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eAppendix Includes: 1. Table 1 2. Table 2 3. Evidence tables 4. Search strings 5. Prisma Figure Table 1. Randomized Trials on Medical Management of Extraesophageal Manifestations of GERD Source Cough Shaheen 2011 Faruqi 2011 Sample Size Intervention Primary Outcome(s) Main Finding(s) P-value 40 Esomeprazole 40 mg bid for 12 weeks versus placebo Change in Cough Specific Quality of Life Questionnaire score Mean improvement in CSQLQ of 9.8 in treatment group vs 5.9 in placebo group. 0.3 Mean improvement in Fisman Cough Severity score of 1 in the treatment group vs 0.8 in the placebo group. 0.7 Mean improvement in Fisman Cough Frequency score of 3.2 in the treatment group vs 2.3 in the placebo group. Change in cough frequency was 1.6 in the treatment group and 1.5 in the placebo group. 0.3 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, citric acid cough challenge Change in cough severity was 1.2 in the treatment group and 1.7 in the placebo group. Change in the Leicester Cough Questionnaire was 2.6 in the treatment group and 0.7 in the placebo group. Change in the RFS was 0.72 in the treatment group and 2.4 in the placebo group. Change in the Hull Airway Reflux Questionnaire was 7.3 in the 0.92 0.8 0.25 0.94 0.61 treatment group and 7.1 in the placebo group. Change in log of inhaled citric acid concentration to produce 2 coughs was -0.15 in the treatment group and -0.04 in the placebo group. Baldi 2006 Kiljander 2000 (randomized case-crossover trial) LPR Lam 2010 35 Lansoprazole 30 mg qd and Changes in cough scoring placebo dose in PM (control) system and VAS versus lansoprazole 30 mg bid for 12 weeks. 21 Omeprazole 40 mg qd for 8 weeks Changes in cough symptom score in the last 3 weeks of each study period. 82 Rabeprazole 20 mg bid for 12 weeks Change in RSI and RFS Change in log of inhaled citric acid concentration to produce 5 coughs was 0.02 in the treatment group and -0.09 in the placebo group. Median change in VAS was 1 in both the treatment and control groups. Median change in cough scoring system was 1 in the treatment group and 0.5 in the control group. 10 of 17 (59%) patients in the treatment group and 11 of 18 (61%) in the control group had complete resolution of their symptoms. Cough symptom score decreased 1.5 in patients who received omeprazole, and increased 0.7 in patients who received placebo. At week 12, RSI decreased 2.8 in the treatment group and increased 0.93 in the placebo group. At week 12, RFS decreased 2.21 in the treatment group and 2.75 in the placebo group. 0.66 0.57 > 0.05 > 0.05 > 0.05 < 0.05 0.002 0.017 At week 18 RSI decreased 0.9 in the treatment group and increased 0.58 in the placebo group. At week 18 RFS decreased 3.2 in the treatment group and 3 in the placebo group. McGlashan 2009 Reichel 2008 45 58 10 mL liquid dose of sodium alginate 1000 mg and potassium bicarbonate 200 mg after meals and at bedtime Esomeprazole 20 mg bid for 3 months Change in RSI and RFS from baseline to 2 month and 6 month follow up Change in RSI and RFS at 6 weeks and 3 months follow up, and subjective report of being symptomfree at 3 months. RSI from baseline to 2 month follow up decreased 12.7 in the treatment group and 7.8 in the no treatment group. 0.12 0.68 0.005 RSI from baseline to 6 month follow up decreased 12.7 in the treatment group and 6.3 in the no treatment group. 0.008 RFS from baseline to 2 month follow up decreased 2.2 in the treatment group and 0.6 in the no treatment group. 0.08 RFS from baseline to 6 months follow up decreased 3.2 in the treatment group and 0.7 in the no treatment group. RSI from baseline to 6 weeks decreased 9.87 in the treatment group and 6.93 in the placebo group. 0.005 RSI from baseline to 3 months decreased 14.27 in the treatment group and 7.79 in the placebo group. < 0.05 RSI from baseline to 6 weeks Not significant Not significant (value unreported Wo 2006 Vaezi 2006 Steward 2004 35 145 37 Pantoprazole 40 mg daily for 12 weeks Esomeprazole 40 mg bid for 16 weeks Rapeprazole 20 mg bid for 8 weeks Change in RFS, and subjective “adequate relief” of laryngeal symptoms. Resolution of primary symptom, change in chronic posterior laryngitis index, and change in LPR-HRQL score. Change in reflux symptom score, subjective report of “significant global improvement”, change in decreased 3.47 in the treatment group and 2.46 in the placebo group. (value unreported) RSI from baseline to 3 months decreased 4.6 in the treatment group and 2.32 in the placebo group. < 0.05 At 3 months 78.6% of patients in the treatment group and 42.3% of patients in the placebo group reported being symptom-free. Median RFS decreased 1 in the treatment group and 3 in the placebo group. 0.006 Adequate relief of laryngeal symptoms was reported by 40% of patients in the treatment group and 42% of patients in the placebo group. Resolution of primary symptom was reported in 14.7% of patients in the treatment group and 16% of patients in the placebo group. 0.89 CPLI decreased 1.6 in the treatment group and 2 in the placebo group. LPR-HRQL score decreased 11.6 in the treatment group and 7.8 in the placebo group. Mean reflux symptom score decreased 9.7 in the treatment group and 6.6 in the control group. Not significant (value unreported) 0.799 0.446 0.424 0.44 laryngeal grading of video-recorded strobelaryngoscopy signs scoring system Ehrer 2003 (placebocontrolled case-crossover trial) 14 Noordzij 2001 30 El-Serag 2001 Asthma Kiljander 2010 20 828 Pantoprazole 40 mg bid for 3 months Omeprazole 40 mg bid for 8 weeks Lansoprazole 30 mg bid for 3 months Three randomization Change in symptom score, change in laryngoscopic signs score Change in symptom score, change in laryngoscopic scores for vocal fold edema, arytenoid erythema, arytenoid edema, interarytenoid irregularity, and mucus accumulation. Resolution of all presenting laryngeal symptoms, complete or partial resolution of all presenting laryngoscopic signs Changes in lung function Significant global improvement was reported in 53.3% of treatment patients and 50% of control patients. Laryngoscopic grade increased 0.6 in the treatment group and 0.5 in the control group. No statistically significant difference in mean symptom scores between groups (values unreported). 1 0.69 Not significant (value unreported) Mean laryngoscopic signs score decreased 8 in the treatment-first group and 5.6 in the placebo-first group. Laryngeal symptom score decreased 1078.6 in the treatment group and 1944.9 in the placebo group. Not significant (value unreported) No significant difference was found in the change in laryngoscopic sign scores between the two groups. Resolution of all presenting laryngeal symptoms was reported in 55% of patients in the treatment group and 11% of patients in the placebo group. Not significant (values unreported) 0.04 Complete or partial resolution of laryngeal signs was found in 58% of patients in the treatment group and 30% of patients in the control group. Mean morning PEF improved 3.5L 0.098 0.123 Not significant groups: esomeprazole 40 mg daily and placebo daily, esomeprazole 40 mg bid, or placebo bid for 26 weeks tests, change in asthma quality of life questionnaire score, and experiencing a severe asthma exacerbation and 5.5L more in patients receiving (values esomeprazole daily and bid, unreported) respectively, compared to placebo. Mean FEV1 improved 0.07L more in patients receiving esomeprazole bid compared to placebo. Esomeprazole once daily was not statistically significantly better than placebo. 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. Severe asthma exacerbations were experienced by 10%, 7.5%, and 10% of patients receiving esomeprazole once daily, bid, and placebo, respectively. 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 miniAQLQ score Subjectively improved exercise tolerance was reported by 70% of patients receiving rabeprazole and 25% of patients receiving placebo bid. There was no statistically significant difference in change in FEV1, FVC, or FEV1/FVC between the rabeprazole groups and placebo (values unreported). There were no statistically significant difference in change in < 0.0042 Not significant (value unreported) < 0.001 Not significant (values unreported) 0.03 Not significant (values unreported) SF-36 or mini-AQLQ scores (values unreported). 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 in the treatment group and 2.3 in the placebo group. Change in FEV1 was 0L in the treatment group and -0.02L in the placebo group. 0.36 Change in FVC was 0 in the treatment group and -0.03 in the placebo group. 0.3 Change in PEF was 9.2 L/min in the treatment group and 3.2 L/min in the placebo group. 0.24 Change in PC20 was 0.3 mg/mL in the treatment group and 1.5 mg/mL in the placebo group. Sharma 2007 198 Omeprazole 20 mg bid and domperidone 10 mg tid for 16 weeks Not significant (values unreported) 0.66 Change in JACQ, ASUI, mini-AQLQ, and SF-36 scores were not statistically significantly different between the treatment and placebo groups. Changes in asthma Daytime asthma symptom score symptom score, rescue decreased 0.48 in the treatment albuterol use, daytime and group and 0.22 in the placebo nighttime PEF, postgroup. bronchodilator FEV1, and FVC Nighttime asthma score decreased 0.51 in the treatment group and 0.14 in the placebo group. 0.04 0.11-0.56 0.0001 0.0001 Rescue albuterol puffs/week decreased 0.76 in the treatment <0.0001 group and 0.1 in the placebo group. Morning PEF increased 22.78 L/min in the treatment group and decreased 0.76 L/min in the placebo group. Evening PEF increased 27.76 L/min in the treatment group and decreased 1.43 L/min in the placebo group. FEV1 increased 0.21L in the treatment group and 0.07L in the placebo group. Kiljander 2006 624 Esomeprazole 40 mg bid for 16 weeks Change in morning and evening PEF FVC increased 0.18L in the treatment group and decreased 0.03L in the placebo group. Morning PEF increased 22.3 L/min in the treatment group and 16 L/min in the placebo group from baseline to the last 28d of the study. Morning PEF increased 5.6 L/min more in the treatment group than in the placebo group after treatment was completed. In patients with GERD and nocturnal respiratory symptoms morning PEF increased 8.7 L/min more in the treatment than the placebo group. <0.004 0.002 0.0013 0.0023 0.061 0.042 0.03 Evening PEF increased 5.9 L/min more in the treatment group than in the placebo group. 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, postbronchodilator FVC and FEV1, AQLQ score, and asthma exacerbations. In patients with GERD and nocturnal respiratory symptoms evening PEF increased 11.2 L/min more in the treatment group than in the placebo group. Asthma symptom scores decreased 0.36 in the treatment group and 0.21 in the placebo group. Morning PEF increased 5 L/min in the treatment group and 10 L/min in the placebo group. Evening PEF increased 4 L/min in the treatment group and 12 L/min in the placebo group. 0.053 0.02 Not significant (value unreported) Not significant (value unreported) < 0.05 Post-bronchodilator FEV1 changed 0L in both groups. Post-bronchodilator FVC changed 0L in the treatment group and decreased 0.1L in the placebo group. AQLQ score increased 0.9 in the treatment group and 0.7 in the placebo group. Albuterol use decreased 1 puff/day in the treatment group and 0.9 puffs per day in the placebo group. Asthma exacerbations were Not significant (value unreported) Not significant (value unreported) < 0.05 Not significant (value experienced by 8.1% of patients in the treatment group and 20.4% of patients in the placebo group. Moderate or severe asthma exacerbations were experienced by 4% of patients in the treatment group and 13.9% of patients in the placebo group. Sontag 2003 62 Three randomization groups: lifestyle Cont modifications and prn 24 medications only (control), Med 22 lifestyle modificaitons and Surg ranitidine 150 mg tid, and 16 lifestyle modificaitons 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. The requirement for pulmonary medications decreased in 9.1% of patients in the medical group but increased in 18.2% of these 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. Overall improvement occurred in 9.1% of patients in the medical group, 75% of the surgical group, and 4.2% of the control group. Jiang 2003 30 Two randomization arms: asthma treatment only, versus asthma treatment plus omeprazole 20 mg qd Change in PFTs and histamine-induced bronchial sensitivity. FVC increased 0.8L in the treatment group vs decreased 0.2L in the no-treatment group. unreported) 0.017 0.016 0.008 (surgery versus control and medical groups combined) Not significant (value unreported) < 0.001 (surgery versus control and medical groups combined) < 0.05 and domperidone 10 mg tid for six weeks FEV1 increased 0.6L in the treatment group and 0.1 L in the no-treatment group. < 0.05 PEF increased 1.3 L/s in the treatment group versus 0.4 L/s in the no-treatment group. < 0.05 Bronchial sensitivity improved 0.51 g/L in the treatment group versus worsened 0.03 g/L in the no-treatment group. < 0.05 Table 2. Level of Recommendation for Systematic Review of Recent Literature Compared to Current Practice Guidelines for Management of Extraesophageal Manifestations of GERD Intervention Current Evidence Review and Guidelines Cough Treating chronic cough with medical antisecretory therapy. Evidence review Randomized controlled trials on treating suspected cough due to reflux with PPIs have had mixed results. Shaheen 2011 (patients with chronic cough and without typical GERD symptoms) and Faruqi 2011 (patients with chronic cough and with or without typical GERD symptoms) showed no improvement in cough-related quality of life, cough severity, cough frequency, induced cough threshold compared to placebo. However, Kiljander 2000 (patients with chronic cough and abnormal esophageal pH monitoring) showed greater improvement in cough symptoms with omeprazole compared to placebo. No randomized trial has directly addressed the question of medical treatment of reflux in patients with persistent chronic cough and non-acid reflux. Patients with persistent chronic cough who do not smoke and are not taking an ACE inhibitor, after