Key points

Introduction

Gastroesophageal reflux disease (GERD) is an acid-based disorder that presents with a wide spectrum of symptoms. In 2006, the modified Delphi process was used to define GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.” Historically, GERD is defined as primary complaints of heartburn and regurgitation ; however, it is now recognized that a range of extraesophageal symptoms may be its sole or accompanying manifestation. For example, chronic cough, asthma, posterior laryngitis, and dental erosion are but a few extraesophageal manifestations of GERD ( Fig. 1 ). Extraesophageal reflux (EER) symptoms can occur concomitantly with or without typical GERD symptoms, which in the latter may delay the diagnosis of reflux as a potential etiologic factor. The prevalence of reflux disease is increasing around the world, with Western Europe, North America, and South America having the highest prevalence rates of approximately 20% to 40%. GERD has become an important public health issue owing to the considerable health care resources used to treat it. The annual direct cost of GERD management is cited at $971 per patient in the United States, with national expenditures ranging from $9.3 billion to $12.1 billion. More concerning are the recent data showing that the cost of caring for patients with EER is 5 times that of GERD, at nearly $50 billion ( Fig. 2 ).

Esophageal and extraesophageal syndromes.

Comparison of estimated economic burden of initial evaluation of extraesophageal reflux (EER) with that of typical GERD, cancer, and heart disease.

The pathophysiologic consequence of reflux in patients with EER symptoms affects both upper and lower respiratory systems, including asthma, chronic cough, hoarseness, otitis media, atypical loss of dental enamel, idiopathic pulmonary fibrosis, recurrent pneumonia, chronic bronchitis, and even sudden infant death syndrome. Two responsible mechanisms comprise direct (aspiration) and indirect (vagally mediated) ( Fig. 3 ).

Reflux and reflex pathophysiologic mechanisms in extraesophageal manifestations of GERD.

The direct mechanism involves aspirate that directly stimulates the pharynx or larynx, causing a tracheal or bronchial cough reflex. The presence of an intact lower esophageal sphincter (LES) and upper esophageal sphincter (UES) barrier usually prevents gastroesophagopharyngeal reflux. Although the LES is frequently breached by gastric contents in both physiologic and pathophysiologic states, the high basal pressure of the UES usually prevents pharyngeal and laryngeal contact with refluxate. Furthermore, the UES pressure is augmented when distal reflux results in increased intraesophageal pressure. The pharynx and upper airway are further protected by the esophagoglottic closure reflex, which protects the airway from contact with proximal refluxate. In addition, swallowing or cough functions to clear refluxate that does breach the UES. These and other physiologic protective mechanisms usually prevent refluxate from violating the pharyngeal and laryngeal space and thereby causing symptoms and tissue damage. Perturbation of any of these, or other less or currently unknown protective mechanisms, could possibly account for the production of pulmonary, laryngeal, pharyngeal, or other extraesophageal symptoms of reflux disease.

The second mechanism involves distal esophageal reflux that produces a cough response by a vagally mediated process (see Fig. 3 ). Given that the esophagus and bronchial tree share a common embryonic origin, it is not surprising that they also share a common neural innervation. Acidification of the distal esophagus can stimulate acid-sensitive receptors that may result in cardiac-type chest pain or interact with pulmonary bronchi and other upper airway structures via a vagally mediated arc. Further, reflux-related chronic cough has been linked to changes in the chronic pressure gradient between the abdominal and thoracic cavities during the act of coughing, leading to a positive feedback cycle between reflux and coughing symptoms. It is currently unknown if gastric acid, duodenal contents, microbial contamination, or some combination of the 3 cause the worsening symptoms in those with extraesophageal manifestations of GERD. Aspiration of gastric acid or duodenal contents has been shown to cause damage to the larynx, pharynx, and lung, and certainly microbial contamination of aspirated contents can cause pulmonary symptoms. Patients receiving immunosuppressive regimens may be particularly susceptible to such damage.

This review discusses the current state of knowledge regarding the relationship between GERD and pulmonary and ear/nose/throat (ENT) manifestations of reflux, and outlines recent developments in the diagnostic and treatment strategies for this difficult group of patients.

