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Optimisation of Vitamin D Status for Enhanced Immuno-protection Against Covid-19

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Abstract

Background Vitamin D deficiency (serum 25(OH)D<50nmol/l) is common in Ireland, particularly amongst older adults, hospital inpatients and nursing home residents. Vitamin D deficiency is associated with increased risk of acute viral respiratory infection and community acquired pneumonia, with several molecular mechanisms proposed to explain this association. Vitamin D supplementation has also been shown to reduce the risk of respiratory infection. Vitamin D and Covid-19 Correction of vitamin D deficiency is thought to suppress CD26, a putative adhesion molecule for Covid-19 host cell invasion. Vitamin D may also attenuate interferon gamma (IFNγ) and interleukin-6 (IL-6) inflammatory responses, both potent predictors of poorer outcome in critically-ill ventilated patients including those with Covid-19. Vitamin D Requirements Irish adults require 25-30µg/d of vitamin D3, an intake not achievable by diet alone, to reliably maintain serum 25(OH)D levels >50nmol/l. Supplementation with doses up to 100µg/d has been shown to be safe for adults, and many agencies and expert groups now advocate supplementation in older adults, albeit at lower levels than this. Conclusions and Recommendations Vitamin D deficiency is common and may contribute to increased risk of respiratory infection including Covid-19. We recommend that all older adults, hospital inpatients, nursing home residents and other vulnerable groups (e.g. those with diabetes mellitus or compromised immune function, those with darker skin, vegetarians and vegans, those who are overweight or obese, smokers and healthcare workers) be urgently supplemented with 20-50µg/d of vitamin D to enhance their resistance to Covid-19, and that this advice be quickly extended to the general adult population.
Issue: Ir Med J; Vol 113; No. 4; P58
Optimisation of Vitamin D Status for Enhanced
Immuno-protection Against Covid-19
D.M. McCartney1, D.G. Byrne2,3
1. School of Biological and Health Sciences, College of Sciences & Health, Technological
University Dublin - City Campus, Kevin Street, Dublin D08 NF82, Ireland
2. Department of Internal Medicine, St. James’s Hospital, James’s Street, Dublin 8, Ireland
3. Dept. of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin 2, Ireland
Abstract
Background
Vitamin D deficiency (serum 25(OH)D<50nmol/l) is common in Ireland, particularly amongst older adults, hospital
inpatients and nursing home residents. Vitamin D deficiency is associated with increased risk of acute viral
respiratory infection and community acquired pneumonia, with several molecular mechanisms proposed to explain
this association. Vitamin D supplementation has also been shown to reduce the risk of respiratory infection.
Vitamin D and Covid-19
Correction of vitamin D deficiency is thought to suppress CD26, a putative adhesion molecule for Covid-19 host cell
invasion. Vitamin D may also attenuate interferon gamma (IFNγ) and interleukin-6 (IL-6) inflammatory responses,
both potent predictors of poorer outcome in critically-ill ventilated patients including those with Covid-19.
Vitamin D Requirements
Irish adults require 25-30µg/d of vitamin D3, an intake not achievable by diet alone, to reliably maintain serum
25(OH)D levels >50nmol/l. Supplementation with doses up to 100µg/d has been shown to be safe for adults, and
many agencies and expert groups now advocate supplementation in older adults, albeit at lower levels than this.
Conclusions and Recommendations
Vitamin D deficiency is common and may contribute to increased risk of respiratory infection including Covid-19. We
recommend that all older adults, hospital inpatients, nursing home residents and other vulnerable groups (e.g. those
with diabetes mellitus or compromised immune function, those with darker skin, vegetarians and vegans, those who
are overweight or obese, smokers and healthcare workers) be urgently supplemented with 20-50µg/d of vitamin D to
enhance their resistance to Covid-19, and that this advice be quickly extended to the general adult population.
Background
Vitamin D is a steroid hormone which may be synthesised endogenously from the effect of UVB irradiation on skin,
or consumed from exogenous dietary sources or supplements. Recent studies have shown an inverse relationship
between serum vitamin D levels and risk of acute respiratory tract infection1. Notably, a September 2019 meta-
analysis by Zhou and colleagues incorporating data from 21,000 subjects across eight observational studies showed
that those with a serum vitamin D level <20ng/ml (i.e. <50nmol/l) had a 64% increased risk of community-acquired
pneumonia2.