ruling out or treating for upper airway cough syndrome, asthma, and non-asthmatic eosinophilic bronchitis should undergo medical treatment for GERD. (ACCP) Treating patients with chronic cough and typical symptoms of GERD with medical antisecretory therapy. Evidence review Two randomized controlled trials have enrolled patients with chronic cough and a diagnosis of GERD, Baldi 2006 and Kiljander 2000. Baldi 2006 compared daily to twice daily lansoprazole, and found that bid therapy was not significantly better than daily therapy. Kiljander 2000 showed greater improvement in cough symptoms with omeprazole compared to placebo. While patients with typical symptoms of GERD should be treated for GERD regardless of what extraesophageal manifestations of GERD they may have, whether or not treating their GERD has a positive impact on their chronic cough is not clear. Recommendation Level Class A IIb B IIb B IIa Practice guidelines Practice guidelines Patients with chronic cough and typical symptoms of GERD should undergo medical treatment for GERD (ACCP). Using esophageal monitoring to diagnose cough due to reflux. Evidence review Studies have sought to evaluate the utility of esophageal monitoring – pH and MII-pH monitoring, on and off antisecretory therapy, with subjective and objective reporting of cough – in diagnosing cough due to reflux. A prospective case-control study found that weakly acidic gas reflux was unique to patients with cough due to reflux compared to patients with GERD and healthy controls. (Kawamura 2011) Retrospective studies found esophageal pH monitoring with SAP analysis with self-reported cough off antisecretory therapy was found to have a positive and negative predictive value of 0.28 and 0.72, respectively (Hersh 2010), and that 26% of patients with cough due to reflux had a positive SI for non-acid reflux during esophageal MII-pH monitoring with self-reported cough on antisecretory therapy (Tutuian 2006). A prospective cohort study on esophageal MII-pH monitoring off antisecretory therapy with SAP analysis and cough recorded with concurrent manometry found 77% of patients with cough due to reflux were SAP positive, while 44% of patients without cough due to reflux were SAP positive. This study also reported that only 39% of cough bursts were not recorded by patients, and those that were recorded were delayed by 28 seconds. (Sifrim 2005) These studies were all small (n ≤ 61) and some had significant methodological flaws. Overall, no strong recommendations about patient selection, whether monitoring should be conducted on or off antisecretory therapy, or the true diagnostic yield of esophageal monitoring can be made with the data currently available. Still, it is reasonable to conclude that patients with chronic cough and typical GERD symptoms should undergo an empiric trial of antisecretory therapy before being subjected to esophageal monitoring. Furthermore, if at all possible, esophageal pH/MII-pH monitoring should be accompanied by concurrent manometry in order to gather superior objective data on cough bursts and their timing. The evidence does not support the guidelines’ assertion that esophageal pH monitoring is the most sensitive and specific test available for cough due to reflux: MII-pH monitoring with objective cough recording and SAP analysis may be superior to esophageal pH monitoring to diagnose GERD in patients with chronic cough. Practice guidelines Patients with typical symptoms of GERD whose cough does not resolve with antisecretory therapy should undergo esophageal pH monitoring while on antisecretory therapy to determine whether medical therapy has failed (ACCP). Antireflux surgery for the treatment of cough due to reflux. Evidence review No randomized controlled trial has compared medical to surgical treatment of cough due to reflux in any patient population. Two prospective cohort studies have observed patients who underwent antireflux surgery after a negative workup for other causes of chronic cough. Allen 2004 reported on 79 patients who had a negative workup for UACS and asthma and complained primarily of respiratory symptoms before undergoing laparoscopic Nissen fundoplication. At B IIb 5-years follow-up patients subjectively reported 36% were cured of cough, 35% were improved, 24% were unchanged, and in 5% cough was worse. Mean cough score decreased 3.9 on a 12-point scale. Brouwer 2003 reported on 28 patients who underwent laparoscopic Nissen fundoplication for predominantly respiratory symptoms. Mean cough score decreased from 4.7 to 0.4 at mean 650 days follow-up. 19 patients had cough or “aspiration-type symptoms”: 53% reported resolution of their symptoms (symptom score of 0/5), 32% had marked improvement (symptom score of 1/5), 11% reported some improvement, and 5% were unchanged. Antireflux surgery for cough due to reflux is promising for cases refractory to medical management. However patient selection to maximize successful resolution of cough is uncertain. In patients who have been ruled out or treated for the three other most common causes of chronic cough and MII-pH monitoring shows acid or non-acid reflux on maximal antisecretory therapy, it may be reasonable to refer for evaluation for antireflux surgery. However, patients should be counseled that success is not guaranteed, and surgery is not without risks. Practice guidelines 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 lifestyle modifications and esophageal monitoring studies show continued reflux while on maximal medical therapy (ACCP). LPR Use of the Reflux Symptom Index to diagnose LPR B Evidence review One prospective study has evaluated the Reflux Symptom Index (Belafsky 2002). The authors reported mean RSI of patients with LPR was 19.9, of healthy controls was 11.6. They considered RSI > 13 abnormal and indicative of LPR. Patients with suspected LPR should be evaluated with the Reflux Symptom Index and Reflux Finding Score. If > 13 and > 7, respectively, patients should undergo an empiric trial of antisecretory therapy (Ford). Use of the Reflux Finding Score to diagnose LPR Evidence review Belafsky 2001: mean RFS of patients with LPR was 11.5. Interrater reliability was 0.9. IIb Practice guidelines Patients with suspected LPR should be evaluated with the Reflux Symptom Index and Reflux Finding Score. If > 13 and > 7, respectively, patients should undergo an empiric trial of antisecretory therapy (Ford). Use of the Laryngoscopic Reflux Index score to diagnose LPR B IIb C IIb Practice guidelines Evidence review Jonaitis 2006: LRI significantly higher in patients with LPR versus healthy controls. LRI > 5 significantly more common in cases than controls, but test characteristics unreported. Practice guidelines Not addressed. Use of laryngoscopy to diagnose LPR Evidence review Three prospective studies have examined the use of laryngoscopy to diagnose LPR. In one case-control study (Vavricka 2007), only posterior pharyngeal wall cobblestoning was more common in cases than controls (66% vs 55%). Agreement between blinded observers on laryngeal findings ranged from good to poor. Another prospective study found that only interarytenoid mucosal inflammation and inflammation of the true vocal cords were significant predictors of response to antisecretory therapy (Park 2005). Yet another prospective study compared transnasal flexible fiberoptic laryngoscopy to transoral rigid laryngoscopy, finding fiberoptic laryngoscopy superior in detecting laryngeal findings. However even with flexible fiberoptic laryngoscopy interrater reliability for findings ranged from poor to moderate. B Laryngoscopic findings are highly suggestive of LPR: posterior laryngitis, contact granuloma, and pseudosulcus (Ford). Esophageal pH or MII-pH monitoring to diagnose LPR B Evidence review Two prospective studies have examined esophageal or pharyngoesophageal pH monitoring to diagnose LPR. One found increased laryngopharyngeal bolus exposure time and increased distal AET were only two significant predictors of response to PPI therapy (Wang 2012), while the other found that 52% of patients with laryngeal symptoms and 38% of patients with typical GERD symptoms had laryngopharyngeal acid reflux episodes during monitoring (Yorulamz 2003). IIa Practice guidelines In patients whose symptoms do not resolve after 6 months or improve after 3 months patients should be evaluated with pharyngoesophageal MII-pH monitoring to demonstrate reflux (Ford). Empiric PPI trial to diagnose LPR Evidence review One prospective trial examined the sensitivity and specificity of an empiric trial of twice daily PPIs to diagnose LPR, reporting positive and negative predictive values of 86% and 25%, respectively (Masaany 2011). IIb Practice guidelines Practice guidelines If patients have RSI > 13 and RFS > 7, initiate 3-6 months of anti-reflux diet, B IIb lifestyle modifications, and twice daily PPI therapy. Treatment of LPR with PPIs Evidence review Eight randomized trials have compared twice daily PPI therapy with placebo. Some followed changes in the RSI and RFS. Six of these trials reported no differences between the placebo and treatment groups (or in the case of Lam 2010, only a transient difference), while 2 did report significant differences. Reichel 2008 showed RSI and RFS both improved at 3 months in patients treated with esomeprazole 20 mg bid for 3 months compared to placebo, while El-Serag 2001 reported a greater percentage of patients in the treatment group reporting complete resolution of their symptoms than in the placebo group (55% vs 11%), but no difference in change in laryngeal signs of inflammation between the two groups (Lam 2010, Reichel 2008, Wo 2006, Vaezi 2006, Steward 2004, Ehrer 2003, Noordzij 2001, El-Serag 2001). Overall, there is little evidence from randomized trials that PPIs are an effective treatment for LPR. This may be due to poor patient selection for randomized trials of LPR. Practice guidelines Recommends treating patients with 3-6 months of twice daily PPI therapy. Treatment of LPR with sodium alginate and potassium bicarbonate. Evidence review One randomized non-placebo controlled trial has evaluated the effect of treating LPR with sodium alginate and potassium bicarbonate found RSI and RFS improved significantly from baseline to 2 months (RSI only) and baseline to 6 months (RSI and RFS both) (McGlashan 2009). Practice guidelines Not addressed. Antireflux surgery for LPR Evidence review No randomized trials have compared medical to surgical therapy for LPR. Swoger 2006 reported a prospective cohort of 25 patients who were unresponsive to PPI therapy. 10 chose to have surgery. At 1 year follow up, 1 patient in the surgery group and 1 patient in the medical groups reported resolved symptoms. Given the paucity of prospective data surgical intervention must be undertaken with the greatest caution, and only in patients whom studies have shown have a reasonable chance of achieving cure. Practice guidelines A IIb B IIa C IIb C IIb In patients whose pharyngoesophageal MII-pH monitoring demonstrates reflux, referral should be made for surgery. Asthma Use of esophageal acidification to diagnose asthma due to reflux Evidence review One prospective case-control study used an increase of 100 μg in PD20 FEV1 of a methacholine inhalation test after esophageal acidification to diagnose asthma due to reflux. Positive and negative predictive values were reported as 86% and 82%, respectively. (Dal Negro 2009) Practice guidelines Not addressed Use of esophageal pH monitoring to diagnose asthma due to reflux Evidence review One randomized case-crossover trial (Kiljander 2001) studied using esophageal pH monitoring to diagnose asthma due to reflux. The authors found that mean distal esophageal acid exposure time (11% vs 8%) and supine distal esophageal acid exposure time (12% vs 8%) were statistically significantly higher in patients whose asthma responded to therapy with omeprazole than in patients whose asthma did not respond to omeprazole. B The Expert Panel recommends that patients with poorly controlled asthma despite maximal medical therapy should be evaluated for GERD with esophageal pH monitoring. (NIH-EPR3) Use of antisecretory therapy in patients with typical GERD symptoms. A Evidence review Three placebo-controlled randomized trials and 1 uncontrolled randomized trial have evaluated the effect of twice daily PPI therapy on asthma symptoms and pulmonary function tests in patients with GERD, diagnosed either by symptoms or esophageal pH monitoring. Three (Kiljander 2010, Sharma 2007, Jiang 2003) found improvement in PFTs, while 1 (Littler 2005) did not. Kiljander 2010 found decreased time to asthma exacerbation, greater asthma-free days, and less bronchodilator use in the treatment group, and Sharma 2007 found decreased bronchodilator use, while Littler 2005 found fewer asthma exacerbations and moderate-severe asthma exacerbations in the treatment group but no difference in bronchodilator use. Jiang 2003 found decreased inhaled histamine sensitivity in the treatment group. Kiljander 2010 found improvement in the Asthma Quality of Life Questionnaire score, while Littler 2005 did not. Overall, symptomatic GERD should be treated regardless of whether or not a patient has asthma, and the evidence indicates that treating GERD with twice daily PPI therapy in patients with asthma improves subjective symptoms and PFTs, and may decrease rescue bronchodilator use and increase asthma-related quality of life. IIb Practice guidelines Practice guidelines The Expert Panel recommended that patients with asthma and GERD symptoms should be treated for GERD. (NIH-EPR3). I Use of antisecretory therapy in patients without typical GERD symptoms but with positive esophageal pH monitoring. Evidence review One randomized trial evaluated the effect of twice-daily PPI therapy on asthma symptoms and PFTs in patients without typical GERD symptoms. Mastronarde 2009 found no difference in episodes of poor asthma control, PFTs, or asthma symptoms in patients without typical GERD symptoms, including patients with silent GERD discovered on esophageal pH monitoring. Kiljander 2006 studied patients without moderate or severe GERD symptoms and found significantly greater improvement in morning PEF in the treatment group, but no significant difference in asthma exacerbations or median time to asthma exacerbation. In a subgroup of patients with mild GERD symptoms and nocturnal asthma symptoms morning and evening PEF increased significantly more in the treatment group. Practice guidelines Not addressed. Antireflux surgery for asthma due to reflux. Evidence review One randomized controlled trial compared antireflux surgery to H2 blocker therapy for asthma due to reflux (Sontag 2003). It found that at 2 years asthma symptom scores decreased significantly more in the surgical group than in the H2 blocker and placebo groups combined. 