The relationship between serum vitamin D level and COVID-19; a review study

1Department of Epidemiology and Biostatistics, School of Public Health, Shahrekord University of Medical Sciences, Shahrekord, Iran 2MD Fellowship of Rheumatology, Tehran University of Medical Sciences, Tehran, Iran 3PhD Student, School of Medical Management and Information, Iran University of Medical Sciences, Tehran, Iran 4Department of Medical Virology, Kerman University of Medical Sciences, Kerman, Iran 5Department of Pathobiology, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran 6Modeling in Health Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran 7Department of Epidemiology and Biostatistics, School of Public Health, Shahrekord University of Medical Sciences, Shahrekord, Iran 8Emergency Medical Specialist, Isfahan University of Medical Sciences, Isfahan, Iran


Introduction
Coronavirus 2019 (COVID-19) from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the most important epidemiological events in the past 100 years has become, with deleterious consequences for public health and economic systems around the world. COVID-19 infection can lead to a mild or very acute respiratory syndrome that is triggered by a change in the secretion of inflammatory cytokines (cytokine storm) which can be fatal in children, elderly populations, chronic lung patients or patients with high blood pressure and people who live in cities with air quality (1). Vitamin D is an important micronutrient and improves immunity and protects against respiratory diseases (2). Vitamin D is known for its activity in the respiratory system, and its deficiency is associated with pneumonia. It has been hypothesized that low levels of vitamin D may play a role in influenza virus infection. According to a recent meta-analysis of 25 trials (11 321 participants), based on studies on different populations showed that vitamin D supplementation reduced the risk of acute respiratory infection (3). Through several mechanisms, vitamin D can reduce the risk of infection. These mechanisms include the induction cathelicidins and defensins, which can slow the replication of the virus and reduce the concentration of pro-inflammatory cytokines, which cause inflammation that damages the lining of the lungs and leads to pneumonia. It also increases the concentration of anti-inflammatory cytokines. Evidence for the role of vitamin D in reducing the risk of COVID-19 suggests that its prevalence occurred in winter, when 25-hydroxyvitamin D (25(OH)D) concentrations were lowest (4). Despite the difficulty of comparing data across countries, COVID-19 mortality is clearly higher in some countries than in others. Many factors may play a role, including differences in the proportion of older people in a population, the level of public health, access and quality of health care and socioeconomic status. The relative status of vitamin D in the population is often overlooked, which can affect the outcome of COVID-19. Because people are advised to stay home as long as possible, British government health agencies have advised people to take vitamin D supplements during an outbreak. Vitamin D supplementation can be very important for the elderly because they are at high risk for COVID-19 and vitamin D deficiency (5). COVID-19 is highly transmissible and can lead to acute lung damage in some patients. By balancing the activity of the renin-angiotensin system, the enzyme converter angiotensin 2, which is a receptor for fusion of the virus, has a protective role against the effects of this viral infection. Vitamin D can induce the expression of the angiotensin-converting enzyme and regulate the immune system through various mechanisms (6).
The main function of vitamin D is to retain calcium homeostasis and skeletal health. With a deficiency of this vitamin, only 10-15% of calcium and 60% of food phosphorus can be absorbed. While vitamin D supplementation enhancement calcium absorption to 30%-40% and phosphorus to 80%. Vitamin D is now known as a prohormone because it is synthesized in the body by the precursor of dehydrocholesterol under the influence of ultraviolet B (UB) rays with a wavelength of 290-315 nm in the skin, which is the main source of vitamin D. However season, latitude, time of day when the body is exposed to sunlight, skin color, age, use of sunscreen and type of coverage change the skin's synthesis capacity (7). Additional sources of vitamin D can be obtained through diet, including fish, eggs, leafy vegetables or fortified foods (8).
Serum levels of 25hydroxyvitamin D less than 20 ng/mL are called vitamin D deficiency. Vitamin D insufficiency is expressed with a serum level of 20-29 ng/mL and a normal state with a serum level of 30 ng/mL and above. It is necessary to mention the level of 30-50 ng/mL is defined as the ideal serum level of vitamin D (9).
Recently, the effects of vitamin D on SARS-CoV-2 infection, such as increased hospitalization and mortality, have been interested in scientific societies and in universities. Numerous data, including known pathways of COVID-19, the physiology of vitamin D and its impact on the immune system, and population-based investigations and the association of vitamin D levels with respiratory infections, suggest that vitamin D deficiency is an important factor in the transmission of COVID-19 and the increase in its complications. Observational data comparing results from different populations show reverse relationship between vitamin D levels and the severity of COVID-19 and its mortality, suggesting a possible effect of vitamin D on the immune response to infection. In particular, Spain and Italy have high rates of vitamin D deficiency as well as some of the highest rates of COVID-19 infection and mortality worldwide. Conversely, Nordic countries have higher levels of vitamin D as a result of fortifying their diets with vitamin D with lower rates of infection and mortality of COVID-19. However, other data call such a link into question. Greece, for example, is one of the regions with the lowest prevalence and mortality of COVID-19 with a prevalence of vitamin D deficiency (25 (OH) D <20 ng/mL) of at least 50% over a wide age range. While Brazil, an equatorial country, has a high rate of COVID-19 deaths (10).
According to previous data that vitamin D can cause acute respiratory infections (ARI) prevent, it is natural to ask whether vitamin D can prevent COVID-19. Therefore, our goal is to review current articles in this field.

