Gastroesophageal reflux disease

Study objectives: Gastroesophageal reflux disease (GERD) and asthma are common causes for consultation in primary care, but the relationship between the two remains unclear. The aim of our study was to investigate the temporal relationship between first diagnoses of GERD and asthma in general practice.

Methods: We used the UK General Practice Research Database to identify a cohort of patients with a first diagnosis of GERD (n = 5,653) and another cohort of patients with a first diagnosis of asthma (n = 9,712) during 1996, which we compared with age-matched and sex-matched control cohorts drawn from the general population without either diagnosis. We investigated the incidence of a GERD diagnosis among the asthma patients and control subjects, and the incidence of an asthma diagnosis among the GERD patients and control subjects during a mean follow-up period of 3 years. We calculated the relative risk (RR) of these diagnoses using Cox regression analysis and examined the risk associated with medication use using nested case-control analysis.

Results: The incidence rates of GERD and asthma among the control cohorts were 4.4 and 3.8 per 1,000 person-years, respectively. During the follow-up period, the RR of an incident asthma diagnosis in patients with a new diagnosis of GERD was 1.2 (95% confidence interval [CI], 0.9 to 1.6), while the RR of an incident GERD diagnosis among patients with a new diagnosis of asthma was 1.5 (95% CI, 1.2 to 1.8) after adjustment for age, sex, smoking, prior comorbidity, and number of health-care contacts. This increased risk was mainly seen during the first year of follow-up. The prior use of prescription medications for asthma and GERD had no significant effects on the risk of GERD and asthma diagnosis, respectively.

Conclusions: Patients with asthma are at a significantly increased risk of developing GERD, mainly during the first year following diagnosis. A nonsignificant increase in the risk of developing asthma was evident among GERD patients. The relationship between GERD and asthma warrants further investigation. (CHEST 2005; 128:85-93)

Key words: asthma; epidemiology; gastroesophageal reflux; incidence; primary health care

Abbreviations: BMI = body mass index; CI = confidence interval; GERD = gastroesophageal reflux disease; GP = general practitioner; GPRD = General Practice Research Database; IBS = irritable bowel syndrome; ICD = International Classification of Diseases; OR = odds ratio; RR = relative risk

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Gastroesophageal reflux disease (GERD) is usually diagnosed by the presence of esophageal symptoms such as heartburn and regurgitation, but many individuals with GERD also experience a range of extraesophageal symptoms, such as chronic cough, hoarseness, and chest pain. (1) Among these, asthma has been the subject of particular investigation. A number of small studies (2-14) have reported an increased prevalence of reflux symptoms, esophagitis, and abnormal esophageal acid exposure in highly selected populations of asthma patients who have been referred to the gastroenterologist for investigation, although the absence of control groups in many of these studies makes their findings difficult to interpret.

Several epidemiologic studies have been published presenting the prevalence of asthma in individuals with GERD compared to control subjects. A hospital study (15) found that a diagnosis of erosive esophagitis and esophageal strictures was associated with asthma. A similar hospital study (16) in children showed a significantly increased risk of asthma in patients with GERD compared to control subjects. A population-based study (17) found a significant association between weekly heartburn or belching after bedtime and physician-diagnosed asthma. In a survey from the general population of Olmsted County, MN, (18) asthma was more common among individuals reporting weekly heartburn and/or acid regurgitation (11.6%) than among those without reflux symptoms (7.9%), although this did not represent a significant association. In contrast, a population survey (19) conducted in Hong Kong showed that individuals with any heartburn and/or acid regurgitation over the last year (only a subset of whom may have had GERD) were no more likely to have asthma than those without reflux symptoms.

The association between GERD and asthma has also been investigated temporally. Longitudinal epidemiologic studies (20-22) have shown that GERD and reflux esophagitis are risk factors for asthma and cough. Ruhl and colleagues (20) found that patients hospitalized with hiatus hernia or reflux esophagitis had an increased risk of subsequent respiratory hospitalization. However, the converse relationship was observed by Kotzan and colleagues, (21) who found a significantly increased risk of GERD diagnosis in patients with preexisting asthma.

