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January - March 2003: 
Volume 16, Issue 1

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Prevalence of gastroesophageal reflux disease symptoms in bronchial asthma patients in Greece
Abstract
A high prevalence of gastroesophageal reflux disease (GERD) symptoms in patients with bronchial asthma has been shown in several reports from North America and Europe. However, no data from Greece are available. The aim of this study is to assess the prevalence of GERD symptoms in Greek asthmatics. A total of 92 asthmatics (50 males and 42 females, aged 42.9±14.2 years) referred to our outpatient clinic, and 85 age- and sex-matched healthy control subjects were asked to complete a structured questionnaire on the presence of GERD symptoms. The prevalence of heartburn and regurgitation was higher in asthmatics (81.5% and 57.6%, respectively) than in controls (32.9% and 7.6%, respectively, p<0.01). None of the medications routinely used in the treatment of asthma was associated with increased prevalence of GERD symptoms. Our results suggest that Greek asthmatics referred to a tertiary care center have a significantly higher prevalence of GERD symptoms compared to controls. Additional studies in the general population of asthmatic patients are required to further clarify the relationship between asthma and GERD in Greece. Pneumon 2003, 16(1):59-66.
Full text

Introduction

In his textbook "The Principles and Practice of Medicine" published in 1892, Sir William Osler was the first to suggest that an overfilled stomach or consumption of certain foods might trigger asthma symptoms.1 The retrograde movement of gastric contents into the esophagus had not yet been defined as gastroesophageal reflux (GER). Osler's theory of a causative association between gastric disorders and asthma attacks did not receive particular attention for almost a century. Gastroesophageal reflux disease (GERD) is now recognized as a distinct clinical entity defined as any clinical and/or pathological condition caused by gastroesophageal reflux. It appears to be highly prevalent in the general population, it presents with heartburn and acid regurgitation, and there is substantial evidence that it may lead to esophagitis and Barrett's esophagus.2

The relationship between GERD and bronchial asthma has been systematically examined in the recent years. Numerous studies in the literature acknowledge the high prevalence of GERD symptoms (heartburn, acid regurgitation) in bronchial asthma patients. However, these reports are based on retrospective data obtained from asthma patients investigated for gastrointestinal symptoms. General asthmatic population data are scant. Studies conducted in asthma treatment centers in Europe and North America report a prevalence of GERD symptoms that varies from 50% to 72%.3‑5 To our knowledge, the Greek literature lacks such data.

The aim of the present study is to assess the prevalence of GERD symptoms in bronchial asthma patients attended in a tertiary care center for respiratory diseases in Greece. Furthermore, the possible relationship between GERD symptoms and the administration of antiasthmatic medications is investigated.

Material - Methods

The duration of the present study was one year, starting from January 1, 2000, through December 31, 2000. All patients consulting our outpatient clinic either with newly diagnosed asthma or for their regular follow-up were considered eligible for inclusion in the study. Inclusion criteria were: a) an increase in FEV1 by >15% following inhalation of bronchodilators, and b) medical history and clinical examination findings compatible with the diagnosis of bronchial asthma.

The control group consisted of healthy, strictly age- and sex-matched adults who consulted our outpatient clinic for a regular screening examination in the same period. The aim of the study was explained to all subjects (both patients and healthy controls) and a written informed consent for their inclusion in the study was obtained.

The time elapsed since the diagnosis of the disease and the medications taken during the study period (e.g. theophylline preparations, β-agonists, ipratropium bromide, inhaled or oral corticosteroids) were recorded for all asthma patients. Patients were also asked to rate on a 0-4 scale any worsening of asthma symptoms in the following situations: i) caffeine intake, ii) alcohol consumption, iii) a large meal, iv) on reclining within 2 hours after the last meal. Finally, all patients underwent spirometry three times (FEV1, FVC, FEV1/FVC measurements) and the higher values were recorded.

Subsequently, both asthma patients and healthy controls were asked to answer a questionnaire specifically designed for the assessment of the prevalence of GERD symptoms. The questionnaire, first employed by Field et al in 1996 and since then used in numerous surveys on the prevalence of GERD symptoms5, was translated in Greek and distributed to the study subjects (Appendix, pages 74-75).

In addition, the use of antacids, H2-receptor antagonists, proton pump inhibitors and prokinetic agents during the last two months prior to inclusion in the study was recorded.

