94 Annals of Clinical & Laboratory Science, vol. 34, no. 1, 2004 Prevalence of Bronchial Asthma in Patients with Endoscopically-Documented Esophagitis G. Riccioni, 1 R. Della Vecchia, 2 V. Menna, 1 C. Di Ilio, 1 P. Conti, 3 and N. D Orazio 1 1 Human Nutrition Division, Department of Biomedical Sciences, University G. D Annunzio, Chieti; 2 Respiratory Pathophysiology Center, Department of Internal Medicine, SS. Annunziata Hospital, Chieti; 3 Immunology Division, Department of Oncology and Neuroscience, University G. D Annunzio, Chieti, Italy Abstract. The association of gastroesophageal reflux, esophagitis, and asthma has been studied for a long time, but the results are often conflicting. The aim of this study is to evaluate the prevalence of bronchial asthma and the presence of extra-esophageal symptoms in subjects with endoscopically-documented reflux esophagitis. Forty patients were divided into 2 groups: group A (22 patients) affected by endoscopicallydocumented esophagitis, and group B (18 patients) with positive endoscopic examination for other pathologies of the gastroenteric tract. All of the patients underwent complete medical examination, skinprick tests, esophageal-gastric-endoscopy, and pulmonary function tests (basal and after methacholine). The prevalence of asthma was 30% in group A vs 10% in group B (odds ratio = 2.57; confidence interval = 0.75-10.25). Relationships between chronic cough and esophagitis (p <0.01) and between chronic cough and asthma (p<0.05) were found. No significant relationships were observed between esophagitis and the other respiratory symptoms considered (wheezing, chest tightness, hoarseness, bronchospasm, and dysphagia). The results confirm the increased prevalence of asthma in patients with esophagitis and they emphasize the role of gastroesophageal reflux as a trigger factor for asthma. Chronic cough represents an important symptom of asthma in subjects with esophagitis. (received 3 October 2003; accepted 8 October 2003) Keywords: bronchial asthma, reflux esophagitis, cough, gastroesophageal reflux disease Introduction Bronchial asthma (BA) is a chronic inflammatory airway disease involving many cells and mediators that may determine recurrent episodes of pharmacologically reversible or spontaneously bronchoconstriction [1]. A relationship between BA and gastroesophageal reflux (GER) was suggested by Osler more than a century ago [2], and later reported by Kennedy [3] as a cause of pulmonary symptoms. Gastroesophageal reflux disease (GERD) refers to the varied clinical manifestations that result from reflux of stomach and duodenal contents into the esophageal mucosa. Several factors cooperate to produce the clinical effects of GER. A normal subject Address correspondence to Graziano Riccioni, M.D., Via F. Ferri 90, 66100 Chieti, Italy; tel 39 333 636 6661; fax 39 0871 355 6705; e-mail griccioni@hotmail.com. may have a few short-duration reflux episodes after a meal or simply when in upright position. The composition and perhaps the quantity of the refluxed material play a role in the production of GERD. Gastric acid and pepsin seem important in the pathogenesis of GERD. Bile salts, and possibly pancreatic enzymes, may be factors in patients in whom gastric acid is absent. Reflux esophagitis, which represents an anatomical disease complication, has several forms of severity, from mild with small isolated erosions, to severe with ulcerations and cicatrizial stenosis [4]. Among the various methods for the study and quantification of GERD, monitoring the esophageal ph is the most important; endoscopy remains the best way for diagnosis of the mucosal lesions consequent to the reflux [4]. Many studies highlight a relationship between GERD and BA and document GERD as an important trigger of asthmatic 0091-7370/04/0100-0094, $1.25. 2004 by the Association of Clinical Scientists, Inc.