Materials and Methods
The present study is a review study in which articles related to studies published in 2020 related to the relationship between COVID-19 and vitamin D in databases such as; Magiran, Science Direct, SID, Google Scholar, and PubMed. Keywords used include; serum levels of 25hydroxyvitamin D, vitamin D, COVID-19, SARS-CoV-2, and coronavirus 2.
The criterion for selecting articles was the study of vitamin D levels in COVID-19 disease with case studies such as case study, cohort, clinical trial, series of cases, cross-sectional, observational. Exclusion criteria were lack of access to the full text of the articles and lack of quality conditions according to STROBE checklist. In addition, due to the outbreak of the disease on the last day of 2019, articles related to 2020 were extracted from databases. Finally, the comparable characteristics of the articles (including study location, study population, number of people studied, type of study and related results) were reported in Table 1.

Results
At first, 309 articles were found, after reviewing the title and removing irrelevant and duplicate titles, 173 articles were deleted and 136 articles were selected to review the abstract ( Figure 1).
After reviewing the abstract (or in articles without abstracts after reviewing the original text), 104 unrelated Patients receiving high doses of vitamin D supplements return to normal levels of vitamin D and promote clinical improvement, which is evident with shorter hospital stays, less oxygen requirements, and reduced inflammatory markers. Vitamin D supplementation may be a good option for reducing acute respiratory distress syndrome in patients in low-income communities where sources of expensive and high-cost drugs may be scarce. This pilot study showed that vitamin C and vitamin D levels were low in most ICU cases with COVID-19 Many were also resistant to insulin or diabetes, overweight or obesity, which are known to be independent risk factors for low levels of vitamin C, vitamin D and COVID-19. Retrospective Case-control Study No differences in serum vitamin D levels were observed between the three groups.
In the COVID-19 group, serum vitamin D levels did not show a significant relationship with mortality risk, intensive care unit admission risk, length of hospital stay, and recovery. articles were discarded and finally 32 articles were considered suitable for this purpose and were reviewed and finalized. Additionally, some references to the mentioned articles that seemed to be relevant to the subject of the study were examined. Of the 32 studies reviewed, only three showed no correlation between vitamin D levels in the blood and COVID-19 disease. Other studies had a relationship between the intensity of the disease, mortality rate, length of hospital stay, in different age, gender, location, etc groups.

