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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 2  |  Page : 26-33

Vitamin D in defense against the terrorism of coronavirus disease 2019: A meta-analysis


1 Department of Biochemistry, Santosh Deemed to be University, Uttar Pradesh, India
2 Department of Surgery, Santosh Deemed to be University, Uttar Pradesh, India
3 Department of Research Scholar Biochemistry, Santosh Medical College and Hospital, Ghaziabad, Santosh Deemed to be University, Ghaziabad, Uttar Pradesh, India

Date of Web Publication6-Dec-2021

Correspondence Address:
Pradeep Kumar
Professor and Head of Biochemistry, State Anonymous Government Medical College, Fatehpur, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2455-1732.331791

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  Abstract 


Background: Coronavirus disease 2019 (COVID-19) pandemic was also spread during winter time in December from Wuhan the city of China to worldwide. Various studies conducted throughout the world have indicated the possible relationship between Vitamin D and COVID-19 infection.
Aim: This narrative review is designed to support Vitamin D role and its efficacy in managing COVID-19 menace.
Materials and Methods: Latest 50 articles for Vitamin D, and COVID-19 relationship and management were scrutinized to summarize this article from data bases of PubMed and Google scholar in English language. Diagrams were created by biorender.com to summarize pictorial relations.
Conclusions: Higher mortality is associated with countries of high-level Vitamin D deficiencies. Many studies have found a significant relation between Vitamin D deficiency and COVID-19 complications and related comorbidities. It is highly supported by many literature to recommend daily dose of Vitamin D3 10,000 IU/day for a few weeks to rapidly increase 25-hydroxyvitamin D levels above 40–60 ng/mL, in population at higher risk.

Keywords: Biochemistry, cathelicidin, coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, Vitamin D, Vitamin D receptor


How to cite this article:
Sharma P, Bhagat TS, Sharma B, Kumar P. Vitamin D in defense against the terrorism of coronavirus disease 2019: A meta-analysis. Santosh Univ J Health Sci 2021;7:26-33

How to cite this URL:
Sharma P, Bhagat TS, Sharma B, Kumar P. Vitamin D in defense against the terrorism of coronavirus disease 2019: A meta-analysis. Santosh Univ J Health Sci [serial online] 2021 [cited 2022 Dec 8];7:26-33. Available from: http://www.sujhs.org/text.asp?2021/7/2/26/331791




  Introduction Top


Upper respiratory tract infections are more common in winters than in summers. Coronavirus disease 2019 (COVID-19) pandemic was also spread during winter time in December from Wuhan the city of China to worldwide. It is the most prone time for virus to infect and transmit. Furthermore, the most common finding in northern countries is hypovitaminosis of Vitamin-D. The current pandemic situation caused by COVID-19 has led to public health crisis; therefore, there is a desperate need to tackle the infection, by checking its progression and severity, causing death. For the last many months, we are continuously hearing about preventive action against coronavirus disease. Vitamin D is obtained when our skin is exposed to sunlight. The vitamin plays a very important role bone growth and development through increasing the rate of intestinal absorption of calcium, magnesium, and phosphate. It also has wide role by regulating cytokine release of leukocytes preventing the situation of cytokine storm a complicated state associated with coronavirus infection which leads to self-destruction of cells and tissues facilitating the virus action. Various studies conducted throughout the world have indicated the possible relationship between Vitamin D and COVID-19 infection. This disease in itself remains a mystery as of “biological weapon or negligence of some laboratory” has imposed a large negative impacts on the economy and healthcare worldwide [Table 1] and [Table 2] depicts data according to WHO dashboard. The current situation is even more tragic as we are left with limited therapeutic options and no registered and/or definite treatment or vaccine until now. Alternative treatment and resources to prevent and control this monster virus are much needful. The current narrative review is aimed to collect literature to support immune role of Vitamin D and its role in risk reduction of respiratory infections and plausible role in COVID-19 management.
Table 1: Data report WHO on September 4, 2020[72]

