Treating silent reflux disease does not improve poorly controlled asthma

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Treating silent reflux disease does not improve poorly controlled asthma
Author(s)
Brent P. Riscili, MD
Jonathan P. Parsons, MD, MSc
John G. Mastronarde, MD, MSc

Should patients with poorly controlled asthma be treated empirically for gastroesphageal reflux disease (GERD)?

Current guidelines1 indicate that trying a proton pump inhibitor may be worthwhile. However, the results of a recent multicenter trial2 indicate that this does not help control asthma symptoms and that we need to reevaluate the guidelines and focus on other factors that can worsen asthma control.

REFLUX DISEASE IS LINKED TO ASTHMA

GERD’s association with asthma has long been recognized. Asthma patients have a higher prevalence of GERD than the general population, with reported rates of 20% to 80%.3–8

GERD may worsen asthma via several mechanisms. If stomach acid gets into the airway, it can induce bronchoconstriction, vagal reflexes, and chronic airway inflammation, all of which can increase airway reactivity.9–16 Chronic reflux can also cause inflammation of the esophagus, which can exacerbate cough and possibly bronchospasm via neurogenic mechanisms.17

In turn, asthma may worsen GERD. Airway restriction can lead to hyperinflation and increased negative inspiratory pleural pressure, both of which may reduce the effectiveness of the lower esophageal sphincter.18 In addition, the beta-agonists and methylxanthines used to treat asthma may impair function of the lower esophageal sphincter and exacerbate reflux.18–20

CURRENT GUIDELINES ARE BASED ON LIMITED INFORMATION

The symptoms of GERD and asthma are nonspecific and can be similar (chest tightness, chest discomfort), which can make it challenging for clinicians or patients to distinguish asthma from GERD.2 Moreover, in asthma patients, GERD often presents without classic symptoms such as heartburn, and thus has been labeled “silent” GERD.

Earlier studies21–29 (Table 1) suggested that treating GERD may improve asthma control. Based on this information, the most recent asthma guidelines from the National Institutes of Health (NIH) recommend trying GERD treatment in patients with poorly controlled asthma, even if they do not have classic GERD symptoms.1

However, these studies all had significant limitations, such as small sample size. Also, the definitions of asthma and GERD differed from study to study. In some cases, the definition of GERD included self-reported GERD, which often fails to correlate with GERD documented with esophageal pH monitoring in asthma patients.1 These limitations were highlighted in a Cochrane review,30 which found that asthma patients with GERD showed no overall improvement in asthma after treatment of reflux. It concluded that small groups of patients may benefit, but that predicting who will respond is difficult.

Larger randomized controlled trials28,29 attempted to address some of these limitations, with varying results.

Littner et al29 gave lansoprazole (Prevacid) 30 mg twice daily or placebo to 207 patients with moderate to severe asthma and symptomatic GERD and saw no improvement in daily asthma symptoms, ie, asthma control in the active-treatment group. While these patients had an improvement in symptoms of severe reflux, their overall quality-of-life scores were similar to those of the placebo group. Of note, patients needing more than one type of drug for asthma control had a lower rate of asthma exacerbations.

Kiljander et al28 gave esomeprazole (Nexium) 40 mg twice daily or placebo to 770 patients who had mild to moderate asthma and symptoms of nocturnal asthma with or without symptoms of GERD. The only benefit was a slight improvement in peak expiratory flow in those with symptoms of both GERD and nocturnal asthma, and this was most significant in patients taking long-acting beta-agonists. Other measures—eg, the forced expiratory volume in the first second (FEV1), use of a beta-agonist, symptom scores, and nocturnal awakenings—did not improve.

In both of these studies,28,29 patients reported symptoms of GERD, so they did not have silent GERD.

THE DESIGN OF SARA

To address the limitations of the studies discussed above and evaluate the effect on asthma control of treating silent GERD, the American Lung Association and the National Heart, Lung, and Blood Institute funded the multicenter Study of Acid Reflux in Asthma (SARA) (Table 2).2

In SARA, 412 patients age 18 and older with inadequately controlled asthma were randomized to receive esomeprazole 40 mg twice a day or placebo for 24 weeks. Inadequate control was defined as a score of 1.5 or higher on the Juniper Asthma Control Questionnaire31 despite treatment with inhaled corticosteroids. Patients had no symptoms of GERD. The 40-mg twice-daily dosage of esomeprazole was chosen because it is known to suppress more than 90% of acid reflux.24,32

All patients completed a baseline asthma diary, recording peak expiratory flow rates, asthma symptoms, nighttime symptoms, and beta-agonist use. This information was collected every 4 weeks throughout the trial.

All participants also underwent esophageal pH monitoring for an objective confirmation of GERD. Patients were randomized independently of the results of the pH probe; in fact, investigators and patients were blinded to these results.

The primary outcome measure was the rate of episodes of poor asthma control, with poor control defined as any of the following:

  • A decrease of 30% or more in the morning peak expiratory flow rate on 2 consecutive days, compared with the patient’s best rate during the run-in period
  • An urgent visit, defined as an unscheduled health care visit, for asthma symptoms
  • The need for a course of oral prednisone for treatment of asthma.

Asthma was defined as doctor-diagnosed, plus either a positive methacholine challenge test (a concentration of methacholine causing a 20% reduction in FEV1 [PC20] < 16 mg/mL) or a positive bronchodilator response (a 12% increase in FEV1) to an inhaled beta-agonist. Participants had no other indication for acid suppression, including symptoms of GERD or previously diagnosed erosive esophageal or gastric disease.

Acid reflux was evaluated by ambulatory pH monitoring, which had to last at least 16 hours and span one meal and 2 hours in the recumbent position. Reflux was present if the pH was less than 4.0 for more than 5.8% of total time, 8.2% of time upright, or 3.5% of time lying down.33 Episodes and severity were measured by the Gastroesophageal Reflux Disease Symptom Assessment Scale.34

 

 

SARA RESULTS: NO IMPROVEMENT IN ASTHMA WITH GERD TREATMENT

The SARA treatment and control groups had similar baseline characteristics, with similar asthma symptoms. Most of the patients were women: 72% of the placebo group and 64% of the esomeprazole group. Most had baseline spirometric results at the lower end of normal (the mean FEV1 was 76% ± 16 SD in the treatment group and 78% ± 15 in the placebo group) and had very poor asthma control, with an average Juniper Asthma Control Questionnaire score of 1.9 (> 1.5 is considered poor control).31 GERD was documented with esophageal pH monitoring in 40% of patients, showing that a significant number had silent GERD.

