Respiratory Symptoms and Nocturnal Gastroesophageal Reflux

Respiratory Symptoms and Nocturnal Gastroesophageal Reflux* A Population-Based Study of Young Adults in Three European Countries Thorarinn Gislason, MD; Christer Janson, MD; Paul Vermeire, MD, FCCP; Peter Plaschke, MD; Eythor Bjo¨rnsson, MD; David Gislason, MD; and Gunnar Boman, MD Study objective: To estimate the possible association between reported symptoms of gastroesophageal reflux (GER) after bedtime, sleep-disordered breathing, respiratory symptoms, and asthma. Design: Cross-sectional international population survey. Participants: Participants consisted of 2,661 subjects (age range, 20 to 48 years) from three countries (Iceland, Belgium, and Sweden), of whom 2,202 were randomly selected from the general population and 459 were added because of reported asthma. Measurements: The investigation included a structured interview, spirometry, methacholine challenge, peak flow diary, skin-prick tests, and a questionnaire on sleep disturbances. Results: In the random population sample, 101 subjects (4.6%) reported GER, which was defined as the occurrence of heartburn or belching after going to bed at least once per week. Subjects with nocturnal GER more often were overweight and had symptoms of sleep-disordered breathing than participants not reporting GER. Participants with GER were more likely to report wheezing (adjusted odds ratio [OR], 2.5), breathlessness at rest (adjusted OR, 2.8), and nocturnal breathlessness (adjusted OR, 2.9), and they had increased peak flow variability compared to the subjects without GER. Physician-diagnosed current asthma was reported by 9% of subjects with GER compared to 4% of those not reporting GER (p < 0.05). Subjects with the combination of asthma and GER had a higher prevalence of nocturnal cough, morning phlegm, sleep-related symptoms, and higher peak flow variability than subjects with asthma alone. Conclusion: The occurrence of GER after bedtime is strongly associated with both asthma and respiratory symptoms, as well as symptoms of obstructive sleep apnea syndrome. The partial narrowing or occlusion of the upper airway during sleep, followed by an increase in intrathoracic pressure, might predispose the patient to nocturnal GER and, consequently, to respiratory symptoms. (CHEST 2002; 121:158 –163) Key words: asthma; epidemiology; gastroesophageal reflux; sleep; snoring. Abbreviations: BHR ⫽ bronchial hyperresponsiveness; BMI ⫽ body mass index; CPAP ⫽ continuous positive airway pressure; ECRHS ⫽ European Community Respiratory Health Survey; GER ⫽ gastroesophageal reflux; OSAS ⫽ obstructive sleep apnea syndrome; PEF ⫽ peak expiratory flow

association between gastroesophageal reflux A n(GER) and lung diseases has for some time been

an operative treatment for GER, 60% also had symptoms related to pulmonary disease. Since then,

known to exist. As early as 1967, Urschel and Paulson1 reported that of 636 patients scheduled for

For editorial comment see page 8

*From the Department of Lung Medicine (Drs. T. Gislason, Bjo¨rnsson, and D. Gislason), Vifilsstadir Hospital, Gardabaer, Iceland; the Department of Medical Sciences, Respiratory Medicine, and Allergology (Drs. Janson and Boman), Akademiska Sjukhuset, Uppsala, Sweden; the Department of Respiratory Medicine (Dr. Vermeire), University of Antwerp, Antwerp, Belgium; and the Asthma and Allergy Research Center (Dr. Plaschke), Sahlgrenska Hospital, Go¨teborg, Sweden. The Icelandic part of this study was supported financially by the Icelandic Research Council. The Swedish part of this study was supported by the Swedish Heart and Lung Foundation, the Swedish Medical Research Council, and the Swedish Association Against Asthma and Allergy. The Belgian part of this study was 158

many studies2,3 have shown a high prevalence ofGER among patients with asthma. In a recent report,4 even asthmatics without reflux symptoms had a high prevalence (62%) of abnormal results for supported by the Belgian Science Policy Office and the National Fund for Scientific Research. Manuscript received December 20, 2000; revision accepted June 28, 2001. Correspondence to: Thorarinn Gislason, MD, Department of Lung Medicine, Vifilsstadir Hospital, 210 Gardabaer, Iceland Clinical Investigations

