ABSTRACT
Peptic ulcer disease, gastro-oesophageal reflux disease (GORD) and weight loss have been associated with chronic obstructive pulmonary disease (COPD). Many studies, especially on peptic ulcer and weight loss, are cross-sectional or were done back in the 1960s or 1970s. Our purpose was to learn more about GORD, ulcer, and weight loss in relation to COPD during long-term follow-up in recent years. We conducted a case-control and a follow-up study using the UK-based General Practice Research Database to assess and compare the prevalence and incidence of GORD, peptic ulcer and weight loss in patients with COPD and in COPD-free patients during the period 1995–2005. We identified 35,772 patients with COPD and the same number of COPD-free patients. Incidence rates of GORD, peptic ulcer and weight loss in COPD patients were 59.2, 14.8 and 134.0 per 10,000 person years, respectively. The risk of weight loss was increased in patients with COPD compared to COPD-free patients (1.81, 95% CI 1.61–2.02), while the risk of GORD (OR 1.19, 95% CI 1.00–1.40) or peptic ulcer (OR 1.24, 95% CI 0.92–1.66) were similar in both groups. The results provide further evidence that COPD is associated with weight loss, while there is no materially increased risk for ulcer or GORD associated with COPD.
INTRODUCTION
As indicated in the recent update of the GOLD definition (Citation1, 2), chronic obstructive pulmonary disease (COPD) has increasingly been recognized to have systemic involvement such as depression, cardiovascular diseases, weight loss or nutritional abnormalities (Citation2). Reasons for weight loss include increased energy expenditure or decreased nutrient in- and/or uptake. Grönberg et al. investigated reasons for weight loss in COPD patients and reported reduced nutrient intake in patients with severe COPD caused by dyspeptic symptoms as the most prevalent reason for dietary problems (Citation3).
Gastro-oesophageal reflux disease (GORD) is a disease of considerable prevalence often seen in COPD patients, and it has been reported to be increasingly diagnosed in the past years (Citation4, 5). There are several hypotheses to explain the association between COPD and GORD, and it is important to distinguish between 2 temporally and thus causally differing approaches. According to approach 1, GORD is a risk factor for developing COPD; GORD is thought to facilitate the development or exacerbation of COPD by irritation of the airways through microaspiration of gastric contents and/or by vagally mediated reflex bronchoconstriction (Citation6, 7). On the other hand, bronchial obstruction in asthma has been reported to affect lower oesophageal sphincter motility (Citation8), which may promote GORD, so COPD would be a risk factor for GORD.
Another explanation for a possible association between COPD and GORD focuses on smoking as a common risk factor for both diseases (Citation9). Smoking is thought to be the most important common factor for COPD and gastric or duodenal ulcer, as reported in the past (Citation10–12). Helicobacter pylori infections are also commonly seen in COPD patients but the seroprevalence is also high in patients without COPD (Citation13). Only few recent studies have investigated this association despite the fact that both diseases have seen opposing time trends (Citation14, 15); the incidence of gastrointestinal ulcers has been decreasing, while the burden of COPD has been projected to increase (Citation16, 17).
It was the goal of the current observational study to assess the incidence of new onset GORD, gastrointestinal ulcer disease and weight loss in patients with COPD compared to patients without COPD, thereby focusing on COPD severity as a risk factor for these outcomes.
MATERIALS AND METHODS
Data source
We used the UK-based General Practice Research Database (GPRD) to conduct a follow-up study with a nested case-control analysis. The GPRD has been described in detail elsewhere (Citation18). It is a large primary-care database established in 1987, which encompasses some 5 million patients who are enrolled with selected general practitioners (GPs) throughout the UK. The General Practitioners (GPs), who contribute data to the GPRD, have been trained to record medical information in a standard manner and to supply it anonymously. The recorded information includes demographics, medical diagnoses, and virtually all drug prescriptions. The patients enrolled in the GPRD are representative of the UK population with respect to age, sex and geographical distribution (Citation18). GPRD data have previously been used in studies of COPD (Citation19), ulcer (Citation16) and GORD (Citation20). The GPRD is managed by the Medicines and Healthcare products Regulatory Agency (MHRA), and the study protocol was approved by the Independent Scientific Advisory Committee for MHRA database research (ISAC). The investigators only had access to anonymized information.
