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2X fewer COVID-19 deaths observed if infrequent vitamin D (2X more deaths if daily dose) – ClinicalTrial Oct 20, 2020

VITAMIN D TREATMENT IS ASSOCIATED WITH REDUCED RISK OF MORTALITY IN PATIENTS WITH COVID-19: A CROSS-SECTIONAL MULTI-CENTRE OBSERVATIONAL STUDY

Stephanie F Ling MBChB,2, Eleanor Broad MBChB1, Rebecca Murphy MBChB1, Joseph M Pappachan MD 2,3,4, Satveer Pardesi-Newton BM5, Marie-France Kong DM6, Edward B Jude MD1,2,4.

Image

VitaminDWiki

986 patients, 3 centers in the UK Clinical Trial
50% had <16 ng of Vitamin D
75% had <20 ng of Vitamin D
3 Vitamin D treatments

  • None = control group (>20 ng?)
  • Maintenance therapy (800-2,000IU daily) - 2X INCREASE in deaths
  • High-dose booster therapy (up to 300,000IU total, split over multiple doses)  PDF
    2X DECREASE in deaths
    • a loading regimen to provide a total of approximately 300,000 units vitamin D, given either as separate weekly or daily doses over 6 to 10 weeks :
    • The exact regimen will depend on local preference and local availability of vitamin D preparations but could include: 20,000 units capsules, two given weekly for 7 weeks (280,000 units)

Suspect why this happened (in the UK)

The UK considers < 12 ng = deficient, and so a loading/restoring dose of 300,000 IU is given
A person with 13 ng to xx ng considered not to be deficient, so is given a maintenance dose
   which keeps them low, and probably vulnerable to COVID-19 infection
Note: This Clinical Trial had no randomization, Dosing was based on pre-existing Vitamin D levels


COVID-19 treated by Vitamin D - studies, reports, videos
As of Oct 18, 2021, the page had:  34 trials 6 trial results,   27 meta-analyses and reviews,   64 observations,   35 recommendations,   55 associations,  89 speculations,  48 videos   see related:   Governments,   HealthProblems,   Hospitals,  Dark Skins,   26 risk factors are ALL associated with low Vit D,   Recent Virus pages   Fight COVID-19 with 50K Vit D weekly   Vaccines

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Background: The 2019 novel coronavirus disease (Covid-19) worldwide pandemic has posed the most substantial and severe public health issue for several generations, and therapeutic options for it have not yet been optimised. Vitamin D has been proposed in the pharmacological management of Covid-19 by various sources. This study aimed to determine whether Covid-19 disease outcomes were affected by vitamin D status, and to elucidate any predictors of Covid-19 outcomes.

Methods: Patients hospitalised with Covid-19 were opportunistically recruited from three different UK hospitals and their data were collected. Logistic regression was used to determine any relationships between vitamin D status and various predictors, including mortality and ventilation, and to determine any relationships between mortality, ventilation, and various predictors.

Findings: Vitamin D status was not associated with any outcomes of Covid-19 investigated, following adjustment for age and sex. However, treatment with vitamin D was significantly associated with a reduced risk of death, following adjustment for age and sex (ORadj 0+48, 95% CI 0+32 - 0+70, p = 1-79x10-4). This relationship remained significant when also adjusted for baseline vitamin D levels (ORadj 0.47, 95% CI 0.33 - 0.70, p = 1.27x10-4).
Interpretation: Treatment with vitamin D, regardless of baseline serum vitamin D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with Covid-19. Further work on large population studies needs to be carried out to determine adequate serum levels of vitamin D, as well as multi-dose clinical trials of vitamin D treatment to assess maximum efficacy.

RESEARCH IN CONTEXT

Evidence before this study: We searched PubMed for articles published between 1st January 2020 and 4th September 2020, with the terms “Covid-19,” “SARS-CoV2,” “vitamin D,” “cholecalciferol,” and “25-hydroxyvitamin D.” We did not restrict outr search by language or type of publication. Due to the rapid onset and clinical severity of Covid-19, large amounts of research have taken place to search for a viable therapeutic agent, either as treatment or adjunct to therapy. Several review and opinion articles postulated that vitamin D therapy might be effective in the management of Covid-19. There are few studies examining vitamin D levels and outcomes in patients with Covid-19, and none have investigated the role of concurrent treatment.