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Table 2: Tropical countries versus cold countries WHO 153 report[73]

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  Materials and Methods Top


This review is formulated by collecting data from databases of PubMed central and Google scholar from published reviews, original studies regarding seasonal influenza, acute respiratory infections, COVID-19 and immunity role of Vitamin D, 25-hydroxyvitamin D (25(OH)D). In this review, we have tried to accumulate around 50 latest studies on Vitamin D and its potential benefits in fighting against infections. We have tried to gather information about role of Vitamin D in COVID-19 management also. In addition, a summarized biochemical perspective of COVID-19 been documented in this review.

Structure of coronavirus disease 2019

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus (about length of 30 kb) with a nuclear capsid, which can enter through endocytosis or fusion to infect cells and thrive on it. Its potential target of action is respiratory, enteric, hepatic, and neurological organs, not only in homo-sapiens but also in other species.[1] This virus has advantages of spike (S) glycoproteins comprised of two functional subunits called the S1 protein (binding unit to the host cell) and the S2 protein (promotion of merging/fusion to cellular membranes).[2] Angiotensin-converting enzyme II receptor (ACE2) has been identified as a functional receptor for SARS-CoV-2 entry into the cell as shown in [Figure 1].[3]
Figure 1: Structure of corona virus

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SARS-CoVs enter the host cell through the ACE2 receptor present on membranes. The SARS-Cov-2 first predominantly infects lower airways and binds to ACE2 on alveolar epithelial cells. These viruses have potency to induce inflammatory cytokines. The “cytokine storm or mob” is the postulated mechanism for organ damage.[4]

Relevance of cytokines cascade in coronavirus disease 2019

Once infected, endothelial dysfunction, vascular damage, and paracrine/metabolic dysregulation all are result of cytokine cascade formation, leading to multiple organ systems damage. In hypercytokinemia levels of acute-response cytokines (tumor necrosis factor [TNF] and interleukin [IL]-1β) and chemotactic cytokines such as IL-8 and monocyte chemoattractant protein-1 (MCP-1) rise, facilitating a sustained surge in IL-6. IL-6 binds to receptor, forming a complex that acts on gp130. This further regulates levels of IL-6, MCP-1, and granulocyte-macrophage colony-stimulating factor by routing through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway.[5] High serum concentration of cytokines are inversely in relation to the total lymphocyte count, thereby low levels of cytotoxic T cells may cause, reduction in viral clearance.[6] Blocking upstream events related to or at the level of cytokine response, such as JAK-STAT signaling of macrophages to reduce IL-1 and IL-6 production, offers a potential therapeutic target for the cytokine storm. This point of pathway is important for researchers as shown in [Figure 2].[7]
Figure 2: Cytokines in coronavirus disease 2019

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Coronavirus disease 2019: Symptomology

COVID-19 has caused severe illness due to sustained human-to-human transmission.[8] The symptoms of the coronavirus are similar to seasonal influenza-like coughing, fever, etc., The COVID-19 can be complicated by interstitial pneumonia together with alveolar destruction resulting in severe acute respiratory distress syndrome (ARDS) and ultimate disaster of death too.[9] Symptoms of COVID19 have wide spectrum coverage, from asymptomatic, mild, ARDS, or multi-organ impairment. The clinically common features include fever (not in all), cough, sore throat, headache, fatigue, myalgia, and breathlessness. Conjunctivitis has also been described. Thus, symptoms are hazy with respect to other respiratory infections. In some, the disease can progress to pneumonia, respiratory failure, and death. Disease progression is also found to be associated with high levels of inflammatory cytokines.[10] Adverse outcomes and death are common in the elders and those with associated co-morbidities. The overall case fatality rate is estimated to range between 2% and 3%.[11]

The Indian Government reported the national recovery rate to be reached 77%, and the case fatality rate is down to 1·8%.[12] Milder form of disease and case fatality rate in patients other than in China[13] may be due to predisposition of the Asian population to the virus due to higher expression of ACE2 receptors on the mucosa of respiratory organs.[14] A study by Dahai Zhao and associates reported comparative analysis on pneumonia-associated COVID-19-positive cases versus pneumonia-associated COVID-19-negative individuals. Symptoms presented by both groups of patients were similar, most common fever and cough, which are similar to other common respiratory virus. In this study, data showed significant differences between COVID-19 and non-COVID-19 patients in computed tomography (CT) images. Most COVID-19 patients were found with bilateral pneumonia and the feature of multiple mottling, ground-glass opacity, and inflammation spreading fast in the lungs of COVID-19 patients.[15]

Endogenous synthesis/action of Vitamin D

Vitamin D/sunshine vitamin, as we call it classically known to regulate calcium and phosphate metabolism. Vitamin D is collected exogenously by food rich in Vitamin D, and endogenous synthesis is through reaction that converts 7-dehydrocholesterol in the skin to D3 (cholecalciferol) after exposure of sun rays rich in Ultraviolet B (UVB). Liver forms 25(OH)D after Enzymatic 25-hydroxylation of D3 and D2. After kidneys make active form of 1,25-dihydroxyvitamin D (1,25[OH] D) it, interacts with the nuclear Vitamin D receptor (VDR) in various tissues to initiate the biological effects.[16]

The fully active form of Vitamin D (1,25[OH]2D3) is hydroxylated in the kidney. Enzyme utilized in this conversion is CYP27B1, which is in turn regulated by parathormone and the fibroblast growth factor 23 (FGF-23).[17] Synthesis of 1,25(OH)2D3 is strictly regulated in a renal negative feedback loop: High levels of 1,25(OH)2D3 and FGF-23 inhibit CYP27B1 and induce the CYP24A1, to shut down the activated form.[18]

Vitamin D or chemically known as calcitriol exerts both skeletal and extraskeletal effects at genomic and nongenomic level. VDR are receptors also known as ligand-activated transcription factors and are responsible for genomic action of Vitamin D. Vitamin D combination with VDR heterodimerizes with retinoid receptors. Ligand for retinoid receptor is active metabolite of Vitamin A, which results in triggering of hormone response element of Vitamin D that eventually regulates the gene expression.[19]

The nongenomic effect of Vitamin D involves the activation of a number of intermediates of signaling pathway finally leading to Vitamin D response element in the gene promoter region of this vitamin. Vitamin D has great potential in immunity boost up of the body as shown in [Figure 3]. Majority of immune cells, including macrophages, T and B lymphocytes, and dendritic cells abundantly express VDR and vitamin stimulated gene expression of these cells generates a peptide named cathelicidin.[20]
Figure 3: Innate immunity and Vitamin D

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Chemistry between Vitamin D and angiotensin-converting enzyme II

25(OH)D or the principal element among Vitamin D metabolites is used as a Vitamin D status index. Vitamin D has bidirectional relation with immunity system Immune cells are not only targets, but also local suppliers of Vitamin D and are able to activate Vitamin D hormone in a localized area. Insufficiency of Vitamin D levels are linked to anomalies in immune systems, such as higher infection rates and autoimmunity.[21] According to the studies, Vitamin D has potential to lower the risk of COVID-19 infections and deaths through different mechanisms including maintenance of cell junctions, strengthening cellular immunity by reducing the cytokines with impacts on TNF-α and interferon γ (IFN-γ), and modulating adaptive immunity by suppressing T helper cell Type 1 responses and promoting T regulatory cells induction.[22] Based on a report by Tian et al., Vitamin D deficiency may be linked with a high risk of severity in COVID-19. Vitamin D deficiency enhances the cytokine cascade formation, thereby, it becomes driver of the excessive and persistent inflammation, which is a main characteristic of ARDS and may be significantly toxic in subjects with SARS-CoV-2 infection.[23],[24],[25] The expression of VDR is high in the lung, ACE2 was well established as the functional host receptor for SARS-CoV-2.[26] This receptor is an important enzyme for the regulation of the Renin-Angiotensin System (RAS) which regulates blood pressure and vascular balance.

