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(Chest. 2006;129:1051-1056.)
© 2006 American College of Chest Physicians

The Relation Between Gastroesophageal Reflux and Respiratory Symptoms in a Population-Based Study*

The Nord-Trøndelag Health Survey

Helena Nordenstedt, PhD; Magnus Nilsson, MD, PhD; Saga Johansson, MD, PhD; Mari-Ann Wallander, PhD; Roar Johnsen, MD, PhD; Kristian Hveem, MD, PhD and Jesper Lagergren, MD, PhD

* From the Unit of Esophageal and Gastric Research (Drs. Lagergren and Nilsson, and Ms. Nordenstedt), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; AstraZeneca R&D (Drs. Johansson and Wallander), Molndal, Sweden; Department of Community Medicine and General Practice (Dr. Johnsen), Norwegian University of Science and Technology, Trondheim, Norway; and HUNT Research Centre (Dr. Hveem), Verdal, Norway.

Correspondence to: Helena Nordenstedt, PhD, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden; e-mail: helena.nordenstedt{at}.ki.se

Abstract

Background: In spite of numerous investigations, the relation between respiratory symptoms and reflux symptoms in the general population remains unclear, since population-based studies are few.

Study objectives: To investigate the relation between respiratory symptoms and reflux symptoms in the population.

Subject and methods: In a cohort of 65,363 individuals representing 71.2% of the adult population in the Norwegian county of Nord-Trøndelag, 58,596 individuals (89.6%) responded to questions concerning reflux symptoms. The 3,153 persons (5.4%) with severe and recurrent reflux symptoms constituted the case group, and the 40,210 persons (68.6%) without reflux symptoms served as the control group. Odds ratios (ORs) with 95% confidence intervals (CIs) represented relative risks. Potential confounding was tested in multivariable logistic regression analysis.

Results: Persons with asthma had reflux to a 60% greater extent than those without asthma after including adjustment for asthma medication (OR, 1.6; 95% CI, 1.4 to 1.9). There was a statistically significant dose-response association between breathlessness and reflux symptoms (p for trend < 0.0001), and the OR of severe breathlessness was 12.0 (95% CI, 9.5 to 15.2). Persons with heavy and wheezy breathing, daily cough, daily productive cough, or chronic cough showed a twofold to threefold statistically significant increase in risk of reflux symptoms. Adjustment for asthma or use of asthma medication did not substantially influence the risk estimates for any of the studied respiratory disorders.

Conclusions: Reflux symptoms commonly coexist with asthma and other respiratory symptoms on a population-based level, seemingly irrespective of asthma medication.

Key Words: asthma • epidemiology • gastroesophageal reflux • respiratory symptoms

Gastroesophageal reflux and respiratory disorders both constitute true public health problems in Western societies. Approximately 20% of the adult population have reflux symptoms at least once a week.123 Reflux is an important risk factor of esophageal adenocarcinoma,4 a malignant disease with poor survival.5 Treatment of reflux, both pharmacologic and surgical, is costly6; left untreated, reflux has a well-documented deteriorative impact on quality of life, with significant expenses to society, mainly as a result of work loss.789

The relation between respiratory disorders and reflux symptoms has been debated since the beginning of the last century, and the interest in this question has increased during the last few decades. Many studies1011 have addressed the issue by estimations of the prevalence of reflux in patients with specific respiratory conditions. Research on the link between reflux and asthma or asthma medication has been particularly intense, and the way of causality is uncertain. Few of these studies included a control population for comparison, however. Moreover, many studies of the association between asthma and reflux had selection bias, since data were obtained in a retrospective manner, ie, from asthmatic persons who had already established contact with medical care. Studies addressing the correlation between respiratory disorders and reflux symptoms in an unselected group of persons are sparse, and the question has not been examined on a true population-based level. Thus, in spite of the large number of studies undertaken, the true relation between respiratory symptoms and reflux symptoms in the population remains unclear. With the aim of investigating the relation between specified respiratory disorders and reflux symptoms in the population, we conducted a large, population-based, case-control study with the ability to adjust the results for several potentially confounding factors, including asthma medication.