Added value of this study: We carried out a retrospective cross-sectional study of 986 participants recruited from three hospital sites in the UK. Participants had been hospitalised with Covid-19. We found that vitamin D status (replete/insufficient/deficient) had no effect on Covid-19 disease outcomes such as death and ventilation. However, we found that treatment with vitamin D (either maintenance or high-dose booster therapy) was associated with a reduced risk of mortality, regardless of baseline vitamin D status.

Implications of all the available evidence: Current definitions of “replete” vitamin D status may be too low for immune benefit in acute Covid-19 infection. Large-scale population studies must be carried out to ascertain what a replete level is in the setting of acute infection, and multi-dose trials must also be considered in order to determine the most efficacious dose of vitamin D.

INTRODUCTION

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide pandemic has presented the largest global public health problem in several generations, and vast amounts of rapid research has taken place to find an effective therapeutic agent to manage the 2019 novel coronavirus disease (Covid-19) caused by SARS-CoV-2. A number of recent studies have raised the possibility of vitamin D (also known as cholecalciferol, and 25-hydroxyvitamin D) as an adjuvant to therapy for Covid-191-3, given its known antiviral effects. Other reviews have suggested that replete vitamin D status may be important in preventing severe manifestations of Covid-195,6. Other sources have proposed the interleukin (IL)-6 inhibitor tocilizumab as a potential treatment for Covid-19, and due to its modulator effect on IL-6, vitamin D has again been postulated as a potential therapeutic option7.

A UK-based study by Panagiotou et al found that low serum vitamin D levels in Covid-19 in-patients were associated with a more severe disease course 8, but this small study of 134 patients only looked at serum levels and not concurrent vitamin D treatment. Furthermore, two meta-analyses have identified low vitamin D as a potential predictor of more severe Covid-19 disease outcomes9,10, again without addressing any effect of treatment. To our knowledge, no study has addressed the effect of vitamin D treatment on outcomes on an individual-level basis, and very few studies exist regarding serum vitamin D levels and the outcomes of Covid-19 in-patient admissions.

Therefore, the primary research questions of this study were to determine whether vitamin D levels and status (i.e. replete/insufficient/deficient) affect outcomes in Covid-19 infection, whether vitamin D deficiency is associated with increased risk of Covid-19 infection, and whether treatment with vitamin D alters disease outcomes. Secondary objectives were to determine whether any patient characteristics were associated with Covid-19 outcomes, namely, mortality, and treatment with ventilation. To reach these objectives, we carried out a retrospective multi-centre cross-sectional observational study.

METHODS

Participants
Patients were opportunistically recruited from three acute hospital Trusts in the UK, namely, Tameside and Glossop NHS Foundation Trust, Lancashire Teaching Hospitals NHS Foundation Trust, and University Hospitals of Leicester NHS Trust. Ethical approval was granted by the Health and Care Research Wales Research Ethics Committee (IRAS number 285337). The study was also registered on Clinicaltrials.gov (reference number NCT04386044), prior to commencement.

Patients recruited were admitted between 27th January 2020 and 5th August 2020, and data were collected between 26th June 2020 and 7th August 2020. In-patients with a clinical diagnosis of Covid- 19 identified by clinical coding (emergency use ICD code U07-1, Covid-19 confirmed by laboratory testing, and code U07+2, Covid-19 diagnosis where laboratory confirmation is inconclusive or not available11) were all included in the study. Patients were excluded if they were younger than 18 years of age and if the final clinical diagnosis was not Covid-19. Demographic and clinical data were obtained from the hospital admission associated with the diagnosis of Covid-19 using a combination of: electronic patient records (EPR), hard-copy patient records, and hospital laboratory data.
Outcome variables were defined as: vitamin D status (replete, >50 nmol/L; low, combining insufficient, 25-50 nmol/L, and deficient, <25 nmol/L; and deficient status alone), death, invasive ventilation via endotracheal intubation, and continuous positive airways pressure (CPAP) therapy. In the case of vitamin D status analysis, predictors also included death, ventilation, length of stay and discharge, which we defined as major adverse admission-related events (MAAREs). Deaths included deaths in hospital, and deaths following admission recorded during the data collection period e.g. following transfer or discharge. Additional predictors in all analysis included age, sex, non-Caucasian ethnicity, hospital-acquired Covid-19, low-flow and high-flow oxygen therapy, treatment with vitamin D (both supplementation dose and high-dose booster therapy), and common medical comorbidities of interest, as listed by clinicians in patient medical records. Hospital-acquired Covid-19 was defined as: (i) if a patient had been admitted with a different acute condition and had gone on to develop Covid-19 whilst an in-patient; or (ii) if a patient had been re-admitted within the 14-day incubation period and the second admission was for Covid-19. All laboratory measurements (including vitamin D levels) were carried out as part of routine clinical care of patients during their acute in-patient admissions. Vitamin D levels up to 12 weeks prior to admission with acute Covid-19 were included, if not measured during each participant’s in-patient stay. A full list of variables measured and how they were obtained is listed in the Supplementary Material.
Statistical methods
Pearson’s chi squared test was used to make between-group comparisons, where appropriate. Logistic regression was used to analyse predictor variables for potential associations with vitamin D status, with adjustment for age, and sex. Either the mean or median value, depending on each variable’s distribution, was used to convert linear variables to binary high/low variables. Again, logistic regression (adjusted for age, and sex) was used to analyse predictor variables for potential associations with secondary Covid-19 outcomes. Variables with significant associations were placed into multivariate logistic models to adjust for any potential interactions between predictors. Missing values were treated as missing data and values were not imputed, because of the nature of the clinical data collected. All analysis was carried out in Stata (StataCorp LLC, College Station, Texas, USA), version 14.0.

