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

Materials and Methods

Study Subjects, Clinical Evaluation, and Radiographic Evaluation

Consecutive patients seen in the University of Cincinnati Interstitial Lung Disease Clinic were enrolled in a longitudinal database and evaluated for serum 25-hydroxyvitamin D3 levels as part of a standardized evaluation protocol between October 2008 and January 2010. Subjects enrolled in the database underwent a detailed questionnaire evaluating symptom and exposure history, past and current medication usage, functional status, family history, and comorbidities. Medical records of all patients in the database were reviewed for information regarding sex, ethnicity, smoking status, physical examination findings, use of supplemental oxygen, pulmonary function tests, 6-min walk distance, high-resolution CT (HRCT) scan findings, serologic tests, and pathologic studies. All testing was ordered for the clinical evaluation of the patient in a standardized fashion and was not performed specifically for the purposes of this study. Prebronchodilator lung function tests and the 6MWT were performed at/around the time of enrollment according to published guidelines and interpreted according to reference values.[27–29] BMI, kg/m2 was calculated from measured height and weight. HRCT scan interpretation was uniformly performed by an expert specializing in ILD (B. W. K.). Patients were assigned a final ILD diagnosis through a multidisciplinary clinical-radiologic-pathologic consensus conference with input from pulmonologists, rheumatologists, radiologists, and pathologists, as has been previously described.[30] This process was performed independently of this study and without knowledge of vitamin D levels. Patients classified as having CTD-ILD met pre-specifi ed criteria according to the American College of Rheumatology criteria for diagnosis of the following conditions: RA, SLE, scleroderma, polymyositis/dermatomyositis, mixed CTD, Wegener granulomatosis, and Sjögren disease. The diagnosis of UCTD was based on previously published criteria.[31,32] Patients enrolled in the database lacking radiographic or clinical evidence of ILD were excluded from the study. Patients without serum 25-hydroxyvitamin D3 levels obtained during the study period were also excluded (n = 38). All subjects were enrolled into a University of Cincinnati institutional review board-approved protocol (07091806) investigating the natural history of ILD. Informed consent was obtained from all subjects at the time of the initial visit.

Vitamin D Measurement

Serum 25-hydroxyvitamin D3 concentrations were assayed by liquid chromatography-tandem mass spectrometry at Esoterix Endocrinology Laboratories (Calabasas Hills, California). By convention, vitamin D insufficiency and deficiency were defined as serum 25-hydroxyvitamin D3 values < 30 ng/mL and 20 ng/mL, respectively.[1]

Statistical Analysis

Comparisons between groups, CTD-ILD vs other forms of ILD, were made using the Student t test, χ2 test, or Fisher exact test as appropriate. Associations with 25-hydroxyvitamin D3 level were investigated with Student ttest, Pearson correlation, analysis of variance,χ2 test, or Fisher exact test as appropriate. In the primary analysis, patients with unclassifiable ILD (n = 8) were grouped with the non-CTD related ILD group. The impact of this grouping was tested in sensitivity analyses, in which these patients were excluded. In addition, we performed a sensitivity analysis excluding subjects with UCTD. All P values corresponded to two-sided tests and statistical significance was defined as a P value of <.05. Variables found to be associated at a P value of < .05 in the unadjusted analysis and those considered important a priori were considered for inclusion in multivariate regression models. Before inclusion, Pearson correlation coefficients between continuous covariates were evaluated to avoid colinearity. The final multivariate models were chosen using stepwise backward deletion. All analyses were performed with STATA statistical software version 9.2 (Stata Corp; College Station, Texas).