Materials and Methods

Data Source
The data source has been described in detail elsewhere.12 In brief, the Nord-Trøndelag Health Survey (HUNT)-2 is a large, population-based health survey carried out in the county of Nord-Trøndelag in Norway during the years 1995 to 1997. The demographic structure of this county is representative of Norway as a whole, although the level of education and the average income are somewhat lower than the Norwegian averages. All 94,197 county residents ≥ 20 years old were invited to participate in the survey. In all, 62,651 persons (67%) agreed to take part. The participants were asked to fill in extensive questionnaires, including questions on symptoms of reflux and respiratory symptoms. Moreover, data regarding several potentially confounding variables were collected: age, sex, tobacco smoking, body weight and height, alcohol consumption, and use of asthma medications.

Ethical approval for HUNT was obtained from the Regional Committee for Medical Research Ethics, Region IV, Norway. The participants gave extensive written consent to the use of the data. The Norwegian Data Inspectorate has given its approval of the establishment of a research register.

Identification of Cases and Controls
Participants of HUNT-2 were asked to report reflux symptoms during the past 12 months together with their severity ("minor" or "major"). The reflux symptoms used in the questionnaire were recurrent heartburn or regurgitation: the cardinal symptoms of reflux.13 The participants were then classified into three groups based on the reported reflux symptoms. Those without reflux symptoms served as the control group, while those reporting severe symptoms were selected as the case group. The group with minor symptoms was excluded from the study, since the possibility of misclassification of reflux was deemed to be higher in this intermediate group. Such misclassification would decrease the specificity of the reflux disease.

Reflux Disease
The use of questionnaires concerning heartburn and acid regurgitation is a well-validated method of assessing the true occurrence of reflux.1415 Nonetheless, we conducted a separate validation study to compare the question regarding reflux symptoms in HUNT-2 with that in another, more comprehensive questionnaire. In this validation study,12 1,102 outpatients from the county of Nord-Trøndelag in Norway and Karolinska Hospital in Sweden were included as previously described. In summary, 95% of the participants with severe reflux symptoms (corresponding to our case group) had reflux symptoms at least once a week, which resulted in a specificity of 99.5% for reflux symptoms occurring at least once per week in our case group.

Respiratory Disorders
The participants were asked about various respiratory disorders experienced during the past 12 months: (1) daily cough and, in the case of a positive answer, for how many months and whether the cough was productive; (2) breathlessness, with three alternative answers: no symptoms, minor symptoms, or major symptoms; (3) attacks of heavy breathing or wheezing during the past 12 months; (4) occurrence of asthma; and (5) use of asthma medication.

Statistical Analysis
All respiratory variables under study except breathlessness were encoded as dichotomous, indicating presence or absence of the symptom or condition. In the logistic regression analysis, severe reflux symptoms, as defined above, served as the outcome variable. Chosen as potentially confounding factors were the following: age (categorized into 10-year intervals); sex; body mass index (BMI) [body weight in kilograms divided by the square of body height in meters; grouped as < 25 kg/m2, 25 to 30 kg/m2, 30 to 35 kg/m2, and > 35 kg/m2]; smoking (years of daily smoking classified into < 1 year, 1 to 10 years, and > 10 years); use of alcohol (number of occasions of drinking alcoholic beverages during the last 2 weeks classified as none, 1 to 4 drinks, 5 to 10 drinks, and > 10 drinks); occurrence of asthma (yes or no); and use of asthma medication (yes or no). For all these variables, the data were cross-sectional, except for smoking, for which we used data representing lifetime exposure. A multivariable, unconditional logistic regression analysis (GENMOD, SAS 8e; SAS Institute; Cary, NC) was performed to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) that were used to estimate the influence of each predictor variable. The potential confounders were tested by introducing them one by one into the model. Since occurrence of asthma and alcohol consumption did not contribute to explaining the variance, these variables were left out of the final multivariable model.

