key: cord-0937863-42480gwe
authors: Jordan, Taja; Siuka, Darko; Rotovnik, Nada Kozjek; Pfeifer, Marija
title: COVID-19 and Vitamin D– a Systematic Review
date: 2022-03-21
journal: Zdr Varst
DOI: 10.2478/sjph-2022-0017
sha: bb63d71aabd1242cf1466c1e1f967fe30b1ee2f1
doc_id: 937863
cord_uid: 42480gwe

INTRODUCTION: The COVID-19 pandemic has strongly affected global healthcare systems. Prior epidemiological studies on different infectious diseases have shown a strong correlation between serum vitamin D levels and the incidence of certain infectious diseases. Vitamin D has an important immunomodulatory effect on innate immunity and exhibits several other mechanisms in the pathogenesis of the cytokine storm, which is one of the main contributing factors to fatality in COVID-19 patients. METHODS: A keyword search was conducted in the PubMed and Google Scholar research databases. The abstracts and/or full texts of selected papers were further evaluated. Articles that fulfilled the inclusion criteria were included in the systematic review. RESULTS: The 28 studies summarized in this review provide observational findings that vitamin D levels are related to the incidence, severity, and mortality rate of COVID-19 infection. The literature does not suggest that COVID-19 could be eliminated with supplementation of vitamin D, but there are implications that vitamin D deficiency might increase the risk for COVID-19 infection and severity of the disease progression. DISCUSSION: Current literature and several guidelines support the supplementation of vitamin D as a reasonable strategy for correcting and preventing vitamin D deficiency. The recommended dose for maintaining normal 25(OH)D levels by consensus is 1000 to 2000 IU vitamin D daily for at-risk teens and adults. CONCLUSION: Vitamin D supplementation might play an important role in protecting from acute respiratory infections like the SARS CoV2, and in high-risk individuals with COVID 19 from progressing to critical clinical condition and reducing mortality.

The COVID-19 pandemic has strongly affected global healthcare systems. In the early spring of 2020, a severe acute respiratory syndrome coronavirus 2 (SARS CoV2) crisis began in European countries, with many critical cases and deaths, particularly in high-risk groups.

Several retrospective analyses were performed, observing the effects on different disease courses, and other reasons for the clinical outcome differences were questioned. According to the reported data, there are seasonal fluctuations of COVID-19 disease severity (1).

It has been known for decades that seasonal changes cause significant immunity variation, including fluctuations in lymphocyte response and circulating levels of lymphocytes and neutrophils (2, 3) . Epidemiological studies have shown also a strong reverse correlation between serum vitamin D (25-hydroxyvitamin D, 25(OH)D) levels, which are normally higher during the summer season, and the incidence of certain infectious diseases (2, 3) . Vitamin D induces cathelicidin and beta defensin transcription and synthesis in macrophages and a favourable anti-inflammatory Th1 to Th2 phenotype ratio. Additionally, vitamin D exhibits a mitigating effect on the pathogenesis of the cytokine storm, which is one of the main contributing factors to fatality in COVID-19 patients (4) . Vitamin D showed also potent activity against SARS CoV 2 in vitro (5) .

Factors that have been shown to contribute to vitamin D deficiency include older age, smoking, higher body mass index (BMI) and obesity, lack of proper sun (UVB) exposure, dark skin and the presence of chronic illnesses, such as diabetes, malignant disease, high blood pressure, various gastrointestinal disorders and many others. Most people with these risk factors have been shown to be at increased risk regarding both severity of the disease and mortality from COVID-19 (6) . Ethnic differences in the prevalence of common genetic polymorphisms of vitamin D receptor (VDR) and a series of cytochrome P450-containing sterol hydroxylases provide an additional explanation for low vitamin D levels. The exact role of genetic background in the responsiveness to vitamin D supplementation is yet to be determined (7) .

In Slovenia, epidemiological data about vitamin D status in the population were investigated by a nationwide Nutrihealth study in 2017/18. A particularly concerning situation was observed during extended wintertime (November-April); severe vitamin D deficiency (defined as 25(OH)D levels below 30 nmol/L) was found in 40.8% of adults (age 18 -64 years) and 34.6% of elderly people (age 65 to 74 years), while levels below 50 nmol/L (vitamin D deficiency) were observed in 81.6% and 78.8%, respectively. The results of the study showed high seasonal variations in serum 25(OH)D levels in both the adult and elderly population. The prevalence of vitamin D deficiency in Slovenia is among the highest in Europe and poses a serious public health risk that needs to be addressed with appropriate recommendations and policy interventions (8) .

In 2021 a Slovenian systematic review of vitamin D status and dietary intake in various Slovenian populations was published. A meta-analysis of 43 studies that addressed serum 25(OH)D status and 16 that addressed vitamin D intake was conducted. The results showed that various population groups across Slovenia are at high risk of vitamin D insufficiency and deficiency, particularly during wintertime. All included studies reported daily intakes below the recommended level (9) .

