Source
Sample size
Intervention
Primary outcomes
Main findings
P-value
Cough
Shaheen 2011
40
Esomeprazole 40 mg bid for 12 weeks versus placebo
Change in Cough Specific Quality of Life Questionnaire score (CSQLQ)
Mean improvement in CSQLQ of 9.8 and 5.9 in treatment versus placebo group.
0.3
Mean improvement in Fisman Cough Severity score of 1.0 vs. 0.8
0.7
Mean improvement in Fisman Cough Frequency score of 3.2 vs. 2.3
0.3
Faruqi 2011
49
Esomeprazole 20 mg bid for 8 weeks
Change in integral response score for cough, change in Leicester Cough Questionnaire, change in Hull Airway Reflux Questionnaire, Reflux Finding Score (RFS), citric acid cough challenge
Change in cough frequency was 1.6 vs. 1.5
0.92
Change in cough severity was 1.2 vs. 1.7
0.8
Change in the Leicester Cough Questionnaire was 2.6 vs. 0.7
0.25
Change in the RFS was 0.72 vs. 2.4
0.94
Change in the Hull Airway Reflux Questionnaire was 7.3 vs. 7.1
0.61
Change in log of inhaled citric acid concentration to produce 2 coughs was −0.15 vs. −0.04
0.66
Change in log of inhaled citric acid concentration to produce 5 coughs was 0.02 vs. −0.09
0.57
Baldi 2006
35
Lansoprazole 30 mg qd and placebo dose in PM (control) versus lansoprazole 30 mg bid for 12 weeks.
Changes in cough scoring system and Visual Analog Scale (VAS)
Median change in VAS was 1.0 in both the treatment and control groups.
> 0.05
Median change in cough scoring system was 1.0 vs. 0.5
> 0.05
59% vs. 61% of patients had complete resolution of their symptoms.
> 0.05
Kiljander 2000
21
Omeprazole 40 mg qd for 8 weeks
Changes in cough symptom score
Cough symptom score −1.5 vs. +0.7
< 0.05
LPR
Lam 2010
82
Rabeprazole 20 mg bid for 12 weeks
Change in Reflux Score Index (RSI) and RFS
At week 12, RSI −2.8 vs. +0.93
0.002
At week 12, RFS −2.21 vs. −2.75
0.017
At week 18, RSI −0.9 vs. + 0.58
0.12
At week 18, RFS −3.2 vs. −3
0.68
McGlashan 2009
45
10 mL liquid dose of sodium alginate 1000 mg and potassium bicarbonate 200 mg after meals and at bedtime
Change in RSI and RFS from baseline at 2 month and 6 month follow up
At 2 months, RSI −12.7 vs. −7.8
0.005
At 6 months, RSI −12.7 vs. −6.3
0.008
At 2 months, RFS −2.2 vs. −0.6
0.08
At 6 months, RFS −3.2 vs. −0.7
0.005
Reichel 2008
58
Esomeprazole 20 mg bid for 3 months
Change in RSI and RFS at 6 weeks and 3 months follow up, and subjective report of being symptom-free at 3 months.
At 6 weeks, RSI −9.87 vs. −6.93
NS
At 3 months, RSI −14.27 vs. −7.79
< 0.05
At 6 weeks, RFS −3.47 vs. −2.46
NS
At 3 months, RFS −4.6 vs. −2.32
< 0.05
At 3 months, 78.6% vs. 42.3% patients reported being symptom-free.
0.006
Wo 2006
35
Pantoprazole 40 mg daily for 12 weeks
Change in RFS, and subjective “adequate relief” of laryngeal symptoms.
Median RFS −1.0 vs. −3.0
NS
Adequate relief of laryngeal symptoms was reported by 40% vs. 42% of patients
0.89
Vaezi 2006
145
Esomeprazole 40 mg bid for 16 weeks
Resolution of primary symptom, change in chronic posterior laryngitis index, and change in LPR-HRQL score.
Resolution of primary symptom was reported in 14.7% vs. 16% of patients
0.799
CPLI −1.6 vs. −2.0
0.446
LPR-HRQL score −11.6 vs. −7.8
0.424
Steward 2004
37
Rapeprazole 20 mg bid for 8 weeks
Change in reflux symptom score, subjective report of “significant global improvement”, change in laryngeal grading of video-recorded strobe-laryngoscopy signs scoring system
Mean reflux symptom score −9.7vs. -6.6
0.44
Significant global improvement was reported in 53.3% vs. 50% of patients.
