Jaspersen D, Kulig M, Labenz J, Leodolter A, Lind T, et al. Prevalence of extra-oesophageal manifestations in gastro-oesophageal reflux disease: an analysis based on the ProGERD Study. Alimentary Pharmacology and Therapeutics, 2003; 17(12):1515–20.

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Авторы: Jaspersen D. / Kulig M. / Labenz J. / Leodolter A. / Lind T.  / Meyer-Sabellek W. / Vieth M. / Willich S.N. / Lindner D. / Stolte M. / Malfertheiner P.

Prevalence of extra-oesophageal manifestations in gastro-oesophageal reflux disease: an analysis based on the ProGERD Study

Jaspersen D.1, Kulig M.2, Labenz J.3, Leodolter A.4, Lind T.5, Meyer-Sabellek W.6,
Vieth M.4, Willich S.N.2, Lindner D.7, Stolte M.8, Malfertheiner P.4

1 Klinikum Fulda, Germany
2 Universitatsklinik Charite, Berlin, Germany
3 Ev.-Jung-Stilling-Krankenhaus Siegen, Germany
4 Otto-Von-Guericke-Universitat Magdeburg, Germany
5 AstraZeneca R&D Molndal, Sweden
6 AstraZeneca GmbH, Wedel, Germany
7 Parexel GmbH Berlin, Germany
8 Klinikum Bayreuth, Institut fur Pathologie, Bayreuth, Germany


Background and aims: Gastro-oesophageal reflux disease (GERD) can be associated with a variety of extraoesophageal disorders (EED) such as chronic cough, asthma, laryngeal disorder or chest pain. The aim of the study was to estimate and compare the prevalence of EED in a population with symptomatic GERD presenting as either erosive reflux disease (ERD) or non-erosive reflux disease (NERD).

Methods: Baseline data were collected from a prospective, multicentre, open cohort study (ProGERD) in which patients will be followed for 5 years after initial treatment with esomeprazole. Within the framework of this trial, all patients underwent gastroscopy and filled out a questionnaire designed to assess EED. The influence of potential prognostic factors on the prevalence of EED was analysed by multivariate (stepwise logistic regression) analysis.

Results: 6215 patients (3303 male, 2912 female; mean age 54 years) presenting with heartburn were included. EED was detected in 32.8% of all patients. The proportion was significantly higher (P = 0.0002) in ERD patients (34.9%) than in NERD patients (30.5%). As judged from the multivariate analysis, female gender, age, oesophagitis of LA grade C/D, duration of GERD disease greater than 1 years and smoking were significantly associated with EED. ERD patients with oesophagitis of LA grade A or B did not have a significantly higher risk of EED than patients with NERD.

Conclusions: Patients with GERD have a high probability of experiencing EED, which may be associated with a number of prognostic factors such as duration and severity of GERD. Extra-oesophageal disorders are slightly, but statistically, more prevalent in ERD than in NERD patients.


Gastro-oesophageal reflux disease (GERD) is a common condition that affects about 20–30% of the adult population, presenting with a broad spectrum of symptoms and varying degrees of severity and frequency.1,2 Other manifestations are being increasingly recognized, the so-called ‘atypical’ or ‘extra-oesophageal’ manifestations, such as laryngitis, hoarseness, chronic cough, asthma or non-cardiac chest pain. There are sufficient data on the prevalence of GERD in patients with laryngeal or respiratory disorders, but little is known about the frequency of extra-oesophageal manifestations in a population with GERD. Up to 50% of patients with an endoscopically proven oesophagitis suffer from symptoms other than heartburn or acid regurgitation. The published estimates of extra-oesophageal disorders in patients with GERD vary widely, which may be a result of referral bias.3–10

ProGERD is a prospective study in which patients with symptoms suggestive of GERD are being followed up for 5 years after they have been healed on esomeprazole treatment. The primary objective of this ongoing trial is to determine the endoscopic and symptomatic progression of GERD in endoscopically assessed GERD patients under routine care, with particular emphasis on the development of Barrett’s oesophagus. A secondary aim is to evaluate the prevalence of concomitant extraoesophageal disorders and to compare their occurrence between patients with either symptomatic erosive reflux disease (ERD) or non-erosive reflux disease (NERD). These baseline data are already collected and are now presented in this paper.


Study design

ProGERD is a prospective, multicentre, open cohort study currently being performed in Germany, Austria and Switzerland in which GERD patients are being followed for 5 years after healing treatment with esomeprazole. Thus, the trial consists of a healing phase lasting 4–8 weeks and a subsequent epidemiological follow-up phase. Recruitment took place from May 2000 to February 2001 and is now complete.

The study population consists of patients who presented with reflux symptoms and who had been referred or came directly to hospital endoscopy clinics or specialized endoscopy units where they were endoscoped with the objective of distinguishing between ERD and NERD. Prior to their participation in the study, all endoscopists took part in training seminars on how to use the LA Classification system for description of GERD and on how to diagnose Barrett’s oesophagus. The possible progression of GERD into Barrett’s is a key feature of the main study. Patient recruitment was based on the following inclusion/exclusion criteria.