While the latter data are associative, and do not in and of themselves indicate a causal role for low vitamin D levels
in community-acquired pneumonia, there is existing experimental evidence which suggests several mechanisms by
which optimisation of vitamin D status contributes to enhanced resistance to viral respiratory tract infection3,4,5.
Moreover, notwithstanding the heterogeneity of infection types included and population groups captured, a recent
systematic review which evaluated the findings of 7 meta-analyses incorporating data from 30 randomised
controlled trials concluded that vitamin D supplementation, particularly in those with low serum levels at baseline, is
likely to reduce the risk of respiratory tract infection6, a finding corroborated by two further systematic reviews the
same year1,7.
Relevance of Vitamin D to Covid-19
With regard to Covid-19, it is salient that while the virulence mechanisms of this virus have not been fully
characterised, a number of molecular virulence mechanisms including dipeptidyl peptidase-4 receptor (DPP-4/CD26)
binding, Papain-like protease (PLpro)-mediated replication, MDA5 and RIG-I host-recognition evasion, and disruption
of M-protein mediated type-1 IFN induction have been identified in the closely-related Covid-MERS virus8. Of these,
human DPP-4/CD26 has recently been shown to interact with the S1 domain of the COVID-19 spike glycoprotein,
indicating that it may also be an important virulence factor in Covid-19 infection9. Critically in this regard, DPP-
4/CD26 receptor expression has been shown to be significantly reduced in vivo upon correction of vitamin D
deficiency10. There is also evidence that optimisation of vitamin D may attenuate some of the critical downstream
immunological sequelae thought to elicit poorer clinical outcome in Covid-19 infection, such as prolonged
interferon-gamma response4, and persistent interleukin 6 elevation, a negative prognostic indicator in acutely-ill
pneumonia patients11, including those with Covid-19.
Prevalence of Deficiency
In Ireland, as a consequence of poor dietary intake, low supplementation rates and sub-optimal sun exposure, the
prevalence of vitamin D deficiency is high, particularly amongst older adults, the most vulnerable constituency to
Covid-19 mortality. In the last nationally representative sample, 35.7% of adults aged 50-64 years, and 44.0% of
adults aged 65-84 years had serum vitamin D levels less than 50nmol/l on a year-round basis, while these figures
rose to 55.4% and 48.1% respectively in winter12. These data are critical, as they suggest that one half of our older
adults currently have serum vitamin D levels below the threshold at which viral respiratory infection risk is known to
increase. It is also noteworthy that vitamin D levels are even poorer amongst nursing home and hospital inpatients in
Ireland, with 37-42% of these individuals having serum levels less than 25nmol/l13.
Intake Requirements and Supplementation Guidelines
Existing guidance from the Food Safety Authority of Ireland (FSAI) recommends that older adults should supplement
with 10 micrograms of vitamin D per day14. However, most countries in Europe now recommend intakes of 15-20
micrograms per day for these older age groups, with the Institute of Medicine (IoM) and the Endocrine Society in the
US recommending intakes of 20 micrograms per day and 37.5-50 micrograms per day respectively for older adults
since 201115. Two well-designed modelling studies have been conducted to estimate the oral dose of vitamin D
required to achieve and maintain adequate serum levels in Irish adults on a year round basis. The first of these
proposed a daily dose of 28.0 micrograms to maintain serum vitamin D levels above the critical 50nmol/l threshold
in 97.5% of healthy Irish adults throughout the year16, while the second suggested a daily requirement of 24.7
micrograms for Irish adults aged 64 years and over to achieve and maintain these serum levels17.
Safety of Vitamin D Supplementation
While documented cases of vitamin D toxicity do appear in the literature, these are rare, and invariably relate to
extremely high doses taken over an extended period of time18. There is no evidence however, that vitamin D
supplementation at 20-50 micrograms per day has any adverse effects on health. Indeed several studies have
explicitly cited the safety of vitamin D3 supplementation at doses of up to 100 micrograms per day19,20, with a
further review proposing a tolerable upper limit (TUL) of 250 micrograms per day21. These findings are perhaps
unsurprising, given that cutaneous synthesis yields a typical ‘dermal dose’ of ~70 micrograms per day from regular
sunlight exposure during the Summer months, and that one single whole-body minimum erythemal dose can
produce a rise in serum vitamin D levels which is equivalent to an oral dose of ~250-625 micrograms22. For context, a
minimum erythemal dose can be produced by as little as 1015min of whole-body sun exposure at mid-day in mid-
summer in a pale-skinned individual, and is therefore not an uncommon occurrence. Further research and clinical
data demonstrating the safety of vitamin D supplementation at doses of 20-50 micrograms per day abound in the
literature23,24, highlighting its viability as a means of addressing this common but important nutritional deficit.