24-h esophageal tests. The simultaneous occurrence of GER and asthma suggests a causal relationship. The aspiration of gastric contents or a vagally mediated bronchoconstriction has been suggested as an explanatory mechanism.5 Medical antireflux therapy6 and antireflux surgery,7 however, have only minimal effect or no effect on lung function, although asthma symptoms improve. The majority of studies in this field have concentrated on highly selected populations at secondary or tertiary referral hospitals. There are few epidemiologic studies of the general population, and little is known about a possible association between respiratory symptoms and GER in an unselected random population. Between 1990 and 1993, an epidemiologic investigation into the prevalence of asthma and allergy, the European Community Respiratory Health Survey (ECRHS), was conducted in different centers throughout the world.8 In four of the participating centers (Reykjavik, Iceland; Uppsala and Go¨ teborg, Sweden; and Antwerp, Belgium), a questionnaire relating to sleep disturbances was added to the second part of the ECRHS study.9 –11 We have previously reported that GER is associated with an increased prevalence of sleep disturbances as well as with symptoms related to obstructive sleep apnea.9,10 In accordance with the results of other studies,12–14 we also found that the quality of sleep often was decreased in subjects with asthma.11 The aim of the present investigation was to estimate the possible association between reported symptoms of GER after bedtime, sleep-disordered breathing, respiratory symptoms, and asthma. Materials and Methods Study Areas and Target Populations The subjects in this study came from the following four centers: Reykjavik, the capital of Iceland, and its surrounding

suburbs (approximate population, 160,000 inhabitants); Uppsala, the fourth largest city in Sweden (approximate population, 170,000 inhabitants); Go¨ teborg, the second largest city in Sweden (the study area comprised the northern part of the city on the island of Hisingen; approximate population, 110,000 inhabitants); and Antwerp, the second largest city in Belgium (the study area comprised the center of the city and 13 municipalities in the southern suburban area; target population, 300,000 inhabitants). Populations In the ECRHS, a random sample of persons in the age range of 20 to 44 years was selected using the population register at each center (Table 1).9 –11 In brief, a postal questionnaire was sent to 3,600 subjects each in Reykjavik, Uppsala, and Go¨ teborg and to 8,029 subjects in Antwerp. The response rates to the questionnaire were 81%, 87%, 80%, and 75%, respectively. From the responses from each site to the initial questionnaire, a random sample of subjects was invited to participate. A sample of symptomatic subjects also was identified as those who reported nocturnal attacks of breathlessness, attacks of asthma, or current use of medication for asthma. The response rates are shown in Table 1. A structured interview was conducted among all participants to include measurements of lung function and allergy testing. A sleep questionnaire also was administered to all participants (see below), and the number of participants is noted in Table 1. The informed consent of all participants was obtained, and the study was approved by all the local ethics committees. The screening questionnaire and the questionnaire used in the structured interview were based on the International Union Against Tuberculosis and Lung Disease questionnaire.15 In the interview, the patients answered questions relating to respiratory symptoms, respiratory disorders, medication, and environmental factors. The following asthma-related symptoms were used in this analysis: (1) wheezing or whistling in the chest; (2) being awakened by a feeling of tightness in the chest; (3) having had an attack of shortness of breath that came during the day when at rest; (4) having had an attack of shortness of breath followingstrenuous activity; and (5) having been awakened by an attack of shortness of breath. The recall period was 12 months for all these symptoms. Asthma was defined as having ever reported an occurrence of asthma in which the diagnosis had been confirmed by a doctor and also having had at least one asthma-related symptom in the preceding 12 months.11 The following cough-related symptoms were used in this analysis: (1) being awakened by an attack of coughing in the last 12 months (nocturnal cough); (2) usually coughing in the morn-

Table 1—Population Selection and Participation Rates (Random and Symptomatic Sample)* Population Screening questionnaire Answered questionnaire Random sample Symptomatic sample Participated in sample Lung function Peak flow Answered sleep questionnaire

