Respiratory Complications of Gastroesophageal Reflux Disease

Role of Gastroesophageal Reflux Disease in Chronic Cough

The American College of Chest Physicians defines chronic cough as one lasting greater than 8 weeks in a nonsmoking, immunocompetent patient who takes no cough-inducing drugs (such as angiotensin-converting enzyme inhibitors) and has a normal chest radiograph. Causative factors of chronic cough represent a vast array of clinical entities. Asthma, postnasal drip, and GER represent the most common etiologies of chronic cough. The epidemiologic link between GER and chronic cough was established in 1981 and subsequently verified across a range of patient cohorts. Despite a clear association in the literature, estimates of prevalence have varied widely from 0% to 73%, driven by differences in populations, methodologies, and clinical awareness related to range of specialists (pulmonary medicine, gastroenterology, otolaryngology, general surgery) that evaluate these patients in the clinic setting.

As a theme that will appear in discussion of the interplay between GER and other respiratory disease states, GER contributes to the development and sequelae of chronic cough by way of a variety of mechanisms. The primary mechanisms for consideration are microaspiration, the esophagobronchial reflex, and an increased sensitivity of the cough reflex.

Microaspiration refers to the presence of gastric contents in the airway as evidenced by detection in bronchoalveolar lavage (BAL) fluid. At bronchoscopy, evidence for aspiration includes subglottic stenosis, hemorrhagic tracheobronchitis, and erythema of the subsegmental bronchi. Plain radiographs and axial imaging may also reveal parenchymal changes consistent with acute or chronic aspiration. Irritation of the lower respiratory tract by aspiration represents the most direct link between GER and cough.

Chronic cough may also be triggered indirectly through activation of an esophagobronchial reflex, a means by which cough may be stimulated by GER in the absence of bronchoscopic or radiographic evidence of aspiration. Mechanistically, esophageal innervation by sensory-type fibers that express acid-sensitive channel TRPV-1 and the subsequent convergence of these sensory afferents with vagal afferent neurons provides a means by which refluxate in the distal esophagus may stimulate a vagal reflex. Ing et al. provide evidence of this mechanism in humans by showing that instillation of acid into the distal esophagus of patients with both GERD and cough increased the frequency, duration, and intensity of cough compared with instillation of normal saline. Such a response was subsequently attenuated by pretreatment with lidocaine. Further studies in humans suggest that repetitive exposure can lead to hypersensitivity and a lowering of the cough threshold. Dynamic changes in the cough threshold may cause cough to become relatively stimulus agnostic, such that nonreflux stimuli precipitate symptoms previously associated with GER.

The approach to the patient with chronic cough attributed to GER may be guided by both national guidelines and systematic review of the available evidence. The American College of Chest Physicians recommends empiric acid suppression in patients thought to experience reflux-induced cough. A Cochrane systematic review identified 13 randomized controlled trials examining GERD therapy for the treatment of cough in adults without primary lung disease. Analysis of H ₂ -receptor antagonist, motility agents, and conservative treatment was not possible in the meta-analysis. The remaining nine trials compared proton pump inhibitor (PPI) with placebo. Although there was no difference in the rate of total resolution of cough, patients receiving PPI therapy were more likely to note improvement in cough scores. Thus, even though the primary outcome was not met, there appears to be a benefit to acid suppression in appropriately selected patients. Nonetheless, the long-term consequences of respiratory complications were not addressed in any of these studies.

To date, controlled studies of the efficacy of fundoplication or other surgical interventions for patients with cough and GER are lacking. In single-center studies, surgical intervention consistently demonstrates efficacy in key metrics. In particular, fundoplication is effective in reducing the number of reflux events by esophageal pH monitoring and produces symptomatic improvement. Traditionally, patients with extraesophageal GER symptoms such as cough have been found to benefit from fundoplication at a rate lower than those with typical GER symptoms, with estimates of approximately 60% of patients with cough subsequently reporting improvements in cough scores, and freedom from PPI therapy. This is most likely due to our inability to better confirm the direct causal effect of GERD on chronic cough in all patients.

