Gastro-esophageal reflux (GER) disease is a common disorder and up to 40% of the Iranian population suffers from its classical symptoms. ¹,² The association of GER with a wide variety of pulmonary disorders was recognized as early as 1887. Mendelson ³ described pulmonary aspirations producing an acute asthma-like syndrome with wheezing in some patients. Researchers have suggested that GER is one of the etiologic factors in the development of pulmonary disorders, ⁴ upper respiratory symptoms such as cough, hoarseness, and throat complaints ⁵ as well as an aggravating factor for the symptoms of asthma. ⁶,⁷,⁸,⁹ Potential mechanisms underlying GER-induced airway symptomatology are thought to be microaspiration of acid into the airways with subsequent induction of an inflammatory response and bronchoconstriction, or stimulation of acid-sensitive receptors in the esophageal wall. The latter may either cause bronchoconstriction mediated by a direct vagal reflex or increase airway hyper-responsiveness through vagally-mediated pathways. ¹⁰,¹¹ Several studies have been done to assess the association of GER and pulmonary disorders but most of these studies evaluated the effect of GER in asthmatics. ¹²,¹³,¹⁴,¹⁵ Bagnato et al., studied 30 patients suffering from GER without any evidence of asthma and 30 normal people using methacholine test. They concluded that subjects with GER had a greater increase in airway reactivity when inhaling methacholine compared to disease-free normal subjects. ¹⁶ In the present study we aimed to approach an asymptomatic respiratory disorder i.e., airway hyper-reactivity (AHR) via gastroenterologic abnormalities (GER symptoms and esophagitis). In addition, we tried to detect AHR in patients with esophagitis, and then the effect of six-month anti-reflux medical treatment on methacholine test and respiratory symptoms was assessed.

In this controlled cohort study 30 patients with complaints of acid reflux symptoms and without respiratory symptoms attending a gastrointestinal clinic from November 2009 to May 2010 were included through convenience sampling. A checklist regarding gastrointestinal symptoms of GER was filled for each patient. All subjects with proven cardiovascular disease, pulmonary symptoms, active pulmonary disease like asthma, prior gastric surgery, pregnant women, active smokers, and patients with scleroderma were excluded. None of the subjects had used H2-blockers or proton pomp inhibitors during the three months preceding the study. All patients were evaluated endoscopically and the patients with esophageal, gastric and duodenal ulcers, patients with gastrointestinal malignancies were excluded. After upper gastrointestinal endoscopy, 15 patients were found to have reflux with esophagitis and another 15 had reflux without any evidence of distal esophagitis. They were organized as case and control groups respectively. The cases and the controls were matched for age and sex. Then all the patients underwent spirometry and methacholine test with asthograph. Asthograph is an apparatus that determines the resistance and conductivity of airways following inspiration of measured methacholine doses. Methacholine test was considered positive with constant doubled resistance or 35-40% decrease in conductivity. ¹⁷ After a six-month period of oral anti-acid therapy (40 mg pantoprazole daily, Adibi Pharmacy Co, Tehran, Iran), patients were evaluated with another spirometry and methacholine test. Relief from acid reflux symptoms was assessed at the sixth month of treatment. The definition of relief was patient-based judgment. There is no consensus indication for Helicobacter pylori eradication in patients without gastric and duodenal ulcers. ¹⁸ Since patients with gastric and duodenal ulcers were excluded, consequently all patients just receive proton pomp inhibitor treatment and Helicobacter pylori eradication was not indicated.

All subjects were completely informed about the study and gave their written informed consent prior to their inclusion in the study. The results were analyzed by Chi-square and independent t-test in SPSS Version 13. P value under 0.05 was considered statistically significant.

Demographic characteristics and spirometric values are shown in Table 1. According to the normal body mass index value (<25), 66.7% of cases and 60% of controls were normal (P = 0.30).{Table 1}

The mean period of symptomatic acid reflux was 24.9 ± 7.5 months in the case group and 24.1 ± 5.8 months in the control group (P = 0.93) and its severity was classified as follows; Class 1-less than once a week, Class 2-once a week, Class 3-two to four times a week, and Class 4-daily. All the patients underwent gastric mucosal biopsy for detection of Helicobacter pylori and it was found that 53.3% of cases and 33.3% of controls were infected (P = 0.04).

