Home Educatione-Learning Respiratory Manifestations of Gastroesophageal Reflux
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Respiratory Manifestations of Gastroesophageal Reflux

PCCSU Volume 25, Lesson 2

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Lindsey B. Roenigk, MD; and Susan M. Harding, MD, FCCP

Dr Roenigk is Associate in Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine; Dr Harding is Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, and Medical Director, UAB Sleep/Wake Disorders Center, University of Alabama at Birmingham, Birmingham, Alabama.

Dr Roenigk and Dr Harding have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Understand mechanisms whereby the esophagus and lung interact.
  2. Discuss the role of gastroesophageal reflux (GER) as an asthma trigger.
  3. Identify and manage GER-related cough.
  4. Examine outcomes data on the treatment of GER in patients with asthma and chronic cough.
  5. Highlight the role that GER and aspiration play in COPD, idiopathic pulmonary fibrosis, cystic fibrosis, and allograft function in lung transplant recipients.

Key words: gastroesophageal reflux, aspiration, asthma, chronic cough, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis

Abbreviations: BOS = bronchiolitis obliterans syndrome; CF = cystic fibrosis; GER = gastroesophageal reflux; PEF = peak expiratory flow; PPI = proton pump inhibitor; SS = systemic sclerosis

Interactions between the esophagus and the lungs exist, as noted by 12th century writers warning of the association of eating, lying down, and wheezing.1 Results from recent outcome studies show that select patients with asthma with gastroesophageal reflux (GER) symptoms and patients with GER-related cough benefit from GER treatment. Data also suggest that GER is a comorbid disease that affects outcomes in several other respiratory diseases. Patients should be assessed to determine whether GER could be affecting their respiratory disease.

There are many knowledge gaps concerning the role of GER in respiratory diseases, including the lack of a diagnostic test or biomarker that correctly indicates GER-triggered asthma, as well as the lack of medications that adequately control GER as a motility disorder.2 We can control the acidity of gastric contents, but we cannot prevent the occurrence of GER events. There are gaps in clinical practice, including that practitioners do not identify patients with GER-responsive cough or adequately identify and treat GER and aspiration in patients with respiratory disease.

Pathophysiologic Mechanisms Between the Esophagus and the Lung

The esophagus and the lung share common embryonic foregut origins. Several mechanisms exist that allow the two organs to affect one another.3 Vagally mediated reflexes result in bronchoconstriction. Local axonal reflexes provide a direct connection between the esophagus and the trachea. Esophageal acid serves as a primer for heightened bronchial reactivity to other asthma triggers. Microaspiration of acid into the trachea stimulates a much greater bronchoconstrictive response than does acid in the esophagus alone. GER initiates the release of inflammatory markers in the lungs. Swallowing dysfunction is common in patients with COPD, predisposing them to aspiration.4 Lastly, bronchoconstriction can trigger transient lower esophageal sphincter relaxations, the primary GER mechanism, leading to more GER events.5

GER and Asthma

GER coexists in as many as 80% of patients with asthma and may be an asthma trigger in select patients with asthma with GER symptoms. GER is linked to asthma onset, is seen frequently in patients with asthma who have frequent asthma exacerbations, and is a comorbid condition in difficult-to-treat asthma. It is also a risk factor for hospitalizations for asthma. However, none of these findings prove causality.2 Asthma with GER is also more costly to diagnose and treat than atopic asthma of the same severity. Table 1 shows GER prevalence in patients with asthma. Multiple factors exist that can predispose patients with asthma to GER development. Bronchoconstriction and airflow obstruction can increase the thoracoabdominal pressure gradient and the frequency of transient lower esophageal sphincter relaxations, both of which promote GER.7 The high prevalence of obesity and hiatal hernia in patients with asthma also predisposes them to GER development. Habits, including bedtime eating, seen in 60% of patients with asthma, predisposes them to GER, as does autonomic dysregulation.7 Lastly, asthma medications, including oral corticosteroids, repeated inhalations of albuterol, and theophylline, increase GER.2


