| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
Boston, MA
Dr. Wright is affiliated with the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, and with the Department of Society, Human Development, and Health, Harvard School of Public Health.
Correspondence to: Rosalind J. Wright, MD, MPH, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115; e-mail: rosalind.wright{at}channing.harvard.edu
Highlighting the article by Black and colleagues1 in the current issue of CHEST (see page 3792) on the association between vitamin D and lung function is important for many reasons. Reduced maximally attained lung function and the accelerated decline of pulmonary function are markers of an individual’s increased susceptibility to COPD, which is a potentially preventable disease with significant health and economic impact in the United States and worldwide.23 Moreover, reduced lung function is a major risk factor for cardiovascular morbidity and mortality, independent of smoking.4 Thus, while historically dubbed the "Cinderella pulmonary condition," we are seeing a well-deserved increase in research support, studies, and publications related to COPD and determinants of lung function given the projected growing public health impact.25 The factors examined thus far in epidemiologic studies, including smoking, which has received the most attention, account for only a portion of the risk,6 suggesting that adult lung function is influenced by as-yet-undefined chemical, psychological, behavioral, or biological factors that influence host susceptibility.
Black and colleagues1 examined the relationship between serum vitamin D levels and lung function in a cross-sectional analysis of the Third National Health, Nutrition and Examination Survey, a large representative sample (approximately 14,000 subjects) of the US population. They examined the relationship between percent predicted FEV1 and FVC values and the circulating concentration of 25-hydroxyvitamin D, and demonstrated a significant relationship between higher vitamin D levels and increased lung function with a suggested dose-response effect
Epidemiologic observational studies suggest associations but do not prove causality. Rather, the inference that the observed association represents a cause-effect relationship should be considered in light of a number of epidemiologic criteria for causality, as follows: biological plausibility; strength of the association; reduced likelihood of alternative explanations due to confounding; temporal sequence of events; dose-response relationship; and consistency across studies in different populations.
Evidence Supporting Biological Plausibility
Evidence is increasing that suggests an expanded role for vitamin D in health outcomes apart from its classic actions on the gut and bone. The vitamin D3 metabolite, 1,25-dihydroxyvitamin D3 and its synthetic analogs also have potent antiproliferative, differentiative, and immunomodulatory activities, exerting these effects through the vitamin D receptor (VDR). The authors cite evidence linking vitamin D to modulation of the formation of metalloproteinases and fibroblast proliferation, which is involved in lung remodeling, as potential pathways through which vitamin D may influence lung function. Other evidence has demonstrated the expression of the VDR in various immune cells with documented effects of vitamin D on many immune cell types involved in both innate and adaptive immunity.7 At the same time, evolving research has demonstrated interrelationships between immune-mediated inflammatory processes and chronic lung disease. Airway inflammation is recognized as a central process in the pathogenesis of COPD.8 Vitamin D has been shown to prevent the induction of experimental inflammatory diseases in mice including allergic asthma.9 In turn, atopy and various asthma-like phenotypes have been linked to reduced lung function10 and increased morbidity and mortality related to COPD.11 Hypovitaminosis D has also been linked in animal studies to enhanced oxidative stress,12 which is another purported mechanism underlying COPD risk.13 Genetic susceptibility studies14 have linked variants in the VDR to an increased risk of COPD. Studies1516 examining the association between VDR variants and the rate of decline in pulmonary function among smokers have had mixed results. These overlapping data suggest a role for vitamin D in chronic inflammatory responses in the lung, which in turn contribute to lung function over time.
Need for Further Epidemiologic Evidence
Consistency across studies provides a compelling basis for causal inferences in epidemiologic research. Examining the same hypothesized relationship between levels of vitamin D and pulmonary function in diverse populations will be important. Seeing a similar relationship across different studies involving different sample populations controlling for potential confounders in various ways, strengthens the case for causality. Observing a dose-response relationship, as suggested in the current study by Black and colleagues,1 provides further suggestive evidence of causality. This cross-sectional analysis cannot discern temporal associations. Longitudinal data supporting the role for vitamin D in the rate of decline of lung function will be important. Before researchers embark on randomized controlled trials, as the authors suggest, they would be helped by taking advantage of other large existing data sets in which the association between vitamin D and lung function can be further examined. It will likely be necessary to design future observational studies that specifically address the influence of vitamin D and lung function in which careful attention is paid to measuring the potential confounders. Often, when secondary data analysis is performed to examine a hypothesis other than the aims intended in the original study, key confounders are measured either inadequately or not at all with consequential effects on any inferences being made.17
It will also be important to consider interactions among a number of these environmental and host factors contributing to lung function rather than simply controlling for them as potential confounders.18 For example, in addition to vitamin D other environmental exposures are known to operate through oxidative stress pathways (eg, tobacco smoke and air pollutants). It has also been suggested19 that hypovitaminosis D increases the susceptibility to psychological stress. There is evidence that psychological stress augments oxidative stress and modifies the host response to other inflammatory oxidative toxins such as tobacco smoke and air pollutants. Thus, cumulative factors that may modify oxidative toxicity may have additive or multiplicative effects on lung function. Vitamin D may interact with stress, tobacco smoke, and air pollutants through an oxidative/antioxidative imbalance, influencing lung inflammation and consequently lung function.20 Future studies should also consider gene-environment interactions that may further elucidate the underlying mechanisms.
Shedding Light on Sociodemographic Factors and Lung Function
Nutritional habits, levels of nutrients, and dietary factors such as vitamin D intake can vary based on sociodemographic factors including gender, age, and socioeconomic status.21 Similarly, physical activity levels may differ across certain subgroups.22 It will be important for future studies to examine how the relationship between vitamin D and these other factors might explain differential effects on lung function and COPD risk in susceptible subgroups (eg, based on socioeconomic status, gender, and race/ethnicity).2324
Further Evidence of the Public Health Importance
Finally, in addition to the disturbing projected trends for COPD, epidemiologic studies have suggested that hypovitaminosis D is reemerging as an important public health problem in the United States and worldwide.25 It will be important to conduct other studies examining the relationship between vitamin D and lung function, as this would be a relatively simple low-cost intervention that would likely have high compliance to potentially prevent or slow the loss of lung function in susceptible subgroups. More data are needed to suggest which groups might be helped most by such interventions.
References
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
