GERD refers to a disease process caused by GER and manifested by symptoms and physical cellular tissue damage.⁶ These symptoms include postprandial heartburn, supine reflux, choking spells at night, regurgitation, taste of acid in the mouth, heartburn, halitosis, retrosternal chest pain, vomiting, and tooth enamel degradation.⁷ GER-related symptoms such as heartburn, regurgitation, and dysphagia are incredibly common, and were found to be present in almost 60% of patients in a recent population-based study.⁸ It is also critically important to remember that the diagnosis of GERD alone does not establish a causal relationship between reflux and chronic cough. The establishment of a GERD-related cause of cough requires at least some assessment of the temporal relationship between reflux episodes and cough bursts.⁹ LPR, however, may not always have direct symptom correlation with reflux events and a cough as has been shown in post-antireflux surgery patients diagnosed with the newest impedance technology.

PREVALENCE OF GERD AS A CAUSE OF COUGH

Cough represents a complex protective reflex that requires an elegant coordination of sensory input, respiratory function, and muscle action in response to noxious stimuli. When looking broadly at causes of chronic cough in patients referred to otolaryngologists, postnasal drip, asthma, and GERD were the cause of cough in 86% of patients. This increased to 99.4% of patients when considering those who were immunocompetent nonsmokers who were also not on ACE inhibitor therapy.¹⁰ It is certainly appropriate and worthwhile to have a pulmonologist evaluate the patient for intrinsic lung pathology such as asthma, COPD, and nonasthmatic eosinophilic bronchitis prior to considering GERD as the sole cause of the patient’s chronic cough.^{11, 12} In 2016, the journal Chest released updated chronic cough care guidelines and an expert panel report that proposed a clinical profile for a patient with chronic cough that was likely due to GER even without concomitant GI symptoms.¹³ There is no question that GERD and LPR have been overly diagnosed as the primary etiology for challenging cough cases over the last 20 years. Studies have shown that most patients with unexplained chronic cough tested for reflux with dual pH impedance testing do not actually demonstrate pathologic proximal or distal reflux events on dual pH impedance testing.¹ This, however, may be called into question as more research is done using impedance catheters that traverse the upper esophageal sphincter and as pathologic hypopharyngeal reflux events are more well defined.

While a small number of patients may present with silent nonacid reflux as a cause of chronic cough, several studies have shown that the vast majority of patients with reflux-related chronic cough are more likely to present with classic heartburn symptoms. Patients with heartburn are also more likely to respond to proton-pump inhibitor medications for treatment, prompting the latest revisions in the 2016 Chest cough guidelines recommending against empiric PPI trials for cough patients.13 It is therefore our opinion, based on the currently available data, that reflux is a relatively rare but important cause of chronic cough symptomatology. That being the case, the most difficult cases of refractory cough can be due to undiagnosed nonacid reflux, and when patients present to quaternary referral centers, this should be thoroughly evaluated. This is discussed in detail in Chapter 9.

MECHANISMS OF COUGH STIMULATION BY REFLUX

The cough reflex is a complicated mechanism under voluntary and involuntary control mediated by C fibers and pulmonary stretch muscles of the tracheobronchial tree. More recently, afferent vagal fibers innervating the esophagus and upper aerodigestive tract have been shown to be present and involved in the cough reflex. There is a convergence of these vagal afferents at sites of brainstem integration at the nucleus tractus solitarius of the medulla, which has been shown to be intimately involved in the cough reflex.^{14, 15} GERD can stimulate the afferent limb of the cough reflex by irritating the upper aerodigestive tract and larynx with gastric contents. Microaspiration or macroaspiration can also irritate the lower respiratory tract, leading to chronic recurrent coughing episodes.¹⁶ There is also strong evidence to support that acid in the esophagus alone is enough to stimulate an esophageal-tracheobronchial cough reflex. A study by Harding et al found episodic chronic cough to have a temporal relationship with acid exposure in the distal esophagus and not proximal aid exposure.¹⁰ Ninety percent of patients with GERD-related cough had coughing within 5 minutes of a reflux event seen on a pH probe placed at the lower esophageal sphincter. Thus, even gastric refluxate into the distal esophagus alone can lead to a sufficient stimulus to trigger a coughing event, and this is in fact a relatively common mechanism for GERD-related chronic cough in symptomatic patients. Coughing alone can also induce GER episodes through increased intra-abdominal pressure, and a cough-GER self-perpetuating cycle may be involved in the pathophysiology of a patient’s chronic cough.¹⁷

