Vitamin D and Covid-19: the current evidence

Vitamin D has been associated with many disease states from osteoporosis, cancer, diabetes, heart disease, impotence etc. There has been an increase in publications in PubMed regarding narrative reviews compared to systematic reviews. However the largest  increase is in registered  clinical trials with regards to Covid-19 and Vitamin D.

This is a live page that will be updated linking the trusted evidence accessible to any person free of charge – Cochrane Library, NICE-UK, CDC/NIH USA, NPS-Australia . 

I have also included the most trustworthy point of care reference evidence from the sources  such as UpToDate, BMJ Best Practice, DynaMed and Cochrane Clinical Answers. In most developed countries these are free to clinicians and academics but in countries like Sri Lanka this depends on individual or institutional subscriptions.  

I have included citation from the New PubMed using search 

There are more than 50 ongoing clinical trials protocols shown in Cochrane library. [Ref -Cochrane] https://www.cochranelibrary.com/search

 


(1) National Institute of Health – updated 17 July 2020

Recommendation: There are insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19.

Vitamin D is critical for bone and mineral metabolism. Because the vitamin D receptor is expressed on immune cells such as B cells, T cells, and antigen-presenting cells, and because these cells can synthesize the active vitamin D metabolite, vitamin D also has the potential to modulate innate and adaptive immune responses.1

Vitamin D deficiency (defined as a serum concentration of 25-hydroxyvitamin D ≤20 ng/mL) is common in the United States, particularly among persons of Hispanic ethnicity and Black race. These groups are overrepresented among cases of COVID-19 in the United States.2 Vitamin D deficiency is also more common in older patients and patients with obesity and hypertension; these factors have been associated with worse outcomes in patients with COVID-19. In observational studies, low vitamin D levels have been associated with an increased risk of community-acquired pneumonia in older adults3 and children.4

Vitamin D supplements may increase the levels of T regulatory cells in healthy individuals and patients with autoimmune diseases; vitamin D supplements may also increase T regulatory cell activity.5 In a meta-analysis of randomized clinical trials, vitamin D supplementation was shown to protect against acute respiratory tract infection.6 However, in two randomized, double-blind, placebo-controlled clinical trials, administering high doses of vitamin D to critically ill patients with vitamin D deficiency (but not COVID-19) did not reduce the length of the hospital stay or the mortality rate when compared to placebo.7,8 High levels of vitamin D may cause hypercalcemia and nephrocalcinosis.9

Vitamin D and COVID-19

The role of vitamin D supplementation in the prevention or treatment of COVID-19 is not known. The rationale for using vitamin D is based largely on immunomodulatory effects that could potentially protect against COVID-19 infection or decrease the severity of illness. Ongoing observational studies are evaluating the role of vitamin D in preventing and treating COVID-19.

Some investigational trials on the use of vitamin D in people with COVID-19 are being planned or are already accruing participants. These trials will administer vitamin D alone or in combination with other agents to participants with and without vitamin D deficiency. The latest information on these clinical trials can be found on ClinicalTrials.gov.


 

(2) NICE-UK

COVID-19 rapid evidence summary: vitamin D for COVID-19: 29th July 2020

Recommendation:

Advisory statement on likely place in therapy: There is no evidence to support taking vitamin D supplements to specifically prevent or treat COVID-19. However, all people should continue to follow UK Government advice on daily vitamin D supplementation to maintain bone and muscle health during the COVID-19 pandemic.

[Ref – NICE –June 29]

covid19-rapid-evidence-summary-vitamin-d-for-covid19-pdf-1158182526661

 

(3) BMJ Best Practice – LINK

Emerging therapies LINK

Recommendation:

Vitamin D supplementation has been associated with a reduced risk of respiratory infections such as influenza in some studies.[842][843][844] Vitamin D is being trialled in patients with COVID-19.[845][846] However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[847] A pilot randomised controlled trial found that high-dose calcifediol, a vitamin D3 analogue, significantly reduced the need for intensive care unit treatment in hospitalised patients, and may improve clinical outcomes.[848] The UK National Institute for Health and Care Excellence states that while there is no evidence to support taking vitamin D specifically to prevent or treat COVID-19, it does recommend that all people should take a vitamin D supplement daily as per UK government advice to maintain bone and muscle health during the pandemic, especially if they are not getting enough sun exposure due to shielding or self-isolating.[849] The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin D.[3]


(4) Australian Prescriber NPS-Australia – LINK

Recommendation

There is currently no evidence to demonstrate that vitamin D supplements can protect people with COVID-19 from more serious health complications. Clinical trials are underway to examine the topic further.  LINK

Having enough vitamin D is important for your overall wellbeing, and looking after your health is crucial during this time. However, taking supplements (including vitamin D) to prevent COVID-19 infection is not supported by any clinical evidence.