In Slovenia, because of the COVID-19 pandemic, medical doctors and the general population were urgently advised by leading experts to supplement vitamin D in fragile, vitamin D deficient high-risk individuals and COVID-19 patients (10, 11) . At the beginning of the COVID-19 pandemic there were no data on the effects of vitamin D in SARS-CoV-2 infection; then again, there were reliable data on the beneficial effects of cholecalciferol in attenuating viral respiratory infections in people with low levels of vitamin D (12) . The European Centre for Disease Prevention and Control encouraged health care professionals to take actions that are logical, based on previously known findings in related fields (13) . However, in more than a year of the COVID-19 pandemic new data has become available to support the important role of vitamin D in SARS-CoV-2 infection, and some recommendations of vitamin D supplementation are already available (8) (9) (10) .

Several studies have investigated the correlation between serum 25(OH)D levels and the incidence, severity and mortality of COVID-19 patients. The objective of this systematic review was to review the studies that explored the relationship between vitamin D and the course of COVID-19. The aim of our study was to explore whether optimal vitamin D status mitigates COVID-19 and if vitamin D supplementation is beneficial in the phase of COVID-19 pneumonia.

The systematic review was prepared following the PRISMA recommendations (17).

We used the PubMed and Google Scholar research databases to search for published research (18, 19) .

The search command consisted of the following MeSH Terms: (Vitamin D AND COVID- 19) and was narrowed to search in titles and abstracts. Abstracts were then examined by two independent observers. Studies available in full text that included key terms in the title or abstract were considered. The abstracts and/or full texts of selected, potentially relevant papers were further evaluated.

Two independent reviewers (D.S., T.J.) completed a study identification and selection search in MEDLINE and Google Scholar, and disagreements were discussed with another reviewer (N.R.K.).

The selection was limited to surveys published in English in 2020. The last inquiry was made on 30th November 2020. By reviewing the titles and abstracts, articles that were assessing the impact of vitamin D on COVID-19 infection in participating subjects or in populations were chosen. We searched for outcomes of COVID-19 (severity or/and mortality or/and incidence). For the purpose of our research the association of vitamin D and COVID-19 was divided into two groups: positive or negative (YES or NO), positive association meaning there was a statistically significant association between higher vitamin D levels and better outcome of COVID-19. Only studies with accessible full text and quantitatively reported outcomes were included.

The exclusion criteria for articles were: no accessible full text, publications with only abstracts, posters, editorials and comments available. Articles for paediatric populations and case studies were also excluded. Studies that did not report specific outcomes quantitatively were also excluded.

The search of PubMed returned 321 articles and Google Scholar returned 574 articles. By following the inclusion and exclusion criteria explained in the method section, and after removing duplicates, the number of articles fell to 361. After reading the abstracts, we found 58 full text articles eligible for full reading. After reading the full texts, we excluded 30 articles not assessing either the severity, mortality or the incidence of COVID-19. We also excluded editorials, systematic reviews, case studies, studies of paediatric population and in vitro studies. A study assessing the impact of vitamin D together with other micronutrients on COVID-19 severity was also excluded.

A total of 28 articles were relevant for the purpose of content analysis (Figure 1 ).

The final number of studies included in the research was 28. All studies were published in 2020. We collected data on the country where the research was conducted, the number of participants, the number of centres included in (20) De Smet D et al (24) Jain A et al (25) Merzon E et al (26) Israel A et al (27) Meltzer DO et al (28) Kaufman HW et al (29) Hastie CE et al (30) Daneshkhah A et al (31) Murai IH et al (21) Rastogi A et al (22) Annweiler G et al ( 

There were 6 population-level studies included, all of them being ecological studies. Only the Canadian study had a negative result and did not find any associations between epidemic growth of COVID-19 infection and latitude and temperature. The other 5 included ecological studies showed a positive correlation, where higher vitamin D levels were associated with lower incidence of COVID-19 infection.

The 28 articles summarized here provide correlational evidence that vitamin D levels impact the incidence, severity and mortality rate of COVID-19 infection. Most of the observational studies show an inverse correlation between vitamin D levels and the severity and mortality of the COVID-19 disease. The same results were found in two other systematic reviews (48, 49) . The majority of included observational studies also showed an inverse correlation between vitamin D levels and incidence of COVID-19, whereas results from the meta-analysis by Pereira et al show that vitamin D deficiency was not associated with higher incidence of COVID-19 infection (48) . The demonstration of a significant correlation between vitamin D status and COVID-19 incidence, severitiy and even mortality may bring important public health implications regarding a major public health issue represented by vitamin D deficiency in the modern age. Five out of 6 ecological studies showed the correlation between vitamin D, COVID-19 mortality rate and latitude. These population-level studies also show big potential in health promotion regarding vitamin D deficiency prevention in different parts of the world. But correlation does not prove causality. Vitamin D levels are usually higher in healthy individuals in whom vitamin D could be an indicator of a healthy lifestyle.

