Title: RAPID EVIDENCE SUMMARY: VITAMIN D IN COVID-19

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Title:

RAPID EVIDENCE SUMMARY:

VITAMIN D IN COVID-19

Author: CMO Office, Louise Hendrick

Organisation: Department of Health

Date: 27

January 2021

Action required:

☐ For noting

☐ For discussion

☒ For decision

Approved for future publication: YES

Version

1.0

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RAPID EVIDENCE SUMMARY: VITAMIN D IN COVID-19

24 JANUARY 2021

INTRODUCTION

▪ National Department of Health guidelines on vitamin D were updated in November

2020 and advise adults aged 65 and older to take a daily vitamin D supplement of 15

micrograms to support bone and muscle health.

▪ In the context of COVID-19, advice has previously issued recommending that

individuals that are self-isolating or unable to go outside should consider

supplementation.

▪ This rapid review was conducted to assess current evidence on the role of vitamin D in

the prevention and treatment of COVID-19 and additional considerations which may

impact decision-making.

▪ This review of the available research evidence up to January 2021 considers recent

rapid reviews, randomised controlled trial (RCT) evidence, observational studies and

laboratory studies.

o A recently updated rapid review conducted by the National Institute for

Health and Care Excellence (NICE) in the UK concluded that there is

currently a lack of evidence linking vitamin D and the incidence and severity

of COVID-19. The report recommends increasing awareness of existing

recommendations relating to vitamin D supplementation.

o Results from a randomised controlled trial (Entrenas Castillo, 2020)

reported reduced admission to ICU and reduced mortality in patients with

COVID-19 receiving standard care plus vitamin D compared to standard care

alone. However, this trial was noted to have significant methodological

limitations including low numbers (n=76) and serious risk of bias.

o Collectively, other evidence provides conflicting reports of an association

between vitamin D supplementation and a reduced risk of and poorer

outcomes with COVID-19 infection.

o A number of studies have suggested an association between low vitamin D

status and increased incidence and severity of COVID-19 infection.

However, causality has not been confirmed as many of the risk factors for

severe COVID-19 outcomes are the same as the risk factors for low vitamin

D status.

▪ Additional considerations outlined within the report include:

o Modest evidence to suggest that vitamin D may slightly reduce the risk of

acute respiratory illness.

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o Existing evidence of vitamin D deficiency in Ireland with TILDA results showing

that 13.1% of adults over 55 are deficient all year round, rising to 21.3% in

winter. Higher levels of deficiency have been reported in those aged 70+

(27.1%) and 85+ (46.6%) in winter, with 11.5% of those aged 70+ reported

taking a vitamin D supplementation. A cross-sectional study also reported

high levels of deficiency in Irish individuals of South Asian descent (66.7% had

vitamin D levels ≤30 nmol/L).

o International public health guidance typically recommends optimisation of

vitamin D status in the context of bone and muscle health. Several countries

have reiterated existing guidance given increased time spent indoors due to

COVID-19 restrictions (England, Scotland, Wales, Northern Ireland, Slovenia,

France).

o England and Scotland have recently launched an opt-in scheme offering a

free 4-month supply of vitamin D supplements for those listed as extremely

clinically vulnerable.

▪ There is insufficient high-quality evidence to support a change to existing guidance,

however this report makes the following recommendations:

o Increase awareness of existing guidance that adults age 65 and over should

take a 15 microgram daily supplement for bone and muscle health

o Adults spending increased time indoors or are housebound or in long-term

residential care or have dark skin are also recommended to take vitamin D

supplementation

o That ongoing developments, particularly RCTs, in this area be monitored

with guidance reviewed accordingly

BACKGROUND

This rapid review was conducted to assess the following question:

“What is the current evidence in relation to the role of vitamin D in prevention and

treatment of COVID-19?”

The potential role of vitamin D in the prevention and treatment of COVID-19 has been

proposed based on:

• Systematic reviews and meta-analyses showing a reduced risk of acute respiratory

tract illness with vitamin D supplementation.

• In vitro studies showing the role of vitamin D in induction of antimicrobial peptides in

response to both viral and bacterial stimuli,

and have demonstrated the

responsiveness of several hundred genes to vitamin D, including activated T cells, B

cells, dendritic cells and macrophages (immune cells).

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• A number of observational studies that have highlighted the relationship between UVB

exposure,

vitamin D supplementation,

vitamin D serum levels

and deficiency

and

COVID-19 incidence and outcomes.

Vitamin D is a group of fat-soluble seco-sterols. Vitamin D is obtained through synthesis in the

skin from 7-dehydrocholesterol under the influence of ultraviolet-B (UVB) light and through

the consumption of vitamin D-rich foods. Vitamin D is metabolised first to 25-hydroxyvitamin

D (25[OH]D), then to the bioactive form 1,25-dihydroxyvitamin D.

The classic function of

vitamin D is in the regulation of calcium absorption and homeostasis, supporting

musculoskeletal health. Deficiency which is typically defined as serum 25[OH]D levels

<25nmol/L, is associated with osteomalacia, low bone mass, fractures, muscle weakness,

increased risk of falls; and rickets in children.

Research suggests that vitamin D may also

play a role in immunity owing to the existence of vitamin D receptors on multiple different cell

types including immune cells, and studies showing an association between autoimmune

disease and vitamin D deficiency.

Ireland resides at the latitude band of 51–55°N resulting in a 5-month period from October to

February during which UVB-induced dermal synthesis of vitamin D does not occur and thus

supplementation is recommended in certain groups.

Characteristics, such as skin

pigmentation, age, clothing style, sunscreen use, outdoor activity and sun exposure behaviour

influence vitamin D status,

with deficiency more common in individuals that are

institutionalised, elderly, obese and with dark skin.

