Gut Feelings About Asthma
1991; Elsevier BV; Volume: 99; Issue: 6 Linguagem: Inglês
10.1378/chest.99.6.1321
ISSN1931-3543
Autores Tópico(s)Neuroendocrine regulation and behavior
ResumoFrom a little spark may burst a mighty flame. Dante, The Divine Comedy, ParadisoMore than a decade has passed since five physicians (four from Chile and one from North America) hunkered down to discuss an interesting observation: improvement in pulmonary symptoms after correction of gastroesophageal reflux (GER). Determined to become involved in meaningful research, they devised a study with a threefold purpose: (1) to identify patients with pulmonary disease not due to allergies or infection; (2) to determine the prevalence of GER in such a group; and (3) to investigate the effects on pulmonary disease of medical and surgical treatment of GER.Were the investigators justified in devising such a clinical study? The answer appears to be, yes! In the medical literature up until that time, at least 16 articles on the relationship between GER and pulmonary disease already had been published.1Mays EE Intrinsic asthma in adults, association with gastroesophageal reflux.JAMA. 1976; 236: 2626-2628Crossref PubMed Google Scholar, 2Friedland GW Yamare M Marinkovich VA Hiatal hernia and chronic unremitting asthma.Pediatr Radiol. 1973; 1: 156-160Crossref PubMed Scopus (38) Google Scholar, 3Babb RR Notrangelo J Smith VM Wheezing: a clue to gastroesophageal reflux.Am J Gastroenterol. 1970; 53: 230-233PubMed Google Scholar, 4Kennedy JH "Silent" gastroesophageal reflux: an important but little known cause of pulmonary complications.Dis Chest. 1962; 42: 42-45Abstract Full Text Full Text PDF Google Scholar, 5Klotz SD Moeller RK Hiatal hernia and intractable bronchial asthma.Ann Allergy. 1971; 29: 325-328PubMed Google Scholar, 6Overholt RH Ashraf MM Esophageal reflux as a trigger in asthma.NY State J Med. 1966; 66: 3030-3032PubMed Google Scholar, 7Clemencon GH Osterman PO Hiatal hernia in bronchial asthma: The importance of concomitant pulmonary emphysema.Gastroenterologia. 1961; 95 (Basel): 110-120Crossref PubMed Scopus (26) Google Scholar, 8Mays EE Dubois JJ Hamilton GB Pulmonary fibrosis associated with tracheobronchial aspiration: A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology.Chest. 1976; 69: 512-515Crossref PubMed Scopus (185) Google Scholar, 9Urschel HC Paulson DL Gastroesophageal reflux and hiatal hernia: Complications and therapy.J Thor Cardiovasc Surg. 1967; 53: 21-32PubMed Google Scholar, 10Meadows CT Clinical observations regarding sliding hiatal hernia.Dis Chest. 1965; 47: 629-631Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 11Davis MV Evolving concepts regarding hiatus hernia and gastroesophageal reflux.Ann Thorac Surg. 1969; 7: 120-133Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 12Bray GW Recent advances in the treatment of asthma and hay fever.Practitioner. 1934; 34: 368-371Google Scholar, 13Belsey R The pulmonary complications of oesophageal disease.Br J Dis Chest. 1960; 54: 342-348Abstract Full Text PDF Scopus (63) Google Scholar, 14Overholt RH Voorhees RJ Esophageal reflux as a trigger in asthma.Dis Chest. 1966; 49: 464-466Abstract Full Text Full Text PDF PubMed Google Scholar, 15Friedland GW Yamata M Marinkovich VA Hiatal hernia and chronic unremitting asthma.Pediat Radiol. 1973; 1: 156-160Crossref PubMed Google Scholar, 16Lichter I Measurement of gastro-oesophageal acid reflux: its significance in hiatus hernia.Br J Surg. 1974; 61: 253-258Crossref PubMed Scopus (43) Google Scholar No less than six of these studies showed improvement in pulmonary status with antireflux surgery. Since 1977, numerous investigators have reported on epidemiology, mechanisms and clinical trials in an effort to piece together the GER/asthma puzzle.Epidemiologic evidence for the GER/asthma association suggests that about three-fourths of asthmatic patients, independent of the use of bronchodilators,17Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Serlovsky R et al.Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990; 99: 613-620Abstract Full Text PDF PubMed Google Scholar, 18O'Connell S Sontag SJ Miller T Kurucar C Brand L Reid S Asthmatics have a high prevalence of reflux symptoms regardless of the use of bronchodilators.Gastroenterology. 1990; 98: A97Google Scholar, 19Sontag S Schnell T Khandelwal S O'Connell S Chejfec G Asthmatics have endoscopic esophagitis with or without bronchodilator therapy.Am J Gastroenterol. 1989; 84: A1153Google Scholar, 20Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Schnell T Serlovsky R Effect of Positions, eating and bronchodilators on gastroesophageal reflux in asthmatics.Dig Dis Sci. 1990; 35: 849-856Crossref PubMed Scopus (28) Google Scholar have acid GER,17Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Serlovsky R et al.Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990; 99: 613-620Abstract Full Text PDF PubMed Google Scholar increased frequency of reflux episodes,17Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Serlovsky R et al.Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990; 99: 613-620Abstract Full Text PDF PubMed Google Scholar or heartburn;18O'Connell S Sontag SJ Miller T Kurucar C Brand L Reid S Asthmatics have a high prevalence of reflux symptoms regardless of the use of bronchodilators.Gastroenterology. 1990; 98: A97Google Scholar and 40 percent have reflux esophagitis.19Sontag S Schnell T Khandelwal S O'Connell S Chejfec G Asthmatics have endoscopic esophagitis with or without bronchodilator therapy.Am J Gastroenterol. 1989; 84: A1153Google ScholarEvidence also suggests that two separate mechanisms are involved in the GER/asthma relationship. The presence of a vagally mediated reflex arc is supported by the findings that (a) acid infusion of the esophagus in asthmatic patients leads to increased airway flow resistance that rapidly reverses with antacids,21Mansfield LE Stein MR Gastroesophageal reflux and asthma: a possible reflex mechanism.Ann Allergy. 1978; 41: 224-226PubMed Google Scholar and (b) infusion of acid into the distal esophagus of asthmatic children during sleep induces bronchoconstriction.22Davis RS Larsen GL Grunstein MM Respiratory response to intraesophageal acid infusion in asthmatic children during sleep.J Allergy Clin Immunol. 1983; 72: 393-398Abstract Full Text PDF PubMed Scopus (109) Google Scholar Microaspiration as a cause of asthma is supported by the findings of (a) a large vagally mediated increase in airway flow resistance when minute quantities of hydrochloric acid are infused into the trachea of cats;23Tuchman DN Boyle JT Pack AI Comparison of airway responses following tracheal or oesophageal acidification in the cat.Gastroenterology. 1984; 87: 872-881PubMed Google Scholar (b) a high prevalence rate of hiatus hernias and GER in patients with idiopathic pulmonary fibrosis24Mays EE Dubois J Hamilton GB Pulmonary fibrosis associated with tracheobronchial aspiration: A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology.Chest. 1976; 69: 512-515Crossref PubMed Google Scholar or severe asthma;7Clemencon GH Osterman PO Hiatal hernia in bronchial asthma: The importance of concomitant pulmonary emphysema.Gastroenterologia. 1961; 95 (Basel): 110-120Crossref PubMed Scopus (26) Google Scholar (c) GER in 60 percent of children with recurrent bronchitis;26Danus O Casar C Larrain A Pope II, CE Esophageal reflux—an unrecognized cause of recurrent obstructive bronchitis in children.J Pediatr. 1976; 89: 220-224Abstract Full Text PDF PubMed Scopus (107) Google Scholar (d) GER in 63 percent of children with chronic asthma or recurrent pneumonia.27Euler AR Byrne WJ Ament ME et al.Recurrent pulmonary disease in children: A complication of gastroesophageal reflux.Pediatrics. 1979; 63: 47-51Crossref PubMed Google ScholarThe evidence of a GER/asthma relationship also has gained support in the results of certain clinical trials. The effect on asthma of medical therapy for GER has been reported previously. An open trial of antacids and postural therapy reported improvement in pulmonary symptoms, but not function.28Kjellen G Tibbling L Wranne B Effect of conservative treatment of oesophageal dysfunction on bronchial asthma.Eur J Respir Dis. 1981; 62: 190-197PubMed Google Scholar Four studies using cimetidine or ranitidine for up to eight weeks produced results ranging from no benefit to modest improvement of only nocturnal asthma symptoms.29Goodall RJR Earis JE Cooper DN Bernstein A Temple JG Relationship between asthma and gastroesophageal reflux.Thorax. 1981; 36: 116-121Crossref PubMed Scopus (150) Google Scholar, 30Harper PC Bergner A Kaye MD Antireflux treatment for asthma. Improvement in patients with associated gastroesophageal reflux.Arch Intern Med. 1987; 147: 56-60Crossref PubMed Scopus (107) Google Scholar, 31Ekstrom T Lindgren BR Tibbling L Effects of ranitidine treatment on patients with asthma and a history of gastro-oesophageal reflux: a double blind crossover study.Thorax. 1989; 44: 19-23Crossref PubMed Scopus (113) Google Scholar, 32Nagel RA Brown P Perks WH Wilson RSE Kerr GD Ambulatory pH monitoring of gastro-oesophageal reflux in "morning dipper" asthmatics.Br Med J. 1988; 297: 1371-1373Crossref PubMed Scopus (88) Google Scholar Unfortunately, such short-term studies using low dosages of H2 blockers are unreliable in assessing improvement. One patient with disabling asthma, however, reportedly obtained dramatic improvement in pulmonary symptoms and function when gastric acid was suppressed with omeprazole.33Depla AC Bartelsman JF Roos CM Tytgat GN Jansen HM Beneficial effect of omeprazole in a patient with severe bronchial asthma and gastro-oesophageal reflux.Eur J Respir Dis. 1988; 1: 966-968Google ScholarThe effect on asthma of surgical correction of GER has also been reported. In earlier, uncontrolled studies, surgical repair of GER resulted in partial or complete remission of asthma in 17 of 18 patients,34Overholt RH Voorhees RJ Esophageal reflux as a trigger in asthma.Dis Chest. 