Conclusions and Recommendations
Vitamin D intakes and status are low in Ireland, particularly amongst older adults, hospital inpatients and nursing
home residents. Low serum vitamin D has been associated with increased risk and severity of viral respiratory
infections including community acquired pneumonia, whilst there is also evidence that vitamin D supplementation
which raises serum vitamin D levels above 50nmol/l may ameliorate this risk. Among the proposed protective effects
of vitamin D are several which may reduce the risk of Covid-19 infection, or which may attenuate the immunological
sequelae responsible for its fulminant respiratory effects. There is existing guidance from health authorities in
Ireland and globally that older adults should supplement with vitamin D, and there now exists a wealth of evidence
which demonstrates the safety of vitamin D3 supplementation at doses of 20-50 micrograms per day.
In the face of the impending Covid-19 epidemic, and in the absence of a vaccine or any effective anti-viral drug
therapy to treat those infected, these findings call for the prioritised supplementation of all hospital inpatients,
nursing home residents and community-dwelling older adults with vitamin D at a minimum daily dose of 20
micrograms per day. It is further recommended that supplementation be targeted at other vulnerable constituencies
(e.g. those with diabetes mellitus or compromised immune function, those with darker skin, vegetarians and vegans,
those who are overweight or obese, smokers and healthcare workers), and ultimately extended to the rest of the
population in order to mitigate the grave public health risks associated with Covid-19 infection.
Declaration of Conflicts of Interest:
The authors declare that they have no conflict of interest.
Corresponding Author:
Dr Daniel McCartney,
School of Biological and Health Sciences,
Technological University of Dublin - City Campus,
Kevin Street,
Dublin D08 NF82,
Ireland.
Email: Daniel.McCartney@TUDublin.ie
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... Conclusion The cost-effectiveness of vitamin D 3 supplementation is most robust in adults ≥70 years. Clinical uncertainty in the magnitude of the benefits of vitamin D 3 supplementation could be further addressed by means of: (1) performing a clinical research study or (2) conducting a pilot/regional study, prior to reaching a decision to invest in a nationwide programme. ...
... Vitamin D deficiency, as measured by serum 25(OH)D, is particularly high among older Irish adults. 2 There is a growing interest in the costeffectiveness of vitamin D to prevent disease. While several previous studies were mainly conducted in the elderly for fall and/or fractures (eg, refs 3 4), more recently, a study estimated the costs and savings for preventing cancer deaths by vitamin D supplementation of the population aged ≥50 years in Germany. ...
... The 'at risk' population of interest (i.e., those with year-round vitamin D deficiency) is estimated to be 13% of the Irish population. 2 This population cohort was estimated by applying 13% to the Irish population statistics for 2016 for all ages. The population data were summarised into 5-year age groups, beginning at age 50 years. ...
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Background This study investigated the cost-effectiveness of vitamin D 3 supplementation in older adults in Ireland, with year-round vitamin D deficiency (serum 25-hydroxyvitamin D concentration <30 nmol/L) (13% of Irish adults), from the perspective of the Health Service Executive. Methods Three age groups were investigated: (1) ≥50 years, (2) ≥60 years and (3) ≥70 years. Based on the clinical literature, vitamin D 3 supplementation may: (1) decrease all-cause mortality by 7% and (2) reduce hip fractures by 16% and non-hip fractures by 20%. A discount rate of 4% was applied to life years and quality-adjusted life years (QALYs) gained, and healthcare costs. The annual healthcare costs per patient used in the model are based on the average annual health resource use over the 5-year time horizon of the model. Results The cost/QALY estimates in all three age groups are below the usually acceptable cost-effectiveness threshold of €20 000/QALY. The most cost-effective and least costly intervention was in adults ≥70 years. For this age group, the average annual costs and outcomes would be approximately €5.6 million, 1044 QALYs gained, with a cost/QALY of approximately €5400. The results are most sensitive to the mortality risk reduction following vitamin D 3 supplementation. Conclusion The cost-effectiveness of vitamin D 3 supplementation is most robust in adults ≥70 years. Clinical uncertainty in the magnitude of the benefits of vitamin D 3 supplementation could be further addressed by means of: (1) performing a clinical research study or (2) conducting a pilot/regional study, prior to reaching a decision to invest in a nationwide programme.
