Prevalence of Gastro-oesophageal Reflux Disease in 'Difficult-to-Control' Asthma and Response to Medical Antireflux Therapy

Prevalence of Gastro-oesophageal Reflux Disease in 'Difficult-to-Control' Asthma and Response to Medical Antireflux Therapy Magdy M. Emara 1, 6, Mohamad A. Habeb 2, Mohamad A. Moharam 3, Mohmad Mosaad 4 Mohamed Fath EL-Bab 5, 7 1 Department of Thoracic Medicine, Mansoura University, 2 Department of Thoracic Medicine, Zagazig University, 3 Department of Internal Medicine, Mansoura University, 4 Department of Endemic and infectious diseases, Suez Canal University, Ismailia, Egypt. 5 Department of Physiology, College of Medicine, Taibah University, AL-Madinah AL-Munawarah, Kingdom of Saudi Arabia, 6 Department of Internal Medicine, College of Medicine, Taibah University, AL- Madinah AL-Munawarah, Kingdom of Saudi Arabia, 7 Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt. Correspondence: Magdy Mahmoud Emara, Associate professor of pulmonology, Department of Thoracic Medicine, Mansoura University, Mansoura 35516, Egypt. E-mail: magdyemara@live.com. Abstract Background: Gastroesophageal reflux disease (GERD) and asthma are two common diseases that afflict millions of people all over the world. It has been indicated that there is a causal relationship between asthma and GERD: asthma may cause or precipitate GERD and vice versa, and so much as a vicious cycle. Gastroesophageal reflux can induce bronchospasm, and antireflux therapy has been shown to improve pulmonary function in patients who have gastroesophageal reflux disease (GERD) associated with asthma. The prevalence of GERD in difficult-to-control asthma is truly increased and that GERD in some way contributes to the refractive nature of the asthma. Aim of the work: The aim of this work was to determine the prevalence of GERD among patients with difficult-to-control asthma and the effect of medical antireflux therapy on asthma symptoms and pulmonary function. Patients and methods: Sixty one (25.52%) patients were diagnosed to have DTC asthma after screening of 239 consecutive asthmatic patients. Twenty nine (55.76%) patients with DTC asthma out of 52 patients who fulfilled the inclusion criteria to participate in this study proved to have GERD and only 20 cases completed the study (Group I), they were 20 males, their ages ranged from 18-52 years with a mean age of (38.75 ± 12.12) years. The remaining 23 DTC asthma patients proved not to have GERD (44.23%) and only 20 cases completed the study (Group II), they were 16 males and 4 females, their ages ranged from 20-54 years with a mean age of (33 ±8.65) years. They received antiasthma therapy only. All patients were subjected to detailed medical history, physical examination, routine laboratory investigations, chest X ray PA, Oesophagogastroduodenoscopy, 24-h esophageal ph monitoring to detect GERD, and spirometry before start and 12 weeks after completion of therapy. Patients were instructed to record mean daily daytime and nighttime asthma symptoms, mean daily reflux symptoms, and salbutamol use as rescue medication (number of puffs) one week before study and 12 weeks after starting medications. The asthmatic medications of both groups remained unchanged throughout the study period. DTC asthma proved to have GERD (group I) were given a course of oral esmoperazole 40 mg once a day and domperidone 10 mg three times a day for 12 weeks. Patients were asked to return for assessment 12 weeks after starting medications. Results: Oesophagogastroduodenoscopy findings revealed that 6 (30%) out of 20 DCT asthmatic patients with GERD had non-erosive reflux disease (NERD), and 14 (70%) had erosive reflux disease (ERD), and 9 patients (45%) had hiatal hernia. On the other hand, 20 DCT asthmatic patients without GERD had 1

