Respiratory disease and the oesophagus: reflux, reflexes and microaspiration

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Abstract

Gastro-oesophageal reflux is associated with a wide range of respiratory disorders, including asthma, isolated chronic cough, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and cystic fibrosis. Reflux can be substantial and reach the proximal margins of the oesophagus in some individuals with specific pulmonary diseases, suggesting that this association is more than a coincidence. Proximal oesophageal reflux in particular has led to concern that microaspiration might have an important, possibly even causal, role in respiratory disease. Interestingly, reflux is not always accompanied by typical reflux symptoms, such as heartburn and/or regurgitation, leading many clinicians to empirically treat for possible gastro-oesophageal reflux. Indeed, costs associated with use of acid suppressants in pulmonary disease far outweigh those in typical GERD, despite little evidence of therapeutic benefit in clinical trials. This Review comprehensively examines the possible mechanisms that might link pulmonary disease and oesophageal reflux, highlighting the gaps in current knowledge and limitations of previous research, and helping to shed light on the frequent failure of antireflux treatments in pulmonary disease.

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High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis.

G Raghu, T D Freudenberger, S. Yang … (2006)

The aim of this prospective study was to determine the prevalence and characteristics of acid gastro-oesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis (IPF). Sixty-five consecutive patients with well-defined IPF were subjected to 24-h pH monitoring and oesophageal manometry. A total of 133 consecutive patients with intractable asthma and symptoms of GER were used as comparisons. The prevalence of abnormal acid GER in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal oesophageal acid exposures, respectively. Abnormal acid GER was significantly more common in IPF patients than asthma patients. Only 47% of IPF patients experienced classic GER symptoms. Despite treatment with standard doses of proton pump inhibitors (PPIs), 12 out of 19 patients receiving PPIs during the 24-h pH monitoring had abnormal oesophageal acid exposures by pH probe. There was no correlation between IPF severity and acid GER severity. In conclusion, abnormal acid gastro-oesophageal reflux is highly prevalent, but often clinically occult in patients with idiopathic pulmonary fibrosis. Standard doses of proton pump inhibitors may not suppress the acid gastro-oesophageal reflux in this population. Therefore, further studies are needed to determine if acid abnormal gastro-oesophageal reflux represents an important risk factor for idiopathic pulmonary fibrosis development or progression, and if optimal suppression of acid gastro-oesophageal reflux slows the progression of idiopathic pulmonary fibrosis and/or decreases episodic exacerbations of idiopathic pulmonary fibrosis.

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Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial.

Nicole Ryan, Surinder Birring, Peter G Gibson (2012)

Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as gabapentin might be effective for refractory chronic cough. We established the efficacy of gabapentin in patients with refractory chronic cough. This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369. 62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56-3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given gabapentin (the most common being nausea and fatigue) and three (10%) given placebo. The treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Acid-suppressive medication use and the risk for hospital-acquired pneumonia.

Edward R. Marcantonio, Nita Ngo, Elizabeth Howell … (2009)

The use of acid-suppressive medication has been steadily increasing, particularly in the inpatient setting, despite lack of an accepted indication in the majority of these patients. To examine the association between acid-suppressive medication and hospital-acquired pneumonia. Prospective pharmacoepidemiologic cohort study. All patients who were admitted to a large, urban, academic medical center in Boston, Massachusetts, from January 2004 through December 2007; at least 18 years of age; and hospitalized for 3 or more days were eligible for inclusion. Admissions with time spent in the intensive care unit were excluded. Acid-suppressive medication use was defined as any order for a proton-pump inhibitor or histamine(2) receptor antagonist. Traditional and propensity-matched multivariable logistic regression were used to control for confounders. Incidence of hospital-acquired pneumonia, defined via codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), in patients exposed and unexposed to acid-suppressive medication. The final cohort comprised 63 878 admissions. Acid-suppressive medication was ordered in 52% of admissions and hospital-acquired pneumonia occurred in 2219 admissions (3.5%). The unadjusted incidence of hospital-acquired pneumonia was higher in the group exposed to acid-suppressive medication than in the unexposed group (4.9% vs 2.0%; odds ratio [OR], 2.6; 95% confidence interval [CI], 2.3-2.8). Using multivariable logistic regression, the adjusted OR of hospital-acquired pneumonia in the group exposed to acid-suppressive medication was 1.3 (95% CI, 1.1-1.4). The matched propensity-score analyses yielded identical results. The association was significant for proton-pump inhibitors (OR, 1.3; 95% CI, 1.1-1.4) but not for histamine(2) receptor antagonists (OR, 1.2; 95% CI, 0.98-1.4). In this large, hospital-based pharmacoepidemiologic cohort, acid-suppressive medication use was associated with 30% increased odds of hospital-acquired pneumonia. In subset analyses, statistically significant risk was demonstrated only for proton-pump inhibitor use.