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4th March 2022
The use of a large oral bolus of cholecalciferol (vitamin D) given to patients with moderate-to-severe COVID-19 upon admission to a hospital failed to improve overall outcomes compared with no treatment.
This was the conclusion of a large, randomised trial by researchers from the Hospital Universitario Central de Asturias (HUCA), Avda. Roma, Spain. However, in a separate subgroup analysis, it did appear that there were positive benefits among those with higher baseline calcidiol levels upon admission.
An inverse relationship has been established between vitamin D levels and the development of several autoimmune diseases although whether this effect on the immune system has a positive impact upon the body’s ability to fight respiratory infections and on chronic diseases is currently uncertain.
Much has been written on the potential benefits of vitamin D among patients with COVID-19 and one systematic review concluded that low vitamin D levels represent an increased risk of acute respiratory distress syndrome, admission to an intensive care unit or mortality due to COVID-19 infection.
Nevertheless, a limitation from the aforementioned systematic review, it how the data were derived from observational studies and there has been a distinct absence of randomised, controlled trials, which can provide more robust evidence.
For the present study, the Spanish team undertook a randomised trial (COVID-VIT-D) to investigate whether a single, large, oral bolus of 100,000 IU of cholecalciferol given upon admission to hospital, could impact on the outcomes associated with a COVID-19 infection.
Eligible patients (18 years and over) were those hospitalised for moderate-to-severe COVID-19 infection and who were randomised 1:1, to receive a single oral bolus of cholecalciferol or nothing. Patients were followed from admission until discharge and demographic, co-morbidity, biochemical, imaging results and all treatments used were recorded.
The three primary outcomes for the trial were: length of hospitalisation; admission to an intensive care unit (ICU) and mortality. In a separate cohort analysis, the researchers examined the relationship between serum calcidiol upon admission with pulmonary involvement and the same three primary outcomes of the trial.
Single oral bolus and COVID-19 outcomes
A total of 543 patients with a median age of 58 years (65% male) were randomised to vitamin D (274) or nothing. The most frequent co-morbidities were hypertension (43.8%), diabetes (24.7%) and cardiovascular disease (21.2%). In addition, pulmonary involvement was diagnosed in 83.1% of those upon admission.
With respect to the primary outcomes, there were no differences between the two groups. The median length of hospital stay was 10 vs 9.5 days (vitamin D vs control), admission to ICU (172.% vs 16.4%) and mortality (8% vs 5.6%).
When considering the lowest (< 10ng/ml) and highest(> 25 ng/ml) baseline levels, the presence of a higher calcidiol level was associated with a lower risk of pulmonary involvement upon admission (odds ratio, OR = 0.21, 95% CI 0.08 – 0.60) and a lower risk of ICU admission (hazard ratio, HR = 0.35, 95% CI 0.13 – 0.95). However, baseline calcidiol levels had no effect on the length of hospitalisation or mortality.
The authors concluded that while a single oral bolus of vitamin D did not improve overall outcomes for those hospitalised with COVID-19, higher baseline calcidiol levels did appear to have better outcomes.
Citation
Cannata‐Andía JB et al. A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D—a randomised multicentre international clinical trial BMC Med 20222
7th February 2022
Vitamin D-deficient individuals have been shown to be much more likely to experience severe COVID-19 and die in comparison to those with normal or sufficient levels of the vitamin. This was an important finding by researchers from the Department of Otolaryngology, Head and Neck Surgery, Galilee Medical Center, Israel.
Previous research has shown how vitamin D has a protective effect against respiratory tract infections when taken as a once daily dosage. Moreover, a 2021 systematic review which included 46 randomised controlled trials with 48,488 individuals, re-affirmed the benefits of daily supplementation with 400 –1000 IU of vitamin D for reducing the risk of acute respiratory tract infections compared with placebo.
Several studies undertaken during the COVID-19 pandemic have suggested that a vitamin D deficient status was associated with increased COVID-19 risk.
Furthermore, other data has shown how the vitamin D level is markedly low in severe COVID-19 patients although this was measured once in hospital. However, what is less clear, is the extent to which pre-infection or baseline vitamin D levels, impact on the clinical outcomes once patients become infected with COVID-19.
For the present study, the Israeli team set out to determine whether COVID-19 disease severity correlated with patient’s most recent vitamin D levels as documented in their medical records. They undertook a retrospective study of hospitalised, adult patients with a PCR-confirmed COVID-19 infection.
The team defined COVID-19 disease severity at the point of highest severity. For instance, if a patient was admitted with mild disease and which subsequently deteriorated, this would be categorised as a critical illness.