Introduction

Gastroesophageal reflux disease (GERD) is an acid-based disorder that presents with a wide spectrum of symptoms. In 2006, the modified Delphi process was used to define GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.” Historically, GERD is defined as primary complaints of heartburn and regurgitation ; however, it is now recognized that a range of extraesophageal symptoms may be its sole or accompanying manifestation. For example, chronic cough, asthma, posterior laryngitis, and dental erosion are but a few extraesophageal manifestations of GERD ( Fig. 1 ). Extraesophageal reflux (EER) symptoms can occur concomitantly with or without typical GERD symptoms, which in the latter may delay the diagnosis of reflux as a potential etiologic factor. The prevalence of reflux disease is increasing around the world, with Western Europe, North America, and South America having the highest prevalence rates of approximately 20% to 40%. GERD has become an important public health issue owing to the considerable health care resources used to treat it. The annual direct cost of GERD management is cited at $971 per patient in the United States, with national expenditures ranging from $9.3 billion to $12.1 billion. More concerning are the recent data showing that the cost of caring for patients with EER is 5 times that of GERD, at nearly $50 billion ( Fig. 2 ).

Esophageal and extraesophageal syndromes.

Comparison of estimated economic burden of initial evaluation of extraesophageal reflux (EER) with that of typical GERD, cancer, and heart disease.

The pathophysiologic consequence of reflux in patients with EER symptoms affects both upper and lower respiratory systems, including asthma, chronic cough, hoarseness, otitis media, atypical loss of dental enamel, idiopathic pulmonary fibrosis, recurrent pneumonia, chronic bronchitis, and even sudden infant death syndrome. Two responsible mechanisms comprise direct (aspiration) and indirect (vagally mediated) ( Fig. 3 ).

Reflux and reflex pathophysiologic mechanisms in extraesophageal manifestations of GERD.

The direct mechanism involves aspirate that directly stimulates the pharynx or larynx, causing a tracheal or bronchial cough reflex. The presence of an intact lower esophageal sphincter (LES) and upper esophageal sphincter (UES) barrier usually prevents gastroesophagopharyngeal reflux. Although the LES is frequently breached by gastric contents in both physiologic and pathophysiologic states, the high basal pressure of the UES usually prevents pharyngeal and laryngeal contact with refluxate. Furthermore, the UES pressure is augmented when distal reflux results in increased intraesophageal pressure. The pharynx and upper airway are further protected by the esophagoglottic closure reflex, which protects the airway from contact with proximal refluxate. In addition, swallowing or cough functions to clear refluxate that does breach the UES. These and other physiologic protective mechanisms usually prevent refluxate from violating the pharyngeal and laryngeal space and thereby causing symptoms and tissue damage. Perturbation of any of these, or other less or currently unknown protective mechanisms, could possibly account for the production of pulmonary, laryngeal, pharyngeal, or other extraesophageal symptoms of reflux disease.

The second mechanism involves distal esophageal reflux that produces a cough response by a vagally mediated process (see Fig. 3 ). Given that the esophagus and bronchial tree share a common embryonic origin, it is not surprising that they also share a common neural innervation. Acidification of the distal esophagus can stimulate acid-sensitive receptors that may result in cardiac-type chest pain or interact with pulmonary bronchi and other upper airway structures via a vagally mediated arc. Further, reflux-related chronic cough has been linked to changes in the chronic pressure gradient between the abdominal and thoracic cavities during the act of coughing, leading to a positive feedback cycle between reflux and coughing symptoms. It is currently unknown if gastric acid, duodenal contents, microbial contamination, or some combination of the 3 cause the worsening symptoms in those with extraesophageal manifestations of GERD. Aspiration of gastric acid or duodenal contents has been shown to cause damage to the larynx, pharynx, and lung, and certainly microbial contamination of aspirated contents can cause pulmonary symptoms. Patients receiving immunosuppressive regimens may be particularly susceptible to such damage.

This review discusses the current state of knowledge regarding the relationship between GERD and pulmonary and ear/nose/throat (ENT) manifestations of reflux, and outlines recent developments in the diagnostic and treatment strategies for this difficult group of patients.

Reflux cough syndrome

In nonsmoking patients with normal chest radiographs who are not taking angiotensin-converting enzyme (ACE) inhibitors, some of the most common causes of chronic cough are postnasal drip syndrome, asthma, chronic bronchitis, and gastroesophageal reflux ( Fig. 4 ). These 4 conditions may represent up to 90% of all cases of chronic cough, defined as cough lasting longer than 8 weeks. Reflux cough syndrome has a well-established association with GERD. Large population-based surveys demonstrate an increased risk of chronic cough among patients with reflux symptoms or esophagitis. Chronic cough and bronchitis are documented symptoms in 30% to 50% of patients suffering from GERD. Similarly, other studies have shown a high prevalence of objective signs of GERD in patients with chronic cough. In a retrospective analysis of pH-monitoring results, pathologic esophageal acid exposure was demonstrated in 52% of patients with chronic cough. Poe and Kallay concluded that GERD alone accounted for cough in 13% of their study population while in 56% of patients it was a contributing factor to chronic cough.

