Gastroesophageal reflux disease in bronchial asthma: What we need to know?

The reflux theory^[2]

This theory refers to a direct mechanism by which gastroduodenal reflux (acid, pepsin, bile acids, and pancreatic enzymes) enter the esophagus and subsequently leads to microaspiration into the lungs and other parts of the pulmonary tree. The aspiration of these contents can result in stimulation of the pharynx or larynx, consequently resulting in extraesophageal symptoms such as tracheal or bronchial cough reflex. The chronic inflammation of lung tissue may lead to airway obstruction, poor gas exchange, acute lung injury, and severe acute respiratory distress syndrome. These mechanisms consequently induce the liberation of proinflammatory cytokines from T-helper Type 2 cells, leading to an increase in airflow resistance and inflammation. Bronchoconstriction is induced by direct HCl intra-esophageal instillation through muscarinic (M3) receptors, which release acetylcholine. This contributes to airway inflammation and the stimulation of smooth muscle contractions in the airways. This contributes to airway inflammation and the stimulation of smooth muscle contractions in the airways. Infiltrates of macrophages, neutrophils, eosinophils, and lymphocytes are detected histologically in GERD-induced airway inflammation.^[12-14]

The reflex theory^[2]

The reflex theory refers to a method otherwise known as an indirect process by which distal esophageal reflux induces stimulation of the vagus nerve leading to bronchoconstriction. This method operates on the basis that the esophagus and tracheobronchial tree share an embryological origin and would therefore share similar innervation. Consequently, this shared innervation could explain why stimuli in the distal esophagus led to extraesophageal symptoms through vagus nerve reflexes.^[15] A study conducted by Harding et al. in 1999 sought to examine the prevalence and severity of GERD in asthmatics with and without reflux symptoms as well as the correlation of respiratory symptoms with intra-esophageal acid. A total 82% of asthmatics had underlying reflux symptoms, 72% asthmatics with reflux symptoms had abnormal 24-h Esophageal pH tests versus 30% asthmatics without reflux symptoms. Among asthmatics with GER, esophageal acid was linked to respiratory symptoms in 78.8% cases.^[15]

H2 receptor antagonists

Inhibition of the H2 receptor on parietal cells in the stomach mucosa by receptor antagonists like cimetidine or ranitidine leads to reduced gastric acid secretion. The majority of studies indicate an improvement in reflux symptoms and, in some cases, recovery from nocturnal asthmatic symptoms. Ranitidine 300 mg was given as a daily dose (unless weight <40 kg, in which case 150 mg twice daily was used). In individuals with pathological GERD, ranitidine showed a small (30%) but statistically significant decrease in nocturnal asthma symptoms. In summary, medical therapy with ranitidine did not improve pulmonary function, medication requirements, survival, or improvement of asthma symptoms.

PPIs

PPIs are an innocuous and relatively well-tolerated family of medications that directly inhibit the proton pump (H+/K+ ATPase) of the parietal cells in the stomach leading to the suppression of acid. PPIs are referred to as the current gold standard in the treatment of GERD because they provide a demonstrable advantage over histamine blockers in terms of GERD symptom alleviation and esophagitis. Many trials have been conducted to establish the beneficial effect of PPIs on asthma symptoms and pulmonary function tests. However, their advantage has not been clearly shown and remains obscure.

Treatment with antireflux therapy did not consistently improve any one measure of pulmonary function in patients with asthma, but some studies did report objective improvement in single measurements of lung function such as FEV1, morning PEF, and evening PEF. The variability in reporting of asthma symptoms in the included studies prevented detailed analysis of any parameter except for nocturnal asthma symptoms which were noted to be improved by some authors in patients treated with histamine antagonists.^[7,17,18]