Previously, it was shown that a specific region within the SARS-CoV-1 spike protein interacts with ACE2, leading to fusion with the host cell membrane.[27],[28] ACE2 was highly expressed on lung alveolar epithelial cells and small intestinal epithelial cells, consistent with potential routes of viral transmission of SARS-CoV-2, as both respiratory and gastrointestinal systems share interfaces with the external environment.[28]

SARS-CoV-2 can infect upper and lower epithelial lung cells simultaneously and anchor its spike (S) protein into ACE2 receptor.[29],[30],[31],[32],[33] ACE2 is also highly presented in patients with hypertension, diabetes mellitus, coronary heart diseases, and cerebrovascular disease, which could explain comorbidities of COVID-19.[34],[35] As concerning interpretations may arise from all these observations, it is important to note that ACE2 receptor has been broadly known to be downregulated by Vitamin D activity.[36] Vitamin D act as a negative endocrine regulator of the RAS via the canonical VDR pathway which can suppress RAS and down regulates the expression of ACE2 both in vitro and in vivo.[34],[37]

Vitamin D strategy in immunity

Vitamin D, not only plays an essential role in maintaining healthy mineralized skeleton, but also is an immunomodulatory hormone.[20] VDR and other specialized metabolizing enzymes are presented by variety of immune cells, including lymphocytes, monocytes, macrophages, and dendritic cells.[20]

Vitamin D can manipulate both the innate and adaptive immune system against invading pathogens. It boosts up the innate immunity by cytokine suppression thereby reducing infection risk. It also supports host innate immunity by augmenting synthesis of anti-microbial peptides such as cathelicidins, IL-37, and defensins.[38],[39] These peptides bring microbial killing by tormenting cell membranes or by neutralizing endotoxin activity of invading organisms.[40] Most important in innate system of immune response is the toll-like receptors (TLR) that recognize pathogenic molecules, and when activated, release cytokines and induce reactive oxygen species and antimicrobial peptides. These TLR affect or are affected by VDR induction.[41] Vitamin D increases innate immunity by secretion of antiviral peptides which improves mucosal defenses.[42]

During the progression of infection, VDR signals activate innate immunity signals for the production of anti-microbial proteins (AMPs), including human cathelicidin AMP.

Cathelicidins/LL-37 exhibit direct antimicrobial activities against a microorganism spectrum, including gram-positive and gram-negative bacteria, viruses capsulated or noncapsulated and various fungi.[43] LL-37 reduced influenza A virus replication in mice study.[44] Decreased dengue virus infection was reported by a clinical trial with supplementation of 4000 IU/d of vitamin D.[45],[46]

Vitamin D and its analogs can raise and control the expression of the cathelicidin LL-37 in a wide range of cell, including keratinocytes, epithelial, and human monocytes/macrophages.[47] Vitamin D also regulates type of AMPs: Defensins. Human beta-defensin 2 is modestly stimulated by 1α,25(OH)2D, and its antiviral effects arise from chemoattractive properties for neutrophils and monocytes.[48] The adaptive immune system overactivity is reduced by Vitamin D that occurs in infections and thereby helps the body to respond sufficiently to infection load. By contact with viral ligands the expression of the VDR present on immune active cells (monocytes, macrophages, dendritic cells, and lymphocytes) is activated.[49] Vitamin D suppresses the release of inflammatory cytokines and chemokines such as IL-2, TNF-α, and IFN-γ, and thus suppresses responses mediated by T helper cell type 1 (Th1).[50],[51] This may help to reduce the cytokine rush that is noted in COVID-19 patients[52] and which is the pathophysiologic driver behind systemic inflammatory response syndrome and ARDS.[53],[54] TLRs are tools in activating adaptive immunity. TLR2 detects lipopeptides of bacteria and leads to activation of NF-kB and cytokine production and release.[55] Ideal vitamin D levels have been shown to improve TLR2 levels and ability to fight infections in body.[20] Viruses (influenza), significantly try to damage the epithelium integrity at tight junctions thereby increasing the risk of infection and complications. Vitamin D on contrary is known to maintain the integrity of these junctions. Low levels of VDR expression leads to increased expression of claudin-2 and inflammation. Vitamin D also promotes superoxide production, phagocytosis, and bacterial destruction.[56]