EXISTING GUIDELINES

Existing guidelines on vitamin D encompass recommendations for infants aged 0 to 12

months; children aged 1 to 4 years and adults aged 65 years and older.

Since 2010 the HSE has recommended a 5 microgram (5μg) daily vitamin D supplement in liquid

or drop form babies for babies from birth to 12 months.

The initial guidance followed a 2007

review by the FSAI’s Scientific Committee which highlighted the re-emergence of rickets in

infants in Ireland with 23 cases reported in the early 2000s at two Dublin-based paediatric

hospitals.

This guidance was updated in 2020 limiting this recommendation to babies that

are breastfed or taking less than 300mls of infant formula a day,

reflecting the European

Food Safety Authority’s approval of increased vitamin D levels in fortified infant formula

and

subsequent FSAI recommendation.

In October 2020 the Department of Health issued guidance recommending a 5 microgram

(5μg) vitamin D only supplement in liquid or drop form to be taken daily from Halloween (31st

October) to St Patrick’s Day (17th March) in children from one to four years (inclusive).

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In November 2020 the Department of Health issued guidance advising adults aged 65 and older

to take a daily vitamin D supplement of 15 micrograms (15μg), either as a multivitamin, a

vitamin D-calcium combination or as a vitamin D only supplement, to support bone and muscle

health.

The guidance also recommends a diet with regular intakes of natural sources of

vitamin D, such as oily fish, eggs, meats and vitamin D-fortified. This follows a 2020 FSAI report,

on vitamin D and older adults, recommending that healthy older adults living independently

and who get sunlight exposure during summer should take 10μg (400 IU) daily dose during the

extended winter months (end of October to March); and for those of darker-skinned ethnicity,

this should be taken throughout the full year. The report recommends a 15µg (600 IU) daily

dose for housebound older adults with minimal or no sunlight exposure taken throughout the

full year. The report notes that such dosing should be sufficient and safe for most older

people.

METHODOLOGY

This rapid review aimed to provide a high-level summary of the evidence on vitamin D and

COVID-19. A scoping methodology was used and considered research evidence on vitamin D

status and prevention of SARS-CoV-2 infection; vitamin D supplementation and COVID-19

outcomes; vitamin D status and prevention of acute respiratory illness, and public health

guidance and measures. The research evidence cited includes literature up to 22

January

2021.

REVIEW OF EVIDENCE FOR THE EFFECTIVENESS OF THE USE OF VITAMIN D IN THE

PREVENTION OF COVID-19

Search Results

Due to the limited time available for the completion of this rapid report, a scoping approach

was adopted to identify relevant studies published. The following table presents examples of

research studies identified, which are discussed under the relevant section.

Sample articles identified

Publication date

Rapid review

informing

national policy

NICE rapid review: Vitamin D for

COVID-19

December 2020

Systematic

Reviews

Yisak et al. Effects of Vitamin D on

COVID-19 Infection and Prognosis: A

Systematic Review

January 2021

Randomised

controlled trials

Entrenas Castillo et al. vitamin D

supplementation in the treatment of

COVID-19

October 2020

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Observational

studies

Hastie C et al. Vitamin D

concentrations and COVID-19 infection

in UK Biobank

April 2020

Laboratory

studies

McCarthy et al. Immuno-protection

against COVID-19

April 2020

National Institute for Health and Care Excellence (NICE) COVID-19 Rapid Guideline:

Vitamin D

The most up-to-date review of the evidence identified within this review comprises a rapid

review performed by the NICE in the UK, which was published on 17 December 2020. The

results of this rapid review are described below.

This review was performed to inform a policy recommendation based on three questions:

“What is the clinical effectiveness and safety of vitamin D supplementation for the

treatment of COVID-19 in adults, young people and children?”

“What is the clinical effectiveness and safety of vitamin D supplementation for the

prevention of SARS CoV2 infection (and subsequent COVID-19) in adults, young

people and children?”

“Is vitamin D status independently associated with susceptibility to developing COVID-

19, severity of COVID-19, and poorer outcomes from COVID-19 in adults, young

people and children?”

This review considered the following outcomes of interest:

▪ Incidence of COVID-19

▪ COVID-19-related ICU admission

▪ All-cause and COVID-19-related mortality

▪ Hospitalisation; ventilation; time to cure; complications; adverse effects and

tolerability

Overall, the categories of research incorporated in the review included: direct evidence

reporting multivariable models for outcomes of interest, systematic reviews and meta-

analyses of Randomised Control Trials (RCTs), observational studies and laboratory studies.

Pre-print research (not peer-reviewed) was included.

With respect to evidence for vitamin D supplementation in the treatment of COVID-19, one

RCT by Entrenas Castillo et al was included. This study reported a lower likelihood (OR 0.03,

95% CI 0.003-0.25) of admission to ICU in those receiving calcifediol treatment plus standard

care compared to those receiving standard care alone. However, the evidence quality was

deemed very low due to a very serious of bias and low number of participants (n=76).

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With respect to evidence for vitamin D supplementation in the prevention of COVID-19, no

articles were identified following review.

With respect to the evidence for an association between vitamin D status and COVID-19

susceptibility and severity 12 studies were included. Six studies explored the association

between vitamin D status and COVID-19 incidence. Results were mixed with one study

reporting a significant association between vitamin D concentration and risk of COVID-19

diagnosis (OR 0.984, 95% CI 0.983, 0.986, N=191,779)

; and two studies reporting no

association ((OR 1.00, 95% CI 0.998, 1.01, N=349,017)

and (OR 1.00, 95% CI 1.00, 1.00,

N=4,510)

) between vitamin D status and COVID-19 cases. The latter two studies utilised

serum vitamin D measurements from the UK biobank study which were collected between

2006 and 2010, which may differ from the populations included in the analysis.