Study population
We identified in the GPRD all patients, age 40–79 years, with a first-time diagnosis of COPD between January 1, 1995 and December 31, 2005. We excluded patients with less than 3 years of active recording history prior to the date of the first COPD diagnosis. In addition, we identified at random from the GPRD one comparison subject without COPD for each COPD patient, matched 1:1 on age (same year of birth), sex, general practice and calendar time (i.e. the date of the first COPD diagnosis of the COPD patient). We applied the same exclusion criteria to the comparison group as to the COPD patients. Within this study population we assessed and compared the prevalence of diagnosed GORD, peptic ulcer as well as recorded weight loss prior to the COPD diagnosis (and prior to the corresponding date in the comparison group).
Follow-up analysis
We excluded all patients from the COPD and the COPD-free comparison group who had a recorded history of cancer (excluding non-melanoma skin cancer), HIV, drug abuse or alcoholism prior to the COPD diagnosis (or the corresponding date in the COPD-free group). For the analysis of GORD we further excluded patients with a history of GORD, or gastric or duodenal ulcer; for the analysis of gastric or duodenal ulcer we excluded patients with a history of these ulcers, and for the analysis on weight loss/anorexia we excluded patients with a history of recorded weight loss or anorexia prior to the COPD diagnosis date or prior to the corresponding date in the COPD-free group. We then followed all remaining patients from the start of follow-up (i.e., the COPD diagnosis date or the corresponding date in the comparison group) and assessed the person-time for each patient until he or she developed an incident diagnosis of GORD, ulcer or weight loss, left the database, died or reached the end of the study period (December 31, 2005), whichever came first. We estimated crude incidence rates (IR) with 95% confidence intervals (CI) separately for COPD patients and COPD-free patients.
Table 1. Characteristics of the study population
Nested case-control analysis
We conducted a nested case-control analysis to further analyze the impact of COPD on the risk of developing an outcome of interest (i.e., GORD, gastric or duodenal ulcer or weight loss), and to adjust for various potential confounders. For this purpose we identified for each case with a study outcome 4 control patients selected at random from the study population (i.e., patients with or without COPD) who did not develop GORD, gastric or duodenal ulcer, or weight loss. These controls were matched to cases on age, sex, practice and index date (i.e., the date when the case had the recorded incident diagnosis of GORD, ulcer or weight loss). Using conditional logistic regression analyses, we compared the prevalence of COPD among cases with new onset GORD, gastric or duodenal ulcer or weight loss and their controls. As a surrogate marker for COPD disease severity we used COPD treatment, similar to a previous approach published by Soriano et al. (Citation19).
We categorized COPD patients into those with an untreated COPD diagnosis (as surrogate for mild COPD), patients with ‘drug treatment’ (as surrogate for moderate COPD, defined as having at least one prescription for short acting anticholinergics, short acting beta agonists, tiotropium, long acting beta agonists, leukotriene receptor antagonists, inhaled steroids or xanthines), or patients requiring ‘oxygen treatment’ as surrogate for severe COPD. We adjusted the analyses for body mass index (BMI; <18.5,18.5–24.9, 25–29.9, 30+ kg/m2, or unknown) and smoking status (no, current, past, unknown) as well as for various comorbidities and drugs. Statistical analyses were performed with the statistical software SAS (release 9.1, SAS Institute, Inc., Cary, NC, USA).
Case validation
We identified all patients with a first-time recorded diagnosis of GORD, ulcer or weight loss/anorexia based on computer-recorded codes. In a computer-aided algorithm we then excluded all patients who had been treated with proton pump inhibitors or H2-antagonist prior to the COPD diagnosis to ensure that we included only incident GORD or ulcer cases. We also excluded patients who had no records of proton pump inhibitor use within one year after the GORD or ulcer diagnosis since proton pump inhibitors are recommended as a first-line treatment for GORD and gastrointestinal ulcer disease (Citation21). We identified patients with recorded weight loss or with an anorexia diagnosis based on specified codes recorded in the computer profile.
RESULTS
We identified 35,772 patients with a first-time COPD diagnosis between 1995 and 2005, and the same number of matched COPD-free patients in the comparison group. The study population encompassed slightly more men (51.3%) than women, and 73% of the study population were 60 years of age or older at the time of the first COPD diagnosis. While the proportion of COPD-patients with a history of recorded GORD (9.5%) was closely similar to that of COPD-free individuals (8.3%), COPD patients were more likely to have had a history of ulcer (8.2% vs. 5.7%) or recorded weight loss (4.4% vs. 1.8%) than patients from the comparison group prior to the first COPD-diagnosis (or the corresponding date in the comparison group). Further characteristics of the study population are displayed in .
