From the Authors:
Heulens and colleagues hypothesize that patients with 25-hydroxyvitamin D (25[OH]D) blood levels greater than 40 ng/ml are likely to be vitamin D supplement users. Although this is a well-reasoned hypothesis, vitamin D supplementation data were not collected in our study (1), so we cannot confirm or refute this hypothesis.
In regard to exclusion of supplement users from observational studies, we agree that supplement use has been associated with many other confounders such as engagement in other healthy behaviors, better adherence to medications, and higher educational status (2–4). Such associations tend to overestimate the potential benefits of dietary supplements, and we found no such potential benefit, making health user bias unlikely. Conversely, Heulens and colleagues suggest that vitamin D supplement users in our study may have had more severe chronic obstructive pulmonary disease (COPD) and therefore biased our results toward the null hypothesis. Again, without supplement data, we cannot perform a formal analysis to address this issue of potential confounding by indication. However, the 107 patients with 25(OH)D greater than or equal to 40 ng/ml had a mean FEV1, the most commonly used marker of COPD severity, that was not different from those at lower 25(OH)D levels (Table 1).
TABLE 1.
MEAN FEV1 PERCENT PREDICTED, STRATIFIED BY BASELINE PLASMA 25(OH)D LEVEL IN THE COPD CLINICAL RESEARCH NETWORK AZITHROMYCIN TRIAL
| 25(OH)D Level (ng/ml) | n | Mean FEV1% Predicted (95% Confidence Interval) |
| 0–9.99 | 82 | 38.4 (34.9–42.0) |
| 10–19.99 | 229 | 37.9 (35.8–39.8) |
| 20–29.99 | 322 | 39.9 (38.2–41.6) |
| 30–39.99 | 233 | 41.0 (39.0–43.1) |
| ≥40 | 107 | 40.6 (37.6–43.5) |
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; 25(OH)D = 25-hydroxyvitamin D.
Randomized controlled trials (RCTs) remain the gold standard for evaluating the effects of medical interventions, and the null results of Lehouck and colleagues’ well-designed RCT in 182 patients with COPD suggest no effect of vitamin D supplementation on COPD exacerbation risk (5). Their post hoc subgroup analysis of 30 patients with 25(OH)D levels less than 10 ng/ml and our post hoc observational data are consistent in suggesting a potential effect of vitamin D on exacerbation rate in patients with COPD with severe vitamin D deficiency. However, placebo-controlled RCT confirmation of these hypothesis-generating data is not ethical due to well-documented skeletal health benefits of vitamin D supplementation in patients with such profoundly low 25(OH)D levels (6).
Supplementary Material
Footnotes
Author Contributions: K.M.K. drafted the letter, directed the statistical analyses, and provided approval of the final letter. D.E.N. revised the letter for critical intellectual content and approved the final manuscript. J.E.C. revised the letter for critical intellectual content, performed the statistical analyses, and approved the final manuscript.
Supported by the Minnesota Veterans Medical Research and Education Foundation (to K.M.K.), National Center for Research Resources grant UL1 RR024150 (to the Mayo Clinic), and National Heart, Lung, and Blood Institute grants to COPD Clinical Research Network sites: U10 HL074407 (Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center), U10 HL 074408 (Temple University), U10 HL074409 (Denver Health Medical Center), U10 HL074416 (Minnesota Veterans Research Institute), U10 HL074418 (University of Alabama at Birmingham), U10 HL074422 (University of Michigan), U10 HL074424 (University of Minnesota), U10 HL074428 (Brigham and Women's Hospital), U10 HL074431 (University of California, San Francisco), U10 HL074439 (University of Pittsburgh), and U10 HL074441 (University of Maryland, Baltimore).
Author disclosures are available with the text of this letter at www.atsjournals.org.
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