Three studies assessed vitamin D deficiency and COVID-19 diagnosis. Two reported an

association with Meltzer et al reported an association between deficiency (˂25nmol/L) and

COVID-19 cases OR 1.77 (95% CI 1.12, 2.81)

and Merzon et al. reporting an association

between suboptimal levels (˂75nmol/L) and COVID cases OR 1.5 (95% CI 1.13 to 1.98)

. The

former did not adjust for demographic factors (e.g. sex, gender, ethnicity). An additional study

found no difference in COVID-19 cases between people above and below the thresholds,

˂25nmol/L OR 0.92 (95% CI 0.71, 1.21) and ˂ 50nmol/L OR 0.88 (95% CI 0.72, 1.08)²⁹. The

quality of all studies was graded as very low with criticism of methodological approach relating

to a failure to adjust for confounding variables (including sex, gender and ethnicity); use of UK

Biobank data (based on vitamin D measurements taken between 2006 and 2010); and lack of

power.

Seven studies assessed vitamin D status and an association with COVID-19 severity. Hernandez

et al. did not identify an association between vitamin D levels and ICU admission, need for

mechanical ventilation or in-hospital mortality OR 1.13 (95% CI 0.27, 4.77) n=197

. Macaya et

al. did not find an association between vitamin D levels (<50nmol/L) and death, ICU admission

or need for high-flow oxygen OR 3.2 (95% CI 0.99 to 11.4)

. A third study reported a significant

association between low vitamin D levels (<30nmol/L) and the composite outcome mechanical

ventilation and death, HR 6.12 (95% CI 2.79 to 13.42), n=185.

Ye et al. also reported an

association between vitamin D levels <50nmol/L and more severe COVID-19, OR 15.18 (95% CI

1.23, 187.45).

Annweiler et al. reported the results of two quasi-experimental studies, and found that

supplementation for a year was significantly negatively associated with the likelihood of severe

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COVID-19, OR 0.08 (95% CI 0.01, 0.81), but identified no difference if those only receiving a

bolus when diagnosed, OR 0.46 (95% CI 0.07, 2.85). These studies also reported on mortality

as a single outcome with one study reporting lower mortality risk in those receiving vitamin D3

bolus supplementation during COVID-19 or in the preceding month compared to those

receiving no treatment (Hazard ratio (HR) = 0.11 [95 %CI 0.03, 0.48], p = 0.003),⁶ and a second

study of 77 patients hospitalised with COVID-19 reported a higher risk of 14-day mortality in

those receiving no supplementation compared to those receiving supplementation in the

preceding year (HR = 0.07 (p = 0.017)) or those supplemented after a COVID-19 diagnosis (HR

= 0.37 (p = 0.28)).

Both studies had limitations including small sample size, lack of use of a

placebo, and use of estimations of vitamin D status based on supplementation which rely on

compliance and thus may be incorrect.

A further two studies reported on vitamin D status and mortality with Karahan et al. finding

that higher vitamin D levels were negatively associated with death OR 0.92 (95% CI 0.88, 0.98)²⁸

and Radujkovic et al. reporting higher mortality with serum vitamin D levels <30nmol/L (HR

14.73 (95% CI 4.16, 52.19)).³⁵

The review excluded numerous observational studies due to the use of unadjusted analysis

and a lack of relevant predictive values.

Taking into consideration all forms of evidence, the recommendations of this review were:

▪ A lack of evidence supporting the use of vitamin D in the treatment of COVID-19

▪ A lack of evidence supporting the use of vitamin D in the prevention of COVID-19

▪ A lack of evidence supporting an association between vitamin D status and the

incidence of COVID-19

▪ A call for urgent research into vitamin D supplementation and prevention of COVID-

19, particularly in Black African and Minority Ethnic (BAME) individuals, and people

categorised as overweight or obese.

Systematic Review

Yisak et al conducted a review of 9 articles and identified 7 studies that reported a correlation

between vitamin D status and COVID-19 infection, prognosis and mortality. 2 studies failed to

demonstrate an association. This review did not address the limitations of included studies

including unadjusted analysis and an absence of relevant predictive values.

Randomised Control Trials

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A pre-publication (not peer reviewed) Brazilian, multicentre, double-blind, RCT randomised

patients with 240 hospitalised patients with COVID-19 (1:1) to receive a single oral dose of

200,000 IU (5,000mcg) or placebo. 86.7% of patients in the supplementation arm achieved

vitamin D serum levels (≥30ng/mL) compared to 11% in the placebo group; however there was

no difference in hospital length of stay in vitamin D and placebo groups (7.0 days [95% CI 6.1,

7.9] and 7.0 days [95% CI 6.2, 7.8 days], HR 1.12, [95% CI 0.9, 1.5]; p = .379) respectively. There

was also no difference reported in secondary outcomes including mortality, admission to ICU

and requirement for ventilation. Study limitations include low power, and heterogeneity of the

patient sample and its treatment.

Rapid Review of evidence for use of vitamin D in the prevention of Acute Respiratory

Illness

Systematic Reviews and Meta-Analyses

Seven systematic reviews and meta-analyses were identified that assessed the role of vitamin

D in the prevention of acute respiratory illness. These suggest a modest reduced risk of acute

respiratory tract infection and asthma exacerbation due to respiratory tract infection with

vitamin D supplementation.

In a 2017 systematic review and meta-analysis of 25 RCTs, Martineau et al. identified patient

data for 10,933 (96.6%) of 11,321 participants aged 0 to 95 years.

