COVID-19: A high intake of vitamins A – E – D is linked to fewer respiratory disorders in adults

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High vitamin A, E, and D intake may be linked to fewer respiratory complaints in adults, suggests an analysis of nationally representative long term survey data, published online in the journal BMJ Nutrition Prevention & Health.

The findings warrant further study among different ethnic groups and geographies in view of the current coronavirus pandemic, suggest the researchers.

Nutrition has a key role in cutting the risk of several infections, although exactly how it boosts immunity is complex and not fully understood. Vitamins A, E, C and D have already been deemed to aid the normal functioning of the immune system in the European Union, and the American Nutrition Association suggests these vitamins may also help stave off respiratory infections.

The researchers wanted to explore whether the intake of these vitamins from both diet and supplements might be linked to the prevalence of respiratory complaints in a nationally representative sample of UK adults.

They drew on information provided by 6115 adult participants in the 2008-2016 National Diet and Nutrition Survey Rolling Programme (NDNS RP) who had completed three or more days of diet diaries.

The NDNS RP is a rolling survey that collects information annually on all food and drink consumed from around 1000 randomly selected people living in private households across the UK.

Respiratory complaints were reported by the participants and had not been diagnosed by a clinician. They were broadly defined, and included both infectious and non-infectious conditions, such as colds, chronic obstructive pulmonary disease, and asthma.

The researchers looked at dietary intake only (continuous exposure) and that from diet and supplements (binary exposure), accounting for potentially influential factors, such as age, sex, weight (BMI), smoking, household income and total energy intake.

In all, there were 33 cases of respiratory complaints. These respondents were generally older and less likely to say they regularly took vitamins A, E, C or D supplements.

There was no obvious association between BMI and vitamin intake, or between BMI and respiratory complaints. And it wasn’t possible to determine any associations with vitamin C supplements as none of the adults with respiratory complaints said they took them.

But vitamin A and E intake from both diet and supplements was associated with a lower prevalence of respiratory complaints in UK adults.

Major dietary sources of vitamin A include liver, whole milk, and cheese, as well as carrots, dark green leafy vegetables, and orange-coloured fruits. Major dietary sources of vitamin E include vegetable oils, nuts, and seeds.

And vitamin D intake from supplements, but not from diet, was associated with fewer respiratory complaints, prompting the researchers to suggest that the findings add to the current scientific debate on the value of vitamin D supplementation.

“It is estimated that around a fifth of the general population in the UK have low vitamin D, and over 30% of older adults aged 65 years and above do not achieve the recommended nutrient intake,” they write.

“Our findings are consistent with the hypothesis that supplementation is critical to ensuring adequate vitamin D status is maintained and potentially indicate that intake of vitamin D from diet alone cannot help maintain adequate vitamin D status.”

This is an observational study, and as such, can’t establish cause, added to which the number of respiratory complaints was small, meaning that no inferences can be made in respect of the coronavirus pandemic, caution the researchers.

“Further research is required to assess the implications of the current study in the context of the current coronavirus disease 2019 pandemic using data from longitudinal cohorts,” they suggest.

“Our study also highlights the need for further data collection on nutrition and respiratory disorders to cover wider geographical areas and high-risk groups, including a focus on other ethnicities,” they add.

Shane McAuliffe, Science Communications Lead for the NNEdPro Nutrition & COVID-19 Taskforce, said: “While acknowledging the limitations of this data, it does add further to a growing body of interest and evidence for the role of vitamin D in respiratory health.

“Given our knowledge of the extent of vitamin D deficiency in the population, balanced with the low cost and low risk of adverse events, it seems sensible to provide supplementation of this key vitamin, particularly to those most likely to be deficient.”

Professor Sumantra Ray, Executive Director of the NNEdPro Global Centre for Nutrition & Health in Cambridge and Visiting Professor of Public Health at Imperial College London, added: ‘Nationally representative data continue to remind us that micronutrient deficiencies are far from a thing of the past, even in higher income nations like the UK, and this trend is mirrored by comparable global data sources from lesser resourced countries to those with advanced health systems.

“Despite this, micronutrient deficiencies are often overlooked as a key contributor to the burden of malnutrition and poor health, presenting an additional layer of challenge during the COVID-19 pandemic.”


Since December 2019, the COVID-19 caused by SARS-CoV-2 is spreading worldwide from China, affecting millions of people and leaving thousands of dead, mostly in older adults. With the lack of effective therapy, chemoprevention and vaccination [1], focusing on the immediate repurposing of existing drugs gives hope of curbing the pandemic.

Importantly, a most recent genomics-guided tracing of the SARS-CoV-2 targets in human cells identified vitamin D among the three top-scoring molecules manifesting potential infection mitigation patterns through their effects on gene expression [2].

In particular, by activating or repressing several genes in the promoter region of which it binds to the vitamin D response element [3], vitamin D may theoretically prevent or improve COVID-19 adverse outcomes by regulating

  • (i) the renin-angiotensin system (RAS),
  • (ii) the innate and adaptive cellular immunity,
  • (iii) the physical barriers [4].