Bronchial asthma in patients with esophagitis 95 disease [5-7]. The scientific community, however, is not yet agreed on this point and does not view the relation between BA and GERD as certain. This uncertainty is confirmed by recent guidelines for the diagnosis and management of asthmatic disease [8]. The pathogenesis of BA in patients with GERD may be caused by: (a) microaspiration of acidic gastric contents into bronchial airways, with consequent irritation and inflammatory action on the respiratory mucosa [9]; (b) stimulation of irritative receptors of the upper airways in response to refluxed acid [10], and (c) a vagally-mediated reflex that induces bronchoconstriction [11]. The last hypothesis is the most credited and is supported by the strongest experimental evidences [12]. The primary goal of this study is to evaluate the prevalence of BA in patients with endoscopicallydocumented reflux esophagitis (EDRE); the secondary goal is to evaluate extra-esophageal symptoms (eg, persistent cough, chest tightness, wheezing, hoarseness, bronchospasm, and dysphagia) in subjects with EDRE. Materials and Methods Subjects. We selected 40 consecutive patients who had undergone endoscopic examination of the upper digestive tract in order to evaluate symptoms from probable esophageal-gastric pathology. The patients were divided into 2 groups: group A included 22 patients with EDRE and group B (controls) included 18 patients with positive endoscopic examination for other pathologies of the gastroenteric tract (ie, chronic or acute gastritis, peptic ulcer disease, gastric carcinoma, gastric lymphoma). The diagnosis of asthma, made by a pulmonologist or internist, was based on typical symptoms and on improvement of the pre-bronchodilatator FEV1 (forced expiratory volume in one second) by at least 15% after administration of salbutamol (200 µg dose). The asthma was classified as mild, moderate, or severe based on the FEV1 value, using the NIH criteria [1]. Exclusion criteria for the study were: recent infections of the upper or lower respiratory airways, acute disease of the paranasal sinuses, therapy with inhaled or oral corticosteroids, long-acting β-stimulating adrenergics, theophylline, antihistamines, allergy to inhalants or foods, and the presence of hiatal hernia, obesity, or pregnancy. Study design. All 40 subjects underwent medical examination, skin-prick tests for inhalant and food allergens, esophageal-gastric-endoscopy (EGE), and pulmonary function tests including basal measurements and a methacholine challenge test (MCHT). Every patient gave informed consent to undergo the EGE and MCHT. The EGE took place in the Service of Digestive Endoscopy of the Department of Internal Medicine and Science of Aging, SS. Annunziata Hospital of Chieti; the pulmonary function tests took place in the Respiratory Pathophysiology Center of the Unit of Clinical Medicine, SS. Annunziata Hospital of Chieti; the skin-prick tests took place in the Service of Allergy and Clinical Immunology of the Internal Medicine Department, SS. Annunziata Hospital of Chieti. Lung function and methacholine challenge test. Each patient performed 3 forced vital capacity (FVC) manoeuvres in accordance with the ATS standards [13], along with measurements of FEV1 and peak expiratory flow (PEF). MCHT was performed according to the ATS protocol [14], using a dosimeter (Mefar MB3, Brescia, Italy). After basal spirometry and inhalation of a buffered saline vehicle solution, the patients began the MCHT by inhaling 6.25 µg/ml of methacholine (lyophilised methacholine 6.4%, Lofarma, Milan, Italy), which was followed by increasing levels of methacholine up to 3200 µg/ml. At 60 sec after each inhalation of methacholine, a new FEV1 measurement was performed. The test was considered positive when the level of methacholine that caused 20% decrease of the FEV1 was <1600 µg/ml. The patient s basal FEV1 value was the best of 3 tests (differences among the responses 5%); the patient s PC 20 value (provocative dose to cause a 20% fall in FEV1) was calculated by linear interpolation between the last two values in the methacholine dose-response curve. Skin-prick tests (Lofarma, Milan, Italy) were performed on the volar side of the forearm according to Guidelines of the Subcommittee on Skin Tests of the European Academy of Allergy and Clinical
