Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults

Abstract

Background: Gastroesophageal reflux disease (GORD) is said to be the causative factor in up to 41% of adults with chronic cough. Treatment for GORD includes conservative measures (diet manipulation), pharmaceutical therapy (motility or prokinetic agents, H(2)-antagonist and proton pump inhibitors (PPI)) and fundoplication.

Objectives: To evaluate the efficacy of GORD treatment on chronic cough in children and adults with GORD and prolonged cough that is not related to an underlying respiratory disease, i.e. non-specific chronic cough.

Search strategy: We searched the Cochrane Airways Group Specialised Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, review articles and reference lists of relevant articles. The date of last search was 8 April 2010.

Selection criteria: All randomised controlled trials (RCTs) on GORD treatment for cough in children and adults without primary lung disease.

Data collection and analysis: Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information.

Main results: We included 19 studies (six paediatric, 13 adults). None of the paediatric studies could be combined for meta-analysis. A single RCT in infants found that PPI (compared to placebo) was not efficacious for cough outcomes (favouring placebo OR 1.61; 95% CI 0.57 to 4.55) but those on PPI had significantly increased adverse events (OR 5.56; 95% CI 1.18 to 26.25) (number needed to treat for harm in four weeks was 11 (95% CI 3 to 232)). In adults, analysis of H(2) antagonist, motility agents and conservative treatment for GORD was not possible (lack of data) and there were no controlled studies of fundoplication. We analysed nine adult studies comparing PPI (two to three months) to placebo for various outcomes in the meta-analysis. Using intention-to-treat, pooled data from studies resulted in no significant difference between treatment and placebo in total resolution of cough (OR 0.46; 95% CI 0.19 to 1.15). Pooled data revealed no overall significant improvement in cough outcomes (end of trial or change in cough scores). We only found significant differences in sensitivity analyses. We found a significant improvement in change of cough scores at end of intervention (two to three months) in those receiving PPI (standardised mean difference -0.41; 95% CI -0.75 to -0.07) using generic inverse variance analysis on cross-over trials. Two studies reported improvement in cough after five days to two weeks of treatment.

Authors' conclusions: PPI is not efficacious for cough associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for cough associated with GORD. Clinicians should be cognisant of the period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Future paediatric and adult studies should be double-blind, randomised controlled and parallel-design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non-acid reflux.

Figure 1

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Forest plot of comparison: 2 PPI versus placebo (> 18 years), outcome: 2.1 Clinical failures (still coughing at end of trial or reporting period).

Figure 4

Forest plot of comparison: 3 PPI versus placebo (children), outcome: 3.1 Coughing (% days/week).

Figure 5

Cates plot: In the control group, 25 out of 1000 had a serious adverse event over 4 weeks, compared to 123 (95% CI 29 to 399) out of 1000 for the PPI group

Figure 6

Funnel plot of comparison: 2 PPI versus placebo (> 18 years), outcome: 2.1 Clinical failures (still coughing at end of trial or reporting period).

Analysis 1.1

Comparison 1 Thickened versus unthickened feeds (infants), Outcome 1 Subjects cured (of cough) at end of study.

Analysis 1.2

Comparison 1 Thickened versus unthickened feeds (infants), Outcome 2 Cough frequency.

Analysis 2.1

Comparison 2 PPI versus placebo (children), Outcome 1 Coughing (% days/week).

Analysis 2.2

Comparison 2 PPI versus placebo (children), Outcome 2 Clinical failures (still coughing at end of trial or reporting period).

Analysis 2.3

Comparison 2 PPI versus placebo (children), Outcome 3 Treatment‐emergent serious adverse events.

Analysis 3.1

Comparison 3 PPI versus placebo (> 18 years), Outcome 1 Clinical failures (still coughing at end of trial or reporting period).

Analysis 3.2

Comparison 3 PPI versus placebo (> 18 years), Outcome 2 Mean cough score at end of trial (1st arm cross‐over/parallel‐group trials).

Analysis 3.3

Comparison 3 PPI versus placebo (> 18 years), Outcome 3 Change in cough scores (end‐beginning of intervention ‐ 1st arm cross‐over/parallel‐group trials).

Analysis 3.4

Comparison 3 PPI versus placebo (> 18 years), Outcome 4 Change in cough scores (cross‐over studies; standardised scale).

Analysis 3.5

Comparison 3 PPI versus placebo (> 18 years), Outcome 5 Absolute cough scores (cross‐over studies, standardised scale).

Analysis 3.6

Comparison 3 PPI versus placebo (> 18 years), Outcome 6 Change in cough score after 4 weeks treatment (1st arm cross‐over/parallel‐group trials).

Analysis 3.7

Comparison 3 PPI versus placebo (> 18 years), Outcome 7 Difference in cough scores at week 8 ‐ week 4 (1st arm cross‐over/parallel‐group trials).