Association Between Chronic Obstructive Pulmonary Disease and Gastroesophageal Reflux Disease

A National Cross-sectional Cohort Study

Jinhee Kim; Jin Hwa Lee; Yuri Kim; Kyungjoo Kim; Yeon-Mok Oh; Kwang Ha Yoo; Chin Kook Rhee; Hyoung Kyu Yoon; Young Sam Kim; Yong Bum Park; Sei Won Lee; Sang Do Lee


BMC Pulm Med. 2013;13(51) 

In This Article


To the best of our knowledge, this is the first nationwide study of the largest number of COPD patients to investigate the prevalence of GERD and the association between COPD and GERD. The prevalence of GERD in patients with COPD was 28%, which is very high since the prevalence in Korean general population is around 12%. It is similar to previous ones reported in Japan,[7,24] and lower than the others, which were 32%–37% in the USA and 53.6% in Iran,[6,20,23] even though these studies investigated only a small number of patients with COPD. Some of them showed higher prevalence in COPD patients compared with controls.[7,20] These support that GERD is one of the most common comorbidities in patients with COPD.

In the present study, several things are different from the previous studies. One is that inhaled anticholingergics may decrease or, at least, not increase risk of GERD, whereas a previous study reported that relative risk of GERD increased with using inhaled anticholinergics.[22] In another study, the effect of medication was not statistically significant or hard to be evaluated because COPD patients are usually treated by multiple medications and have both pulmonary and other systemic problems.[21] Our hypothesis is that inhaled anticholinergics might reduce GER through suppressing cough. They have been used for chronic cough,[25] which is one of the most common symptoms in COPD patients. Chronic bronchitis and GERD are the most common causes of chronic cough.[26] Ipratropium has been effective even for cough hypersensitivity induced by upper respiratory tract infection.[27] Tiotropium inhibits cough reflex sensitivity to capsaicin in subjects with acute viral upper respiratory tract infection.[28] The antitussive effect of tiotropium may occur through a mechanism other than bronchodilation. Additionally, tiotropium reduced lung inflammation in a mouse model of chronic GER.[29] Even though ICSs have been known to be effective for chronic cough, especially asthma,[26] our subjects exclusively had COPD. The prevalence of GER was reported to increase according to use of ICS in COPD patients,[22] which is consistent with our result. Combined inhalers of ICS and LABA have been popular in Korea, whereas use of LABA alone was very limited because representative LABAs such as salmeterol or formoterol were no longer imported or produced. The reason was that salmeterol as a single agent without ICS seemed to increase respiratory mortality in patients with asthma,[30] which made physicians hesitate to prescribe LABA without ICS even for COPD. Therefore it is inadequate to evaluate their effects on GERD. When a patient takes variable drugs at the same time, as well as COPD medication, drug interaction will happen.

Another different thing is that ICU admission due to COPD exacerbation was not associated with GERD. It may be possible for COPD patients with GERD to complain more cough or heartburn and feel exacerbation earlier than do those without GERD, which make them more frequently have unscheduled visit or ER visit, leading to hospitalization to general ward but not to ICU. The other possibility is that patients with COPD to be admitted to ICU do not have chance to be examined whether they have GERD or they are too dyspneic to present any symptoms of GERD. Despite of higher proportion of comorbidities in patients with COPD and GERD, the rate of ICU admission was lower than those in those without GERD, even though total hospitalization rate was higher. There would be the third possibility. In this study, prescriptions of proton pump inhibitors (PPIs) were given for COPD patients with GERD more frequently than those without GERD (data are not shown). PPIs decrease frequency of GERD symptoms such as cough,[31] which would rather prevent COPD patients from progression to ICU admission. One small prospective study demonstrated that PPIs reduced the number of exacerbation in COPD patients without GERD.[32]

In this study, the logistic regression analysis, even after adjusting several factors such as age, gender, type of health insurance, and COPD severity, showed that the presence of GERD was independently associated with COPD exacerbation such as hospitalization or frequent ER visits. Since lung function data were not available in the present study, definition of severe COPD was based upon medication information and health care resource utilization. Although the degree of airflow limitation has been used as one of the most important criteria of COPD severity, it does not always reflect dyspnea, exercise capacity, quality of life, or exacerbation frequency.[33] Recently updated Global initiative for chronic Obstructive Lung Disease (GOLD) emphasizes combined assessment of COPD, which includes symptoms and risk of exacerbations as well as degree of airflow limitation.[3] To supplement our weakness, patients with severe COPD were defined as those who satisfied both of the followings. One is that they used a tertiary health care resource, which means respiratory specialist's care, and the other is that they received medications for maximum effect such as triple therapy (ICS + LABA + LAMA) or OCS-containing long-acting bronchodilator, which may mean medication for exacerbations. These are possible under nationwide health insurance system of Korea, which divide health care resources into primary, secondary and tertiary and recommend people to use those step by step. Previous studies observed very small number of patients and simply compared frequency of exacerbation in COPD patients with GERD with in those without GERD.[6,7,23,24] They did not fully consider clinically important confounding factors such as age, gender, and COPD severity. Moreover, in two reports of them, COPD patients with GERD showed lower lung function as well as higher frequency of exacerbation than did those without GERD.[23,24] Therefore it might be hard to conclude whether frequent exacerbation was related to the presence of GERD or severe airflow limitation. Our study is also limited by its retrospective and cross-sectional design, and thus we cannot definitely conclude that GERD causes exacerbations of COPD. However, in a recent prospective study, patients with COPD and GERD had more exacerbation and hospitalization than in those without GERD, with crude relative risks of 3.42 and 3.66, respectively.[24] Since they excluded patients taking drugs for acid suppression, their relative risks may be higher than odds ratio in this study reflecting real world.

There are several limitations of this study. GERD was defined only by diagnosis codes even though about one third of GERD patients performed diagnostic tests related to GERD. In Korea, diseases of upper gastrointestinal (UGI) tract are more common than those in western countries and the incidence of stomach cancer has been the highest among all types of cancer. Therefore, as a health screening program of the Korean National Health Insurance System, all people can receive one of EGD or UGI series every two years from the age of 40 years. Nevertheless there might be a selection bias since symptomatic patients are likely to receive a diagnostic test. Definition of COPD was based on both of diagnosis codes and prescription data, which were exclusively determined by physicians. Although 37% of our subjects performed spirometry, this figure includes both general physicians and specialists. To exclude asthma patients, we excluded those receiving only LTRA or only ICS or only SABA. Nevertheless, there was still a possibility that some of our subjects may have asthma. As considering this, we additionally analyzed each data from only male or from subjects with prescription including LAMA, which is specific for COPD (Additional file 1: Table S1 and Table S2). Both analyses showed the same trend as Table 5. Since we used health insurance claim data, relatively important clinical data such as smoking history, lung function, and body mass index cannot be quantified although we tried to exclude patients with asthma or those with obesity or other diseases increasing risk of GERD by using both diagnosis codes and prescription data. Relatively not severe exacerbation such as unscheduled clinic visits or medication change were not included. Also, our definition of exacerbation might exclude some patients receiving only antibiotics without systemic corticosteroid. However, despite of these limitations, the present study clearly exhibits various interactive relationships between COPD and GERD. Although it would be hard to conclude complex relationship between COPD and GERD considering own severity and specific medications for both diseases and their interactions, we need to pay more attention to unraveling the heterogeneous causes of exacerbations.