1966; 49: 464-466Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar 24 of 27 patients,35Urschel HC Paulson DL Gastroesophageal reflux and hiatal hernia: Complications and therapy.J Thor Cardiovasc Surg. 1967; 53: 21-32PubMed Google Scholar all of 16 patients,36Lomasney TL Hiatus hernia and the respiratory tract.Ann Thorac Surg. 1977; 24: 448-450Abstract Full Text PDF PubMed Scopus (38) Google Scholar and 70 percent of adolescent asthmatic patients.37Johnson DG Syme WC Matlak ME Black RE Herbst SJ Gastro-oesophageal reflux and respiratory disease: the place of the surgeon.Aust N Z J Surg. 1984; 54: 405-415Crossref PubMed Scopus (16) Google Scholar Pulmonary function tests, unfortunately, were not performed before and after surgical repair. Despite the lack of objective data, many patients had dramatic subjective improvement in asthma from antireflux surgery.Three uncontrolled but more recent surgical studies do provide objective data both before and after treatment: (1) 12 of 13 asthmatic patients improved after antireflux surgery, and most were able to reduce or discontinue completely the pulmonary medications;38Sontag SJ O'Connell SA Greenlee HB Schnell TG et al.Is gastroesophageal reflux a factor in some asthmatics.Am J Gastroenterol. 1987; 82: 119-126PubMed Google Scholar (2) seven of ten asthmatics had at least temporary improvement in pulmonary function;39Tardiff C Nouvet G Denis P Tombelaine R Pasquis P Surgical treatment of gastroesophageal reflux in ten patients with severe asthma.Respiration. 1989; 56: 110-115Crossref PubMed Scopus (43) Google Scholar 13 of 44 asthmatic patients who received surgical correction of GER at least five years earlier, marked improvement or cure occurred in 41 percent and moderate improvement was achieved in 27 percent.40Perrin-Fayolle M Gormand F Braillon G Lombard-Platel F Vignol J Azzar D et al.Long-term results of surgical treatment for gastroesophageal reflux in asthmatic patients.Chest. 1989; 96: 40-45Abstract Full Text Full Text PDF PubMed Scopus (96) Google ScholarUnfortunately, there is no acceptable diagnostic method available to confirm the presence of GER-induced asthma. Scintigraphic monitoring under controlled conditions has been largely unsuccessful. Therefore, it appears that clinical trials are the only available means to assess whether medical or surgical treatment of GER in patients with both GER and asthma improves the symptoms of asthma and decreases the need for pulmonary medications. Now, here comes a group from the Americas to report on how to do it right.In this issue (see page 1330) Larrain et al report the results of their initial six-month study, as well as the five or more years of followup. The methodology was impressive. Patients presented to the pulmonary clinic because of pulmonary symptoms. They were not a selected group with reflux symptoms who incidentally had pulmonary disease. The study was placebo-controlled and randomized. Few patients dropped out after randomization. Treatment (including surgery) was started within two weeks of randomization. Followup was done by two chest physicians who were not involved in the selection or randomization process. Private physicians, not the investigator, adjusted their patient's medications. The investigators enrolled only patients with intrinsic asthma and excluded those with atopic asthma and COPD.Of the 142 patients screened, 94 had GER and 90 consented to randomization. Nine patients dropped out or refused their assigned treatment, leaving 28 patients in the placebo group, 27 patients in the cimetidine 300 mg qid group, and 26 patients in the surgical group.The clinical response to treatment was based on four parameters: (1) symptom score; (2) medication score; (3) response to questions about improvement; and (4) the need for corticosteroids.Although the symptom score of all three groups improved from baseline by the end of six months, the mean score was significantly better in the surgical group and cimetidine group than in the placebo group. Thus, reflux treatment either by medicine or by surgery improved asthmatic symptoms when compared with placebo. Similar results were obtained for the mean medication score. At six months, the cimetidine group required less medication, the surgical group required substantially less medication, but the placebo group required the same or needed even more.When asked whether the wheezing