Vitamin D supplementation

reduced the risk of acute respiratory tract infection among all participants (adjusted OR 0.88,

95% CI 0.81 to 0.96; P for heterogeneity <0.001). Protective effects were seen with daily or

weekly dosing between 20μg and 50μg (adjusted OR 0.81, 0.72 to 0.91) with stronger effects

in those with baseline deficiency defined as serum 25[OH]D levels<25 nmol/L (adjusted OR

0.30, 0.17 to 0.53). No effect was seen with bolus dosing and no reduction in adverse events

was observed.

A 2020 pre-publication, non-peer reviewed systematic review of 45 RCTs conducted by Joliffe

et al. reported patient data for 46,331 (98%) of 47,262 individuals in 42 trials (in total 73,384

patients were involved in 45 trials).

The study reported a reduced risk of acute respiratory

tract infection overall in those receiving vitamin d supplements vs placebo (OR 0.91, 95% CI

0.84, 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen

for any of the sub-groups defined by baseline 25[OH]D concentration. Protective effects were

seen in trials using daily dosing regimen (OR 0.75, 95% CI 0.61, 0.93) at daily dose equivalents

of 10 micrograms to 25 micrograms or 400 to 1000 IU, but not above (OR 0.70, 95% CI 0.55,

0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72, 0.94). There was no impact of

supplementation on adverse events. Limitations of this research included inconsistency

between study results, and differences between vitamin D supplementation doses and

regimens, durations, populations, settings and definition of outcomes, between studies.

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A 2021 systematic review and meta-analysis on micronutrient supplementation reported a

reduced the risk of ARI (risk ratio (RR)=0.97; 95% CI 0.94 to 1.00; p=0.028) based on 20 studies

and shortened the duration of symptoms (per cent difference: −6% (95% CI −9% to −2%;

p=0.003)), with an optimal dosing regimen proposed as daily dose ≥2000 IU (50mcg) vitamin D

and a <60000IU (1500mcg) loading dose.

A 2016 systematic review and meta-analysis of 15 RCTs reported patient data for 7,053

individuals and failed to demonstrate a statistically significant association between vitamin D

supplementation and risk of clinical respiratory tract infection (RR 0.94; 95% CI 0.88, 1.00).

Similarly, Wang et al. reported data for 2312 healthy participants aged 19 to 61 years in 8 RCTs

and reported no different between vitamin D and placebo groups in risk of self-reported cold,

cold duration and cold severity.

Additionally, included studies differed with respect to

population, baseline vitamin D levels and study length.

A 2015 systematic review of 7 RCTs in those aged 18 or younger found insufficient evidence

supporting vitamin D supplementation and reduction of acute respiratory illness (relative risk

(RR) 0·79, 95%CI 0·55, 1·13), all-cause mortality (RR 1·18, 95% CI 0·71, 1·94), or the rate of

hospital admission due to respiratory infection in healthy children (RR 0·95, 95% CI 0·72, 1·26),

however this study did identify a reduction in the risk of asthma exacerbation due to acute

respiratory illness with vitamin D supplementation (RR 0·26, 95% CI 0·11, 0·59).

A 2019

systematic review and meta-analysis incorporating patient data from 7 RCTs and 955

participants reported an overall reduction in the rate of asthma exacerbations requiring

treatment with systemic corticosteroids with vitamin D supplementation.

A systematic review on non-skeletal effects of Vitamin D found that those with low levels are

underrepresented in RCTs (inclusion criteria in 67 of 210 RCTs),

with a systematic review of

83 trials noting the poor quality of many meta-analyses.

Randomised Control Trials

Two randomised, double-blind, placebo-controlled clinical trials were identified that evaluated

the administration high dose vitamin D to critically ill patients with vitamin D deficiency (but

not COVID-19). A phase 3 trial of 1360 patients reported no difference in 90-day mortality in

those receiving early administration of high-dose enteral vitamin D (mortality difference, 2.9%;

95%CI, -2.1-7.9%; P = 0.26).

The VITdAL-ICU is the largest published ICU-based RCT on vitamin

D supplementation to date. This single-centre study was conducted from May 2010 through

September 2012 at 5 ICUs. 492 adult white patients with Vitamin D deficiency (≤20 ng/mL)

were randomised to receive high-dose vitamin D

or placebo over a 5-month period. The study

showed no reduction in hospital length of stay, hospital mortality, or 6-month mortality. Lower

hospital mortality was observed in a severely deficient subgroup and requires further study.

Multiple RCTs, included in the systematic reviews and meta-analysis discussed above, show

conflicting evidence on vitamin D and prevention of acute respiratory illness.

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Laboratory Studies

Several laboratory-based simulation studies, or, mechanistic studies, have been published

which demonstrate a role for vitamin D in the induction of antimicrobial peptides in response

to both viral and bacterial stimuli. ¹ ²

A possible mechanism proposed to explain the

association between vitamin D deficiency and poor COVID-19 outcome is that correction of

vitamin D deficiency may suppress CD26, reducing adhesion of COVID‐19; in addition to

attenuation of interferon gamma and interleukin-6 inflammatory responses which are

predictors of poorer outcome in critically-ill ventilated patients including those with COVID‐

19.

It is important to note that vitamin D is a negative acute phase reactant i.e. serum levels fall in

response to acute stress response, therefore single sample 25-OHD levels during critical illness

may provide an inaccurate assessment of vitamin D status due to several confounders including

albumin levels, interstitial extravasation, decreased synthesis of binding proteins, and renal

wasting of 25-hydroxyvitamin D.

Conclusions on the evidence

• Significant limitations with existing research were identified:

o Systematic reviews and meta-analysis identified large heterogeneity and poor

study quality;

o Association studies included use of historic and inaccurate vitamin D status

measurements, lack of generalisability, high likelihood of confounding or

failure to adjust for confounders and general low quality of the evidence.