1
Laryngoscopic grade +0.6 vs. +0.5
0.69
Ehrer 2003
14
Pantoprazole 40 mg bid for 3 months
(Placebo-controlled case-crossover trial)
Change in symptom score, change in laryngoscopic signs score
No statistically significant difference in mean symptom scores between groups (values unreported).
NS
Mean laryngoscopic signs score −8.0 vs. −5.6 in the placebo-first group.
NS
Noordzij 2001
30
Omeprazole 40 mg bid for 8 weeks
Change in symptom score, change in laryngoscopic scores for vocal fold edema, arytenoid erythema, arytenoid edema, interarytenoid irregularity, and mucus accumulation.
Laryngeal symptom score −1078.6 vs. 1944.9
0.098
No significant difference was found in the change in laryngoscopic sign scores.
NS
El-Serag 2001
20
Lansoprazole 30 mg bid for 3 months
Resolution of all presenting laryngeal symptoms, complete or partial resolution of all presenting laryngoscopic signs
Resolution of all presenting laryngeal symptoms was reported in 55% vs. 11% of patients
0.04
Complete or partial resolution of laryngeal signs was found in 58% vs. 30% of patients
0.123
Asthma
Kiljander 2010
828
Three randomization groups: esomeprazole 40 mg daily and placebo daily, esomeprazole 40 mg bid, or placebo bid for 26 weeks
Changes in lung function tests, change in asthma quality of life questionnaire score, and experiencing a severe asthma exacerbation
Mean morning PEF improved +3.5 L and +5.5 L more in patients receiving esomeprazole daily and bid, respectively, compared to placebo.
NS
Mean FEV1 improved 0.07 L more in patients receiving esomeprazole bid compared to placebo.
<0.0042
Esomeprazole once daily was not statistically significantly better than placebo.
NS
Mean AQLQ score increased 0.2 in patients receiving esomeprazole 40 mg daily, 0.3 in patients receiving esomeprazole bid, and 0.1 in patients receiving placebo.
< 0.001
Severe asthma exacerbations experienced by 10%, 7.5%, and 10% of patients on esomeprazole once daily, bid, and placebo, respectively.
NS
Peterson 2009
30
Three randomization groups: rabeprazole 20 mg daily and placebo daily, rabeprazole 20 mg bid, or placebo bid
Subjective determination by subjects of improved exercise symptoms, changes in pulmonary function test, spirometry, SF-36 score, and mini-AQLQ score
Subjectively improved exercise tolerance was reported by 70% vs. 25% in patients on rabeprazole
0.03
No statistically significant difference in change in FEV1, FVC, or FEV1/FVC between the rabeprazole groups and placebo.
NS
There were no statistically significant difference in change in SF-36 or mini-AQLQ scores.
NS
Mastronarde 2009
393
Esomeprazole 40 mg bid
Rate of episodes of poor asthma control, change in PFTs, asthma symptoms, or asthma control
No. of episodes of poor asthma control per person-year was 2.5 vs. 2.3
0.66
Change in FEV1 was 0 L vs. −0.02 L
0.36
Change in FVC was 0 vs. −0.03
0.3
Change in PEF was 9.2 L/min vs. 3.2 L/min
0.24
Change in PC20 was 0.3 mg/mL vs. 1.5 mg/mL
0.04
Change in JACQ, ASUI, mini-AQLQ, and SF-36 scores were not statistically significantly different between the treatment and placebo groups.
0.11–0.56
Sharma 2007
198
Omeprazole 20 mg bid and domperidone 10 mg tid for 16 weeks
Changes in asthma symptom score, rescue albuterol use, daytime and nighttime PEF, post-bronchodilator FEV1, and FVC
Daytime asthma symptom score decreased −0.48 vs. −0.22.
0.0001
Nighttime asthma score decreased −0.51 vs. −0.14
0.0001
Rescue albuterol puffs/week decreased −0.76 vs. −0.1
<0.0001
Morning PEF increased +22.78 L/min vs. −0.76 L/min
<0.004
Evening PEF increased +27.76 L/min vs. −1.43 L/min
0.002
FEV1 increased +0.21 L vs. +0.07 L
0.0013
FVC increased +0.18 L vs. −0.03 L
0.0023
Kiljander 2006
624
Esomeprazole 40 mg bid for 16 weeks
Change in morning and evening PEF
Morning PEF increased +22.3 L/min vs. +16 L/min in the last 28d of the study.
0.061
Morning PEF increased +5.6 L/min more in the treatment group than in the placebo group after treatment was completed.