Results

Study Participants
Of the 65,363 individuals participating in the HUNT-2 survey, 58,596 persons (89.6%) answered the questions regarding reflux symptoms. Of these, 40,210 persons (68.6%) had no reflux symptoms and thus represented the control group, whereas the 3,153 persons (5.4%) with severe reflux symptoms constituted the case group. Table 1 outlines some characteristics of the study participants. The mean ages of the case and control participants were 52 years and 48 years, respectively. The proportion of men was slightly higher in the case group (49%) than in the control group (47%). Case participants were more likely to be overweight (BMI > 25) and to have smoked for > 1 year compared to the control persons, while the distribution of alcohol consumption was similar between the groups (Table 1).


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  		Table 1. Characteristics of the Case Participants With Reflux Symptoms and Control Participants Without Reflux Symptoms*

 
Associations Between Respiratory Disorders and Reflux Symptoms
Strong statistically significant associations between a number of respiratory symptoms and reflux symptoms were found (Table 2 ). The occurrence of any of the respiratory symptoms listed in Table 2 was almost three times more common among the persons with reflux symptoms than among the control persons. The multivariable analysis revealed that the persons with asthma had reflux symptoms twice as often as those without asthma (OR, 2.0; 95% CI, 1.8 to 2.2), and this association remained after adjustment for use of asthma medication (OR, 1.6; 95% CI, 1.4 to 1.9). Persons with heavy and wheezy breathing, daily cough, daily productive cough, or chronic cough (daily productive cough for > 3 months during the past 2 years) showed a statistically significantly twofold to threefold increase in the risk of reflux symptoms (Table 2). Furthermore, breathlessness showed a significant dose-response association with reflux symptoms (p for trend < 0.0001). The OR of reflux symptoms was 12.0 (95% CI, 9.5 to 15.2) among persons with severe breathlessness compared to those without such symptoms. The occurrence of asthma or the use of asthma medication did not substantially influence the risk estimates for any of the studied respiratory disorders, indicating a lack of strong confounding by these covariates (Table 2).


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  		Table 2. Respiratory Disorders and Reflux Symptoms*

 
Discussion

This large population-based study provides evidence that several respiratory disorders, including asthma, are linked with gastroesophageal reflux symptoms on a population-based level. Strong or moderate associations between a variety of respiratory symptoms and symptoms of reflux were identified, with breathlessness showing a particularly strong and dose-response association with reflux symptoms.

The single most important advantage of this study compared to previous research is the population-based design, with a high participation rate, that acted against selection bias. Selection bias has been an important source of error in many previous studies addressing reflux in relation to respiratory conditions, where the participants had been referred and therefore selected with a special hypothesis in mind. Further advantages of the present study are the ability to adjust the results for all biologically plausible confounding variables, and the large sample size. Limitations of our study include the cross-sectional assessment of respiratory symptoms and reflux symptoms, which prevented us from addressing the temporal, and hence also causal, relation between these conditions. The symptoms used for case classification, heartburn and acid regurgitation, are well validated as representative of true reflux,1617 but we did not use a validated questionnaire to assess reflux symptoms. For this latter reason, a separate validation study was performed and showed that the questions used in the HUNT-2 survey were highly specific for reflux as compared to a more detailed and previously used reflux questionnaire.12 However, some data indicate poor correlation between esophageal pH monitoring of acid reflux and respiratory symptoms of reflux.18 Moreover, we excluded survey participants reporting minor reflux symptoms, since this group was more heterogeneous than the group with severe symptoms. Another potential limitation of our study was the assessment of the respiratory disorders. Since no objective methods could be used to estimate these respiratory disorders, we were only able to reliably investigate respiratory symptoms, and could only indirectly consider defined respiratory diseases. Nevertheless, any misclassification based on this limitation could not have explained our positive finding, since such an error would probably be nondifferential and would therefore only dilute the risk estimates. Confounding could never be completely ruled out. Obesity, for instance, is a well-known risk factor for reflux that recently has been recognized as a risk factor for asthma as well.1219 To reduce the risk of confounding, we adjusted statistically for all plausible confounding variables, including obesity represented by BMI. However, residual confounding cannot be excluded. An additional limitation of our study is that we had no data on antireflux therapy. Finally, the risk of chance findings clouding the results is diminished by the large size of the study.

