Lung VITAL: Rationale, design, and baseline characteristics of an ancillary study evaluating the effects of vitamin D and/or marine omega-3 fatty acid supplements on acute exacerbations of chronic respiratory disease, asthma control, pneumonia and lung function in adults

Abstract

Laboratory and observational research studies suggest that vitamin D and marine omega-3 fatty acids may reduce risk for pneumonia, acute exacerbations of respiratory diseases including chronic obstructive lung disease (COPD) or asthma, and decline of lung function, but prevention trials with adequate dosing, adequate power, and adequate time to follow-up are lacking. The ongoing Lung VITAL study is taking advantage of a large clinical trial—the VITamin D and OmegA-3 TriaL (VITAL)—to conduct the first major evaluation of the influences of vitamin D and marine omega-3 fatty acid supplementation on pneumonia risk, respiratory exacerbation episodes, asthma control and lung function in adults. VITAL is a 5-year U.S.-wide randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of supplementation with vitamin D3 ([cholecalciferol], 2000 IU/day) and marine omega-3 FA (Omacor® fish oil, eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/day) for primary prevention of CVD and cancer among men and women, at baseline aged ≥ 50 and ≥ 55, respectively, with 5107 African Americans. In a subset of 1973 participants from 11 urban U.S. centers, lung function is measured before and two years after randomization. Yearly follow-up questionnaires assess incident pneumonia in the entire randomized population, and exacerbations of respiratory disease, asthma control and dyspnea in a subpopulation of 4314 randomized participants enriched, as shown in presentation of baseline characteristics, for respiratory disease, respiratory symptoms, and history of cigarette smoking. Self-reported pneumonia hospitalization will be confirmed by medical record review, and exacerbations will be confirmed by Center for Medicare and Medicaid Services data review.

Introduction

Acute exacerbations of chronic respiratory diseases including chronic obstructive lung disease (COPD) or asthma [1]; pneumonia (www.cdc.gov/nchs); and decline of lung function [2] are major risk factors for lost disability-adjusted life-years, and increased morbidity and mortality in adults world-wide [3], [4], [5], [6], [7], [8]. Vitamin D and fish oil/marine omega-fatty acid supplementation have been postulated to help reduce these risk factors. While there have been significant advances in understanding their potential role in improving respiratory health in adults, significant gaps remain. In its 2011 report, the IOM comprehensively reviewed the scientific literature on vitamin D and health, concluding that although there is clear evidence that vitamin D confers bone benefits, available research is insufficient to determine whether vitamin D is beneficial for nonskeletal diseases, stating that adequately powered randomized clinical trials were needed to assess whether supplementation should be recommended for other disorders [9], [10], [11].

Vitamin D is both a nutrient and a prohormone (Fig. 1), and blood levels are dependent on dietary intake and exposure to sunlight. The National Health and Nutrition Examination Surveys estimate that a third of Americans have insufficient levels of vitamin D (defined as a 25-hydroxivitamin D[25((OH)D] level of < 20 ng/ml). Aging, obesity, black race/ethnicity, and COPD are predictors of lower vitamin D levels [12]. Viral and bacterial infections are the most common precipitants of exacerbations of chronic respiratory disease. Vitamin D has beneficial effects on antimicrobial, oxidant [13], and immune pathways relevant to lung infection, airway inflammation and airway remodeling [14]. In laboratory studies vitamin D upregulates antimicrobial peptides [3], [15], [16] and reduces inflammatory and allergic responses through modulating innate, T regulatory and adaptive immunity [17]. Mechanistic studies also support a role for vitamin D supplementation in the improvement of the many co-morbidities associated with COPD progression and ultimately, death. These co-morbidities include osteopenia, osteoporosis and fractures, respiratory infections, myopathy and weakness, diabetes, cancer, deep venous thrombosis, and cardiovascular diseases [12]. We and others have published observational studies of associations of higher vitamin D levels with reduction of serious infection [18], [19], [20], lower lung function decline [21], and improvement in asthma control in adults [22], but clinical trials in adults are conflicting [23], often limited by low power, suboptimal follow-up time or dosing schedule [24]. Fish contain omega-3 fatty acids (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]), which modulate the innate inflammatory response by a pathway distinct from Vitamin D (Fig. 2). Laboratory studies suggest that omega-3 FAs have beneficial anti-inflammatory effects on arachidonic acid metabolic pathways and the downstream balance of eicosanoids, including prostaglandins and leukotrienes [25] that influence neutrophil recruitment and bronchoconstriction [26]. Particularly in children, fish intake has been associated with reduced wheeze and asthma in many (but not all) epidemiologic cohort studies. Despite compelling biologic data suggesting that marine omega-3 FA beneficially influences pathways relevant to airflow obstruction or asthma, prior trials of omega-3 FAs for adults are few (10 for asthma reported in the 2014 Wendell review [25]) and underpowered (16 to 46 subjects), though 9 of the 10 suggested potential benefits in inflammatory, lung function or symptom outcomes. It is important to clarify these relationships in larger randomized clinical trials.