• There is no data from interventional trials showing that vitamin D supplementation may

prevent COVID‐19.

• Circumstantial evidence linking COVID-19 outcomes and Vitamin D status has led to

some supporting supplementation in vulnerable populations given safety profile and

low risk of harm

Evidence review: additional considerations

Several studies have estimated the prevalence of vitamin D deficiency in the Irish population.

The National Adult Nutrition Survey sampled of 1132 adults between October 2008 and April

2010. This representative survey found 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, with

these figures increasing to 55.4% and 48.1% respectively in winter. This study also assessed

dietary intake of vitamin D and reported the mean daily intakes of vitamin D from diet and

supplements was 5.2μg for men and 8.5μg for women (≥65 years), and 27% of both men and

women regularly consumed a nutritional supplement containing vitamin D (males: 21%;

females: 32%). Mean daily intake of vitamin D from natural foods was 3.6μg and increased to

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4.7μg when the contribution of fortified foods was included. Fish, meats, eggs, and vitamin D-

fortified foods contributed 23%, 19%, 7% and 17%, respectively.

Results from the Irish Longitudinal Study on Ageing (TILDA) measured 25-hydroxyvitamin D

levels in 5,356 adults over 50 years of age. The prevalence of deficiency (25OHD < 30 nmol/L)

was 13.1% (95% CI: 12.1–14.2), with higher prevalence in winter, in smokers, in obese adults,

the physically inactive, those living alone, and in those over 80 years. Through extrapolation

they estimate that 1 in 8 (13%, 149,049) adults over 55 are deficient all year round;; 21.3%

(244,209) adults over 55 are deficient in winter; 27%.1 (115,536) of Irish adults over 70 that

were ‘cocooning’ in the springtime in 2020 are deficient and 46.6% (31,480) of all adults aged

>85 are deficient in winter. The report also identified that 9.4% (107,773) of those aged 55+

and 11.5% (49,028) of those aged 70+ reported taking a vitamin D supplement during winter.

A cross-sectional study of 186 individuals of South East Asian descent between 2013 and 2016

found that 66.7% had vitamin D levels ≤30 nmol/L (i.e. deficient) and 6.7% had levels ≥50

nmol/L (the 25(OH)D concentration defined by the EU as ‘sufficient’). Whilst average levels

were higher in females than males (25.0 vs. 18.0 nmol/L; p = 0.001) both groups had a

significant proportion with deficient status (56% and 76.8%, respectively).

A cross-sectional study assessed 24,302 eligible patient samples processed through University

Hospital Galway between January 2011 and December 2015. They reported vitamin D

deficiency was more common in nursing home residents compared to inpatients, outpatient

clinic patients or community-based patients (42% vs 37% vs 17% vs 13%; p < .001). Inpatients

with a LOS (≥3 days) had greater Vitamin D deficiency than those with LOS ≤2 days (p = .007).

Vitamin D deficiency was more common in Winter/Spring, in males, and in those aged ≥80

years.

Three Irish studies have demonstrated that daily 20µg vitamin D supplementation of

at least 10 weeks duration is sufficient to correct deficiency in nursing home residents

and

adults aged 50 and over.

A prospective cross-sectional study of healthy children attending the Children’s University

Hospital for elective surgery (26%), medical outpatients (62%), or the emergency department

(12%) for a minor complaint conducted from March 2010 to March 2011 found that of 252

children aged 1 to 17 years 21.9% had 25OHD levels <30 nmol/L, 32.7% were between 30 and

50 nmol/L, and 45.4% had levels >50 nmol/L. Higher levels were associated with younger age

(<4 years) and April-September sampling.

Recent review articles cited the high prevalence of

low vitamin D levels (25[OH]D<30nmol/L) in preterm infants and (25OHD<50nmol/L) in older

adults, hospital inpatients and nursing home residents, along with the potential anti-

inflammatory and immunomodulatory properties of Vitamin D as justification for ensuring

baseline Vitamin D sufficiency for potential enhancement of immune-protection against

CoVID-19.

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International Measures: England and Scotland

From January 2020 the Department of Health and Social Care in the UK are operating a 4-

month opt-in scheme for extremely clinically vulnerable people to receive a supply of daily

vitamin D supplements, this includes nursing home residents (Appendix A).

This follows a

Scottish initiative offering a free 4-month supply of daily vitamin D supplements to everyone

on the shielding list (Appendix B). Pregnant women, breastfeeding women and children under

12 months are already eligible for free supplements.

This followed the NICE rapid review

previously referred to which reported insufficient evidence supporting a benefit of vitamin D

supplementation in relation to COVID-19 prevention or response but advised supplementation

during winter due to increased time indoors and proven bone and muscle health benefits

(Appendix C). The NICE review recommended a 10μg (400 IU) dose per day or 25μg (1000IU)

if 10mcg unavailable. The review acknowledged that low vitamin D status was associated with

more severe outcomes from COVID-19, emphasising that this does not imply causality and

given Vitamin D levels fall during a systematic inflammatory response that it has not been

determined whether vitamin D status causes poorer outcomes or vice versa.

Conclusion

The role of vitamin D in bone and muscle health is well documented. Public health guidelines

support supplementation in older adults based on these benefits and the risk of deficiency in

older adults particularly those spending increased time indoors or in long-term nursing home

care. A possible immunomodulatory role has been suggested by in vitro studies and association

studies. There is currently insufficient evidence linking vitamin D use in the prevention and

treatment of COVID-19. Evidence reporting an association between low vitamin D status and

poorer outcomes in COVID-19 infection do not confirm causality and in most cases are of low

quality. Previous research shows a modest reduction in the risk of acute respiratory illness with

daily vitamin D3 supplementation over weeks to months. This evidence also has limitations,

including publication and reporting bias and heterogeneity in study populations, interventions,

and definitions of respiratory infections that include upper and lower respiratory tract

involvement.

