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Ann Thorac Surg 2005;80:1254-1260
© 2005 The Society of Thoracic Surgeons

Original article: General thoracic

Prevalence of Gastroesophageal Reflux in End-Stage Lung Disease Candidates for Lung Transplant

Frank D'Ovidio, MD, PhD * , Lianne G. Singer, MD, Denis Hadjiliadis, MD, Andrew Pierre, MD, Thomas K. Waddell, PhD, Marc de Perrot, MD, Micheal Hutcheon, MD, Linda Miller, RN, Gail Darling, MD, Shaf Keshavjee, MD

Toronto Lung Transplant Program, University of Toronto, Toronto, Ontario, Canada

Accepted for publication March 28, 2005.

* Address reprint requests to Dr Keshavjee, Toronto Lung Transplant Program, Toronto General Hospital, 200 Elizabeth St EN10-224, Toronto ON, Canada, M5G 2C4 (Email: s.keshavjee{at}utoronto.ca).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Aspiration secondary to gastroesophageal reflux has been postulated to be a contributing factor in bronchiolitis obliterans after lung transplantation. It is not clear whether gastroesophageal reflux is a preexisting condition or secondary to intraoperative vagal injury or drug-induced prolonged gastric emptying.

METHODS: The prevalence of gastroesophageal reflux was examined in 78 consecutive end-stage lung disease patients assessed for lung transplantation: emphysema, 21; cystic fibrosis, 5; idiopathic pulmonary fibrosis, 26; scleroderma, 10; and miscellaneous diseases, 16. All underwent esophageal manometry. Two-channel esophageal 24-hour pH testing was completed in 76 patients. Gastric emptying studies were conducted in 36 patients.

RESULTS: Typical gastroesophageal reflux symptoms were documented in 63% of patients. The lower esophageal sphincter was hypotensive in 72% of patients, and 33% had esophageal body dysmotility. Prolonged gastric emptying was documented in 44%, and 38% had abnormal pH testing. The overall DeMeester score was above normal in 32% of patients, and 20% had abnormal proximal pH probe readings.

CONCLUSIONS: Gastroesophageal reflux is highly prevalent in end-stage lung disease patients who are candidates for lung transplantation. Further investigation is needed to study the prevalence of gastroesophageal reflux after lung transplantation and its contribution to chronic allograft dysfunction.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
During the last decade, improvements in surgical techniques, lung preservation, immunosuppression, and management of ischemia–reperfusion injury and infections have contributed to an increase in the 1-year patient survival after lung transplantation to 70% to 80% [1]. However, long-term survival is threatened by the development of bronchiolitis obliterans, or chronic lung dysfunction. Bronchiolitis obliterans and its clinical correlate, bronchiolitis obliterans syndrome identified by a persistent decline in forced expiratory volume in 1 second, is usually progressive and poorly responsive to augmented immunosuppression. Furthermore, it accounts for 30% of all deaths after the third postoperative year, with a 5-year survival after its onset of only 30% to 40% [2–4].

Many probable or hypothetical risk factors for bronchiolitis obliterans syndrome have been reported, including recurrent acute rejection, ischemia–reperfusion injury, and cytomegalovirus infection [5]. High gastroesophageal reflux with resultant aspiration has recently been suggested as another potential contributor to bronchiolitis obliterans syndrome [6–12]. Immunosuppressive drugs (ie, calcineurin inhibitors) or intraoperative vagal nerve injury possibly may induce gastroesophageal reflux after transplantation. However, interstitial lung disease secondary to connective tissue disorders, idiopathic pulmonary fibrosis, and cystic fibrosis have been associated with gastroesophageal reflux [13–18].

We sought to determine the prevalence of gastroesophageal reflux in end-stage lung disease patients who were potential candidates for lung transplantation. This will provide a clearer understanding of the magnitude of gastroesophageal reflux within end-stage lung disease patients, which may in turn contribute to posttransplant allograft dysfunction.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Starting January 2002, we evaluated 78 consecutive patients (38 women; median age, 55 years; range, 19 to 68 years) with advanced lung disease who were candidates for lung transplantation. The various lung diseases and the relative numbers of patients affected are listed in Table 1. Table 2 shows the demographics and the pulmonary function test results for each lung disease subgroup with 5 or more patients.