normal Oesophagogastroduodenoscopy findings. Results of ambulatory 24-h oesophageal ph monitoring showed that the percentage time ph <4.0 was 4.7 ± 1.82 in DCT asthmatic patients with GERD and 1.2 ± 0.8 in DCT asthmatic patients without GERD. Four out of 6 NERD patients had a positive ph test, and two had a negative ph test but frequent predominant symptoms of heartburn and acid regurgitation. In twelve patients out of 14 with ERD, 24-h oesophageal ph test was positive. Our results showed statistically significant increase in PEF and statistically insignificant differences in FEV1, FVC, FEF25%, FEF50%, FEF75 in DCT asthma without GERD group12 weeks after compared to that before antiasthma therapy. On the other hand, there were statistically significant increase in FEV1, FVC and statistically insignificant difference in PEF, FEF25%, FEF50%, FEF75 in DCT asthma with GERD group12 weeks after compared to that before antiasthma plus antireflux therapy. Our results showed statistically significant increase in FEV1 and statistically insignificant differences in FVC, PEF, FEF25%, FEF50%, and FEF75 Introduction: Gastroesophageal reflux disease (GERD) and asthma are two common diseases that afflict millions of people all over the world (1). Previous studies have estimated the prevalence of GERD in adult asthmatics at between 34% and 80 % (2, 3). GERD is reportedly the most common trigger in difficult-to-control asthma (4). Potential mechanisms to explain the causal relationship between asthma and GERD include microaspiration of acid into the airway (5), vagal acid reflex response to acid aspiration (6), neuroinflammatory reflex to acid stimuli induced synergistic interactions between esophageal nociceptors and airway sensory nerves (7), and airway PH deviation induced inflammatory cell activation in the airway (8). These mechanisms imply that the elimination of acid from the airway would contribute to an (9). improvement in patients with asthma Esophageal acidification altered the pulmonary function and antireflux therapy has reduced the requirement of drugs for management of asthma by 75 % (10, 11). Few studies have been carried out in DTC asthma patients. Littner et in DCT asthmatic patients without GERD 12 weeks after antiasthma therapy compared to that of DCT asthmatic patients with GERD 12 weeks after antiasthma plus antireflux therapy. Our results showed statistically significant improvement in daytime symptoms, nighttime symptoms, use of rescue medication, and daily reflux symptoms 12 weeks after antiasthma plus antireflux therapy compared to that before in DCT asthma with GERD group. Conclusion: GERD was diagnosed in more than half of our studied patients with difficultto-control asthma. Antireflux therapy in such patients has minimal effect on pulmonary function, but significantly improves asthma symptoms, nighttime symptoms, rescue medication use, daily reflux symptoms suggesting that these patients might benefit from antireflux therapy. Key words: Difficult-to-control asthma; Gastro esophageal reflux disease; Antireflux therapy; Prokinetic; esmoprazole; Pulmonary function tests. Abbreviations: Difficult -to-control asthma (DTCA), Gastroesophageal reflux disease (GERD). al, 2005 reported that a subgroup of DTC asthmatic patient who had GERD achieved the greatest benefit of asthma control after being treated for GERD compared with those patients who had milder form of asthma (12). Patients and methods: Asthmatic patients who attended the outpatient pulmonary clinic of king Fahd hospital, Al-Madinah Al-Monawara, Kingdom of Saudi Arabia and followed up within the period from April, 2009 to May, 2011were enrolled in this prospective study. Patients were considered to have asthma when there was a typical history of asthma within the past 12 months. All asthmatic patients had paroxysmal attacks of wheezy chest, dyspnea, cough and expectoration or documented reversible airway obstruction as determined by a 12% improvement in FEV1 after bronchodilator (salbutamol) inhalation or Peak expiratory flow rate variability (>20%). Screening of 239 consecutive asthmatic patients for cases with difficult-to-control 2

(DTC) asthma as defined by persistent and recurrent symptoms and who patients had poor asthma control despite being on optimal asthmatic medications and requiring frequent rescue b2-agonist inhaler therapy were recruited for the study. Sixty one (25.52%) patients were diagnosed to have DTC asthma and only 52 patients fulfilled the inclusion criteria to participate in this study. Twenty nine (55.76%) patients with DTC asthma proved to have GERD and only 20 cases completed the study (Group I), they were 20 males their ages ranged from 18-52 years with a mean age of (38.75 ± 12.12) years. The remaining 23 DTC asthma patients proved not to have GERD (44.23%) and only 20 cases completed the study (Group II), they were 16 males and 4 females, their ages ranged from 20-54 years with a mean age of (33 ±8.65) years. The asthmatic medications of both groups remained