Vitamin D status and longitudinal lung function decline in the Lung Health Study

RESULTS

Rapid and slow decliners (cases and controls) were similar in Y5 age, sex distribution and smoking intensity (table 1). Most participants were Caucasian, due to the sample recruited in the original LHS trial, and there was a statistically significant difference in ethnicity of rapid and slow decliners. Matching resulted in a mean±sd difference in clinic visit days between rapid and slow decliners of 25±16.5 days (range 0–60 days). The distribution of participants matched by clinical centre was as follows: Baltimore, MD, USA (n = 24), Birmingham, AL, USA (n = 10), Cleveland, OH, USA (n = 14), Detroit, MI, USA (n = 24), Los Angeles, CA, USA (n = 20), Pittsburgh, PA, USA (n = 24), Portland, OR, USA (n = 22), Rochester, MN, USA (n = 12), Salt Lake City, UT, USA (n = 18), and Winnipeg, MB, Canada (n = 28).

Our selection criteria for cases and controls resulted in clinically and statistically significant differences in the rate of FEV₁ decline between rapid and slow decliners. While FEV₁ was similar between rapid and slow decliners at the Y5 visit, rapid decliners had a mean FEV₁ that was >1 L worse than slow decliners at the LT visit (table 1). This resulted in a rate of FEV₁ decline of -152 mL·yr⁻¹ (-4.3% pred·yr⁻¹) in rapid decliners versus -0.3 mL·yr⁻¹ (+0.7% pred·yr⁻¹) in slow decliners (p<0.001) (table 2).

Despite the large differences in rate of FEV₁ decline, and appropriate control of latitude (through matching on clinical centre) and time of year (through matching on date of phlebotomy), the difference in Y5 25(OH)D level between rapid and slow decliners was not statistically significant (25.0 ng·mL⁻¹ versus 25.9 ng·mL⁻¹, respectively; p = 0.54) (table 2). Additional multiple regression and paired logistic regression analysis for baseline Y5 covariates also demonstrated no association between Y5 25(OH)D level and rapid or slow decliner status (see online supplementary material for details).

We applied current widely accepted definitions of vitamin D insufficiency and deficiency 12, which classify patients with 25(OH)D <20 ng·mL⁻¹ as vitamin D-deficient, and ≥20 ng·mL⁻¹ but <30 ng·mL⁻¹ as vitamin D-insufficient. Applying such criteria, we found 35% (n = 69) of this LHS 3 sample was vitamin D-insufficient and 31% (n = 60) was vitamin D-deficient. Only 34% (n = 67) of the sample would currently be classified as vitamin D-sufficient, with levels ≥30 ng·mL⁻¹. 14 (7%) participants had severe vitamin D deficiency, such that their 25(OH)D levels were ≤10 ng·mL⁻¹.

There was also significant seasonal variation in 25(OH)D levels (fig. 1 and online supplementary figure). As expected, 25(OH)D levels peaked in late summer, with a nadir observed in the winter months. The magnitude of the seasonal variation was both clinically and statistically significant, with a mean winter 25(OH)D level of 18.3 ng·mL⁻¹ compared to 31.7 ng·mL⁻¹ in the summer (Bonferroni-corrected p<0.001). Of 48 samples drawn in the winter months, 46 (96%) were under the recommended goal level of ≥30 ng·mL⁻¹.

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Figure 1–

Box plots of 25-hydroxyvitamin D (25(OH)D) levels by season (winter: January–March; spring: April–June; summer: July–September; autumn: October–December). —: median; ▓: interquartile range; whiskers: range; •: outliers. Statistical testing of means listed in table 3 (one-way ANOVA with Bonferroni-corrected p-value) are shown. ***: p<0.001; ^#: p = 0.11; ^¶: p = 0.055; ⁺: p = 1.000.

DISCUSSION

We found no differences in baseline 25(OH)D levels between continuously smoking LHS 3 participants with rapid and slow declines in lung function over ∼6 yrs of prospective follow-up. Therefore, our data do not support the notion that low 25(OH)D levels lead to faster rates of lung function decline.