Kiljander and associates assessed the effects of esomeprazole 40 mg twice daily versus placebo for 16 weeks among 770 patients with moderate-to-severe asthma. The study included asthmatics with moderate-to-severe asthma based on FEV1 (50–80% predicted) and evidence of bronchodilator reversibility. The presence of GERD was based primarily on patient reported clinical symptoms.^[19] They included 961 patients with moderate-to-severe asthma with demonstrated reversibility of airflow obstruction and ≥1 clinically important asthma exacerbation within the preceding 12 months with symptomatic GERD (as determined by the Reflux Disease Questionnaire. After 26 weeks of therapy, there was no improvement noted in the primary endpoint of the study, change from baseline mean morning PEF, in either study group. In addition, no differences were noted in use of rescue bronchodilators, percentage of asthma symptom-free days, or frequency of severe asthma exacerbations. Treatment with esomeprazole at both doses was associated with a statistically significant improvement in FEV1 and asthma-related quality of life throughout the study period. However, the improvement in FEV1 was small and likely of small clinical significance.^[20]

Therefore, in some asthmatics with symptoms suggestive of GERD, the available literature suggests that there may be a small benefit of treatment of GERD on some aspects of asthma-related quality of life and possibly on exacerbations, but no clear evidence supports objective benefits in pulmonary function or overall asthma control. However, one could argue that treatment for symptomatic GERD is warranted in patients with asthma independent of any potential benefit on asthma outcomes if the underlying GERD warrants treatment on its own. The current NIH guidelines recommend an empiric trial of GERD therapy in poorly controlled asthmatics even if they do not have GERD symptoms.^[21]

The American Lung Association Asthma Clinical Research Centers conducted a multicenter, randomized, and placebo-controlled trial of esomeprazole 40 mg twice daily for 24 weeks in patients with poorly controlled asthma and minimal or no symptoms of (silent) GER, using ambulatory esophageal pH monitoring to confirm the presence or absence of GER in participants. Four hundred and twelve patients on moderate or high doses of inhaled corticosteroids with inadequately controlled asthma (defined as either a Juniper Asthma Control Questionnaire of 1.5 or higher or the presence of more than one unscheduled health-care visit for asthma in the preceding 12 months) underwent pH testing and were randomly assigned to treatment with esomeprazole or placebo independent of pH study results. The diagnosis of asthma was based on physician diagnosis with either a positive methacholine challenge test or evidence of bronchodilator reversibility of the FEV1 with an increase of ≥12% after short-acting bronchodilator administration.^[22,23] After 6 months of therapy, episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 vs. 2.5 events/person-year respectively; P = 0.66). Although night-time awakenings due to asthma occurred on more than one occasion in over half of the subjects, there was no significant difference between groups. Similarly, there was no difference with respect to lung function (including PEF, FEV1, and methacholine responsiveness), asthma symptoms, or asthma related quality of life when patients treated with esomeprazole were compared with those who received placebo. Ambulatory pH monitoring demonstrated acidic GER in approximately 40% of both groups of participants, but failed to identify a subgroup of patients that was likely to benefit from therapy with the PPI. From these findings, Mastronarde et al. concluded that the empiric use of acid suppression in patients with poorly controlled asthma but minimal or no GERD symptoms should not be routinely recommended.^[22]

The potential importance of the location of reflux in the esophagus (proximal vs. distal) has also been considered as a potential important factor in the clinical relationship between asthma and GERD. In a small study (n = 133) of subjects with upper airway symptoms attributed to GERD, dual-probe esophageal pH monitoring demonstrated a significantly higher incidence of nocturnal cough in those participants with acid reflux detected at both the proximal and distal probe than in those in whom reflux was detected at the distal probe alone. While the possibility that the participants’ nocturnal cough may have been related to uncontrolled asthma was not specifically addressed by the authors, the study still raises the important issue that symptoms from proximal GERD such as cough may mimic asthma and may confound measurements of asthma control in the clinical and research setting.^[24] A subgroup (n = 242) of participants in the American Lung Association’s Study of acid reflux and asthma underwent dual-probe pH esophageal monitoring. Thirty-eight percent of participants demonstrated proximal GERD, but concordance between proximal and distal GERD on pH probe was poor.^[22] While the presence of proximal GERD was associated with worse asthma-related quality of life, no differences were noted in other the asthma-related clinical outcomes measures described above. It has been hypothesized that nonacidic or alkali reflux may affect asthma control parameters, but, to date, this interesting theory remains untested.^[25]