... [1][2][3][4] Vitamin D may have a role in extraskeletal health such as the immune response to acute respiratory illnesses, 5 which is pertinent during the COVID-19 pandemic. 6 Following the onset of the pandemic, some reports advocated blanket oral supplementation to entire populations with doses ranging from 20 to 50 µg daily, [7][8][9][10] which are in excess of vitamin D intake requirement as specified by governmental agencies in Europe and North America. [1][2][3][4] By contrast, other groups have countered this blanket recommendation, favouring a targeted approach based on modelling of total vitamin D intakes. ...
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Full-text available
Objectives Since the onset of the COVID-19 pandemic in 2020, there have been plausible suggestions about the need to augment vitamin D intake by supplementation in order to prevent SARS-CoV2 infection and reduce mortality. Some groups have advocated supplementation for all adults, but governmental agencies have advocated targeted supplementation. We sought to explore the effect of the COVID-19 pandemic on both vitamin D status and on the dose of new-to-market vitamin D supplements. Setting University hospital, Dublin, Ireland. Participants Laboratory-based samples of circulating 25-hydroxyvitamin D (25OHD) (n=100 505). Primary and secondary outcome measures Primary outcomes: comparing yearly average 25OHD prior to the pandemic (April 2019 to March 2020) with during the pandemic (April 2020 to March 2021) and comparing the dose of new-to-market vitamin D supplements between 2017 and 2021 (n=2689). Secondary outcome: comparing prevalence of vitamin D deficiency and vitamin D excess during the two time periods. Results The average yearly serum 25OHD measurement increased by 2.8 nmol/L (61.4, 95% CI 61.5 to 61.7 vs 58.6, 95% CI 58.4 to 58.9, p<0.001), which was almost threefold higher than two similar trend analyses that we conducted between 1993 and 2016. There was a lower prevalence of low 25OHD and a higher prevalence of high 25OHD. The dose of new-to-market vitamin D supplements was higher in the years 2020–2021 compared with the years 2017–2019 (p<0.001). Conclusions We showed significant increases in serum 25OHD and in the dose of new-to-market vitamin D supplements. The frequency of low vitamin D status reduced indicating benefit, but the frequency of vitamin D excess increased indicating risk of harm. Rather than a blanket recommendation about vitamin D supplementation for all adults, we recommend a targeted approach of supplementation within current governmental guidelines to at-risk groups and cautioning consumers about adverse effects of high dose supplements on the market.
... Among all processes, the dipeptidyl peptidase-4 receptor is associated with the S1 domain of the spike glycoprotein in COVID-19. The expression of this virulence factor causes misconception in the influence of vitamin D deficiency in animal models [133,134]. Elderly and patients with immunological deficiencies, which have the minimum amount of vitamin D, are more prone to get COVID-19. Low vitamin D levels are also correlated with several types of diseases such as cardiovascular diseases, diabetes, and obesity. ...
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... Supplementation with natural micronutrients may positively impact the course of COVID-19 and can be potentially beneficial at the level of treatment and prophylaxis as well (10). ...
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... The S1 domain of the spike glycoprotein of SARS-CoV-2 has recently been discovered to interact with the human dipeptidyl peptidase-4 receptor (DPP-4/CD26), suggesting that it might be a critical virulence component in COVID-19 [145]. DPP-4/CD26 receptor expression has been shown to be considerably decreased in vivo when vitamin D insufficiency has been corrected, therefore indicating a reason for vitamin D supplementation in COVID-19 patients [146,147]. ...
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... 16 It has been proposed that vitamin D deficiency has a possible function in pathogenic mechanisms related to COVID-19. 17 Treatment of vitamin D deficiency is supposed to suppress CD26, which is assumed to be an adhesion molecule for COVID-19 host cell invasion 18 and then ameliorate respiratory failure. 19 Vitamin D has an extensive variety of antioxidant, antifibrotic, immunomodulatory, and anti-inflammatory effects. ...
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As the COVID-19 infection emerges to be the third and most extensive pandemic in the world, the sudden need for researches regarding its preventive and curative management raises. Vitamin D, especially in deficient subjects, has been shown to be prophylaxis and therapy for COVID-19. This study is a report of two confirmed cases of COVID-19 in Bethesda Hospital Yogyakarta Indonesia and its data of clinical symptoms, clinical signs, and laboratory examinations including vitamin D status, measured by a standardized laboratory method which deficiency of vitamin D was found in both cases of COVID-19. This evidence-based case report examined the association between Vitamin D status and COVID-19 severity. A literature search was done on PubMed, CENTRAL, EbscoHost and ProQuest database with keywords : 'vitamin D', 'deficiency', 'status', 'COVID-19', 'severity', 'risk factor'. We found a valid and recent article which includes a cohort study that showed a significant association between Vitamin D deficiency and higher risk along with the severity of COVID-19.