RESULTS

A total of 986 participants were recruited from all three centres combined. The mean age of participants was 70-10 years (SD 17-39) and 451 participants were female (45-65%). Full summary statistics are detailed in Table 1.
Associations with vitamin D states
Replete vitamin D status was associated with reduced odds of intubation (OR 0-47, 95% CI 0-24 - 0-94, p = 0+032), but this relationship lost significance when adjusted for age and sex (ORadj 0+55, 95% CI 0-27 - 1-10, p = 0-090). Conversely, insufficient vitamin D status (<50 nmol/L) was associated with proceeding to intubation (OR 2+12, 95% CI 1 + 07 - 4+22, p = 0+032), but again, this association lost significance when adjusted for age and sex (ORadj 1 + 83, 95% CI 0+91 - 3 + 69, p = 0+090). Deficient vitamin D status (<25 nmol/L) was associated with obesity, as documented in participants’ clinical records (OR 2-24 (1-15 - 4-39, p = 0-018), and this remained significant following adjustment for age and sex (ORadj 2+21, 95% CI 1 + 12 - 4+37, p = 0+023). Solid organ transplant was also associated with vitamin D deficiency (OR 7*19, 95% CI 1*38 - 37*36, p = 0*019), and this remained significant following adjustment for age and sex (OR_ 7+04, 95% CI 1 + 35 - 36+72, p = 0+021). Vitamin D status was not associated with ethnicity, even following adjustment for whether patients were treated with vitamin D.
Associations with death from Covid-19
Several predictors were associated with death from Covid-19 in univariate analysis, and are detailed in Table 2. These predictors were then placed in a multivariate model, along with sex (Table 3, Figure 1). The following variables remained significantly associated with death from Covid-19:

  • age >74 years (ORadj 3.69, 95% CI 2.41 - 5.64, p = 1.57x10-9),
  • high-flow O2 treatment (ORadj 5.80 (3.71 - 9.08, p = 1-3 x10-14),
  • ischaemic heart disease, IHD (OR— 1*98, 95% CI 1+23 - 3 + 18, p = 0+005),
  • creatinine >83 pmol/L (ORadj 1.56, 95% CI 1.05 - 2.31, p = 0.027), and
  • female sex (ORadj 1.48, 95% CI 1.00 - 2.18, p = 0-048).

