Vitamin D Deficiency and Reduced Lung Function in Connective Tissue-associated Interstitial Lung Diseases

Jared T. Hagaman, MD; Ralph J. Panos MD, FCCP; Francis X. McCormack, MD, FCCP; Charuhas V. Thakar, MD; Kathryn A. Wikenheiser-Brokamp, MD, PhD; Ralph T. Shipley, MD; Brent W. Kinder, MD, FCCP


CHEST. 2011;139(2):353-360. 

In This Article



One hundred eighteen patients were included in the study (67 with CTD-ILD and 51 with other forms of ILD). Clinical characteristics of the cohort and comparisons between patients with CTD-ILD and other forms of ILD are shown in Table 1. The distribution of patients with ILDs not associated with CTD was the following: idiopathic interstitial pneumonias (n = 22), granulomatous diseases (n = 16), unclassifiable ILD (n = 8), and miscellaneous forms of ILD (n = 5). The CTD-ILD subjects were more likely to be women, younger, and have taken corticosteroids (all P < 001). In addition, they had lower pulmonary function as measured by FVC (P = .01) and were more likely to have undergone surgical lung biopsy as part of their diagnosis (P =.04).

Vitamin D deficiency and insufficiency were highly prevalent in the cohort (Table 2), as 58% were vitamin D insufficient (25-hydroxyvitamin D3 < 30 ng/mL) and 38% were deficient (25-hydroxyvitamin D3 < 20 ng/mL). The mean 25-hydroxyvitamin D3 level was significantly lower for those with CTD-ILD as compared with other forms of ILD (including granulomatous diseases, idiopathic interstitial pneumonias and miscellaneous forms of ILD) (20.8 vs 33.1 ng/mL, P<0001) (Table 2). For the entire cohort, blacks had lower 25-hydroxyvitamin D3 levels than whites/Asians (17.2 vs 28.9 ng/mL, P = .0001). An inverse association was also seen between BMI and 25-hydroxyvitamin D3 levels; 25-hydroxyvitamin D3 levels declined with increasing BMI (P = .009).

Notably, 25-hydroxyvitamin D3 levels were not significantly lower for underweight patients (P = .9) or those with subjective reports of weight loss (P = .9) (data not shown). There was no observed association between 25-hydroxyvitamin D3 levels and sex, smoking status, or season drawn (P = .08, .94, .13, respectively, data not shown). Notably, there was also no statistically significant association between prednisone use and 25-hydroxyvitamin D3 levels (mean of 2 = ng/mL on steroids vs 28 ng/mL not on steroids, P = .30) A minority of subjects were receiving vitamin D supplementation at the time of testing (n =16, 14%); however, there was no observed association between supplementation and 25-hydroxyvitamin D3 levels (mean 31 ng/mg [95% CI, 21.6–40.1] on supplementation [n = 16] vs 26 ng/mL [95% CI, 22.8–28.3] for those not on supplementation [n =99, P = .17]).

Vitamin D Levels and CTD-ILD

Of those with CTD-ILD, 80% had vitamin D insufficiency, and more than one-half were vitamin D deficient (Table 2). The distribution of specific CTDs in the population was the following: UCTD (n = 28), scleroderma (n =12), RA (n =10), polymyositis/dermatomyositis (n = 7), Sjögren disease (n = 4), Sjögren disease/SLE (n = 2), SLE (n =1), mixed CTD (n = 1), and Wegener granulomatosus (n = 2). In sensitivity analyses, when the UCTD subjects were removed, the observed association between CTD and vitamin D insufficiency remained (OR, 6.3; CI, 2.5–16; P < 001; data not shown). Reduced mean 25-hydroxyvitamin D3 levels were consistent across all subsets of CTD-ILD (data not shown).

Although vitamin D deficiency/insufficiency was still highly prevalent in patients with ILDs not associated with CTD, mean serum 25-hydroxyvitamin D3 levels were significantly higher in this group (P ≤ .0001) (Table 2). These groups all had higher mean 25-hydroxyvitamin D3 than those with CTD-ILD (Fig 1).

Figure 1.

Histogram of serum vitamin D (25(OH)D3, ng/mL) by patient subgroup (analysis of variance [ANOVA], P <.00001). 25(OH)D3 = 25-hydroxyvitamin D3; CTD-ILD = connective tissue disease-associated interstitial lung disease; granulomatous disease = sarcoidosis and hypersensitivity pneumonitis; IIP = idiopathic interstitial pneumonias; Misc = miscellaneous ILD.

Vitamin D Levels and Lung Function

Across the entire cohort, there was a significant association between lower percent predicted FVC and reduced serum 25-hydroxyvitamin D3 levels (R = 0.31, P = .01). In contrast, there was no statistically significant association observed between lower 25-hydroxyvitamin D3 levels and percent predicted diffusing capacity for carbon monoxide (DLCO) (R = 0.13, P = .18), percent predicted total lung capacity (R = 0.17, P = .09), and 6MWT distance (R =0.08, P = .47) (data not shown). However, when the analysis was restricted to those with CTD-ILD, there was a strong inverse association between serum vitamin D insufficiency and FVC, as well as D lco (OR, 0.42; P = .01=and OR, 0.33; P =.004 respectively) (Fig 2, Table 3).

Figure 2.

A, Plot of serum vitamin D(25(OH)D3, ng/mL) by FVC tertiles (first < 64% predicted, second = 64%-83% predicted, third > 83% predicted) among subjects with CTD-ILD (ANOVA, P = .045). B, Plot of serum vitamin D (25(OH)D3, ng/mL) by diffusing capacity for carbon monoxide tertiles (first < 45% predicted, second = 45%-58% predicted, third > 58% predicted) among subjects with CTD-ILD. (ANOVA, P = .032). DLCO = diffusing capacity for carbon monoxide. See Figure 1 legend for expansion of the other abbreviations.

Adjusted Models

Variables found to be associated with vitamin D insufficiency in the unadjusted analysis in addition to those considered important a priori (age, corticosteroid usage, race, and season drawn) were included as predictors in a multivariate linear regression model (with 25-hydroxyvitamin D3 levels as a continuous variable) and a multivariate logistic regression model (looking at categorical vitamin D insufficiency) (Table 4 and Table 5). In the adjusted analysis, linear regression models showed that patients with an underlying CTD diagnosis had mean 25-hydroxyvitamin D3 levels 11 ng/mL less than those with other forms of ILD, even after adjustment for other potentially confounding variables (P < 0001; Table 4). The presence of CTD-ILD was a strong independent predictor of vitamin D insufficiency (OR, 11.8; CI, 3.5–40.6; P < 0001) (Table 5). Black race was also strongly associated with vitamin D insufficiency (OR, 12.9; CI, 2.6–64; P =.002). In sensitivity analyses, when the UCTD subjects were removed, the observed association between CTD and vitamin D insufficiency remained (OR, 10.0; CI, 2.4–41; P = .001; data not shown).