Objectives

1. Understand the mechanisms of gastroesophageal reflux (GER).
2. Understand the spectrum of supraesophageal complications of GER.
3. Describe GER-related cough.
4. Describe the association between GER and asthma.
5. Understand the treatment of GER.

Key words

asthma; cough; gastroesophageal reflux disease; interstitial lung disease; supraesophageal; treatment

Abbreviations

CF = cystic fibrosis; GER = gastroesophageal reflux; H₂A = histamine₂ antagonist; IPF = idiopathic pulmonary fibrosis; LES = lower esophageal sphincter; PPI = proton-pump inhibitor

Gastroesophageal reflux (GER) is defined as reflux of gastric or intestinal contents into the esophagus. This is dependent on increased gastric volume, gastric contents being located near the gastroesophageal junction, increased gastric pressure, and decreased lower esophageal sphincter (LES) tone. The cumulative effects of GER depend on the amount of refluxed material per episode, the frequency of reflux episodes, the rate of clearance of the esophagus by gravity and peristaltic contraction, and the rate of neutralization of gastric acid by salivary secretion.

Several mechanisms predispose patients with pulmonary disease to GER. Transient LES relaxation may be the result of a vagally mediated reflex that is provoked by lung inflation; alternatively, transient LES relaxation may be the result of increased transdiaphragmatic pressure from cough and/or wheeze. There also may be mechanical incompetence of the LES secondary to alteration in the chest wall and depression of the diaphragm, as seen in patients with obstructive lung disease. In addition, medications used to treat pulmonary disease such as b-adrenergic agonists, prednisone, and the methylxanthine compounds are associated with decreased LES tone.¹

Although multiple modalities have been used to diagnose GER, 24-h pH-metry has been considered by most to be the gold standard, with a reported sensitivity of 85% and specificity >95%.² However, the emerging technology of multichannel intraluminal impedance is likely to become the new gold standard. Not only can multichannel intraluminal impedance be used to evaluate bolus transport and GER, it can differentiate acid from nonacid reflux (Fig 1), determine the precise level of refluxate, and determine the efficacy of clearance mechanisms.

Figure 1. Examples of acid and nonacid impedance-detected GER. Note the distal-proximal (Z6–Z1) progression of impedance drop with (acid) and without (nonacid) concomitant drop in pH below 4.0.

“Typical” GER symptoms include heartburn, regurgitation, and water brash and are very common, with 7% of the US population complaining of daily symptoms, 14 to 19% complaining of weekly symptoms, and 40% complaining of symptoms at least once per month.^3-5 However, there are many supraesophageal and pulmonary manifestations of GER that commonly occur without typical GER symptoms (Fig 2).

GER and Otitis/Sinusitis

Adults with GER are 60% more likely to have sinusitis and the presence of GER is a predictor of poor symptomatic outcome after sinus surgery.⁶ Sinusitis and otitis are likely a result of aspiration of refluxate into the sinuses and/or eustachian tubes. Patients with chronic resistant sinusitis have been found to have increased proximal acid exposure time compared with GER control subjects.⁷ The majority of patients with chronic tubotympanal disorders have pathologic GER by 24-h pH-metry⁸ and in one study, pepsin and/or pepsinogen was found in 91% of middle ear effusions from patients undergoing myringotomy.⁹

Laryngopharyngeal Signs and Symptoms Associated With GER Patients with GER may present with globus, which is a sensation of something being stuck in the back of the throat. As a result, patients may have excessive throat clearing, chronic hoarseness, vocal cord dysfunction, or a persistently sore throat. In one study,¹⁰ 80% of patients with chronic hoarseness had abnormal 24- h pH-metry with a pattern of reflux similar to a matched cohort of patients with esophagitis. However, the patients with chronic hoarseness had increased amounts of upright reflux and 85% of these patients did not have any symptoms of heartburn or regurgitation.

Laryngeal cancer has also been associated with GER. Laryngopharyngeal reflux has been documented in a majority of patients with laryngeal cancer and nearly 40% of laryngeal cancer patients with GER do not have any of the typical symptoms of GER.¹¹ In another study,¹² 100% of nonsmokers with laryngeal cancer had GER.