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Emerging evidence has shown that vitamin D deficiency may be related with community-acquired pneumonia (CAP), but individually published studies showed inconclusive results. The aim of this study was to quantitatively summarize the association between vitamin D and the CAP.We conducted this meta-analysis though a systematic literature search of PubMed, Medline, and EMBASE up to 31 September 2018 with the following keywords 'vitamin D' or 'cholecalciferol' or '25-hydroxyvitamin D' or '25(OH)D' in combination with 'community-acquired pneumonia' or 'CAP' or 'pneumonia' with no limitations. This meta-analysis was performed following the guidelines of Meta-analysis of Observational Studies in Epidemiology. The association between vitamin D levels and CAP were measured as odds ratio (OR) and weighted mean difference (WMD). Results were combined using a random-effect or a fix-effect meta-analysis, and sensitivity analyses were conducted to explore potential factors.Eight observational studies involving 20,966 subjects were included. In this meta-analysis, CAP patients with vitamin D deficiency (serum 25(OH)D levels <20 ng/mL) experienced a significantly increased risk of CAP (odds ratio (OR) = 1.64, 95% confidence intervals (CI): 1.00, 2.67), and an obvious decrease of -5.63 ng/mL (95% CI: -9.11, -2.14) in serum vitamin D was demonstrated in CAP patients. Sensitivity analysis showed that exclusion of any single study did not materially alter the overall combined effect.The evidence from this meta-analysis indicates an association between vitamin D deficiency and an increased risk of CAP patients. However, well-designed trails are required to determine the explicit effect of vitamin D supplementation.
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Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an emerging zoonotic virus considered as one of the major public threat with a total number of 2 298 laboratory-confirmed cases and 811 associated deaths reported by World Health Organization as of January 2019. The transmission of the virus was expected to be from the camels found in Middle Eastern countries via the animal and human interaction. The genome structure provided information about the pathogenicity and associated virulent factors present in the virus. Recent studies suggested that there were limited insight available on the development of novel therapeutic strategies to induce immunity against the virus. The severities of MERS-CoV infection highlight the necessity of effective approaches for the development of various therapeutic remedies. Thus, the present review comprehensively and critically illustrates the recent aspects on the epidemiology of the virus, the structural and functional features of the viral genome, viral entry and transmission, major mechanisms of pathogenesis and associated virulent factors, current animal models, detection methods and novel strategies for the development of vaccines against MERS-CoV. The review further illustrates the molecular and computational virtual screening platforms which provide insights for the identification of putative drug targets and novel lead molecules toward the development of therapeutic remedies.
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Background Approximately 1 billion people worldwide have Vitamin D deficiency. The aim of this study was to compare Vitamin D status and serum 25-hydroxyvitamin D (25(OH)D) concentrations among adults sampled in the community, in outpatient clinics, as hospital inpatients and in nursing homes in the West of Ireland. The secondary aim was to determine the associations between length of hospital stay (inpatients) at time of serum 25(OH)D sampling and Vitamin D status. Methods A cross-sectional study was carried out. Patients who had serum 25(OH)D analysis carried out in Galway University Hospitals (January 2011-December 2015) were identified following interrogation of the electronic laboratory data system. Baseline demographics, location and date of sample collection were recorded. Vitamin D deficiency was defined as a serum 25(OH)D concentration<25nmol/L. Results In total, 24,302 patient samples were eligible for inclusion: community n=15,319; outpatient clinics n=6,371; inpatients n=2,339; nursing home residents n=273. Vitamin D deficiency was more common in nursing home residents than inpatients, or those sampled in outpatient clinics or in the community (42%-v-37%-v-17%-v-13%; p<0.001). Inpatients sampled further into their hospital stay (≥3days) had greater Vitamin D deficiency than inpatients sampled on 0-2 days (p=0.007). Season(p<0.001), sex(p<0.001) and age(p<0.001) were associated with 25(OH)D concentrations. Vitamin D deficiency was more common in Winter/Spring, in males and in those aged ≥80years. Conclusions Nursing home residents and inpatients are at the highest risk for Vitamin D deficiency. Season, sex, age and day of hospital stay on which serum 25(OH)D concentrations were sampled were associated with Vitamin D status.