Our results are consistent with the findings in most earlier, large-scale studies, although a lack of association between self-reported asthma and reflux symptoms has been reported.1 In a study of the comorbid occurrence of laryngeal and pulmonary disease with esophagitis, comprising > 100,000 military veterans in the United States, the ORs ranged between 1.2 and 1.5 for the respiratory diseases investigated.20 The possible reason why those ORs are slightly lower than ours is that their study population consisted of patients with esophagitis and other inpatients with a higher rate of respiratory disorders in general. In another study, hospitalization due to hiatal hernia or reflux esophagitis increased the risk of future respiratory disease hospitalization to the same extent as our results.21

Several possible mechanisms underlying a relation between reflux and respiratory symptoms have been proposed. In anesthesia literature, it is well known that ventilation rates can increase as a result of pain. Field et al22 reported increased minute ventilation due to sensations of discomfort during acid perfusion of the esophagus in patients with normal lung function. Increased minute volume could cause breathlessness in otherwise pulmonary healthy individuals. The majority of additional explanations suggest that reflux causes respiratory symptoms rather than vice versa. Heightened bronchial reactivity, microaspiration, and a vagally mediated reflex mechanism are possible pathways.23 Exposure to small amounts of acid has recently been proposed to result in impaired laryngopharyngeal sensitivity and thereby potentially increasing the risk of aspiration.24 It has also been suggested, however, that asthma causes or aggravates reflux. Airflow obstruction due to asthma might increase the negative pleural pressure and thereby increase the pressure gradient over the diaphragm. Furthermore, it has been suggested that bronchodilator medication might predispose to gastroesophageal reflux.25 Theophylline has been shown to stimulate gastric acid secretion and lower the pressure of the lower esophageal sphincter,26 effects that could cause or intensify reflux symptoms. Similarly, ß-adrenergic agonists might relax the lower esophageal sphincter, especially when systemically administered.2728 Hence, the literature on the mechanism underlying the association between reflux and respiratory symptoms is not conclusive. Avidan et al29 investigated the temporal association between coughing or wheezing and reflux episodes in asthmatics and concluded that even though occasional coughing can lead to reflux, the opposite is far more common. They found that almost half of all coughs and wheezes were associated with reflux. This finding implies that the respiratory symptoms might be alleviated by antireflux treatment. Indeed, several studies30313233 have focused on this issue; in the majority of them, improvements in asthma symptoms but not in objective measures of pulmonary function were noted after antireflux therapy, both medical and surgical. However, in a recent study,34 treatment with esomeprazole twice daily did improve morning peak expiratory flows in adult asthmatics.

Our results might have clinical relevance. The associations reported point to the need to consider reflux symptoms as a cause or contributory factor of respiratory disorders, particularly those respiratory problems that do not respond well to conventional treatment. Antireflux therapy might be an alternative treatment that could better help some of these patients. It is important that primary health-care physicians be aware of the association between respiratory disorders and reflux symptoms, since they are the ones who will treat the majority of these patients.

In conclusion, our large population-based study has revealed a strong link between gastroesophageal reflux symptoms and various respiratory disorders. This finding is of clinical relevance, and antireflux therapy might be a valuable therapeutic tool in some patients with respiratory disorders.

Acknowledgements

We thank the Norwegian Institute of Public Health and the HUNT Research Centre, Verdal, Norway, for performing the two HUNT surveys, and the HUNT Research Centre, Verdal, Norway, and the medical faculty of the Norwegian University of Science and Technology, Trøndheim, Norway, for allowing access to the database.

Footnotes

Abbreviations: BMI = body mass index; CI = confidence interval; HUNT = Nord-Trøndelag Health Survey; OR = odds ratio

This study was supported by AstraZeneca R&D, Mölndal, Sweden.

Received for publication August 21, 2005. Accepted for publication October 7, 2005.

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