unchanged throughout the study period. DTC asthma proved to have GERD (group I) were given a course of oral esmoperazole 40 mg once a day and domperidone 10 mg three times a day for 12 weeks. Patients were asked to return for assessment 12 weeks after starting medications. All studied cases of DTC asthma were subjected to the following: 1. A detailed medical history including age, sex, smoking habits, onset of asthma. Patients were instructed to record mean daily daytime and nighttime asthma symptoms, mean daily reflux symptoms, and salbutamol use as rescue medication (number of puffs) one week before study and 12 weeks after starting medications. Asthma symptoms included wheezing, chest tightness, dyspnea and cough and were graded on a scale of 0-4 (1-none, 2- mild, 3-moderate, 4-severe). Reflux symptoms included heartburn, regurgitation, dysphagia, belching and hoarseness and were graded similarly. 2. Routine laboratory investigations. 3. Chest x-ray PA view. 4. Oesophagogastroduodenoscopy for both asthmatic groups. Olympus gastrointestinal fiberoptic endoscope GIF-K2 type. Diagnosis and grading of oesophagitis was made according to the Los Angeles (LA) (13). classification Patients with these changes were considered to have erosive reflux disease (RE). Patients were considered to have non-erosive reflux disease (NERD) if they had typical symptoms of GERD but a negative EGD. A hiatal hernia was considered to be present if during endoscopy gastric folds were seen extending at least 2 cm above the diaphragmatic hiatus during quite respiration. The Los Angeles classification of esophagitis Grade A One (or more) mucosal break no longer than 5 mm, that does not extend between the tops of two mucosal folds. Grade B One (or more) mucosal break more than 5 mm long that does not extend between the tops of two mucosal folds. Grade C One (or more) mucosal break that is continuous between the tops of two or more mucosal folds but which involves less than 75% of the circumference. Grade D One (or more) mucosal break which involves at least 75% of the oesophageal circumference. 5. 24-h esophageal ph monitoring to detect GERD. Acid exposure was measured in six components which included number of acid refluxes, number of long refluxes, longest reflux, total fraction time ph <4 (%), upright fraction time ph <4 (%) and supine fraction time ph <4 (%).The presence of GERD was defined as the total fraction time ph <4 greater than 4.6% of a 24-h period. 6. Pulmonary function testing (spirometry): Baseline computerized spirometry for all cases, and follow up 12 weeks after completion of therapy. Informed consent was taken from all patients before inclusion in this research. 3

The inclusion criteria of the study at screening included the following: (1) Age 18 (2) No exacerbations or significant change in asthma medications during past weeks of screening; and (3) Patients who were already on proton pump inhibitor had to stop the drug for 2 weeks prior to the study. Exclusion criteria included the following: (1) any unstable chronic medical condition; (2) history of smoking in past or present; and (3) history of any other lung disease except asthma; (4) Patients with previous gastric or oesophageal surgery and patients with scleroderma or other causes of secondary gastro-oesophageal reflux. Statistical analysis: Analyses, using SPSS version 12 were performed with respect to the main study aim. t-test was used to compare normally distributed continuous variables. P 0.05 was considered statistically significant and P 0.001 was considered highly statistically significant. Results: This study comprised 40 DTC asthmatic patients. They were divided into 2 groups: Group I Included 20 DCT asthmatic patients with GERD, they were 20 males, their ages ranged from 18-52 years with a mean age of (38.75 ± 12.12) years. Group II: Included 20 DCT asthmatic patients without GERD, they were 16 males and 4 females, their ages ranged from 20-54 years with a mean age of (33 ± 8.65) years. Oesophagogastroduodenoscopy findings revealed that 6 (30%) out of 20 DCT asthmatic patients with GERD had non-erosive reflux disease (NERD), and 14 (70%) had erosive reflux disease (ERD), and 9 patients (45%) had hiatal hernia. On the other hand, 20 DCT asthmatic patients without GERD had normal Oesophagogastroduodenoscopy findings. Results of ambulatory 24-h oesophageal ph monitoring showed that the percentage