Longitudinal studies, therefore, support the case for GERD predisposing toward new cases of asthma, and asthma predisposing toward new cases of GERD. However, no studies have looked at these relationships in the same source population over the same time period. Therefore, we conducted two longitudinal cohort studies to investigate the relationship between the first diagnoses of GERD and asthma in patients consulting a UK general practice. In the first study performed, patients with newly diagnosed GERD were identified and followed up to assess their risk of a first asthma diagnosis compared to a control cohort without a diagnosis of GERD or asthma at baseline. In the second study, we identified and followed up patients with newly diagnosed asthma to assess their risk of a first diagnosis of GERD compared to a control cohort without a diagnosis of GERD or asthma at baseline. In addition, we assessed the potential risk associated with the use of prescription drugs for GERD and asthma using a nested case-control analysis.

MATERIALS AND METHODS

Source Population and Study Design

The source population for our studies was drawn from approximately 3 million UK residents who were registered with general practitioners (GPs) participating in the General Practice Research Database (GPRD). Participating GPs record medical information, including patient demographics, medical diagnoses, consultant referral, hospitalization, and a register of written prescriptions. These data are sent anonymously to the Medicines and Healthcare Products Regulatory Agency, which makes them available for use in research projects. The accuracy and completeness of the GPRD has been documented in previous validation studies, (23-26) and in previous studies of patients with GERD (22,27) and asthma. (28,29)

Two cohort studies with nested case-control analyses were performed. The source population for both studies fulfilled the following criteria: age 2 to 79 years during 1996; registered with a GP participating in the GPRD for at least 2 years, with a computerized prescription history for at least the previous year; no previous diagnosis of cancer; and not pregnant in 1996. The selection of the source population and participants in both studies is shown in Figure 1.

[FIGURE 1 OMITTED]

Study Cohorts and Case Ascertainment

Study 1: In study 1, which evaluated the risk of asthma following a GERD diagnosis in the source population, we used a previously identified cohort of patients with a first recorded diagnosis of GERD during the year 1996 (n = 7,159). (22) We removed from the cohort patients with a recorded diagnosis of asthma prior to 1996. We also removed long-term users of acid-suppressing drugs without a clear indication for this use to exclude potential prevalent cases of GERD. We manually reviewed the computerized patient profile of all GERD patients to verify the recorded diagnosis and excluded prevalent cases of GERD, as has been described in detail previously. (22)1 Finally, 5,653 patients constituted the GERD cohort (Fig 1).

A comparison cohort (n = 10,000), frequency-matched by age and sex to the GERD cohort, was randomly sampled from the source population. Alter applying the same exclusion criteria as were applied to the GERD cohort, 8,105 individuals without a GERD diagnosis at the study start date constituted the comparison cohort for study 1 (Fig 1).

Individuals in both the GERD and comparison cohorts were followed up from the start date (ie, the date of GERD diagnosis for patients in the GERD cohort and a random date in 1996 for individuals in the control cohort) until the earliest occurrence of one of the following end points: asthma diagnosis; death; or the end of the study period (December 31, 2001). To ensure that the study population continued to reflect the inclusion criteria, data collection ceased once subjects reached the age of 80 or received diagnoses of any type of cancer. The computerized patient profiles of all patients identified with a code of asthma during the follow-up period were manually reviewed to exclude prevalent cases and to confirm the diagnosis of asthma recorded in the database. For this purpose, an incident case of asthma was defined as a computer-recorded diagnosis of asthma (International Classification of Diseases [ICD] codes 4930, 4931, and 4939) together with a specific recorded symptom of asthma (ie, nocturnal cough, wheeze, or shortness of breath) and/or a prescription for oral steroids, inhaled steroids, or bronchodilators.

The incidence rates of asthma were computed according to age and sex among both the GERD cohort and the comparison cohort drawn from the general population without a GERD diagnosis. We estimated the relative risk (RR) of asthma associated with GERD using Cox proportional hazard regression and adjusting for potential risk factors. We also performed a nested ease-control analysis within the GERD cohort to evaluate the association between the use of acid-suppressing drugs and the risk of asthma by comparing all asthma cases (n = 103) within the GEBD cohort with a random sample of GERD patients without an asthma diagnosis (n = 1,000) as control subjects.