96 Annals of Clinical & Laboratory Science Immunology (EAACI) [15]. Histamine phosphate (10 mg/ml) and saline solutions were used as positive and negative controls, respectively. Skin-prick tests were read after 15 min and were considered positive if the largest diameter of the weal was 3 mm more than that of the negative control. Statistics. Results were expressed as means ± SD for quantitative variables and as percentages for qualitative variables. The p values were computed by the Chi-square test, and when appropriate, by Fisher s exact test, using the SPSS 7.0 statistical package. Risks were evaluated by odds ratios (OR) and 95% relative confidence intervals (IC). A p value of <0.05 was required for statistical significance. Results Characteristics of the two study groups and baseline values of the pulmonary function tests (FEV1, FVC, PEF, and PC 20 ) are listed in Table 1. Group A comprised 22 patients with EDRE (12 men, 10 women) with mean age of 45.1 ± 8.7 yr; group B comprised 18 patients without esophagitis but with positive endoscopic examination for other pathology (10 men, 8 women), with mean age 46.3 ± 9.7 years. No significant differences of BMI values (kg/m 2 ), gender, or age were observed in the groups. Group B included 3 patients with acute gastritis, 7 with chronic gastritis, 5 with peptic ulcer disease, 2 with gastric carcinoma, and 1 with gastric lymphoma. Results of the FEV1, FVC, and PEF tests were reported as % of predicted values. The basal FEV1 value averaged 95.2 ± 11.2 for group A vs 93.7 ± 11.2 for group B. The basal FVC value averaged 94.8 ± 10.1 for group A vs 97.2 ± 10.4 for group B. The basal PEF value averaged 94.8 ± 12.8 for group A vs 94.4 ± 12.7 for group B. The PC 20 iaveraged 826 ± 428 µg/ml for group A vs 876 ± 345 mg/ml for group B. No statistically significant differences were found between the two groups in respect to the results of pulmonary function tests. The prevalence of asthmatic disease was 30% in group A (with EDRE), compared to 10% in group B (without esophagitis, but positive endoscopic examination for other pathologies), yielding an odds ratio (OR) of 2.57 (IC = 0.75-10.25). Table 1. Baseline characteristics of the patients and results of their pulmonary function tests. Parameter Group A Group B (esophagitis) (other pathologies) Number of patients 22 18 Gender (M/F) 12/10 10/8 Age (yr*) 45.1 ± 8.7 46.3 ± 9.7 BMI (kg/m 2 *) 23.2 ± 3.2 22.3 ± 3.9 FEV1 (% predicted value*) 95.2 ± 11.2 93.7 ± 11.2 FVC (% predicted value*) 96.1 ± 10.1 97.2 ± 10.4 PEF (% predicted value*) 94.8 ± 12.8 94.4 ± 12.7 PC 20 (mg/ml*) 825 ± 428 876 ± 345 * mean ± SD The study documented significant associations between chronic cough and esophagitis (p <0.01) and between chronic cough and asthma (p <0.05). No statistically significant associations were found between esophagitis and other respiratory symptoms that were considered (ie, wheezing, chest tightness, hoarseness, bronchospasm, and dysphagia). Discussion Gastroesophageal reflux (GER), the spontaneous retrograde passage of gastric contents into the esophagus, represents a physiological event that may occur in healthy subjects. Many individuals with reflux symptoms are free from respiratory symptoms, while others report persistent respiratory symptoms, such as cough (mostly nocturnal) and hoarseness [4,16-18]. Studies of this subject are quite definite about a primary role of GERD in the induction of asthma [19]. Many of the published reports have evaluated the prevalence of GERD in patients treated with broncho-active therapies (theophylline, inhaled and oral corticosteroids, long-acting and short-acting β-stimulating receptor drugs). The presence of GERD was based on 24-hr monitoring of esophageal ph, a diagnostic method with limited sensitivity and specificity [20,21]. In accordance with other reports, in the present study the prevalence of BA in patients with esophagitis (group A) was higher than in the controls (group B). However, the prevalence of BA in patients with esophagitis was less than was reported
Bronchial asthma in patients with esophagitis 97 in other studies. This finding probably reflects the restrictive selection criteria. Unlike other studies, the patients enrolled in this study were not receiving treatments for BA or other pathologies, which may influence the lower esophageal sphincter (LES) tone. Moreover, the presence of esophagitis was endoscopically-documented. Asthma medications may be a promoting factor for GER in asthmatic subjects. Defective function of the LES and its incomplete valvular competence can result from anatomical-topographical alteration of the structures induced by persistent lowering of the diaphragm, as may happen in cases of BA or other serious chronic obstructive pathology of the airways. In such cases the anatomical-functional situations, which represent necessary and sufficient conditions for establishing GER, may easily be present. Similarly, the postprandial phase represents in these patients a period particularly at risk, because it corresponds to the period of greatest reflux. Undertaking physical exertion or assuming a supine position can make this phase worse. Furthermore, oral prednisone therapy results in prolonged intervals of esophageal exposure to gastric acidity [22]. In patients of group A, we observed a significant relationship between esophagitis and chronic cough. Although the number of patients is small, the results support the evidence that subjects with EDRE have higher prevalence of BA than subjects without EDRE. The association cannot, however, establish a cause-effect relationship. The association is difficult to explain because it involves two physiological systems, raising the possibility of an underlying disorder. Possible