Reykjavik

Uppsala

Go¨ teborg

Antwerp

3,600 2,903 (81) 800 90 570 (71) 84 (93) 535 80 92 63 535 78

3,600 3,147 (87) 705 216 623 (88) 201 (93) 536 176 421 131 542 182

3,600 2,884 (80) 772 220 682 (88) 184 (81) 600 162 424 109 426 114

8,029 6,027 (73) 1,665 230 1,121 (67) 162 (70) 304 22

699 85

*Values given as No. (%). CHEST / 121 / 1 / JANUARY, 2002

159

ing in the winter (morning cough); and (3) usually bringing up phlegm from the chest in the morning in the winter (morning phlegm). Lung Function and Bronchial Hyperresponsiveness FEV1 was measured using a computerized dry-rolling seal spirometer system (Spiro Medics system 2130; SensorMedics; Anaheim, CA) [Table 1]. The predicted values were calculated for each patient.16 Methacholine challenge was performed using a dosimeter (Mefar; Brescia, Italy).17 Patients with a decrease in FEV1 of ⬎ 20% accompanying an accumulated methacholine dose of ⱕ 2 mg were defined as having bronchial hyperresponsiveness (BHR). All the participants in Uppsala and Go¨ teborg, a random sample of 25% of the participants in Reykjavik, and all of those with symptoms indicating asthma were asked to record peak expiratory flow (PEF) [ie, the best of three measurements] twice daily during 1 week with a flowmeter (Mini-Wright Peak Flow Meter; Clement Clarke; London, UK). The number of patients who managed to record PEF measurements twice a day on at least 4 of 7 days was 155 in Reykjavik, 552 in Uppsala, and 533 in Go¨ teborg (Table 1). PEF variability was calculated by dividing the difference between the highest and lowest daily PEF readings by the daily mean PEF value.18 Allergy Testing Skin-prick tests (Phazet; Pharmacia Diagnostics; Uppsala, Sweden) were conducted on 2,144 individuals. Those with a positive result (ie, a mean weal diameter of ⱖ 3 mm) to at least one of the following allergens were defined as having atopy: birch; timothy grass; Dermatophagoides pteronyssinus; cat; dog; Cladosporium herbarum; or Alternaria alternata.19 Sleep Questionnaire After completing the interview and examination, all the subjects were asked to fill out a separate questionnaire addressing their quality of sleep during the last few months. The questionnaire was a slightly modified version of a questionnaire used in previous Swedish and Icelandic studies.20,21 The questionnaire, which has been described in detail previously,10 comprised 14 multiple-choice questions in which the subjects were asked to estimate the frequency of different symptoms on the following 5-point scale: 1, never; 2, less than once a week; 3, 1 to 2 nights a week; 4, 3 to 5 nights a week; and 5, almost nightly/daily. The question about GER was “Do you have heartburn or belching when you have gone to bed?” The questionnaire was translated and then back-translated from Swedish to Dutch to enable its use in Antwerp. The numbers of subjects in the random and symptomatic samples who completed the sleep questionnaire were 2,202 and 459, respectively (Table 2). Those subjects who reported GER 1 to 2 nights per week (3 points) or more often are in this article referred to as reporting nocturnal GER. Statistical Analysis The relationships among nocturnal GER, respiratory symptoms, and symptoms of sleep-disordered breathing were estimated in the randomly selected population. The symptomatic subjects were included in the comparison of asthmatic subjects with or without reported GER. The variation in the prevalence of symptoms and subjects with and without nocturnal GER was studied using the ␹2 test and unpaired t test. When the analysis was limited to subjects with asthma, Fisher’s Exact Test was used 160

Table 2—Population Characteristics in Subjects Without and With Reported Nocturnal GER After Bedtime Once a Week or More* No Nocturnal Nocturnal GER (n ⫽ 2,096) GER (n ⫽ 101)