During the COVID-19 pandemic, many Australians have been spending more time indoors than usual, because of the restrictions in place to limit transmission of the virus. In addition to reducing the spread of COVID-19, restrictions have also helped slow down the spread of many common infectious diseases including influenza (flu), measles and chicken pox. However, there are health-related drawbacks to spending less time outside.

International health authorities have been concerned that reduced exposure to sunlight has left some people vulnerable to a vitamin D deficiency. Vitamin D is important for bone, muscle and dental health. Some recent reports have also suggested that vitamin D levels may influence risk of COVID-19 infection and severity. 

 


(4) UpToDate – LINK

Vitamin D and extra skeletal health

Update September 2020 

COVID-19 — There is growing interest in vitamin D supplementation during the COVID-19 pandemic. Serum 25(OH)D levels are reportedly lower in critically ill (intensive care unit) patients than in patients on the general medical unit [77]. Although small observational studies report an inverse association between mean vitamin D levels and COVID-19 cases [78], the association is confounded by common risk factors for both vitamin D deficiency and SARS-CoV-2 (eg, obesity).

Larger observational studies report mixed findings. As examples: In a large cohort study from the United Kingdom (UK) Biobank (348,598 participants, 499 with COVID-19), after adjustment for confounders, there was no association between 25(OH)D levels and risk of [79,80] or mortality from [81] COVID-19.

In a subsequent study of 489 individuals who had a 25(OH)D level measured within one year of testing for COVID-19, the risk of a positive COVID-19 test was higher in those who were likely vitamin D deficient (25[OH]D level <20 ng/mL without increase in supplementation) than in those who were not (estimated mean rate 21.6 versus 12.2 percent in the unlikely deficient groups, RR 1.77, 95% CI 1.12-2.81) [82].

There is no clear evidence that vitamin D supplementation reduces the risk or severity of COVID-19 [78,83]. In a pilot study from Spain, 76 hospitalized patients with COVID-19 and acute respiratory infection were randomly assigned to oral calcifediol (0.532 mg, followed by 0.266 mg on day 3 and 7 of hospitalization, and then weekly) or to no supplementation [84]. All patients received standard care for COVID-19. Fewer patients assigned to calcifediol required intensive care unit (ICU) admission (2 versus 50 percent). Despite randomization, more patients in the unsupplemented group had diabetes (19 versus 6 percent) and hypertension (58 versus 24 percent), known risk factors for severe COVID-19. In another preliminary report from Singapore, fewer patients with COVID-19 who received vitamin D (1000 international units), magnesium, and vitamin B12 required oxygen therapy [85]. There are several larger scale, placebo-controlled vitamin D trials in progress [83,86].

In patients with COVID-19, vitamin D supplementation may be necessary to meet the recommended intake; however, doses exceeding the upper level intake are not recommended. It is reasonable for all individuals to take 15 to 25 mcg (600 to 1000 international units) of vitamin D daily.

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Adequate vitamin D intake — Adequate intake of vitamin D is necessary for bone health. Vitamin D supplementation may be necessary to meet the recommended intake (table 1), particularly for children with limited exposure to sunlight (eg, those remaining inside while self-isolating). However, the role of vitamin D in the treatment and prevention of COVID-19 is uncertain, and doses exceeding the upper level intake are not recommended [18,67-69]. (See “Vitamin D and extraskeletal health”, section on ‘COVID-19’ and “Overview of vitamin D”.). Whether vitamin D deficiency increases the risk of SARS-CoV-2 infection in children is uncertain. The association may be confounded by other risk factors for both vitamin D deficiency and SARS-CoV-2 infection (eg, obesity). Vitamin D deficiency in children, including indications for screening (which are unchanged by the COVID-19 pandemic), is discussed separately. (See “Vitamin D insufficiency and deficiency in children and adolescents”.) LINK

 


(5) PubMed

The new interface for searching PubMed came into effect in 2020.  The interface introduces new features is the use of artificial intelligence built into the interface. This means that when we type a word or a phrase automatically the interface tries to interpret the meaning of the phrase and assists inn searching. PubMed uses fuzzy algorithms using machine learning to be very intuitive.