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  		Table 1. Lung Diseases a
 

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  		Table 2. Demographics and Functional Data a
 
The same health professional (L.M.) interviewed all patients before esophageal function testing regarding the presence or absence of typical gastroesophageal reflux symptoms: heartburn, regurgitation, and dysphagia. Patients underwent esophageal manometry by stationary technique using a six-channel probe that has a Dent sleeve distally, one perfusion port at the proximal end of the sleeve, and four more ports at 5-cm intervals proximally (Dentsleeve Pty Ltd, Wayville, Australia), perfused by a perfusion pump (Mui Scientific, Mississauga, Ontario, Canada). After 4 hours of fasting, patients were intubated through the nose with the distal perfusion ports positioned in the stomach. The motility catheter was then withdrawn at 1-cm intervals until the Dent sleeve was positioned in the lower esophageal sphincter. Patients were given 5 mL of water at 30-second intervals to record at least 10 wet swallows. The catheter was then withdrawn at 1-cm intervals to record the upper esophageal sphincter and pharyngeal contractions.

After the manometric study, 24-hour esophageal pH monitoring was performed using a 2-channel pH-probe with 15-cm spacing between sensors connected to a continuous pH recording device (Comfortec, Sandhill Scientific, Highlands Ranch, CO). Before the study the patients were instructed to stop proton pump inhibitors for 5 days and H2-blocking agents for 48 hours. The study was carried out only if the gastric pH was less than 4. The probe was positioned with the sensors 5 and 20 cm above the lower esophageal sphincter. Continuous pH recordings were obtained for 24 hours.

Patients were asked to maintain normal activity and diet excluding acidic foods and drinks. They were instructed to record the occurrence of episodes of heartburn, cough, time and duration of meals, and time and duration of supine and upright position. The DeMeester score was applied for the distal pH findings, considering six components of physiologic relevance: percentage total time pH less than 4; percentage upright time pH less than 4; percentage supine time pH less than 4; number of reflux episodes in 24 hours; number of reflux episodes greater than 5 minutes; and longest episode [19]. The proximal pH findings were analyzed according to the method of Dobhan and Castell [20].

Gastric emptying studies for liquids was completed in 29 patients, and for solids in 36 patients. Gastric emptying was considered prolonged when the half-time of the radiotracer was greater than 45 minutes for liquids and greater than 120 minutes for solids.

Statistical analysis was performed using StatView 5 software (StatView, SAS Institute Inc, Cary, NC). The Kruskal-Wallis test followed by the Mann-Whitney U test was used for comparison of continuous variables among groups. The analysis was performed on the entire series of patients and among lung disease subgroups with a number of patients of 5 or more.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Gastroesophageal reflux–related symptoms were found in 63% (49 of 78) of all patients. Table 3 shows the symptom frequency according to the types of lung disease.


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  		Table 3. Symptom Distribution
 
All patients tolerated the manometric assessment. The pH study was completed satisfactorily in 97% (76 of 78) of patients. The manometric findings in all patients and in patients grouped with respect to presence or absence of symptoms is shown in Table 4. Esophageal dysmotility, either characterized by abnormal peristalsis or abnormal wave amplitude, was present in 33% (26 of 78) of patients. No difference in the motility findings, both for median values and for proportion of patients with abnormal findings, was found when the data were examined according to the presence or absence of symptoms. When looking at the different lung diseases (Table 5), the manometric findings revealed a significant reduction in lower esophageal sphincter pressure tone for all groups. Significant dysmotility was revealed in patients with restrictive lung disease, although no difference was found with respect to the presence of abnormal peristalsis among groups. The Kruskal-Wallis test applied to the esophageal wave amplitudes showed a p = 0.0001; the Mann-Whitney test for the comparisons of the emphysema group (93 mm Hg median wave amplitude; range, 23 to 195 mm Hg) versus idiopathic pulmonary fibrosis (62 mm Hg; range, 12 to 182 mm Hg) and scleroderma (19 mm Hg; range, 0 to 63 mm Hg) showed a p = 0.01 and p = 0.0001, respectively; and the comparison between scleroderma versus idiopathic pulmonary fibrosis and versus cystic fibrosis (60 mm Hg; range, 48 to 120 mm Hg) showed a p = 0.001 and p = 0.007, respectively.