Study 2: In study 2, which evaluated the risk of GELID following asthma diagnosis, we identified patients from the source population who had received a first diagnosis of asthma during 1996 (n = 11,265). We removed patients with a diagnosis of GERD, as well as those who had received > 6 months of treatment with [[beta].sub.2]-agonists during the previous 2 years to exclude potential cases of asthma. The computerized patient profiles of all asthma patients were manually reviewed to verify their diagnosis and to exclude prevalent cases. Finally, 9,712 patients constituted the asthma cohort (Fig 1).

A comparison cohort that was frequency-matched by age and sex (n = 20,000) was randomly sampled from the source population. We applied the same exclusion criteria as the those applied to the asthma cohort. Finally, the comparison cohort for study 2 constituted 19,334 individuals without an asthma diagnosis at the start date (Fig 1).

Persons in both the asthma and the comparison cohort were followed up from the start date (ie, the date of asthma diagnosis for patients in the asthma cohort and a random date in 1996 for individuals in the control cohort) until the occurrence of GE1RD diagnosis, death, or the end of the study period (December 31, 2001). Other reasons to stop data collection were a diagnosis of any type of cancer or reaching the age of 80 years. The computerized profiles of all patients who had been identified with a code of GERD during the follow-up period were manually reviewed to exclude prevalent cases. An incident ease of GERD was defined as the presence for the first time of a computer-recorded code for GERD (ICD codes 5300, 5301, 5305, 5309, 5369, and 7817).

The incidence rates of GERD were computed according to age and sex in both the asthma cohort and the comparison cohort without an asthma diagnosis drawn from the general population. We also estimated the RR of GERD associated with asthma using Cox proportional hazard regression and adjusting for potential risk factors. A nested case-control analysis was performed within the asthma cohort to evaluate the association between the use of [[beta].sub.2]-agonists, or inhaled or oral steroids, and the; risk of GERD, using all GERD cases (n = 219) within the asthma cohort and a random sample of asthma patients without a GERD diagnosis (n = 1,000) as control subjects.

For both studies, we collected information on the following potential risk factors prior to start date: smoking; body mass index (BMI); alcohol consumption; and a medical history of COPD, allergic rhinitis, peptic ulcer disease, and irritable bowel syndrome (IBS). We also collected information on prescriptions issued for [H.sub.2]-receptor antagonists, proton pump inhibitors, prokinetic drugs (ie, domperidone, metoclopramide, and cisa-pride), antacids, inhaled or oral steroids, and [[beta].sub.2]-agonists. All of the above information was extracted from patients' computerized records. For prescription medication use, current use was defined as a supply of medication lasting until the date of asthma diagnosis (study 1) or GERD diagnosis (study 2), or ending in the month prior to this date. Health-care utilization was assessed using the recorded number of visits to the GP, referrals to a consultant, and hospitalizations in the year prior to the study start date.

RESULTS

Study 1: Risk of Asthma Following GERD Diagnosis

During a mean follow-up period of 3.0 years (SD, 1.7 years), we identified 10:3 cases of asthma in the GERD cohort (n = 5,653), corresponding to an incidence rate of 6.0 cases per 1,000 person-years (95% confidence interval [CI], 4.9 to 7.3). During the same period, there were 99 cases in the control cohort (n = 8,105), corresponding to an incidence rate of 3.8 cases per 1,000 person-years (95% CI, 3.1 to 4.6). The age and sex-adjusted RR of asthma in the GERD cohort was 1.5 (95% CI, 1.1 to 2.0). When adjusting for age, sex, smoking, prior morbidity, and health-care utilization (ie, visits to the GP and hospitalization) in the multivariate analysis, there was a nonsignificant increase in the risk of asthma (RR, 1.2; 95% CI, 0.9 to 1.6) among patients with GERD in comparison with those without GERD (Table 2). This risk was the same during the first year after diagnosis of GERD (RR, 1.1; 95% CI, 0.7 to 1.8) as during the remaining follow-up period (RR, 1.2; 95% CI, 0.9 to 1.8). Patients who were [greater than or equal to] 20 years of age were less likely to develop asthma than children and younger adult patients (Table 2). No significant difference in risk was found between men and women (RR, 1.3; 95% CI, 0.9 to 1.7). No clear association was observed with smoking status, BMI, or alcohol consumption (Table 2). Patients with a history of allergic rhinitis were at an almost twofold increased risk of asthma (RR, 2.0; 95% CI, 1.3 to 2.9). Those persons who made frequent visits (eg, 3 to 10 visits) to their GP in the year prior to the study were at greater risk of a first diagnosis of asthma (RR, 1.8; 95% CI, 1.3 to 2.6). In the case-control analysis conducted in the GERD cohort, we observed no significant association between the current use of GI drugs and the occurrence of asthma (Table 3).