There were significantly more female patients in the age category >74 years (p = 0-016) in the study population, but when analysis was stratified by age (older and younger than 74 years), female sex had no association with mortality (OR 0+88, 95% CI 0+56-1 + 39, p = 0+590, in patients aged <74 years; OR 0+82, 95% CI 0+57-1 + 18, 0+288, in patients aged >74 years). Two variables remained significantly protective of death from Covid-19: treatment with vitamin D (ORadj 0*48, 95% CI 0-32 - 0*70, p = 1*79x10-4), and asthma (ORadj 0*29, 95% CI 0*13 - 0*63, p = 0*002). Furthermore, treatment with vitamin D also remained significant following adjustment for baseline vitamin D levels (ORadj 0+47, 95% CI 0+33 - 0+70, p = 1 + 27x10-4). Patients with asthma were significantly younger, with fewer patients in the age >74 years category (p = 4-29x10'8). When stratified by age, the protective effect of asthma was only preserved in patients <74 years (ORadj0*16, 95% CI 0-06-0-44, p = 4-09x10'4; versus ORadj 0*80, 95% CI 0-37-1-72, p = 0-561, in patients aged >74 years). Mortality was not associated with the presence of diabetes mellitus (either type 1 or type 2), nor with baseline HbAlc, nor random glucose on admission.
Associations with invasive ventilation and CPAP
Again, several predictors were associated with participants receiving invasive ventilation via endotracheal tube (Table 4) or with CPAP (Table 6). Many patients receiving invasive ventilation had failed to respond to CPAP, hence the similarities in predictors associated with the two, and similarly, patients had failed to respond to both low-flow and high-flow oxygen delivery in order to require CPAP.
Following adjustment in a multivariate model including all significant associations with invasive ventilation from univariate analysis (Table 5), along with female sex, excluding oxygen treatment, intubation was associated with length of stay >10 days (ORadj 29+50, 95% CI 3 + 74 - 232+79, p = 0+001). Participants aged >74 years (ORadj 0*07, 95% CI 0-01 - 0-34, p = 0-001) or who had developed hospital- acquired Covid-19 (ORadj 0*09, 95% CI 0-01 - 0-75, p = 0-026) were less likely to receive invasive ventilation. Patients with hospital-acquired Covid-19 had a significantly higher proportion of patients in the age >74 years category (p = 0-005). Similarly, following adjustment in a multivariate model and excluding oxygen treatment (Table 7), age >74 was associated with less use of CPAP (ORadj 0*16, 95% CI 0-07 - 0-37, p = 1-16x10-5), and this was the only significantly associated predictor, excluding oxygen treatment.

DISCUSSION

To our knowledge, this is the largest observational study of hospital in-patients with Covid-19 to examine any potential associations between the treatment of the acute infection and vitamin D status, and vitamin D treatment. We found that vitamin D status (replete/insufficient/deficient) was not associated with Covid-19 MAAREs, neither was it associated with ethnicity. However, treatment with vitamin D appeared to be protective against mortality, regardless of baseline vitamin D levels.
Our findings regarding vitamin D status appear to fit with a study utilising participants from the UK Biobank, which found no association between vitamin D levels and risk of Covid-19 infection12. The UK Biobank study looked at 348,598 participants, of whom, 449 had a confirmed diagnosis of Covid- 19 as defined by a positive laboratory test for SARS-CoV-2 (only 0-13% of study population). However, it is likely that the Covid-19 cases from that study were managed in a mixture of hospitals and the community and vitamin D was measured between 2006 and 2010, and not contemporaneously with Covid-19 infection 10-14 years after recruitment to the UK Biobank. Our study adds extra information regarding patients who, by their nature, have more severe disease, as they have been hospitalised. Additionally, our study provides information on vitamin D status as close to Covid-19 infection as possible, giving a more accurate picture of any interactions; we imposed a limit of 12 weeks on vitamin D levels prior to admission to mitigate for seasonal variation. Rhodes et al suggest that countries at a latitude above 35 degrees North have experienced increased mortality from Covid-19, suggesting a potential role for vitamin D in Covid-19 outcomes 13, but our findings do not implicate vitamin D in the role of increasing mortality rates in these countries. Two independent studies from Israel14 and the USA15 found that deficient vitamin D status was associated with increased risk of Covid- 19, but did not address other outcome measures, apart from hospitalisation. Our findings appear to differ from those of other studies, but this could be due to power issues or a differing population. Given the emerging nature of this research, large meta-analyses will be required in the future when more data is available from multiple international sites.
Interestingly, treatment with vitamin D was associated with reduced odds of death, even following adjustment for baseline vitamin D levels. Treatment with vitamin D constituted either

  • maintenance therapy (800-2,000IU daily) or
  • high-dose booster therapy (up to 300,000IU total, split over multiple doses)16.