Laryngopharyngeal Reflux

The earliest reports of acid-driven injury to the larynx (manifest by laryngeal ulcerations and granulomas) were noted by Cherry in 1968. Pellegrini was among the first in 1979 to note that acid-containing reflux of gastric contents may then be a causative factor in this laryngeal pathology. Although at the time the potential for a surgical cure of extraesophageal symptoms of reflux was noted to be achievable by way of an antireflux procedure, laryngitis was not formally recognized as an extraesophageal manifestation of GER until 2006 by the Montreal Definition and Classification System. Data regarding the prevalence of laryngopharyngeal reflux (LPR) are relatively limited, in part stemming from controversy in the professional organizations with respect to the appropriate diagnostic criteria for LPR. In particular, controversy exists with respect to the extent to which symptoms related to LPR should be attributed to reflux in the absence of traditional heartburn symptoms.

A high index of suspicion should be maintained for LPR in the patient with hoarseness, cough, globus, and throat clearing. A minority of patients (35%) found to have LPR report heartburn symptoms. Scoring systems such as the Reflux Symptom Index (RSI) or Hull Airway Reflux Questionnaire (HARQ) may be of utility in the screening of these patients for LPR and associated extraesophageal manifestations of GERD as a cause of symptoms. Patients who are subsequently evaluated by direct laryngoscopy following history and physical exam are assessed for posterior laryngeal edema, true vocal fold edema, and pseudosulcus. Although these findings may be sensitive for the diagnosis of LPR, they often are not specific because they are common findings in the general population and are not strictly linked to exposure of the larynx to gastric contents.

Detection of reflux into the pharynx requires diagnostic strategies that differ from the detection of reflux in the distal esophagus, on account of the neutralization of refluxate as it ascends the esophagus into the more alkaline environment of the pharynx. As such, pharyngeal pH monitoring is of low sensitivity in the diagnosis of LPR. Currently, pH/impedance monitoring offers a superior strategy for diagnosis, with a significant benefit of detection of both acid and nonacid reflux. pH/impedance monitoring may also identify the proximal extent of reflux. Reflux into the laryngopharynx is very rare in healthy patients, such that any evidence of reflux so far proximal from the gastroesophageal junction may be considered abnormal and thereby warrant treatment. The use of a dual-probe (or bifurcated) impedance pH catheter permits detection of both impedance and pH changes across the upper esophageal sphincter, thereby permitting detection of pharyngeal reflux. More novel techniques aim to detect the pH of aerosolized reflux, which reveal the finding that patients with chronic cough may reflux both liquid and gaseous stomach contents. Patients with predominantly cough-related symptoms may benefit from techniques that make use of physiologic changes associated with cough (such as pressure changes above and below the diaphragm) to demonstrate a temporal link between cough and reflux.

Mechanistically, as with exposure of other nonstomach structures to acid, the larynx has relatively little protection against both acid and enzymatic activity. The thinner epithelium and lack of peristalsis to wash away acid contribute to injury seen with relatively brief and short-duration exposures in animal models. In addition to the consequences of direct exposure to acid and other gastric contents, laryngeal injury may also manifest as an indirect consequence of exposure of the esophagus to refluxate. In the indirect model, irritation of the esophagus can generate vagally mediated reflexes such as cough and bronchoconstriction that can contribute to chronic laryngeal injury.

Successful treatment of LPR again requires adequacy of diagnosis. In the patient with modifiable risk factors, behavior modification such as minimization of tobacco and alcohol consumption is recommended. Those patients with LPR and evidence of esophageal symptoms of GERD should be treated with acid suppression. The role of acid suppression in patients with suspected or confirmed LPR but without evidence of esophageal manifestations of GERD is controversial, and success of therapy likely depends on the extent to which acid is a contributing factor in the symptoms associated with LPR. The American Gastroenterological Association recommends against PPI and H ₂ -receptor blockade for the treatment of suspected LPR in the absence of a concomitant GERD syndrome. In contrast, the American Academy of Otolaryngology-Head and Neck Surgery recommends twice-daily PPI for no less than 6 months for patients with LPR. Data regarding the use of acid suppression in the absence of esophageal manifestations are weak and are limited by a lack of standardized diagnostic criteria. Trials have also been limited by the possibility of placebo effect, such that, in small studies, for example, patients with no measurable pH response to PPI report symptom improvement. Uncontrolled trials of surgery have shown some promise in patients with medication-refractory LPR, but a controlled trial of antireflux surgery in patients who failed aggressive acid suppression did not improve laryngeal symptoms despite showing successful control of reflux by way of pH studies.