Episodes of poor asthma control occurred with similar frequency in the esomeprazole and placebo groups (2.5 vs 2.3 events per personyear, P = .66). Treatment made no difference in this end point regardless of the baseline results of pH monitoring. No treatment effect was noted in the individual components of the episodes of poor asthma control or in secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life.

In addition, subgroup analysis failed to identify any group—including those with documented reflux on pH probe testing or those receiving a long-acting beta-agonist—who benefited from proton pump inhibitor therapy.

The investigators concluded that these data suggest treatment of silent GERD does not improve asthma control and thus that a reevaluation of current guidelines and clinical practice is warranted.2

ISSUES REMAIN

This large clinical trial, in which asthma and GERD were well defined and objectively measured, was robustly negative in terms of showing any benefit of treatment of silent GERD on asthma control. The study population was representative of those for whom such a treatment is recommended in the current NIH guidelines, which are based on data published prior to SARA.

However, while SARA was well designed and had clear results, it had some limitations, and some issues regarding GERD and asthma remain unanswered.

Is acid the only problem in GERD? SARA focused on acidic GERD. Aspiration of substances such as pancreatic enzymes, pepsin, and bile has also been shown to induce symptoms in asthma patients.2,32,35 In addition, distention of the esophagus and stimulation of neurogenically mediated reflexes can cause symptoms or neurogenic airway inflammation that is not mitigated by drugs that target acid reflux.32

Indirectly supporting this theory is evidence that surgical interventions such as fundoplication can improve asthma symptoms. 36 However, this evidence is only from small studies with significant limitations.

Is proximal GERD worse than distal GERD? SARA did not address whether proximal and distal reflux may affect asthma differently. The importance of proximal reflux in asthma has not been clearly established, but there is evidence that patients with proximal GERD have a higher incidence of nocturnal cough than patients who have only distal reflux. 37

Dimango et al38 recently reported additional data from SARA in which patients with poorly controlled asthma underwent both proximal and distal esophageal pH monitoring to see if proximal GERD was associated with poor asthma control: 304 patients underwent dual pH-probe assessment and 38% of them had proximal reflux. The authors found no difference between those with and without proximal GERD with regard to nocturnal awakenings, need to use a rescue inhaler, inhaled controller medication dose, lung function, or airway reactivity by methacholine challenge. However, they did find that those with proximal GERD had worse asthma quality-of-life scores, and worse health-related quality-of-life scores and were more likely to complain of cough.

Thus, it appears that proximal GERD may worsen quality of life in asthmatic patients but does not worsen asthma control.

SARA RESULTS: IMPLICATIONS FOR MANAGEMENT

The SARA results suggest that patients with poorly controlled asthma who are on adequate controller medications should not be treated empirically for silent GERD in the expectation that the asthma will improve. Rather, they suggest that the focus should be on other factors that can worsen asthma control, such as the ability to properly use an inhaler, the ability to afford medications, compliance with drug treatment, and adequate control of other significant comorbidities such as allergic bronchopulmonary aspergillosis, sinusitis, allergic rhinitis, vocal cord dysfunction, and occult heart disease. The most recent NIH guidelines also suggest considering referral to an asthma specialist if symptoms persist despite adequate controller therapy.