75% of surgical patients had improvement, marked improvement, or cure of asthma after 2 years follow up. However pulmonary function tests and asthma medication requirements were not significantly different between the groups. Rakita 2006 found mean asthma symptom scores decreased from 4.7 to 1.7 after antireflux surgery (laparoscopic Nissen fundoplication) in patients who presented with a mean asthma symptom score of at least 4. Practice guidelines Surgical treatment has been reported to reduce the symptoms of asthma and medication requirements (NIH-EPR3) B IIb B IIb Q1a: How is reflux cough diagnosed? Source Study participants Xu 2014 126 patients with either: chronic cough and typical reflux symptoms, persistence of chronic cough after prior workup failed to identify a cause, or persistence of chronic cough after attempted interventions failed to resolve a chronic cough Diagnostic studies evaluated GerdQ Vs MII-pH off antisecretory therapy Gold standard Study design Main finding(s) Complete resolution or cough symptom score decreased by at least two points after 8-weeks of omeprazole 20 mg bid and domperidone 10 mg tid, and further treatment with omeprazole 80 mg/day or replacement of domperidone with baclofen 20 mg tid if unresponsive after initial 8 weeks Response to empiric therapy with PPIs Prospective cohort GerdQ vs MII-pH sensitivity: 66.7% vs 97.1% (p < 0.001) specificity: 91.7% vs 62.5% (p < 0.001) PPV: 97.1% vs 91.7% (p = 0.121) NPV: 42.9% vs 83.3% (p < 0.001) Prospective cohort Simultaneous measurement with both modalities Prospective cohort The presence of heartburn had a sensitivity of 72% and a specificity of 68% for GERD as the cause of chronic cough. The presence of an acid taste in the mouth had a sensitivity of 50% and a specificity of 80%. No correlation between reflux events or positive-SAP for cough and reflux between MII-pH and oropharyngeal pH monitor Only patients with GERD-cough had weakly acidic gaseous esophagopharyngeal reflux, which was eliminated on PPI therapy. 21 (40%) patients reported cough without typical GERD symptoms. Ojoo 2013 112 patients with chronic cough Symptoms Ummarino 2013 10 patients with unexplained chronic cough referred for suspected reflux cough Oropharyngeal monitoring MII-pH Kawamura 2011 10 patients with GERD-cough, 10 with GERD alone, and 10 healthy controls MII-pH Resolution of cough on PPI therapy and recurrence off PPI therapy Hersh 2010 53 patients with a primary complaint of chronic cough who underwent ambulatory pH monitoring off antisecretory therapy pH monitoring and SAP SI, SAP, acid-exposure time High degree of response to treatment A high degree of response to treatment (either submaximal or maximal antisecretory therapy, or antireflux surgery) was predicted by female sex (p = 0.02) and positive SAP (p = 0.03) in univariate and multivariable analysis. Positive-predictive value of a positive SAP predicting high degree of response to treatment was 0.28, while negative predictive value was 0.72. PPV and NPV of elevated acidexposure time was 0.47 and 0.53, respectively. Patterson 2009 19 patients with asthma, 17 with chronic cough Oropharyngeal monitoring MII-pH Prospective cohort Combining AET, SAP, and SI yielded greater negative predictive value. 142/144 pharyngeal reflux episodes were non-acidic. There was a significant correlation between the number of reflux episodes reaching the pharynx and the total number reaching the distal (r = 0.59, p < 0.002) and mid-esophagus (r = 0.53, p < 0.001). There was no significant difference between asthma and cough patients for any impedence or pH parameter. Songur 2008 Everett 2007 55 patients with chronic cough and reflux symptoms, thought to have reflux cough by Montreal definition, having all of the following: complaint of heartburn or regurgitation, upper GI endoscopic findings and histology of reflux esophagitis, normal CXR, nonsmoker, not using ACE inhibitors, normal PEF rate variability, and failure of cough to resolve after treatment for postnasal drip, asthma and/or nonasthmatic bronchitis. And, 12 healthy volunteers. 47 patients referred for chronic cough without respiratory disease or history of GERD Gastroesophageal scintigraphy Montreal definition of reflux cough Prospective cohort History and symptomatology Chronic cough and any two of: esophageal acid reflux on pH probe, esophageal dysmotility on manometry, or low LES pressure on manometry Retrospective cohort SAP-positive cough patients experienced more reflux episodes crossing the UES over 24h (5 vs 2, p < 0.05), and had a higher percentage of reflux episodes cross the UES (25% vs 6.7%, p < 0.02) than SAP-negative cough patients. GES showed pathologic reflux in 51 of 55 (92.7%) patients with reflux cough, 19 (37%) of whom had proximal reflux and 32 (63%) of whom had distal reflux. After treatment with omeprazole 20 mg bid for 8 weeks, cough had resolved completely in 19 (37%) patients, and sleep and daytime quality of life had improved in another 22 (43%). Of the 10 patients who did not improve, 9 (90%) had proximal reflux and grade B or C esophagitis. Cough on phonation, on rising from bed, after throat clearing, with certain foods, and with eating generally were the symptoms most commonly associated with reflux cough (90%, 86.7%, 82.5%, 76.5%, and 74.4% respectively). Mainine 2006 144 patients referred for symptoms refractory to PPI therapy MII-pH Positive SI during MII-pH Prospective cohort Tutuian 2006 50 patients with persistent cough despite twice daily PPI therapy MII-pH on PPI therapy Positive SI during MII-pH Retrospective cohort Sifrim 2005 22 patients with chronic cough and a normal CXR, negative workup for asthma and postnasal drip syndrome, and not on ACEi, who had more than 5 cough bursts during monitoring MII-pH and manometry and SAP Esophageal pH monitoring Prospective cohort For patients with atypical symptoms (cough, hoarseness, abdominal discomfort, nausea, belching, throat discomfort, throat mucous, globus sensation, hiccups, wheezing, or sour taste), 3% had a positive SI for acid reflux, 19% had a positive SI for nonacid reflux while on twice-daily PPI therapy. 13 (26%) patients had a positive SI for non-acid reflux. 6 of 13 underwent laparoscopic Nissen, 1 of whom was lost to follow-up. At median follow-up of 17 months, the 5 laparoscopic Nissen patients were asymptomatic and off PPI therapy. 966 reflux events were detected, and 647 cough bursts. 198 of 647 (30.6%) cough busts occurred within 2 minutes of a reflux episode. In 49% of these 198, reflux proceeded cough. 13 of 22 (59%) patients had abnormal pH findings and/or typical GERD symptoms. 10 (77%) were SAP positive (77%), 3 (23%) were SAP negative. 9 of 22 (41%) patients had normal pH findings and no typical GERD symptoms. 5 (56%) were SAP negative, 4 (44%) were SAP positive. Of the 4 patients with normal pH findings and no typical GERD symptoms but positive SAP, 3 had a positive SAP with weakly acidic reflux. Overall, inclusion of SAP changed the diagnosis from reflux cough to idiopathic cough in 3 of 22 patients, and from idiopathic cough to reflux cough in 4 of 22 patients. 9 patients recorded cough as occurring after reflux episodes, while manometry recorded coughs prior to the patient Wunderlich 2003 Avidan 2001 61 patients referred for chronic cough, 23 on and 38 not on antisecretory medications 128 asthmatic patients not on antisecretory therapy Esophageal pH monitoring SAP Esophageal pH monitoring and SAP Esophageal pH monitoring with SI and SSI None Retrospective cohort Prospective cohort recording, changing these events from reflux-cough to cough-reflux. SAP detected significantly more temporal associations than SI/SSI in patients on and off PPIs (p < 0.002). SAP and SI/SSI had moderate agreement (κ = 0.41) Cough and reflux were temporally associated in 46% of patients using a 2minute window (p < 0.001) and in 62% of patients using a 5-minute time window (p < 0.001). In a 2-minute window, reflux preceded cough in 40% of coughs (p < 0.001), while cough preceded reflux in 6% of coughs (p = 0.043). In a 5-minute time window, reflux preceded cough in 50% of coughs (p < 0.001), while cough preceded reflux in 12% of coughs (p = 0.014). Q1b How is reflux laryngitis/LPR diagnosed? Source Study participants Wang 2012 92 patients with chronic laryngitis diagnosed with laryngoscopy Masaany 2011 55 patients with either Reflux Symptom Index > 13 or Reflux Finding Score > 7 132 patients with esophagoscopic findings of GERD, and 132 sexand age-matched controls Vavricka 2007 Jonaitis 2006 Ylitalo 2005 108 patients with hoarseness lasting more than 3 months, chronic throat clearing, or throat itching, had laryngitis on laryngoscopy, and esophagitis on endoscopy or biopsy pathology; and 90 healthy controls 50 patients with chronic heartburn, 25 of whom had GERD diagnosed on pH monitoring Diagnostic studies evaluated Laryngoscopy, EGD, MII-pH Gold standard Study design Main finding(s) Decrease of 50% in laryngeal symptom score after rabeprazole 10 mg bid therapy Prospective cohort Response to empiric treatment with pantoprazole 40 mg bid Structured examination of the laryngopharyngeal area during upper gastrointestinal endoscopy Symptoms of LPR and positive pH monitoring None Prospective double-blind cohort Matched casecontrol On multivariate analysis, increased distal esophageal acid exposure time (hazard ratio 2.6, p = 0.011) and increased laryngopharyngeal bolus exposure time (hazard ratio 2.6, p = 0.004) were associated with response to rabeprazole therapy. Sensitivity of empiric treatment was 92.5%, specificity 14.2%. PPV 86%, NPV 25%. No significant difference between cases and controls in prevalence of abnormal interarytenoid bar findings (32% vs 32%), arytenoid medial wall erythema (47% vs 43%), posterior commissure changes (36% vs 34%), or posterior cricoid wall edema (1 vs 3%). Posterior pharyngeal wall cobblestoning was more common in cases than controls (65.5% vs 49.7%, p = 0.004). A novel laryngoscopic reflux index scoring findings on the arytenoids, intraarytenoid notch, vestibular folds, and vocal cords, calculated after examination by a single laryngoscopist Laryngoscopy Definition of LPR as patient with consistent complaints, laryngitis on laryngoscopy, and esophagitis on endoscopy or biopsy pathology Oropharyngeal reflux on pH monitoring Case-control Prospective cohort Agreement between four blinded observers (3 gastroenterologists and 1 otolaryngologist) on laryngopharyngeal findings ranged from fair/good to poor. Erythema and edema of the whole laryngeal mucosa, reduced mucosal light reflex on the aryetnoids, interaretynoid notch, vocal folds, vocal cords, hypertrophy, roughness, and granulomas were all significantly more common in LPR patients than in controls (p ranging from < 0.001 to 0.01). Both the laryngoscopic reflux index and its individual components were significantly different between cases and controls (p < 0.001). No laryngoscopic sign was statistically significantly different between patients with and without GERD, or those with Park 2005 72 patients with signs and symptoms of LPR who underwent adequate video-recorded laryngoscopy Laryngoscopy Response to therapy Prospective cohort Qadeer 2005 10 patients who underwent laparoscopic Nissen fundoplication after failure (< 50% symptomatic improvement) of laryngeal symptoms (cough, throat clearing, sore/burning throat, hoarseness, or globus sensation) to respond to 4 months of omeprazole 40 bid or lansoprazole 60 bid Laryngoscopy by one otolaryngologist at 6 and 12 months after surgical fundoplication Symptomatic improvement Prospective cohort Milstein 2005 52 healthy volunteers, 26% of whom were former smokers and none of whom were current smokers, with mild or no complaints of cough, hoarseness, throat clearing, sore throat, globus sensation, heartburn, regurgitation, dysphagia, chest pain, odynophonia. Transoral laryngoscopy with rigid telescopic laryngoscope None Crosssectional Vs Transnasal laryngoscopy with flexible fiberoptic laryngoscope and without oropharyngeal reflux on pH monitoring Pretherapy presence of abnormal laryngoscopic findings in the interarytenoid mucosa and the true vocal folds was associated with response to PPI therapy (OR 2, p = 0.02). Sore/burning throat, hoarseness, and chronic cough were the most common persistent complaints (70%, 50%, 30%, respectively). At 12-month follow-up, heartburn had resolved in all patients, while laryngeal symptoms had improved in 1 of 10 (10%) patients. Laryngoscopic signs improved in 80% of patients: 5 of 10 (50%) had a normalized laryngoscopic exam at 6month follow-up, another 3 (30%) had a normalized exam at 12-month followup. 2 patients (20%) had improvement in laryngeal symptoms after treatment for asthma and allergies after completion of the study. Patients complained of mild cough, hoarseness, throat clearing, sore throat, globus sensation, heartburn, and regurgitation (13%, 4%, 27%, 4%, 2%, 4%, 2%, respectively). None complained of odynophagia, chest pain, or odynophonia. 71% consumed alcohol 2-3 times per month or less. Video of laryngoscopic examination was reviewed by three independent otolaryngologists. With the flexible and rigid laryngoscopes, 145 of 156 observations (93%) and 130 of 156 observations (83%), respectively, detected at least 1 sign of laryngeal irritation. In 7 of 13 common laryngoscopic findings, the flexible laryngoscopic examination discovered the sign significantly more often (p < 0.01 for all). Hicks 2002 105 healthy volunteers without heartburn more than three times per month, or chronic throat clearing, sore throat, coughing, hoarseness, or globus sensation, or with known GERD, and not on antisecretory medications. Flexible laryngoscopic examination by one licensed speech-language pathologist None Crosssectional Interrater reliability was calculated for 11 signs. 