-analysis. This article does include some biases/limitations but overall I still ranked it number 2 as it has high level evidence.

Article 1: I would rank this article as third on my weight of evidence as it Systematic Review article. This article directly answers my search question by showing evidence that Vitamin D decreases rates of mortality. The number of primary studies included in the systematic review ranged from 3 to 13.

Article 5: I am ranking this as fourth of my weight of evidence. This article discusses the therapeutic effects of Vitamin D in patients with COVID-19. The article included 19 RCTs. The article does contain biases/limitations that may have impacted results so I ranked it number 5.

Article 6: I ranked this as fifth on my weight of evidence. This article explores whether Vitamin D supplementation modifies the disease course of COVID-19. This article included 11 studies involving RCTs. However, this article included studies that were not double blinded and lack of placebo which can impact results.

Article 3: I ranked this as last on my weight of evidence because although it is a Meta-Analysis and Systematic Review article, the article emphasized the need for more high quality evidence since this article had a limited number and quality of studies. This article also contained many biases/limitations which may have affected the results.

Magnitude of any effects: 

– Majority of the articles mentioned that Vitamin D provides benefit in patients with COVID-19, however it mentioned the need for more research on the dosage and duration of supplementation for therapeutic effect.

Clinical Significance:

– Overall, the clinical bottom line is that Vitamin D supplementation not only reduces the rates of mortality but also decreases the rates of ICU admission and the need for ventilation/intubation. All the articles except for 3 support this conclusion. However, article 3 mentioned that the studies included only a limited number and quality of studies and needed higher level of evidence to confirm the results. The articles mention that there is further evidence and research required to further determine the dosing and duration of supplementation to patients with COVID-19.