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Due to the “overwhelming” data surrounding the importance of vitamin D status in the risk for the development and progression of COVID-19, increasing pressure is mounting from doctors and health researchers for governments and health policy makers to recommend vitamin D daily dosing at higher levels.

In October 2020, Nutraingredients reported that a group of UK researchers and doctors had formed an international alliance aiming to encourage governments to increase recommendations for vitamin D intake to 4,000 IU daily (and in some cases up to 10,000 IU for a short period of time), as they believe this would reduce COVID-19 hospitalisations. The group asserts that much of the confusion around vitamin D stems from the fact it is so poorly understood, and rather than being a “vitamin”, it is in fact an “essential hormone which the immune system requires in order to function adequately”.

Also in October 2020, a new clinical trial was launched in the UK that has “the potential to give a definitive answer” to the question of whether vitamin D offers protection against COVID-19, according to the researchers, who will be using higher doses of vitamin D than regular supplements. “Vitamin D supplements are low in cost, low in risk and widely accessible; if proven effective, they could significantly aid in our global fight against the virus”, said David Joliffe, lead researcher at Queen Mary University London.

As research gathers apace, here’s an overview of some of the most recent research developments relating to vitamin D and Covid-19.

Low vitamin D status is associated with coronavirus disease 2019 outcomes: A systematic review and meta-analysis.
-Liu N, Sun J et al. International Journal of Infectious Diseases. 2021 Jan 2; S1201-9712(20)32600-X.

In a systematic review and meta-analysis published in the International Journal of Infectious Diseases in January 2021, researchers selected a total of 10 articles with 361,934 participants for meta-analysis. The researchers concluded that, “this systematic review and meta-analysis indicated that low vitamin D status may be associated with an increased risk of COVID-19 infection. Further studies are needed to evaluate the impact of vitamin D supplementation on the clinical severity and prognosis in patients with COVID-19.”

Low 25-Hydroxyvitamin D levels on admission to the Intensive Care Unit may predispose COVID-19 pneumonia patients to a higher 28-day mortality risk: a pilot study on a Greek ICU cohort.
-Vassiliou AG, Jahaj E et al. Nutrients 2020 Dec; 12(12);3773

In a small pilot, prospective, observational study on 30 critically ill patients of Greek ethnicity, suffering from COVID-19 pneumonia and directly admitted to the ICU, researchers found low ICU admission vitamin D levels to be associated with worse outcomes of COVID-19 pneumonia.

Increased risk for COVID-19 in patients with vitamin D deficiency
-Katz J, Yue S, Xue W. Nutrition 2020 Dec 4; 84:111106.

In the absence of large-scale longitudinal studies, a study published online in Nutrition in December 2020 investigated the patient registry of the University of Florida Health Center, to examine the strength of the association between vitamin D deficiency and COVID-19. After adjusting for likely covariates such as demographic characteristics and inflammation-associated comorbidities, the authors found vitamin D deficiency to be significantly associated with increased risk for COVID-19.

Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomised clinical study
-Entrenas Castillo ME, Entrenas Costa LM, et al. J Steroid Biochem Mol Biol. 2020 Oct; 203: 105751

In a pilot study on 76 patients hospitalised with COVID-19 infection in the Reina Sofia University Hospital, Cordoba, Spain, researchers evaluated the effect of calcifediol (25-hydroxyvitamin D) treatment, on ICU admission and mortality rate among Spanish patients hospitalised for COVID-19. They found that administration of high dose of calcifediol significantly reduced the need for ICU treatment of patients requiring hospitalisation due to proven COVID-19. They found that calcifediol seems to be able to reduce severity of the disease, but that larger trials with properly matched groups are required.

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection.
- Hernandez JL, Nan D, Fernandez-Ayala M et al. Journal of clinical Endocrinology & Metabolism Oct 2020

A retrospective case-control study of 216 COVID-19 patients at a hospital in northern Spain, and 197 population-based controls. The study found that over 80% of the COVID-19 group were vitamin D deficient, and men had lower vitamin D levels than women. In addition, the COVID-19 patients with lower vitamin D levels had raised levels of serum inflammatory markers such as ferritin and D-dimer, that are markers of the hyperinflammatory state that can worsen the outcome of the disease.

Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results.
- Meltzer DO, Best TJ, Hui Zhang et al. JAMA Netw Open Sep 2020;3(9):e2019722

An observational study in which the authors looked at vitamin D levels of a cohort of 489 patients who had been tested for their vitamin D levels in the year prior to COVID-19 testing, and found that those who showed low levels of vitamin D were 1.77 times more likely to test positive for the virus. The findings appear to support a role of vitamin D status in COVID-19 risk. The authors recommend further randomized clinical trials amongst the broader population, as well as at risk groups, to determine if vitamin D intervention can reduce COVID-19 incidence.

Vitamin D Status and Outcomes for Hospitalised Older Patients with COVID-19.
- Vadir Baktash, Tom Hosack, Nishil Patel et al. BMJ Postgrad Med J August 2020

Results were reported from a prospective cohort study of older patients (65 years+) diagnosed with Covid-19 in March and April this year. Older adults who tested positive for the virus were more likely to have worse morbidity outcomes if they were vitamin D deficient (less than 30nmol/L), than were patients attributed to the replete group. Morbidity was measured by NIV support and high dependency unit admission. No increased mortality was observed between the groups, however. The authors concluded that Vitamin D status may be a useful prognosticator for morbidity outcomes in older adults.

The Possible Role of Vitamin D in Suppressing Cytokine Storm an Associated Mortality in COVID-19 Patients
– Daneshkhah A, Agrawal V, Eshein A et al. April 30, 2020

Initial analysis of patient data from 10 countries showed that patients with severe vitamin D deficiency are twice as likely to experience major complications with COVID-19. Led by Northwestern University, the researchers discovered a strong correlation between vitamin D levels and cytokine storm, a hyper-inflammatory condition that can severely damage lungs and lead to acute respiratory distress syndrome and death in patients. The researchers concluded that the fundamental role vitamin D plays in preventing the immune system from becoming dangerously overactive may prove to be key, as cytokine storm is “what seems to kill a majority of COVID-19 patients, not the destruction of the lungs by the virus itself. It is the complications from the misdirected fire from the immune system”.

Association between vitamin D levels and mortality from COVID-19
– Laird E & Kenny RA. Irish Medical Journal May 2020 Vol 11 No 5

Researchers from Trinity College Dublin, the University of Liverpool and the Irish Longitudinal Study on Ageing (TILDA) examined the association between vitamin D levels and COVID-19 mortality rates. In this analysis of more than 20 years’ worth of European data on vitamin D, a statistically significant link was shown between the highest infection and death rates of COVID-19 and populations with low vitamin D concentrations, including Spain and Italy. The northern latitude countries of Norway, Finland and Denmark which have recorded comparatively lower Covid-19 infection and death rates, have higher vitamin D levels despite less sunlight exposure, because supplementation and fortification of foods is more common, they noted.

Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths.
- Grant WB, Lahore H, McDonnell SL et al. Nutrients 2020 Apr 2;12(4)

A review of the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. The researchers recommend that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d; the goal being to raise 25(OH)D concentrations above 40-60ng/mL (100-150 nmol/L).

The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.
- Ilie PC, Stefanescu S, Smith L. Aging Clin Exp Res 2020 May 6.

Negative correlations between mean levels of vitamin D across 20 European countries and the number of COVID-19 cases (per million) and mortality rates (per million) were observed. The researchers noted that Vitamin D levels are severely low in the most vulnerable to COVID-19 – ie., the aging population – especially in Spain, Italy and Switzerland. A further study into vitamin D levels in COVID-19 patients with different degrees of disease severity was advised.

Considerations for obesity, vitamin D, and physical activity amidst the COVID-19 pandemic.
- Carter SJ, Baranauskas MN, Fly AD. Obesity (Silver Spring) 2020 Apr 16.

A consideration of the link between diminished immune function and individuals with obesity, and how this raises important questions about the possibility for greater viral pathogenicity in this population. The authors note that low vitamin D may add to the complications in this population. They caution against pinning all hopes on a “silver bullet” treatment approach and recommend that the contribution of modifiable lifestyle factors such as diet and physical activity not be ignored.

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