had improved greatly, 80 percent of the cimetidine and surgical groups but only 40 percent of the placebo group answered "yes." Furthermore, half of the cimetidine group and 40 percent of the surgical group but only 7 percent of the placebo group said that the pulmonary symptoms had vanished. Regarding the need for corticosteroids, 2 of 13 cimetidine patients (15 percent), 3 of 11 surgical patients (27 percent), but none of 28 placebo patients were able to discontinue prednisone.As would be expected, pH testing at the end of six months showed that in almost all patients GER was still present if surgery had not been performed.The investigators analyzed numerous variables to demonstrate improvement in asthma. Indeed, the symptom and medication scores, the improvement questions, and the need for corticosteroid therapy were consistent in each group: no improvement with placebo; improvement with cimetidine or surgery. Why, then, did no group have significant improvement in the pulmonary function tests (FVC, FEV1 and MMEFR)? The authors do not address this potential inconsistency. One possible explanation could be that the results of the pulmonary function tests do not matter; that pulmonary function testing does not necessarily correlate with the short-term clinical results. Important changes that may occur during a six-month study include an alteration in the need for pulmonary medications. Indeed, the investigators reported a decrease or discontinuation of prednisone and bronchodilators in the medical and surgical patients. It may be unrealistic to expect pulmonary function to improve in such a short period, while at the same time bronchodilators and corticosteroids are being reduced or stopped, it should not be surprising that pulmonary function parameters do not improve. Furthermore, infrequent measurement of the FVC, FEV1, and MMEFR are not the most clinically reliable indicators of asthma improvement. More appropriate clinical indicators, such as daily PEFRs and percentage of variation, may have demonstrated stability and improvement in the pulmonary status.41Williams MH Evaluation of asthma.Chest. 1979; 76: 3-4Crossref PubMed Scopus (12) Google Scholar,42Hetzel MR The pulmonary clock.Thorax. 1981; 36: 481-486Crossref PubMed Scopus (88) Google Scholar Therefore, the inability to demonstrate improvement in the measured pulmonary function variables is not necessarily inconsistent with the reported clinical improvement.There are, of course, bound to be some criticisms of the study. These might include the methods used to detect reflux, the definition of reflux and asthma, the use of scoring systems for symptoms and medications, and the absence of endoscopic followup. Although endoscopic changes in the esophageal mucosa would have provided additional information, the chaotic years in Chile between 1976 and 1978 may have prevented such internal inspection. Minor deficiencies in the six-month study should not detract from the overall importance of the results.The most exquisite folly is made of wisdom spun too fine.Benjamin Franklin.It is to the credit of these investigators that data from 42 patients were available after more than five years. Twenty-two of 28 surgical patients and 20 of 28 placebo patients were available for follow-up. In patients who had undergone surgery, 11 of 22 (50 percent) still reported freedom from respiratory symptoms for a mean of 77 months after the six-month study was finished. Only 1 of 20 patients (5 percent) who had received 6 months of placebo treatment reported freedom from respiratory symptoms for a mean follow-up of 72 months. The investigators conclude that the study supports the hypothesis that GER can initiate or promote pulmonary symptoms.This is the first study of its kind to implicate so strongly the role of GER in the asthmatic state. No longer can we ignore the coexistence of both wheezing and indigestion. Nevertheless, how and in whom these two common afflictions coexist needs further study. The authors, using their clinical acumen, came up with certain markers that, they suggest, might help identify patients who could benefit from antireflux treatment. These predictors include (1) onset of reflux symptoms before the onset of pulmonary symptoms; (2) the presence of nocturnal asthma; (3) signs of laryngeal irritation; and (4) an initial pulmonary response to medical reflux management.Without doubt, the controversy among investigators from different disciplines on the exact role of GER in asthma is likely to remain heated. Accordingly, Larrain et al have provided the fuel to keep the pulmonologists and gastroenterologists in flames. It would be a tribute to Drs. Larrain, Carrasco, Galleguillos, Sepulveda and Pope if the results of their efforts stimulated further research into the poorly understood relationship