Alcohol consumption has been described as an independent risk factor for COPD-related mortality. Based on this prior research and because of the biological plausibility that heavy alcohol consumption may increase risk of exacerbation either through immune suppression or risk of aspiration, we hypothesized that moderate-to-heavy alcohol consumption when compared to light drinking would be associated with an increased risk for COPD exacerbations in a large, predominantly male cohort of veterans. While we found that screening positive for alcohol misuse (AUDIT C score > 4), frequent binge drinking, and alcohol use disorders (CAGE score > 2) all serve as markers for increased risk of COPD exacerbation, after adjustment for tobacco use there was no association between alcohol use or misuse and risk of exacerbation. This suggests that the association initially observed in age-adjusted models may not be due to the direct effects of alcohol but rather is due to the confounding by tobacco exposure that is strongly associated with alcohol consumption.
Alcohol exposure could contribute to COPD (http://www.copdfoundation.org/) exacerbation via several mechanisms. At the tissue level, alcohol may significantly decrease levels of the antioxidant glutathione within the lung, thereby raising susceptibility to injury, an effect of alcohol well-characterized in other organs like the liver. Additional studies, suggest that alcohol impairs the innate immune response of both the upper and lower respiratory tract in animal models via adverse effects on mucociliary clearance, alveolar macrophage phagocytosis, and alveolar epithelial barrier integrity. Physiologic responses to acute intoxication, namely impaired consciousness and reduced gag reflex, together facilitate entry of virulent organisms to the lower respiratory tract, which is known to be associated with COPD exacerbation risk.
Tabak et al demonstrated a U-shaped distribution of risk between alcohol consumption and 20-year COPD mortality among a cohort of 3,000 European men. After adjustment for age, body mass index, and smoking status in pack-years, they found a trend toward the lowest COPD mortality risk in light drinkers, an intermediate risk in heavy drinkers, and the highest COPD mortality among nondrinkers. However, these data were not adjusted for markers of COPD severity or other comorbidities, and for all point estimates reported, the 95% CI included 1.0. We found a similar distribution of risk prior to adjusting for several measures of tobacco and other covariates. After adjustment for these variables, however, the association was no longer apparent. Based on our results, we hypothesize that some of the previously described association between alcohol exposure and COPD may be in part due to incomplete adjustment for tobacco use and other unmeasured residual confounding variables.
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Given that alcohol consumption and tobacco use are highly correlated, we performed several analyses adjusted for smoking variables. In all three models, only the nondrinkers were at a statistically significant increased risk for COPD exacerbation, arguing that alcohol use did not have an effect on COPD exacerbation risk independent of tobacco use. The nondrinkers in this cohort represent a heterogeneous population that potentially includes a number of distinct groups: never drinkers, former drinkers who are well, and patients who are no longer healthy enough to drink alcohol. In addition, after adding markers of COPD severity and other comorbidities (SIC scores) to our multivariate and age-stratified models, this increased risk initially observed among the nondrinking population (ie, AUDIT-C score of 0) was either absent or significantly diminished.
This study has a number of potential limitations. First, some degree of ascertainment bias is likely present because we were unable to assess clinic visits and hospital admissions to non-VA facilities. Second, our cohort definition of COPD was not based on spirometric assessment, and our outcome measure was based on the combination of a COPD diagnosis in conjunction with antibiotics and/or systemic steroids. These definitions may lead to potential mis-classification of those with a prior diagnosis of COPD as well as the outcome. However, the results of two additional sensitivity analyses including only those individuals who were more likely to have COPD did not demonstrate a significant association between alcohol consumption and risk of COPD exacerbation. Third, our use of validated alcohol screening tests as measures of alcohol use and misuse may have resulted in some misclassification, potentially obscuring a modest association between alcohol use and COPD exacerbation. For example, social desirability could have led to underreporting of alcohol consumption, biasing the study to the null. We did not assess changes in alcohol consumption over the median 3.35 years and used baseline AUDIT-C results to predict events over the follow-up period. Patients may have changed their consumption pattern during follow-up, leading to misclassification and a subsequent inability to detect differences in risk. Fourth, as in most studies, we examined risk of the first COPD exacerbation event only and did not examine whether higher alcohol consumption leads to more frequent recurrent events. Fifth, despite attempts at follow-up with multiple mailings, nonresponse may have affected our results. We have previously reported a response rate of 56%. Using data from the VA computerized medical record system to compare those who did and did not respond to the questionnaire, respondents were older and had a higher prevalence of a number of chronic conditions including COPD. After stratifying by age, however, the prevalence of chronic conditions was largely similar among respondents and nonrespondents. Lastly, with clear underrepresentation of women in this cohort, additional studies are required to comment on the association of alcohol exposure with COPD exacerbations in women.
The strengths of the study derive from the use of a large outpatient cohort, including > 1,800 subjects with severe alcohol misuse. These analyses combined survey data, including validated measures of alcohol use and comorbidity, with diagnostic, healthcare utilization, and pharmacy data. The study included patients from seven sites, thereby minimizing the chance that idiosyncratic patterns of diagnosis and/or treatment by any single physician or clinic biased the results. Moreover, the use of data from several geographically dispersed institutions enhanced the generalizability of our results. In addition, given our sources of data, we were able to follow up all patients who stayed within the VA system for the entire duration of the study period.
In summary, we found no association between alcohol use or misuse and risk of COPD exacerbation that was independent of tobacco consumption. It appears from the modest association between alcohol use and COPD exacerbation risk evident in our initial analyses, as well as that described in the literature regarding alcohol and COPD mortality, that alcohol use and misuse may serve as a marker of other important adverse health behaviors, namely tobacco use. Nevertheless, recognizing alcohol consumption in patients with COPD may help identify individuals at increased risk of exacerbation due to either concomitant tobacco use or potential negative effects of alcohol use on medication adherence. Our results underscore the importance of carefully accounting for tobacco use when studying the relationships between alcohol consumption and COPD-related outcomes.
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