References
  1. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007; 120( suppl 5):S94–S138.
  2. Mastronarde JG, Anthonisen NR, Castro M, et al., American Lung Association Asthma Clinical Research Centers Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009; 360:1487–1499.
  3. Harding SM, Guzzo MR, Richter JE. 24-h Esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events. Chest 1999; 115:654–659.
  4. Sontag SJ, O’Connell S, Khandelwal S, et al Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613–620.
  5. Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000; 162:34–39.
  6. Vincent D, Cohen-Jonathan AM, Leport J, et al Gastro-oesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur Respir J 1997; 10:2255–2259.
  7. Simpson WG. Gastroesophageal reflux disease and asthma. Diagnosis and management. Arch Intern Med 1995; 155:798–803.
  8. Irwin RS, Curley FJ, French CL. Difficult-to-control asthma. Contributing factors and outcome of a systematic management protocol. Chest 1993; 103:1662–1669.
  9. Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest 1997; 111:1389–1402.
  10. Richter JE. Asthma and gastroesophageal reflux disease: the truth is difficult to define. Chest 1999; 116:1150–1152.
  11. Ekstrom T, Tibbling L. Esophageal acid perfusion, airway function, and symptoms in asthmatic patients with marked bronchial hyperreactivity. Chest 1989; 96:995–998.
  12. Herve P, Denjean A, Jian R, Simonneau G, Duroux P. Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am Rev Respir Dis 1986; 134:986–989.
  13. Wu DN, Tanifuji Y, Kobayashi H, et al Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma. Chest 2000; 118:1553–1556.
  14. Cuttitta G, Cibella F, Visconti A, Scichilone N, Bellia V, Bonsignore G. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med 2000; 161:177–181.
  15. Jack CI, Calverley PM, Donnelly RJ, et al Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastrooesophageal reflux. Thorax 1995; 50:201–204.
  16. Harding SM, Schan CA, Guzzo MR, Alexander RW, Bradley LA, Richter JE. Gastroesophageal reflux-induced bronchoconstriction. Is microaspiration a factor? Chest 1995; 108:1220–1227.
  17. Irwin RS, Madison JM, Fraire AE. The cough reflex and its relation to gastroesophageal reflux. Am J Med 2000; 108( suppl 4a):73S–78S.
  18. Choy D, Leung R. Gastro-oesophageal reflux disease and asthma. Respirology 1997; 2:163–168.
  19. Zerbib F, Guisset O, Lamouliatte H, Quinton A, Galmiche JP, Tunon-De-Lara JM. Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Am J Respir Crit Care Med 2002; 166:1206–1211.
  20. Lacy BE, Mathis C, DesBiens J, Liu MC. The effects of nebulized albuterol on esophageal function in asthmatic patients. Dig Dis Sci 2008; 53:2627–2633.
  21. Ford GA, Oliver PS, Prior JS, Butland RJ, Wilkinson SP. Omeprazole in the treatment of asthmatics with nocturnal symptoms and gastrooesophageal reflux: a placebo-controlled cross-over study. Postgrad Med J 1994; 70:350–354.
  22. Teichtahl H, Kronborg IJ, Yeomans ND, Robinson P. Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma. Aust N Z J Med 1996; 26:671–676.
  23. Meier JH, McNally PR, Punja M, et al Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double-blind, placebo-controlled crossover study. Dig Dis Sci 1994; 39:2127–2133.
  24. Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996; 100:395–405.
  25. Levin TR, Sperling RM, McQuaid KR. Omeprazole improves peak expiratory flow rate and quality of life in asthmatics with gastroesophageal reflux. Am J Gastroenterol 1998; 93:1060–1063.
  26. Boeree MJ, Peters FT, Postma DS, Kleibeuker JH. No effects of highdose omeprazole in patients with severe airway hyperresponsiveness and (a)symptomatic gastro-oesophageal reflux. Eur Respir J 1998; 11:1070–1074.
  27. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999; 116:1257–1264.
  28. Kiljander TO, Harding SM, Field SK, et al Effects of eso-meprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006; 173:1091–1097.
  29. Littner MR, Leung FW, Ballard ED, Huang B, Samra NKLansoprazole Asthma Study Group. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128:1128–1135.
  30. Gibson PG, Henry R, Coughlan JJL. Gastro-oesophageal reflux treatment for asthma in adults and children. Coch-rane Database Syst Rev 2000;CD001496. Also available online at www.cochrane.org/reviews/en/ab001496.html. Accessed January 28, 2010.
  31. Juniper EF, Bousquet J, Abetz L, Bateman EDGOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med 2006; 100:616–621.
  32. Canning BJ, Mazzone SB. Reflex mechanisms in gastro-esophageal reflux disease and asthma. Am J Med 2003; 115( suppl 3A):45S–48S.
  33. Richter JE, Bradley LA, DeMeester TR, Wu WC. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age, and gender. Dig Dis Sci 1992; 37:849–856.
  34. Damiano A, Handley K, Adler E, Siddique R, Bhattacharyja A. Measuring symptom distress and health-related quality of life in clinical trials of gastroesophageal reflux disease treatment: further validation of the Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS). Dig Dis Sci 2002; 47:1530–1537.
  35. Asano K, Suzuki H. Silent acid reflux and asthma control [editorial]. N Engl J Med 2009; 360:1551–1553.
  36. Rakita S, Villadolid D, Thomas A, et al Laparoscopic Nissen fundoplication offers high patient satisfaction with relief of extraesophageal symptoms of gastroesophageal reflux disease. Am Surg 2006; 72:207–212.
  37. Tomonaga T, Awad ZT, Filipi CJ, et al Symptom predictability of reflux-induced respiratory disease. Dig Dis Sci 2002; 47:9–14.
  38. Dimango E, Holbrook JT, Simpson E, et al., American Lung Association Asthma Clinical Research Centers. Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity. Am J Respir Crit Care Med 2009; 180:809–816.
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Author and Disclosure Information

Brent P. Riscili, MD
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus

Jonathan P. Parsons, MD, MSc
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, and Investigator in the Study of Acid Reflux in Asthma (SARA)

John G. Mastronarde, MD, MSc
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, and Principal Investigator in the Study of Acid Reflux in Asthma (SARA)

Address: John G. Mastronarde, MD, The Ohio State University Medical Center, 201 Davis Heart/Lung Research Institute, 473 W. 12th Avenue, Columbus, OH 43210; e-mail john.mastronarde@osumc.edu

Dr. Parsons has received honoraria from GlaxoSmithKline, Merck, and AstraZeneca.

Issue
Cleveland Clinic Journal of Medicine - 77(3)
Publications
Cleveland Clinic Journal of Medicine
Topics
Pulmonology
Gastroenterology
Page Number
155-160
Sections
Interpreting Key Trials
Author(s)
Brent P. Riscili, MD
Jonathan P. Parsons, MD, MSc
John G. Mastronarde, MD, MSc
Author(s)
Brent P. Riscili, MD
Jonathan P. Parsons, MD, MSc
John G. Mastronarde, MD, MSc
Author and Disclosure Information

Brent P. Riscili, MD
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus

Jonathan P. Parsons, MD, MSc
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, and Investigator in the Study of Acid Reflux in Asthma (SARA)

John G. Mastronarde, MD, MSc
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, and Principal Investigator in the Study of Acid Reflux in Asthma (SARA)

Address: John G. Mastronarde, MD, The Ohio State University Medical Center, 201 Davis Heart/Lung Research Institute, 473 W. 12th Avenue, Columbus, OH 43210; e-mail john.mastronarde@osumc.edu

Dr. Parsons has received honoraria from GlaxoSmithKline, Merck, and AstraZeneca.

Author and Disclosure Information

Brent P. Riscili, MD
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus

Jonathan P. Parsons, MD, MSc
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, and Investigator in the Study of Acid Reflux in Asthma (SARA)

John G. Mastronarde, MD, MSc
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, and Principal Investigator in the Study of Acid Reflux in Asthma (SARA)

Address: John G. Mastronarde, MD, The Ohio State University Medical Center, 201 Davis Heart/Lung Research Institute, 473 W. 12th Avenue, Columbus, OH 43210; e-mail john.mastronarde@osumc.edu

Dr. Parsons has received honoraria from GlaxoSmithKline, Merck, and AstraZeneca.

Article PDF
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Article PDF
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Should patients with poorly controlled asthma be treated empirically for gastroesphageal reflux disease (GERD)?

Current guidelines1 indicate that trying a proton pump inhibitor may be worthwhile. However, the results of a recent multicenter trial2 indicate that this does not help control asthma symptoms and that we need to reevaluate the guidelines and focus on other factors that can worsen asthma control.