2 signs had poor, 2 slight, 5 fair, and 2 moderate agreement. On rigid laryngoscopy interrater reliability was calculated for 8 signs. 1 sign had slight, 4 fair, and 3 moderate agreement. Patients most commonly complained of throat clearing, heartburn, cough, thick drainage, and throat tickle (33%, 24%, 14%, 13%, and 13%, respectively). 86% of patients had at least 1 laryngoscopic finding, while 64% had 2 or more. 12% had 4 or 5 signs, and 3% had more than 5 signs. Intrarater reliability was calculated for 5 signs with the same reviewer observing the recorded examination 5 months apart, with substantial agreement (κ = 0.63, 0.7, 0.78, 0.68) between the 2 observers for posterior pharyngeal wall cobblestoning, arytenoid medial wall erythema, interarytenoid bar presence, and true vocal cord edema, respectively, and fair agreement for interarytenoid bar erythema (κ = 0.26). Yorulmaz 2003 139 patients who underwent esophageal pH monitoring, 97 with primarily laryngopharyngeal symptoms (chronic or intermittent Esophageal and laryngopharyngeal pH monitoring None Retrospective cohort Interrater reliability between two independent observers was calculated for 3 signs, with interarytenoid bar presence showing moderate agreement (κ = 0.58), and posterior pharyngeal wall cobblestoning and arytenoid medial wall erythema showing fair agreement (κ = 0.33 and 0.32, respectively). 50 of 97 (52%) patients with primarily laryngopharyngeal symptoms and 16 of 42 (38%) patients with primarily typical symptoms had laryngopharyngeal acid hoarseness, frequent throat clearing, chronic cough, laryngospasm, globus sensation, or sore throat), 42 with primarily typical symptoms (heartburn or regurgitation) Branski 2002 100 patients with primary complaint of dysphonia Transoral rigid laryngoscopy None Prospective cohort reflux episodes (p < 0.005). Supine acid reflux episodes were more frequent in patients with typical symptoms than patients with laryngopharyngeal symptoms (p < 0.005). There were no significant differences in acid clearance parameters or esophageal acid exposure times between the groups. 6 independent otolaryngologists evaluated video recordings of each patient’s laryngoscopic examination. Intrarater reliability from 20 repeated recording observations was calculated. 1 of 5 observers had consistent intrarater reliability for across multiple laryngoscopic signs. Belafsky 2002 25 patients with LPR and 25 ageand gender-matched controls Reflux symptom index (RSI) pH monitoring Prospective matched cohort Single measure interclass correlation coefficients for 7 laryngoscopic signs, for otolaryngologist’s opinion of the severity of GERD, and for the likelihood of GERD contributing to patient dysphonia were calculated, and ranged from 0.161 to 0.461, corresponding to poor agreement for all but one measure, which had fair agreement. Mean RSI on 2 different days correlated well in LPR patients (Pearson correlation coefficient = 0.81, p < 0.001). Mean RSI after 6 mo of PPI therapy decreased from 20.9 to 12.8 (p < 0.001). Mean RSI in controls was 11.6, not statistically significantly different from LPR patients after 6 mo of PPI therapy. Q1c: How is reflux asthma diagnosed? Source Study participants Komatsu 2013 31 patients with adult-onset asthma Dal Negro 2009 Kiljander 2001 27 patients non-atopic patients with mild asthma and symptomatic GERD confirmed on esophageal pH monitoring, and 29 atopic asthmatics without symptoms of heartburn or regurgitation and no diagnosis of GERD after esophageal pH monitoring 52 asthmatic patients with GERD on pH monitoring Diagnostic studies evaluated MII-pH off antisecretory therapy Gold standard Study design Main finding(s) Retrospective cohort Abnormal proximal esophageal exposure in 19 (70%) patients. 9 (33%) also had laryngopharyngeal reflux. 20% of laryngopharyngeal reflux episodes and 36% of proximal esophageal acid exposures were nonacidic. LFTs and bronchial response to methacholine before and after esophageal acid infusion Defined reflux asthma as asthmatic patients without atopy and with symptomatic GERD confirmed on esophageal pH monitoring Case-control pH probe findings Increase > 20% in symptom scores, PEF, or FEV1 on omeprazole compared to placebo Randomized placebocontrolled casecrossover 18 of 19 patients with laryngopharyngeal or high esophageal exposure underwent antireflux surgery, as did 2 patients without these reflux events but with type III paraesophageal hernias. 18 of 20 (90%) patients undergoing antireflux surgery had complete (2) or significant (18) improvement in asthma symptoms. 6 reduced or discontinued pulmonary medications at mean follow-up of 4.6 months. Response to antireflux surgery did not differ by DeMeester scores. Sensitivity: 82.8% (72.9-92.7%) Specificity: 85.2% (75.9%-94.5% PPV: 85.7% (76.6%-94.9%) NPV: 82.1% (72.1%-92.2%) Total distal acid exposure time was the strongest predictor of response to omeprazole therapy (OR 1.8, p = 0.04), and the only significant predictor on multivariable analysis. Q2a: What effect does treating GERD medically have on reflux cough? Source Sample size Study design Diagnosis of reflux cough/selection of patients Xu 2013 16 Prospective cohort All 4 of: 1) chronic cough, 2) MII-pH confirmed reflux with DeMeester score >= 14.72 and/or SAP >= 95%, 3) failure of cough to improve on omeprazole 20 mg bid and domperidone 10 mg tid for 8 weeks, and 4) exclusion of upper airway cough syndrome, cough variant asthma, and esoinophilic bronchitis excluded Length of follow up 8 weeks Intervention Outcome(s) Main finding(s) Discontinuation of domperidone and initiation of baclofen 20 mg tid for 8 weeks 1) Relief from cough by changes in cough symptom score (controlled if resolved completely, improved if cough symptom score decreased by at least 1, or failed), 2) capsaicin cough threshold causing 2 and 5 coughs 4 of 16 (25%) patients withdrew due to nausea and diarrhea (1) and worsened or unimproved symptoms (3). Cough was controlled in 7 of remaining 12 (58%) patients, improved in 2 (16%), and failed to improve in 3 (25%). Of the 9 controlled or resolved patients, 6 (67%) had acid refluxinduced cough, while 3 (33%) had non-acid reflux-induced cough. In the same 9 patients, capsaicin cough threshold for 2 coughs increased from 0.98 umol/L to 1.95 umol/L (p = 0.024), for 5 coughs increased from 1.95 umol/L to 7.8 umol/L (p = 0.014). Shaheen 2011 40 Randomized double-blind placebocontrolled All 5 of: 1) chronic cough > 8 weeks duration, 2) symptom severity criteria >= 2 on Fisman Cough Severity Questionnaire, 3) >= 3 on Fisman Cough Frequency Questionnaire, 4) failure of cough to respond to postnasal drip therapy, 5) heartburn no more than 2 times per month 12 weeks Omeprazole 40 bid for 12 weeks Change in CoughSpecific Quality of Life Questionnaire score, change in Fisman Cough Severity and Cough Frequency scores, and Reflux Finding Score. 5 patients (31%) No significant difference in change in Cough Specific Quality of Life Questionnaire score (p = 0.3), Fisman Cough Severity score (p = 0.7), Fisman Cough Frequency score (p = 0.3), or Reflux Finding Score (p = 0.5). Faruqi 2011 49 Randomized double-blind placebocontrolled 1) clinical features consistent with reflux cough, with or without dyspepsia, 2) chronic cough > 8 weeks duration, 3) normal CXR, 4) not on ACEi, 5) with cough score >= 3 Esomeprazole 20 mg bid for 8 weeks Hersh 2010 53 Retrospective cohort 1) patients referred for ambulatory pH monitoring with chronic cough as a dominant symptom, 2) not taking ACEi Mean of 3 years Baldi 2006 35 Randomized double-blind comparative effectiveness 1) cough >= 3 days per week for >= 3 months, 2) diagnosis of GERD with either EGD, esophageal pH monitoring, or resolution of improvement >= 5 on VAS after empiric trial of lansoprazole 30 mg bid for 4 weeks 12 weeks Lansoprazole 30 mg qd (placebo dose qPM) and lansoprazole 30 mg bid for 12 weeks Change in integral response score for cough, change in Leicester Cough Questionnaire, change in Hull Airway Reflux Questionnaire, Reflux Finding Score, citric acid cough challenge High degree response, defined as > 3 months without cough on stable PPI doses, or discontinuation of PPIs after antireflux surgery Changes in cough scoring system, VAS, from baseline to end of 4 week lansoprazole trial, and at end of 12week lansoprazole treatment In subgroup analysis of patients with positive esophageal pH study, still no significant differences in these outcomes (p = 0.2, 0.4, 0.8, and 0.8). No significant difference between the treatment and placebo groups in any measured parameter. High degree response was achieved by 19 of 53 (35.8%) of patients. Independent predictors of high degree response included female sex, positive SAP, and undergoing maximal antireflux therapy (high dose PPI or antireflux surgery) (p = 0.02, 0.03, and 0.02, respectively). No significant difference between two treatment groups in changes in cough scoring system, VAS, complete resolution of cough after 12-week treatment. 18 of 22 (82%) patients with positive response to empiric PPI trial and 3 of 13 (23%) patients with negative response to PPI trial had complete symptom relief at the end of the 12 week treatment period. El Hennawi 2004 80 Prospective cohort 1) cough for >= 4 weeks, 2) normal CXR, 3) no ACEi 3 months Famotidine 40 mg qPM and dompridon 10 mg tid for 6 weeks; or omeprazole 20 mg qd; or omeprazole 20 mg bid Various combinations of PPI, H2 blocker, and/or prokinetic agents ? ? Poe 2003 183 Retrospective cohort 1) chronic cough >= 3 weeks, 2) normal CXR, 3) no ACEi, 4) negative workup for post-nasal drip syndrome (empiric trial of antihistamine/decongestant) and asthma (methacholine challenge) 3 months Resolution of cough symptoms 18 weeks Omeprazole 40 mg qd for 8 weeks Change in asthma symptom score in last 3 weeks of each study period 60 days Omeprazole 40 mg qd for 5 days and for 60 days Change in inhaled methacholine and capsaicin sensitivity Of 183 patients 67 were diagnosed with cough caused by PNDS (37%), 59 with cough caused by asthma (32%), and 56 with suspected reflux cough (31%), based on response to empiric medical therapy or esophageal pH monitoring if no response to empiric therapy was observed. Of the 56 suspected reflux cough, 44 (79%) resolved cough symptoms after 12 weeks of medical therapy. Cough score decreased 1.5 in patients who received omeprazole and increased 0.7 in patients who received placebo (p < 0.05). Inhaled capsaicin sensitivity decreased significantly after 5d (p = 0.001) and further after 60 days (p = 0.002). Kiljander 2000 21 Prospective cohort (designed as casecrossover) Benini 2000 21 Prospective cohort (designed as casecrossover) 1) chronic persistent cough >= 2 months, 2) negative sinus XR, CXR, methacoline inhalation challenge, physical exam findings for PNDS, 3) no diagnosis of asthma or bronchitis, 4) no ACEi 1) endoscopic findings of erosive esophagitis, 2) increased esophageal acid exposure on pH monitoring, 3) without other chronic respiratory or ENT conditions, 4) non-smokers, 5) not on ACEi, 6) not on antisecretory medications No significant difference in change in cough sensitivity between patients with grade 1 and grade 2 esophagitis. Patients without posterior laryngitis on laryngoscopy had decreased capsaicin sensitivity after 5d (p = 0.014) but not after 60d (p = 0.64). Patients with posterior laryngitis had decreased capsaicin sensitivity after 5d (p = 0.002) and after 60d (0.001). After 5d of treatment a direct correlation between grade of laryngitis and capsaicin sensitivity was found (r = 0.67, p < 0.001). Q2b: What effect does treating GERD medically have on chronic laryngitis/LPR? Source Sample size Study design Diagnosis of LPR/selection of patients Masaany 2011 47 Prospective double-blind cohort 1) presenting with globus sensation, hoarseness, cough, excess mucus in throat, choking, or dysphagia, and 2) with either Reflux Symptom Index > 13 or Reflux Finding Score > 7 Lam 2010 Karoui 2010 82 33 Prospective double-blind placebocontrolled Prospective cohort 1) presenting with hoarseness, globus sensation, persistent throat discomfort, or frequent throat clearing for at least 1 month in preceding 1 year, and 2) Reflux Finding Score > 7 1) clinical diagnosis of chronic pharyngitis (symptoms of parasthesia of the pharynx, scraping, sore throat, or globus sensation) and/or laryngitis (symptoms of hoarseness, chronic cough, wheezing, stridor) suspected due to GERD, 2) proximal esophageal acid reflux on pH monitoring Length of follow up 4 months 18 weeks 9 weeks Intervention Outcome(s) Main finding(s) Pantoprazole 40 mg bid for four months Improvement in Reflux Symptom Index or Reflux Finding Score at 2, 3, and 4 months Reflux Symptom Index improved from baseline (19.87) after 2 months (10.87), improved at 3 months (6.78), and improved at 4 months (4.27, p < 0.001 for all). Rabeprazole 20 mg bid for 12 weeks Pantoprazole 40 mg bid for 8 weeks Reflux Symptom Index Clinical improvement in laryngeal or pharyngeal symptoms appreciated by the patient, and improvement in laryngopharyngoscopic signs of inflammation. Reflux Finding Score improved from baseline 12.79 after 2 months (7.61), 3 months (4.09), and 4 months (2.77, p < 0.001 for all). Change in Reflux Symptom Index was significantly greater in the treatment group compared to the placebo group at week 6 (-3.03, p = 0.003) and week 12 (-3.73, p = 0.002), not significantly reduced at week 18. Change in Reflux Finding Score was not significantly different at week 6, 12, or 18 between treatment and placebo groups. After treatment the proportion of patients complaining of pharyngeal discomfort, pharyngeal parasthesia, scraping, globus sensation, hoarseness, and dry cough all significantly improved (p < 0.0001 – 0.02), while the proportion of patients complaining of sore throat was not statistically significantly different. The proportion of patients with signs of pharyngeal