Consistently, epidemiology shows that hypovitaminosis D is more common from October to March at northern latitudes above 20 degrees [3], which corresponds precisely to the latitudes with the highest lethality rates of COVID-19 during the first months of winter 2020 [1].

In line with this, significant inverse associations were found in 20 European countries between serum 25-hydroxyvitamin D (25(OH)D) concentration and the number of COVID-19 cases, as well as with COVID-19 mortality [5].

This suggests that increasing serum 25(OH)D concentration may improve the prognosis of COVID-19. However, no randomized controlled trial (RCT) has tested the effect of vitamin D supplements on COVID-19 outcomes yet.

We had the opportunity to examine the association between the use of vitamin D3 supplements and COVID-19 mortality in a sample of frail elderly nursing-home residents infected with SARS-CoV-2.

The main objective of this quasi-experimental study was to determine whether bolus vitamin D3 supplementation taken during or just before COVID-19 was effective in improving survival among frail elderly COVID-19 patients living in nursing-home.

The secondary objective was to determine whether this intervention was effective in limiting the clinical severity of the infection.

DISCUSSION

The main finding of this nursing-home-based quasi-experimental study is that, irrespective of all measured potential confounders, bolus vitamin D3 supplementation during or just before COVID-19 was associated with less severe COVID-19 and better survival rate in frail elderly. No other treatment showed protective effect.

This novel finding provides a scientific basis for vitamin D replacement trials attempting to improve COVID-19 prognosis.

To our knowledge we provide here the first quasi-experimental data examining the effect of vitamin D supplementation on the survival rate of COVID-19 patients. To date, only rare observational data, all of which are consistent, are available on the link between vitamin D and COVID-19.

The first reports in COVID-19 patients indicated that hypovitaminosis D is highly prevalent in this population, reaching 85% [13], and that serum 25(OH)D concentrations are lower in COVID-19 patients compared to controls [14]. Similarly, significant inverse correlations were found in 20 European countries between the mean serum 25(OH)D concentrations and the number of COVID-19 cases/1 M, as well as with mortality/1 M [5].

The severity of hypovitaminosis D appears to relate to the prognosis of COVID-19 since the mortality rate was multiplied by 7.6 among people with hypovitaminosis D <75 nmol/L, and by 10.1 among those with hypovitaminosis D <50 nmol/L (P < 0.001) [15].

Similarly, another observational study in 212 COVID-19 cases showed that, for each standard deviation increase in serum 25(OH)D, the probability of mild rather than severe COVID-19 was multiplied by 7.9 (P < 0.001), while the probability of mild rather than critical COVID-19 was multiplied by 19.6 (P < 0.001) [16].

These results suggest that increasing serum 25(OH)D concentration may improve the prognosis of COVID-19. Interventional studies dedicated to COVID-19 are yet warranted for investigating the role of vitamin D supplementation on COVID-19 outcomes.

Interestingly, previous meta-analyses found that high-dose prophylactic vitamin D supplementation was able to reduce the risk of respiratory tract infections [17]. Based on this observation, we and others are conducting an RCT designed to test the effect of high-dose versus standard-dose vitamin D3 on 14-day mortality in COVID-19 older patients (https://clinicaltrials.gov/ct2/show/NCT04344041).

While waiting for the recruitment of this RCT to be completed, the findings of the present quasi-experimental study strongly suggest a benefit of bolus vitamin D3 supplementation on COVID-19 outcomes and survival.

How vitamin D supplementation may improve COVID-19 outcomes and survival is not fully elucidated.

Three mechanisms are possible: regulation of

  • (i) the RAS,
  • (ii) the innate and adaptive cellular immunity, and
  • (iii) the physical barriers [4].

First, vitamin D reduces pulmonary permeability in animal models of acute respiratory distress syndrome (ARDS) by modulating the activity of RAS and the expression of the angiotensin-2 converting enzyme (ACE2) [18]. This action is crucial since SARS-CoV-2 reportedly uses ACE2 as a receptor to infect host cells [19] and downregulates ACE2 expression [20].

ACE2 is expressed in many organs, including the endothelium and the pulmonary alveolar epithelial cells, where it has protective effects against inflammation [21]. During COVID-19, downregulation of ACE2 results in an inflammatory chain reaction, the cytokine storm, complicated by ARDS [22].

In contrast, a study in rats with chemically-induced ARDS showed that the administration of vitamin D increased the levels of ACE2 mRNA and proteins [23]. Rats supplemented with vitamin D had milder ARDS symptoms and moderate lung damage compared to controls.

Second, many studies have described the antiviral effects of vitamin D, which works either by induction of antimicrobial peptides with direct antiviral activity against enveloped and non-enveloped viruses, or by immunomodulatory and anti-inflammatory effects [24].

These are potentially important during COVID-19 to limit the cytokine storm. Vitamin D can prevent ARDS [25] by reducing the production of pro-inflammatory Th1 cytokines, such as TNFα and interferon γ [24]. It also increases the expression of anti-inflammatory cytokines by macrophages [24]. Third, vitamin D stabilizes physical barriers [4].

