Vitamin D, lung functions, and chronic obstructive pulmonary disease: Quod non erat demonstrandum.

Sir,

Apropos the article, “Should Vitamin D be routinely checked for all chronic obstructive pulmonary disease (COPD) patients,”[1] we would like to raise certain relevant points.

The population recruited in this study seems to be a “heterogeneous” one as the following questions beg to be answered:

Were COPD patients with exacerbation also included?

Were included patients admitted for respiratory or only nonrespiratory causes?

The exclusion criteria as mentioned by the authors included “hemodynamically unstable patients” but were the patients critically ill? Low 25(OH) Vitamin D is known to be associated with various disease processes apart from COPD, e.g., sepsis[2]

As 82% of COPD cases had neutrophilic leukocytosis, it might imply that patients with active infection were also included in the study?

Were cases and controls on Vitamin D? And if yes for what duration? – as it can potentially confound the results.

Various factors have an influence on lung volume and lung capacities (e.g., forced vital capacity [FVC] =5.048 − 0.014 × age + 0.054 × ht + 0.006 × wt) of which stature and ethnicity are two of the important factors. Studies have shown that tall stature is associated with higher lung volumes than say weight.[3] In this study,[1] body mass index has been matched between cases and controls, but height and ethnicity were not compared between two groups. Without “matching” these factors, e.g., height, weight, etc., the comparison between the two groups (Group I and Group II) might have been inappropriate [Figure 1]

Figure 1

We consider x and y, where x and y are two patients with the same age (20 years), gender, ethnicity, and body mass index (but with different weights and heights); their predicted forced vital capacity using the abovementioned formula is as shown in the figure. Hence, a difference of 153 ml is expected between X and Y even if their body mass index is the same

The difference in forced expiratory volume in 1 s (FEV1) between the first and third quartiles of Vitamin D level in the two groups was 1.08 l or 47% (of FEV1 in the first quartile). In a similar study by Black and Scragg, the mean difference between highest (25-hydroxyvitamin D ≥85.7 nmol/L) and lowest quintile Vitamin D (≤40.4 nmol/L) was 126 ml for FEV1 and 172 ml for FVC.[4] Clearly, the results of the present study are quantitatively different from that of aforementioned study and other studies in literature, and the degree of variation of lung volume is higher by a factor of around 9–10 raising concerns of overestimation of effect of Vitamin D on lung function in the present study.

We conducted a short systematic review using the MEDLINE database using keywords such as “COPD,” “Vitamin D,” and “lung function” including clinical studies to look at the present evidence on the effect of Vitamin D on lung function [Table 1].

