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

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Daniel MA McCartney at Technological University Dublin
Daniel MA McCartney
Declan Byrne at St. James's Hospital
Declan Byrne
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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.
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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 10–15min 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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... However, public awareness regarding vitamin D and its beneficial effects on the immune system has increased since the COVID-19 pandemic [95][96][97][98]. This can be attributed partly to the persistent efforts of small groups of scientists despite negative publicity from pharmaceutical companies and health agencies. ...
... Many studies have reported that elevated circulating 1,25(OH) 2 D levels or a lower ratio of 25(OH)D to 1,25(OH) 2 D serve as predictors of poor health outcomes in individuals with cardiovascular diseases (CVD) [189,190], particularly regarding vascular calcification [191] and heart failure, leading to premature death [13,192,193]. Additionally, circulating 25(OH)D concentrations show an inverse association with the severity of various disorders, including metabolic syndrome [194,195], immunity [196,197], autoimmune disorders [12,198], the ability to combat infections [95,96,98,199], and the progression of calcified plaque in coronary arteries [200]. ...
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Full-text available
  • Apr 2020
Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.
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The role of Vitamin D in the prevention of Coronavirus Disease 2019 infection and mortality
Preprint
Full-text available
  • Apr 2020
Background/Aims: WHO declared SARS-Cov-2 a global pandemic. The aims of this paper are to assess if there is any association between mean levels of vitamin D in various countries and cases respectively mortality caused by COVID-19. Methods: We have identified the mean levels of vitamin D for 20 Europeans Countries for which we have also got the data regarding the morbidity and mortality caused by COVID-19. Results: The mean level of vitamin D (average 56mmol/L, STDEV 10.61) in each country was strongly associated with the number of cases/1M (mean 295.95, STDEV 298.73 p=0.004, respectively with the mortality/1M (mean 5.96, STDEV 15.13, p < 0.00001). Discussion: Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of population for COVID-19. Conclusions: We believe, that we can advise Vitamin D supplementation to protect against SARS-CoV2 infection.
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Vitamin D deficiency in Ireland – implications for COVID 19. Results from the Irish Longitudinal Study on Ageing (TILDA)
Technical Report
Full-text available
  • Apr 2020
Vitamin D - a supportive role for the immune system in COVID-19? A report using the Irish Longitudinal Study on Ageing data (TILDA)
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Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths
Article
Full-text available
  • Apr 2020
The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
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Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26
Article
Full-text available
  • Mar 2020
The recent outbreak of pneumonia-causing COVID-19 in China is an urgent global public health issue with an increase in mortality and morbidity. Here we report our modelled homo-trimer structure of COVID-19 spike glycoprotein in both closed (ligand-free) and open (ligand-bound) conformation, which is involved in host cell adhesion. We also predict the unique N- and O-linked glycosylation sites of spike glycoprotein that distinguish it from the SARS and underlines shielding and camouflage of COVID-19 from the host the defence system. Furthermore, our study also highlights the key finding that the S1 domain of COVID-19 spike glycoprotein potentially interacts with the human CD26, a key immunoregulatory factor for hijacking and virulence. These findings accentuate the unique features of COVID-19 and assist in the development of new therapeutics.
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The association between Vitamin D deficiency and community-acquired pneumonia: A meta-analysis of observational studies
Article
Full-text available
  • Sep 2019
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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Recent Aspects on the Pathogenesis Mechanism, Animal Models and Novel Therapeutic Interventions for Middle East Respiratory Syndrome Coronavirus Infections
Article
Full-text available
  • Mar 2019
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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Vitamin D Status of Adults in the Community, in Outpatient Clinics, in Hospital, and in Nursing Homes in the West of Ireland
Article
  • Jan 2020
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.
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