wall erythema and posterior laryngitis significantly decreased after treatment (p = 0.003 and 0.001, respectively), while the proportion of patients with five other laryngopharyngoscopic findings did not significantly change after treatment. McGlashan 2009 Reichel 2008 45 58 Randomized assesor-blind non-placebo controlled Randomized double-blind placebo controlled 1) RSI > 10, 2) RFS > 5, 3) not on antisecretory therapy, 4) without significant dysphagia, pain, or hemoptysis 1) complaint of chronic cough, dysphagia, throat clearing, globus sensation, hoarseness, sore throat, and heartburn, 2) RFS > 7, 3) RSI > 13 2-6 months 3 months Change in RSI and RFS from baseline to 2 month follow up and from 0 month to 6 month follow up Change in RSI and RFS at 6 weeks and 3 months follow up, and subjective report of being 1000 mg sodium alginate and 200 mg potassium bicarbonate liquid (Gaviscon® Advance), delivered in 10 mL qid Symptom improvement was seen in 15 of 22 (68%) patients without proximal acid reflux on esophageal pH monitoring after treatment and in 2 of 11 (18%) patients with persistent proximal acid reflux (p = 0.006). RSI from baseline to 2 month follow up decreased 12.7 in the treatment group and 7.8 in the no treatment group (p = 0.005). RSI from baseline to 6 month follow up decreased 12.7 in the treatment group and 6.3 in the no treatment group (p = 0.008). The decrease in the treatment group from baseline to 2 months and baseline to 6 months follow up was identical (12.7). Esomeprazole 20 mg bid for 3 months There was no significant difference in change in RFS from 0 to 2 months follow up. RFS from baseline to 6 months follow up decreased 3.3 in the treatment group and 0.5 in the no treatment group (p = 0.005). At 6 weeks follow up changes in RSI and RFS between treatment and placebo groups were not statistically significant. Diffuse laryngeal edema on laryngoscopic exam improved significantly more in the symptom free at 3 months. Oridate 2008 45 Prospective cohort Qua 2007 32 Prospective cohort Wo 2006 35 Randomized double-blind placebo- Complaint of throat clearing, annoying cough, hoarseness, problem with voice, globus sensation, or dysphagia 1) persistent symptoms of cough, sore throat, throat clearing, globus sensation, or hoarseness for >= 3 months, 2) laryngoscopically proven laryngitis, 3) no allergic causes for laryngitis 1) chief complaint of hoarseness, sore throat, throat buring or pain, Up to 6 months 8 weeks 16 weeks Change symptom score and in modified Reflux Finding Score Change in 1week laryngeal symptom score from before initiation of treatment to last week of treatment Pantoprazole 40 mg qd treatment than the placebo group (p < 0.05), but change no other RFS component sign was significantly different between the two groups. Rabeprazole 20 mg qd or lansoprazole 30 mg qd for up to six months Lansoprazole 30 mg bid for 8 weeks At 3 months follow up, RSI improved 14.27 in the treatment group and 7.79 in the placebo group (p < 0.0001). RFS improved 4.6 in the treatment group and 2.32 in the placebo group (p < 0.05). 22 of 28 (79%) patients in the treatment group and 11 of 26 (42%) patients in the placebo group felt themselves to be free of symptoms (p = 0.006). Laryngopharyngeal symptoms resolved more slowly than heartburn in patients after initiation of PPI therapy (p = 0.003). 21 of 32 (66%) patients had GERD diagnosed on esophageal pH monitoring. LSS significantly improved from 29 to 20 (p < 0.001) in patients with positive pH monitoring, but not in patients without positive pH monitoring (26 to 20, p = 0.134). Change in LSS was significantly greater in patients with positive pH monitoring than in patients without (p = 0.01). Change in laryngeal symptom score based on weekly diaries of symptom 14 of 21 (67%) patients with positive pH monitoring and 2 of 11 (18.2%) without positive pH monitoring had marked or moderate improvement in symptoms (p = 0.026). No significant difference between groups in change in laryngeal symptom score. controlled Vaezi 2006 145 Multicenter prospective double-blind placebocontrolled Park 2005 85 Prospective cohort throat clearing, voice loss, cough, excessive throat mucus, globus sensation, or choking for > 3 days per week in past 2 months, 2) LPR signs on laryngoscopic exam, 3) positive pH monitoring of hypopharynx or distal esophagus 1) complaint of throat clearing, cough, globus sensation, sore throat, or hoarseness for >= 3 months, 2) moderate-tosevere heartburn for no more than 3 or more days per week for 3 months, 3) no allergic causes of laryngitis, 4) chronic posterior laryngitis index score >= 5 1) chronic symptoms of hoarseness, throat clearing, sore throat, cough, globus sensation, or dysphagia, 2) laryngoscopic signs suspicious for LPR assessment for globus sensation, cough, sore throat, hoarseness, throat clearing, and excessive mucus, and change in RFS 16 weeks Omeprazole 40 mg bid for 16 weeks Proportion of patients with resolution of their primary symptom (score of 0 for the last 7 days of treatment or score of 1 for up to 3 days), resolution of laryngoscopic signs, and change in LPRHRQL score 16 weeks Lansoprazole 30 mg bid; omeprazole 20 mg bid and ranitidine 300 mg at bedtime; esomeprazole 40 mg qd for 8 weeks Self-reported improvement, changes in laryngoscopic signs In nonresponders to 8week therapy, PPI dose was doubled Williams 2004 19 Prospective cohort 1) laryngeal symptoms for >= 3 months, 2) laryngoscopic signs of laryngitis, 3) without chronic cough 12 weeks Omeprazole 20 mg tid for 12 weeks Improvement of at least one point on 4-point laryngoscopic score at 12 week follow-up, improvement in symptoms on symptom questionnaire No significant difference in change in RFS between treatment and placebo groups. In subgroup analysis of patients with heartburn > 2 days per week, no significant differences between treatment and placebo. No difference in resolution of primary symptom at 16 weeks follow-up (p = 0.799), patient diary card assessments (p = 0.621-1), complete resolution of laryngoscopic signs (no p-value reported), or change in LPRHRQL score (p = 0.424) between treatment and placebo groups. At 8-week follow-up 50% of the lansoprazole group, 50% of the omeprazole group, and 28% of the esomeprazole group reported >= 50% improvement. The lansoprazole and omeprazole groups combined had significantly higher >= 50% improvement than the esomeprazole group (p = 0.03). At 16-week follow-up (with increased PPI dose in nonresponders) 63% of the lansoprazole group, 80% of the omeprazole group, and 65% of the esomeprazole group reported >= 50% improvement. At 12 weeks 12 of 19 (63%) patients improved at least one point on the laryngoscopic score (p < 0.0001). Of 4 patients with GERD diagnosed on esophageal pH monitoring, Steward 2004 37 Randomized double-blind placebocontrolled 1) complaint of hoarseness, throat clearing, nonproductive cough, globus sensation, or sore throat > 4 weeks, 2) laryngoscopic findings of edema, erythema, or pachydermia 8 weeks Rabeprazole 20 mg bid Change in reflux symptom score from GERD questionnaire modified to include laryngopharyngeal symptoms, change in laryngoscopic signs by scoring system Ehrer 2003 14 Placebocontrolled casecrossover 26 weeks Pantoprazole 40 mg bid for 3 months Changes in symptom score and laryngoscopic signs score Noordzij 2001 30 Randomized double-blind placebocontrolled 1) hoarseness >= 2 months, other laryngeal symptoms, and laryngoscopic signs of laryngitis, 2) GERD diagnosed with esophageal pH monitoring 1) hoarseness, excessive phlegm, throat clearing, throat pain, lump in throat, or cough >= 3 months, 2) no strong history of seasonal allergies, 3) >= 4 episodes of laryngopharyngeal reflux on esophageal/OP ph monitoring 8 weeks Omeprazole 40 mg bid for 8 weeks Change in symptom score, laryngoscopic sign score, 1) hoarseness, frequent clearing of the throat, dry cough, globus sensation, or persistent sore throat for >= 3 weeks, 2) laryngoscopic signs of posterior laryngitis, 3) no allergic causes of laryngitis 3 months El-Serag 2001 20 Randomized double-blind placebo Lansoprazole 30 mg bid for 3 months Resolution of all presenting laryngeal symptoms, resolution of all laryngeal signs, partial resolution of laryngeal signs all had improvement in the laryngoscopic score. In 16 patients without positive esophageal monitoring, 8 (50%) improved on the laryngoscopic score. No significant differences were found in change in total reflux symptom score or individual score components for typical, laryngeal, or pharyngeal symptoms between treatment and placebo groups. No significant difference in change in laryngoscopic signs scoring system between treatment or placebo groups. No significant difference in changes in symptom or laryngoscopic scores between treatment and placebo groups. Changes in total symptom scores and laryngoscopic sign scores were not significantly different between the omeprazole and placebo groups. Mean throat clearing score decreased 197.4 in the omeprazole group and 79.6 in the placebo group (p = 0.043). 6 of 12 patients (50%) in the lansoprazole group and 1 in 10 patients (10%) in the placebo group had complete resolution of laryngeal symptoms (p = 0.04). There was no significant difference in complete or partial resolution of laryngoscopic signs. Eubanks 2001 14 Prospective cohort ? 3 months Double-dose PPI therapy Resolution of symptoms Esophageal pH monitoring parameters did not differ between patients with complete resolution of symptoms and those with persistent symptoms. 7 patients reported cough. 5 reported improvement after treatment and had elimination or > 70% reduction in pharyngeal acid reflux episodes. 1 patient reported consistent cough and only 33% reduction in pharyngeal acid reflux episodes. 1 patient did not have pharyngeal acid reflux at baseline. 7 patients reported hoarseness. 4 reported elimination or reduction after treatment. 2 patients without pharyngeal acid reflux at baseline reported no improvement. 1 patient had persistent hoarseness despite elimination of pharyngeal acid reflux. Q2c: What effect does treating GERD medically have on reflux asthma? Source Sample size Study design Diagnosis of reflux asthma/selection of patients Kiljander 2013 12 Prospective cohort 1) scheduled to undergo antireflux surgery for GERD, 2) diagnosis of asthma Kiljander 2010 828 Multicenter international randomized double-blind placebocontrolled Peterson 2009 30 Randomized double-blind placebocontrolled Length of follow up 3 months Intervention Outcome(s) Main finding(s) Esomeprazole 40 mg bid Change in doseresponse slope in methacholine inhalation challenge, exhaled nitric oxide, and FEV1 1) clinical diagnosis of asthma >= 6 months duration, 2) FEV1 reversibility >= 12% with inhaled short-acting betaagonists, 3) receiving inhaled corticosteroids and LABA treatment for >= 3 months, 4) >= 1 clinically important asthma exacerbation in past 12 months, 5) >= 3 month history of heartburn, regurgitation, or abnormal esophageal pH monitoring 26 weeks Esomeprazole 40 mg qd or esomeprazole 40 mg bid Changes morning PEF, evening PEF, FEV1, use of rescue bronchodilators, percent asthma-free days, time to first asthma exacerbation, number of severe asthma exacerbations, and Asthma Quality of Life Questionnaire, No significant change in methacholine inhalation sensitivity, exhaled nitric oxide, or FEV1 in asthmatic patients after treatment. Improvement in morning PEF, FEV1, and Asthma Quality of Life Questionnaire was significantly greater in the treatment groups compared to placebo. 1) complaint of cough, shortness of breath, or chest tightness occurring during or directly after moderate exercise, 2) selfreported reflux symptoms less than twice weekly, 3) not on antisecretory therapy, 4) not hospitalized in preceding 6 months 10-12 weeks Rabeprazole 20 mg qd (with placebo qPM), rabeprazole 20 mg bid, or placebo bid Subjective determination by subjects (yes or no) on improved exercise symptoms, pre- and post-exercise PFTs, spirometry, SF-36 score, and mini-AQLQ score. There was no significant difference in changes in evening PEF, time to first asthma exacerbation, number of severe asthma exacerbations, use of rescue bronchodilators, or asthma-free days. 16 of 23 (70%) patients receiving rabeprazole and 2 of 8 (25%) patients receiving placebo reported subjectively improved exercise symptoms (p = 0.03). In subgroup analysis for those with GERD seen on 24h esophageal pH probe, 15 of 17 (88%) patients receiving rabeprazole and 1 of 5 (20%) patients receiving placebo reported subjectively improved exercise symptoms (p = 0.009). In subgroup analysis for those who had esophageal acid reflux during tredmill test, 15 of 19 (79%) patients receiving rabeprazole and 1 of 5 (20%) receiving placebo reported subjectively improved exercise symptoms (p = 0.03). Mastronarde 2009 393 Multicenter randomized double-blind placebocontrolled Bucknall 2009 51 Prospective cohort 1) diagnosis of asthma supported by methacholine challenge test or >= 12% increase in FEV1 after bronchodilation, 2) >= 8 weeks stable inhaled corticosteroid use at doseequivalent of 400 ug fluticasone/day or greater, 3) JACQ >= 1.5 or >= 1 acute episode of asthma requiring medical attention in previous year, 4) < 2 episodes per week of heartburn, 5) not taking antisecretory mediations Patients with diagnosis of asthma confirmed objectively and therapy optimized but with 24 weeks Esomeprazole 40 mg bid Rate of episodes of poor asthma control (decrease of 30% or more in morning PEF on 2 consecutive days, an unscheduled healthcare visit for asthma symptoms, or need for course of oral prednisone, PFTs, asthma symptoms, asthma control Unclear Low-dose PPI therapy, increased stepwise after serial esophageal pH monitoring studies Reduction in required asthma therapy There was no significant difference in subjectively improved exercise symptoms between the rabeprazole qd and bid groups, or in PFTs, spirometry, SF-36 score, or mini-AQLQ score. There were no significant differences in change in any of the parameters measured between the treatment and placebo groups. Subgroup analysis of patients with GERD on esophageal pH monitoring also revealed no differences between changes in treatment and placebo groups. 