DIAGNOSIS OF REFLUX

Clinical Presentation and Initial Evaluation

GERD-related cough is difficult to clinically characterize, as cough presentation can be incredibly variable.¹⁸ Most patients with cough related to reflux have a dry, nonproductive cough. Patients with comorbid pulmonary disease such as bronchiectasis or chronic bronchitis may conversely present with mixed or even frankly productive cough, and having these comorbidities does not rule out the contribution of LPR. A general evaluation of cough is appropriate prior to consideration of reflux as a cause. This evaluation should include the following:19

■ Current or heavy prior tobacco use may obviate further testing for cause aside from appropriate pulmonary consultation and evaluation.

■ Medications that can cause cough such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be held for a trial period.

■ Chest x-ray or computed tomography (CT) should be performed in all patients with cough for more than 4 weeks. Low-dose lung cancer screening CT may also be considered for appropriate patients.

■ Common pulmonary causes of cough such as cough-variant asthma or nonasthmatic eosinophilic bronchitis should be ruled out with pulmonary function testing with methacholine challenge, sputum studies, and possible bronchoscopy with bronchoalveolar lavage. Many authors would further suggest a trial of several weeks of inhaled corticosteroid.

■ Allergies and sinusitis have been properly evaluated and trials of appropriate medications have been performed to rule out upper airway cough syndrome (UACS).

Patients with pathologic reflux may be clinically “silent” up to 75% of the time, meaning overt GERD-related symptoms may be absent. Many of these patients may have esophageal hypersensitivity with referred laryngeal irritation. However, chronic cough due to reflux should always be considered seriously with concurrent GERD-related symptoms of frequent heartburn and regurgitation.

ENDOSCOPY

Endoscopic evaluation of the larynx has traditionally been used to examine for the standard laryngeal harbingers of LPR. These include edema of the supraglottic structures and pharyngeal walls, posterior laryngeal pachydermia (“piled up” interarytenoid mucosa), diffuse laryngeal erythema, ventricular obliteration, laryngeal pseudosulcus (a linear furrow in the anteroposterior plane of the true vocal fold that appears due to inferior true vocal fold swelling and is not a true scar/sulcus vocalis), and thickened laryngeal secretions. It is imperative that physicians not assume inflammatory laryngeal changes are specific solely to GERD. These findings are associative at best, and are generalized signs of laryngeal inflammation that could be from many potential other sources including obstructive sleep apnea, laryngeal allergy, or even systemic diseases such as sarcoidosis or amyloidosis.20

The initial diagnostic test of choice for GER evaluation from the gastroenterology perspective is traditionally esophagogastroduodenoscopy (EGD) with biopsy to evaluate for inflammation or dysplasia. Patients with reflux esophagitis often will present with endoscopic and/or histopathologic changes indicative of ongoing esophageal mucosal injury and inflammation. The presence of these typical findings of reflux esophagitis on EGD may have a specificity as high as 97%. EGD can unfortunately be negative in up to 50% of patients with reflux symptoms, with findings therefore suggestive of nonerosive reflux disease.²¹ Severity of GERD symptom presentation correlates poorly with the degree of underlying esophageal damage on EGD biopsies, likely due to the ability of the esophageal mucosa to tolerate insult and heal rapidly once injured. Many patients with significant LPR/GERD-related symptoms may in fact suffer from esophageal motility disorders and may benefit from further testing with high-resolution manometry (HRM). HRM can detect altered esophageal peristalsis, esophageal sphincter incompetence, and neurologic injury, and may further be combined with esophageal impedance to detect bolus passage and regurgitation.