This could be for a number of reasons. Firstly, it may be because it is not clear what an adequate amount of vitamin D is required to maintain immune health. UK guidance is that levels >25nmol/L are required to maintain musculoskeletal health17, but this is within the range for deficiency16 and does not take into account vitamin D5s role outside of musculoskeletal health. It is possible that serum vitamin D levels might need to be higher than the recommended range in order to provide protection from more severe Covid-19 outcomes. An alternative hypothesis might be that not all patients had vitamin D measured during admission (755/986 participants), and the patients that had levels measured and acted on may have received overall more intensive treatment, resulting in better outcomes. From the level of data collected, it is not clear what the mechanisms are behind our findings. Nonetheless, vitamin D as a potential therapeutic option for Covid-19 is an attractive prospect, given its wide availability and low cost, particularly in developing nations, as well as its relatively safe side-effect profile in conjunction with regular monitoring of serum levels and serum adjusted calcium.
We found that obesity was significantly associated with deficient vitamin D status, and this is in keeping with a large meta-analysis of SNPs associated with body mass index (BMI) and with vitamin D in 42,024 patients, which found that increased BMI was associated with lower vitamin D levels18. A more recent meta-analysis of observational studies also found a dose-response association between vitamin D levels and reduced risk of abdominal obesity19. We also found an association between vitamin D deficiency and patients who had received a solid organ transplant. Again, these agree with other previous findings, which have demonstrated that low vitamin D levels are very common following solid organ transplantation, even in the long-term20.
It is unsurprising that predictors such as age >74 years, IHD and baseline creatinine >83 per mol/L are associated with increased risk of death from Covid-19, as these are likely to represent patients with a poorer baseline of health with less physiological reserve to adequately cope with acute Covid-19 infection. The June 2020 report from the Office of National Statistics, ONS (covering England and Wales, where this study population was recruited from) shows an exponential rise in age-specific mortality rates as age increases21, and this would fit with our data. Furthermore, a large multi-centre study in Italy found that older age, chronic kidney disease and coronary artery diseases were more common in patients who died 22, and our findings agree with this. We also found that the requirement for high-flow O2 treatment was significantly associated with death; this is likely to represent more severe disease in patients who may then have gone on not to be deemed to be suitable for either invasive ventilation or CPAP, or who declined it. This would agree with our findings that patients aged >74 years were less likely to have received invasive ventilation and/or CPAP.
More interestingly, in our study population, females were more likely to die from Covid-19, although this could be explained by a significantly increased number of patients in the age >74 years category compared to those who were not in this category, although analysis was adjusted for age. This differs from a Spanish study that is still awaiting peer-review, which found an increased infection-related fatality risk of Covid-19 in males when compared to females, even when stratified by age23. Our study is much smaller with fewer centres, by comparison, so this may account for a difference in findings. However, the multi-centre nature of our study, based in varied geographical locations, means that it is likely to be representative of the UK.
Also of interest is the apparently protective characteristic of a patient having asthma. Asthma has long been thought of as a risk factor for a more severe Covid-19 disease course, but given that patients with asthma in our study population had significantly fewer patients in the age >74 years category, this is likely to be skewed in favour of younger patients. A US study had similar findings, where patients with asthma tended to be younger and did not have worse outcomes than patients without asthma24. In addition, Iaccarino et al found that chronic obstructive pulmonary disease (COPD), but not asthma, was associated with increased mortality from Covid-1922.
We found that intubation was associated with increased length of stay, and logically, this would fit with a more severe disease course and often prolonged weaning of invasive ventilation, although we cannot say this conclusively from our data. Patients who had developed hospital-acquired Covid-19 were also significantly less likely to receive invasive ventilation, but this group had a higher proportion of older patients when compared with patients with community-acquired Covid-19. Therefore, patients with ? ? ?

This study’s strengths lie in its recruitment of almost 1,000 acute Covid-19 hospital in-patients from three separate centres, with a high proportion of patients with available vitamin D levels. Our study population is generalisable to the rest of the UK, with similar demographics compared with the ONS figures. Patients were recruited from throughout the pandemic, so our population reflects changing treatment recommendations as the pandemic evolved and evidence increased. However, not all patients had vitamin D levels available, so power may have been improved with more vitamin D results. In addition, while results are potentially generalisable to the UK, results would need to be replicated in different populations to assess transferability of findings globally. Finally, due to the cross-sectional nature of this study, we are unable to ascertain cause and effect between associations, and we do not have a mechanistic understanding of our findings as yet. Longitudinal analysis of outcomes must be carried out in the future to determine any long-term sequelae of deficient vitamin D status during acute Covid-19 infection. There is also the potential for studies in whole blood and/or tissue to understand the mechanisms behind vitamin D status and Covid-19 severity.