32 of 51 (63%) patients had negative esophageal pH monitoring. 19 of 32 persistent symptoms Sharma 2007 198 Randomized double-blind placebo controlled 1) > 12% improvement in FEV1 with bronchodilators, 2) mildto-moderate persistent asthma, 3) no acute exacerbations or changes in asthma medications in past weeks, 4) GERD on esophageal pH monitoring 16 weeks Omeprazole 20 mg bid and domperidone 10 mg tid for 16 weeks Asthma symptom score, rescue albuterol use, daytime and nighttime PEF, postbronchodilator FEV1 and FVC Wong 2006 27 Prospective cohort 1) asthma meeting the American Thoracic Society diagnostic criteria or with typical history of asthma in past 12 months, 2) moderate-to-severe asthma as defined by 8 weeks Lansoprazole 30 mg qd for 8 weeks Patient-assessed global improvement of asthma symptoms, changes in 1-week PSS, PEF, FEV1 (59%) patients underwent repeated pH monitoring up to 3 episodes, increasing PPI dose until monitoring parameters normalized. 8 of 11 (73%) patients whose esophageal acid exposure normalized on pH monitoring reduced their required asthma therapy, while 0 of 8 patients without normalized esophageal acid exposure reduced their required asthma therapy (p = 0.0034). In the treatment and placebo groups, respectively, mean daytime asthma symptom score decreased 0.48 and 0.22, mean nighttime asthma score decreased 0.51 and 0.14, albuterol puffs/week decreased 0.76 and 0.1, morning PEF increased 22.78 and decreased 0.56, evening PEF increased 27.76 and decreased 1.43, FEV1 increased 0.21L and 0.07 L, FVC increased 0.18 L and decreased 0.03 L (p = 0.0001-0.0023) 16 of 27 (59%) patients were diagnosed with GERD based on weekly symptoms for 6 months, findings of erosive esophagitis on EGD, or positive esophageal pH GINA guidelines and with poor asthma control, 3) optimized asthma treatment medications Shimzu 2006 30 Prospective parallel comparative effectiveness cohort 1) diagnosis of asthma based on American Thoracic Society definition, 2) meeting GINA guidelines for asthma medications, 3) with endoscopically diagnosed GERD or QUEST score >= 4 Kiljander 2006 624 Multicenter international randomized double-blind placebocontrolled trial 1) asthma treated with inhaled corticosteroids and.or leukotriene pathway modifiers for >= 3 months before study entry and with no medication changes in previous 30 days, 2) FEV1 50-80% predicted and >= 12% reversibility with bronchodilators and mean morning PEF < 80% monitoring. 12 of these 16 (75%) reported global improvement in asthma symptoms. Median PSS decreased from 35 to 21 (p = 0.002). 11 of 27 (41%) patients were not diagnosed with GERD. 1 of these 11 (9%) reported global improvement. Median PSS did not decrease significantly (p = 0.18). 16 weeks Roxatidine 150 mg qd or lansoprazole 30 mg qd for 2 months Changes in ACQ, PEF, FEV1 Esomeprazole 40 mg bid for 16 weeks Change in morning PEF Median PSS, median PEF, and median FEV1 improved significantly more in GERD than in non-GERD patients (p = 0.01, 0.04, and 0.017, respectively). Morning PEF significantly increased in the lansoprazole group (p = 0.002) but not in the roxatidine group (p = 0.08). ACQ scores significantly improved in the lansoprazole group but not in the roxatidine group. FEV1 did not significantly improve in either group. Change in morning PEF observed over the treatment period was 5.6 L/min greater in the treatment than placebo groups (p = 0.042). Change in evening PEF was 5.4 L/min greater in the treatment than the placebo groups (p = 0.053). predicted, 2) no recurrent moderate or severe GERD symptoms in previous year in patients > 40 years old No significant difference in asthma exacerbations or median time to asthma exacerbation between treatment and placebo groups. In subjects with GERD (diagnosed as >= 2 episodes per week of heartburn, or 1 episode per week of acid regurgitation in 3 months before enrollment) and nocturnal asthma symptoms morning PEF increased 8.7 L/min more in the treatment than the placebo groups (p = 0.03), and evening PEF increased 10.2 L/min more in the treatment than the placebo groups (p = 0.012). Littner 2005 173 Multicenter double-blind randomized placebocontrolled 1) investigator-determined history of or currently symptomatic GERD, 2) moderate-to-severe persistent asthma, 3) FEV1 50-85% predicted, 4) >= 12% improvement in FEV1 with bronchodilators, 5) on inhaled corticosteroids, 6) without marked seasonal 24 weeks Lansoprazole 30 big bid 24-week average of asthma symptom score by diary, albuterol use, changes in PEF, postbronchodilator FVC and FEV1, AQLQS, asthma exacerbations In subjects who did not have both GERD and nocturnal asthma symptoms did not have significantly greater improvement in morning PEF or evening PEF compared to placebo. No significant difference between treatment and placebo groups in daily asthma symptoms by patient diary, rescue albuterol use, morning PEF, evening PEF, FEV1, FVC, or AQLQS score. 8.1% of patients in the variability or allergy symptoms, 7) reporting >= 5 nocturnal asthma awakenings in prior 4 weeks, 8) on stable doses of asthma medications for past 4 weeks Calabrese 2005 Bocskei 2005 34 126 Prospective cohort Prospective cohort Intrinsic mild persistent asthma by diagnostic criteria of American Thoracic Society 1) mild to moderate asthma diagnosed by American Throacic Society criteria >= 12 months before enrollment, 2) chronic dry cough for >= 3 months, 3) low to moderate dose inhaled corticosteroids, 4) no changes in asthma medications in prior 6 weeks 6 months 12 weeks Pantoprazole 80 mg qd for 6 months Esomeprazole 40 mg qd for 3 months FEV1, patient-reported asthma symptom score, of rescue inhalers FEV1, PEF, symptom score treatment group and 20.4% in the placebo group experienced an asthma exacerbation (OR = 2.9, p = 0.017). 4% of patients in the treatment group and 13.9% in the placebo group experienced a moderate to severe exacerbation (OR = 3.8, p = 0.016). 27 of 34 (21%) patients had GERD diagnosed endoscopically either by interstitial space on biopsy > 0.74 um or by reflux esophagitis. 23 of 27 (85%) patients with GERD had improved mean asthma symptom score from 4.37 to 0.33 (p < 0.001) and FEV1 increased 2.8 L (p < 0.01). 94 of 126 (75%) patients were diagnosed with GERD by report of heartburn and/or regurgitation or esophageal pH monitoring. Mean FEV1 increased from 79.21% predicted to 82.92% predicted (p < 0.001), and PEF increased from 73.7% predicted to 78.42% predicted (p < 0.001) before and after treatment in patients with GERD. Mean 2week use of rescue inhalers also decreased from 20.24 to 4.56 (p < 0.001). Mean symptom score decreased from 6.46 to 2 (p-value not reported). 26 of 126 (21%) patients were not diagnosed with GERD. These patients had no significant change in FEV1, PEF, or rescue inhaler use from baseline to 12-week follow-up. Tsugeno 2003 49 Prospective cohort 1) bronchial asthma diagnosed according to American Thoracic Society guidelines 8 weeks Rabeprazole 20 mg qd for 8 weeks (for all patients), followed by ranitidine 300 mg bid (for GERD patients only) Changes in morning PEF, evening PEF, FEV1, FVC FEV1 and PEF increased significantly more in GERD patients treated for GERD than in non-GERD patients (p < 0.0001 for both). Rescue inhaler use was significantly lower in GERD patients treated for GERD than in nonGERD patients (p < 0.0001). 21 of 53 (42%) patients were diagnosed with GERD based on endoscopy or QUEST score > 4. Among patients with GERD, morning and evening PEF improved from 286 L/min to 323 L/min and 304 L/min to 334 L/min, respectively (p < 0.0001 for both). FEV1 and FVC did not significantly change. Among patients without GERD, morning and evening PEF, FEV1, and FVC did not signifincalty change. Sontag 2003 Jiang 2003 62 30 Randomized trial, no placebo Randomized no placebo 1) mild asthma causing no impairment of in activities, defined as both a) history of wheezing, coughing, or dyspnea and b) either increase in FEV1 >= 20% with bronchodilators or decrease FEV1 >= 20% on methacholine challenge, 2) GERD defined as both a) positive esophageal pH monitoring, and b) esophagoscopic findings or biopsy pathology consistent with reflux esophagitis, 3) FEV1 >= 50% predicted and >= 1.5L 1) asthma according to GINA criteria, 2) GERD diagnosed as postprandial chest pain, sour regurgitation, signs of erosive esophagitis on barium esophagram, or lower esophageal erosions on 2 years Ranitidine 150 mg tid vs Nissen fundoplication vs aluminum hydroxide/magnesium hydroxide/simethicone and H2 blockers prn (control) Change in asthma symptom score, mean PEF, mean PEF % variation, PFTs, requirement for pulmonary medications, overall clinical response of asthma Mean asthma symptom score at 2 years decreased significantly in the surgical group (p < 0.05) but not in the medical or control groups. The surgical group’s mean asthma symptom score improved significantly more than the ranitidne and control groups combined (p = 0.0009). Overall clinical response of asthma reached improvement, marked improvement, or cure in 74.9% of surgical patients, 9.1% of ranitidine patients, and 4.2% in the control group. The improvement was significant in the surgical group compared to the combined ranitidine and control groups (p < 0.001). 6 weeks Salbutamol 200 ug qid and budesonide 400 bid for six weeks (control) versus same asthma regimen plus omeprazole 20 mg qd and domperidone 10 mg tid for six weeks Change in PFTs and histamine-induced bronchial sensitivity Change in mean PEF, mean PEF % variation, PFTs, and asthma medication requirements were not significantly different between groups. In the control and treatment groups, changes in FVC (-0.2 vs +0.8 L), FEV1 (0.1 vs 0.6 L), PEF (0.4 vs 1.3 L/s), and bronchial sensitivity (-0.03 vs 0.51 g/L inhaled histamine causing 20% decrease esophagoscopy and mucosal biopsy in FEV1) were significantly better in patients receiving GERD therapy (p < 0.05 for all). Q3a: What effect does treating GERD surgically have on reflux cough? Source Sample size Study design Diagnosis of reflux cough/selection of patients Hoppo 2013 36 Retrospective cohort 1) persistent cough >= 8 weeks, 2) no ACEi or seasonal allergies, 3) no known pulmonary disease Zhang 2012 198 Retrospective cohort Koch 2012 100 Randomized comparative effectiveness 1) coughing, asthma, wheezing, shortness of breath, or choking, 2) GERD diagnosed on esophageal pH monitoring with DeMeester score >= 14.7 1) persistent or recurrent GERD despite medical treatment and a) DeMeester score >= 14.7 and b) symptom correlation >= 50% or reflux episodes > 73 during MII-pH Length of follow up 0.5-13 months Intervention Outcome(s) Main finding(s) Nissen (10), Dor (2), Toupet (1), esophagojejunostomy (3) Improvement in cough symptoms 12 months Laparoscopic Nissen (197), laparoscopic converted to open Nissen (1) Improvement in Reflux Diagnostic Questionnaire 13 of 16 (81%) patients with abnormal proximal refluxate exposure on MII-pH had resolution of cough, while the other 3 had significant improvement (19%) Mean cough scores improved from 7.23 to 2.79 (p < 0.01) after ARS. 1 year Laparoscopic floppy Nissen (50) or Toupet fundoplication (50) Change in symptom questionnaire score 98 patients were available at 3-month follow-up. Mean cough score improved 2.46 in the Nissen group and 1.77 in the Toupet group, both of which were significant changes from baseline (p < 0.001 and p = 0.001, respectively). 89 patients were available at 1 year follow-up. Mean cough score improved 1.74 in the Nissen group and 2.14 in the Toupet group, both of which were significant changes from baseline (p = 0.007 and 0.004, respectively). There were no statistically van der Westhuizen 2011 244 Retrospective cohort Patients who underwent antireflux surgery for reflux Unclear Nissen Reported change in symptom intensity Brown 2011 113 Prospective cohort Mean 28 months Laparoscopic Nissen Change in VAS symptom score Francis 2011 27 Retrospective cohort 1) GERD diagnosed on esophageal pH monitoring, 2) underwent laparoscopic Nissen 1) chief complaint of atypical symptom, 2) without improvement after 12 weeks of bid PPI therapy, 3) with abnormal esophageal acid exposure on bid PPI therapy, 4) who underwent antireflux surgery Median 33 months Antireflux surgery Resolution or > 50% improvement in primary atypical symptom significant differences in improvement of cough scores between the two procedures. > 50% improvement in symptom intensity was reported by 84 of 135 (62%) patients who reported chronic cough preoperatively. Mean cough score decreased from 3.78 to 0.95 (p < 0.0001) after surgery. 12 patients presented with cough and 7 with asthma/wheezing. No significant difference in response to surgery was found according to the specific presenting atypical complaint. After 1 year of follow-up, 59% of patients reported improvement (11%) or complete resolution (48%) of their presenting atypical symptom. Patients with concomitant heartburn or with > 12% acid exposure time had greater likelihood of symptom resolution after fundoplication than patients without heartburn (OR 6.6, p = 0.05; OR 10.5, p = 0.02). Patients without concomitant heartburn and acid exposure time < 12% resolved their symptoms after fundoplication 8.5% of the time, while patients with both factors resolved their Iqbal 2009 Retrospective cohort 1) underwent ARS, 2) predominance of extraesophageal symptoms before surgery Mean 53.3 months Open (9) or laparoscopic (31) Nissen (33) or partial (7) fundoplication Change in cough symptoms Oelschlager 2008 (same cohort as Oelschlager 2002) 288 Retrospective cross-section Underwent ARS between 1993 and 1999 for reflux indication Median 69 months Laparoscopic Nissen Reported resolution or improvement in cough symptoms Ranson 2007 69 Prospective cohort Underwent ARS after GERD diagnosis by empiric PPI trial or esophageal pH monitoring Mean 24.6 months Laparoscopic Nissen Improvement in modified Allen symptom score Tutuian 2006 50 Retrospective review Patients with persistent cough on day of MII-pH monitoring while on bid PPI therapy with or without nighttime H2 blocker therapy Median 17 months Laparoscopic Nissen Resolution of cough Rakita 2006 813 Prospective cohort Mean 50 months Laparoscopic Nissen Improvement of symptoms Kaufman 128 Retrospective 1) underwent laparoscopic Nissen, 2) had preoperative symptom scores of 4 or 5 on 5 point scale for extraesophageal symptoms (asthma [diagnosed by having symptoms of asthma and having been cared for by a physician for asthma], cough, gas/bloat, chest pain, odynophagia) 1) Underwent laparoscopic Median Laparoscopic Nissen Improvement of symptoms 90.7% of the time. 32 of 40 (80%) patients reported cough preoperatively. 