Characteristics Age, yr BMI, kg/m2 Male gender, % Current smoker, % Rhinitis, % Sleep-related symptoms, % Snoring (ⱖ 3 nights/wk) Reported apneas (ⱖ 1 nights/wk) Nighttime sweating (ⱖ 3 nights/wk) Nightmares (ⱖ 1 nights/wk) Daytime symptoms, % Morning headache (ⱖ 3 mornings/wk) Daytime sleepiness (ⱖ 3 days/wk) Involuntarily falling asleep (ⱖ 1 days/wk)

33 ⫾ 7 23.3 ⫾ 3.4 47 34 27

34 ⫾ 7 25.1 ⫾ 3.6† 49 41 40‡

5 1

16† 5‡

3

11†

4

17†

2

6§

14

30†

4

8§

*Values given as mean (⫾ SD) or percentages. †p ⬍ 0.001. ‡p ⬍ 0.01. §p ⬍ 0.05.

instead of the ␹2 test. In these analyses, PEF variability was log-transformed to achieve normal distribution. Logistic regression was used when calculating the effect of nocturnal GER on symptoms and asthma while adjusting for possible confounders. A p value ⬍ 0.05 was regarded as statistically significant. A statistical software package (StatView, version 5.0; SAS Institute Inc; Cary, NC) was used for all calculations.

Results In the randomly selected population sample, nocturnal GER was reported by 3.4% in Reykjavik, 4.8% in Uppsala, 6.3% in Go¨ teborg, and 4.3% in Antwerp, for a total of 101 subjects (4.6%). The age and gender of these patients were similar to those subjects not reporting nocturnal GER, but they were more often overweight (ie, higher body mass index [BMI]) and more often reported both day and night symptoms related to sleep-disordered breathing (Table 2). Those subjects who reported GER after bedtime had a prevalence of all respiratory symptoms and asthma two to three times higher than did subjects not reporting GER (Table 3). All these differences, except for GER and morning cough, remained significant after adjusting for the medical center, gender, age, smoking, BMI, and symptoms related to sleep-disordered breathing (Table 3). Thirteen subjects (0.6%) in the random population had theophylline therapy. Adjusting for the use of theophylline did not change any of the associations reported. Clinical Investigations

Table 3—Respiratory Symptoms and Asthma in Subjects Without and With Reported Nocturnal GER* Symptoms

No nGER (n ⫽ 2,096)

nGER (n ⫽ 101)

Adjusted OR (95% CI)

Wheeze Nocturnal chest tightness Breathlessness at rest Breathlessness after effort Nocturnal breathlessness Current physician-diagnosed asthma Nocturnal cough Morning cough Morning phlegm

24 11 5 15 4 4 31 12 13

47† 23† 14† 31† 13† 9‡ 59† 20‡ 31†

2.5 (1.6–3.9) 2.3 (1.4–3.8) 2.8 (1.5–5.3) 2.7 (1.7–4.4) 2.9 (1.5–5.6) 2.2 (1.04–4.7) 3.0 (1.9–4.9) 1.7 (0.96–2.9) 3.0 (1.9–4.9)

*Values given as %, unless otherwise indicated. OR ⫽ odds ratio; CI ⫽ confidence interval; nGER ⫽ nocturnal GER. †p ⬍ 0.001. ‡p ⬍ 0.05.

In the general population, subjects with nocturnal GER showed a significantly higher mean (⫾ SD) peak flow variability than the subjects without nocturnal GER (5.4 ⫾ 4.2% vs 4.2 ⫾ 3.5%, respectively; p ⬍ 0.05), but there was no difference in the prevalence of atopy (39% vs 30%, respectively), BHR (19% vs 13%, respectively), or the predicted mean FEV1 (107 ⫾ 12% vs 107 ⫾ 12%, respectively). When the random and symptomatic samples were combined, a total of 276 subjects with asthma were identified. Subjects with the combination of nocturnal GER and asthma had a significantly higher BMI and a higher prevalence of several sleep-related symptoms (Table 4). Subjects with the combination of both asthma and nocturnal GER had a higher prevalence of nocturnal cough and morning phlegm and an increased peak flow variability than did subjects with asthma alone. No significant differences were found in the prevalence of atopy, BHR, or mean FEV1 between these two groups of asthmatic subjects (Table 5). Discussion Our study, which was based on random samples of young adults in three European countries, shows that individuals who report GER after bedtime have an increased likelihood of having respiratory symptoms and asthma. This nocturnal GER group also had a much higher prevalence of symptoms related to sleep-disordered breathing, like snoring, nighttime sweating, reported apneas, and daytime sleepiness. Our results draw attention to the partial narrowing or the complete occlusion of the upper airway during sleep, in both obstructive sleep apnea syndrome (OSAS)22 and in the so-called upper airway resistance syndrome.23 The consequence was the same for patients in both situations: the patient tries to get air to the lungs, with increasing inspira-