0.042
In patients with GERD and nocturnal respiratory symptoms, morning PEF increased +8.7 L/min more in the treatment than the placebo group.
0.03
Evening PEF increased +5.9 L/min more in the treatment group than in the placebo group.
0.053
In patients with GERD and nocturnal respiratory symptoms evening PEF increased +11.2 L/min more in the treatment group than in placebo group.
0.02
Littner 2005
173
Lansoprazole 30 mg bid for 24 weeks
24-week average of asthma symptom score calculated from patient diaries, albuterol use, changes in PEF, post-bronchodilator FVC and FEV1, AQLQ score, and asthma exacerbations.
Asthma symptom scores decreased −0.36 vs. −0.21 in the placebo group.
NS
Morning PEF increased +5 L/min vs. +10 L/min
NS
Evening PEF increased +4 L/min vs. +12 L/min in the placebo group.
< 0.05
Post-bronchodilator FEV1 changed 0 L in both groups.
NS
Post-bronchodilator FVC changed 0 L vs. −0.1 L in the placebo group.
NS
AQLQ score +0.9 vs. +0.7
< 0.05
Albuterol use decreased 1 puff/day vs. −0.9 puffs per day
NS
Asthma exacerbations were experienced by 8.1% vs. 20.4% of patients
0.017
Moderate or severe asthma exacerbations were experienced by 4% vs. 13.9% of patients
0.016
Sontag 2003
Total: 62
Control:
24
Medical: 22
Surgical:
16
Three randomization groups: lifestyle modifications and prn medications only (control), lifestyle modifications and ranitidine 150 mg tid, and lifestyle modifications and Nissen fundoplication, followed for 2 years
Change in asthma symptom score, requirement for pulmonary medications, and overall clinical response
Mean asthma symptom score improved significantly in 75% of surgical patients, 20% of control patients, and 0% of medical treatment patients.
0.008 (surgery vs. control and med. Groups combined)
Need for rescue pulmonary medications decreased in 9.1% of patients in the medical group but increased in 18.2% of control patients. Pulmonary medication requirement decreased in 50% of patients in the surgical group. Zero patients in the control group changed their need for pulmonary medications.
NS
Overall improvement occurred in 9.1% of medical, 75% of surgical, and 4.2% of control patients.
< 0.001 (surgery versus control and medical groups)
Jiang 2003
30
Two randomization arms: asthma treatment only versus asthma treatment plus omeprazole 20 mg qd, and domperidone 10 mg tid, for 6 weeks
Change in PFTs and histamine-induced bronchial sensitivity.
FVC increased +0.8 L vs. −0.2 L
< 0.05
FEV1 increased +0.6 L vs. +0.1 L
< 0.05
PEF increased +1.3 L/s vs. + 0.4 L/s
< 0.05
Bronchial sensitivity improved +0.51 g/L vs. −0.03 g/L
< 0.05
The surgical treatment of cough due to reflux is hampered by many of the same problems discussed for medical therapy and the difficulty of performing blinded, placebo-controlled trials. Observational studies varied in patient selection and the definition of outcomes measured [28–36]. With these limitations, most studies reported success rates of 65–74% [30, 32, 37, 38]. Patients who are more likely to report resolution of symptoms are those with concomitant typical GERD symptoms or positive esophageal pH monitoring [39]. The use of MII-pH monitoring in patients on bid PPI therapy has been limited but has shown that in patients with a positive non-acid symptom index for cough, antireflux surgery can achieve complete resolution of cough [40].
Laryngopharyngeal Reflux
Nine randomized trials have evaluated the efficacy of antisecretory therapy, primarily twice-daily PPIs, on LPR. These studies were relatively small, ranging in sample size from 14 to 145 subjects, and enrolled patients based on a varied combination of symptoms and laryngoscopic findings (Table 5.1). Six trials found no difference between treatment and placebo groups [17, 19, 41–44], whereas three trials reported statistically significant results [18, 45, 46]. Again, the difference in results might be explained by the placebo effect and the varied patient inclusion criteria.
No randomized controlled trials have compared medical and surgical intervention for LPR and only few small observational studies have been published [31, 47]. It is important to note that, as with other extraesophageal manifestation of GERD, patients who are more likely to report resolution of symptoms (up to 72% of cases) are those with concomitant typical GERD symptoms and positive esophageal pH monitoring [47, 48].