Study 2: Risk of GERD Following Asthma Diagnosis

During a mean follow-up period of 2.8 years (SD, 1.6 years), 219 cases of GERD were identified in the asthma cohort (n = 9,712), corresponding to an incidence rate of 8 per 1,000 person-years (95% CI, 7.0 to 9.1). During the same period, 241 cases were identified in the control cohort (n = 19,334), corresponding to an incidence rate of 4.4 (95% CI, 3.9 to 5.0) [Table 4]. The age and sex-adjusted RR of GELID in the asthma cohort was 1.9 (95% CI, 1.6 to 2.2). When adjusting for age, sex, smoking, prior morbidity, and health-care utilization (ie, visits to the GP and hospitalization), there was a small but significant increase in the RR of an incident GERD diagnosis among patients with new diagnoses of asthma (RR, 1.5; 95% CI, 1.2 to 1.8) [Table 5]. The greater increased hazard for GERD among asthma patients was seen during the first year after asthma diagnosis, with a RR of 2.1 (95% CI, 1.5 to 2.9), while the RR in the remainder of the follow-up period declined to 1.2 (95% CI, 1.0 to 1.6). The risk of developing GERD increased with increasing age, such that patients aged > 60 years were 13 times more likely than those < 20 years of age to receive a diagnosis of GERD (RR, 13.6; 95% CI, 8.7 to 21.4). The risk of a new diagnosis of GERD was increased among patients who visited their GP the most frequently (for > 10 visits per year compared with 0 to 2 visits per year: RR, 2.6; 95% CI, 1.8 to 3.4) and among those referred for specialist care or hospitalized (RR, 1.3; 95% CI, 1.1 to 1.6) in the year prior to the study start date. A prior diagnosis of IBS was also a risk factor for having a diagnosis of GERD (RR, 1.5; 95% CI, 1.0 to 2.1) [Table 5].

When adjusting for other potential risk factors, we did not find that the current use of oral or inhaled steroids or [[beta].sub.2]-agonists was associated with a significantly increased risk of GERD among patients with a first diagnosis of asthma, although the current use of oral steroids (odds ratio [OR], 1.6; 95% CI, 0.7 to 3.4) and inhaled steroids (OR, 1.4; 95% CI, 0.9 to 2.3) was associated with a nonsignificant increase in the risk of GERD (Table 6). This increased risk of GERD was particularly marked in asthma patients who had been treated with oral steroids for > 3 months (n = 11) (OR, 4.5; 95% CI, 1.0 to 19.5).

DISCUSSION

The studies presented here reported that in the general population in the United Kingdom diagnoses of asthma and GERD had similar incidence rates (3.8 and 4.4 cases per 1,000 person-years, respectively), which were in the range that has been reported by most studies over the past few years, (21,22,30-37) although they were somewhat lower than those reported by some other studies. (28,38-42) The data presented in our observational studies related to diagnoses made by GPs in routine primary care, making our findings directly applicable to UK general practices. GPs have the advantage of observing large numbers of patients over considerable time periods, factors that are helpful in determining whether there is any relation between GERD and asthma. The estimated incidence rates of GERD and asthma were calculated from GP consultations, possibly leading to many cases going unrecorded, as only a quarter of patients with symptoms of gastroesophageal reflux (43) consult their GP about their symptoms in a given year, and more than one in five schoolchildren reporting moderate-to-severe asthma symptoms remain without diagnoses. (44) Furthermore, the diagnosis of GERD or asthma was reliant on the clinical judgment of GPs rather than on uniform criteria laid down in a prospective study. These factors may have led to a number of delayed or missed diagnoses for patients in the GERD, asthma, or control groups. Misdiagnosis may also have influenced our analyses, since asthma and COPD may be confused with one another in patients > 40 years of age, particularly in those with mild disease. (45) Yet, all of these potential sources of misclassification will have been nondifferential and would have resulted in a small underestimation of the associations discussed below.