17 (53%) reported their cough cured, 10 (32%) reported it improved, 4 (13%) reported no change, and 1 (3%) reported worsened cough. 88 of 288 (31%) of patients reported cough preoperatively. 40% reported symptom resolution, another 29% reported symptom improvement. 55 of 69 (80%) patients reported cough preoperatively. Their mean cough symptom score decreased from 1.2 to 0.5 (p < 0.01) after ARS. 35 (64%) reported their cough resolved, another 7 (10%) reported their cough improved, 6 (10%) reported no change, and 7 (13%) reported worsened cough. 13 of 50 patients had positive non-acid SI for reflux-cough. 6 of these 13 underwent laparoscopic Nissen (1 lost to follow up). All patients reported complete resolution of cough at follow-up. 132 patients presented with cough scores of 4-5. Mean cough score decreased from 4.3 to 2 (p < 0.0001). 108 patients presented with 2006 cohort Nissen, 2) experienced cough, hoarseness, or wheezing > once per week 53 months (123) and Toupet (5) symptoms 1) underwent laparoscopic Nissen for GERD, 2) without evidence of postnasal drip or having received treatment for it, 3) with negative methacholine inhalation challenge, 4) with primarily respiratory complaints 1) underwent laparoscopic Nissen, 2) predominantly respiratory symptoms (cough, aspiration, voice changes) 1) underwent laparoscopic ARS 5-years Laparoscopic Nissen Mean 650 days Laparoscopic Nissen Symptoms cured (score = 0), better (score improved > 2), no significant change (score change <= 2), or worse (score decreased 2 or more) Symptom score Unclear Laparoscopic Nissen or Toupet Patient-reported resolution or significant improvement in cough symptoms 1) cough > 8 weeks, normal CXR, non-smoker, no ACEi, no relief with treatment of post-nasal drip, no asthma, 2) failure of intensive medical therapy, 3) underwent ARS 1) underwent ARS, 2) reported wheezing, sputum production, cough, choking, hoarseness, or pneumonia Underwent laparoscopic Nissen 1 year Laparoscopic Nissen (18), open Nissen (3) Patient report of improvement, ACOS, SIP Median 65 months Wide variety of open and laparoscopic antireflux operations Patient-reported improvement in symptoms 6 months Laparoscopic Nissen Change in cough score Allen 2004 209 Prospective cohort Brouwer 2003 28 Prospective cohort Thoman 2002 129 Retrospective cohort Novitsky 2002 21 Retrospective cohort Greason 2002 62 Retrospective cohort Allen 2002 483 Prospective cohort cough. 80 (74%) patients reported improved cough. There was a statistically significant decrease in the frequency of cough (p < 0.001). 79 of 209 (38%) patients with primarily respiratory complaints were available for 5-year follow-up. Mean cough score decreased 3.9. 36% of patients were cured, 35% were better, 24% had no significant change, and 5% were worse. Mean cough score decreased after ARS from 4.7 to 0.36 (p < 0.001) 37 of 129 patients complained of cough preoperatively. 24 (65%) patients reported their cough completely resolved (p = 0.002), while another 10 (27%) reported significant improvement. 18 of 21 (86%) reported improved cough at 1-year follow-up, with 13 (62%) having complete resolution. ACOS improved from 15.1 to 5.8 (p < 0.01), SIP improved from 15 to 4.2 (p < 0.01). 30 patients reported cough preoperatively, 10 after ARS. 287 of 483 patients presented with cough. Mean cough score decreased from 35.1 to 13.2 (p < 0.0001). Patients with a positive esophageal acid infusion test were significantly more likely Patti 2000 340 Prospective cohort 1) underwent laparoscopic Nissen, 2) complaint of heartburn and/or regurgitation Median 28 months Laparoscopic NIssen Patient-reported resolution of symptoms Ekstrom 2000 24 Prospective cohort 1) severe GERD refractory to maximal medical therapy, 2) simultaneous asthma (according to American Thoracic Society criteria) or chronic cough 12 months Open (20) or laparoscopic (4) Nissen Improvement in symptoms by patient diary, FEV1, FVC, to respond to ARS (p = 0.02). 39 of 340 (11%) patients had cough or wheezing attributed to GERD on clinical grounds. All 39 complained of cough preoperatively. Cough resolved in 74%. 11 patients had chronic cough. 12 months postoperatively all had significant improvement in FEV1, FVC, cough day score, cough night score, hoarseness score, and expectoration score (p < 0.01 - < 0.05). Q3b: What effect does treating GERD surgically have on chronic laryngitis/LPR? Source Sample size Study design Diagnosis of LPR/selection of patients Koch 2012 100 Randomized comparative effectiveness 1) persistent or recurrent GERD despite medical treatment and a) DeMeester score >= 14.7 and b) symptom correlation >= 50% or reflux episodes > 73 during MII-pH Length of follow up 1 year Intervention Outcome(s) Main finding(s) Laparoscopic floppy Nissen (50) or Toupet fundoplication (50) Change in symptom questionnaire score 98 patients were available at 3-month follow-up. Mean hoarseness score improved 0.76 (p = 0.004) in the Nissen group and nonsignificantly in the Toupet group. 89 patients were available at 1-year follow-up. Mean hoarseness score improved 1.35 (p = 0.034) in the Nissen group and 1.11 (p = 0.003) in the Toupet group. Johannessen 2012 243 van der Westhuizen 2011 244 Matched (age, sex, geographic location, follow-up time, degree of esophagitis, presence of hiatal hernia, and presence of Barrett esophagus) crosssectional Retrospective cohort GERD diagnosed endoscopically or on esophageal pH monitoring Mean 6-6.3 years Laparoscopic or open fundoplication versus medical therapy Mean RASQ items and subscale for laryngopharyngitis Patients who underwent antireflux surgery for reflux Unclear Nissen Reported change in symptom intensity There were no statistically significant differences in improvement of asthma scores between the two procedures. Mean score for globus sensation (0.76 vs 1.11, p = 0.01) and sore throat (0.86 vs 1.13, p = 0.04) and the laryngopharyngitis subscale (1.06 vs 1.27, p = 0.04) were significantly lower in the ARS group than the medically treated group. > 50% improvement in symptom intensity was reported by 99 of 140 (71%) patients who reported sore throat preoperatively, 86 of 124 (69%) who reported lump in throat preoperatively, 96 of 139 (69%) who reported dysphagia preoperatively, and 89 of 162 (55%) who reported Brown 2011 113 Iqbal 2009 Ranson 2007 Prospective cohort Retrospective cohort 69 Prospective cohort 1) GERD diagnosed on esophageal pH monitoring, 2) underwent laparoscopic Nissen 1) underwent ARS, 2) predominance of extraesophageal symptoms before surgery Underwent ARS after GERD diagnosis by empiric PPI trial or esophageal pH monitoring Mean 28 months Laparoscopic Nissen Change in VAS symptom score Mean 53.3 months Open (9) or laparoscopic (31) Nissen (33) or partial (7) fundoplication Change in globus sensation symptoms Mean 24.6 months Laparoscopic Nissen Improvement in modified Allen symptom score repetitive throat clearing preoperatively. Mean hoarseness score decreased from 3.16 to 0.82 (p < 0.0001) after surgery. 29 of 40 (73%) patients reported globus sensation preoperatively. 12 (41%) reported globus cured, 7 (24%) reported it improved, 7 (24%) reported no change, and 3 (10%) reported worsened globus. 31 of 40 (78%) reported throat clearing, mucous, or postnasal drip. 16 (51%) reported these symptoms cured, 10 (32%) reported them improved, 4 (13%) reported no change, and 1 (3%) reported worsened symptoms. 47 (68%), 41 (59%), and 60 (87%) of 69 patients preoperatively reported hoarseness, sore throat, and throat clearing, respectively. Their mean hoarseness symptom score decreased from 1.2 to 0.6 (p < 0.01) after ARS. 22 (47%) reported their hoarseness resolved, another 11 (23%) reported their hoarseness improved, 6 (13%) reported no change, and 8 (17%) reported worsened hoarseness. Their mean sore throat symptom score decreased from 0.9 to 0.4 (p < 0.01) after ARS. 25 (61%) reported their sore throat resolved, another 6 (15%) reported their sore throat improved, 2 (5%) reported no change, and 8 Swoger 2006 Kaufman 2006 72 128 Prospective cohort Retrospective cohort 1) chronic laryngeal signs and symptoms (cough, throat clearing, sore/burning throat, hoarseness, or globus sensation), 2) treated with omeprazole 40 mg bid or lansoprazole 60 mg bid for 4 months with < 50% symptomatic improvement, 3) abnormal esophageal pH monitoring or evidence of reflux on barium esophagram off PPI therapy, 4) with normal esophageal acid exposure parameters on bid PPI therapy 1) Underwent laparoscopic Nissen, 2) experienced cough, hoarseness, or wheezing > once per week 1 year Laparoscopic Nissen Symptom resolution or improvement on symptom score questioinnaire (20%) reported their sore throat worsened. 26 (43%) reported their throat clearing resolved, another 14 (23%) reported their throat clearing improved, 12 (20%) reported no change, and 8 (13%) reported worsened throat clearing. 25 of 75 (35%) patients were unresponsive to bid PPI therapy. 10 chose to have surgery while 15 refused. At 1 year follow-up, 1 of 10 (10%) ARS patients and 1 of 15 (7%) medical patients had resolved laryngeal symptoms. Median 53 months Laparoscopic Nissen (123) and Toupet (5) Improvement of symptoms 82 patients presented with hoarseness. 54 (66%) patients reported improved hoarseness. There was a statistically significant decrease in the frequency of hoarseness (p < 0.001). 41 patients presented with sore throat. 29 (70%) patients reported improved sore throat. There was a statistically significant decrease in the frequency of sore throat (p = 0.001). Fernando 2005 74 Prospective cohort 1) primary complaint of heartburn, regurgitation, or water brash, 2) pulmonary symptoms of bronchospasam, Median 12 months Laparoscopic fundoplication Resolution of laryngeal symptoms 46 patients complained of hoarseness before the operation. 33 (72%) had complete resolution after the operation (p < 0.01). Patients hoarseness, aspiration, or laryngitis, 3) underwent laparoscopic Nissen 1) underwent ARS, 2) reported wheezing, sputum production, cough, choking, hoarseness, or pneumonia did not report significantly less laryngitis after ARS. Greason 2002 62 Retrospective cohort Median 65 months Patti 2000 340 Prospective cohort 1) underwent laparoscopic Nissen, 2) complaint of heartburn and/or regurgitation Median 28 months Lindstrom 2002 29 Retrospective cohort Underwent Nissen for extraesophageal manifestations of GERD 6-108 months Wide variety of open and laparoscopic antireflux operations Laparoscopic Nissen Patient-reported improvement in symptoms 17 patients reported hoarseness preoperatively, 11 after ARS. Patient-reported resolution of symptoms Laparoscopic Nissen (n = 28) or open Nissen (n = 1) Reported resolution of symptoms on chart review? 13 of 340 (4%) patients had hoarseness attributed to GERD on clinical grounds. Hoarseness resolved in 82% of patients. 27 of 29 patients reported near-total relief of extraesophageal symptoms. 2 patients had wrap breakdown after 2 years, 1 from abdominal trauma. 1 patient with persistent symptoms had both typical and atypical manifestations of GERD: typical symptoms resolved while atypical symptoms persisted. Was diagnosed with cricopharyngeal muscle myositis caused by Lyme disease. 1 patient with chronic cough did not improve after Nissen. Q3c: What effect does treating GERD surgically have on reflux asthma? Source Sample size Study design Diagnosis of reflux asthma/selection of patients Kiljander 2013 12 Prospective cohort 1) scheduled to undergo antireflux surgery for GERD, 2) diagnosis of asthma Komatsu 2013 27 Retrospective review 1) diagnosed adult onset asthma adult onset wheezing, coughing, or shortness of breath and using at least 1 bronchodilator or corticosteroid, 2) no additional pulmonary diagnoses Zhang 2012 198 Retrospective cohort Koch 2012 100 Randomized comparative effectiveness 1) coughing, asthma, wheezing, shortness of breath, or choking, 2) GERD diagnosed on esophageal pH monitoring with DeMeester score >= 14.7 1) persistent or recurrent GERD despite medical treatment and a) DeMeester score >= 14.7 and b) symptom correlation >= 50% or reflux episodes > 73 during MII-pH Length of follow up 3 months Intervention Outcome(s) Main finding(s) Antireflux surgery No significant change in methacholine inhalation sensitivity, exhaled nitric oxide, or FEV1 in asthmatic patients after treatment. 0.615.2 months Nissen (15), Dor (2), roux-en-Y esophagojejunostomy (1) (together, ARS) Change in doseresponse slope in methacholine inhalation challenge, exhaled nitric oxide, and FEV1 Symptomatic improvement, reduction or discontinuation of asthma medications, change in PFTs 19 of 27 patients (70%) had abnormal proximal reflux exposure on MII-pH, 18 of whom underwent ARS. 8 of 27 patients (30%) had no abnormal proximal exposure, 2 of whom underwent ARS. 2 of 20 patients who underwent ARS had complete resolution of asthmas symptoms, 16 had significant improvement. 12 months Laparoscopic Nissen (197), laparoscopic converted to open Nissen (1) Improvement in Reflux Diagnostic Questionnaire 1 year Laparoscopic floppy Nissen (50) or Toupet fundoplication (50) Change in symptom questionnaire score No significant difference in ARS patients with symptomatic improvement by DeMeester score > 14.7. Mean wheezing scores decreased from 7.5 to 2.53, and mean shortness of breath scores decreased from 5.83 to 1.37 (p < 0.01 for both). 98 patients were available at 3month follow-up. Mean asthma score improved 0.63 (p = 0.004) in the Nissen group and nonsignificantly in the Toupet group. 