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  		Table 4. Manometric Findings for All Patients a
 

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  		Table 5. Manometric Findings in Patients by End-Stage Pulmonary Disease a
 
The esophageal length (the manometrically measured distance between the upper esophageal sphincter and the lower esophageal sphincter; mean ± standard deviation) was 23 ± 2 cm in emphysema patients; 22 ± 1.6 cm in cystic fibrosis; 20 ± 2 cm in idiopathic pulmonary fibrosis; and 20 ± 2 cm in scleroderma. The Kruskal-Wallis multiple group comparison test among the lung disease groups, performed using the ratio of the esophageal length and the height of the patient, showed a p = 0.0001. To correct for the influence of height on esophageal length, the ratio of esophageal length to patient height was examined. The comparisons among the emphysema group and the idiopathic pulmonary fibrosis group and the scleroderma group showed p = 0.0001 and p = 0.008, respectively; the cystic fibrosis group compared with the idiopathic pulmonary fibrosis group showed a p = 0.02. There was no influence of age on the esophageal length findings. No difference for age was found between the emphysema group and the idiopathic pulmonary fibrosis group.

Prolonged gastric emptying was identified in 44% (16 of 36) of patients for solids, and in 24% (7 of 29) of patients for liquids. A greater prevalence of delayed gastric emptying for solids was found for patients with idiopathic pulmonary fibrosis and, as expected, for patients with scleroderma as shown in Table 6. In all patients the half-life of the radiotracer in the stomach was a median of 31 minutes and a range of 9 to 100 minutes for the liquid gastric emptying study, and it was median of 101 minutes with a range of 40 to 272 minutes for the solid gastric emptying study. The statistical comparison among lung disease groups showed significant differences only for the liquid emptying studies (p = 0.04; Kruskal-Wallis test): the comparison between scleroderma and emphysema, and between scleroderma and idiopathic pulmonary fibrosis showed a p = 0.03 and p = 0.01, respectively (Table 6).


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  		Table 6. Gastric Emptying Findings
 
In Table 7 are shown the median and range of the findings relative to the various pH-testing factors, although abnormal DeMeester score or abnormal proximal pH testing were recorded in 38% (29 of 76) of patients. Nonsymptomatic patients had an abnormal DeMeester score in 14% (4 of 28) of cases, and in 11% (3 of 28) there were also abnormal proximal pH findings (Table 7). The proximal pH probe readings in the supine or in the upright position were abnormal in 20% (15 of 76) of patients, 5 as previously stated of whom had a normal DeMeester score. Of these 5 patients, 4 had emphysema and 1 had idiopathic pulmonary fibrosis. An abnormal DeMeester score or abnormal proximal pH testing were recorded in 38% (8 of 21) of the emphysema patients, 36% (9 of 25) of the pulmonary fibrosis patients, 56% (5 of 9) of the patients with scleroderma, and 60% (3 of 5) of the cystic fibrosis patients (Table 8). Patients with emphysema presented with a greater proportion of abnormal pH testing in the proximal rather than distal esophagus when compared with the patients with idiopathic pulmonary fibrosis (Table 8).


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  		Table 7. pH Findings a
 

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  		Table 8. pH Findings a
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The association between lung disease and gastroesophageal reflux has been recognized for some time [21–25]. More recently gastroesophageal reflux has been documented to be highly prevalent in patients with a variety of lung diseases, in particular patients with asthma, cystic fibrosis, and idiopathic pulmonary fibrosis [13–18]. Moreover gastroesophageal reflux has also been associated with the development of bronchiolitis obliterans–associated pneumonia [26]. A lesion identified as diffuse bronchiolitis secondary to aspiration, characterized by chronic inflammation of the bronchioles because of recurrent bronchoaspiration of foreign material, has been also documented at autopsy in 31 of 4,880 patients, many of whom had no clinical history of bronchoaspiration [27].