tory effort.22,23 In theory, the increasingly negative intrathoracic pressure possibly could suck the acid content of the stomach up to the distal esophagus. Based on this cross-sectional epidemiologic study, we can only speculate on whether the acid already in the distal esophagus exerts its harmful effects through an esophageal-tracheobronchial cough reflex24 or whether the gastric fluid reaches the larynx area where the acid is met by the turbulent inspiratory (snoring) airflow and becomes an aerosol that is inhaled down the trachea, thus directly causing mucosal airway damage. Table 4 —Asthmatic Subjects Without and With Reported Nocturnal GER After Bedtime Once a Week or More Often* Characteristics

No nGER (n ⫽ 250)

Age, yr 33 ⫾ 7 Male gender 45 BMI, kg/m2 23.6 ⫾ 3.6 Smokers 35 Rhinitis 72 Asthma medication Inhaled ␤2-agonists 72 Inhaled corticosteroids 29 Oral ␤2-agonists 10 Theophylline 9 Sleep-related symptoms Snoring (ⱖ 3 nights/wk) 13 Reported apneas (ⱖ 1 nights/wk) 3 Nighttime sweating (ⱖ 3 nights/wk) 6 Nightmares (ⱖ 1 nights/wk) 5 Daytime symptoms Morning headache (ⱖ 3 mornings/wk) 3 Daytime sleepiness (ⱖ 3 days/wk) 23 Involuntarily falling asleep (ⱖ 1 days/wk) 6

nGER (n ⫽ 26) 33 ⫾ 6 27 26.7 ⫾ 6.9† 36 62 73 35 12 19 27 6 29‡ 16§ 16§ 46§ 16

*Values given as mean ⫾ SD or %. See Table 3 for abbreviations not used in the text. †p ⬍ 0.001. ‡p ⬍ 0.01. §p ⬍ 0.05. CHEST / 121 / 1 / JANUARY, 2002

161

Table 5—Respiratory Symptoms in Asthmatic Subjects Without and With Reported Nocturnal GER After Bedtime Once a Week or More Often* Symptoms

No nGER (n ⫽ 250)

nGER (n ⫽ 26)

Wheeze Nocturnal chest tightness Breathlessness at rest Breathlessness after effort Nocturnal breathlessness Nocturnal cough Morning cough Morning phlegm Atopy BHR FEV1, % predicted Peak flow variability, %

88 55 32 61 35 49 26 26 67 69 100 ⫾ 15 6.6 ⫾ 5.8

96 54 27 78 46 73† 42 58‡ 65 72 101 ⫾ 13 8.9 ⫾ 6.6†

*Values given as % or mean ⫾ SD. See Table 3 for abbreviations not used in the text. †p ⬍ 0.05. ‡p ⬍ 0.01.

There are several methodologic issues that should be discussed in this investigation. The main one is that our definition of nocturnal GER is based on self-reported symptoms; it is well-known that the association between reported GER and objective measurements, such as 24-h esophageal pH monitoring, is weak.4 Having in mind how very prevalent symptoms of GER are,24 our rather strict criterion for the inclusion of GER symptoms at least once per week has probably resulted in a study population that represents the part of the general population that is more severely affected. A second issue is that in this study the use of three different languages carries the possibility of a translation bias. The questionnaire used in this study is based on the basic Nordic sleep questionnaire.25 The main change in that questionnaire, compared to many earlier sleep questionnaires, was the introduction of a 5-point scale to indicate how many nights or days per week the symptoms occurred. This was done in order to facilitate comparisons when the questionnaire was used in different countries. As we have reported from our previous analysis of the randomly selected sample, the variation in the prevalence of sleep disturbances between the two Swedish centers was of the same magnitude as that between the Swedish and the non-Swedish centers.9,10 Therefore, we do not think that translation bias was a major problem in this study. A validation study26 of the ECRHS interview-led questionnaire also showed good internal consistency, suggesting that the experience of reporting symptoms is not affected by cross-cultural differences. The definition of asthma used in this study was 162