REFLUX DISEASE IS LINKED TO ASTHMA

GERD’s association with asthma has long been recognized. Asthma patients have a higher prevalence of GERD than the general population, with reported rates of 20% to 80%.3–8

GERD may worsen asthma via several mechanisms. If stomach acid gets into the airway, it can induce bronchoconstriction, vagal reflexes, and chronic airway inflammation, all of which can increase airway reactivity.9–16 Chronic reflux can also cause inflammation of the esophagus, which can exacerbate cough and possibly bronchospasm via neurogenic mechanisms.17

In turn, asthma may worsen GERD. Airway restriction can lead to hyperinflation and increased negative inspiratory pleural pressure, both of which may reduce the effectiveness of the lower esophageal sphincter.18 In addition, the beta-agonists and methylxanthines used to treat asthma may impair function of the lower esophageal sphincter and exacerbate reflux.18–20

CURRENT GUIDELINES ARE BASED ON LIMITED INFORMATION

The symptoms of GERD and asthma are nonspecific and can be similar (chest tightness, chest discomfort), which can make it challenging for clinicians or patients to distinguish asthma from GERD.2 Moreover, in asthma patients, GERD often presents without classic symptoms such as heartburn, and thus has been labeled “silent” GERD.

Earlier studies21–29 (Table 1) suggested that treating GERD may improve asthma control. Based on this information, the most recent asthma guidelines from the National Institutes of Health (NIH) recommend trying GERD treatment in patients with poorly controlled asthma, even if they do not have classic GERD symptoms.1

However, these studies all had significant limitations, such as small sample size. Also, the definitions of asthma and GERD differed from study to study. In some cases, the definition of GERD included self-reported GERD, which often fails to correlate with GERD documented with esophageal pH monitoring in asthma patients.1 These limitations were highlighted in a Cochrane review,30 which found that asthma patients with GERD showed no overall improvement in asthma after treatment of reflux. It concluded that small groups of patients may benefit, but that predicting who will respond is difficult.

Larger randomized controlled trials28,29 attempted to address some of these limitations, with varying results.

Littner et al29 gave lansoprazole (Prevacid) 30 mg twice daily or placebo to 207 patients with moderate to severe asthma and symptomatic GERD and saw no improvement in daily asthma symptoms, ie, asthma control in the active-treatment group. While these patients had an improvement in symptoms of severe reflux, their overall quality-of-life scores were similar to those of the placebo group. Of note, patients needing more than one type of drug for asthma control had a lower rate of asthma exacerbations.

Kiljander et al28 gave esomeprazole (Nexium) 40 mg twice daily or placebo to 770 patients who had mild to moderate asthma and symptoms of nocturnal asthma with or without symptoms of GERD. The only benefit was a slight improvement in peak expiratory flow in those with symptoms of both GERD and nocturnal asthma, and this was most significant in patients taking long-acting beta-agonists. Other measures—eg, the forced expiratory volume in the first second (FEV1), use of a beta-agonist, symptom scores, and nocturnal awakenings—did not improve.

In both of these studies,28,29 patients reported symptoms of GERD, so they did not have silent GERD.

THE DESIGN OF SARA

To address the limitations of the studies discussed above and evaluate the effect on asthma control of treating silent GERD, the American Lung Association and the National Heart, Lung, and Blood Institute funded the multicenter Study of Acid Reflux in Asthma (SARA) (Table 2).2

In SARA, 412 patients age 18 and older with inadequately controlled asthma were randomized to receive esomeprazole 40 mg twice a day or placebo for 24 weeks. Inadequate control was defined as a score of 1.5 or higher on the Juniper Asthma Control Questionnaire31 despite treatment with inhaled corticosteroids. Patients had no symptoms of GERD. The 40-mg twice-daily dosage of esomeprazole was chosen because it is known to suppress more than 90% of acid reflux.24,32

All patients completed a baseline asthma diary, recording peak expiratory flow rates, asthma symptoms, nighttime symptoms, and beta-agonist use. This information was collected every 4 weeks throughout the trial.

All participants also underwent esophageal pH monitoring for an objective confirmation of GERD. Patients were randomized independently of the results of the pH probe; in fact, investigators and patients were blinded to these results.

The primary outcome measure was the rate of episodes of poor asthma control, with poor control defined as any of the following:

  • A decrease of 30% or more in the morning peak expiratory flow rate on 2 consecutive days, compared with the patient’s best rate during the run-in period
  • An urgent visit, defined as an unscheduled health care visit, for asthma symptoms
  • The need for a course of oral prednisone for treatment of asthma.

Asthma was defined as doctor-diagnosed, plus either a positive methacholine challenge test (a concentration of methacholine causing a 20% reduction in FEV1 [PC20] < 16 mg/mL) or a positive bronchodilator response (a 12% increase in FEV1) to an inhaled beta-agonist. Participants had no other indication for acid suppression, including symptoms of GERD or previously diagnosed erosive esophageal or gastric disease.

Acid reflux was evaluated by ambulatory pH monitoring, which had to last at least 16 hours and span one meal and 2 hours in the recumbent position. Reflux was present if the pH was less than 4.0 for more than 5.8% of total time, 8.2% of time upright, or 3.5% of time lying down.33 Episodes and severity were measured by the Gastroesophageal Reflux Disease Symptom Assessment Scale.34

 

 

SARA RESULTS: NO IMPROVEMENT IN ASTHMA WITH GERD TREATMENT

The SARA treatment and control groups had similar baseline characteristics, with similar asthma symptoms. Most of the patients were women: 72% of the placebo group and 64% of the esomeprazole group. Most had baseline spirometric results at the lower end of normal (the mean FEV1 was 76% ± 16 SD in the treatment group and 78% ± 15 in the placebo group) and had very poor asthma control, with an average Juniper Asthma Control Questionnaire score of 1.9 (> 1.5 is considered poor control).31 GERD was documented with esophageal pH monitoring in 40% of patients, showing that a significant number had silent GERD.

Episodes of poor asthma control occurred with similar frequency in the esomeprazole and placebo groups (2.5 vs 2.3 events per personyear, P = .66). Treatment made no difference in this end point regardless of the baseline results of pH monitoring. No treatment effect was noted in the individual components of the episodes of poor asthma control or in secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life.

In addition, subgroup analysis failed to identify any group—including those with documented reflux on pH probe testing or those receiving a long-acting beta-agonist—who benefited from proton pump inhibitor therapy.

The investigators concluded that these data suggest treatment of silent GERD does not improve asthma control and thus that a reevaluation of current guidelines and clinical practice is warranted.2

ISSUES REMAIN

This large clinical trial, in which asthma and GERD were well defined and objectively measured, was robustly negative in terms of showing any benefit of treatment of silent GERD on asthma control. The study population was representative of those for whom such a treatment is recommended in the current NIH guidelines, which are based on data published prior to SARA.