mechanisms that have proposed for this are: (a) a generalized common smooth muscle disorder of the bronchial and gastrointestinal systems [23], (b) a complex neuromuscular disorder [24], and (c) involvement of inflammatory mediators that cause respiratory and gastrointestinal symptoms [25]. The prevalence of respiratory or other extraesophageal manifestations of GERD remains unknown, however, because in any given patient it is difficult to decide if GERD is causing the extraesophageal condition or if the two conditions coexist independently. In our study, pulmonary functions were unaltered in both groups of patients. Although gastroesophageal reflux (GER) with esophagitis causes asthmatic symptoms, it has minimal effects on pulmonary function. Data in the literature suggest a strong association between GER and asthma, and indicate that GER worsens the asthmatic symptoms without affecting indices of pulmonary function [26]. GERD has practical importance in respect to the recent guidelines for the diagnosis and treatment of asthma [8]. The presence of GERD should be considered in asthmatic patients who suffer from pyrosis, those with frequent episodes of nocturnal asthma, and those with asthma that is insufficiently controlled. Multicentric and placebo-controlled studies are needed to evaluate asthma symptoms, therapy, outcome, costs and their influence on quality of life in patients with EDRE. References 1. National Institute of Health, National Hearth, Lung and Blood Institute. Global Initiative for Asthma - NHLBI/ WHO Report, Bethesda, 1995, NIH Publication 95-3659. 2. Osler W. Bronchial asthma. In: The Principles and Practice of Medicine. Appleton, New York, 1892; pp 497-501. 3. Kennedy GH. Silent gastroesophageal reflux: an important but little known cause of pulmonary complications. Dis Chest 1962;42:42-45. 4. Kahrilas PJ. Gastroesophageal reflux disease and its complications. In: Sleisenger and Fordtran s Gastrointestinal and Liver Disease. Saunders, Philadelphia, 1998, pp 498-517. 5. Sontag SJ. Gastroesophageal reflux and asthma. Am J Med 1997;103:83-90. 6. Irwin RS, Curley FJ, French CL. Difficult to control asthma. Contributing factors and outcome of systematic management protocol. Chest 1996;103:1662-1665. 7. Harding SM, Sontag SJ. Asthma and gastroesophageal reflux. Am J Gastroenterol 2000;95:23-32. 8. National Asthma Education Prevention Program. Expert Panel Report II: Guidelines for the Diagnosis and Management of Asthma. National Institute of Health, Bethesda, 1997, NIH Publication 97-4051. 9. Harding SM, Schan CA, Guzzo MR, Alexander RW, Bradley LA, Richter JE. Gastroesophageal reflux induced bronchoconstriction. Is microaspiration a factor? Chest 1995;108:1220-1224. 10. Vincent D, Cohen-Jonatan AM, Leport J, Merrouche M, Geronimi A, Pradalier A, Soule JC. Gastroesophageal reflux prevalence and relationship with bronchial reactivity in asthma. Eur Respir J 1997;10:2255-2258. 11. Lodi U, Harding SM, Coghlan HC. Autonomic
98 Annals of Clinical & Laboratory Science regulation in asthmatics with gastroesophageal reflux. Chest 1997;111:65-70. 12. Field SK. Gastroesophageal reflux and asthma: are they related? J Asthma 1999;36:631-644. 13. American Thoracic Society. Standardization of spirometry. Am J Respir Crit Care Med 1995;152:1107-1136. 14. American Thoracic Society. Guidelines for methacholine and exercise challenge testing. Am J Respir Crit Care Med 2000;161;309-329. 15. D Amato G, Spieksma G, Liccardi G, Russo M, Kountou- Fili K, Nikkels H, Wuthrich B, Bonini S. Pollen-related allergy in Europe, a position paper. Allergy 1998;53:567-578. 16. Sontag SJ, O Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, Serlovsky R. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990;99:613-620. 17. Dent J. Gastro-esophageal reflux disease. Digestion 1998; 59:433-445. 18. Harding SM. Gastroesophageal reflux and asthma: insight into the association. J Allergy Clin Immunol 1999;104: 251-259. 19. Compte L, Garrigues V, Perpina M, Ponce J. Prevalence of gastroesophageal reflux in asthma. J Asthma 2000;37: 175-182. 20. Wiener GJ, Morgan TM, Cooper JB, Wu WC, Castell DO, Sinclair JW, Ricter JE. Ambulatory 24-hour esophageal ph monitoring. Reproducibility and variability of ph parameters. Dig Dis Sci 1988;33:1127-1133. 21. Klauser AG, Leinrich C, Schindlbeck NE, Muller-Lissner SA. Is long term esophageal ph monitoring of clinical value? Am J Gastroenterol 1989;84:362-366. 22. Lazemby GP, Guzzo MR, Harding SM, Patterson PE, Johnson LF, Bradley LA. Oral corticosteroids increase esophageal acid contact times in patients with stable asthma. Chest 2002;121:625-634. 23. Jones R, Lyderad S. Prevalence of symptoms of dyspepsia in the community. Br Med J 1989;298:30-32. 24. Collins SM. Is the irritable gut an inflammed gut? Scand J Gastroenterol 1992;27:102-105. 25. Paterson WG. Extraesophageal manifestations of reflux disease: myths and reality. Chest Surg Clin N Am 2001; 11:523-538. 26. Field SK. Gastroesophageal reflux and asthma: can the paradox be explained? Can Respir J 2000;7:167-176.