time ph <4.0 was 4.7 ± 1.82 in DCT asthmatic patients with GERD and 1.2 ± 0.8 in DCT asthmatic patients without GERD. Four out of 6 NERD patients had a positive ph test, and two had a negative ph test but frequent predominant symptoms of heartburn and acid regurgitation. In twelve patients out of 14 with ERD, 24-h oesophageal ph test was positive Table (1). Table (2) showed statistically significant increase in PEF and statistically insignificant differences in FEV1, FVC, FEF25%, FEF50%, FEF75 in DCT asthma without GERD group12 weeks after compared to that before antiasthma therapy. On the other hand, there were statistically significant increase in FEV1, FVC and statistically insignificant differences in PEF, FEF25%, FEF50%, FEF75 in DCT asthma with GERD group12 weeks after compared to that before antiasthma plus antireflux therapy. Table (3) showed statistically significant increase in FEV1 and statistically insignificant differences in FVC, PEF, FEF25%, FEF50%, and FEF75 in DCT asthmatic patients without GERD 12 weeks after antiasthma therapy compared to that of DCT asthmatic patients with GERD 12 weeks after antiasthma plus antireflux therapy. Our results showed statistically significant decrease in the use of rescue medication and statistically insignificant decrease in the daytime symptoms, and nighttime symptoms 12 weeks after compared to that before antiasthma therapy in DCT asthma without GERD group. On the other hand, there were statistically significant improvement in daytime symptoms, nighttime symptoms, use of rescue medication, and daily reflux symptoms 12 weeks after antiasthma plus antireflux therapy compared to that before in DCT asthma with GERD group Table (4). 4

Table (1): Patient characteristics at baseline. DCT asthma with GERD (Group I). DCT asthma without GERD (Group II). No. of patients 20 20 Age (years): Range: Mean±SD 18-52 38.75 ± 12.12 20-54 33 ± 8.65 Sex (M/F) 20 (100%) /0 16 (80%) /4 (20%) Oesophagogastroduodenoscopy (EGD) findings Normal 6 (30%) (NERD) 20 Reflux esophagitis (ERD). 14 (70%) 0 Grade A: 4 Grade B: 6 Grade C: 3 Grade D: 1 Hiatus hernia 9 (45%)/20 0 24-h oesophageal ph test (% Total time ph < 4) Mean±SD 4.7 ± 1.82 1.2 ± 0.8 Range 1.9± 8.10 0.4 2.3 Normal/abnormal (>4.6%) 4/16 20/0 NERD 4/6 ERD 12/14 Non-erosive reflux disease (NERD), erosive reflux disease (ERD). 0 Table (2): Pulmonary function data in DCT asthmatic patients without GERD and DCT asthmatic patients with GERD 12 weeks after versus before therapy. Pulmonary DCT asthma without GERD. No=20 DCT asthma with GERD. No =20 Function Data Before therapy 12 weeks After therapy Before therapy 12 weeks After therapy FVC. 77.85 ± 16.49 83.6 ± 12.69 68.7 ± 14.65 79 ± 8.14 P <.05 FEV1. 79.65 ± 15.02 86.25 ± 5.23 70.5 ± 16.57 79.85 ± 6.44 P <.05 PEF. 59.55 ± 22.70 75±20.97 P <.05 64.3 ± 8.38 65.52 ± 14.73 FEF25% 60.05 ± 21.31 72.85 ± 18.006 69.95 ± 8.14 68.28 ± 11.94 FEF50% 73.85 ± 23.80 77.65 ± 15.79 76.4 ± 20.07 75.28 ± 10.62 FEF75% 91 ± 33.54 82.8 ± 20.08 81.75 ± 18.63 79.57 ± 21.46 5

Table (3): Pulmonary function data in DCT asthmatic patients without GERD 12 weeks after antiasthma therapy versus DCT asthmatic patients with GERD 12 weeks after antiasthma plus antireflux therapy. Pulmonary Function Data DCT asthma without GERD. No=20 DCT asthma with GERD. No =20 FVC. 83.6±12.69 79 ± 8.14 FEV1. 86.25±5.23 79.85 ± 6.44 P<0.01 PEF. 75±20.97 65.52 ± 14.73 FEF25% 72.85±18.006 68.28 ± 11.94 FEF50% 77.65±15.79 75.28 ± 10.62 FEF75% 82.8±20.08 79.57 ± 21.46 Table (4): Asthmatic and GER symptoms in DCT asthmatic patients without GERD 12 weeks after antiasthma therapy and DCT asthmatic patients with GERD 12 weeks after antiasthma plus antireflux therapy versus that before therapy. DCT asthma without GERD. DCT asthma with GERD. No=20 Before therapy 12 weeks After therapy. Daytime symptoms/ week 2.95±1.39 2.1±.85 Nighttime symptoms/ week 1±1.21.75±.96 Rescue medication 6.1±4.27 3.6±2.94 (number of puffs / week) P <.05 Daily reflux symptoms / week No =20 Before 12 weeks therapy After therapy. 2.95±1.57 1.05±.99 P <.01 1.05±1.05.35±.48 P <.05 7.8±+4.14 3.3±2.92 P <.01 - - 3.75±1.68 1.55±1.09 P <.01 Discussion: Bronchial asthma is likely to be associated with gastroesophageal reflux disease (GERD) (14). It has been indicated that there is a causal relationship between asthma and GERD: asthma may cause or precipitate GERD and vice versa, and so much as a vicious cycle (3, 15). The prevalence of GERD in asthma patients has been reported to be increased compared with the normal population. Conversely, the prevalence of asthma has also been shown to be increased in GERD patients compared with normal controls (16). GERD may cause or facilitate asthma. Mechanisms of bronchospasm inspired by reflux include (17,18) : (1) acid in the inflamed esophagus may stimulate exposed acid sensitive receptors which act through vagal afferents to the airways to cause an increase in bronchial hyper-responsiveness which leads to bronchoconstriction; (2) microaspiration, with stimulation of upper-airway vagal receptor, causes bronchoconstriction; and (3) microaspiration of gastric contents into the lung results into exudative mucosal reaction. GERD is reported to adversely impact the pulmonary functions. GERD is associated with 6

symptomatic asthma and chronic cough. Treatment of GERD improves the respiratory symptoms and decreases the medication needed for the management of asthma (19). Gastroesophageal reflux can induce bronchospasm, and antireflux therapy has been shown to improve pulmonary function in patients who have gastroesophageal reflux disease (GERD) associated with asthma (20). 'Dificult-to-control' asthma, as we have defined, selects out a group of patients who are already on optimal medication for asthma but yet experiencing symptoms and requiring frequent rescue β2-agonist inhaler therapy. It is thought, that in this subgroup of patients the prevalence of GERD is truly increased and that GERD in some way contributes to the refractive nature of the asthma (12, 21,22,23). Few studies have been carried out in DTC asthma patients. In the present study we have carefully selected consecutive DTC asthma patients. Diagnosis of GERD has been based on a clinical history of frequent heartburn and acid regurgitation, objective findings of reflux oesophagitis and positive 24-h oesophageal ph monitoring. In this study we found that (55.76%) of patients with DTC asthma have GERD. This figure approximates the prevalence rates seen in two other studies. Heaney et al, 2003 (22) reported that gastrooesophageal reflux symptoms were common among patients who had therapy resistant asthma and 57% of them had abnormal results on 24-h oesophageal ph measurements. Also, Leggett et al, 2005 (24) studied a group of difficult asthma patients with 24-h oesophageal ph measurement and found that 75% of them had GERD. The results of the present study showed statistically significant increase in PEF and statistically insignificant differences in FEV1, FVC, FEF25%, FEF50%, FEF75 in DCT asthma without GERD group12 weeks after compared to that before antiasthma therapy. On the other hand, there were statistically significant increase in FEV1, FVC and statistically insignificant differences in PEF, FEF25%, FEF50%, FEF75 in DCT asthma with GERD group12 weeks after compared to that before antiasthma plus antireflux therapy. Harding et al, 1996 had reported improvements in both symptoms and pulmonary function in asthmatic patients with GERD after antireflux therapy (25). Also, Levin (26) et al, 1998 had demonstrated that omeprazole improved PEF and quality of life in asthmatic patients with GERD. Similarly, Meier et al, 1994 (27) indicated that medical antireflux therapy by omeprazole might predispose to improve respiratory function in asthmatics with GERD. On the other hand, Wong et al, 2006 (28) reported that there was no significant change in peak expiratory flow rate and forced expiratory volume in their patients with difficult-to-control asthma after antireflux therapy. Also, Boeree et al, 1998 (29) do not support a role for intensive antireflux therapy to improve pulmonary symptoms and function in patients with asthma and chronic obstructive pulmonary disease, who have severe airway hyperresponsiveness despite maintenance treatment with inhaled corticosteroids. Similarly, Gibson et al, 2003 (30) reported that anti-reflux treatment did not consistently improve lung function, asthma symptoms, nocturnal asthma, or the use of asthma (31) medications. Also, Isaac et al, 2009 reported that lung function tests did not differ between the treatment and control groups. The results of the present work showed statistically significant improvement in daytime symptoms, nighttime symptoms, use of rescue medication, and daily reflux symptoms 12 weeks after antiasthma