However, while SARA was well designed and had clear results, it had some limitations, and some issues regarding GERD and asthma remain unanswered.

Is acid the only problem in GERD? SARA focused on acidic GERD. Aspiration of substances such as pancreatic enzymes, pepsin, and bile has also been shown to induce symptoms in asthma patients.2,32,35 In addition, distention of the esophagus and stimulation of neurogenically mediated reflexes can cause symptoms or neurogenic airway inflammation that is not mitigated by drugs that target acid reflux.32

Indirectly supporting this theory is evidence that surgical interventions such as fundoplication can improve asthma symptoms. 36 However, this evidence is only from small studies with significant limitations.

Is proximal GERD worse than distal GERD? SARA did not address whether proximal and distal reflux may affect asthma differently. The importance of proximal reflux in asthma has not been clearly established, but there is evidence that patients with proximal GERD have a higher incidence of nocturnal cough than patients who have only distal reflux. 37

Dimango et al38 recently reported additional data from SARA in which patients with poorly controlled asthma underwent both proximal and distal esophageal pH monitoring to see if proximal GERD was associated with poor asthma control: 304 patients underwent dual pH-probe assessment and 38% of them had proximal reflux. The authors found no difference between those with and without proximal GERD with regard to nocturnal awakenings, need to use a rescue inhaler, inhaled controller medication dose, lung function, or airway reactivity by methacholine challenge. However, they did find that those with proximal GERD had worse asthma quality-of-life scores, and worse health-related quality-of-life scores and were more likely to complain of cough.

Thus, it appears that proximal GERD may worsen quality of life in asthmatic patients but does not worsen asthma control.

SARA RESULTS: IMPLICATIONS FOR MANAGEMENT

The SARA results suggest that patients with poorly controlled asthma who are on adequate controller medications should not be treated empirically for silent GERD in the expectation that the asthma will improve. Rather, they suggest that the focus should be on other factors that can worsen asthma control, such as the ability to properly use an inhaler, the ability to afford medications, compliance with drug treatment, and adequate control of other significant comorbidities such as allergic bronchopulmonary aspergillosis, sinusitis, allergic rhinitis, vocal cord dysfunction, and occult heart disease. The most recent NIH guidelines also suggest considering referral to an asthma specialist if symptoms persist despite adequate controller therapy.

Should patients with poorly controlled asthma be treated empirically for gastroesphageal reflux disease (GERD)?

Current guidelines1 indicate that trying a proton pump inhibitor may be worthwhile. However, the results of a recent multicenter trial2 indicate that this does not help control asthma symptoms and that we need to reevaluate the guidelines and focus on other factors that can worsen asthma control.

REFLUX DISEASE IS LINKED TO ASTHMA

GERD’s association with asthma has long been recognized. Asthma patients have a higher prevalence of GERD than the general population, with reported rates of 20% to 80%.3–8

GERD may worsen asthma via several mechanisms. If stomach acid gets into the airway, it can induce bronchoconstriction, vagal reflexes, and chronic airway inflammation, all of which can increase airway reactivity.9–16 Chronic reflux can also cause inflammation of the esophagus, which can exacerbate cough and possibly bronchospasm via neurogenic mechanisms.17

In turn, asthma may worsen GERD. Airway restriction can lead to hyperinflation and increased negative inspiratory pleural pressure, both of which may reduce the effectiveness of the lower esophageal sphincter.18 In addition, the beta-agonists and methylxanthines used to treat asthma may impair function of the lower esophageal sphincter and exacerbate reflux.18–20

CURRENT GUIDELINES ARE BASED ON LIMITED INFORMATION

The symptoms of GERD and asthma are nonspecific and can be similar (chest tightness, chest discomfort), which can make it challenging for clinicians or patients to distinguish asthma from GERD.2 Moreover, in asthma patients, GERD often presents without classic symptoms such as heartburn, and thus has been labeled “silent” GERD.

Earlier studies21–29 (Table 1) suggested that treating GERD may improve asthma control. Based on this information, the most recent asthma guidelines from the National Institutes of Health (NIH) recommend trying GERD treatment in patients with poorly controlled asthma, even if they do not have classic GERD symptoms.1

However, these studies all had significant limitations, such as small sample size. Also, the definitions of asthma and GERD differed from study to study. In some cases, the definition of GERD included self-reported GERD, which often fails to correlate with GERD documented with esophageal pH monitoring in asthma patients.1 These limitations were highlighted in a Cochrane review,30 which found that asthma patients with GERD showed no overall improvement in asthma after treatment of reflux. It concluded that small groups of patients may benefit, but that predicting who will respond is difficult.

Larger randomized controlled trials28,29 attempted to address some of these limitations, with varying results.

Littner et al29 gave lansoprazole (Prevacid) 30 mg twice daily or placebo to 207 patients with moderate to severe asthma and symptomatic GERD and saw no improvement in daily asthma symptoms, ie, asthma control in the active-treatment group. While these patients had an improvement in symptoms of severe reflux, their overall quality-of-life scores were similar to those of the placebo group. Of note, patients needing more than one type of drug for asthma control had a lower rate of asthma exacerbations.

Kiljander et al28 gave esomeprazole (Nexium) 40 mg twice daily or placebo to 770 patients who had mild to moderate asthma and symptoms of nocturnal asthma with or without symptoms of GERD. The only benefit was a slight improvement in peak expiratory flow in those with symptoms of both GERD and nocturnal asthma, and this was most significant in patients taking long-acting beta-agonists. Other measures—eg, the forced expiratory volume in the first second (FEV1), use of a beta-agonist, symptom scores, and nocturnal awakenings—did not improve.

In both of these studies,28,29 patients reported symptoms of GERD, so they did not have silent GERD.