After excluding patients with prevalent GORD, ulcer, weight loss, cancer, alcoholism, drug abuse or HIV, we identified among the remaining study population 961 patients who had a pharmacologically treated incident GORD-diagnosis, 247 patients who had a treated incident ulcer diagnosis of the stomach or duodenum, and 1937 patients with an incident recording of weight loss. Incidence rates of GORD, ulcer and weight loss were higher among COPD patients (59.2, 14.8 and 134.0 per 10,000 py, respectively) than among patients in the COPD-free comparison group (44.4, 10.8 and 63.9 per 10,000 py, respectively). The IR was lowest for ulcer and highest for weight loss in patients with or without COPD. The IRR was highest for weight loss (IRR 2.08, 95% CI 1.91–2.28). The IRs and IRRs for the three outcomes of interest, stratified by sex, are displayed in .
Table 2. Incidence rates of GORD, ulcer and weight loss in COPD patients and in the COPD-free comparison group stratified by gender
To evaluate the effects of COPD severity on the study outcomes we conducted a nested case-control analysis where we stratified COPD patients according to treatment into mild, moderate or severe COPD. Differences in the risk of developing GORD or ulcer in relation to COPD severity were small. The relative risk of developing GORD was highest in patients with mild COPD, while the ulcer risk increased with COPD disease severity, although the trend was not statistically significant. Patients with severe COPD were at a significantly increased risk of having an incident recording of weight loss compared to patients without COPD (OR 3.45, 95% CI 2.56–4.64). The detailed findings for the various associations between COPD and gastrointestinal outcomes, stratified by COPD severity, are displayed in .
Table 3. Risk of GORD, Ulcer and weight loss stratified by COPD severity
DISCUSSION
We explored in this large observational study the association between COPD and GORD, ulcer and weight loss. We quantified the prevalence of these diseases prior to the first COPD diagnosis, and we assessed incidence rates of newly diagnosed GORD, ulcer and weight loss in COPD patients as well as in a comparison group of COPD-free patients.
Our results support previous findings (Citation22) of an increased prevalence of weight loss in COPD patients as compared to COPD-free patients. We observed the highest risk of developing weight loss in patients with severe COPD. In a review of pulmonary cachexia syndrome, Congleton stated that 24–35% of patients with moderate to severe COPD are malnourished (Citation22). A study with 103 stable outpatients, 23% of them malnourished, reported an association between reduced nutritional intake / malnourishment and severe lung disease (Citation23). Grönberg et al. described various factors contributing to a reduced nutrient intake in patients with severe COPD, one of them being dyspeptic symptoms (Citation3). COPD has also been associated with increased resting energy expenditure (Citation24). Comparison of results of previous studies is complicated as many of these studies were small, cross-sectional, included only a specific subset of COPD patients, or used different definitions of malnutrition or weight loss.
We found that the prevalence of diagnosed GORD prior to the index date was similar among COPD patients and the COPD-free comparison group. The GORD prevalence in the current study population is in the range of what has been reported in the literature, but a comparison across studies is not easy due to use of a variety of selection criteria, such as self-reported symptoms of heartburn or acid regurgitation, a physician-based diagnosis (as in the case of our study), as well as different methods of data collection (Citation4). The GORD incidence rates we found are similar to incidence rates reported in two other studies investigating the frequency of GORD in the general population (Citation20, Citation25). Our GORD incidence in the COPD population, however, is lower than recently reported by Garcia Rodriguez et al. Different case definitions might explain this difference, for example we excluded patients with a history of PPI or histamine 2 receptor antagonists use (Citation26). We did not observe an increasing risk of GORD with increasing COPD severity, which is in contrast to previous reports of a higher risk of reflux oesophagitis among patients with severe COPD and a higher GORD prevalence in more severe COPD.(Citation27–30) Ruigomez et al., who investigated the natural history of GORD, also reported that COPD was only weakly associated with GORD (OR: 1.3 (1.0–1.8) 95% CI), which is similar to our results (Citation20).
