Why has there been growing interest in the potential role of vitamin D in asthma management?
In the past vitamin D was just thought to be important in regulating calcium homeostasis and bone health as vitamin D deficiency is best known for causing rickets in children and osteomalacia in adults.
Then, in the 1980s it was first found that the vitamin D receptor is expressed not just in bone, but in a whole range of other tissues, 35 to date and, in particular, white blood cells and respiratory epithelium. This raised the possibility that vitamin D could modulate immune function as well as bone mineralization.
A series of map studies then followed to characterize how vitamin D modulates immune function. In particular, two functions were highlighted. First, was the ability of vitamin D to induce immunity to respiratory virus infection.
The second was the ability of vitamin D to suppress inflammatory responses, particularly by induction of the regulatory cytokine interleukin 10.
On top of that, observational, epidemiological literature then started emerging that linked lower vitamin D status to poor asthma control, both in children and in adults. These associations were found to be independent when adjusted for confounders.
They were found to operate in a very diverse range of settings and ages and so a compelling hypothesis emerged that vitamin D could have a role in protecting against asthma exacerbation.
How much evidence is there that low blood levels of vitamin D could be linked to an increased risk of asthma attacks?
There's extensive evidence from observational studies that there are associations which are independent when adjusted for potential confounders, but the evidence that comes from this Cochrane review is all from double-blind, placebo controlled, randomized trials.
We identified nine such studies that have been conducted to date. This Cochrane review focuses on the results of those nine trials.
Can you tell us a little bit more about the Cochrane Collaboration and the studies you looked at in this review?
The Cochrane Collaboration is an international, independent network of researchers, health professionals, patients and carers who are involved in identifying and summarizing the best available evidence to guide patients and doctors on evidence-based treatments for disease.
They have a very rigorous approach whereby a very strict set of standards is used to identify the most robust and methodologically sound studies and then standard statistical tests and assessments of quality of evidence are applied to get an overall readout of whether an intervention is effective for a given condition or not.
We searched through 81 studies to identify the nine that were of the highest quality. By high quality, I mean that they were all double-blind, placebo controlled, randomized trials.
Double-blind means that neither the participants nor the people conducting the trial were aware of whether the participants were taking vitamin D or placebo during the study. The reason this is important is that it minimizes the risk of generating biased results.
By randomizing patients to receive one or the other, we end up with two groups of patients who are, as far as we know, similar to each other in every respect except that one gets vitamin D and one gets placebo.
Therefore, when we see a difference between them, we can confidently say that the difference is going to be due to the treatment they received, as opposed to any potential confounder.
We extracted data from these trials on a primary outcome, which was severe asthma exacerbation. We define that as worsening of asthma symptoms that become severe enough to either require treatment with oral corticosteroids, and/or precipitate attendance at an emergency department, and/or precipitate hospital admission. That's a pretty standard definition of a severe asthma exacerbation.
We also looked at a range of other outcomes relating to asthma control, in particular a test called the asthma control test which is a very well validated questionnaire that evaluates people's symptom control day-to-day in asthma. We also looked at other outcomes such as lung function, exhaled nitric oxide and other biomarkers of airway inflammation.
What were your main findings?
The headline finding was that we found vitamin D had significant protective effects against asthma exacerbations severe enough to precipitate emergency department attendance or hospitalization. There was about a 50% reduction.
Vitamin D also reduced the rate of asthma exacerbations that were severe enough to require treatment with oral steroids. That analysis was actually based on just three of the nine trials that were included in the review because the other six trials either didn't report that outcome or no patient experienced that outcome in either arm of the trial.
This reflects the fact that those other trials tended to enroll patients with milder disease, so the finding relating to exacerbations requiring oral steroid treatment was restricted to these three trials that included patients with more severe disease and even they included quite a lot of patients with mild-to-moderate disease as well.
The hospitalization finding was related to a broader range of the trials, in fact seven of the trials, so that's more generalizable. The interesting thing was that, although we saw a protective effect of vitamin D on the asthma attack outcome, we didn't see significant effects on the other outcomes we looked at such as day-to-day symptom control, lung function or other biomarkers of airway inflammation.
Were your surprised by the results?
We were quite surprised actually because we, ourselves, conducted one of the larger trials to be included in this review. When we analyzed it on its own, although it showed a trend towards protection against exacerbation, this wasn't statistically significant. Similarly, other trials published in the area individually have tended not to show protective effects, certainly not in adults.