Statistical analysis: Descriptive values for quantitative variables are reported as mean±standard deviation (SD). Associations between binary variables were evaluated using Fischer's exact test. Spearman's rank correlation coefficient was used for comparisons between ordinal variables. The difference in the prevalence of GERD symptoms in asthmatics and controls was evaluated using the Yates corrected chi-square test. The statistical package SPSS (SPSS Inc, IL, USA) was used for data processing and analysis. A p value equal to or less than 0.05 suggested statistical significance.

Results

A total of 92 bronchial asthma patients (50 male, 42 female, mean age 42.9±14.2 years) and 85 sex- and age-matched healthy controls were included in the study. Detailed demographic data and spirometry results of all study subjects are presented in Table 1. Statistical analysis of spirometric values showed no difference in FEV1/FVC values between patients with GERD symptoms and patients without GERD symptoms (65.2±13.8 vs 69.1±12.8, p=0.1).

 

 

Table 1. Demographic data of all study subjects and spirometric values of asthmatic patients.

                          Asthmatic patients       Controls

                                   (N=92)                 (N=85)

Age (years)              42.9 ± 14.2          44.5 ± 13.5

Male/female                 50/42                   45/40

FEV1 (% predicted)   86.5 ±12.3

FVC (% predicted)   71.4 ± 16.1

FEV1/FVC (%)         67.2 ± 14.1

Table 2 shows the prevalence of GERD symptoms in asthma patients and controls. Prevalence data analysis indicated a significantly higher prevalence of both heartburn and acid regurgitation in bronchial asthma patients. Furthermore, asthma symptoms and the need for inhaled bronchodilators increased in the presence of GERD symptoms in a large number of asthma patients (65.2% and 52.1%, respectively). It was also found that asthma patients are more likely to suffer respiratory symptoms after a meal (asthma patients 38%, controls 5.8%, p<0.01) or if they lied down within 2 hours after eating (asthma patients 23.1%, controls 1.1%, p<0.01). In contrast, the prevalences of respiratory symptoms after caffeine intake (asthma patients 4.3%, controls 2.3%, p<0.7) or alcohol consumption (asthma patients 10.8%, controls 5.8%, p<0.2) were similar in the asthma and control groups.

 

Table 2. Prevalence of GERD symptoms in asthmatic patients and controls.

                              Asthmatic      Controls

GERD symptoms patients N (%)  N (%)    p value

Heartburn              75 (81.5)      28 (32.9)   0.009

Acid regurgitation   53 (57.6)      15 (17.6)   0.006

 

 

The great majority of asthma patients were on β-agonists (85 patients, 92.3%) and inhaled corticosteroids (80 patients, 87%). A much lower percentage of patients were taking theophylline preparations (29 patients, 31.5%) or oral corticosteroids (21 patients, 22.8%). Statistical analysis showed no relationship between any of those medications and the prevalence of heartburn and/or acid regurgitation (p<0.01% in all cases).

Antireflux medication use rates in the two study groups are presented in Table 3. Comparative analysis of the use of the four major antireflux medications categories (i.e. antacids, H2-receptor antagonists, proton pump inhibitors and prokinetic agents) indicated higher use rates in the asthma group.

 

 

Table 3. Antireflux medications used in by asthmatic patients and controls.  

Medication class           Asthmatic patients N (%)         Controls N (%)                  p value

Antacids                                    52 (56.5)                          12 (14.1)                        0.007

H2-receptor antagonists             48 (52.1)                          12 (14.1)                        0.006

Proton pump inhibitors              34 (36.9)                          10 (11.7)                        0.009

Prokinetic agents                        35 (38)                             4 (4.7)                          0.003

 

Discussion

The results of our study indicate high prevalence of heartburn (81%) and acid regurgitation (57%) in bronchial asthma patients, Heartburn and acid regurgitation are generally considered the primary clinical manifestations of GERD. The lack of association between those symptoms and any of the routinely used asthma medications implies a high prevalence of GERD in asthmatics.