Laryngeal endoscopy and videostroboscopy facilitate the detection of other causes of dysphonia, globus, or throat clearing due to glottic insufficiency and should be performed on all patients with chronic cough to rule out other organic sources of laryngeal irritation. Most recent research in the field of LPR has used survey-based instruments to establish an LPR clinical diagnosis, a process that is uncertain at best. Patient-based survey instruments such as the RSI and endoscopic reflux severity indexes such as the RFS are fraught with deep variability due to the vague nature of traditional LPR patient complaints and the overlap of these symptoms with other possibly confounding conditions.²² The RFS in particular is often used in clinical practice by the general otolaryngology community to infer reflux-related damage to the laryngopharynx by the potential association of reflux with laryngeal edema, erythema, and thickened secretions. Studies have shown that laryngeal endoscopy may be suggestive of ongoing reflux but is far from a certain association due to the myriad other causes of these nonspecific laryngeal findings.

OBJECTIVE REFLUX TESTING

This intrinsic challenge in establishing an appropriate diagnosis for the patient with suspected LPR on endoscopy alone often necessitates further objective testing in many patients, particularly when symptoms are severe or surgical intervention is being considered. There is no single standardized approach to objective reflux testing in clinical practice. Several testing options are currently utilized in the otolaryngology and gastroenterology communities, each with specific benefits and controversies for evaluation of chronic cough. We feel strongly that objective reflux testing for the patient with suspected LPR should include proximal esophageal and pharyngeal impedance data if possible. Many patients can demonstrate physiologic distal esophageal reflux but have extensive proximal excursion of reflux boluses, which would be overlooked with testing modalities that only evaluate distal esophageal reflux. Multichannel intraluminal impedance with dual pH (MII-pH) probe testing provides the most useful data in this regard in our estimation. MII-pH probes include dual pH sensors located in the distal esophagus and proximal esophagus or hypopharynx, depending on probe selection and placement. These probes also include paired impedance arrays straddling the distal pH sensor and a third set in the proximal esophagus, which allows for detection of anterograde and retrograde bolus transit. New impedance/pH probes have specifically been designed for use in the LPR patient to assess proximal acid and nonacid reflux in this regard, such as the ComforTec LPR probe array (Diversatek, Milwaukee, WI, USA). The term HEMII-pH probes will be used to describe the LPR probes due to the hypopharyngeal-esophageal multichannel intraluminal impedance and dual pH nature of the catheter. This term is used and referenced later in this book (see Chapter 9). These studies allow for determination of a DeMeester score for evaluation of traditional GERD, and facilitate the study of symptom association with both distal and proximal reflux events. There continues to be significant controversy in the interpretation of proximal esophageal impedance data in the literature due to varying probe array utilization and placement, but most studies support that frequent proximal esophageal and hypopharyngeal reflux events are abnormal in healthy adult patients.^{23, 24}

The standard approach to LPR evaluation in the gastroenterology clinic is via EGD and placement of a single distal esophageal wireless capsule-based sensor for pH evaluation (such as the Bravo reflux testing system, Medtronic, Minneapolis, MN, USA). These wireless systems are well tolerated by the patient, and provide excellent data for evaluation of traditional GERD, including calculation of a DeMeester score. Current recommendations from the gastroenterology literature support the use of these ambulatory pH testing systems for all patients with classic GERD. They do not, however, provide any information regarding nonacid reflux and do not measure proximal extent of reflux. We have found that many patients may demonstrate normal distal reflux but have abnormal proximal migration of refluxate, much of which may be nonacid and therefore missed by wireless capsule testing.

Temporal symptom association correlations between coughing spells and reflux episodes can be very helpful in assessing reflux-related cough pathology. A recent blinded, cross-sectional study by Francis et al used concurrent time-synchronized audio and MII-pH to measure reflux events and phonation triggers in patients with idiopathic chronic cough.25 They found that the probability of cough increased with higher burdens of reflux. Also of note was that antecedent pH-impedance events were immediately found to be associated with an increased rate of de novo cough, and this was statistically significant. Seventy percent of patients with chronic cough exhibited a temporal relationship between reflux and cough.