Inclusion criteria

(1) Female or male, ⩾ 18 years of age. (2) ERD or NERD with or without oesophageal mucosal breaks. NERD patients were identified on the basis of their main symptom being heartburn, i.e. a burning feeling rising from the stomach or lower part of the chest up towards the neck. (3) Written informed consent.

Exclusion criteria

(1) History of gastrointestinal surgery and/or gastrooesophageal malignancies. (2) Continuous treatment with any acid-suppressive drug for more than 7 days within the last 4 weeks prior to inclusion. (3) Contraindications to esomeprazole treatment. (4) Any ‘alarm symptoms’ such as significant unintentional weight loss, haematemesis, melaena, fever, jaundice or any other sign indicating serious or malignant disease (suspected or confirmed malignancy) or other significant cardiovascular, pulmonary (e.g. severe emphysema), renal, pancreatic or liver disease likely to interfere with study procedures as judged by the investigator. (5) Pregnancy and lactation. (6) Alcohol or drug addiction. Subjects with hypertension or ischaemic heart disease who reported chest pain were not counted as subjects with EED ‘non cardiac chest pain’, and, if no further EED was present, they were counted as subjects without any EED. Risk factors such as obesity [body mass index (BMI)] and smoking were documented. (7) All patients had their symptoms assessed and received treatment for 4–8 weeks according to the endoscopic findings, with either 40 mg esomeprazole o.d. for healing and resolution of ERD, or 20 mg esomeprazole once a day for symptom resolution of NERD.

Patients were asked to fill out a standardized ‘upper abdominal symptom questionnaire’ asking about the frequency and severity of typical reflux symptoms. Before treatment with esomeprazole, i.e. at baseline, the presence of any extra-oesophageal disorders were recorded. In particular, patients were interviewed and filled out a questionnaire regarding the occurrence of chronic cough, asthma, laryngitis, or chest pain. Chronic cough was defined as recurrent and persistent cough for 2 months and longer. Asthma was defined as recurrent episodes of diffuse wheezing with airflow obstruction. Laryngeal disorder was defined as chronic hoarseness, sore throat, persistent throat clearing or globus sensation. Non-cardiac chest pain was defined as recurrent angina-like or substernal chest pain believed to be unrelated to the heart.


Statistical methods

The proportions of patients with each type of EED were calculated for all patients and were also compared between ERD and NERD groups using the chi-square test (χ2-test). The prognostic influence of seven variables on the occurrence of EED was then assessed as follows: age ( ⩽ 60 years vs. > 60 years); gender (male vs. female); overweight [no vs. yes (BMI > 25)]; erosive GERD (no vs. yes); LA grading of disease (A/B vs. C/D); duration of disease ( ⩽ 1 year vs. > 1 year); cigarette smoking (non vs. current smoker). A multivariate analysis was utilized using logistic regression analysis (according to the method of maximum likelihood) of the factors: erosive GERD (nonerosive vs. erosive GERD); erosive GERD with LA C/D (non-erosive or erosive GERD with LA A/B vs. LA C/D); current smoker (non vs. current smoker).


6215 patients were included in the evaluation of extraoesophageal disorders, of whom 3245 were diagnosed as having ERD and 2970 as having NERD. The demographic characteristics of the population are shown in Table 1. There were no differences in the social status (with regard to school education) of patients with and without EED. The prevalence of extra-oesophageal disorders amongst all patients was 32.8%, and these were slightly (but significantly) more common in ERD patients (34.9%) than in patients with NERD (30.5%). Chest pain was the most common extraoesophageal disorder (14.5%), followed by chronic cough (13%), laryngeal disorder (10.4%) and asthma (4.8%). Chronic cough, laryngeal disorder and chest pain were significantly more prevalent in patients with ERD than in NERD patients, although the differences were small (Table 2).

Table 1. Baseline demographic and clinical characteristics of the study population (n=6215)

Table 2. Extra-oesophageal disorders by GERD finding

Multivariate analysis

In the multivariate analysis, female gender, higher age, oesophagitis of LA grade C/D, a GERD duration of more than one year and smoking proved to be significant risk factors for the occurrence of extra-oesophageal disorders. In ERD patients with LA grade A/B oesophagitis, extra-oesophageal disorders were no more prevalent than in patients with NERD (Table 3). Chronic cough occurred significantly more frequently in female patients, with increasing age, ERD and smoking. The prevalence of asthma was significantly related to female gender or a GERD duration of more than 1 year, but bore no significant relationship to the type of GERD (ERD or NERD), obesity or smoking habits. The prevalence of laryngeal disorder was significantly related to higher age, a GERD duration of more than 1 year and obesity, and was inversely related to nicotine consumption. Chest pain was significantly associated with higher age and smoking.