Asthma
Nine randomized trials evaluated the effect of medical treatment of GERD on asthma due to reflux. Six randomized trials enrolled patients based on some combination of asthma and GERD [49–54]. Most studies reported changes in self-reported asthma symptoms and/or asthma-related quality of life indexes [49–53, 55, 56], and some reported differences in rescue bronchodilator use [49, 50, 52, 53] or in unscheduled healthcare visits for asthma [50, 56] (Table 5.1).
Among the three randomized trials that enrolled patients with both asthma and GERD, all reported greater improvement in the treatment than the placebo (or no treatment) groups. However, the differences in outcomes varied. Kiljander et al. found significant improvement in morning PEF, FEV1, and the Asthma Quality of Life Questionnaire in subjects treated with esomeprazole 40 mg QD or BID compared to placebo. However they found no difference in changes in evening PEF, time to asthma exacerbation, number of severe asthma exacerbations, use of rescue inhalers, or asthma-free days [49]. Sharma et al. found greater improvement in mean daytime asthma symptom scores, mean nighttime asthma symptom scores, rescue inhaler use, morning PEF, evening PEF, FEV1, and FVC in subjects treated with omeprazole 20 mg BID and domperidone 10 mg TID for 16 weeks compared to placebo [50]. Littner et al. found no significant differences in changes in diary-recorded asthma symptoms, rescue inhaler use, morning or evening PEF, FEV1, FVC, or the Standardized Asthma Quality of Life Questionnaire score. However, they found significantly fewer patients in the treatment group experienced an asthma exacerbation or a moderate-severe asthma exacerbation [52].
The differences in outcomes between these trials may be explained by patient selection, both in terms of the severity of asthma and the severity of reflux in the study subjects. None of these trials utilized MII-pH monitoring to assess for non-acid esophageal reflux, and only one study enrolled patients with clinically silent GERD discovered on esophageal pH monitoring.
Only one trial randomized patients with both asthma and GERD (on pH monitoring and esophagitis on endoscopy) to medical or surgical treatment. After 2 years of follow-up, mean asthma symptom scores decreased more in the surgical group than in the medical group. Furthermore, 75% of surgical patients improved, markedly improved, or were cured of asthma when compared to 9% of the medical group. However changes in mean PEF, mean PEF percentage variation, PFTs, or asthma medication requirements were not significantly different [53].
Current Guidelines
Cough
The American College of Chest Physicians (ACCP) guidelines define chronic a cough lasting 8 weeks or longer. In patients who do not smoke and do not take an ACE inhibitor, ACCP recommends to evaluate for upper airway cough syndrome (UACS, also known as post-nasal drip syndrome), asthma, non-asthmatic eosinophilic bronchitis (NAEB), and GERD – the most common causes of chronic cough. Patients with chronic cough and typical symptoms of GERD, or patients whose chronic cough persists after ruling out or treating UACS, asthma, and NAEB should undergo medical treatment for GERD – dietary and lifestyle modifications with acid suppression therapy, and prokinetic therapy if there is no response to the initial therapy. Response should be assessed 1–3 months after initiation of therapy. Patients with typical symptoms of GERD whose cough does not resolve with antisecretory therapy should undergo esophageal pH monitoring while on therapy to determine if antisecretory therapy has failed. Maximal medical therapy includes an antireflux diet (<45 g of fat per day, elimination of coffee, tea, soda, chocolate, mints, citrus, and alcohol), eliminating smoking, and limiting activities that increase intraabdominal pressure, maximal PPI therapy, and prokinetic therapy. Antireflux surgery is recommended in patients who have positive esophageal pH monitoring, in whom cough has not improved after a minimum of 3 months of maximal medical therapy, and in whom reflux is present while on maximal medical therapy. The ACCP guidelines do not address the diagnostic role of MII-pH monitoring or association tests, and they state that esophageal pH monitoring is the most sensitive and specific test for cough due to reflux [4, 57, 58]. However, more recent data support using combined MII-pH monitoring with SAP analysis while continuing medical therapy when patients fail to respond to antisecretory therapy, instead of using pH monitoring alone. Furthermore, more recent data might support using in selected patients concomitant esophageal manometry to objectively record cough episodes instead of less reliable patient recordings. Finally, patients who have been ruled out or treated for the three other most common causes of chronic cough and in whom MII-pH monitoring shows acid or non-acid reflux while on maximal antisecretory therapy, might be considered for evaluation for antireflux surgery (Table 5.2).
Table 5.2
Level of recommendation for systematic review of recent literature compared to current practice guidelines for management of extraesophageal manifestations of GERD
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