The gastric digestive enzyme pepsin has been shown to be a reliable molecular marker for the diagnosis of reflux.²⁶ It is solely produced by chief cells located in the gastric mucosa and, therefore, all refluxate, both nonacidic and acidic, has pepsin as a constituent. Pepsin has further been shown to be a causative agent of laryngeal damage and inflammation in acidic and nonacidic reflux, as it can be activated by acidic dietary elements once deposited in the pharynx and larynx. Pepsin found within laryngeal tissues and oropharyngeal secretions may therefore link LPR with GERD. Ongoing studies are attempting to delineate a causal relationship between pepsin presence in the endolarynx and symptoms of LPR.²⁷ Recently, in a small prospective study, seven of eight adults experienced improvement in symptoms such as heartburn and cough, as well as elimination of pepsin from laryngeal biopsies after antireflux surgery.²⁸ A molecular marker such as pepsin would be of great use. See Chapter 5 for further information on the current state of pepsin testing in the management of cough.

TREATMENT

Diet and Lifestyle Management

Diet and lifestyle changes have been shown in prior studies to be effective in reducing reflux, and may have an impact on chronic cough issues due to this. Weight loss in general has a beneficial effect on reflex, as increased abdominal fat increases basal intra-abdominal pressure and risk of obstructive sleep apnea and reflux events. Randomized, controlled trials of weight loss in severely obese individuals have documented decreases in esophageal reflux with lowered body mass index. Weight loss is challenging for most patients, however, and maintaining weight loss long term is even harder. Other general lifestyle recommendations may also include suggestions to quit smoking, decrease caffeine consumption, and limit use of carbonated beverages, as these have all been shown to reduce GERD symptoms. Specific low-fat, low-acid, and antireflux diets have recently become popular among many patients, and are of low risk but have little data to support beneficial outcomes. Chocolate, red wine, and mint have also been shown to decrease lower esophageal sphincter tone and may increase reflux. Elevating the head of the bed even 3 to 4 inches above the foot (extra pillows, including a wedge, are often ineffective due to the patient sliding down to a flat position during sleep) also reduces the frequency and strength of reflux episodes due to the effect of gravity, as can sleeping in left lateral decubitus position. Certain medications have also been shown to increase esophageal reflux, such as aspirin, nitrates, and calcium channel blockers.2

Medication Trials

Patients with chronic cough who have symptoms consistent with GERD (such as heartburn, regurgitation, or pyrosis) should be evaluated for reflux as a primary intervention after pulmonary causes of cough are ruled out. This may include EGD with biopsies, barium esophagram if solid food dysphagia is present, and/or empiric medication trials. If significant GERD symptoms are present without dysphagia warning signs (odynophagia, weight loss, food impaction, hematemesis), no further testing is necessarily required before the option of starting a trial of medical antireflux therapy after visualization of the larynx. Maximum medication trials for GERD include using a proton-pump inhibitor (PPI) twice daily, taken 30 minutes before breakfast and dinner for 2 to 3 months.³⁰ Clinicians may also consider addition of an adjunct therapy of nighttime H2 blocker. Prokinetics such as metoclopramide are generally reserved for treatment of GERD in children.³¹ Adherence to a medication trial is important as PPI therapy may not be effective if taken in intermittent fashion.²⁷ Sodium alginate suspensions (such as those present in Gaviscon Advance from the UK) may also be of use for patients with nonacid reflux or inability to take PPI medication due to allergy or medical contraindications. These medications are thought to prevent liquid regurgitation through the lower esophageal sphincter by resting on top of gastric contents as a physical barrier, and have been shown in some studies to decrease GERD and LPR symptoms.³² Alginates must be taken four or more times throughout the day (typically after meals and at bedtime) as they are digested and gone when the stomach empties. It is crucial that the clinician follow up with the patient, preferably 3 months after a medication trial is initiated, to assess response to treatment. If successful, the patient may be able to be slowly weaned off medication. Further objective reflux testing, preferably HEMII-pH testing if available, is often indicated if the patient does not respond despite a strong supportive history of possible ongoing reflux.³³

ANTIREFLUX SURGERY

Surgical intervention is traditionally used to treat the more typical reflux symptoms such as heartburn, regurgitation, and severe hiatal hernia, but it may also be of significant value in the management of reflux-related cough. Studies relating to outcomes of surgical treatment of GERD often suffer from lack of controls and blinding, and different preoperative/postoperative evaluation criteria. Kaufman and colleagues reported their long-term outcomes of 128 patients treated with laparoscopic antireflux surgery. Cough and hoarseness was improved in 65% to 75% of cases, compared to heartburn and regurgitation in more than 90% of patients.34 A study by Jobe et al also demonstrated significant improvement in cough symptoms in carefully selected patients with increased proximal reflux following fundoplication, with 13 out of 16 patients showing total resolution.³⁵ Another review of treatment options for GERD-related cough summarized the findings of nine prospective studies of surgical management, reporting that 85% of surgically treated patients had a “significant cough response.”³⁶ Studies have continued to show that many patients with reflux-related cough have normal DeMeester scores and significant nonacid reflux burden, suggesting that HEMII-pH testing may be necessary to truly evaluate these patients for possible surgical intervention.³⁷