based on self-reported physician-diagnosed asthma. This definition has been suggested as optimal for epidemiologic studies as it has a high specificity for clinical asthma.27 In order to exclude subjects who had asthma only in childhood, we included only individuals who reported having had asthma-related symptoms in the preceding 12 months. As we have not included adults over the age of 44 years, we have probably avoided most of the problems of separating asthma from COPD. Theophylline is known to cause GER28 and might be a confounding factor in our study. However, as only five of the asthmatic subjects reporting GER had undergone theophylline therapy, the power to detect a significant relationship between the use of theophylline and GER was low in this study. The clear association between GER and asthma shown in the present investigation and in several previous studies1– 4 gives rise to the question of how patients who have both these diseases should be managed. The inclusion of a 3-month trial of a high-dose proton pump inhibitor in the management of adult asthma patients if GER symptoms are present has been recommended.29 Investigations evaluating the effect of antireflux therapy in patients with asthma and GER have shown a subjective improvement but no effect on lung function.6 The strong association between symptoms of sleep-related breathing disturbances and reported GER after bedtime in our study also indicates that asthmatic subjects with nocturnal GER and daytime sleepiness or other symptoms related to sleep-disordered breathing should be referred for sleep studies, including the monitoring of esophageal pH. In asthmatic subjects with sleep-disordered breathing, a treatment trial with continuous positive airway pressure (CPAP) should be considered. Among the outcome variables of such a CPAP study, both respiratory symptoms and symptoms of sleep-related breathing disturbances should be included. Although previous studies30,31 have not involved the possible role of nocturnal GER, there have been reports32 on improved asthma control after CPAP therapy and also on the presence of less BHR among snoring and OSAS patients after receiving CPAP therapy for 2 to 3 months. Even if a patient is only undergoing a 24-h monitoring of esophageal pH and the results reveal a sleep-related reflux, such a finding warrants at least basic questions about symptoms of sleep-disordered breathing. We conclude that GER reported to occur after bedtime is strongly associated with a high prevalence of both asthma and respiratory symptoms, as well as symptoms of OSAS. The partial narrowing or occlusion of the upper airway during sleep, followed by more negative swings in intrathoracic pressure, Clinical Investigations

might predispose the patient to nocturnal GER and, consequently, to respiratory symptoms. ACKNOWLEDGMENTS: We thank Mrs. Elsbeth Scholtes at the Department of Medicine, Uppsala University, for assistance with the translation of the sleep questionnaire into Dutch. Professor Wilfried de Backer is acknowledged for his help in carrying out the sleep survey in Antwerp.