In conclusion, treatment with vitamin D, regardless of baseline serum vitamin D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with Covid-19. This suggests that further work should be carried out to determine what an adequate serum level of vitamin D might be from large-scale population studies, and paves the way for future clinical trials of vitamin D treatment, at multiple doses in order to assess maximum efficacy. This inexpensive and widely available treatment could have positive implications for the management of Covid-19 worldwide, particularly in developing nations.

References

  1. Jakovac H. COVID-19 and vitamin D-Is there a link and an opportunity for intervention? Am J Physiol EndocrinolMetab 2020; 318(5): E589.
  2. Caccialanza R, Laviano A, Lobascio F, et al. Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol.池trition 2020; 74: 110835.
  3. Carter SJ, Baranauskas MN, Fly AD. Considerations for Obesity, Vitamin D, and Physical Activity Amid the COVID-19 Pandemic. Obesity (Silver Spring) 2020; 28(7): 1176-7.
  4. Teymoori-Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol 2019; 29(2): e2032.
  5. Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020; 12(4).
  6. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal Nutritional Status for a WellFunctioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients 2020; 12(4).
  7. Silberstein M. Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Med Hypotheses 2020; 140: 109767.
  8. Panagiotou G, Tee SA, Ihsan Y, et al. Low serum 25-hydroxyvitamin D (25OHD) levels in patients hospitalized with COVID-19 are associated with greater disease severity. Clin Endocrinol (O:xf) 2020.
  9. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin E^p Res 2020; 32(7): 1195-8.
  10. Munshi R, Hussein MH, Toraih EA, et al. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. J Med Virol 2020.
  11. WHO. International Guidelines for Certification and Classification (Coding) of Covid-19 as Cause of Death. 2020. https://www.who.int/classifications/icd/Guidelines Cause of Death COVID- 19-20200420-EN.pdf?ua=1 (accessed 31/08/2020).
  12. Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 2020; 14(4): 561-5.
  13. Rhodes JM, Subramanian S, Laird E, Kenny RA. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Aliment Pharmacol Ther 2020; 51(12): 1434-7.
  14. Merzon E, Tworowski D, Gorohovski A, et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS J 2020. #11
  15. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open 2020; 3(9): e2019722.
  16. GMMMG. Treatment of Vitamin D Deficiency and Insufficiency in Adults. 2016. http://gmmmg.nhs.uk/docs/nts/NTS-Recommendation-on-Vitamin-D-deficiency-and-insufficiency-adults.pdf (accessed 03/09/2020).
    • Note: VitaminDWiki was unable to access it Nov 9, even when going thru a UK VPN
    • Did find this  PDFi however
    • a loading regimen to provide a total of approximately 300,000 units vitamin D, given either as separate weekly or daily doses over 6 to 10 weeks :
    • The exact regimen will depend on local preference and local availability of vitamin D preparations but could include:
    • 20,000 units capsules, two given weekly for 7 weeks (280,000 units)
    • 800 units capsules, five a day given for 10 weeks (280,000 units)
  17. SACN U. Vitamin D and Health. 2016. https://www.gov.uk/govemment/groups/scientific- advisory-committee-on-nutrition (accessed 03/09/2020).
  18. Vimaleswaran KS, Berry DJ, Lu C, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013; 10(2): e1001383.
  19. Hajhashemy Z, Shahdadian F, Ziaei R, Saneei P. Serum vitamin D levels in relation to abdominal obesity: A systematic review and dose-response meta-analysis of epidemiologic studies. Obes Rev 2020.
  20. Stein EM, Shane E. Vitamin D in organ transplantation. Osteoporos Int 2011; 22(7): 2107-18.
  21. ONS. Deaths involving COVID-19, England and Wales: deaths occurring in June 2020. 2020.
  22. Iaccarino G, Grassi G, Borghi C, et al. Age and Multimorbidity Predict Death Among COVID- 19 Patients: Results of the SARS-RAS Study ofthe Italian Society of Hypertension. Hypertension 2020; 76(2): 366-72.
  23. Pastor-Barriuso R, Perez-Gomez B, Hernan MA, et al. SARS-CoV-2 infection fatality risk in a nationwide seroepidemiological study. 2020.
  24. Lovinsky-Desir S, Deshpande DR, De A, et al. Asthma among hospitalized patients with COVID-19 and related outcomes. J Allergy Clin Immunol 2020.

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