GERD is the third most common cause of chronic cough after asthma and postnasal drainage (PND). These 3 causes can account for 86% of all etiology for chronic cough, and often multiple causes exist in a given patient. BRONCHIECT, bronchiectasis; MISC, miscellaneous.

Reflux cough syndrome may essentially be considered a diagnosis of exclusion. As such, the 2 other common causes of chronic cough, asthma and postnasal drip syndrome (PDS), must be initially ruled out. According to Irwin, the evaluation of chronic cough begins with patients with normal chest radiographs and who are not taking ACE inhibitors so as to avoid their confounding influence. It is surprisingly common to find patients with chronic cough who are referred to gastroenterology for evaluation of GERD who continue to be on ACE inhibitors. Thus, this important cause of chronic cough must be explored in every patient presenting with the condition. In addition, the authors strongly recommend identification and treatment of all potential contributing factors because reflux therapy alone may not be adequate in achieving symptom resolution in this group of patients.

One complexity in attributing reflux as a contributing etiologic factor in chronic cough is that many patients do not exhibit the classic symptoms of GERD. In fact, Ing and colleagues reported that up to 75% of patients with reflux cough syndrome may not exhibit regurgitation or heartburn. Similarly, Poe and Kallay found that 43% of their sample population exhibited no GERD symptoms at all. Another study by Everett and Morice found that nearly 40% of patients presenting with chronic cough did not report typical symptoms of reflux. Therefore, lack of concomitant typical reflux symptoms cannot be used to exclude GERD as a potential cause in patients with chronic cough.

Further complicating the diagnosis of reflux cough syndrome is the low sensitivity of common diagnostic tests for GERD, including esophagogastroduodenoscopy (EGD) and pH monitoring. Typically, EGD is used to evaluate for the presence of esophagitis and other mucosal irregularities associated with GERD, including Barrett’s esophagus. However, esophagitis is a diagnosis of low prevalence in this group of patients and its presence is not causally linked to chronic cough, thus making EGD a poor diagnostic tool for reflux cough syndrome. For example, in the study by Baldi and colleagues of 45 patients with chronic cough evaluated using EGD, 55% of the study group complained of classic reflux symptoms, whereas only 15% had EGD-proven esophagitis.

Ambulatory 24-hour esophageal pH monitoring was previously considered to be the gold standard for diagnosing GERD. However, in patients with chronic cough its specificity is as low as 66%. pH monitoring in such patients has also been used to correlate reflux episodes with coughing fits. Using this technique, Baldi and colleagues found that in their population of patients with chronic cough, 53% had pathologic reflux correlating with cough fits. However, compared with less invasive tests such as empiric proton-pump inhibitor (PPI) therapy, esophageal pH monitoring is found to have low diagnostic gain. For example, Ours and colleagues found that pH monitoring was not a reliable predictor of acid reflux–induced chronic cough because only 35% of patients in their study population with abnormal pH monitoring responded to PPI therapy. One important advantage of pH monitoring in chronic cough may be the ability to correlate esophageal reflux episodes with cough symptoms by using the 2 most commonly used indices, symptom index (SI) or symptom association probability (SAP). However, a recent study by Slaughter and colleagues concluded that both SI and SAP indices can be overinterpreted and are prone to misinterpretation. The investigators suggested that unless patients with GERD refractory to PPI therapy have high rates of esophageal acid exposure, both SI and SAP accuracy are essentially chance occurrences at best. Furthermore, using ambulatory acoustic monitoring it was recently reported that up to 71% to 91% of patients do not accurately report their cough events ( Fig. 5 ), which further reduces the enthusiasm regarding the use of symptom indices in pH monitoring. Another study using an acoustic cough monitoring device showed that cough temporally associates with reflux irrespective of proposed diagnoses and that it may be self-perpetuating in some patients, likely because of central processes and not just reflux. Thus, given the low predictive value of pH testing, lack of reliability of symptom-association probability, and temporal association, which may not be causal, pH testing in patients with chronic cough may be problematic.

( A ) Positioning of the acoustic cough sensors in the chest wall and neck. Cough events were detected via phonopneumography sensors positioned at 2 sites: to the right of the trachea at the midpoint between the Adam’s apple and the substernal notch, and at the midclavicular line in the second intercostal space. An ambient microphone was affixed to the patient’s shirt collar. ( B ) Box-plot illustration of the median (interquartile range) percentage of cough events missed by the individual subjects compared with the audio recording by 1-, 2-, and 5-minute time windows. Patients did not report 91%, 82%, and 71% of cough events detected by audio recording within 1, 2, and 5 minutes of those detected by audio recording, respectively.