During the last two decades lung transplantation has become standard life-prolonging therapy for patients with end-stage lung disease, and increasing numbers of transplants are being performed throughout the world. A major limitation to the long-term success of lung transplantation is the development of posttransplant bronchiolitis obliterans, a process of fibrous obliteration of the small airways with progressive airflow obstruction and accompanying recurrent pulmonary infections. The clinical correlate, bronchiolitis obliterans syndrome, is identified as a persistent drop in the forced expiratory volume in 1 second after transplantation, which affects 50% to 60% of patients at 5 years after transplantation [3]. Alloimmune-mediated injury directed against endothelial and epithelial structures has been thought to be the underlying cause of bronchiolitis obliterans; however, non-alloimmune inflammation, including viral infections or ischemic injury, appears also to play a role [5]. Among the possible inflammatory conditions, retrograde aspiration secondary to gastroesophageal reflux has been suggested as a potential contributor to lung allograft dysfunction and in particular to development of bronchiolitis obliterans [6–12]. In fact two forms of bronchiolitis obliterans have been identified in heart-lung transplant recipients: a relatively acellular concentric fibrosing process limited to the terminal bronchioles, and a focal and cellular process, extending into the distal alveolar spaces, associated with aspirated material and foreign body-type giant cells [28]. The latter pathologic finding is indeed supportive of a possible role for gastroesophageal reflux in the development of bronchiolitis obliterans [6–12].

Because of the use of immunosuppressive drugs that prolong gastric emptying and the potential for iatrogenic vagal nerve injury during the course of lung transplantation, gastroesophageal reflux may indeed be further promoted after lung transplantation [7–12, 29–31]. Marked esophageal motor function abnormalities and increased gastroesophageal reflux has in fact been previously documented in patients after pneumonectomy alone [29, 30].

In lung transplant patients, lung defense mechanisms, including the cough reflex and mucociliary clearance of foreign bodies, are markedly impaired. Mucociliary clearance has been measured to be less than 15% of normal in transplanted lungs [6–11]. It is conceivable that a prolonged contact time of aspirated gastric contents may therefore lead to substantially greater lung parenchymal injury. Moreover, although gastroesophageal reflux may cause direct lung injury, it is also possible that it may play a role in augmenting the alloimmune response by creating an upregulated inflammatory milieu locally [12]. It should be noted that the injurious agent may be gastric acid or other components of the gastroduodenal juices (bile, pepsin, trypsin, and so forth).

In our study we investigated the prevalence of gastroesophageal reflux in end-stage lung disease patients who were candidates for lung transplantation, in an attempt to better understand the magnitude of the disease in relation to lung transplantation. We have shown that the prevalence of gastroesophageal reflux is indeed high in the advanced lung disease patient population. The disease appears to be associated with the presence of abnormal foregut motility. In fact esophageal dysmotility along with a hypotensive lower esophageal sphincter was present in almost 80% of patients, and furthermore, 44% of the patients suffered from a delayed gastric emptying. The combination of defective lower esophageal sphincter function and delayed gastric emptying leads to increased abnormal reflux findings given that both conditions per se are independent determinants in the pathophysiology of gastroesophageal reflux in the general population [32, 33]. Of importance is the fact that these patients are candidates for lung transplants, and further deterioration of foregut motility is likely with the potential for intraoperative vagal nerve injuries and the use of postoperative calcineurin inhibitors as part of the standard immunosuppressive management protocols [10, 11, 29, 30].