These barriers are made up of closely linked cells to prevent outside agents (such as viruses) from reaching tissues susceptible to viral infection. Although viruses alter the integrity of the cell junction, vitamin D contributes to the maintenance of functional tight junctions via E-cadherin [4]. All these antiviral effects could potentiate each other and explain our results.

We also found that none of the other dedicated drugs used in this quasi-experimental study was associated with better survival rate in COVID-19 patients. The interest of these drugs in COVID-19 is still debated, whether for corticosteroids [26], hydroxychloroquine [27] or azithromycin [28].

However, it should be noted that these drugs were given here as part of patient care in the most severe clinical situations, which could have biased and masked their effectiveness (if any).

The strengths of the present study include i) the originality of the research question on an emerging infection for which there is no scientifically validated treatment, ii) the detailed description of the participants’ characteristics allowing the use of multivariate models to measure adjusted associations, and iii) the standardized collection of data from a single research center.

Regardless, a number of limitations also existed. First, the study cohort was restricted to a limited number of nursing-home residents who might be unrepresentative of all older adults. Second, although we were able to control for the important characteristics that could modify the association, residual potential confounders might still be present such as the serum concentration of 25(OH)D at baseline – a low level classically ensuring the effectiveness of the supplementation [29].

As this analysis was not initially planned, no concerted efforts were made to systematically measure the serum 25(OH)D concentration before and after supplementation.

Third, the quasi-experimental design of our study is less robust than an RCT. Participants in the Comparator group did not receive vitamin D placebo, and there was no randomization. It should yet be noted that the characteristics of the two groups did not differ at baseline, which allows interpreting the survival difference as linked to the vitamin D3 supplementation.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553119/


Vitamins modulating immune system during COVID-19

The activity of the immune system is affected by the elements present in the microenvironment, among which nutrient and more specifically vitamins play outstanding roles. Vitamin A and D influence the immune system directly [159].

Vitamin D (1,25(OH)2VD3) exerts its immunomodulatory effects by inhibiting T cell proliferation [160], expression of IL-2 [161], and IFN-γ [161]. 1,25

(OH)2VD3 directs differentiation of Th cells toward the Th2 responses by inducing of IL-4 production [162] and blocking differentiation to Th1 responses by suppressing the IL-12 production [163]. Given the downregulatory effects on IL-6 and IL-23, 1,25(OH)2VD3 inhibits the differentiation of naïve T cells to Th17 cells.

Vitamin D also raises the production of IL-10 along with downregulation of IL-12 synthesis, leading to deviation of Th1 response to IL-10-producing Treg cells [162].

In addition to its modulatory effects on T cells, 1,25(OH)2VD3 also downregulates B cell proliferation and consequently IgG production by indirect affecting on the immunologic synapse in the antigen presenting cells (APCs)-Th cells interface [160]. Although vitamin D exhibits inhibitory function on adaptive immunity, it has stimulatory effects on the innate immune responses [164].

In contrast to vitamin D, vitamin A (Retinoic acid) promotes cytotoxic capability of the immune system and also T cells expansion that may be beneficial responses in case of COVID-19. It assists signal transduction in T cells and enhances the secretions of IL-2.

The definite effect of retinoic acid on B cells is not clear, however, it presumably inhibits B cells apoptosis [165]. Similar to vitamin D, retinoic acid also aids differentiation of T cells towards Th2 response.

In addition, vitamin A stimulates the production of type I interferon, thereby, exerting antiviral activities [166]. In addition, vitamin A confers a therapeutic potential in autoimmunity by modulating the Th17/Treg balance [167], [168].

Taking together, vitamin A might be beneficial in COVID-19 patients by modulating immune system toward an anti-inflammatory setting during remission phase of the disease and by stimulation of anti-viral state.

Other vitamins including C, E, and B complex have also been reported to be involved in some nonspecific reactions. For instance, vitamin C exhibits antioxidant activity and vitamin E acts as a scavenger or key cellular regulator. There are scattered studies reporting that vitamin C and E perform anti-inflammatory activities. Furthermore, vitamin E has been reported to stimulate the production of type I IFN in the cells [169], [170].

Briefly, vitamins are necessary for the normal function of immune system. Vitamin deficiency in patients with chronic infections, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Human immunodeficiency viruses (HIV) have reported to be associated with a higher viral replication rate and dysregulated cytokine response. Additionally, insufficient levels of serum 25(OH)D has been associated with respiratory disorders and promoted proneness to acute respiratory infections [171], which have been attributed to main death cause in COVID-19 patients.

Therefore, vitamins, particularly vitamin D supplementation may potentially have beneficial effects in soothing the manifestations of respiratory syndrome in COVID-19 patients [172]. However, no direct evidence is currently available on the efficacy of vitamins in COVID-19 patients and anti-viral effects of vitamins on SARS-CoV-2 infection require further investigations.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547582/


More information: Association between vitamin intake and respiratory complaints in adults from the UK National Diet and Nutrition Survey years 1-8, BMJ Nutrition Prevention & HealthDOI: 10.1136/bmjnph-2020-000150

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