In patients with chronic cough suspected to be GERD related, most experts recommend empiric PPI therapy, often with twice-daily dosing. This recommendation is based solely on open-label trials, and placebo-controlled studies do not support a benefit to PPI therapy in this group. For example, Poe and Kallay diagnosed 79% of patients with cough secondary to GERD, with resolution of symptoms after an empiric trial of PPI therapy. A recent study by Baldi and colleagues suggested that once-daily PPI therapy may be similar to twice-daily therapy. However, a meta-analysis of 5 placebo-controlled studies in adult patients with chronic cough found insufficient evidence in favor of PPI therapy. In agreement with the conclusions of this meta-analysis, most recently 2 additional randomized controlled studies did not find any benefit to PPI therapy in comparison with placebo in adult subjects with chronic cough. Taken together, these studies suggest the uncertainty of association between chronic cough and GERD, most likely attributable to poor diagnostic tests leading to inappropriate patient selection in the controlled studies. Nevertheless, a short course of PPI therapy is a reasonable initial approach. A positive response to initial empiric PPI therapy is the best indicator for eventual resolution. However, it is important that the patient response is assessed shortly after initiation of PPI therapy to avoid prolonged use of such therapies. A recent cost analysis of subjects with chronic cough found that the most costly aspect of evaluation and treatment of this group of patients is the prolonged, often unnecessary, use of PPI therapy at high doses. With respect to the role of surgical fundoplication, the authors recently showed that the response to surgical intervention of patients with chronic cough may be dependent on the concomitant presence at baseline of typical symptoms of GERD (heartburn and regurgitation).

In recent years, the term sensory neuropathic cough has been used to describe patients with recalcitrant cough after excluding other causes including GERD. This condition seems to result from a lowered response threshold to stimuli, just as in post-herpetic neuralgic pain, and does not respond to the usual therapies including PPIs. It is sudden and comes in attacks, and can be triggered by a factor such as eating, talking, or deep breathing. It can result in oculorrhea and rhinorrhea, vomiting, laryngospasm, and syncope or near-syncope. It is estimated that up to 31% of patients with chronic cough may have sensory neuropathic cough. Recent study suggested symptomatic improvement of this type of cough with gabapentin. Thus, in patients with chronic cough in whom other causes are excluded, there may be some benefit in off-label use of neuromodulator medications such as amitriptyline (10 mg/d), gabapentin (100–900 mg/d), and pregabalin (150 mg, twice a day maximum). Amitriptyline is a tricyclic antidepressant. Pregabalin and gabapentin are very similar in structure, and are analogues of γ-aminobutyric acid (GABA). These agents do not bind to GABA _A or GABA _B ; instead they bind to the subunits on presynaptic calcium channels, and decrease the release of the neurotransmitters glutamate, noradrenaline, and substance P.

In conclusion, a systematic approach with an anatomy-based protocol should be followed in diagnosing the cause of chronic cough. Common causes including medication (ACE inhibitors), postnasal drip, and asthma must be excluded. In those with concomitant heartburn and/or regurgitation or those with high degree of suspicion for GERD, an empiric trial of PPI therapy for 1 to 2 months is a reasonable approach. EGD and 24-hour esophageal pH and/or impedance monitoring should be reserved for patients in whom GERD is still suspected and for whom treatment does not eliminate the cough. In this group, complete lack of response to PPI therapy may be an indicator that causes other than GERD should be sought. Such causes include other lung-related diseases as well as sensory neuropathic cough.

Reflux asthma syndrome

Based on pH probe monitoring, gastroesophageal reflux disease is present in up to 80% of asthmatic patients and often occurs without gastrointestinal symptoms. The triggers that incite an inflammatory response can also exacerbate asthma, which is made possible because the esophagus and lung share embryonic origins that may permit complex interactions. For instance, acid-induced bronchoconstriction can be provoked by a vagally mediated reflex, neural enhanced bronchial reactivity, or microaspiration. Neurogenic inflammation in the lung may occur with either vagally mediated mechanisms or with microaspiration. These findings lend biological plausibility to the theory that GERD may induce asthma symptoms either by direct effects on airway hyperresponsiveness or via aspiration-induced inflammation. Conversely, bronchoconstriction seen in asthma may induce acid reflux. Lung hyperinflation in asthmatic patients increases the pressure gradient between the abdomen and chest and may cause the LES to herniate into the chest, where its barrier function is impaired.