Table 1GER Prevalence in Adult Patients With Asthma


Reflux Symptoms Prevalence (%)

Heartburn 59-77
Reflux-associated symptoms 41a
Clinically silent reflux 62a
Abnormal esophageal pH 51-82
Hiatal hernia 51-58
Esophagitis 37-43

GER = gastroesophageal reflux. (Adapted from Harding2 and Havemann et al.6) aThis information is not assessed in Havemann et al.6


Currently, no diagnostic test or biomarker can be used to identify patients with asthma with GER therapy-responsive disease. Barium esophagram; esophageal manometry; esophageal pH and impedance testing; endoscopy; exhaled breath condensate pH and biomarker analysis; and sputum analysis for biomarkers, bile, and lipid-laden macrophages are not useful for identifying GER therapy-responsive asthma.2

Esophageal pH testing offers the ability to correlate asthma symptoms with GER events, diagnose silent GER, and assess for adequacy of acid suppression in patients receiving GER medication.2 However, it cannot be used to predict which patients with asthma will respond to acid-suppression therapy. Esophageal impedance combined with pH testing can be used to evaluate for both acid and nonacid reflux in patients with asthma, but the role of nonacid reflux in asthma is still largely unknown. It is our opinion that the current best diagnostic test for GER-related asthma in patients with asthma with reflux symptoms is a 3-month empiric trial of pharmacologic acid suppression with lifestyle modification GER therapy. Prospective studies are needed to evaluate this method’s diagnostic accuracy.

As of 2010, investigators in four multicenter, double-blind, placebo-controlled trials evaluated asthma outcomes with GER therapy with proton pump inhibitors (PPIs). Littner and colleagues8 examined 207 patients with moderate to severe persistent asthma with reflux symptoms who were randomly assigned to receive lansoprazole 30 mg twice daily or placebo for 24 weeks. Although the primary outcome (asthma symptoms) did not improve, quality of life did improve. Furthermore, results of a post hoc analysis indicated that, compared with patients in the placebo group, fewer patients in the lansoprazole-treated group had asthma exacerbations (20.4% vs 8.1%; P=.017) or required prednisone (13.9% vs 4%; P=.016). The lansoprazole-treated group had a longer asthma exacerbation-free period than did the placebo group (P=.009).8 Kiljander and colleagues9 examined 767 patients with moderate to severe persistent asthma who received esomeprazole 40 mg twice daily or placebo for 16 weeks. The primary outcome was morning peak expiratory flow (PEF) rate. Improvement in PEF was not seen in patients with asthma who did not have reflux symptoms. Improvement in PEF was noted in patients with asthma with both reflux and nocturnal asthma symptoms (P=.03) and in patients with asthma using inhaled long-acting β-agonists.

Kiljander and colleagues10 examined another group of 838 patients with moderate to severe asthma with reflux symptoms, randomly assigned to receive placebo or esomeprazole 40 mg once or twice daily. The primary outcome was morning PEF. Relative to baseline, PEF, FEV1, and asthma, and quality of life improved in both treated groups, although the magnitude of these findings was modest.

The American Lung Association Asthma Clinical Research Centers reported the results of its randomized trial of esomeprazole 40 mg twice daily in 412 patients with inadequately controlled asthma without GER symptoms.11 No differences were noted in PEF, number of urgent visits, or corticosteroid use between the treated group and the placebo group. To date, these are the strongest data showing that patients with asthma without GER symptoms are unlikely to benefit from GER therapy.11

Surgical trials in which investigators examined asthma outcomes have study design flaws. In a 1999 review, investigators identified 417 patients with asthma undergoing fundoplication, with 90% reporting GER improvement.12 Asthma symptoms and medication use decreased by 79% and 88%, respectively; however, pulmonary function improved in only 27% of patients. Investigators in other studies13 compared medical therapy, surgical therapy, and placebo in patients with asthma with GER using histamine (H2)-blockers as opposed to PPIs; the results were inconsistent, some showing better outcomes from fundoplication and some having similar outcomes with surgical and medical therapy.