Our study was primarily prompted by the study of Black and Scragg 1, which examined cross-sectional data from 14,076 NHANES III participants. They demonstrated a graded relationship between lower 25(OH)D levels and lower lung function, such that those in the lowest 25(OH)D quintile (≤16.2 ng·mL⁻¹) had a mean FEV₁ that was 126 mL lower than those in the highest quintile (≥34.3 ng·mL⁻¹), after adjusting for sex, age, ethnicity, body mass index and cigarette smoking. Among a small subgroup with self-reported emphysema (n = 251), the differences were even greater, such that when comparing those with 25(OH)D ≤16.2 ng·mL⁻¹ to those with ≥34.3 ng·mL⁻¹, FEV₁ was 344 mL worse in the low 25(OH)D group. The actual spirometry values from these 251 patients were not reported, so confirmation of COPD and assessment of COPD severity could not be made. While intriguing, a major limitation of these data is the cross-sectional nature of NHANES data. To our knowledge, ours is the first study examining relationships between baseline 25(OH)D levels and subsequent prospective, longitudinal rates of lung function decline.

Our study design allowed us to compare two groups of COPD patients of significant clinical interest: those who continuously smoke and have rapid lung function decline (rapid decliners) and those who continuously smoke, yet have preserved lung function over time (slow decliners). Because smoking is controlled for in both of these groups, we were able to investigate the hypothesis that the rapid decliners would have lower 25(OH)D levels as one potential mechanism by which their lung function rapidly declines. However, our data do not support this hypothesis.

Our study has several strengths. The longitudinal assessment of lung function was rigorously standardised, with the same equipment and procedures used by experienced study staff (who had performed annual spirometry for 5 yrs prior to the Y5 measure in this study). Our matching criteria and the seasonal variation observed suggest that misclassification of 25(OH)D levels is unlikely. We had excellent power to detect small differences in 25(OH)D levels: 90% power to detect a difference as small as 2.4 ng·mL⁻¹. It seems unlikely that a difference any smaller than this could explain differences in rates of subsequent lung function decline.

Our study has several important limitations. One limitation is that assessment of 25(OH)D levels was only possible from a single study visit. Therefore, this single assessment may not be fully reflective of an individual's overall vitamin D status. For example, a wintertime assessment could be a poor indicator of overall vitamin D status throughout the year, especially in more extreme latitudes. We attempted to correct for seasonal variation and latitude effects as best as we could by matching rapid and slow decliners on date of phlebotomy and clinical centre, but this cannot correct for seasonal changes, which might vary significantly both within and between individuals. We were also unable to assess whether or not the presence of low 25(OH)D levels at Y5 were associated with persistent low levels at the LT follow-up visit, as there was no blood draw at the LT follow-up visit. It is possible that some participants might have begun activities during that time interval which could have affected their subsequent 25(OH)D levels. For example, participants could have begun vitamin D supplementation and subsequently increased their 25(OH)D levels after the Y5 visit. Conversely, they could have begun using sunscreen products, which could have decreased their 25(OH)D levels after the Y5 visit.

Another limitation of our data is that these analyses were restricted to continuous smokers with evidence of mild-to-moderate COPD at baseline. Because smoking has such a significant impact on rate of lung function decline, smoking is important to control for in a study such as ours. We chose to restrict our analysis to continuous smokers in order to focus on those COPD patients at greatest risk of progressive lung function decline and reduce effects of variables other than vitamin D (e.g. intermittent smoking) that might also affect rate of lung function decline. Thus, we can not extrapolate these findings to nonsmokers or to intermittent smokers. We also can not extrapolate these findings to persons without COPD confirmed by spirometry, nor to persons with very advanced COPD.