The bronchoscopist should be aware of laryngopharyngeal signs that may be associated with GER (Table 1).¹⁰

Table 1. Laryngopharyngeal Signs Associated with GER*

GER and Chronic Cough

GER is one of the three most common causes of chronic cough. The act of coughing can provoke GER events perpetuating a cough-reflux cycle and the onset of GER-related cough frequently occurs after an upper respiratory tract infection. In patients with GER-related cough, GER occurs predominantly during the day and in the upright position. Cough may be the sole clinical manifestation of GER up to 75% of the time.¹³ Although cough may be due to microaspiration in some patients, in the majority, receptors in the stomach and esophagus are triggered by gastric acid that stimulates the cough center through a vagally mediated pathway. In some patients, however, GER-induced cough may be caused by nonacid mediators.¹³ Multiple studies have shown resolution of cough with diet and lifestyle modifications combined with either histamine₂ antagonists (H₂As) or proton-pump inhibitors (PPIs), although improvement may take as long as 3 months. Fundoplication has a very high success rate in treating GERrelated cough, and may be indicated when cough is secondary to nonacid mediators.

GER and Obstructive Lung Disease

GER is highly prevalent in patients with asthma and is likely secondary to a vagally mediated pathway that causes the release of inflammatory mediators that increase bronchial reactivity, although microaspiration of gastric acid can also result in bronchoconstriction. In a study of asthmatics using 24-h pHmetry, ¹⁴ 82% of patients had abnormal esophageal acid contact times and 48% had abnormal proximal esophageal acid contact times. In addition, the severity of asthma was found to be directly proportional to the amount of esophageal acid. In another study, 79% of asthma symptoms during 24-h pH-metry were temporally associated with esophageal acid.¹⁵ Patients with asthma may be predisposed to GER because of a high incidence of hiatal hernia.¹⁶ Conversely, patients with esophagitis or esophageal strictures have a high likelihood of having asthma.⁶ Although asthma may be clinically silent in up to 62% of patients,¹⁷ another study reported that 57% of patients with asthma complained of heartburn, 37% complained of regurgitation, 24% reported dysphagia, and 41% noted reflux associated with respiratory symptoms and inhaler use.¹⁸ Furthermore, the presence of heartburn was found to be associated with a higher rate of future asthma hospitalizations.¹⁹ Medical²⁰ and surgical²¹ therapies for GER have been shown to improve asthma symptoms, reduce asthma medication use, and increase pulmonary function.

Patients with COPD were found to have a higher incidence of heartburn and dysphagia and were more likely to use GER medications than matched control individuals.²² Twenty-six percent of respiratory symptoms in patients with COPD and GER were reported to be associated with GER symptoms, and GER symptoms were more prevalent in the patients with a FEV₁<50% predicted.²²

GER is also associated with bronchiectasis, particularly in patients with cystic fibrosis (CF). The prevalence of GER in CF has been reported to be as high as 80 to 94%,²³ and a correlation between lung function and esophageal function has been demonstrated.²⁴ Tracheal acidification during episodes of GER has also been demonstrated in CF patients,²³ leading to the hypothesis that microaspiration may contribute to the deterioration of lung function or result in exacerbations. Furthermore, in a small cohort of patients, fundoplication resulted in a 92% reduction in hospital days for CF exacerbations.²⁵

GER and Interstitial Lung Disease

In both animal models and humans, pulmonary fibrosis may occur after the aspiration of gastric contents. In a study using 24-h pH-metry, patients with idiopathic pulmonary fibrosis (IPF) had a greater percentage of total acid contact time and a greater percentage of proximal acid contact time than matched controls.²⁶ Twenty-five percent of the IPF patients with GER did not have the “typical” symptoms associated with GER.²⁶ Patients with IPF are more likely to have a hiatal hernia than age-matched control subjects,²⁷ and an association between erosive esophagitis and pulmonary fibrosis has been demonstrated.²⁷ Although a correlation between GER and lung function in IPF has not been found, multiple studies of scleroderma interstitial lung disease do show an inverse correlation between lung function and GER.^28-30