Data suggest that some subgroups, such as patients with asthma with GER symptoms, could benefit from GER therapy. A major question remaining in this area surrounds the predictors of response to therapy. Investigators in some trials identified predictors that are outlined in Table 2. These predictors should be validated in independent studies. Select patients with asthma with GER have asthma improvement with GER therapy, so all patients with asthma should be screened for the presence of GER symptoms. If GER symptoms are not present, then GER therapy, in general, is not recommended. Because no tests or biomarkers can be used to identify GER treatment-responsive asthma, patients with asthma with GER symptoms should undergo an empiric 3-month GER therapy trial using lifestyle modification GER therapy along with twice-daily PPI therapy 30 min before breakfast and dinner. Although not examined in placebo-controlled trials, behavioral and lifestyle modifications for GER should be implemented in patients with asthma with GER symptoms. Surgical GER therapy for an asthmatic indication should be reserved for patients with asthma who have asthma improvement with medical GER therapy. If surgical therapy is being considered in a patient with asthma who did not have asthma improvement, documentation of inadequate control of acid and nonacid GER (despite medical GER therapy) using combined esophageal pH/impedance monitoring should be performed at a specialized esophageal center. Conservative lifestyle measures are outlined in Table 3.


Table 2Potential Predictors of Asthma Response


Asthma Characteristics
  • Difficult-to-control asthma
  • Nonallergic intrinsic asthma
  • Nocturnal asthma
  • Obesity (BMI > 29.7 kg/m2)
GER Characteristics
  • Reflux-associated respiratory symptoms
  • Regurgitation more than once weekly
  • Proximal acid on pH testing
  • Distal acid on pH testing

See Table 1 for expansion of abbreviations. (From Harding.2 Reprinted with permission from Elsevier.)


Table 3Lifestyle Therapy for GER


  • Weight loss, if obese
  • Avoid tight-fitting clothes
  • Avoid large, high-fat meals
  • Avoid eating within 3 h before bedtime
  • Sleep with left side down
  • Smoking cessation
  • Avoid caffeine, chocolate, peppermint, citrus, alcohol, and carbonated drinks
  • If possible, avoid medications that can worsens GER, such as anticholinergics, β-agonists, bisphosphonates, calcium channel blockers, corticosteroids, benzodiazepines, estrogens, opiates, progesterone, prostaglandins, theophylline
  • Continuous positive airway pressure if sleep apnea present
  • Avoid exercises that increase intraabdominal pressure

See Table 1 for expansion of abbreviations. (Adapted with permission from Chandra and Harding.17)


Because PPIs inhibit gastric acid secretion and do not alter GER events or esophageal motility, it is imperative that patients adhere to conservative lifestyle measures. During the empiric GER therapy trial, asthma symptoms and PEF should be monitored. If asthma improves, then continue GER therapy and consider tapering the PPI to once daily. In patients who do not respond, consider 24-h pH monitoring and/or impedance testing to determine if GER is controlled. We also would consider empiric PPI therapy in patients with asthma that is difficult to control, particularly those requiring long-term use of oral corticosteroids, even in the absence of GER symptoms, although this approach is more controversial.

GER-Related Cough

In outcome studies, GER is the second or third most common cause of chronic cough.14 Approximately 10% of patients with chronic cough have GER symptoms.14 GER-related cough is defined as cough that responds to GER therapy.14 GER may be silent in as many as 75% of patients with GER-related cough, making its diagnosis difficult.15 Determining the cause of chronic cough is a diagnostic challenge because more than 30 causes of chronic cough have been identified.14 Furthermore, a patient’s cough often has more than one cause.16 Cough is attributable to two causes in 18% to 62% of patients and is attributable to three or more causes in as many as 42% of patients.16 In an immunocompetent nonsmoker, not taking an angiotensin-converting enzyme inhibitor, with a normal chest radiograph, the five most common causes of chronic cough are upper airway cough syndrome (previously known as “postnasal drip syndrome”), GER, asthma, eosinophilic bronchitis, and postinfectious cough.14,16 GER has been estimated to be the cause of cough in 21% to 41% of cases.17 Furthermore, nonacid reflux also causes cough, so GER-related cough may persist despite PPI treatment, and cough may resolve only with surgical fundoplication.18,19