Seasoning of Vitamin D levels

Vitamin D deficiency is very easily detectable. In temperate regions (colder countries), UVB irradiation is not sufficient to induce cutaneous vitamin D3 synthesis in winters, especially at higher latitudes. Cutaneous synthesis of active Vitamin D is also strongly influenced by skin color.[57] Deficiency of Vitamin D synthesis by skin, together with vitamin D-poor diets, has contributed to severe Vitamin D insufficiency or deficiency in European and North American populations.[58],[59],[60],[61] For example, a survey of healthy females across northern Europe found that there was widespread Vitamin D deficiency More than one-third of their adolescent females have Vitamin D below 25 nmol/l, and nearly all are below 50 nmol/l,[62] and a recent study found that 42% of African-American women in the United States were seriously 25D deficient (15 ng/ml).[63] In a national survey of the United States of America, a negative correlation between Vitamin D levels and upper respiratory infections was demonstrated.[64] Patients with severe Vitamin D deficiency have been found to be in association with not only increased cases of pneumonia infections but also more rate of admission to intensive care units and mortalities.[65],[66],[67]

Sun exposure benefit for Southeast Asia

There are potential benefits of sun exposure to yearlong sun availability in south and east of Asia as studied by Nimitphong and Holick who provide evidences of negative association of mortality rates for all cancers with average daily UV radiation exposure in 263 countries in China during 1990–1992,[68] another scientist Juzeniene et al. studied and found the correlation between seasonal discrepancies in Vitamin D synthesis and nonpandemic influenzas in Singapore and Japan.[69] A small seasonal variation in influenza has been observed in Singapore, since it is close to the equator and has less seasonal variation in vitamin D synthesis throughout the year. Whereas in subtropical region of Okinawa, Japan, which the rate of vitamin D synthesis decrease to only ¼ in winter than summer, there is a yearly, major outbreak of influenza in the winter and a minor outbreak in the summer.[70] Similarly, as COVID-19 made its appearance and started spreading across the northern hemisphere in the winter of 2019. Levels of vitamin D in inhabitants residing in northern cold zones have been found to be at their lowest during winter.[20] The association between Vitamin D and mortality from COVID-19 has been found in few studies, with mortality rates found to be higher in countries with populations with lower prevalent Vitamin D levels, like in middle eastern country, for example, Iran. With exception of Nordic countries of Norway, Finland, where Vitamin D levels are sufficient due to food fortifications hence these are protected from atrocities of COVID-19.[20]

Vitamin D in relation to coronavirus disease 2019

Since COVID-19 was recognized in winter 2019 and mainly influenced middle-aged and elderly subjects, it has been supposed that virus-infected subjects may not have adequate vitamin D levels.[9] Even when mortality per million is plotted against latitude, it can be seen that all countries that lie below 35° North have relatively low mortality. Above 35 degree north latitude people do not receive sufficient sunshine to retain or synthesize adequate Vitamin D levels during winter. This could be a possible reason in determining outcomes from COVID-19. Italy and Spain are surprisingly having relatively high prevalences of Vitamin D deficiency and brutality of COVID-19 is quite clear. Vitamin D deficiency has also been shown to correlate with hypertension, diabetes, obesity, and ethnicity all features associated with increased risk of severe COVID-19.[71] There is experimental data showing that Vitamin D is significant in regulating and suppressing the inflammatory cytokine response of respiratory epithelium and macrophages to various pathogens including respiratory viruses. Evidence that Vitamin D might protect against infection is less but it is importance lies in prevention hypothesis that Vitamin D would protect against SARS-CoV-2 infection by preventing the cytokine storm and subsequent ARDS that is main culprit to deal with.[71]