A large number of papers in the literature report high prevalences of GERD symptoms among asthmatics. A meticulous review of those papers, though, reveals that the majority emanates from gastroenterology hospital departments.6‑8 Therefore, our results should not be compared with those deriving from selected populations of asthmatics undergoing investigation for gastrointestinal symptoms. Nevertheless, three large series from pulmonary medicine centers demonstrate a prevalence of GERD symptoms similar or even higher than that found in the present study. In particular, Perrin-Foyalle et al report GERD symptoms in 65% of asthmatics.3 O' Connel et al found that 72% of asthma patients suffered from heartburn and 50% from nocturnal acid regurgitation.4 High prevalence of GERD symptoms in asthmatics is also reported by Field et al (heartburn in 70%, acid regurgitation in 55%).5

It should be noted, however, that the present study as well as the three above-mentioned reports are not representative of the general population of asthmatics, since they were conducted in reference centers for respiratory diseases where the most severe cases of asthma (those requiring tertiary care) are attended. A recent report, the only one employing an unselected population of asthma patients, did not find a statistically significant difference in the prevalence of GERD symptoms between asthmatics and controls.9 It is generally recognized, however, that more studies in the general population of asthmatics are required before we can arrive at definite conclusions.

The observation that asthmatic symptoms worsen in the presence of GERD symptoms, as e.g. after a meal or on reclining, was reconfirmed in the present study; a causative association between GERD and asthma is, therefore, likely. It has been shown that GERD is the result of the movement of gastric contents and acid from the stomach into the lower esophagus. The frequency of episodes of gastroesophageal reflux is higher in the postprandial period and on reclining soon after eating.2 Gastric acid reflux into the lower esophagus has been established as a cause of respiratory symptoms that resemble bronchial asthma. Four distinct mechanisms have been proposed to explain the harmful effects of GERD on the respiratory system:

i) Reflex bronchospasm (esophagobronchial reflex): The reflux of gastric contents has been suggested to activate vagal receptors on the esophageal mucosa, thus triggering a reflex arch that leads to bronchospasm. Many studies both in animal models and in asthma patients with or without symptomatic GERD have shown a decrease in expiratory flow and an increase in airway resistance following instillation of acid in the esophagus. These effects are not reproducible after medical or surgical inhibition of vagal activity.

ii) Bronchial hyperreactivity: According to this theory, the exposure of the esophageal mucosa to gastric acid increases the reactivity of the tracheobronchial tree to exogenous stimuli.19-21 Bronchial hyperreactivity to challenge testing either with metacholine or with isocapnic hyperventilation with dry air following acid instillation into the esophagus has been clearly shown.22 Increased vagus nerve reactivity to excitatory stimuli has been held responsible for this effect, since bronchial hyperreactivity is abolished if atropine administration precedes the instillation of acid.

iii) Microaspiration: Aspiration of gastric acid is another mechanism thought to precipitate asthmatic attacks in patients with GERD. Animal studies have demonstrated that tracheal exposure to a minute quantity of gastric acid can trigger bronchospasm.21 Furthermore, studies in experimental models have shown that the instillation of acid and pepsin into the pharynx predisposes to repeated episodes of microaspiration.15 Studies in asthmatics with GERD have confirmed that intense bronchial hyperreactivity follows each episode of microaspiration.23

The three above-mentioned theories, alone or in combination, provide the theoretical background that might explain the high prevalence of GERD symptoms in asthmatics. The hypothesis of a causative association between GERD and asthma is particularly attractive. Nevertheless, confirming that hypothesis has so far turned out to be a daunting task owing to the lack of diagnostic modalities capable of confirming or excluding the presence of GER as a trigger of asthmatic attacks.

An additional consideration in the evaluation of the studies addressing the relationship between GERD and asthma is the limited ability to perform esophageal pH measurements (the gold standard for the diagnosis of GERD) in large numbers of patients.24 The present study also suffers from this limitation, since it only assesses the prevalence of GERD symptoms among asthmatics but not the presence of the disease itself. Of particular interest are the results of recent studies where the methodologies of lower esophageal sphincter manometry and esophageal pH monitoring were applied in patients with asthma; those studies have shown a high prevalence of episodes of reflux, including in asthmatics with no symptoms of GERD,25,26 as well as a temporal association between episodes of reflux and asthma attacks.27

Our study shows that the prevalence of GERD symptoms is high among Greek asthmatics attended in a tertiary health care center. Further studies are required in order to: i) confirm these results in the general population of asthmatics, and ii) explore the theory of a causative association between GERD and asthma, which, if proven correct, would offer a convincing explanation for our observations.

 

 

References

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References