There is no test or biomarker currently available that can be used to determine which patients with chronic cough will respond to GER therapy. The same tests used to evaluate for GER-related asthma are available for GER-related cough, with the addition of tussigenic challenge.14 Irwin14 identified a clinical profile that can be used to predict GER-related chronic cough. Table 4 shows this profile. The diagnostic test recommended by the American College of Chest Physicians and the British Thoracic Society clinical practice guidelines is an empiric trial of medical GER therapy for 1 to 3 months in patients with chronic cough with GER symptoms or in those who are likely to have silent GER.14,20 Only when this empiric trial fails is more objective GER testing recommended to evaluate for potential causes of failure.14,20 Poe and Kallay21 studied this approach in a 2003 trial in 214 patients with chronic cough. They were able to diagnose GER-related cough in 79% of patients. Eighty-six percent of those patients had cough improvement within 4 weeks after initiating empiric medical GER therapy.21 If the empiric trial fails, the next test should be 24-h esophageal pH with impedance testing, if available. More recently, the temporal association of cough with reflux during esophageal pH testing (with or without impedance), analyzed in a systematic way by using symptom association probability, showed that a positive symptom association probability indicated long-term cough symptomatic response with GER therapy.22,23 More work is needed in this area.


Table 4Clinical Profile for Predicting GER-Related Cough


  • Not exposed to environmental irritants nor a present smoker
  • Not taking an angiotensin-converting enzyme inhibitor
  • Chest radiograph is normal or shows nothing more than stable, inconsequential scarring
  • Symptomatic asthma has been ruled out
              Cough has not improved with asthma therapy or
              Methacholine inhalation challenge result is negative
  • Upper airway cough syndrome due to rhinosinus diseases has been ruled out
              First-generation H1-antagonist has been used and cough failed to improve and
              Silent sinusitis has been ruled out
  • Nonasthmatic eosinophilic bronchitis has been ruled out
              Results from properly performed sputum studies are negative or
              Cough has not improved with use of inhaled or systemic corticosteroids

See Table 1 for expansion of abbreviations. (From Irwin.14 Reprinted with permission from the American College of Chest Physicians.)


All patients with GER-related cough should be encouraged to follow lifestyle GER measures. In addition, we recommend twice-daily PPI for 1 to 3 months. Cough improvement can occur in as little as 2 weeks, but there are reports of it taking as long as 53 days.17 We recommend PPIs over other GER medications because results from trials in which other acid suppressors were used showed a longer time for cough improvement.24 The clinician should be aware that the esomeprazole package insert notes that 1% of patients report cough as a side effect of the medication.25

Surgical fundoplication for GER-related cough is another option in select patients. Fundoplication has the advantage of simultaneously managing both acid and nonacid GER. Currently, it is recommended only for patients who clearly have GER as the cause of their cough but who have not responded to maximal medical therapy and lifestyle changes.14

Results from a systematic review and meta-analysis of randomized controlled trials indicate that use of a PPI in adults to treat GER-associated cough improves cough outcomes.26 Results of controlled trials in adults indicate that 35% to 57% of patients report cough improvement with PPI therapy.17,26

The outcomes associated with fundoplication for GER-related cough are good, but these studies were performed in highly selected populations. Fundoplication also has the advantage of treating nonacid reflux. In one study, at 6-month, 2-year, and 5-year follow-up, patients complaining of preoperative cough reported cough improvement 83%, 74%, and 71% of the time, respectively.27 Although these are good rates of improvement, it is important that patients be aware of the possible diminishing effects across time.27 We need more long-term outcome data to determine better which patients are appropriate surgical candidates.