between gastroesophageal reflux and asthma. From a little spark may burst a mighty flame. Dante, The Divine Comedy, Paradiso More than a decade has passed since five physicians (four from Chile and one from North America) hunkered down to discuss an interesting observation: improvement in pulmonary symptoms after correction of gastroesophageal reflux (GER). Determined to become involved in meaningful research, they devised a study with a threefold purpose: (1) to identify patients with pulmonary disease not due to allergies or infection; (2) to determine the prevalence of GER in such a group; and (3) to investigate the effects on pulmonary disease of medical and surgical treatment of GER. Were the investigators justified in devising such a clinical study? The answer appears to be, yes! In the medical literature up until that time, at least 16 articles on the relationship between GER and pulmonary disease already had been published.1Mays EE Intrinsic asthma in adults, association with gastroesophageal reflux.JAMA. 1976; 236: 2626-2628Crossref PubMed Google Scholar, 2Friedland GW Yamare M Marinkovich VA Hiatal hernia and chronic unremitting asthma.Pediatr Radiol. 1973; 1: 156-160Crossref PubMed Scopus (38) Google Scholar, 3Babb RR Notrangelo J Smith VM Wheezing: a clue to gastroesophageal reflux.Am J Gastroenterol. 1970; 53: 230-233PubMed Google Scholar, 4Kennedy JH "Silent" gastroesophageal reflux: an important but little known cause of pulmonary complications.Dis Chest. 1962; 42: 42-45Abstract Full Text Full Text PDF Google Scholar, 5Klotz SD Moeller RK Hiatal hernia and intractable bronchial asthma.Ann Allergy. 1971; 29: 325-328PubMed Google Scholar, 6Overholt RH Ashraf MM Esophageal reflux as a trigger in asthma.NY State J Med. 1966; 66: 3030-3032PubMed Google Scholar, 7Clemencon GH Osterman PO Hiatal hernia in bronchial asthma: The importance of concomitant pulmonary emphysema.Gastroenterologia. 1961; 95 (Basel): 110-120Crossref PubMed Scopus (26) Google Scholar, 8Mays EE Dubois JJ Hamilton GB Pulmonary fibrosis associated with tracheobronchial aspiration: A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology.Chest. 1976; 69: 512-515Crossref PubMed Scopus (185) Google Scholar, 9Urschel HC Paulson DL Gastroesophageal reflux and hiatal hernia: Complications and therapy.J Thor Cardiovasc Surg. 1967; 53: 21-32PubMed Google Scholar, 10Meadows CT Clinical observations regarding sliding hiatal hernia.Dis Chest. 1965; 47: 629-631Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 11Davis MV Evolving concepts regarding hiatus hernia and gastroesophageal reflux.Ann Thorac Surg. 1969; 7: 120-133Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 12Bray GW Recent advances in the treatment of asthma and hay fever.Practitioner. 1934; 34: 368-371Google Scholar, 13Belsey R The pulmonary complications of oesophageal disease.Br J Dis Chest. 1960; 54: 342-348Abstract Full Text PDF Scopus (63) Google Scholar, 14Overholt RH Voorhees RJ Esophageal reflux as a trigger in asthma.Dis Chest. 1966; 49: 464-466Abstract Full Text Full Text PDF PubMed Google Scholar, 15Friedland GW Yamata M Marinkovich VA Hiatal hernia and chronic unremitting asthma.Pediat Radiol. 1973; 1: 156-160Crossref PubMed Google Scholar, 16Lichter I Measurement of gastro-oesophageal acid reflux: its significance in hiatus hernia.Br J Surg. 1974; 61: 253-258Crossref PubMed Scopus (43) Google Scholar No less than six of these studies showed improvement in pulmonary status with antireflux surgery. Since 1977, numerous investigators have reported on epidemiology, mechanisms and clinical trials in an effort to piece together the GER/asthma puzzle. Epidemiologic evidence for the GER/asthma association suggests that about three-fourths of asthmatic patients, independent of the use of bronchodilators,17Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Serlovsky R et al.Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990; 99: 613-620Abstract Full Text PDF PubMed Google Scholar, 18O'Connell S Sontag SJ Miller T Kurucar C Brand L Reid S Asthmatics have a high prevalence of reflux symptoms regardless of the use of bronchodilators.Gastroenterology. 1990; 98: A97Google Scholar, 19Sontag S Schnell T Khandelwal S O'Connell S Chejfec G Asthmatics have endoscopic esophagitis with or without bronchodilator therapy.Am J Gastroenterol. 1989; 84: A1153Google Scholar, 20Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Schnell T Serlovsky R Effect of Positions, eating and bronchodilators on gastroesophageal reflux in asthmatics.Dig Dis Sci. 1990; 35: 849-856Crossref PubMed Scopus (28) Google Scholar have acid GER,17Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Serlovsky R et al.Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990; 99: 613-620Abstract Full Text PDF PubMed Google Scholar increased frequency of reflux episodes,17Sontag S O'Connell S Khandelwal S Miller T Nemchausky B Serlovsky R et al.Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy.Gastroenterology. 1990; 99: 613-620Abstract Full Text PDF PubMed Google Scholar or heartburn;18O'Connell S Sontag SJ Miller T Kurucar C Brand L Reid S Asthmatics have a high prevalence of reflux symptoms regardless of the use of bronchodilators.Gastroenterology. 1990; 98: A97Google Scholar and 40 percent have reflux esophagitis.19Sontag S Schnell T Khandelwal S O'Connell S Chejfec G Asthmatics have endoscopic esophagitis with or without bronchodilator therapy.Am J Gastroenterol. 1989; 84: A1153Google Scholar Evidence also suggests that two separate mechanisms are involved in the GER/asthma relationship. The presence of a vagally mediated reflex arc is supported by the findings that (a) acid infusion of the esophagus in asthmatic patients leads to increased airway flow resistance that rapidly reverses with antacids,21Mansfield LE Stein MR Gastroesophageal reflux and asthma: a possible reflex mechanism.Ann Allergy. 1978; 41: 224-226PubMed Google Scholar and (b) infusion of acid into the distal esophagus of asthmatic children during sleep induces bronchoconstriction.22Davis RS Larsen GL Grunstein MM Respiratory response to intraesophageal acid infusion in asthmatic children during sleep.J Allergy Clin Immunol. 1983; 72: 393-398Abstract Full Text PDF PubMed Scopus (109) Google Scholar Microaspiration as a cause of asthma is supported by the findings of (a) a large vagally mediated increase in airway flow resistance when minute quantities of hydrochloric acid are infused into the trachea of cats;23Tuchman DN Boyle JT Pack AI Comparison of airway responses following tracheal or oesophageal acidification in the cat.Gastroenterology. 1984; 87: 872-881PubMed Google Scholar (b) a high prevalence rate of hiatus hernias and GER in patients with idiopathic pulmonary fibrosis24Mays EE Dubois J Hamilton GB Pulmonary fibrosis associated with tracheobronchial aspiration: A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology.Chest. 1976; 69: 512-515Crossref PubMed Google Scholar or severe asthma;7Clemencon GH Osterman PO Hiatal hernia in bronchial asthma: The importance of concomitant pulmonary emphysema.Gastroenterologia. 1961; 95 (Basel): 110-120Crossref PubMed Scopus (26) Google Scholar (c) GER in 60 percent of children with recurrent bronchitis;26Danus O Casar C Larrain A Pope II, CE Esophageal reflux—an unrecognized cause of recurrent obstructive bronchitis in children.J Pediatr. 1976; 89: 220-224Abstract Full Text PDF PubMed Scopus (107) Google Scholar (d) GER in 63 percent of children with chronic asthma or recurrent pneumonia.27Euler AR Byrne WJ Ament ME et al.Recurrent pulmonary disease in children: A complication of gastroesophageal reflux.Pediatrics. 1979; 63: 47-51Crossref PubMed Google Scholar The evidence of a GER/asthma relationship also has gained support in the results of certain clinical trials. The effect on asthma of medical therapy for GER has been reported previously. An open trial of antacids and postural therapy reported improvement in pulmonary symptoms, but not function.28Kjellen G Tibbling L Wranne B Effect of conservative treatment of oesophageal dysfunction on bronchial asthma.Eur J Respir Dis. 1981; 62: 190-197PubMed Google Scholar Four studies using cimetidine or ranitidine for up to eight weeks produced results ranging from no benefit to modest improvement of only nocturnal asthma symptoms.29Goodall RJR Earis JE Cooper DN Bernstein A Temple JG Relationship between asthma and gastroesophageal reflux.Thorax. 1981; 36: 116-121Crossref PubMed Scopus (150) Google Scholar, 30Harper PC Bergner A Kaye MD Antireflux treatment for asthma. Improvement in patients with associated gastroesophageal reflux.Arch Intern Med. 1987; 147: 56-60Crossref PubMed Scopus (107) Google Scholar, 31Ekstrom T Lindgren BR Tibbling L Effects of ranitidine treatment on patients with asthma and a history of gastro-oesophageal reflux: a double blind crossover study.Thorax. 1989; 44: 19-23Crossref PubMed Scopus (113) Google Scholar, 32Nagel RA Brown P Perks WH Wilson RSE Kerr GD Ambulatory pH monitoring of gastro-oesophageal reflux in "morning dipper" asthmatics.Br Med J. 1988; 297: 1371-1373Crossref PubMed Scopus (88) Google Scholar Unfortunately, such short-term studies using low dosages of H2 blockers are unreliable in assessing improvement. One patient with disabling asthma, however, reportedly obtained dramatic improvement in pulmonary symptoms and function when gastric acid was suppressed with omeprazole.33Depla AC Bartelsman JF Roos CM Tytgat GN Jansen HM Beneficial effect of omeprazole in a patient with severe bronchial asthma and gastro-oesophageal reflux.Eur J Respir Dis. 1988; 1: 966-968Google Scholar The effect on asthma of surgical correction of GER has also been reported. In earlier, uncontrolled studies, surgical repair of GER resulted in partial or complete remission of asthma in 17 of 18 patients,34Overholt RH Voorhees RJ Esophageal reflux as a trigger in asthma.Dis Chest. 