Acid reflux symptoms were relieved in 20% of the case group and 80% of the control group patients after anti-acid therapy with a significant difference (P < 0.0001). There was a significant difference in the rate of positive methacholine test between cases (40%) and controls (6.7%) prior to anti-acid therapy (P < 0.0001). After six months of anti-acid therapy, the rate of positive methacholine test diminished from 40 to 13.3% in the case group (P < 0.05) but did not change in the controls (P = 0.15). Mean spirometric values and their statistical analysis before and after methacholine test at the sixth month showed no difference between patients with and without esophagitis Table 2.{Table 2}

The prevalence of positive methacholine test in subjects with proven esophagitis was more than in patients with GER symptoms without evidence of esophagitis (40% vs. 6.7%), and it diminished after treatment with pantoprazole. There are several studies that have proved the high prevalence of GER in patients with asthma ¹⁹ but few ones have evaluated the effect of GER on bronchial hyper-reactivity in patients with no respiratory symptoms. Although the physiopathology and significance of asymptomatic bronchial hyper-reactivity are not definitively clarified, several investigations suggested that individuals with bronchial hyper-reactivity who have absolutely no symptoms may be in a latent phase of asthma that may become clinically active over the course of time. ²⁰,²¹,²²,²³ Bagnato et al., in a study showed that subjects with GER and no clinical evidence of asthma had a greater increase in airway reactivity when inhaling methacholine compared to disease-free normal controls. They concluded that GER is associated with increased bronchial responsiveness following challenge with methacholine. ¹⁶ In a population-based birth cohort followed to age 26, Hancox et al., confirmed that there is a strong association between symptoms of GER and symptoms of asthma. Acid regurgitation tended to be a stronger predictor of respiratory symptoms than heartburn, but those with both heartburn and acid regurgitation had the highest risk of respiratory symptoms. The Hancox study provided longitudinal follow-up of asthma, wheeze and airway responsiveness since childhood, data on GER symptoms were not collected during childhood or adolescence and they were unable to establish the temporal sequence between respiratory symptoms, airway responsiveness and GER. ²⁴ In another study by Demetrios et al., it was shown that patients with symptomatic GER and positive PH studies with no history of respiratory symptoms had significantly higher upper respiratory symptoms′ (laryngeal, nasal, sinus, pharyngeal and aural) scores than subjects with heartburn and negative PH probe studies. In their study, upper respiratory symptoms′ scores were proportional to the severity of GER expressed in numbers of reflux episodes recorded by 24-h monitoring. The proportional increase of scores with reflux episodes supports an association between GER and upper respiratory symptoms. ²⁵

Another aim of the present study was to determine whether acid-suppressive medical therapy would decrease AHR or not. Interestingly, after six-month anti-reflux treatment with pantoprazole, the rate of AHR decreased from 40% to 13.3% in the case group. In contrast, no change in AHR was observed after six-month treatment in the control group. This finding highlights the effect of GER and esophagitis in the pathogenesis of AHR, in which AHR responds to a proton pomp inhibitor with no direct medication for the respiratory system. Various studies have demonstrated controversial results about the effect of anti-reflux treatment with proton pomp inhibitors on asthma. Some studies revealed that treatment with proton pomp inhibitors had improved asthma symptoms and pulmonary function, ²⁶,²⁷ while Boeree et al., concluded that no clinical benefit of high-dose omeprazole could be established in asthma and chronic obstructive lung disease patients with severe airway hyper-responsiveness and increased GER. ²⁸ In another study by Littner et al., it was shown that in patients with moderate to severe persistent asthma and symptoms of acid reflux, treatment with lansoprazole did not improve asthma symptoms or pulmonary function, or reduce albuterol use. It has been shown that lansoprazole could reduce asthma exacerbations and improve quality of life in patients with asthma. ²⁹ However, in this study we focused on AHR patients without asthma and found a positive effect of acid-suppressive medical therapy on results of methacholine test.

The small sample size is a major limitation of our study. We did not perform esophageal biopsy and eosinophilic esophagitis although a rare disorder could not be ruled out. ³⁰ Further studies with random selection and crossover design are recommended to improve both internal and external validity.

We concluded that the presence of esophagitis due to GER would increase the AHR, and a decrease in AHR in patients with proven esophagitis and no previous history of asthma receiving six months′ treatment with pantoprazole 40 mg daily was shown, as well.

This study was financially supported by the Baqiyatallah University of Medical Sciences, Tehran, Iran.