THE DESIGN OF SARA

To address the limitations of the studies discussed above and evaluate the effect on asthma control of treating silent GERD, the American Lung Association and the National Heart, Lung, and Blood Institute funded the multicenter Study of Acid Reflux in Asthma (SARA) (Table 2).2

In SARA, 412 patients age 18 and older with inadequately controlled asthma were randomized to receive esomeprazole 40 mg twice a day or placebo for 24 weeks. Inadequate control was defined as a score of 1.5 or higher on the Juniper Asthma Control Questionnaire31 despite treatment with inhaled corticosteroids. Patients had no symptoms of GERD. The 40-mg twice-daily dosage of esomeprazole was chosen because it is known to suppress more than 90% of acid reflux.24,32

All patients completed a baseline asthma diary, recording peak expiratory flow rates, asthma symptoms, nighttime symptoms, and beta-agonist use. This information was collected every 4 weeks throughout the trial.

All participants also underwent esophageal pH monitoring for an objective confirmation of GERD. Patients were randomized independently of the results of the pH probe; in fact, investigators and patients were blinded to these results.

The primary outcome measure was the rate of episodes of poor asthma control, with poor control defined as any of the following:

  • A decrease of 30% or more in the morning peak expiratory flow rate on 2 consecutive days, compared with the patient’s best rate during the run-in period
  • An urgent visit, defined as an unscheduled health care visit, for asthma symptoms
  • The need for a course of oral prednisone for treatment of asthma.

Asthma was defined as doctor-diagnosed, plus either a positive methacholine challenge test (a concentration of methacholine causing a 20% reduction in FEV1 [PC20] < 16 mg/mL) or a positive bronchodilator response (a 12% increase in FEV1) to an inhaled beta-agonist. Participants had no other indication for acid suppression, including symptoms of GERD or previously diagnosed erosive esophageal or gastric disease.

Acid reflux was evaluated by ambulatory pH monitoring, which had to last at least 16 hours and span one meal and 2 hours in the recumbent position. Reflux was present if the pH was less than 4.0 for more than 5.8% of total time, 8.2% of time upright, or 3.5% of time lying down.33 Episodes and severity were measured by the Gastroesophageal Reflux Disease Symptom Assessment Scale.34

 

 

SARA RESULTS: NO IMPROVEMENT IN ASTHMA WITH GERD TREATMENT

The SARA treatment and control groups had similar baseline characteristics, with similar asthma symptoms. Most of the patients were women: 72% of the placebo group and 64% of the esomeprazole group. Most had baseline spirometric results at the lower end of normal (the mean FEV1 was 76% ± 16 SD in the treatment group and 78% ± 15 in the placebo group) and had very poor asthma control, with an average Juniper Asthma Control Questionnaire score of 1.9 (> 1.5 is considered poor control).31 GERD was documented with esophageal pH monitoring in 40% of patients, showing that a significant number had silent GERD.

Episodes of poor asthma control occurred with similar frequency in the esomeprazole and placebo groups (2.5 vs 2.3 events per personyear, P = .66). Treatment made no difference in this end point regardless of the baseline results of pH monitoring. No treatment effect was noted in the individual components of the episodes of poor asthma control or in secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life.

In addition, subgroup analysis failed to identify any group—including those with documented reflux on pH probe testing or those receiving a long-acting beta-agonist—who benefited from proton pump inhibitor therapy.

The investigators concluded that these data suggest treatment of silent GERD does not improve asthma control and thus that a reevaluation of current guidelines and clinical practice is warranted.2

ISSUES REMAIN

This large clinical trial, in which asthma and GERD were well defined and objectively measured, was robustly negative in terms of showing any benefit of treatment of silent GERD on asthma control. The study population was representative of those for whom such a treatment is recommended in the current NIH guidelines, which are based on data published prior to SARA.

However, while SARA was well designed and had clear results, it had some limitations, and some issues regarding GERD and asthma remain unanswered.

Is acid the only problem in GERD? SARA focused on acidic GERD. Aspiration of substances such as pancreatic enzymes, pepsin, and bile has also been shown to induce symptoms in asthma patients.2,32,35 In addition, distention of the esophagus and stimulation of neurogenically mediated reflexes can cause symptoms or neurogenic airway inflammation that is not mitigated by drugs that target acid reflux.32

Indirectly supporting this theory is evidence that surgical interventions such as fundoplication can improve asthma symptoms. 36 However, this evidence is only from small studies with significant limitations.

Is proximal GERD worse than distal GERD? SARA did not address whether proximal and distal reflux may affect asthma differently. The importance of proximal reflux in asthma has not been clearly established, but there is evidence that patients with proximal GERD have a higher incidence of nocturnal cough than patients who have only distal reflux. 37

Dimango et al38 recently reported additional data from SARA in which patients with poorly controlled asthma underwent both proximal and distal esophageal pH monitoring to see if proximal GERD was associated with poor asthma control: 304 patients underwent dual pH-probe assessment and 38% of them had proximal reflux. The authors found no difference between those with and without proximal GERD with regard to nocturnal awakenings, need to use a rescue inhaler, inhaled controller medication dose, lung function, or airway reactivity by methacholine challenge. However, they did find that those with proximal GERD had worse asthma quality-of-life scores, and worse health-related quality-of-life scores and were more likely to complain of cough.

Thus, it appears that proximal GERD may worsen quality of life in asthmatic patients but does not worsen asthma control.

SARA RESULTS: IMPLICATIONS FOR MANAGEMENT

The SARA results suggest that patients with poorly controlled asthma who are on adequate controller medications should not be treated empirically for silent GERD in the expectation that the asthma will improve. Rather, they suggest that the focus should be on other factors that can worsen asthma control, such as the ability to properly use an inhaler, the ability to afford medications, compliance with drug treatment, and adequate control of other significant comorbidities such as allergic bronchopulmonary aspergillosis, sinusitis, allergic rhinitis, vocal cord dysfunction, and occult heart disease. The most recent NIH guidelines also suggest considering referral to an asthma specialist if symptoms persist despite adequate controller therapy.

