TABLE 1.

Studies of gastro-oesophageal reflux treatment in asthma

First author [ref] Study type	n	Treatment	Asthma symptoms	Exacerbations	FEV1	Other outcomes
H2RAs
Goodall [46] RCT crossover	18	Cimetidine 200 mg 5 times a day for 6 weeks	Improvement in nocturnal asthma symptom score	N/A	Unchanged	Improvement in evening PEFR
Nagel [47] RCT crossover	14	Ranitidine 400 mg four times daily for 1 week	N/A	N/A	Unchanged	No change in use of asthma medications
Ekstrom [48] RCT crossover	48	Ranitidine 150 mg twice daily for 4 weeks	Improvement in nocturnal asthma symptom score	N/A	Unchanged	N/A
Larrain [49] RCT placebo or surgery parallel	27	Cimetidine 300 mg four times daily for 6 months	N/A	N/A	Minor improvement in FEV1 after 6 months	N/A
PPIs
Meier RCT crossover [50]	15	Omeprazole 20 mg twice daily for 6 weeks	N/A	N/A	27% asthma patients with GORD had a ≥20% net improvement in FEV1 after treatment	N/A
Teichtahl [51] RCT crossover	20	Omeprazole 40 mg once daily for 4 weeks versus placebo	Unchanged	N/A	N/A	Improvement in evening but not morning PEFR; improved reflux symptoms
Harding [52] RCT crossover	30	Omeprazole 20–60 mg four times daily for 12 weeks	Improved	N/A	Improved FEV1 and FVC	Improved PEFR; improved reflux symptoms
Levin [16] RCT crossover	9	Omeprazole 20 mg once daily for 8 weeks	Improved	N/A	Trend toward higher FEV1 (mean difference 15.6%)	Improved Asthma Quality of Life Score (AQLS) including sutwice dailyomains of activity limitation, symptoms and emotions
Boeree [53] RCT crossover	36	Omeprazole 40 mg b for 12 weeks versus placebo	Unchanged	N/A	Unchanged	Improved reflux symptom scores and proportion of time with pH<4; no effect on peak flow or reversibility
Kiljander [54, 55] RCT crossover	107	Omeprazole 40 mg once daily for 8 weeks versus placebo	Improved nocturnal asthma symptoms	N/A	Improved	No effect on peak flow; 18 (35%) patients had improved pulmonary symptom scores while receiving omeprazole
Tsugeno [56] Prospective observational		Rabeprazole 20 mg once daily for 8 weeks	Unchanged	N/A	N/A	Improved PEFR; improved reflux symptoms
Jiang [57] RCT	30	Omeprazole 20 mg once daily plus domperidone 10 mg three times daily for 6 weeks versus usual care	N/A	N/A	Improved	Improved PEFR and bronchial hyperresponsiveness
Littner [58] RCT	207	Lansoprazole 30 mg once daily for 24 weeks versus placebo	Unchanged	N/A	Unchanged	Improved AQLS emotional function; no change in PEFR or use of asthma rescue medications
Stordal [59] RCT	38	Omeprazole 20 mg for 12 weeks versus placebo	Unchanged	N/A	Unchanged	Improved quality of life; improved reflux scores on pH; no change in asthma rescue medications
Shimizu [60] RCT	30	Lansoprazole 30 mg·day−1 for 8 weeks versus roxatidine (H2RA), 150 mg·day−1	Improved	N/A	Unchanged	Improved peak flow and ACQ score
Kiljander [61] RCT	770	Esomeprazole 40 mg twice daily versus placebo for 16 weeks	Unchanged	N/A	Unchanged	Improved PEFR in patients with GORD and nocturnal symptoms only; no safety concerns noted
Wong [62] Prospective observational	30	Lansoprazole 30 mg once daily	Improved	N/A	Unchanged	No effect on PEFR; improved pulmonary symptom scores
Sharma [63] RCT		Omeprazole 20 mg twice daily plus domperidone 10 mg three times daily versus placebo for 16 weeks	Improved day and night-time symptom scores	N/A	Improved FEV1 and FVC	Improved reflux symptom scores; improved PEFR; reduction in asthma rescue medications
Khorasani [64] RCT Adolescents	36	Omeprazole 20 mg twice daily for 6 weeks versus placebo	N/A	N/A	Improved FEV1 and FVC	Improved reflux symptoms
Mastronarde [65] RCT	412	Esomeprazole 40 mg twice daily for 24 weeks versus placebo	Unchanged	N/A	Unchanged	No effect on airway reactivity, asthma control, asthma symptom scores, nocturnal awakening or quality of life; no increase in adverse events compared to placebo