Table 3. Results of the multivariate analysis for risk factors of extra-oesophageal disorders*


It has been speculated that GERD represents a risk factor for the occurrence of extra-oesophageal complications.11–17 These associations, which were initially based on clinical observations, have been supported by physiological studies and treatment trials.7,18–20 Recent data indicate that many patients with GERD also present with EED.9,13,19,21–23

The majority of studies in this field have concentrated on highly selected populations recruited at secondary or tertiary referral centres.4,18,22 There are only a few epidemiological trials conducted in a population with GERD, and little is known about a possible association between GERD and respiratory symptoms or chest pain. The published estimates of extra-oesophageal disorders in patients with GERD vary widely, depending on the particular population studied.4,6–10,14,18,19 These studies have derived their estimates from relatively small samples of patients, and in some cases concentrate on only one EED.9 In comparison, our analysis is based on the ProGERD study, which is one of the largest prospective reflux studies. It includes more than 6000 patients with symptomatic GERD, and we have evaluated the prevalence of several potential EEDs. Investigating such a large number of patients may provide a unique opportunity for the analysis of the relationship between GERD and the entirety of the most important EED.

The results obtained corroborate previous evidence from epidemiological and therapeutic trials that have indicated a strong relation between GERD and extraoesophageal disorders. Within the ProGERD study, GERD seems to be a contributory factor to the occurrence of extra-oesophageal manifestations. A high prevalence of respiratory disorders or chest pain was present in our patients. The potential EED, such as chronic cough or chest pain, are relatively common and thus likely to coexist with GERD by chance. Therefore, it is difficult to estimate the real association, as there was no control group without GERD. Extraoesophageal disorders were detected in 34.9% of patients with ERD and in 30.5% of NERD patients with a statistically significant difference. This difference is small, however, and may have been amplified by the large population size. Of the individual EED assessed in our study, chronic cough, laryngeal disorders and chest pain were significantly more common in ERD patients than in NERD patients. Correspondingly, Raiha et al. also found that extra-oesophageal symptoms such as chronic cough or hoarseness were significantly more prevalent in patients with ERD than NERD (n = 157; 57% vs. 33%; P < 0.001).22 This supports the findings in the ProGERD study, and therefore even a small difference could be significant when patients with ERD suffer from a more painful extra-oesophageal disorder than patients with NERD.

The multivariate analysis indicated that female gender, higher age, severity of erosive reflux disease, duration of GERD and smoking were risk factors for the occurrence of extra-oesophageal disorders, whereas obesity was not. However, as in most studies on this topic, it was impossible to differentiate cause and effect of these two conditions, i.e. whether GERD was actually triggering the EED or the two conditions coexisted and were diagnosed simultaneously.

Several studies have suggested a significant relationship between chronic cough and GERD,4,8,18 and the broad variance in reported prevalence rates (10–56%) is probably the result of referral bias to centres with specialized interest.4,8,18 Therefore, the strength of the association between chronic cough and GERD remains controversial.13 We found that chronic cough could be attributed to GERD in 13% of patients. This small percentage may be due to the recruitment method that we used, as our patients presented primarily with typical reflux symptoms such as heartburn and were asked about additional extra-oesophageal disorders such as chronic cough incidentally.

The possible association of asthma with GERD has attracted particular attention because around 50% of people with asthma also have GERD.6,18,20,23 However, little is known about the prevalence of asthma in patients with GERD. We found symptoms of asthma in only 4.8% of cases. Regarding GERD as one common trigger for the development of asthma, only a minority of the study population complained of asthma whereas the other EEDs were much more prevalent.

Laryngeal disorder was detected in 10.4% of patients and was significantly related to higher age, a longer GERD duration and obesity. Unexpectedly, an inverse relationship between smoking and laryngeal disorder was observed, and smokers had laryngeal disorders significantly less often than non-smokers. Perhaps the patients were desensitized to laryngeal symptoms and did not perceive them as a problem.We found that chest pain was the most frequent extra-oesophageal symptom, occurring in 14.5% of patients. Contrary to other reports in the literature,21 our patients with ERD suffered significantly more frequently from chest pain than the NERD patients, possibly because they may have had greater acid reflux. A strong relationship with increasing age and nicotine consumption was found. The risk for patients with ERD grade A/B was not significantly higher than the risk for patients with NERD. In view of the fact that patients with hypertension or ischaemic heart disease who reported chest pain were not counted as subjects having EED, we feel that the non-cardiac chest pain reported was a genuine EED.

We are aware that there are potential limitations of our trial. According to previous studies, the true prevalence of respiratory symptoms or chest pain is difficult to determine, primarily because it is difficult to evaluate whether GERD is causing the extra-oesophageal condition or whether the two conditions coexist independently of each other.12 In addition, the relevance of GERD to respiratory symptoms is difficult to establish because there are a number of other important factors such as voice use, environmental exposure and allergy that may relate to this symptom.18 The lack of a control group with EED but without GERD is one drawback, and the large sample size may lead to some statistically significant differences which are small and have little clinical relevance. However, the major asset of the large sample size is that it permits the evaluation of not only one EED, but of several important extraoesophageal manifestations.

In summary, the results demonstrate a large spectrum of associations between GERD and EED. Reflux patients are at increased risk of experiencing a variety of respiratory symptoms or chest pain, particularly with increased age, a longer duration of their GERD and the presence of more severe erosive disease.


This study was sponsored by a grant from AstraZeneca and was presented in part at the annual DDW 2002, San Francisco, California.

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