1966; 49: 464-466Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar 24 of 27 patients,35Urschel HC Paulson DL Gastroesophageal reflux and hiatal hernia: Complications and therapy.J Thor Cardiovasc Surg. 1967; 53: 21-32PubMed Google Scholar all of 16 patients,36Lomasney TL Hiatus hernia and the respiratory tract.Ann Thorac Surg. 1977; 24: 448-450Abstract Full Text PDF PubMed Scopus (38) Google Scholar and 70 percent of adolescent asthmatic patients.37Johnson DG Syme WC Matlak ME Black RE Herbst SJ Gastro-oesophageal reflux and respiratory disease: the place of the surgeon.Aust N Z J Surg. 1984; 54: 405-415Crossref PubMed Scopus (16) Google Scholar Pulmonary function tests, unfortunately, were not performed before and after surgical repair. Despite the lack of objective data, many patients had dramatic subjective improvement in asthma from antireflux surgery. Three uncontrolled but more recent surgical studies do provide objective data both before and after treatment: (1) 12 of 13 asthmatic patients improved after antireflux surgery, and most were able to reduce or discontinue completely the pulmonary medications;38Sontag SJ O'Connell SA Greenlee HB Schnell TG et al.Is gastroesophageal reflux a factor in some asthmatics.Am J Gastroenterol. 1987; 82: 119-126PubMed Google Scholar (2) seven of ten asthmatics had at least temporary improvement in pulmonary function;39Tardiff C Nouvet G Denis P Tombelaine R Pasquis P Surgical treatment of gastroesophageal reflux in ten patients with severe asthma.Respiration. 1989; 56: 110-115Crossref PubMed Scopus (43) Google Scholar 13 of 44 asthmatic patients who received surgical correction of GER at least five years earlier, marked improvement or cure occurred in 41 percent and moderate improvement was achieved in 27 percent.40Perrin-Fayolle M Gormand F Braillon G Lombard-Platel F Vignol J Azzar D et al.Long-term results of surgical treatment for gastroesophageal reflux in asthmatic patients.Chest. 1989; 96: 40-45Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Unfortunately, there is no acceptable diagnostic method available to confirm the presence of GER-induced asthma. Scintigraphic monitoring under controlled conditions has been largely unsuccessful. Therefore, it appears that clinical trials are the only available means to assess whether medical or surgical treatment of GER in patients with both GER and asthma improves the symptoms of asthma and decreases the need for pulmonary medications. Now, here comes a group from the Americas to report on how to do it right. In this issue (see page 1330) Larrain et al report the results of their initial six-month study, as well as the five or more years of followup. The methodology was impressive. Patients presented to the pulmonary clinic because of pulmonary symptoms. They were not a selected group with reflux symptoms who incidentally had pulmonary disease. The study was placebo-controlled and randomized. Few patients dropped out after randomization. Treatment (including surgery) was started within two weeks of randomization. Followup was done by two chest physicians who were not involved in the selection or randomization process. Private physicians, not the investigator, adjusted their patient's medications. The investigators enrolled only patients with intrinsic asthma and excluded those with atopic asthma and COPD. Of the 142 patients screened, 94 had GER and 90 consented to randomization. Nine patients dropped out or refused their assigned treatment, leaving 28 patients in the placebo group, 27 patients in the cimetidine 300 mg qid group, and 26 patients in the surgical group. The clinical response to treatment was based on four parameters: (1) symptom score; (2) medication score; (3) response to questions about improvement; and (4) the need for corticosteroids. Although the symptom score of all three groups improved from baseline by the end of six months, the mean score was significantly better in the surgical group and cimetidine group than in the placebo group. Thus, reflux treatment either by medicine or by surgery improved asthmatic symptoms when compared with placebo. Similar results were obtained for the mean medication score. At six months, the cimetidine group required less medication, the surgical group required substantially less medication, but the placebo group required the same or needed even more. When asked whether the wheezing had improved greatly, 80 percent of the cimetidine and surgical groups but only 40 percent of the placebo group