Table 1

Brief systematic review of clinical studies on effect of vitamin D in COPD

Study name, Author, place of the study, year	Type of the study, sample size, and methods	Results	Conclusion
Effect of Monthly, High-Dose, Long-Term Vitamin D on Lung Function: A Randomized Controlled Trial, Sluyter JD et al., New Zealand, 2017	Randomized clinical trial  Population (n=442): 50-84 years old patients  Intervention (n=223): Vitamin D3  Comparator (n=216): Placebo  Outcome: FEV1 time: 1.1 years	There were no significant lung function improvements between the two groups	Vitamin D supplementation benefited only smokers, especially with Vitamin D deficiency or asthma or COPD
Effects of daily Vitamin D supplementation on respiratory muscle strength and physical performance in Vitamin D-deficient COPD patients: A pilot trial Rachida Rafiq et al., The Netherlands, 2017	Randomized clinical trial  Participants (n=50): Vitamin D-deficient COPD  patients (age: 40-70 years)  Intervention: Vitamin D3 (n=24)  Comparator: Placebo (n=26)  Time: 6 months  Outcome: Respiratory muscle strength	Primary outcome did not differ between the groups after 6 months	Vitamin D supplementation did not affect (respiratory) muscle strength or physical performance in Vitamin D-deficient COPD patients
Effects of Vitamin D Intake on FEV1 and COPD Exacerbation: A Randomized Clinical Trial Study, Abolfazl Zendede et al., Iran, 2014	Randomized clinical trial  Participants (n=88): Patients with severe and very severe COPD  Intervention: Oral Vitamin D  Comparator: Placebo  Outcome: FEV1 and the number of COPD exacerbations	FEV 1 (before intervention) cases: (34.6±8.5), control: (34.4±9.2) and FEV1 (after intervention) cases: (51.6±9.4), control (31.9±7.6) (P<0.001)	Vitamin D intake decreased COPD exacerbation and improved FEV1 in the patients with severe and very severe COPD
Serum Mg and not Vitamin D is associated with better QoL in COPD: A cross-sectional study, Sarah Hashim Ali Hussein et al., Denmark, 2015	Cross-sectional study  Population (n=143): Stable COPD patients  Serum Vitamin D, Mg, and Ca in COPD patients and their associations with both (FEV1) and QoL	FEV1 was not correlated with serum Vitamin D, Mg, or Ca in COPD	Serum levels of Vitamin D, Mg, and Ca were not related to FEV1 Only serum Mg was associated with QoL in COPD
ViDiCO: A multicentre, double-blind, randomised controlled trial, Adrian R Martineau et al., UK, 2015	Randomized clinical trial  Population (n=240): Patients with COPD  Intervention: Vitamin D3  Comparator: Placebo  Coprimary outcomes: Time to first moderate or severe exacerbation and first upper respiratory infection	Vitamin D3 compared with placebo did not affect time to first moderate or severe exacerbation or time to first upper respiratory infection (adjusted hazard ratio: 0.95, 95% CI:0.69-1.31, P=0.75)	Vitamin D3 supplementation protected against moderate or severe exacerbation, but not upper respiratory infection, in patients with COPD with baseline 25-hydroxyvitamin D levels of less than 50 nmol/L
Supplemental Vitamin D and physical performance in COPD: A pilot randomized trial, Sonja M Bjerk et al., USA, 2013	Randomized clinical trial  Population (n=36): COPD patients  Intervention: Vitamin D  Comparator: Placebo  Primary outcome: 6 weeks change in SPPB score	There was no difference in improvements in either SPPB scores (95% CI: −0.8-1.5; P=0.56) or SGRQ scores (95% CI: −2.3-6.9; P=0.32)	Vitamin D supplementation had no discernible effect on a simple measure of physical performance
Serum Vitamin D in Patients with Chronic Obstructive Lung Disease Does Not Correlate with Mortality - Results from a 10-Year Prospective Cohort Study, Dennis Back Holmgaard et al., Denmark, 2013	Prospective cohort  Population (n=462): Patients with moderate to very severe COPD  Outcome measure: Mortality in a 10-year follow-up period	No association between baseline serum levels of 25-OHD and mortality rate could be demonstrated	Serum level of 25-OHD does not seem to be associated with mortality rate
High doses of Vitamin D to reduce exacerbation in COPD: A randomised trial, An Lehouck et al., Belgium, 2012	Randomized clinical trial  Population (n=182): Patients with moderate-to-very severe COPD and a history of recent exacerbations  Intervention: Vitamin D  Comparator: Placebo  Primary outcome: Time to first exacerbation	The median time to first exacerbation did not significantly differ between the groups	High-dose Vitamin D supplementation in patients with COPD did not reduce the incidence of exacerbations but may reduce exacerbations in patients with severe deficiency
Vitamin D levels and risk of AECOPD: A prospective cohort study, Ken M. Kunisak et al., Minnesota, 2012	Prospective cohort study  Population (n=973): Patients with COPD	Baseline 25(OH)D levels had no relationship to time to first AECOPD or AECOPD rates	Among patients with COPD at high risk of AECOPD, baseline blood 25(OH) D levels are not related to the risk of subsequent AECOPDs

Mg: Magnesium, Ca: Calcium, SPPB: Short Physical Performance Battery, COPD: Chronic obstructive pulmonary disease, FEV1: Forced expiratory volume 1 s, ViDiCO: Vitamin D3 supplementation in patients with COPD, QoL: Quality of life, CI: Confidence interval, AECOPD: Acute exacerbations of COPD

The results showed that serum Vitamin D levels had no bearing on the lung function, except a single trial,[5] which showed that Vitamin D intake decreased COPD exacerbation and improved FEV1 in the patients with severe and very severe COPD. However, it was a very small study with some methodological peculiarities, making it difficult to generalize the result.

In conclusion, we would like to reiterate that though the last word has not been said about the role of Vitamin D in COPD, the available evidence do imply a very weak “effect,” if at all, of Vitamin D on lung functions in COPD.

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Conflicts of interest

There are no conflicts of interest.