Discussion
The present study was a systematic review of published studies on the relationship between vitamin D levels and SARS-CoV-2. According to published studies, the effect of serum vitamin D concentration on COVID-19 was observed. Although most of the studies showed a significant relationship between vitamin D levels and COVID-19, however it is possible to publish studies with more positive results, the publication bias is not far from expectation and this can be one of the limitations of this study. Another limitation could be the new and unknown disease and the lack of sufficient studies in this field.
The main findings of our study show that most patients with lower than normal serum vitamin D concentrations have complications more severe than in patients with adequate vitamin D levels. Possible cause for this observation can be explained by the role of vitamin D in a variety of immune responses.
Through several mechanisms, vitamin D can reduce the risk of infection. Understanding these mechanisms 309 articles were found 173 articles were deleted based on their title 7 article were omitted becuase they were repeated 136 articles were selected to review the abstract After reviewing the abstract, 104 unrelated articles were discarded and finally 32 articles were considered for this systematic review can logically indicate that patients with 25 (OH) D deficiency are at greater risk for more severe SARS-CoV-2 manifestations or a worse prognosis. Such as the behavior of seasonal viral respiratory tract infections, the distribution of SARS-CoV-2 prevalence in the community also shows seasonal patterns along latitude, specific temperature and humidity. Without considering age, ethnicity, and latitude, recent data show that 40% of People in Europe with a high prevalence of SARS-CoV-2 are deficient in vitamin D, and 13% are severely deficient in vitamin D (43).
In a study to survey the association between latitude and SARS-CoV-2 mortality, 88 countries were selected based on the possibility of providing reliable information. With using the mortality rate per million for each country from the "worldometers" website, a correlation analysis was performed among the mortality rate and the latitude of these countries. There was a positive and significant relationship between the lower mortality rates with the neighborhood of a country with the equator, which means that 16% of changes in mortality rates among countries are calculated in terms of latitude. Evidence has been provided that there is a clear link between sun exposure and reduced mortality. This survey demonstrates for the first time a statistically significant relationship between a country's latitude and its SARS-CoV-2 mortality and is consistent with other studies on latitude, vitamin D deficiency and SARS-CoV-2 mortality (44).
In another systematic review and meta-analysis study that was performed to investigate whether vitamin D deficiency exacerbates SARS-CoV-2, limited evidence of the effect of vitamin D in people with COVID-19 was found. In this study, the relationship between vitamin D deficiency and the severity of SARS-CoV-2 was analyzed by analyzing the prevalence of vitamin D deficiency and insufficiency in patients with this disease. The result was that vitamin D deficiency was not more likely to be associated with SARS-CoV-2 but was associated with severe cases of SARS-CoV-2. Serum vitamin D deficiency was also positively associated with hospitalization and COVID-19 mortality (45).
Another systematic and meta-analysis of the role of vitamin D in COVID-19 was performed. Around 16 studies with a total of 4922 participants were included in the meta-analysis. Meta-analysis showed that 48% of COVID-19 patients suffered from vitamin D deficiency and in 41% of patients the vitamin D level was insufficient. Serum vitamin D concentration among SARS-CoV-2 patients was 18 ng/mL. 47.4% of them have hypertension, 32.1% diabetes, 30.4% cardiovascular disease, 27.1% chronic kidney disease, 22.0% obesity, 17.5% respiratory disease, 14.5% depression/anxiety, 7.4% cancer and 5.1% dementia in addition to COVID-19 and the ethnic groups participating in this study were 1.0% Caribbean African, 10.3% Asian and 92.1% Caucasian. This survey showed that the mean serum level of 25-hydroxyvitamin D was low in all SARS-CoV-2 patients and most of them suffered from vitamin D deficiency. Most participants were Caucasian, and the highest comorbidity with COVID-19 was in patients with hypertension, diabetes, cardiovascular disease, chronic kidney disease, obesity, and respiratory disease, which may be directly or indirectly affected by vitamin D deficiency (46).
In another survey, a second-class relation was found between the prevalence of vitamin D deficiency in most commonly affected countries by SARS-CoV-2 and the latitudes. Vitamin D deficiency is more common in the subtropical and mid-latitude countries than the tropical and high-latitude countries. The most commonly affected countries with severe vitamin D deficiency are from the subtropical (Saudi Arabia 46 %; Qatar 46 %; Iran 33·4 %; Chile 26·4 %) and mid-latitude (France 27·3 %; Portugal 21·2 % and Austria 19·3 %) regions. Severe vitamin D deficiency was found to be nearly 0 % in some high-latitude countries (e.g. Norway, Finland, Sweden, Denmark and Netherlands) (43).
Although the protective effect of vitamin D against COVID-19 is still not completely valid, there are reasons why it is recommended to maintain normal levels of vitamin D in the blood, especially in this epidemic, in conditions of social isolation and winter to prevent severe deficiency. In addition to the specific effects of vitamin D on respiratory function, vitamin D supplementation is usually recommended for the general public because of its obvious benefits to the musculoskeletal system.
The recommended doses of vitamin D vary from 400 to 2000 IU per day depending on age groups and clinical conditions. These doses are sufficient to prevent severe deficiency and are very safe without the risk of poisoning.

Conclusion and recommendations
This systematic review has shown that having optimal levels of vitamin D in individuals can play a protective role against respiratory infections, especially infections caused by COVID-19.
Therefore, people who are exposed to vitamin D deficiency should try to increase their serum vitamin D levels by using proper nutrition, exposure to sunlight at the right time, and taking vitamin D supplements, therefore they may be safe from COVID-19