Interpretations of coronavirus disease 2019 researches around the globe

  1. In a study of United Kingdom COVID-19-positive cases confirmed lower median serum 25(OH)D level of 27 nmol/L compared with COVID-19-negative cases, with median level of 52 nmol/L. Older adults with Vitamin D deficiency and COVID-19 demonstrated worse morbidity outcomes[74]
  2. Countries like Italy and Spain had very high rates of infection and mortality rates, but it is also well documented that these regions are endorsed with high prevalence of Vitamin D deficiency[20]
  3. In A large study from 20 European countries. The mean levels of Vitamin D and morbidity and mortality caused by COVID-19 were acquired. Negative relation was established between average levels of Vitamin D (average 56 mmol/L, STDEV 10.61) in each country, and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed[75]
  4. An Indian study observed inverse correlation was observed among mean 25(OH)D and SARS-CoV-2 infection rate/million in the Indian population. Interestingly, the mortality rate due to SARS-CoV-2 infection was also negatively correlated with Vitamin D status of healthy Indian subjects (r = −0.42, P = 0.02)[76]
  5. Recent Italian scientist Isaia and Medico, 2020 has demonstrated a significant Vitamin D deficiency in a cohort of COVID-19 infected elderly women.[77]
  6. A study from France surmise that sunlight exposure may have a protective effect against COVID-19 mortality, with a P value of 1.532 × 10−32 possibly depicting role of benefit of Vitamin D synthesis[78]
  7. In Chicago, around 70% of COVID-19 deaths were observed in African-American individuals[79] who were also at the greater risk for Vitamin D deficiency[80]
  8. In a cohort study of Singapore, supplement therapy of Vitamin D/magnesium/vitamin B12 was given in older COVID-19 patients, and it was associated with a significant reduction in patients with adverse outcome and requiring oxygen support and/or intensive care support[81]
  9. In cohort study in Switzerland, polymerase chain reaction-positive for SARS-CoV-2 patients were compared with negative patients, significantly lower 25(OH)D levels (P = 0.004) were found with median value (11.1 ng/mL, 24.6 ng/mL), respectively. On the basis of this preliminary observation, vitamin D supplementation was recommended[82]
  10. Significant relationship was observed by Ilie et al. between Vitamin D levels, and the number COVID-19 caused mortality. The most vulnerable group of population for COVID-19 is also the one that has the most deficit in Vitamin D.[83]



  Conclusions Top


Mechanism of Vitamin D function in host immunity has been briefed in this review, but interactions between viral infections and Vitamin D are not that modest. ACE2, a part of the RAS, serves as the major gate of entrance into cells causing SARS and COVID-19, respectively. The expression of ACE2 is reduced by SARS-COV2 and further leads on to lung injury and pneumonia. Therefore, considering the reputation of Vitamin D in RAS regulation and its power to control innate and adaptive immunity. Vitamin D may seem conceivable as prophylaxis and may decrease the ruthlessness caused by SARS-CoV-2 infection, especially in areas where hypovitaminosis D is common, provided overdose are avoided.

For reduction the risk of infection and initiating defense mechanism in COVID-19, it is suggested daily dose of Vitamin D3 10 000 IU/day for a few weeks to rapidly increase 25(OH)D levels above 40–60 ng/mL, is suggested for people at risk. For treatment after getting infected with COVID-19, higher Vitamin D3 doses might be helpful if recommended. It would be certainly thoughtful to provide Vitamin D supplements for musculoskeletal strengthening or to those who are at risk of deficiency due to isolation or quarantine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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