There was only a weak association between COPD and ulcer disease, a smaller association than was reported in studies analysing the association between ulcer and COPD back in the 1960s and 1970s. Most of these studies investigated the association between ‘emphysema’ and ulcer, and it was hypothesized that pulmonary emphysema may change the ‘blood acid balance’, thereby increasing the ‘acid attack factors’ and causing peptic ulceration (Citation10, 11). Since then, a decrease in peptic ulcer cases was observed (Citation16, Citation31). Currently, Helicobacter pylori infection, NSAID use and tobacco smoking are thought to be the main risk factors for ulcer (Citation12, Citation21). Only a few recent studies investigated the association between COPD and ulcer. A Danish study assessed the association between COPD and 30-day mortality of severe peptic ulcer (i.e., hospitalization-requiring perforated or bleeding ulcers) and reported that COPD was associated with less favourable outcomes (Citation14). A recent, cross-sectional, American study based on self-reported data reported a crude increased risk of GI ulcer disease in patients with COPD compared to COPD-free patients (OR: 2.34 (2.21–2.47) 95% CI) (Citation15).
We found an incidence rate of ulcer disease of 14.8 / 10,000 person-years (py) among COPD patients, which was slightly higher than the 10.8/10,000 py among COPD-free patients. Kang et al. analysed the period prevalence of peptic ulceration in England and Wales between 1994 and 1998 and reported falling age-standardized rates from 3.3 and 1.8 / 1000 in male or female patients, respectively, in 1994 to 1.5 and 0.9 / 1000 in male and female patients, respectively, in 1998 (Citation16). In Belgium, incidence rates of duodenal and gastric ulcer were also reported to be decreasing between 1994 and 2003; the age-standardized rates for gastric ulcer decreased from 2.22 (1.94–2.50) in 1994/95 to 0.85 (0.70–1.00) in 2002/03 (per 1000 patient years), and rates for duodenal ulcer decreased from 1.75 (1.50–2.00) to 1.01 (0.84–1.18) (per 1000 patient years) in the same period (Citation31).
We adjusted all analyses on the risk of developing GORD or ulcer for the potential confounders smoking and NSAID use. We also did sensitivity analyses stratified by smoking status which provided evidence that non-smokers with COPD were at a similar relative risk of developing GORD as non-smokers without COPD, while the relative risk of developing weight loss was increased in non-smokers with COPD as compared to non-smokers without COPD (data not shown). We accounted for the possible role of alcohol abuse by excluding patients with known alcoholism from the analysis. We also tried to adjust for Helicobacter pylori infections but had only limited information so that we could not include this factor in the analyses. Despite these efforts we cannot fully exclude residual confounding by Helicobacter pylori infection and/or drinking and/or smoking when reporting the results for the analyses on COPD and ulcer risk.
We identified weight loss as a GP-recorded diagnosis, independent of recorded body weight since too many patients only had a BMI recorded at one point in time, but not on a regular basis over time. We adjusted the analyses for the presence of cardiovascular diseases as body weight is associated both with cardiovascular morbidity and COPD. We further adjusted this analysis for use of antidepressants, since these drugs may have a direct impact on body weight and may be a surrogate marker for stressful events that could have an influence on body weight. However, we are aware that residual confounding by life style may still be present.
It is both a strength and a limitation of the current study that diagnoses were based on GP-recorded diagnoses. It is a strength because all diagnoses in the GPRD are recorded on a routine basis and independently from any study hypothesis, which is superior to interview-based assessments of diagnoses with a particular study hypothesis in mind. On the other hand, we cannot rule out a certain amount of misclassification for both COPD and the various gastrointestinal outcomes of interest. Some diagnoses may have been missed due to underreporting of symptoms to the GP (e.g., for mild forms of COPD), or because patients may have treated themselves (e.g., antacids for GORD, which are available over the counter). Thus, reported incidence rates for these outcomes might be underestimated to some degree. Other diagnoses may be slightly overrepresented in COPD patients, for example because COPD patients may have a higher likelihood of getting a diagnosis recorded because they may see the GP more often. Thus, these results represent incidence rates of GP-recorded GORD, ulcer and weight loss in the UK primary-care setting based on a large, well validated database which has been used for previous published studies on COPD, ulcer and GORD (Citation16, Citation19, Citation20, Citation32).
In summary, the findings of this large observational study suggest that the risks of newly diagnosed ulcer may be slightly increased in patients with COPD as compared to COPD-free patients, while the GORD risk is comparable in both groups. The association between COPD and weight loss was more pronounced. The risk of developing weight loss, and to some degree of developing an incident ulcer, increased with increasing COPD severity, which was not the case for GORD.
ACKOWLEDGEMENTS
This study was funded by an unconditional grant by Nycomed GmbH.
Declaration of interest
Financial disclosure: Dr. Bothner was employed by Nycomed GmbH at that time. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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