References
  1. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007; 120( suppl 5):S94–S138.
  2. Mastronarde JG, Anthonisen NR, Castro M, et al., American Lung Association Asthma Clinical Research Centers Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009; 360:1487–1499.
  3. Harding SM, Guzzo MR, Richter JE. 24-h Esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events. Chest 1999; 115:654–659.
  4. Sontag SJ, O’Connell S, Khandelwal S, et al Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613–620.
  5. Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000; 162:34–39.
  6. Vincent D, Cohen-Jonathan AM, Leport J, et al Gastro-oesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur Respir J 1997; 10:2255–2259.
  7. Simpson WG. Gastroesophageal reflux disease and asthma. Diagnosis and management. Arch Intern Med 1995; 155:798–803.
  8. Irwin RS, Curley FJ, French CL. Difficult-to-control asthma. Contributing factors and outcome of a systematic management protocol. Chest 1993; 103:1662–1669.
  9. Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest 1997; 111:1389–1402.
  10. Richter JE. Asthma and gastroesophageal reflux disease: the truth is difficult to define. Chest 1999; 116:1150–1152.
  11. Ekstrom T, Tibbling L. Esophageal acid perfusion, airway function, and symptoms in asthmatic patients with marked bronchial hyperreactivity. Chest 1989; 96:995–998.
  12. Herve P, Denjean A, Jian R, Simonneau G, Duroux P. Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am Rev Respir Dis 1986; 134:986–989.
  13. Wu DN, Tanifuji Y, Kobayashi H, et al Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma. Chest 2000; 118:1553–1556.
  14. Cuttitta G, Cibella F, Visconti A, Scichilone N, Bellia V, Bonsignore G. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med 2000; 161:177–181.
  15. Jack CI, Calverley PM, Donnelly RJ, et al Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastrooesophageal reflux. Thorax 1995; 50:201–204.
  16. Harding SM, Schan CA, Guzzo MR, Alexander RW, Bradley LA, Richter JE. Gastroesophageal reflux-induced bronchoconstriction. Is microaspiration a factor? Chest 1995; 108:1220–1227.
  17. Irwin RS, Madison JM, Fraire AE. The cough reflex and its relation to gastroesophageal reflux. Am J Med 2000; 108( suppl 4a):73S–78S.
  18. Choy D, Leung R. Gastro-oesophageal reflux disease and asthma. Respirology 1997; 2:163–168.
  19. Zerbib F, Guisset O, Lamouliatte H, Quinton A, Galmiche JP, Tunon-De-Lara JM. Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Am J Respir Crit Care Med 2002; 166:1206–1211.
  20. Lacy BE, Mathis C, DesBiens J, Liu MC. The effects of nebulized albuterol on esophageal function in asthmatic patients. Dig Dis Sci 2008; 53:2627–2633.
  21. Ford GA, Oliver PS, Prior JS, Butland RJ, Wilkinson SP. Omeprazole in the treatment of asthmatics with nocturnal symptoms and gastrooesophageal reflux: a placebo-controlled cross-over study. Postgrad Med J 1994; 70:350–354.
  22. Teichtahl H, Kronborg IJ, Yeomans ND, Robinson P. Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma. Aust N Z J Med 1996; 26:671–676.
  23. Meier JH, McNally PR, Punja M, et al Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double-blind, placebo-controlled crossover study. Dig Dis Sci 1994; 39:2127–2133.
  24. Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996; 100:395–405.
  25. Levin TR, Sperling RM, McQuaid KR. Omeprazole improves peak expiratory flow rate and quality of life in asthmatics with gastroesophageal reflux. Am J Gastroenterol 1998; 93:1060–1063.
  26. Boeree MJ, Peters FT, Postma DS, Kleibeuker JH. No effects of highdose omeprazole in patients with severe airway hyperresponsiveness and (a)symptomatic gastro-oesophageal reflux. Eur Respir J 1998; 11:1070–1074.
  27. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999; 116:1257–1264.
  28. Kiljander TO, Harding SM, Field SK, et al Effects of eso-meprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006; 173:1091–1097.
  29. Littner MR, Leung FW, Ballard ED, Huang B, Samra NKLansoprazole Asthma Study Group. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128:1128–1135.
  30. Gibson PG, Henry R, Coughlan JJL. Gastro-oesophageal reflux treatment for asthma in adults and children. Coch-rane Database Syst Rev 2000;CD001496. Also available online at www.cochrane.org/reviews/en/ab001496.html. Accessed January 28, 2010.
  31. Juniper EF, Bousquet J, Abetz L, Bateman EDGOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med 2006; 100:616–621.
  32. Canning BJ, Mazzone SB. Reflex mechanisms in gastro-esophageal reflux disease and asthma. Am J Med 2003; 115( suppl 3A):45S–48S.
  33. Richter JE, Bradley LA, DeMeester TR, Wu WC. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age, and gender. Dig Dis Sci 1992; 37:849–856.
  34. Damiano A, Handley K, Adler E, Siddique R, Bhattacharyja A. Measuring symptom distress and health-related quality of life in clinical trials of gastroesophageal reflux disease treatment: further validation of the Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS). Dig Dis Sci 2002; 47:1530–1537.
  35. Asano K, Suzuki H. Silent acid reflux and asthma control [editorial]. N Engl J Med 2009; 360:1551–1553.
  36. Rakita S, Villadolid D, Thomas A, et al Laparoscopic Nissen fundoplication offers high patient satisfaction with relief of extraesophageal symptoms of gastroesophageal reflux disease. Am Surg 2006; 72:207–212.
  37. Tomonaga T, Awad ZT, Filipi CJ, et al Symptom predictability of reflux-induced respiratory disease. Dig Dis Sci 2002; 47:9–14.
  38. Dimango E, Holbrook JT, Simpson E, et al., American Lung Association Asthma Clinical Research Centers. Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity. Am J Respir Crit Care Med 2009; 180:809–816.
References
  1. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007; 120( suppl 5):S94–S138.
  2. Mastronarde JG, Anthonisen NR, Castro M, et al., American Lung Association Asthma Clinical Research Centers Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009; 360:1487–1499.
  3. Harding SM, Guzzo MR, Richter JE. 24-h Esophageal pH testing in asthmatics: respiratory symptom correlation with esophageal acid events. Chest 1999; 115:654–659.
  4. Sontag SJ, O’Connell S, Khandelwal S, et al Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990; 99:613–620.
  5. Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000; 162:34–39.
  6. Vincent D, Cohen-Jonathan AM, Leport J, et al Gastro-oesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur Respir J 1997; 10:2255–2259.