A significant portion of patients with asthma also exhibit typical symptoms of GER, such as heartburn and regurgitation ( Fig. 6 ). However, as in those with chronic cough, lack of the classic symptoms does not rule out physiologic acid reflux. Havemann and colleagues found that the average prevalence of GERD in asthma was 59.2%, a potential underestimation because many patients may not exhibit typical symptoms of reflux. Another study by Kiljander and colleagues found that 35% of asthma patients in their study did not have typical reflux symptoms, but were instead found to have reflux by 24-hour esophageal pH monitoring.

Asthma and GERD may exacerbate each other. GERD may induce bronchospasm and asthma may induce GERD. Breaking the cycle by aggressively treating both is the key to improvement of patients’ symptoms.

Ambulatory pH monitoring has been used to assess reflux and its association with asthma. Meier and colleagues concluded that 50% of their patients with asthma had abnormal esophageal pH parameters. Similarly, Kiljander and colleagues found 53% of patients with asthma had pathologic GER diagnosed by ambulatory pH monitoring. Furthermore, 35% of these patients did not have typical reflux symptoms of heartburn and regurgitation. In 2005, Leggett and colleagues evaluated GER in patients with difficult-to-control asthma by dual 24-hour ambulatory pH probes configured with both distal and proximal probes. The prevalence of reflux at the distal and proximal probes was 55% and 35%, respectively. In 2007, Havemann and colleagues reviewed the association between GER and asthma and estimated the prevalence of abnormal acid exposure diagnosed by pH monitoring to be 51%. However, given the less than optimal sensitivity of pH monitoring, its use is often confined to those who continue to be symptomatic despite therapy.

As is the case for most EER conditions, there is controversy regarding the benefit of PPI use in patients suspected of having reflux-induced asthma. Studies have used different end points regarding efficacy of acid-suppressive therapy in this group. Some use objective measurements such as improvement in forced expiratory volume in 1 second (FEV ₁ ), whereas others rely on patient-reported questionnaires or decreasing need for asthma medications. Early trials reported improvements in pulmonary symptoms and pulmonary function in patients treated with acid-suppressive therapy. In 1994, Meier and colleagues conducted a double-blind, placebo-controlled crossover study, which evaluated pulmonary function of asthma patients treated with 20 mg of omeprazole twice a day for 6 weeks. This study found that 27% (4 of 15) patients with reflux had a 20% or greater increase in FEV ₁ .

In another study, Sontag and colleagues evaluated 62 patients with both GERD and asthma, and divided the group into 3 treatment arms: control, treatment of reflux with ranitidine 150 mg 3 times a day, or surgical treatment with Nissen fundoplication. After a 2-year follow-up, 75% of surgical patients had improvement in nocturnal asthma exacerbations, compared with 9.1% and 4.2% of patients on medical therapy and controls, respectively. In addition, there was a statistically significant improvement in mean asthma symptom score, but no improvement in pulmonary function or reduction in the need for medication between the groups. Littner and colleagues followed 207 patients with symptomatic reflux who were treated with either placebo or a PPI twice a day for 24 weeks. The primary outcome of the study was daily asthma symptoms by patient diary, and secondary outcomes included the need for rescue albuterol inhaler use, pulmonary function, asthma quality of life, investigator-assessed asthma symptoms, and asthma exacerbations. The study showed that medical treatment of reflux did not reduce daily asthma symptoms or albuterol use and did not improve pulmonary function in this group of asthmatic patients. Similarly, a study conducted by the American Lung Association Asthma Clinical Research Center randomized 412 patients with poor asthma control to either esomeprazole 40 mg twice daily or placebo. After 24 weeks of follow-up, no treatment benefit was shown by PPI therapy in asthma control. Most recently, a randomized controlled trial in children with asthma without overt GERD did not show a benefit of lansoprazole in improvement of symptoms or lung function. A Cochrane review of therapy for GERD patients with asthma found only minimal improvement of asthma symptoms with reflux therapy. Encouragingly, a recent controlled trial in asthmatics suggested a therapeutic benefit of PPIs in the subgroup of asthmatics with both nocturnal respiratory and GERD symptoms. Thus, the issue of asthma control by treating reflux in patients who have asthma is not yet clear.

Therefore, the current recommendation in patients with asthma (with or without concomitant heartburn or regurgitation) is similar to that for patients with chronic cough and laryngitis, suggesting the initial empiric trial of once- or twice-daily PPIs for 2 to 3 months. In those responsive to therapy for both heartburn and/or asthma symptoms, PPIs should be tapered to the minimal dose necessary to control symptoms. In unresponsive patients, testing for reflux, by pH testing and/or impedance/pH monitoring, may be needed to measure for continued reflux of acid or nonacid material, or, more commonly, to exclude reflux as the cause of patients’ continued symptoms.