If a patient is suspected of having GER-related cough, we recommend an empiric trial of twice daily PPI for 1 to 3 months along with lifestyle GER measures. If the patient responds, the PPI can be decreased to use once daily. In patients who do not respond, consider 24-h combined esophageal pH impedance testing to confirm acid suppression and to correlate cough with acid or nonacid reflux events. Lastly, remember that the cause of cough is more often multifactorial, and patients may require other therapies for cough resolution.

GER and COPD

GER is a common comorbid disorder in patients with COPD and may predispose patients to COPD exacerbations. Acute COPD exacerbations requiring hospitalization significantly affect mortality and have a 21% all-cause mortality rate at 1 year.28 Interventions preventing COPD exacerbations potentially can affect COPD outcomes. Heartburn and/or regurgitation at least weekly is present in between 17% to 30% of patients with COPD, and approximately 25% of patients use GER medications.29 Esophageal pH testing shows that 62% of patients with severe COPD have abnormal esophageal acid contact times, with proximal acid noted in as many as 50% of these patients, placing them at risk for aspiration.30,31 Furthermore, as many as 58% of patients with COPD with abnormal esophageal acid contact times do not have GER symptoms and do not realize that GER is present.30 Patients with COPD also have swallowing difficulties, further increasing aspiration risk. Abnormal swallowing reflexes are present in approximately 33% of patients with COPD.32

Data suggest that GER symptoms and/or swallowing dysfunction are associated with an increased frequency of COPD exacerbations. For instance, in a prospective study, GER symptoms were associated with a relative risk of COPD exacerbation of 6.55 (P<.01) across 6 months compared with that in matched patients with COPD without GER.33 Abnormal swallowing reflexes in another cohort were associated with more than three COPD exacerbations a year, with a relative risk of 4.86.32

There are minimal outcome data for examining whether GER therapy improves COPD outcomes. In a recent investigation, 100 elderly patients with COPD who did not have GER symptoms were randomly assigned to receive either lansoprazole 15 mg/d for 12 months or usual care, and the COPD exacerbation frequency was lowest in the PPI-treated group, with an adjusted odds ratio (compared with the control group) of 0.23 (P=.004).34 More research is needed in this area.

Management of GER in patients with COPD is similar to that in patients with other respiratory disease states; however, swallowing function also should be assessed. Aspiration risk-reduction strategies should be implemented if swallowing problems are present.

GER and Aspiration Syndromes

Aspiration plays a role in other respiratory diseases, including pneumonia, idiopathic pulmonary fibrosis, pulmonary fibrosis associated with systemic sclerosis (SS), CF, and bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. The effect of the aspirate on the lungs and the lungs’ response depends on multiple factors—primarily, the nature of what is aspirated, the volume of the aspirate, and the frequency of aspiration.35

In a patient who has risk factors for GER-related aspiration or symptoms suggesting GER-related aspiration, all of the previously mentioned tests apply for evaluating GER. An essential component in diagnosing aspiration is assessment of the patient’s swallowing function, which usually involves a consultation with a speech therapist and a fiberoptic or videofluoroscopic swallowing assessment.35

Direct evidence of aspiration of gastric contents into the lung also may be useful. Induced sputum can be tested for the presence of pepsin or bile acids. BAL fluid can be examined for pepsin, bile, or lipid-laden macrophages.36 Radionuclide scanning can show evidence of aspirate in the lungs, although with a low sensitivity.

Management of aspiration includes therapy provided by speech pathologists to improve airway protective mechanisms. Avoidance of substances that decrease muscle tone or arousal during sleep, such as alcohol, benzodiazepines, or opiates, is also important. Furthermore, during sleep, nasal continuous positive airway pressure reduces refluxate.37 Positional therapy with head-of-bed elevation may prevent GER episodes and, potentially, aspiration during sleep. Fundoplication should be considered in select patients.

