CME Author: Zeena Nackerdien
Study Authors: David A. Joliffe, Lauren Greenberg et al.
Target Audience and Goal Statement: Pulmonologists, primary care physicians, and family physicians
The goal was to determine whether vitamin D supplementation can reduce the overall rate of exacerbation of chronic obstructive pulmonary disease (COPD), and if so, to explore whether the effects of the intervention varies according to various factors, including baseline vitamin D status.
Background and Questions Addressed:
- Does vitamin D supplementation protect against moderate/severe COPD exacerbations in particular subgroups of patients?
- Do the effects of this intervention vary according to potential effect modifiers, including baseline vitamin D status?
Study Synopsis and Perspective:
COPD – a complex lung disease encompassing bronchitis and emphysema – affects more than 170 million people worldwide (2015 estimates) and is projected to become the third leading cause of global deaths in 2020, according to the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report. Mortality is usually attributed to disease exacerbations — i.e., episodes of acute worsening.
Such episodes are generally classified as follows:
- Mild (treated with short-acting bronchodilators [SABD] only)
- Moderate (treated with SABD and oral corticosteroids)
- Severe (may be linked to acute respiratory failure; patients visit the emergency room or require hospitalization)
Exacerbations of COPD are commonly triggered by bacterial or respiratory viral infections, which, in turn, can increase airway inflammation. Vitamin D metabolites are known to induce antiviral and antimicrobial effector mechanisms and attenuate inflammatory responses.
The Institute of Medicine has stated that 50 nmol/L is the serum level of the major vitamin D metabolite 25-hydroxyvitamin D (25[OH]D) that covers the needs of 97.5% of the population. Vitamin D deficiency is common in patients with COPD, but consistent associations between circulating concentrations of 25(OH)D and the risk of COPD exacerbations await clarification.
For the current study, Adrian Martineau, PhD, of Queen Mary University of London, and colleagues pooled individual participant data (IPD) from 469 of 472 (99.4%) eligible participants who were enrolled in three trials in Belgium (n=182), the U.K. (n=240), and the Netherlands (n=47). Trials in which vitamin D3 or vitamin D2 were administered in combination with other micronutrients were excluded.
The patients included in the meta-analysis were mostly white (97%), older (age range: 40-86), and male (67%), and had baseline serum 25(OH)D concentrations ranging from undetectable to 160 nmol/L. The Dutch study enrolled only patients with moderate to very severe COPD and a history of recent exacerbations (38.6%). Inclusion of this data likely drove the overall high rates of moderate/severe exacerbations reported in the meta-analysis, Martineau and co-authors noted.
Investigators of the three separate randomized controlled trials (RCTs) administered oral vitamin D3 in the respective intervention arms. Schedules and doses varied from 220,000 IU in 6 months to 1.2 million IU per year.
The primary outcome was the rate of COPD exacerbations requiring treatment with systemic corticosteroids or antibiotics, or both — i.e., those classified by the GOLD report as moderate, severe, or both.
Secondary outcomes were as follows:
- Time from the first dose of the study medication to the first moderate or severe exacerbation
- Proportion of participants with at least one moderate or severe exacerbation
- Proportion of COPD exacerbations resulting in emergency department attendance or hospitalization, or both
- Proportion of participants experiencing at least one serious adverse event (AE), episode of hypercalcemia, or episode of renal stones
- Mean percent predicted forced expiratory volume in one second and forced vital capacity at final follow-up
- Mean body mass index at final follow-up
- Mortality (both COPD-related and all-cause)
The researchers found that vitamin D supplementation:
- Nearly halved moderate/severe COPD exacerbation rates among patients who were deficient in vitamin D (baseline 25[OH]D <25 nmol/L: adjusted incident rate ratio [aIRR] 0.55, 95% CI 0.36-0.84)
- Did not affect patients with baseline 25[OH]D levels ≥25 nmol/L (aIRR 1.04, 95% CI 0.85-1.27)
- Did not influence the overall rate of moderate/severe COPD exacerbations (aIRR 0.94, 95% CI 0.78-1.13)
- Did not influence the proportion of patients experiencing at least one serious AE, suggesting that supplementation was safe (adjusted odds ratio [OR] 1.16, 95% CI 0.76- 1.75); no other secondary outcomes were influenced by the intervention
A study limitation cited by the researchers was the small number of RCTs examining vitamin D supplementation in COPD available for inclusion — i.e., too few trials to justify construction of a funnel plot to assess publication bias.
Source Reference: Thorax, online Jan. 10, 2019; DOI: 10.1136/thoraxjnl-2018-212092
Study Highlights: Explanation of Findings
Overall, vitamin D supplementation did not have an effect on the rates of moderate or severe COPD exacerbations. This finding in keeping with a statement from the GOLD 2019 report that “there is no evidence that supplementation with vitamin D has a positive impact on exacerbations in unselected patients.” However, significant protective effects of this intervention were seen among patients with baseline 25(OH)D concentrations <25 nmol/L.
Results from this prespecified subgroup analysis matched that of a 2017 meta-analysis by the same researchers, which examined vitamin D trials for preventing asthma exacerbations. In another prior study, the authors also reported on the protective effects of vitamin D supplementations against respiratory infection in those with baseline 25(OH)D<25 nmol/L.
“Since acute respiratory infections commonly precipitate exacerbations of both asthma and COPD, it may be that protective effects of vitamin D against these outcomes are mediated by a common mechanism — namely, induction of antiviral and antimicrobial responses,” the researchers wrote.
A strength of the meta-analysis, they said, was the inclusion of three eligible studies, all of which were assessed to be at low risk for bias. In addition, because the study included patients with varying disease severities from three different countries, it enhanced the generalizability of the results.
Key outcomes from the meta-analysis are in accordance with some, but not all, literature findings, the team noted. For example, the lack of a link between vitamin D deficiency and a higher exacerbation risk in some observational studies may be due to the low prevalence of participants with baseline 25(OH)D levels <25 nmol/L. Moreover, low vitamin D levels may largely drive exacerbation risk in the vitamin D-deficient COPD patient subgroup, while other factors (e.g., inherently increased viral susceptibility, or exposure to an as-yet uncharacterized environmental factor) may be the primary drivers of exacerbation risk in patients with higher baseline vitamin D levels.
“New treatments are urgently needed to prevent COPD attacks,” Martineau said in a news release. “Our study shows that giving supplements to vitamin D-deficient COPD patients nearly halves their rate of potentially fatal attacks. Vitamin D supplementation is safe, and it costs just a few pence to supplement a person for a year, so this is a potentially highly cost-effective treatment that could be targeted at those who have low vitamin D levels following routine testing.”
He added that a Dutch multicenter RCT focused only on COPD patients (n=240) with low vitamin D levels (25[OH]D <50 nmol/L) is scheduled to complete follow-up in 2019.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco