Prevalence of gastro-esophageal reflux disease in patients with difficult to control asthma and effect of proton pump inhibitor therapy on asthma symptoms, reflux symptoms, pulmonary function and requirement for asthma medicationsV Sandur1, M Murugesh1, V Banait1, PM Rathi1, SJ Bhatia1, JM Joshi2, A Kate2
1 Department of Gastroenterology, TNMC - BYL, Nair Hospital, Mumbai, India
2 Department of Chest Medicine, TNMC - BYL, Nair Hospital, Mumbai, India
Background: The hypothesis that GER can trigger or exacerbate asthma is supported by several clinical trials that have shown amelioration in asthma symptoms and/or an improvement in pulmonary function after antireflux therapy. Aims: To investigate the prevalence of GER in patients with difficult to control asthma and to determine the effect of omeprazole on asthma symptoms, reflux symptoms, pulmonary function and on the requirement of asthma medications. Materials and Methods: Patients with difficult to control asthma were recruited into the study. All patients underwent esophageal manometry and 24 hour esophageal pH monitoring. Pulmonary function tests were done before and after treatment. The severity of asthma and reflux was assessed by a 1 week pulmonary symptom score(PSS) and reflux symptom score(RSS) respectively before and after treatment. Those who had an abnormal pH study (pH <4 in the distal esophagus for >5% of the time) underwent anti-GER treatment with lifestyle changes, and a proton pump inhibitor (omeprazole 40 mg, bid) for 3 months. Asthma medications were added or deleted based on severity of asthma. Results: Out of 250 asthmatic patients screened, forty patients fulfilled the inclusion criteria. Twenty eight of 40 patients(70%) were diagnosed to have GERD. Of the patients 28 with GER, 8 patients(28.5%) had no reflux symptoms. On 24 hr pH metry, the percentage time pH <4.0 was 10.81 ± 4.72 and 1.11 ± 1.21; Deemester score was 37.65 ± 14.54 and 4.89 ± 6.39 (p-value is 0.0001) in GERD and non-GERD patients respectively.In GERD group, post treatment reflux symptom score(RSS) improved from 22.39 ± 14.99 to 1.04 ± 1.07, pulmonary symptom score(PSS) improved from27.14 ± 7.49 to 13.82 ± 4.21and night time asthma symptom score(NASS) improved from 6.71 ± 1.80 to 3.04 ± 1.23 (p-value <0.0001). After treatment, FEV1 and PEFR increased from 1.38 ± 0.57 and 4.14 ± 1.97 to 1.47 ± 0.54 and 5.56 ± 1.72, respectively (p-value 0.00114). Conclusions: PPI therapy improves nocturnal asthma symptoms, daytime asthma symptoms, pulmonary function and decreases requirement of asthma medications in these patients.
Keywords: Gastroesophageal reflux disease, bronchial asthma, proton pump inhibitor therapy, pulmonary function test
Gastroesophageal reflux disease (GERD) has been found to occur in 32% to 80% of asthmatic patients. , Asthma is known to promote reflux by increasing the pressure gradient between the thorax and the abdomen. , Two mechanisms by which GER can aggravate or even cause asthma have been proposed, namely micro-aspiration of gastric contents , and vagally-mediated esophagobronchial reflex. ,, The hypothesis that GER can trigger or exacerbate asthma is supported by several studies that have shown a reduction in asthma symptoms and/or an improvement in pulmonary function after antireflux therapy. ,, The present study was conducted to investigate the prevalence of GERD in the patients with difficult to control (DTC) asthma attending the out-patient department and to determine the effect of omeprazole a proton pump inhibitor on asthma symptoms, reflux symptoms, pulmonary function and on the requirement for asthma medications.
The study protocol was approved by the institutional review board and written informed consent was taken from all participants.
A prospective study in consecutive patients.
Case definition of asthma and selection criteria
The patients were considered to have asthma if they had reversible bronchial obstruction, as documented by a 15% increase in FEV1 after sympathomimetic inhalation (as per diagnostic criteria of the American Thoracic Society).  Moderate-to-severe asthma was defined as per GINA guidelines.  Patients who had poor asthma control despite being on optimal medication and requiring frequent rescue β2-agonist inhaler therapy were defined as DTC asthma. Patients already on acid suppressive therapy with proton pump inhibitors were required to stop the drug for a week prior to the study. Exclusions were patients with chronic pulmonary airway disease, previous gastric or esophageal surgery, scleroderma or other causes of secondary gastro-esophageal reflux, history of chronic smoking and those who were unable or refused consent to participate in the study.
Baseline (pre-treatment) assessment
The basic demographic data was recorded. The severity of asthma was assessed by a 1 week pulmonary symptom score (PSS) as previously described by Kiljander et al.  Pulmonary Function Tests: Flow volume studies, peak expiratory flow rate (PEFR) and forced expiratory volume in 1 s (FEV1) were obtained by using pulmonary function test analyzer (Medgraphics, profiler, USA). All patients underwent an esophagogastroduodenoscopy (EGD) and diagnosis and grading of esophagitis was made according to the Los Angeles (LA) classification. Patients with these changes were considered to have erosive reflux disease. Patients were considered to have non-erosive reflux disease (NERD) if they had typical symptoms of GERD but a negative EGD. A standardized method of ambulatory 24-h esophageal pH monitoring was performed in all patients. A diagnosis of GERD was made when patients had a positive 24-h esophageal pH monitoring (pH <4 in the distal esophagus for >5% of the time); these patients were further classified as symptomatic GER based on whether they had predominant symptoms of heartburn and/or acid regurgitation at least once a week for the past 6 months. The rest of the patients were grouped as and asymptomatic GER. The pH monitoring was then repeated after 2 months of therapy. If abnormal esophageal acid was still present, the dose of omeprazole was increased to 60 mg/day for an additional month, followed again by pH monitoring.
All asthma medications were continued uninterrupted. Care was taken to ensure that no antacids were consumed during or up to 7 days before the study. Those who had an abnormal pH study (pH <4 in the distal esophagus for >5% of the time) underwent anti-GER treatment with suggested lifestyle changes and treatment with omeprazole (40 mg/d). These patients then underwent regular follow up at intervals of 4 weeks for asthma management based on symptoms in the preceding 4 weeks. Medications were added or deleted based on this assessment. Patients were also assessed for acute exacerbation, and medications were adjusted accordingly. The patients with a normal pH probe study finding were not given anti-GER treatment. The inhaled corticosteroid used was fluticasone propionate, 100 to 250 μg bid. The short-acting bronchodilator MDI used was salbutamol, administered as directed, depending on the severity of the symptoms. Salmeterol MDI, oral theophylline and salbutamol were used as add on. depending upon severity. The short-acting bronchodilators were used as and when needed basis for wheezing. Oral corticosteroids are used for breakthrough symptoms. Data on asthma medications used was collected from the parent's daily log and corroborated by the patient's medical records in the asthma clinic. Data were gathered for a 6-month period prior to referral for GER workup and for 3 months after initiation of anti-GER treatment.
Post-treatment assessment of reflux symptoms
Assessment of reflux symptoms was two pronged. First patients were asked to assess their global improvement in reflux symptoms after the treatment based on a Likert scale (0-no improvement, 1-mild, 2-moderate, 3-marked improvement). Secondly, a 1-week RSS, as was used during baseline assessment, was scored for the week before completion of treatment.
Post-treatment assessment of asthma symptoms
Patients were also asked to assess on their global asthma symptom improvement based on a similar Likert scale as with reflux symptoms. A 1-week baseline or pre-treatment assessment PSS and night time asthma symptom score were also obtained for the week prior to the treatment given and for the week before the completion of treatment. In addition the assessment of the PEFR and FEV1 which was recorded at the beginning was also carried out post-treatment. The use of short- and long-acting bronchodilators and corticosteroids (before and at the end of 3 months after initiation of anti-GER treatment) were used as the outcome variables.
A total of 250 patients were screened from August 2005 to February 2006. Forty patients (25 males, 15 females, median age 42 years, range 17-70 years) who fulfilled the selection criteria completed the study. All patients were on medium to high dose of inhaled glucocorticoid therapy and inhaled long-acting β-2 agonist. Sixteen were on oral β-2 agonist and 22 patients were on oral theophylline, in addition to their inhaled therapy. Twenty-eight patients with GERD (on omeprazole) and 12 patients without GERD (without omeprazole) completed the 12-week treatment
Prevalence of GERD
Twenty-eight of 40 patients (70%) were diagnosed to have GERD. On endoscopy, esophagitis was documented in 13 of 28 (46.4%). Hiatus hernia was noted in 4 of 28 (14.3%) of GERD patients. On 24 hr pH metry, the percentage time pH <4.0 was 10.81 ± 4.72 in GERD patients and 1.11 ± 1.21 in non-GERD patients. Of the patients 28 with GERD, 8 patients (28.5%) had no typical reflux symptoms. Out of 28 patients, 14 (50%) each were having chronic moderate persistent and chronic persistent severe asthma, respectively.
Changes in symptom scores
In GERD group reflux symptom score (RSS) at baseline was 22.39 ± 14.99 and was 04 ± 1.07 post therapy (P <0.0001). The PSS at baseline was 27.14 ± 7.49 and improved to 13.82 ± 4.21 post therapy (P-value<0.0001). The night time asthma symptom score (NASS), at baseline was 6.71 ± 1.80 and improved to 3.04 ± 1.23 post therapy (P-value<0.0001). FEV1 at baseline was 1.38 ± 0.57 and increased to 1.47 ± 0.54 post therapy (P-value is 0.00114). PEFR at baseline was 4.14 ± 1.97 and increased to 5.56 ± 1.72 post therapy (P-value<0.0001). In non-GERD group there was no change in RSS, PSS, NASS, FEV1 and PEFR post therapy [Table 1].
In GERD patients, there was a significant reduction in use of asthma medications. Oral salbutamol dose decreased from 8 mg to 4.67 mg/day (P < 0.0001). Oral theophylline dose decreased from 400.00 ± 0.00 mg to 270.37 ± 60.86 mg per day (P-value is 0.018). In the GERD group there was a significant reduction in the requirement of, long-acting inhaler bronchodilator salmeterol and fluticasone propionate inhaler from 153 ± 50.79 to 76.79 ± 25.39 (P < 0.0001). In both the groups there was a significant reduction in oral prednisolone usage (P < 0.0001) [Table 2].
Post-treatment assessment of pulmonary and reflux symptoms (Likert scale) in GERD and non GERD patients
In the GERD group, nine patients (32.10%) had marked improvement in asthma symptoms; 18 patients (64.3%) had moderate improvement in asthma symptoms. In the non-GERD group no patients had marked improvement in asthma symptoms, two patients (16.7%) had moderate improvement and six patients (50%) had mild improvement in asthma symptoms. No improvement in four (33.3%) of patients. All 20 (100%) symptomatic GERD patients reported significant improvement in their reflux symptoms. Five of 20 (25%) had total resolution of their symptoms.
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. Studies using 24-hour ambulatory esophageal pH monitoring report a GERD prevalence ranging from 32% to 82%. ,,, The present study with its small sample of patients found GERD in 70% of the subjects with asthma investigated. It is of interest that often these patients did not have any typical reflux symptoms. , In our study asymptomatic GER was found in 8 of 28 (28.57%) patients. Irwin et al. have similarly shown GER to be clinically "silent" in 24% of asthmatic patients. 
In this study, esophageal acid exposure time was normalized with omeprazole 40 mg in 73% of the cases. Omeprazole 40 mg resulted in acid suppression in 93% of the cases, but 7% of the patients required 60 mg of omeprazole. Thus, a higher dose of omeprazole appears to inhibit acid reflux in 93% of patients with asthma and GERD.  Although no PPIs other than omeprazole have been studied, it is likely that other PPIs can be equally effectively.
In the study by Harding, 30 patients with asthma were maintained on an acid-suppressive dose of omeprazole until the end of the 3-month study.  After 1 month of acid-suppressive therapy, the group of asthma responders had a 30% reduction in asthma symptoms compared with baseline; at 2 months responders had a 43% reduction, and at 3 months responders had a 57% reduction. This reflects slow, steady improvements with sustained treatment for up to 3 months. We therefore chose the 3 month study period.
In the present study, GERD group all scores in cases improved significantly over controls while in the non-GERD group there was no change in RSS, PSS, NASS, FEV1 and PEFR post therapy.
Using the guideline that a minimum of 2 months of treatment and a double-standard dose of PPI are required to control asthma symptoms, all the studies except those by Boeree et al.  and Kiljander et al.,  likely used inadequate acid suppression, , smaller treatment duration, , and were devoid of a control group.  Moreover, all of the studies were underpowered with the largest investigation including only 52 patients. 
There are the only two studies reporting an improvement in PEF values after PPI therapy, , whereas in the majority of the studies, no improvement in pulmonary function has been detected, ,, or very few patients have responded. , Regarding pulmonary function or daytime asthma symptoms, there is evidence that not all patients with asthma and GERD respond favorably to PPI therapy. ,,. In the present study in GERD patients, there was a significant reduction in asthma medications. In both the groups there was a significant reduction in oral prednisolone usage (P-value<0.001). In the GERD group nine patients (32.10%) had marked improvement in asthma symptoms; 18 patients (64.3%) had moderate improvement in asthma symptoms. In non-GERD group no patients had marked improvement in asthma symptoms, two patients (16.7%) had moderate improvement and six patients (50%) had mild improvement in asthma symptoms. No improvement in four (33.3%) of patients. This is comparable to the meta analysis by Field et al.  and other authors. ,,
In conclusion, GERD co-exists with asthma and is often clinically silent. In the management of GERD-related asthma, PPIs can be used at twice the standard dose for a three month duration to assess benefits. It appears that adequate dose and duration of PPI therapy may improve nocturnal asthma symptoms; PPI therapy also seems to improve daytime asthma symptoms and pulmonary function in some patients with asthma who also have GERD. There is evidence that more severe GERD might predict favorable asthma outcome after PPI therapy. The present study is however limited by a small sample size, lack of blinding and use of a placebo control.
[Table 1], [Table 2]