However I used the basics combining the Mesh words [Coronavirus infection] AND [Vitamin D] ended up with 100+ articles. Limiting for past 10 years and first asking for a systematics review, I got 1 article

 

PM-1 Could Vitamins Help in the Fight Against COVID-19?

The major topics extracted for narrative synthesis were physiological and immunological roles of each vitamin, their role in respiratory infections, acute respiratory distress syndrome (ARDS), and COVID-19. 

LINK

The important paragraph is given below.

3.4.4. Relevance to COVID-19

This picture is confounded somewhat in the case of COVID-19, which acquires entry to cells through binding to ACE2 []. However, the binding of the viral S1 spike protein to ACE2 causes both the virus and the enzyme to be translocated into the cell through endocytosis, thereby effectively reducing the surface expression of ACE2 and possibly contributing to the progression of pulmonary disease []. There does appear to be associations between high levels of ACE2 and survival benefit, implicating the attenuation of the RAS system as a means of protection against ARDS []. Ethnic variations in the expression of ACE2 receptors have also been noted, with the highest expression seen in East Asian males []. The ethnic disparities in ACE2 expression and polymorphisms may be a contributor to disease severity either independently or in conjunction with vitamin D status, and warrants further investigation. Additionally, the higher preponderance of male:female sex-specific COVID-19 mortality may in part be related to hormonal dependency of expression and/or activity of ACE2 seen in animal studies []. The effects of severe vitamin D deficiency have been explored in humans: Following the inhalation of bacterial cell wall constituent, lipopolysaccharide (LPS), a marked increase in alveolar inflammation (IL-1B) was noted in vitamin D-deficient individuals compared to those with mild deficiency []. Specifically, there has been increasing speculation that vitamin D deficiency may underpin the likelihood of mortality and disease severity in COVID-19 [,,,,,,,,,,,,,,,,]. Observed differences in COVID-19 mortality between the northern and southern hemispheres also add to the case for vitamin D having a role in the pathogenesis of COVID-19 []. The emergence of Brazil as a disease hotspot may change these findings in time. Crude pan-European analysis, however, showed a negative correlation between mean levels of vitamin D in each country and the number of COVID-19 cases and mortality [,]. These associations, along with the physiological and immunological roles of vitamin D summarized in Figure 8, have prompted clinical trials in vitamin D supplementation in COVID-19 patients and warrant further mechanistic investigation [,].


 

PM-2

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.


PM-4

Vitamin D for COVID-19: a case to answer? LINK

Pending results of such trials, it would seem uncontroversial to enthusiastically promote efforts to achieve reference nutrient intakes of vitamin D, which range from 400 IU/day in the UK to 600–800 IU/day in the USA. These are predicated on benefits of vitamin D for bone and muscle health, but there is a chance that their implementation might also reduce the impact of COVID-19 in populations where vitamin D deficiency is prevalent; there is nothing to lose from their implementation, and potentially much to gain. LINC


PM-5

Need for Measures in India
Healthcare providers should expect an increase in cases of COVID-19 as well as other infectious diseases and prepare for an increase in hospital capacity. Further, healthcare practitioners might need to consider factors such as diet, sunlight exposure and consider administering vitamin D supplementation to correct any vitamin D deficiency.
The increased possibility of COVID-19 transmission, potential vitamin D deficiency and the increased pressure on the healthcare systems due to other infectious diseases may lead to an increased mortality rate from COVID-19 in India during monsoon. Establishing the efficacy of vitamin D supplementation/sunlight exposure would be a significant advance in the control of COVID-19 pandemic in India during monsoon. This topic in India needs urgent attention from medical researchers around the world. Additionally, government and healthcare providers need to urgently plan to mitigate the impact of COVID-19 on public health by addressing these topics as early as possible. Ref – Post Graduate Medical Journal


PM-6

Vitamin D concentrations and COVID-19 infection in UK Biobank

Conclusions: Our findings do not support a potential link between vitamin D concentrations and risk of COVID-19 infection, nor that vitamin D concentration may explain ethnic differences in COVID-19 infection.

Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis

There is still limited evidence regarding the influence of vitamin D in people with COVID-19. In this systematic review and meta-analysis, we analyze the association between vitamin D deficiency and COVID-19 severity, via an analysis of the prevalence of vitamin D deficiency and insufficiency in people with the disease. Five online databases-Embase, PubMed, Scopus, Web of Science, ScienceDirect and pre-print Medrevix were searched. The inclusion criteria were observational studies measuring serum vitamin D in adult and elderly subjects with COVID-19. The main outcome was the prevalence of vitamin D deficiency in severe cases of COVID-19. We carried out a meta-analysis with random effect measures. We identified 1542 articles and selected 27. Vitamin D deficiency was not associated with a higher chance of infection by COVID-19 (OR = 1.35; 95% CI = 0.80-1.88), but we identified that severe cases of COVID-19 present 64% (OR = 1.64; 95% CI = 1.30-2.09) more vitamin D deficiency compared with mild cases. A vitamin D concentration insufficiency increased hospitalization (OR = 1.81, 95% CI = 1.41-2.21) and mortality from COVID-19 (OR = 1.82, 95% CI = 1.06-2.58). We observed a positive association between vitamin D deficiency and the severity of the disease. LINK

 


PM – 7

Population vitamin D supplementation in UK adults: too much of nothing?


PM-8

Perspective: Vitamin D deficiency and COVID-19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis

Substantial evidence supports a link between vitamin D deficiency and COVID-19 severity but it is all indirect. Community-based placebo-controlled trials of vitamin D supplementation may be difficult. Further evidence could come from study of COVID-19 outcomes in large cohorts with information on prescribing data for vitamin D supplementation or assay of serum unbound 25(OH) vitamin D levels. Meanwhile, vitamin D supplementation should be strongly advised for people likely to be deficient. Perspective: Vitamin D deficiency and COVID-19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis [Ref PubMed


PM – 9

Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19LINK

Low levels of micronutrients have been associated with adverse clinical outcomes during viral infections. Therefore, to maximize the nutritional defense against infections, a daily allowance of vitamins and trace elements for malnourished patients at risk of or diagnosed with coronavirus disease 2019 (COVID-19) may be beneficial. Recent studies on COVID-19 patients have shown that vitamin D and selenium deficiencies are evident in patients with acute respiratory tract infections. Vitamin D improves the physical barrier against viruses and stimulates the production of antimicrobial peptides. It may prevent cytokine storms by decreasing the production of inflammatory cytokines. Selenium enhances the function of cytotoxic effector cells. Furthermore, selenium is important for maintaining T cell maturation and functions, as well as for T cell-dependent antibody production. Vitamin C is considered an antiviral agent as it increases immunity. Administration of vitamin C increased the survival rate of COVID-19 patients by attenuating excessive activation of the immune response. Vitamin C increases antiviral cytokines and free radical formation, decreasing viral yield. It also attenuates excessive inflammatory responses and hyperactivation of immune cells. In this mini-review, the roles of vitamin C, vitamin D, and selenium in the immune system are discussed in relation to COVID-19.

 

 

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Miscellaneous 

Combating COVID-19: Vitamin D the vital cog-in-the-wheel − Prof. Wimalawansa LINK

Professor Wimalawansa said that the capsulesare a custom-synthesised mega-dose, made in a reputed laboratory named,Bioinnovations-Pharmacal in Arkansas, USA.  He added that since these are custom-made it is currently not available for purchase.  He alleged that it is company assured that ingredients in the capsule have been tested and proven to be pure and added that it is suitable for consumption. “For those who have just contracted the virus, when you have this mega-dose nutrient in the body, he or she will experiencemilder symptoms.  Those with sufficient micro-nutrients, including vitamin D and zinc, will have either no symptomatic disease or have minor symptoms.” He added.

Professor Wimalawansa further said that maintaining a healthy level of Vitamin D will strengthen one’s immunity and added that the response of the immune system is positively related to the vitamin D concentration in the blood.  He emphasized that many recent studies report that, individuals who require Intensive Care and those who have passed away, had their serum vitamin D [25(OH)D] concentrations at less than 5 nanograms per millilitre (ng/mL). 

 

  1. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881-886. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21527855.
  2. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31(1):48-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21310306.
  3. Lu D, Zhang J, Ma C, et al. Link between community-acquired pneumonia and vitamin D levels in older patients. Z Gerontol Geriatr. 2018;51(4):435-439. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28477055.
  4. Science M, Maguire JL, Russell ML, Smieja M, Walter SD, Loeb M. Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013;57(3):392-397. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23677871.
  5. Fisher SA, Rahimzadeh M, Brierley C, et al. The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: a systematic review. PLoS One. 2019;14(9):e0222313. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31550254.
  6. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28202713.
  7. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520-1530. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25268295.
  8. National Heart Lung and Blood Institute PCTN, Ginde AA, et al. Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med. 2019;381(26):2529-2540. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31826336.
  9. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. Available at: https://www.ncbi.nlm.nih.gov/books/NBK56070/.

Last Updated: July 17, 2020