  7. Simpson WG. Gastroesophageal reflux disease and asthma. Diagnosis and management. Arch Intern Med 1995; 155:798–803.
  8. Irwin RS, Curley FJ, French CL. Difficult-to-control asthma. Contributing factors and outcome of a systematic management protocol. Chest 1993; 103:1662–1669.
  9. Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest 1997; 111:1389–1402.
  10. Richter JE. Asthma and gastroesophageal reflux disease: the truth is difficult to define. Chest 1999; 116:1150–1152.
  11. Ekstrom T, Tibbling L. Esophageal acid perfusion, airway function, and symptoms in asthmatic patients with marked bronchial hyperreactivity. Chest 1989; 96:995–998.
  12. Herve P, Denjean A, Jian R, Simonneau G, Duroux P. Intraesophageal perfusion of acid increases the bronchomotor response to methacholine and to isocapnic hyperventilation in asthmatic subjects. Am Rev Respir Dis 1986; 134:986–989.
  13. Wu DN, Tanifuji Y, Kobayashi H, et al Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma. Chest 2000; 118:1553–1556.
  14. Cuttitta G, Cibella F, Visconti A, Scichilone N, Bellia V, Bonsignore G. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med 2000; 161:177–181.
  15. Jack CI, Calverley PM, Donnelly RJ, et al Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastrooesophageal reflux. Thorax 1995; 50:201–204.
  16. Harding SM, Schan CA, Guzzo MR, Alexander RW, Bradley LA, Richter JE. Gastroesophageal reflux-induced bronchoconstriction. Is microaspiration a factor? Chest 1995; 108:1220–1227.
  17. Irwin RS, Madison JM, Fraire AE. The cough reflex and its relation to gastroesophageal reflux. Am J Med 2000; 108( suppl 4a):73S–78S.
  18. Choy D, Leung R. Gastro-oesophageal reflux disease and asthma. Respirology 1997; 2:163–168.
  19. Zerbib F, Guisset O, Lamouliatte H, Quinton A, Galmiche JP, Tunon-De-Lara JM. Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Am J Respir Crit Care Med 2002; 166:1206–1211.
  20. Lacy BE, Mathis C, DesBiens J, Liu MC. The effects of nebulized albuterol on esophageal function in asthmatic patients. Dig Dis Sci 2008; 53:2627–2633.
  21. Ford GA, Oliver PS, Prior JS, Butland RJ, Wilkinson SP. Omeprazole in the treatment of asthmatics with nocturnal symptoms and gastrooesophageal reflux: a placebo-controlled cross-over study. Postgrad Med J 1994; 70:350–354.
  22. Teichtahl H, Kronborg IJ, Yeomans ND, Robinson P. Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma. Aust N Z J Med 1996; 26:671–676.
  23. Meier JH, McNally PR, Punja M, et al Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? A double-blind, placebo-controlled crossover study. Dig Dis Sci 1994; 39:2127–2133.
  24. Harding SM, Richter JE, Guzzo MR, Schan CA, Alexander RW, Bradley LA. Asthma and gastroesophageal reflux: acid suppressive therapy improves asthma outcome. Am J Med 1996; 100:395–405.
  25. Levin TR, Sperling RM, McQuaid KR. Omeprazole improves peak expiratory flow rate and quality of life in asthmatics with gastroesophageal reflux. Am J Gastroenterol 1998; 93:1060–1063.
  26. Boeree MJ, Peters FT, Postma DS, Kleibeuker JH. No effects of highdose omeprazole in patients with severe airway hyperresponsiveness and (a)symptomatic gastro-oesophageal reflux. Eur Respir J 1998; 11:1070–1074.
  27. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999; 116:1257–1264.
  28. Kiljander TO, Harding SM, Field SK, et al Effects of eso-meprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006; 173:1091–1097.
  29. Littner MR, Leung FW, Ballard ED, Huang B, Samra NKLansoprazole Asthma Study Group. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128:1128–1135.
  30. Gibson PG, Henry R, Coughlan JJL. Gastro-oesophageal reflux treatment for asthma in adults and children. Coch-rane Database Syst Rev 2000;CD001496. Also available online at www.cochrane.org/reviews/en/ab001496.html. Accessed January 28, 2010.
  31. Juniper EF, Bousquet J, Abetz L, Bateman EDGOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med 2006; 100:616–621.
  32. Canning BJ, Mazzone SB. Reflex mechanisms in gastro-esophageal reflux disease and asthma. Am J Med 2003; 115( suppl 3A):45S–48S.
  33. Richter JE, Bradley LA, DeMeester TR, Wu WC. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age, and gender. Dig Dis Sci 1992; 37:849–856.
  34. Damiano A, Handley K, Adler E, Siddique R, Bhattacharyja A. Measuring symptom distress and health-related quality of life in clinical trials of gastroesophageal reflux disease treatment: further validation of the Gastroesophageal Reflux Disease Symptom Assessment Scale (GSAS). Dig Dis Sci 2002; 47:1530–1537.
  35. Asano K, Suzuki H. Silent acid reflux and asthma control [editorial]. N Engl J Med 2009; 360:1551–1553.
  36. Rakita S, Villadolid D, Thomas A, et al Laparoscopic Nissen fundoplication offers high patient satisfaction with relief of extraesophageal symptoms of gastroesophageal reflux disease. Am Surg 2006; 72:207–212.
  37. Tomonaga T, Awad ZT, Filipi CJ, et al Symptom predictability of reflux-induced respiratory disease. Dig Dis Sci 2002; 47:9–14.
  38. Dimango E, Holbrook JT, Simpson E, et al., American Lung Association Asthma Clinical Research Centers. Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity. Am J Respir Crit Care Med 2009; 180:809–816.
Issue
Cleveland Clinic Journal of Medicine - 77(3)
Issue
Cleveland Clinic Journal of Medicine - 77(3)
Page Number
155-160
Page Number
155-160
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Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
Pulmonology
Gastroenterology
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Treating silent reflux disease does not improve poorly controlled asthma
Display Headline
Treating silent reflux disease does not improve poorly controlled asthma
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Interpreting Key Trials
Inside the Article

KEY POINTS

  • Acid reflux is more prevalent in patients with asthma, and it often occurs without classic symptoms such as heartburn.
  • Current guidelines, based on data from older studies with significant limitations, recommend considering treatment for reflux disease, even without the classic symptoms, in patients with uncontrolled asthma.
  • The recent Study of Acid Reflux in Asthma found not only that treating silent acid reflux does not improve asthma control, but also that esophageal pH monitoring does not detect a subgroup of asthma patients who might respond to a proton pump inhibitor. These data suggest that we should reconsider clinical practice based on current guidelines.
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