89 patients were available at 1year follow-up. Mean asthma score improved 0.62 (p = 0.048) in the Nissen group and nonsignificantly in the Toupet group. Brown 2011 113 Prospective cohort Francis 2011 27 Retrospective cohort 1) GERD diagnosed on esophageal pH monitoring, 2) underwent laparoscopic Nissen 1) chief complaint of atypical symptom, 2) without improvement after 12 weeks of bid PPI therapy, 3) with abnormal esophageal acid exposure on bid PPI therapy, 4) who underwent antireflux surgery Mean 28 months Laparoscopic Nissen Change in VAS symptom score Median 33 months Antireflux surgery Resolution or > 50% improvement in primary atypical symptom There were no statistically significant differences in improvement of asthma scores between the two procedures. Mean wheeze score decreased from 2.03 to 0.56 (p < 0.0001) after surgery. 12 patients presented with cough and 7 with asthma/wheezing. No significant difference in response to surgery was found according to the specific presenting atypical complaint. After 1 year of follow-up, 59% of patients reported improvement (11%) or complete resolution (48%) of their presenting atypical symptom. Patients with concomitant heartburn or with > 12% acid exposure time had greater likelihood of symptom resolution after fundoplication than patients without heartburn (OR 6.6, p = 0.05; OR 10.5, p = 0.02). Rakita 2006 813 Prospective cohort 1) underwent laparoscopic Nissen, 2) had preoperative symptom scores of 4 or 5 on 5 point scale for extraesophageal Mean 50 months Laparoscopic Nissen Improvement of symptoms Patients without concomitant heartburn and acid exposure time < 12% resolved their symptoms after fundoplication 8.5% of the time, while patients with both factors resolved their symptoms 90.7% of the time. 135 patients presented with asthma scores 4-5. Mean asthma score decreased from 4.7 to 1.7 (p < 0.0001). Kaufman 2006 128 Retrospective cohort Sontag 2003 62 Randomized trial, no placebo Brouwer 2003 28 Prospective cohort Kiljander 15 Prospective symptoms (asthma [diagnosed by having symptoms of asthma and having been cared for by a physician for asthma], cough, gas/bloat, chest pain, odynophagia) 1) Underwent laparoscopic Nissen, 2) experienced cough, hoarseness, or wheezing > once per week 1) mild asthma causing no impairment of in activities, defined as both a) history of wheezing, coughing, or dyspnea and b) either increase in FEV1 >= 20% with bronchodilators or decrease FEV1 >= 20% on methacholine challenge, 2) GERD defined as both a) positive esophageal pH monitoring, and b) esophagoscopic findings or biopsy pathology consistent with reflux esophagitis, 3) FEV1 >= 50% predicted and >= 1.5L 1) underwent laparoscopic Nissen, 2) predominantly respiratory symptoms (cough, aspiration, voice changes) Underwent laparoscopic Median 53 months Laparoscopic Nissen (123) and Toupet (5) Improvement of symptoms 2 years Ranitidine 150 mg tid vs Nissen fundoplication vs aluminum hydroxide/magnesium hydroxide/simethicone and H2 blockers prn (control) Change in asthma symptom score, mean PEF, mean PEF % variation, PFTs, requirement for pulmonary medications, overall clinical response of asthma 37 patients presented with hoarseness. 25 (69%) patients reported improved hoarseness. There was a statistically significant decrease in the frequency of wheezing (p < 0.001). Mean asthma symptom score at 2 years decreased significantly in the surgical group (p < 0.05) but not in the medical or control groups. The surgical group’s mean asthma symptom score improved significantly more than the ranitidne and control groups combined (p = 0.0009). Overall clinical response of asthma reached improvement, marked improvement, or cure in 74.9% of surgical patients, 9.1% of ranitidine patients, and 4.2% in the control group. The improvement was significant in the surgical group compared to the combined ranitidine and control groups (p < 0.001). Mean 650 days Laparoscopic Nissen Symptom score 5 Laparoscopic Nissen Airway Change in mean PEF, mean PEF % variation, PFTs, and asthma medication requirements were not significantly different between groups. Mean wheezing/bronchospasam score decreased after ARS from 2.8 to 0.8 (p < 0.05) 5 months after laparoscopic 2002 cohort Nissen months 1) underwent ARS, 2) reported wheezing, sputum production, cough, choking, hoarseness, or pneumonia 1) underwent laparoscopic Nissen, 2) complaint of heartburn and/or regurgitation 1) severe GERD refractory to maximal medical therapy, 2) simultaneous asthma (according to American Thoracic Society criteria) or chronic cough Median 65 months Wide variety of open and laparoscopic antireflux operations Median 28 months 12 months Greason 2002 62 Retrospective cohort Patti 2000 340 Prospective cohort Ekstrom 2000 24 Prospective cohort responsiveness during methacholine inhalation challenge, changes in PFTs Patient-reported improvement in symptoms Nissen patients had a significantly improved FEV1/FVC (p = 0.03) and FEV1 (p = 0.03). Laparoscopic NIssen Patient-reported resolution of symptoms Open (20) or laparoscopic (4) Nissen Improvement in symptoms by patient diary, FEV1, FVC, 14 of 340 (4%) patients had wheezing attributed to GERD on clinical grounds. Wheezing resolved in 64% of patients. 13 patients had asthma. 12 months post-operatively there was no significant change in FEV1, FVC, cough day score, cough night score, hoarseness score, or expectoration score. 43 patients reported wheezing preoperatively, 21 after ARS. PubMed Search Terms/Strategies Q1 Search. What is the pathophysiology of pulmonary diseases in those w/GERD? Terms/Concepts: Pulmonary Diseases AND (pathophysiology OR etiology OR pathogenesis) AND GERD n=765 (Chronic Bronchitis[title] OR COPD[title] OR chronic cough[title] OR pulmonary disease[title] OR asthma*[title] OR hoarseness[title] OR hoarse[title] OR “idiopathic pulmonary fibrosis”[title] OR “end stage pulmonary disease”[title] OR “chronic laryngitis”[title] OR “throat clearing”[title] OR “sore throat” [title] OR “Globus pharyngeus”[title] OR “excessive phlegm”[title]) AND (pp[sh] OR pathophysiolog*[tiab] OR physiopathology*[tiab] OR etiology[sh] OR etiolog*[tiab] OR pathogenesis[tiab] OR causality[tiab]) OR (“Asthma/physiopathology"[Majr] OR "Cough/physiopathology"[Majr] OR "Pulmonary Disease, Chronic Obstructive/physiopathology"[Mesh] OR "Lung Diseases, Obstructive/physiopathology"[Majr] OR “Asthma/etiology"[Majr] OR "Cough/etiology"[Majr] OR "Pulmonary Disease, Chronic Obstructive/etiology"[Mesh] OR "Lung Diseases, Obstructive/etiology"[Majr]) AND ("Gastroesophageal Reflux"[Majr] OR respiratory aspiration of gastric contents[majr] OR Laryngopharyngeal Reflux[majr]) OR (“oesophageal Reflux”[title] OR “acid reflux”[title] OR “gastroesophageal reflux”[title] OR GERD[title] OR “Esophageal Reflux”[title] OR “gastro oesophageal Reflux”[title] OR “Gastric Acid Reflux”[title] OR “laryngopharyngeal reflux”[title] OR “Gastric Acid Reflux Disease”[title]) With application of limits to years and English language: 1/1/2000 to 9/1/2014; n=458 Q2 Search. What is the natural history of pulmonary diseases in those w/GERD? Terms/Concepts: ("natural history"[tiab] OR outcome[tiab] OR outcomes[tiab] OR prognosis[tiab] OR "clinical epidemiology"[tiab] OR “end stage”) AND Pulmonary Diseases AND GERD n=16633 ("natural history"[tiab] OR outcome[tiab] OR outcomes[tiab] OR prognosis[tiab] OR "clinical epidemiology"[tiab] OR “end stage”) AND (Chronic Bronchitis[title] OR COPD[title] OR chronic cough[title] OR pulmonary disease[title] OR asthma*[title] OR hoarseness[title] OR hoarse[title] OR “idiopathic pulmonary fibrosis”[title] OR “end stage pulmonary disease”[title] OR “chronic laryngitis”[title] OR “throat clearing”[title] OR “sore throat” [title] OR “Globus pharyngeus”[title] OR “excessive phlegm”[title] OR “Asthma"[Majr] OR "Cough"[Majr] OR "Pulmonary Disease, Chronic Obstructive"[Mesh] OR "Lung Diseases, Obstructive"[Mesh]) AND (("Gastroesophageal Reflux"[Majr] OR respiratory aspiration of gastric contents[majr] OR Laryngopharyngeal Reflux[majr]) OR (“oesophageal Reflux”[title] OR “acid reflux”[title] OR “gastroesophageal reflux”[title] OR GERD[title] OR “Esophageal Reflux”[title] OR “gastro oesophageal Reflux”[title] OR “Gastric Acid Reflux”[title] OR “laryngopharyngeal reflux”[title] OR “Gastric Acid Reflux Disease”[title])) Combined Results n=103 with application of limits to years and English language: 1/1/2000 to 9/1/2014 n=94 Q3 Search. What is the outcome of treating GERD medically, on pulmonary diseases in patients with GERD? Terms/Concepts: (Medical therapy of GERD AND Pulmonary OR Lung Diseases) with years applied; n=334 GERD Therapy MESH and Free Text search (("Respiratory Aspiration of Gastric Contents/therapy"[Mesh]) OR ( "Laryngopharyngeal Reflux/drug therapy"[Mesh] OR "Laryngopharyngeal Reflux/therapy"[Mesh] OR "Gastroesophageal Reflux/drug therapy"[Majr]) OR ("Gastroesophageal Reflux"[Majr] AND ("Proton Pump Inhibitors/therapeutic use"[Majr] OR "Proton Pump Inhibitors"[Pharmacological Action] OR PPI[tiab] OR proton pump*[tiab] OR medical therap*[tiab] OR drugs[title] OR drug[title] OR medical manag*[tiab] OR TU[sh] OR "drug therapy*”[subheading] OR acid blocker*[tiab])) OR (“oesophageal Reflux”[title] OR “acid reflux”[title] OR “gastroesophageal reflux”[title] OR GERD[title] OR “Esophageal Reflux”[title] OR “gastro oesophageal Reflux”[title] OR “Gastric Acid Reflux”[title] OR “laryngopharyngeal reflux”[title] OR “Gastric Acid Reflux Disease”[tiab])) AND ((PPI[tiab] OR proton pump*[tiab] OR medical therap*[tiab] OR drugs[title] OR drug[title] OR medical manag*[tiab] OR TU[sh] OR "drug therapy*”[subheading] OR acid blocker*[tiab] OR drug therapies*[tiab] OR “non surgical*”[tiab] OR drug therapy[tiab]) AND (Chronic Bronchitis[title] OR COPD[title] OR chronic cough[title] OR pulmonary disease[title] OR asthma*[title] OR hoarseness[title] OR hoarse[title] OR “idiopathic pulmonary fibrosis”[title] OR “end stage pulmonary disease”[title] OR “chronic laryngitis”[title] OR “throat clearing”[title] OR “sore throat” [title] OR “Globus pharyngeus”[title] OR “excessive phlegm”[title] OR “Asthma"[Majr] OR "Cough"[Majr]) OR ("Pulmonary Disease, Chronic Obstructive"[Mesh] OR "Lung Diseases, Obstructive"[Mesh])) With application of study filters: Medline study type filters below, plus the PubMed McMaster created filters (RCTs OR placebo OR case series OR systematic [tiab] OR meta analy* OR metaanalys* OR randomise* OR randomize* OR clinical trial* OR clinical stud* OR RCTs OR clinical trials OR clinical studies OR case series OR systematic review OR meta-analysis OR comparative study OR controlled clinical trial OR evaluation study OR multicenter study OR pragmatic clinical trial OR practice guideline; with application of limits to years and English language: 1/1/2000 to 9/1/2014; n=89 Q4 Search. What is the outcome of treating GERD surgically (fundoplication) on pulmonary diseases in patients with GERD? Terms/Concepts: (surgical therapy of GERD) AND (Pulmonary OR Lung Diseases) Combined Search Results n=1890 (("Laryngopharyngeal Reflux/surgery"[Mesh] OR "Gastroesophageal Reflux/surgery"[Majr]) OR ("Gastroesophageal Reflux"[Majr] AND (surgery*[subheading] OR “antireflux*”[tiab] OR “reflux*”[tiab] OR fundoplication*[tiab] OR fundoplication[mesh])) OR (“oesophageal Reflux”[tiab] OR “acid reflux”[tiab] OR “gastroesophageal reflux”[tiab] OR GERD[tiab] OR “Esophageal Reflux”[tiab] OR “gastro oesophageal Reflux”[tiab] OR “Gastric Acid Reflux”[tiab] OR “laryngopharyngeal reflux”[tiab] OR “Gastric Acid Reflux Disease”[tiab]) AND (fundoplication OR anti reflux surg* OR antireflux surg* OR reflux surg* OR surgical therap* OR (surgical[tiab] AND treat*[tiab])) OR (surgical*[title] OR surgery[title] OR surgeon*[title] OR non medical* manag*[tiab] OR nonmedical* manag*[tiab])) AND (Chronic Bronchitis OR COPD OR cough OR coughing OR pulmonary disease OR asthma* OR hoarseness OR hoarse OR “idiopathic pulmonary fibrosis” OR “end stage pulmonary disease” OR “chronic laryngitis” OR “throat clearing” OR “sore throat” OR “Globus pharyngeus” OR “excessive phlegm” OR “Asthma"[Majr] OR "Cough"[Majr] OR "Pulmonary Disease, Chronic Obstructive"[Mesh] OR "Lung Diseases, Obstructive"[Mesh]) With application of limits to years and English language: 1/1/2000 to 9/1/2014 n=1215. With application of Medline study type filters, plus the PubMed McMaster created filters (RCTs OR placebo OR case series OR systematic [tiab] OR meta analy* OR metaanalys* OR randomise* OR randomize* OR clinical trial* OR clinical stud* OR RCTs OR clinical trials OR clinical studies OR case series OR systematic review OR meta-analysis OR comparative study OR controlled clinical trial OR evaluation study OR multicenter study OR pragmatic clinical trial OR practice guideline n=407. Q5 SEARCH. What are the current best practices for diagnosing pulmonary diseases (cough, hoarseness, asthma) caused by GERD or LPR, Laryngo-pharyngeal Reflux? Terms/Concepts: (pulmonary diseases or cough or hoarseness or asthma) and diagnosis and (reflux or LPR or GERD) n=389 ((chronic cough[title] OR cough[title] OR asthma*[title] OR hoarse[title] OR hoarseness[title]) AND (diagnos*[title]OR evaluat *[title] OR assess*[title] OR consensus[title]) OR ("Cough/diagnosis"[Majr] OR "Hoarseness/diagnosis"[Majr] OR "Lung Diseases, Obstructive/diagnosis"[Majr] OR "Asthma/diagnosis"[Majr])) AND (Laryngopharyngeal reflux OR gastroesophageal reflux OR reflux[title] OR gerd[title] OR esophageal reflux[title] OR gastro-oesophagealreflux[title] OR laryngo-pharyngealreflux[title] OR "Respiratory Aspiration of Gastric Contents"[Mesh] OR "Laryngopharyngeal Reflux"[Mesh] OR "Laryngopharyngeal Reflux"[Mesh] OR "Gastroesophageal Reflux"[Majr] OR "Gastroesophageal Reflux"[Majr]) With application of limits to years and English language: 1/1/2000 to 9/1/2014, and application of Medline study type filters, plus the PubMed McMaster created filters (RCTs OR placebo OR case series OR systematic [tiab] OR meta analy* OR metaanalys* OR randomise* OR randomize* OR clinical trial* OR clinical stud* OR RCTs OR clinical trials OR clinical studies OR case series OR systematic review OR meta-analysis OR comparative study OR controlled clinical trial OR evaluation study OR multicenter study OR pragmatic clinical trial OR practice guideline n=86. Total PubMed n=728 PRISMA TABLE