What the review really brought to the table was increased statistical power. By pooling trials that individually hadn't yielded a statistically significant effect but had all actually shown a trend toward protection, we were able to show an effect that was both statistically and clinically significant.
What potential mechanisms could explain the findings?
First, we think vitamin D may be working by boosting innate immune responses to viral respiratory pathogens such as rhinovirus, which we know are common precipitants of asthma exacerbations. So it may be that vitamin D is upper respiratory infections such as colds and flu, which would otherwise trigger exacerbations.
The second potential mechanism (and these mechanisms are not mutually exclusive; there could be a complementary mode of action) is that vitamin D may be inducing anti-inflammatory responses.
For example, it may be inducing secretion of interleukin 10 and other regulatory cytokines, which can also serve to dampen down symptoms of asthma because a lot of exacerbation symptoms relate to uncontrolled airway inflammation. If you can put a brake on that, then you can attenuate, terminate or prevent an exacerbation.
These observations are really based on lab work that suggests these mechanisms and also on other trials of vitamin D to prevent upper respiratory infection that haven't necessarily been done in asthmatics.
What further research is needed to improve our understanding of the role of vitamin D in asthma?
Although this finding is exciting, it doesn't actually take us quite yet to a point where we can make a clinical recommendation and include it in guidelines.
This is because we did what's called aggregate data analysis; that is, we used summary statistics from individual papers to reach our conclusion. We weren't able to test whether vitamin D helped everybody or whether it just helped people who started off with low vitamin D levels.
We suspect, from a biological perspective, a priori, that vitamin D might be more likely to be beneficial if you happen to be vitamin D deficient, but we weren't able to test that hypothesis because we didn't have access to individual patient data.
Now, we've contacted all the principal investigators of the trials. We've formed a consortium and they're now contributing individual patient data on a collaborative basis; that's raw data that we're putting together and pooling in a single database.
That gives us a series of rows of data, with each row representing a single patient. We can then do sub-group analyses to see whether there is a threshold vitamin D level below which patients benefit from vitamin D, and above which they don’t.
We anticipate that, by doing this exercise, we'll be able to establish if there is a vitamin D threshold below which supplementation confers benefit or not. Once we've got to that point, I think we will be in a position to make a more concrete clinical recommendation.
Another point is that only about half of asthma sufferers actually experience severe exacerbations of the sort that we're reporting on. Our review doesn't suggest that vitamin D will benefit the group who doesn't suffer these exacerbations.
For example, we haven't found an effect on day-to-day symptoms or lung function or any of the rest of that. Our review suggests that the non-exacerbator population may not get much benefit from vitamin D; the benefit seems to be restricted to the people who get these attacks.
Finally, I’d like to emphasize that these trials investigated the effect of vitamin D when it was given in addition to standard asthma treatment. We are certainly not advocating that vitamin D be a replacement for that treatment and nobody should stop taking their asthma medication and replace it with vitamin D. This is an adjunctive therapy, an add-on.
The bottom line is that this is an exciting finding. We're not quite in a position yet where we can make a strong clinical recommendation. It's unlikely that vitamin D is going to benefit everyone, but it might have very significant potential benefits for deficient people and we're trying to answer that question at the moment.
Where can readers find more information?
The full paper can be found at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011511.pub2/full
For more information on the Cochrane Collaboration, please visit their website: http://uk.cochrane.org/
About Professor Adrian Martineau
Adrian Martineau is Professor of Respiratory Infection and Immunity at Barts and the London School of Medicine and Dentistry, Queen Mary University of London (http://www.blizard.qmul.ac.uk/staff/51-centre-for-primary-care-and-public-health/333-martineau-adrian.html).
He is a respiratory physician with a research interest in the effects of vitamin D on human health. His work combines laboratory investigation of the effects of vitamin D on the immune system with a series of multi-centre clinical trials conducted in the UK, South Africa and Mongolia, investigating the potential for vitamin D supplementation to prevent and treat tuberculosis, acute respiratory infections and exacerbations of asthma and chronic obstructive pulmonary disease (COPD).
Adrian’s work is funded by the MRC, the NIHR, the Wellcome Trust and the US National Institutes of Health among others. He is a member of the NICE Public Health Advisory Committee on implementation of measures to eliminate profound vitamin D deficiency in the UK population.
He is Principal Investigator for the MRC-funded ViDiKids Study, a n=5,400 randomised controlled trial of vitamin D supplementation to prevent tuberculosis in Cape Town primary schoolchildren (https://clinicaltrials.gov/ct2/show/NCT02880982).