Further testing is required by many gastric surgeons to document the extent of reflux prior to referral for surgical consultation. This testing can include upper endoscopy of the aerodigestive tract, barium esophagram, esophageal manometry, and formal pH probe testing (MII-pH, HEMI-pH, or wireless capsule). It is generally recommended that the following indicators be met:^{38, 39}

■ 24-hour ambulatory pH monitoring study is positive (either dual pH-MII, HEMII-pH, or distal esophageal wireless pH system).

■ Patient symptom profile fits diagnosis of GERD, and other obvious causes of cough have been adequately ruled out as described above.

■ Lack of response to medical regimen or failure to tolerate medication.

■ Ongoing sequelae of GERD (esophagitis, Barrett’s esophagus, hiatal hernia).

■ Adequate esophageal motility present to allow for fundoplication and avoid postoperative dysphagia.

■ Cough severity is sufficient to impede patient quality of life (and in these cases, with patient understanding risks of surgery, typical GERD complaints such as known heartburn and regurgitation may not be required before proceeding).^{40, 41}

Nissen fundoplication is a time-tested surgical treatment modality for patients with refractory reflux, and studies have published outcome data for more than 20 years. Studies have consistently shown that carefully selected patients may benefit from fundoplication procedures to improve chronic cough, globus, dysphonia, and other LPR-related symptoms with proper patient selection.42, 43 Cough patients have generally been shown to have the best improvement if they had pre-existing heartburn and traditional GERD symptoms. The Linx Reflux Management System is designed to augment the LES through magnetomechanical means.⁷ It utilizes a circular ring of magnetic beads that are designed to resist expansion mimicking the native LES. This does impact the ability for a patient to undergo an MRI though the newer versions of the system are compatible with 1.5 tesla MRIs. Laparoscopic Rou-en-Y gastric bypass has been demonstrated as the most effective bariatric surgical procedure for the improvement of symptoms related to GERD for obese patients. Qualifications beyond the previously mentioned surgical referral criteria include patients with BMI >40 or >35 with two or more obesity-related comorbidities such as type II diabetes, hypertension, obstructive sleep apnea, heart disease, or lipid abnormalities, among others. Long-term evidence shows improvement in patients with GERD who undergo surgical intervention, justifying early referral for surgical evaluation when patients meet criteria.^{7, 28}

CONCLUSIONS

Management of a patient with reflux-related chronic cough requires astute clinical evaluation and the use of objective data. This begins with careful history taking and evaluation of other potential and more common causes of cough, including thorough pulmonary evaluation. Patients with wet productive cough, ongoing tobacco use history, ACE inhibitor use, and abnormal chest imaging are not likely to have reflux-related chronic cough. Further testing for reflux-related cough in properly selected patients may include empiric PPI trials and/or ambulatory objective reflux testing depending on patient and treating center preference. Close follow-up examination and discussion of symptom improvement or persistence is crucial in the management of patients with suspected reflux-related chronic cough. Research continues to evolve regarding the association between gastric enzymes such as pepsin and its role in LPR and symptoms such as chronic cough, as well as normative data for proximal esophageal and hypopharyngeal impedance. It is crucial to document the presence of abnormal esophageal acid exposure when antireflux surgery is to be considered, and we vastly prefer HEMII-pH testing with proximal hypopharyngeal impedance and pH to truly assess the extent of nonacid reflux in symptom presentation. The results of objective testing help to establish the presence of abnormal esophageal reflux and assist with intensity of treatment through careful cost and benefit analysis of medical versus surgical intervention. Additional randomized studies with long-term follow-up are required to evaluate the diagnostic and therapeutic benefit of new technologies such as HEMII-pH and pepsin testing.

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