GER and Allograft Dysfunction

Based on two small case series^31,32 and one case report,³³ more transplant physicians are evaluating their lung transplant patients for GER either pre- or postoperatively because of the concern that GER may be linked to chronic rejection. Five out of 11 heart-lung transplant recipients had chronic cough, bronchiectasis, and decreased gastric emptying with aspiration.³¹ Three of these five patients had obliterative bronchiolitis and four improved with treatment. In the other case series, obliterative bronchiolitis developed in four of nine transplant patients with documented gastroparesis.³² In a case report involving a repeat transplant patient, there was an improvement in lung function and bronchial inflammation after fundoplication.³³

GER and Sleep

During sleep, gastric motility and emptying are decreased, and basal acid output is increased in the late evening hours. Sleep also results in marked prolongation of acid-clearance times secondary to suppression of swallowing and cough reflexes, decreased salivary flow, and the suppression of arousal mechanisms. The upper esophageal sphincter pressure is greatly reduced during sleep and nocturnal aspiration of pharyngeal secretions is common.³⁴ Seventy-five percent of patients with heartburn complain of sleep disruption and as a result, the majority of these patients have excessive daytime somnolence. Sleep studies in conjunction with 24-h pH-metry have shown that GER results in awakenings and sleep fragmentation. There is also a strong relationship between respiratory symptoms (wheeze, cough) and sleep-related GER and heartburn.³⁴ Patients with obstructive sleep apnea have been shown to have more reflux episodes, a greater percentage of acid-contact time, and a reduced clearance of the esophagus compared with control individuals matched for age, sex, and body mass index. When treated with continuous positive airway pressure, both groups of patients had a significant improvement in all parameters.³⁴

GER and Exercise

Exercise, particularly high-impact aerobics, may induce GER in patients without regular symptoms of GER.³⁵ Exertional GER accounted for 43% of chest pain symptoms in patients who were believed to have angina but were found to have normal coronary arteries,³⁶ and 46% of patients with chest pain and normal coronary arteries had abnormal 24-h pH-metry findings.³⁷

GER and Smoking

Smoking is a predisposing factor for GER; smoking may result in decreased LES tone, and deep inspiration and cough may result in increased transdiaphragmatic pressure.³⁸ In one study, the percentage of time when pH was <4.0 was significantly greater while smoking³⁹; another study demonstrated that heartburn episodes were significantly increased in patients after the resumption of smoking.⁴⁰

Treatment of GER

GER is a chronic condition that may wax and wane in intensity, and relapses are common; therefore, most patients require long-term therapy. Medical or surgical treatment must be adjunctive to dietary and lifestyle modifications (Table 2). Medical therapy may include prokinetic drugs, H₂As, and PPIs, either alone or in combination.

Table 2. Dietary/Lifestyle Modifications for Patients With GER

The prokinetic drugs include bethanechol, metoclopramide, and cisapride. Bethanechol is a cholinergic antagonist that causes increased LES pressure, peristalsis, and salivary flow. However, this agent is contraindicated in patients with asthma. Metoclopramide is a dopamine antagonist that may improve gastric emptying but is associated with extrapyramidal side effects. Cisapride has been taken off the market because of significant drug-drug interactions leading to dysrhythmias. However, it is available through compassionate release.⁴¹

The H₂As are all equally effective. For GER, they should be dosed 2 to 4 times per day. GER treatment, in general, requires higher doses than peptic ulcer disease therapy. In addition, esophagitis healing rates are estimated to be <60%. For severe GER, H₂As may be combined with a prokinetic agent or changed to or added to a PPI.⁴²

The PPIs diminish acid secretion by inhibiting the H-K+ ATPase pump. They are superior to high-dose H₂As and have an 80% esophagitis healing rate within 8 weeks. Typically, the PPIs abolish symptoms of GER in most patients within 2 weeks.⁴³ There is no clinical evidence for carcinogenesis, iron deficiency anemia, or B12 deficiency with prolonged use of PPIs.⁴⁴

Fundoplication may be performed through an open, laparoscopic, or endoscopic approach and should be considered when medical treatment fails (Table 3).

Table 3. Potential Causes of Gastroesophageal Treatment Failures

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