In idiopathic pulmonary fibrosis, some hypothesize that GER initiates alveolar epithelial injury, resulting in an abnormal wound healing response characterized by fibrosis. In 65 patients with idiopathic pulmonary fibrosis, abnormal esophageal pH test results were present in 87%.38 Investigators in a case series of four patients with idiopathic pulmonary fibrosis with GER reported stabilization or improvement of pulmonary function test results with appropriate acid suppression (by means of PPI or fundoplication).39 Prospective trials are currently under way.

Pulmonary fibrosis is a common manifestation of SS. Patients with SS frequently have severe esophageal dysfunction and GER. In a study of 40 patients with SS, the patients with pulmonary fibrosis had statistically more acid and nonacid GER than did patients with SS without pulmonary fibrosis.40 Currently, aggressive treatment of GER is recommended in all patients with SS with pulmonary fibrosis; however, future studies are needed in this area.41

The prevalence of GER in patients with CF approaches 55% to 90%, yet 57% of patients with CF lack typical GER symptoms.42 Aspiration has been associated with CF exacerbations. GER is associated with reduced lung function. Results in an uncontrolled study showed that fundoplication reduced the frequency of CF exacerbations in adults.43

Aspiration may play a pivotal role in lung transplant outcomes, too. Despite multiple advances, lung transplant recipients face a 50% 5-year mortality rate.44 Much of this mortality is attributed to BOS. BOS is driven by multiple factors, including GER and aspiration.45 Lung transplant recipients have many risk factors for aspiration, including vagal nerve injury occurring during surgery, chest wall and diaphragm deformity, delayed gastric emptying because of immunosuppressive medications, impaired cilia function, and decreased cough reflex. Fundoplication within 90 days of transplantation has been shown to decrease the rate of BOS development.46 Research is ongoing, but the hope is that controlling acid and nonacid GER and aspiration could lead to lower rates of BOS development and improved survival in these patients.

Long-term PPI Use: Cautions

The first PPI was approved by the US Food and Drug Administration in 1989, and, in general, PPIs are safe. However, their long-term use is associated with potential hazards. Their use increases the risk of community-acquired pneumonia by 30% and increases the risk of acquiring Clostridium difficile infections.47,48 Long-term PPI therapy may decrease vitamin B12 absorption.49 Data from the Women’s Health Initiative and six other epidemiologic studies published since 2006 indicate a relationship between PPI use and increased risk of fractures, especially in patients aged 50 years or older.50,51 The US Food and Drug Administration issued a warning about the increased risk of bone fracture with the use of PPIs for 1 year or longer or at high doses.50,52 Consider tapering the PPI dose, if possible, and consider working with a gastroenterologist for long-term management of GER-related respiratory disease.

Conclusions: Beyond Acid Suppression

GER is a comorbid condition or trigger in many respiratory diseases. Refluxate includes acid, bile salts, pepsin, and trypsin. Both acid and nonacid refluxate can injure airway mucosa. Pepsin is endocytosed by epithelial cells in a nonacid environment and then retained in intracellular vesicles having a low pH, such that the proteolytic activity of pepsin is restored.53 Currently available medical therapy only suppresses acid and does not control GER episodes. Metoclopramide, a prokinetic agent, is associated with tardive dyskinesia and is not recommended.54 Baclofen is the only medication currently available in the United States that inhibits transient lower esophageal sphincter relaxations, the primary cause of individual GER events.55 Lesogaberan increases lower esophageal sphincter pressure and inhibits transient lower esophageal sphincter relaxations.56 We hope newer agents, such as lesogaberan, will be available in the future. Alginates, available for more than 30 years, combine with gastric contents and form a gel that floats on top of gastric juice, producing a physical barrier. Alginates also inhibit pepsin activity.57 In patients who have continued GER despite lifestyle and PPI therapy, a trial of baclofen and/or alginates may be helpful. Nasal continuous positive airway pressure reduces sleep-related GER.37 Appropriate candidates with continued GER despite medical therapy should be considered for surgical fundoplication after careful esophageal evaluation.

Aspiration evaluation and aspiration risk-reduction strategies should be considered in patients with respiratory diseases. Future research will help clinicians better identify patients with respiratory disease who have GER treatment-responsive disease.


 

References

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