Bucknall [66] Prospective observational	51	Omeprazole up to 80 mg daily	N/A	N/A	N/A	Improved GORD symptoms and pH readings with increased therapy dose
Kiljander [67] RCT	828	Esomeprazole 40 mg once/twice daily for 26 weeks	Unchanged	N/A	Improved FEV1 in 40 mg TWICE DAILY group after 26 weeks compared to control	No effect on PEFR; improved AQLS score in both treatment groups compared to control
Adamko [68] Infants RCT	19	Combined omeprazole 10 mgonce daily plus bethanacol versus either treatment alone versus placebo	Improved daytime coughing and respiratory symptom scores	N/A	N/A	Improved GORD symptoms and GORD measured by pH; no adverse events noted
Holbrook [69] Children RCT	306	Lansoprazole 15 mg·day−1 if <30 kg or 30 mg·day−1 if ≥30 kg versus placebo	Improved	N/A	Unchanged	Improved ACQ score but no effect on asthma-related quality of life or rates of episodes of poor asthma control; in the subgroup with a positive pH study, no treatment effect was observed for any asthma outcome; increased respiratory infections noted in treatment group
Sandur [70] Prospective observational	28	Omeprazole 40 mgonce daily for 3 months; increased to 60 mgonce daily at 2 months if pH study remained abnormal	Improved pulmonary symptom and night-time asthma symptom scores	N/A	Improved FEV1	Improved reflux symptom score and peak flow readings
Yamaji [71] RCT	60	Omeprazole 10 mgonce daily plus mosapride 5 mg three times daily versus omeprazole alone for 4 weeks	N/A	N/A	N/A	No additional amelioration of GORD symptoms when combined
Surgery
Perrin-Fayolle [73] Prospective observational	44	Nissen fundoplication	Improved	N/A	N/A	Pulmonary improvement classified as total cure 25%, marked improvement 16%, moderate improvement 25%, no improvement 34% 95% long-term improved reflux symptoms
Larrain [49] RCT	26	Nissen fundoplication	Improved	N/A	N/A	Clinical improvement and reduced use of asthma rescue medications
Spivak [74] Prospective observational	39	Nissen fundoplication (median follow-up 2.7 years)	Improved	N/A	N/A	Improved asthma scores; reduction in use of systemic steroids
Ekstrom [75] Prospective observational	13	Transabdominal/ laparoscopic fundoplication	N/A	N/A	Unchanged	N/A
Sontag [76] RCT	62	Antacids p.r.n. versus ranitidine 150 mg three times daily versus Nissen fundoplication for follow-up of 2 years	Surgery improves asthma symptoms	N/A	Unchanged	No effect of PEFR, rescue medications or survival
Khoshoo [77] Children Prospective observational	18	Medical treatment (lifestyle changes, proton pump inhibitors and prokinetics) or surgical treatment (Nissen fundoplication)	Improved	N/A	N/A	Reduction in need for rescue medications
Khoshoo [78] Children Prospective observational	44	Esomeprazole plus metoclopraminde 10 mg three times daily versus ranitidine versus Nissen fundoplication	N/A	Increased exacerbations in ranitidine group compared to other treatment groups	N/A	N/A
Kiljander [79] Prospective observational	69	Esomeprazole 40 mg twice daily versus Nissen fundoplication after 3 months	Improved cough and dyspnoea with both treatment groups	N/A	Unchanged	Improved SGRQ quality of life after fundoplication
Silva [80] Retrospective observational	30	Nissen fundoplication	Improved	N/A	N/A	Improvement in daily crises of asthma
Hu [81] Prospective observational	137	Stretta radiofrequency (n=82) or laparoscopic Nissen fundoplication (n=55)	Improved	N/A	N/A	Improved reflux, respiratory and ENT symptoms in both groups, better in Nissen fundoplication group at both 1 and 5 years follow-up

Abbreviations: FEV₁: forced expiratory volume in 1 s; H2RAs: histamine-2 receptor antagonists; PEFR: peak expiratory flow rate; RCT: randomised controlled trial; GORD: gastro-oesophageal reflux; FVC: forced vital capacity; AQLS: Asthma Quality of Life Score; ACQ: Asthma Control Questionnaire; SGRQ: St. George's Respiratory Questionnaire; ENT: ears, nose and throat; N/A: not available.