They used the most recent medical record for vitamin D status and then categorised patients as vitamin D deficient (< 20 ng/ml), insufficient (20 – 29.9 ng/ml), adequate (30 – 39.9 ng/ml) and high-normal (40 ng/ml). They used multivariable analysis to examine the relationship between vitamin D status and COVID-19 disease severity.
Vitamin D deficient status and COVID-19 severity
A total of 253 individuals with a mean age of 63.3 years (56.9% female) were included in the analysis. Among the cohort, 52.5% were vitamin D-deficient, 14.2% had levels between 20 and 30ng/ml and 15.8% had a level of 40ng/ml or above.
Mortality from COVID-19 occurred in 2.3% of those with adequate vitamin D levels and 25.6% of individuals who were vitamin D deficient (p < 0.001). When stratifying COVID-19 disease severity with vitamin D status, among those with the lowest vitamin D levels, a higher proportion (87.4%) developed severe or critical COVID-19 compared to mild to moderate disease, 34.3% (p < 0.001).
In regression analysis, patients with vitamin D deficiency compared to those with high-normal levels (40 ng/ml) were 14 times more likely to develop severe or critical illness (odds ratio, OR = 14, 95% CI 4 – 51, p < 0.001). Overall, when comparing pre-hospital vitamin D levels with COVID-19 disease severity, there was a clear inverse relationship such that as vitamin D levels reduced, COVID-19 disease severity increased.
Further analysis revealed that age was an independent risk factor for more severe disease and the strongest correlation between vitamin D status and COVID-19 severity occurred in those aged 50 years and over (r = – 0.74, p < 0.001). However, this correlation was still significant among those under 50 years of age (r = -0.66, p < 0.001).
The authors described how early on in the current pandemic, there was much debate on the role of vitamin D in protecting against COVID-19. They suggested that their study provided further evidence of how vitamin D deficient patients were at a much higher risk of more severe COVID-19 infection and called for further studies to investigate if and when vitamin D supplementing in those who are deficient, impacts on COVID-19-related outcomes.
Citation
Dror AA et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness PloS One 2022
2nd February 2022
Vitamin D and omega-3 fatty acids taken by adults over a 5-year period led to a 22% reduction in the incidence of autoimmune disease compared to placebo. This was the conclusion of a randomised trial by researchers from the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.
An autoimmune disease develops due to an immune-mediated attack on the body’s own organs although the underlying pathology for most conditions remains uncertain. Moreover, an estimated 4% of the global population is affected by one of the 80 different autoimmune disease which include conditions such as type 1 diabetes, rheumatoid arthritis, lupus, Crohn’s disease and scleroderma. Although epidemiological evidence indicates a potential preventative role for vitamin D in autoimmune diseases, prospective data are lacking. In addition, a Danish cohort study found that each additional 30g intake of fatty fish containing omega-3 oils was associated with 49% reduction in the risk of rheumatoid arthritis.
However, little is known about the potential synergistic effect of vitamin D and omega-3 fatty acids on the development of an autoimmune disease and this was the purpose of the present study by the US team. They undertook a randomised, placebo-controlled trial, VITAL, which was designed to investigate whether taking daily supplements of vitamin D3 (2000 IU) or omega-3 fatty acids reduced the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. However, for the present analysis, the team focused on the development of the autoimmune diseases such as rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease and psoriasis. For the trial, participants were randomised to vitamin D or matching placebo and omega-3 fatty acids or matched placebo and self-reported all incidence autoimmune diseases which were confirmed by a review of their medical records. The primary outcome of interest was the incidence of all autoimmune diseases.
Vitamin D and omega-3 fatty acids and autoimmune diseases
A total of 25,871 individuals with a mean age of 67.1 years (50.6% female) were enrolled and followed for a median of 5.3 years. In the vitamin D arm, 123 individuals and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio, HR = 0.78, 95% CI 0.61 – 0.99, p = 0.05). In the separate omega-3 fatty acids arm, 130 compared with 148 in the placebo group developed an autoimmune disease although this difference was non-significant (HR = 0.85, 95% CI 0.67 – 1.08, p = 0.19).
Using a Cox model adjusted for age, sex and race, the authors found that among those randomised to both vitamin D and omega-3, the incidence of confirmed autoimmune disease was lower (HR = 0.69, 95% CI 0.49 – 0.96) compared with placebo.
They concluded that vitamin D supplements with or without omega-3 fatty acids reduced the development of autoimmune diseases.