Despite this, research has identified a high prevalence of low vitamin D levels in winter

months in Ireland, and given its role in bone and muscle health this report recommends the

following:

• Increase awareness of existing guidance that adults age 65 and over should take a 15

microgram daily supplement for bone and muscle health

• Adults spending increased time indoors or are housebound or in long-term residential

care or have dark skin pigmentation are also recommended to take vitamin D

supplementation

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• That ongoing developments, particularly RCTs, in this area be monitored with

guidance reviewed accordingly

Appendix

Appendix 1: Summary of COVID-19 Treatment Study

Study

Entrenas Castillo 2020 RCT Spain

Murai 2021 RCT Brazil (PRE-PRINT)

Population

N=76 patients admitted to hospital with

confirmed COVID-19

N=240 patients admitted to hospital

with confirmed COVID-19

Patients were randomised 2:1 into

intervention (n=50) and comparator arms

(n=26)

Patients were randomised 1:1 into

intervention (n=120) and comparator

arms (n=120)

Intervention

Patients in the intervention arm received

calcifediol treatment calcifediol (0.532 mg)

on admission, then 0.266 mg on days 3 and

7, then weekly until discharge, along with

standard care

Patients in the intervention arm

received a single oral dose of 200,000

IU (5,000mcg)

Patients in the comparator arm received

standard care only

Patients in the comparator arm

received a placebo

Analysis

Univariate and multivariable logistic

regressions were used to estimate the

probability of admission to intensive care

unit (ICU)

Univariate and multivariate regression

models for hospital length of stay,

admission to ICU and mechanical

ventilation requirement were adjusted

by potential confounders

Mortality was reported as number of

deaths

Mortality was reported as number of

deaths

Outcomes

1) ICU admission

2) COVID-19 mortality

1) Hospital length of stay

2) Mortality, admission to ICU and

requirement for ventilation

3) Vitamin D serum levels ≥30ng/mL

Results

Patients in the intervention arm were less

likely to be admitted to intensive care

versus those in the comparator group (OR

0.03 (95% CI 0.003, 0.25))

No difference in hospital length of

stay in vitamin D and placebo groups

(7.0 days [95% CI 6.1, 7.9] and 7.0

days [95% CI 6.2, 7.8 days], HR 1.12,

[95% CI 0.9, 1.5]; p = .379)

respectively

Patients in the intervention arm had lower

mortality versus those in the comparator

group (OR 0.097, 95%CI 0.004, 2.099)

No difference in the reported rate of

mortality (7.0% vs 5.1%; P = .59);

admission to ICU (15.8% vs 21.2%; P =

.314), and mechanical ventilation

requirement (7.0% vs 14.4%; P = .090)

86.7% of patients in the

supplementation arm achieved

vitamin D serum levels ≥30ng/mL

compared to 11% in the placebo

group

Limitations

Small sample size; serious risk of bias

Low power, and heterogeneity of the

patient sample and its treatment

Page 15 of 26

Appendix 2: Summary of COVID-19 Association Studies²⁶

Study

Vitamin D

Measurement

Adjusted for

Association

Quality

Hastie 2020

Vitamin D

level (nmol/L)

Cases

n=449

Control

n=348,598

Ethnicity, sex, month of

assessment, Townsend

deprivation quintile,

household income, self-

reported health rating,

smoking status, BMI

category, age at

assessment, diabetes,

SBP, DBP, and

longstanding illness,

disability or infirmity

OR 1.00

(0.998 to

1.01)

Very

low

Vitamin D

level (nmol/L)

by ethnicity

OR 0.90

(0.66 to

1.23)

Very

low

Vitamin D

deficiency

OR 0.92

(0.71 to

1.21)

Very

low

Vitamin D

insufficiency

OR 0.88

(0.72 to

1.08)

Very

low

Hernandez

2020

Vitamin D

level (ng/ml)

Cases

n=197

Control

n=197

Age, smoking,

hypertension, diabetes

mellitus, history of

cardiovascular events,

immunosuppression,

body mass index (BMI),

serum corrected calcium,

glomerular filtration rate

and the month of

vitamin D determination

MD: -9.3;

p<0.001

Very

low

Kaufman

2020

Vitamin D

level (ng/ml)

Cohort

N=191,779

Gender, age, latitudes,

ethnicity

OR 0.984

(0.983 to

0.986)

Very

low

Meltzer 2020

Vitamin D

insufficiency

Positive

n=71

Negative

n=418

Hypertension, diabetes,

chronic pulmonary

disease, pulmonary

circulation disorders,

depression,

immunosuppression,

liver disease, and chronic

kidney disease.

OR 1.77

(1.12 to

2.81)

Very

low

Merzon 2020

Vitamin D

suboptimal

Cases

n=782

Control

n=7025

Age, gender, ethnicity,

smoking,

depression/anxiety,

schizophrenia, dementia,

diabetes, hypertension,

cardiovascular disease,

chronic lung disease,

obesity, BMI and

socioeconomic status

OR 1.45

(1.08‐1.95)

Very

low

Page 16 of 26

Raisi-

Esrabragh

2020

Vitamin D

level (nmol/L)

Cases

n=1326

Control

n=3184

Sex, age and ethnicity

OR 1 (1 to 1)

Very

low

Page 17 of 26

Appendix 3: Summary of Systematic Reviews and Meta-analyses of Vitamin D and Acute Respiratory Illness

Studies

Martineau et al (2017)

Jolliffe et al (2020)

Trials included

25 trials (11,321 participants) from 14 countries up to 31 December 2015

45 trials (73,384 participants) from 18 countries up to 1 May 2020

Individual patient

data

10,933 participants

46,331 participants (in 42 trials)

Study duration

7 weeks - 1.5 years

8 weeks - 5 years

Mean baseline

25(OH)D conc.