16 17

18

References 1 Urschel HC, Paulson DL. Gastroesophageal reflux and hiatal hernia: complications and therapy. Thorac Cardiovasc Surg 1967; 53:21–32 2 Sontag SJ. Gastroesophageal reflux and asthma. Am J Med 1997; 103(suppl):84S–90S 3 Harding SM, Sontag SJ. Asthma and gastroesophageal reflux. Am J Gastroenterol 2000; 95(suppl):S23–S32 4 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 5 Harding SM. Nocturnal asthma: role of nocturnal gastroesophageal reflux. Chronobiol Int 1999; 16:641– 662 6 Field SK, Sutherland LR. Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux. Chest 1998; 114:275–283 7 Field SK, Gelfand GAJ, McFadden SD. The effects of antireflux surgery on asthmatics with gastroesophageal reflux. Chest 1999; 116:766 –774 8 Burney PGJ, Luczynska CM, Chinn S, et al. The European Community Respiratory Health Survey. Eur Respir J 1994; 7:954 –960 9 Janson C, Gislason T, De Backer W, et al. Daytime sleepiness, snoring and gastroesophageal reflux among young adults in three European countries. J Intern Med 1995; 237:277– 285 10 Janson C, Gislason T, De Backer W, et al. Prevalence of sleep disturbances among young adults in three European countries. Sleep 1995; 18:589 –597 11 Janson C, De Backer W, Gislason T, et al. Increased prevalence of sleep disturbances and daytime sleepiness in subjects with bronchial asthma: a population study of young adults in three European countries. Eur Respir J 1996; 9:2132–2138 12 Douglas NJ. Nocturnal asthma [editorial]. Thorax 1993; 48:100 –102 13 Fitzpatrick MF, Engleman H, Whyte KF, et al. Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance. Thorax 1991; 46:569 –573 14 Klink M, Quan SF. Prevalence of reported sleep disturbances in a general adult population and their relationship to obstructive airways disease. Chest 1987; 91:540 –546 15 Burney PGJ, Laitinen LA, Pedrizet S, et al. Validity and repeatability of the IUATLD (1984) bronchial symptoms

19

20 21

22

23

24 25

26

27 28

29 30 31 32

questionnaire: an international comparison. Eur Respir J 1989; 2:940 –945 European Community for Coal and Steel. Standardization of lung function tests. Clin Respir Physiol 1983; 19(suppl):22–27 Knox AJ, Wisniewski A, Cooper S, et al. A comparison of the Yan and a dosimeter method for methacholine challenge in experienced and inexperienced subjects. Eur Respir J 1991; 4:497–502 Higgins BG, Britton JR, Chinn S, et al. Comparison of bronchial reactivity and peak expiratory flow variability measurements for epidemiological studies. Am Rev Respir Dis 1992; 145:588 –593 Bjo¨ rnsson E, Janson C, Håkansson L, et al. Serum eosinophil cationic protein in relation to bronchial asthma in a young Swedish population. Allergy 1994; 49:730 –736 Janson C, Gislason T, Boman G, et al. Sleep disturbances in patients with asthma. Respir Med 1990; 84:37– 42 Gislason T, Reynisdo´ ttir H, Kristbjarnarson H, et al. Sleep habits and sleep disturbances among the elderly: an epidemiological survey. J Intern Med 1993; 234:31–39 Berg S, Hybinette JC, Gislason T, et al. Intrathoracic pressure variation in obese habitual snorers. J Otorhinolaryngol 1995; 24:238 –241 Guilleminault C, Stoohs R, Clerk A, et al. A cause of excessive daytime sleepiness: the upper airway resistance syndrome. Chest 1993; 104:781–787 Howard PJ, Heading RC. Epidemiology of gastro-esophageal reflux disease. World J Surg 1992; 16:288 –293 Partinen M, Gislason T. Basic Nordic sleep questionnaire (BNSQ): a quantitated measure of subjective sleep complaints. J Sleep Res 1995; 4(suppl):150 –155 Sunyer J, Basagana X, Burney P, et al. European Community Respiratory Health Survey: international assessment of the internal consistency of respiratory symptoms. Am J Respir Crit Care Med 2000; 162:930 –935 Tore´ n K, Brissman J, Ja¨ rvholm B. Asthma and asthma-like symptoms in adults assessed by questionnaires: a literature review. Chest 1993; 104:600 – 608 Ruzkowski CJ, Sanowski RA, Austin J, et al. The effects of inhaled albuterol and oral theophylline on gastroesophageal reflux in patients with gastroesophageal reflux disease and obstructive lung disease. Arch Intern Med 1992; 152:783–785 Harding SM. Gastroesophageal reflux and asthma: insight into association. J Allergy Clin Immunol 1999; 104:251–259 Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988; 137:1502–1504 Guilleminault C, Quera-Salva MA, Powell N, et al. Nocturnal asthma: snoring, small pharynx and nasal CPAP. Eur Respir J 1988; 1:902–907 Lin CC, Lin CY. Obstructive sleep apnea syndrome and bronchial hyperreactivity. Lung 1995; 173:117–126

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