Citation
Hahn J et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial BMJ 2022
3rd August 2021
Colorectal cancer is the third most common cancer worldwide, accounting for an estimated 1.8 million new cases and over 880,000 deaths in 2018. However, the incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer in those under 50 years of age, is increasing by approximately 7.9% per year among those aged 20 – 29 years. Moreover, EOCRC is more often diagnosed at an advanced stage. While the reasons for this are uncertain, it could be linked to sedentary behaviour or obesity. A further compounding factor, is the delay in seeking advice with one study in 1089 patients with EOCRC, reporting that nearly two-thirds of patients waited 3 – 12 months before seeking medical advice, with many indicating that they were initially misdiagnosed.
One potential protective factor against colorectal cancer is vitamin D and there is evidence of a strong inverse relationship between vitamin D levels and the risk of colorectal cancer. Nevertheless, whether reduced plasma levels of vitamin D are also associated with the development of early-onset colorectal cancer is uncertain. In trying to ascertain the relationship between these two factors, a team from the Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, US, turned to the Nurses’ Health Study II which is a prospective cohort study of 116,429 female nurses aged between 25 and 42 years and which began in 1989. Study participants are followed every 2 years by self-administered questionnaires which captures information on demographics, lifestyle factors, the presence of co-morbidities etc and a food frequency questionnaire, every 4 years. For the present study, the researchers set the primary end point as the development of EOCRC, identified from medical records. In addition, the researchers collected data on the presence of adenomas and serrated polyps, which are pre-cancerous lesions. The plasma vitamin D levels were estimated based on factors such as dietary intake, age, race etc using a previously defined model.
Findings
A total of 94,205 women were included in the analysis and there were 111 documented cases of early-onset colorectal cancer detected between 1991 and 2015. The median vitamin D intake was 372 IU/day and vitamin D levels > 450 IU/day were associated with a reduced risk of developing EOCRC compared to intakes < 300 IU/day (hazard ratio, HR = 0.49, 95% CI 0.26–0.93). The HR per 400 IU/day increases was 0.46 (95% CI 0.26–0.83). Interestingly, the researchers also found that the HR for dietary vitamin D intake had a stronger inverse association with the development of EOCRC per 400 IU/day increase than among supplement users (0.34 vs 0.77, dietary vs supplements). There were 1439 newly diagnosed adenomas and 1878 serrated polyps in those aged less than 50 years and again, higher vitamin D intake was associated with a lower risk of developing either lesion.
The authors concluded that given the association between higher vitamin D intake and early-onset colorectal cancer, strategies to ensure adequate intake of the vitamin could serve as an important preventative measure in younger adults.
Citation
Kim H et al. Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors. Gastroenterology. 2021
29th September 2020
Although in a recent review, NICE concluded that there was no evidence to support either a preventative or treatment role for vitamin D, new evidence from an analysis of a large patient cohort, suggests an inverse relationship between levels and positive COVID-19 status, implying that the vitamin has a protective role.
A team of US researchers retrospectively analysed a large, anonymous patient data set 50 US states and the District of Columbia between March and June 2020, for whom 25-hydroxyvitamin D (25(OH)D) levels were recorded in the previous 12 months. They limited their analysis to one COVID-19 test result per patient and included all available demographics including ethnicity and categorised 25(OH)D status as either low (<20ng/ml), adequate (30-34ng/ml) or higher ( >60ng/ml).
Findings
In total, 191,779 patients were included with a mean age was 54 years (68% female) and overall the COVID-19 positivity rate was 9.3%. When examining the relationship between 25(OH)D levels and COVID-19 positivity, the rate was highest among those with a low vitamin D status (12.5%) and decreased as it improved, being 8.1% for those with adequate levels and 5.9% among those with the highest levels.
In terms of ethnicity, COVID-19 positive rates were highest in black individuals (15.7%) compared to Hispanics (12.8%) and lowest in white, non-Hispanics (7.2%, p< 0.001 for both comparisons). Furthermore, the difference in positivity rates between ethnic groups was reflected in mean 25(OH)D levels, which were 33.0 vs 29.1 vs 28.8 ng/ml for white, blacks and Hispanic individuals (p< 0.001) respectively. In regression analysis, there was a strong association between vitamin D levels and lower COVID-19 after adjustment for all demographic factors (adjusted odds ratio = 0.98 per ng/ml increment).
The authors concluded that their findings provide a further rationale to explore the role of vitamin D supplementation to reduce the risk of COVID-19 infection.
Reference
Kaufman HW et al. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS ONE 15(9): e0239252. https://doi.org/ 10.1371/journal.pone.0239252
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