The literature does not suggest that COVID-19 could be substantially reduced with supplementation of vitamin D, but there are indications that vitamin D deficiency increases the risk for COVID-19 infection and severity of the disease progression, as it does for other acute viral respiratory infections (12) . However, there were some studies published that did not confirm this hypothesis. As for the Brazilian randomized controlled trial, it is important to note that the patients received vitamin D supplementation in a single very high dose (200.000 IU or 5000µg) more than a week after the onset of symptoms. Patients who required invasive mechanical ventilation and those admitted to the ICU were excluded. Additionaly, the proportion of patients with 25(OH)D deficiency was considerably lower than in other cohorts. (12, 44) . A single dose of vitamin D might cause long-term induction of the inactivating 24-hydroxylase, and induction of fibroblast growth factor 23 (FGF23) that can suppress the 1-alphahydroxylase enzyme required for activation of vitamin D. Thus regular daily vitamin D supplementation or daily loading doses at the beginning of the disease (as soon as possible after confirmation of the infection) might have better immunomodulatory effects in COVID-19, rather than large bolus dosing at the time of severe disease (51, 52) . In the Indian randomized study, a high-dose cholecalciferol turned a greater proportion of COVID-19 infected patients to become negative, supporting the thesis of the important impact of vitamin D on the innate immunity allowing macrophages to lower the viral burden and mitigate the COVID-19 course (22) . A single study included an analysis of VDR and hydroxylase polymorphisms, which could affect results obtained across different populations and ethnic groups, as well as determine the effect of vitamin D levels in certain individuals. One Mendelian randomization study, using summary data from genome-wide association studies and 25(OH)D concentration-related single nucleotide polymorphisms as instrumental variables of genes associated with vitamin D deficiency, showed that there might be no linear causal relationship between 25(OH)D concentrations, susceptibility to COVID-19 infection and severity of disease. This randomization did not consider other factors influencing serum vitamin D levels, such as ambiental UVB (53) . Interestingly, a recent Mendelian randomization study analysing the relationship between genetically determined 25(OH)D levels and all-cause mortality found that there was a negative relation only in a vitamin deficient area that was exponential but no relation between 25(OH)D levels above 50 nmol/L and mortality (48) . As poor nutritional status compromises the immune response and reduces the treatment response to COVID-19 infection, not just supplementation with vitamin D but proper nutritional therapy in combination with vitamin D supplements would probably improve the effectiveness of COVID-19 treatments (54) . Moreover, intake of vitamin D supplements is often limited by relatively poor adherence, especially in individuals with low-socioeconomic status (lower education, marginal groups), who are at the highest risk for vitamin D deficiency. Vitamin D deficiency is a known challenging public health issue, especially during the winter months with high incidence of viral respiratory infections (9) . An effective approach to improve vitamin D status in the general population could be systematic vitamin D food fortification, since it is economical, safe and decreases deficiency risk in the entire population, including people that would not use supplements (55 The strength of this systematic review is its compliance with international standardized guidelines on reporting of systematic reviews and a high heterogeneity of included studies resulting from the baseline study design and the variability of the baseline characteristics. In this review different endpoints such as the incidence of COVID-19, the severity of COVID-19, length of hospitalizations, the need for an intensive care unit and mortality are reported, and our results could have a significant impact on clinical practice and public health. In view of the fact that COVID-19 is a new disease and there is a low number of well-planned intervention studies, this was the main limitation that influenced the conclusion of this research. An additional limitation of our study is that we only searched through two bibliographic databases (we searched the two largest ones) and there was a relatively large number of excluded articles which did not fulfil our carefully chosen criteria for inclusion.

This systematic review with a large number of articles included has considerable public health importance because it presents a summation of the latest research of the immunomodulative impact of vitamin D on the COVID-19 course. This review article presents some possibilities and ideas for future research. In future, randomized double blinded studies are needed, with vitamin D supplementation as a preventive measure prior to potential infection.

Vitamin D supplementation might play a pivotal role in protecting individuals from COVID-19. Optimal levels of 25(OH)D in the early phase of COVID-19 infection could prevent progression to severe or critical clinical condition and reduce mortality associated with COVID-19. The role of acute supplementation of vitamin D in severely deficient patients in the late phases of COVID-19 pneumonia is still unclear. Therefore, further randomized double blinded clinical trials are needed to provide conclusive evidence.

We declare no competing interests.

This work was unfunded.

The method used in this systematic literature review involves no ethical issues and ethical approval was not necessary.

Coronavirus update (Live): 42,271,844 cases and 1,146,211 deaths from COVID-19 virus pandemic -Worldometer

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