answered "yes." Furthermore, half of the cimetidine group and 40 percent of the surgical group but only 7 percent of the placebo group said that the pulmonary symptoms had vanished. Regarding the need for corticosteroids, 2 of 13 cimetidine patients (15 percent), 3 of 11 surgical patients (27 percent), but none of 28 placebo patients were able to discontinue prednisone. As would be expected, pH testing at the end of six months showed that in almost all patients GER was still present if surgery had not been performed. The investigators analyzed numerous variables to demonstrate improvement in asthma. Indeed, the symptom and medication scores, the improvement questions, and the need for corticosteroid therapy were consistent in each group: no improvement with placebo; improvement with cimetidine or surgery. Why, then, did no group have significant improvement in the pulmonary function tests (FVC, FEV1 and MMEFR)? The authors do not address this potential inconsistency. One possible explanation could be that the results of the pulmonary function tests do not matter; that pulmonary function testing does not necessarily correlate with the short-term clinical results. Important changes that may occur during a six-month study include an alteration in the need for pulmonary medications. Indeed, the investigators reported a decrease or discontinuation of prednisone and bronchodilators in the medical and surgical patients. It may be unrealistic to expect pulmonary function to improve in such a short period, while at the same time bronchodilators and corticosteroids are being reduced or stopped, it should not be surprising that pulmonary function parameters do not improve. Furthermore, infrequent measurement of the FVC, FEV1, and MMEFR are not the most clinically reliable indicators of asthma improvement. More appropriate clinical indicators, such as daily PEFRs and percentage of variation, may have demonstrated stability and improvement in the pulmonary status.41Williams MH Evaluation of asthma.Chest. 1979; 76: 3-4Crossref PubMed Scopus (12) Google Scholar,42Hetzel MR The pulmonary clock.Thorax. 1981; 36: 481-486Crossref PubMed Scopus (88) Google Scholar Therefore, the inability to demonstrate improvement in the measured pulmonary function variables is not necessarily inconsistent with the reported clinical improvement. There are, of course, bound to be some criticisms of the study. These might include the methods used to detect reflux, the definition of reflux and asthma, the use of scoring systems for symptoms and medications, and the absence of endoscopic followup. Although endoscopic changes in the esophageal mucosa would have provided additional information, the chaotic years in Chile between 1976 and 1978 may have prevented such internal inspection. Minor deficiencies in the six-month study should not detract from the overall importance of the results. The most exquisite folly is made of wisdom spun too fine. Benjamin Franklin. It is to the credit of these investigators that data from 42 patients were available after more than five years. Twenty-two of 28 surgical patients and 20 of 28 placebo patients were available for follow-up. In patients who had undergone surgery, 11 of 22 (50 percent) still reported freedom from respiratory symptoms for a mean of 77 months after the six-month study was finished. Only 1 of 20 patients (5 percent) who had received 6 months of placebo treatment reported freedom from respiratory symptoms for a mean follow-up of 72 months. The investigators conclude that the study supports the hypothesis that GER can initiate or promote pulmonary symptoms. This is the first study of its kind to implicate so strongly the role of GER in the asthmatic state. No longer can we ignore the coexistence of both wheezing and indigestion. Nevertheless, how and in whom these two common afflictions coexist needs further study. The authors, using their clinical acumen, came up with certain markers that, they suggest, might help identify patients who could benefit from antireflux treatment. These predictors include (1) onset of reflux symptoms before the onset of pulmonary symptoms; (2) the presence of nocturnal asthma; (3) signs of laryngeal irritation; and (4) an initial pulmonary response to medical reflux management. Without doubt, the controversy among investigators from different disciplines on the exact role of GER in asthma is likely to remain heated. Accordingly, Larrain et al have provided the fuel to keep the pulmonologists and gastroenterologists in flames. It would be a tribute to Drs. Larrain, Carrasco, Galleguillos, Sepulveda and Pope if the results of their efforts stimulated further research into the poorly understood relationship between gastroesophageal reflux and asthma.
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