Reported in 19/25 trials: range 19 - 89 nmol/L

Reported in 34/42 trials: range 19-91 nmol/L

Population

10 (40%) in populations with pre-existing disease (including asthma,

chronic obstructive pulmonary disease, pneumonia)

13 (31%) in populations with pre-existing disease (including asthma, chronic

obstructive pulmonary disease, pneumonia)

1 (4%) in low birthweight infants

1 (2.4%) in low birthweight infants and 2 (4.8%) in preterm infants

1 (4%) in older care home residents with range of comorbidities (including

asthma, chronic obstructive pulmonary disease, congestive heart failure,

diabetes, dementia)

1 (2.4%) in older care home residents with range of comorbidities (including

asthma, chronic obstructive pulmonary disease, congestive heart failure,

diabetes, dementia)

Comparison

vitamin D vs placebo

higher vs lower dose vitamin D

Vitamin D dosing

daily (12 RCTs; 7.5 to 100µg; 7 weeks to 13 months)

daily (21 trials; 7.5 to 100µg; 7 weeks to 2 years)

weekly (3 RCTs; 35 to 500 µg; 8 weeks to 6 months)

weekly (6 trials; 35 to 500 µg; 8 weeks 3 years)

bolus (10 RCTs; once, monthly, 2-monthly, 3-monthly; 750-5000µg; 3 to

18 months)

bolus (13 trials; once, monthly, 2- monthly, 3-monthly; 750-5000µg; 3 to 3

years)

bolus doses combined with daily vitamin D supplementation (3 studies)

bolus doses combined with daily vitamin D supplementation (2 studies

control group also received vitamin D (2 studies)

control group also received vitamin D (7 studies)

intervention group given vitamin D + calcium (1 study)

Subgroup analyses

Baseline 25(OH)D <25 nmol/l vs ≥25 nmol/l

Baseline 25(OH)D <25 vs 25-49.9 vs 50-74.9 vs ≥75nmol/l

Dosing regimen: daily or weekly without bolus vs ≥1 bolus of ≥750µg

Dosing regimen: daily vs weekly vs monthly or less frequent

Dose size daily equivalent: <20µg vs 20µg to <50µg vs ≥50µg

Dose size daily equivalent: <10µg vs 10-25µg vs > 25-50µg vs >50µg

Age: ≤1 year vs 1.1-15.9 years vs 16-65 years vs >65 years

Age: ≤1 year vs 1.1-15.9 years vs 16-64.9 years vs >65 years

Presence versus absence of asthma, COPD and previous influenza

vaccination

Presence of airway disease (asthma vs COPD) vs those without airway

disease

Page 18 of 26

Results

Vitamin D supplementation reduced the risk of ARI among all participants

(adjusted odds ratio 0.88, 95% CI 0.81, 0.96: heterogeneity p < 0.001)

Vitamin D supplementation reduced the risk of ARI among all participants

(OR, 0.91; 95% CI, 0.84, 0.99; I 2=37.2% p for heterogeneity =0.014)

2 step IPD meta-analysis reported a reduced risk of ARI (OR, 0.80; 95% CI,

0.69, 0.93; p=0.004; I^2=53.3%, p= for heterogeneity 0.001)

No statistically significant difference of higher versus lower vitamin D dosing

(OR 0.87, 95% CI 0.73, 1.04 (I2 =0.0%, p for heterogeneity 0.496)

Sensitivity analyses

Excluding the 2 studies at unclear risk of bias: (OR, 0.82; 95% CI, 0.70,

0.95, p = 0.01; 10,744 participants).

Excluding the 4 studies at unclear risk of bias: (OR, 0.93; 95% CI, 0.86, 1.00)

Restricted to 14 trials where ARI a primary or coprimary outcome:

protective effects with vitamin D supplementation (OR, 0.82; 95% CI, 0.68,

1.00; p = 0.05, 5,739 participants)

Restricted to 18 trials with ARI as a primary or coprimary outcome: no

significant protective effect (OR, 0.89; 95% CI, 0.77, 1.03; 7,537

participants)

Subgroup analyses:

Dosing Frequency

Protective effect of vitamin D seen with daily or weekly vitamin D dosing

(OR, 0.81; 95% CI, 0.72, 0.91; p<0.001) but not bolus doses (OR, 0.97; 95%

CI, 0.86, 1.10; p=0.05)

Significant protective effect of vitamin D with daily dosing (OR 0.75, 95% CI

0.61, 0.93) but not weekly (OR 0.97, 95% CI 0.88, 1.06) or monthly to 3-

monthly (OR 0.98, 95% CI 0.93, 1.03)

Subgroup analyses:

Baselined 25(OH)D

concentration

Protective effect of vitamin D in those with levels <25 nmol/L (OR, 0.89;

95% CI, 0.77, 1.04; p=0.15; 19 RCTs; 3634 participants)

No significant effect in any of the subgroups

Page 19 of 26

Appendix 4: UK Definition of clinically extremely vulnerable groups: Summary of

Systematic Reviews and Meta-analyses of Vitamin D and Acute Respiratory Illness

People who are defined as clinically extremely vulnerable are at very high risk of severe

illness from coronavirus. Patients are identified as clinically extremely vulnerable either by

addition to the shielded patient list by a clinician or GP; or by having one or more of the

following:

• solid organ transplant recipients

• people with specific cancers:

• people with cancer who are undergoing active chemotherapy

• people with lung cancer who are undergoing radical radiotherapy

• people with cancers of the blood or bone marrow such as leukaemia,

lymphoma or myeloma who are at any stage of treatment

• people having immunotherapy or other continuing antibody treatments

for cancer

• people having other targeted cancer treatments that can affect the

immune system, such as protein kinase inhibitors or PARP inhibitors

• people who have had bone marrow or stem cell transplants in the last 6

months or who are still taking immunosuppression drugs

• people with severe respiratory conditions including all cystic fibrosis, severe

asthma and severe chronic obstructive pulmonary disease (COPD)

• people with rare diseases that significantly increase the risk of infections (such as

severe combined immunodeficiency (SCID), homozygous sickle cell disease)

• people on immunosuppression therapies sufficient to significantly increase risk of

infection

• problems with your spleen, for example splenectomy (having your spleen

removed)

• adults with Down’s syndrome

• adults on dialysis or with chronic kidney disease (stage 5)

• women who are pregnant with significant heart disease, congenital or acquired

• other people who have also been classed as clinically extremely vulnerable, based

on clinical judgement and an assessment of their needs. GPs and hospital clinicians

have been provided with guidance to support these decisions

Page 20 of 26

Appendix 5: Scottish Government Coronavirus (COVID-19): shielding list

Those recognised as being at the highest risk of severe illness from coronavirus will be notified

by post by the Chief Medical Officer. This includes the list below. Individuals in this list are

advised to contact their GP or specialist care provider if they have not received a letter.

Grouping

How would I know if I am in this group?

Solid organ

transplant

recipients

People who have had a transplant of heart, lung, stomach or other part of

intestine, liver and kidney. This is because of the medication taken to stop

rejection of the transplanted organ.

People with specific

cancers

• People with cancer who are undergoing active chemotherapy.

Or people who have had radical radiotherapy for lung cancer.

• People with cancers of the blood or bone marrow who are at

any stage of treatment. This includes cancers such as

leukaemia, lymphoma or myeloma.

• People with cancer who are having immunotherapy or other

continuing antibody treatments.

• People with cancer who are having specialised treatments

that can affect the immune system. This includes protein

kinase inhibitors or PARP inhibitors.

• People who have had bone marrow or stem cell transplants in

the last 6 months. Or people who are still taking

immunosuppression drugs.

People with severe

respiratory

conditions

• People with cystic fibrosis.

• People who are on home oxygen for a lung condition.

• People with severe asthma and on regular inhalers and long-

term steroid tablets. For example, Prednisolone or regular

injections to control your asthma.

• People with severe COPD. This usually means being on several

different inhaler medications in the last year. As well as a

steroid inhaler, this must include two long acting preventers.

For example, Long Acting Beta Agonists and Long Acting Anti-

Muscarinic Antagonists. Severe COPD means that:

o You are too breathless to walk 100 yards

o You have 2 or more lung infections a year or

o You need oxygen to help with your breathing

People with rare

diseases including

all forms of

This includes inborn errors of metabolism that significantly increase the risk

of infections. For example, SCID and homozygous sickle cell disease and

adults with Down's syndrome.

Page 21 of 26

Grouping

How would I know if I am in this group?

interstitial lung

disease /

sarcoidosis

There are many conditions classed as a rare disease. Not everyone with a

rare disease will be in the shielding group

People on

immunosuppression

therapies that

significantly

increase risk of

infection. Or people

who have had their

spleens removed

Immunosuppressive therapy helps to stop rejection of a bone marrow or

organ transplant. It can also treat conditions in which the immune system

is overactive. For example, autoimmune diseases and allergies.

In some cases these treatments may put people into the shielding group.

Your clinician can determine if your medications put you in this group.

• People on high dose corticosteroids (equal to Prednisolone

20mg or more) for 4 weeks or more.

• People on specific single therapies, e.g. Cyclophosphamide.

These medications are usually prescribed by specialists in

hospitals.

• People on lower dose of corticosteroids in combination with

other disease modifying medication.

• People on disease modifying medications who also have other

chronic medical conditions.

• People who take some medication and are otherwise healthy

may not need to be in the shielding group. This includes single

Disease Modifying medications (DMARD). It also includes

Biologic medications such as Methotrexate, Azathioprine,

Ciclosporin, Leflunomide plus others. Discuss this with your

specialist or GP if you are not sure.

People who are

pregnant with

significant heart

disease, congenital

or acquired

If you are being followed up by a specialist heart clinic during your

pregnancy.

People who are

receiving renal

dialysis

treatment and

people who have

chronic kidney

disease stage 5

People receiving or starting renal dialysis, and people who have chronic

kidney disease stage 5.

Page 22 of 26

Appendix 6: Pre-COVID NHS Vitamin D Recommendations

The NHS recommends that:

• breastfed babies and formula-fed babies consuming ≤500ml of infant formula per day

from birth to 1 year of age should be given a daily Vitamin D supplement containing 8.5

to 10 micrograms;

• children aged 1 to 4 years old should be given a daily supplement containing 10

micrograms;

• adults (including women who are pregnant or breastfeeding), young people and

children over 4 years should consider taking a daily supplement containing 10

micrograms (400IU) of vitamin D between October and early March;

• adults that are not often outdoors; are in an institution like a care home; usually wear

clothes that cover up most of their skin when outdoors; have dark skin (e.g. those from

an African, African-Caribbean or south Asian background) should consider taking a daily

supplement containing 10 micrograms of vitamin D throughout the year.

Caution should be taken in:

• those under the care of a renal, endocrinology or cancer specialist

• people with high vitamin D levels

• people with kidney stones (now or in the past)

• people with too much parathyroid hormone (hyperparathyroidism),

• people with cancer (some cancers can lead to high calcium levels)

• people with severe kidney disease

• people with a rare illness called sarcoidosis

Page 23 of 26

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