plus antireflux therapy compared to that before in DCT asthma with GERD group. This is in accordance to Sharma et al, 2007 (1) who reported that comparison of mean change from baseline between antireflux therapy and placebo groups revealed significant reduction in daytime asthma symptom score (17.4% vs 8.9 %), nighttime asthma symptom score (19.6% vs 5.4%), reflux symptom score (8.7% vs 1.6%) and rescue medication use (23.2% vs 3.1%) after antireflux therapy compared to mean change in placebo group (P < 0.001). (12) Also, Littner, et al, 2005 using lansoprazole 30 mg twice daily for 24 weeks in 207 asthmatics with acid reflux symptoms reported (reduction in asthma exacerbations and improved asthma quality of life, but no improvement in asthma symptoms or pulmonary function. On reviewing the combined results of 12 studies examining medical therapy in 326 treated asthmatics with 7

GERD in a meta-analysis, asthma symptoms improved in 69%, medication use was reduced in 62%, and evening PEFR rates improved in 26% of patients; however, pulmonary function did not improve (32). Wong et al, 2006 (28) reported that Pulmonary symptom score improved significantly only in patients with GERD (35.0 to 21.0; P ¼ 0.002). Twelve of 16 (75%) patients with GERD reported an improvement in asthma symptoms; 1 of 11 (9.1%) without GERD reported mild symptom improvement. The lack of response of lung function tests to acid suppression therapy has been reported in many studies (15, 25, 29, and 33). Field et al, 1998 (32) reported that respiratory symptoms can occur without an objective change in pulmonary function tests and concluded that subjective respiratory symptoms could be due to increase in minute ventilation and respiratory rate in asthmatic patients. The other explanation is that subjective improvement in asthma symptoms takes place before objective improvement in pulmonary function testing. In conclusion: GERD was diagnosed in more than half of our studied patients with difficultto-control asthma. Antireflux therapy in such patients has minimal effect on pulmonary function, but significantly improves asthma symptoms, nighttime symptoms, rescue medication use, daily reflux symptoms suggesting that these patients might benefit from antireflux therapy. References: 1. Sharma B., Sharma M., Daga M. K., Sachdev G.K., & Bondi E.: Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux. World J Gastroenterol 2007 March 21; 13(11): 1706-1710. 2. Harding S.M.: GERD, airway disease, and the mechanisms of interaction. In: Stein MR. Lung biology in health and disease, volume 129: gastroesophageal disease and airway disease. New York: Marcel Dekker, 1999: 139-178. 3. Sontag S.J., O Connell S., Khandelwal S., Miller T., Nemchausky. B., Schnell T.G, & Serlovsky R.: Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology, 1990; 99: 613-620. 4. Richter J.E.: Gastroesophageal reflux disease and asthma: the two are directly related. Am J Med 2000; 108 Suppl 4a: 153S-158S. 5. Tuchman D.N., Boyle J.T., Pack A.L.M, Sewartz J., Kokonos M., Spitzer A.R., & Cohen S.: Comparison of airway responses following tracheal or esophageal acidification in the cat. Gastroenterology, 1984: 87,872-881. 6. Altschuler S.M.: Laryngeal and respiratory protective reflexes. Am J Med, 2001: 111, 90s-94s. 7. Canning B., and Mazzone S.B.: Reflex mechanisms in gastroesophageal reflux disease and asthma. Am J Med, 2000;115, 45s-48s. 8. Riciardodlo F.L., Gaston B., & Hunt G.: Acid stress in the pathology of asthma. J. allergy Clin. Immunol, 2004; 113: 610-619. 9. Shimizu Y., Dobashi K., Kobayashi S., Ohki I., Tokushima M., Kusano M., Kawamura O., Shimoyama Y., Utsugi M., Sunaga N., Ishizuka T. & Mori M.: A Proton Pump Inhibitor, Lanzoperazole, ameliorates asthma symptoms in asthmatic patients with gastroesophageal reflux disease. Tohuku J. Exp. Med., 2006, 209, 181-189. 10. Mathew J.L., Singh M., & Mittal S.K.: Gastro-esophageal reflux and bronchial asthma: current status and future direction. Postgrad Med J 2004; 80: 701-5. 11. Field S.K.: A critical review of studies of the effects of simulated or real gastroesophageal reflux on pulmonary function in asthmatic adults. Chest, 1999; 115: 848-56. 12. Littner M.R., Leung F.W., Ballard.ED. II, & Samra N.: Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with reflux symptoms. Chest, 2005; 128: 1128 35. 8

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