Significant acid gastroesophageal reflux was documented in 38% of patients: 32% had an elevated DeMeester score and 20% had pathologic esophageal acid reflux in to the proximal probe in the upper esophagus, particularly when in the supine position, during the nocturnal period of the 24-hour test. The observed high prevalence may in fact be underestimated inasmuch as we performed a single 24-hour investigation. Recent reports are advocating the use of novel devices that permit continuous pH testing for 48 hours to reduce false-negative studies [34].

When stratifying our patients with regard to the symptoms noted on clinical history, 14% of nonsymptomatic patients had pathologic lower esophageal acid reflux and 7% had upper esophageal acid reflux. Gastroesophageal reflux may of course be present in nonsymptomatic patients as previously described [35]. This is of particular concern in this patient population in which it may be difficult to discern atypical gastroesophageal reflux symptoms from typical end-stage lung disease symptoms. Thus, assuming that posttransplant aspiration is injurious to the lung allograft, symptoms alone cannot be the determining factor guiding treatment strategies. Given the high incidence of delayed gastric emptying in candidates for lung transplantation, both acid and nonacid gastroesophageal reflux should be addressed. A prokinetic agent may be helpful because duodenopancreatic refluxate may be more injurious to the lung than acid per se [36–38].

It is evident from our study that gastroesophageal reflux is relevant to all patients with advanced lung disease. Our findings are consistent with previous reports of a higher prevalence in cystic fibrosis and pulmonary fibrosis [14–18]. Of concern is the incidence of proximal acid reflux in 20% of the patients. Previous studies have reported that the upper esophageal sphincter has no baseline tone during sleep along with no reflex augmentation of upper esophageal sphincter pressure in response to reflux. Therefore the pharynx and laryngeal aditus are at greater risk of being bathed with gastric content if upper esophageal reflux occurs with consequent nocturnal aspiration of gastric content [33, 39, 40].

A novel finding is the relatively lower prevalence of an abnormal DeMeester score in the emphysema patients, although interestingly, with a greater prevalence of upper esophageal acid reflux in the supine position as shown in Table 8. This may be related to the stretched condition of the esophagus in these patients as documented manometrically in our study. A significant difference in esophageal length was documented between end-stage lung diseases with an obstructive pattern compared with restrictive ones. The explanation for this observation is intuitive given the chest and diaphragmatic deformations associated with the different lung diseases. The extent to which this impacts on esophageal function and on gastroesophageal reflux is not known, although patients with emphysema and cystic fibrosis had no reduction in the esophageal wave amplitudes.

In future studies it will be interesting to compare the preoperative and postoperative manometric and pH findings of the lung transplant patients. After transplantation the remodeling of the rib cage and normalization of the esophagodiaphragmatic boundaries, both in obstructive and restrictive lung disease patients along with, respectively, a reduced or increased length of the esophagus, could be helpful in normalizing the lower esophageal high-pressure zone. In fact, the double sphincter action that is normally present at the lower esophageal sphincter because of the effect of the diaphragmatic hiatus action on it during the respiratory phases may be optimized. This, therefore, may be helpful in reducing the severity of the gastroesophageal reflux within these patients [41, 42]. Furthermore, normalizing the length of the esophagus may reduce abnormal motility patterns that may favor proximal rather than distal esophageal reflux as observed in our series of patients with emphysema rather than idiopathic pulmonary fibrosis.

In conclusion, gastroesophageal reflux as confirmed by pH findings is highly prevalent in the end-stage lung disease patient population. This reflux disorder is characterized by a high incidence of proximal esophageal reflux in the nocturnal phase of the test, thus favoring chronic silent aspiration. This finding is supportive of the growing literature suggesting a role of gastroesophageal reflux in the development of or deterioration of certain end-stage lung diseases. Whether gastroesophageal reflux worsens after lung transplantation and whether this predisposes to the development of bronchiolitis obliterans are important questions for future studies.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
Dr D'Ovidio was supported by a Canadian Institutes of Health Regenerative Medicine Research Training Award. Dr Waddell was supported by a Canadian Institutes of Health Research Scientist Award.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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Frank D'Ovidio
Andrew Pierre
Thomas K. Waddell
Marc de Perrot
Gail Darling
Shaf Keshavjee
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