We studied, for the first time, the nature of the temporal relationships between cases of GERD and asthma in the same population and over the same time period. We found that patients with a first diagnosis of asthma had a significantly increased risk of a subsequent GERD diagnosis during a mean follow-up period of 3 years, most notably during the first year. This is in line with the hypothesis that the altered respiratory physiology in asthma patients may predispose them toward GERD. (4) Respiratory obstruction can result in negative pleural pressures, increasing the pressure gradient between the thorax and abdominal cavity, thus promoting reflux. (4)

Conversely, we found that patients with a first diagnosis of GERD were not at a significantly increased risk of a subsequent diagnosis of asthma when other risk factors were taken into account. While these results do not support a role for GERD in predisposing patients to asthma, (46,47) it remains possible that GERD may trigger asthma episodes in individuals with preexisting asthma by one of two potential mechanisms. The reflux theory states that gastroesophageal refluxate may access the respiratory tract via the epiglottis, leading to local irritation and inflammation. (48) The reflex theory has also been proposed, (49,50) and it states that acidity in the esophagus can cause irritation elsewhere in the body through a vagally mediated reflex. (51)

Other risk factors for GERD and asthma were also examined. We found that asthma was significantly associated with a history of allergic rhinitis in patients with GERD, and that GERD was significantly associated with a history of IBS in patients with asthma. Similar associations have been seen in previous cross-sectional studies. (15,52-54)

Several other theories have been advanced to explain why GERD and asthma seem to be linked. It remains possible that a third factor, such as obesity or smoking, increases the risk of both diseases, (32,33,35,36,38,39,55-63) although a significant association between these risk factors and the diagnosis of GELID or asthma was not evident in our analyses.

A potential role for prescription medications also has been proposed. A number of asthma medications, such as anticholinergic agents, theophylline, and [[beta].sub.2]-agonists, are known to relax the lower esophageal sphincter through their action on smooth muscle, (64-66) and may predispose a patient to gastroesophageal reflux. It has been shown, however, that the abnormal gastroesophageal reflux seen in many asthma patients is not dependent on the use of a medication, (6,67) and we did not find a clear association between the use of respiratory medications and a subsequent diagnosis of GELID.

Conversely, the treatment of GERD is thought to protect a patient from asthma, rather than predispose them to asthma. Acid-suppressive therapy has, in general, been shown to lead to better control of asthma symptoms, if not better objective measures of pulmonary function. (4,13,68,69) We were, however, unable to demonstrate any such effect in our study population, although the number of current users of acid-suppressive medications was small.

Whether or not treatment for GERD or asthma is useful for the prevention of asthma and GERD, respectively, although it is of general interest, should not be driving management decisions in primary care, as both conditions need appropriate treatment regardless of any relationship or association between them. It is more important that the association between these conditions be more widely recognized so that primary care physicians, in particular, are alert to their possible comorbid occurrence. This may result in better diagnosis and treatment for individuals affected by both GERD and asthma. Further research is needed to elucidate the pathophysiologic mechanisms linking asthma and GERD, and to further evaluate the potential avenues for effective treatment.

ACKNOWLEDGMENT: The authors are grateful to Chris Winchester for editorial advice and comments on a previous version of the manuscript.

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* From the Centro Espanol de Investigacion Farmacoepidemiologica (Drs. Ruigomez and Garcia Rodriguez), Madrid, Spain; AstraZeneca R&D (Drs. Wallander and Johansson), Molndal, Sweden; the Department of General Practice and Primary Care (Mr. Thomas and Mr. Price), University of Aberdeen, Aberdeen, UK. This study was supported by a research grant from AstraZeneca. Manuscript received September 30, 2004; revision accepted December 14, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Ana Ruigomez, MD, PhD, Centro Espanol de Investigacion Farmacoepidemiologica (CEIFE), C/ Almirante 28, [2.sup.o], 28004 Madrid, Spain; e-mail: aruigomez@ceife.es

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