We feel it important to highlight the high prevalence of vitamin D insufficiency and deficiency we found, such that only 34% of these LHS 3 participants had 25(OH)D levels that would currently be considered as adequate. In winter, we found only two out of 48 25(OH)D measurements to be in the accepted normal range. Riancho et al. 13 studied 44 males with COPD (mean FEV₁ 39% pred) between 1983 and 1985, and showed the mean 25(OH)D level was <10 ng·mL⁻¹ for most of the year, with peak mean 25(OH)D level in late summer still <20 ng·mL⁻¹. They measured 25(OH)D using a competitive protein-binding assay after high-performance liquid chromatography purification, a method that is now rarely used, so a direct comparison to more current 25(OH)D assay methods may be limited. Shane et al. 14 reported a mean 25(OH)D level of 20 ng·mL⁻¹ in 28 patients with COPD awaiting lung transplantation between 1993 and 1995. 10 (36%) of these patients had levels ≤10 ng·mL⁻¹. Forli et al. 15 reported vitamin D deficiency (<20 ng·mL⁻¹) in >50% of 71 consecutive nonsmoking patients (of whom 46 had COPD) undergoing lung transplantation evaluation between 1993 and 1998.

These data are of particular concern in light of recent NHANES data demonstrating that, between the surveys conducted in 1988–1994 and 2001–2004, the mean population 25(OH)D level decreased by 6 ng·mL⁻¹ and the percentage with inadequate 25(OH)D levels (<30 ng·mL⁻¹) increased from 55 to 77% 16. Because our 25(OH)D data are based on samples collected between 1991 and 1994, it seems likely that the current prevalence of inadequate 25(OH)D levels in patients with mild-to-moderate COPD is even higher than the 66% we found.

In support of this, Franco et al. 17 recently reported a spring 2005 mean 25(OH)D level of 20.8 ng·mL⁻¹ in a small cohort of 49 Brazilian patients with mostly mild and moderate COPD. Of these 49 patients, only three (6%) had 25(OH)D levels ≥30 ng·mL⁻¹, 29 (59%) were vitamin D-insufficient and 17 (35%) were vitamin D-deficient. Janssens et al. 18 also recently reported that, among 262 Belgian patients with COPD, the mean 25(OH)D level was 19.9 ng·mL⁻¹ and 52% were vitamin D-deficient, with levels <20 ng·mL⁻¹.

Our cohort also demonstrated significant seasonal variation in 25(OH)D levels, which varied around the accepted cut-off points for normal, insufficient and deficient levels. As such, there was a substantial seasonal shift in the distribution of participants classified as normal or vitamin D-deficient. While these blood samples from 1991–1994 are no longer a contemporary assessment, clinicians and researchers may need to consider the substantial effect of seasonality on 25(OH)D measures. It is important to note that LHS 3 participants were generally quite healthy, with mostly mild COPD. One might hypothesise that in patients with more severe COPD, there may be less of a seasonal effect, due to their being more confined to the home and, hence, less exposed to sunlight. However, we are unaware of any contemporary data to either support or refute such a hypothesis. In addition, the mechanisms leading to vitamin D insufficiency/deficiency may be quite complex. Dietary vitamin D intake in patients with COPD has been shown to be low 19, but multiple other mechanisms may lead to inadequate vitamin D status 12.

Although we found no association between 25(OH)D levels and subsequent rates of lung function decline, patients with COPD suffer from many comorbidities potentially associated with low 25(OH)D levels. The one COPD comorbidity with well-studied links to low 25(OH)D levels is osteoporosis 20. Multiple other COPD complications and comorbidities have been linked to vitamin D insufficiency, including respiratory infections 21–23, cardiovascular disease 24, 25 and muscle dysfunction 26, 27. However, it is important to note that there are no clinical trial data to support to the hypothesis that improving 25(OH)D levels in patients with COPD will improve any of these COPD comorbidities, but these remain topics requiring further investigation.

In conclusion, although we found a high prevalence of low 25(OH)D levels in continuous smokers with established mild and moderate COPD, we found no difference between baseline 25(OH)D levels among those with subsequent rapid declines in lung function and slow declines in lung function. Our data suggest that normalisation of 25(OH)D levels is not likely to affect subsequent rates of lung function decline in such patients.