Introduction

End-stage lung disease (ESLD) represents a spectrum of pulmonary processes culminating in pulmonary failure. These entities may include idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and connective tissue diseases such as scleroderma. A precipitating factor contributing to the severity of these diseases includes gastroesophageal reflux disease (GERD). The definition of GERD incorporates a wide breadth of pathophysiologic consequences and is not solely limited to increased acid exposure in the esophagus. Even though increased aspiration of gastric acid has been described as one of the etiologies responsible for some aspects of ESLD , other factors leading to the aspiration of gastrointestinal contents play a role in some of the findings associated with ESLD. These pathways include upper esophageal sphincter disorders and esophageal dysmotility of various categories, including connective tissue disorders, impaired lower esophageal sphincter function, pepsin reflux, biliary reflux, abnormal gastric emptying, and duodenal reflux. The correlation with GERD may need to incorporate several of these pathways resulting in aspiration and lung damage. These pathways leading to lung damage may also occur in patients undergoing lung transplant resulting in different degrees of chronic lung allograft dysfunction (CLAD) , specifically the phenotype resulting in bronchiolitis obliterans syndrome [1]. The initial etiology of either ESLD or chronic lung allograft dysfunction progression is not as clear. Lo et al. proved that increase total reflux, not just acid reflux, may be associated with poorer early posttransplant outcomes [2].

There have been several case reports that suggest that early management of patients with evidence of GERD may benefit from medical or surgical management of their reflux. Most studies have been clear that early surgical management of gastroesophageal reflux symptoms stabilizes the progression of decreasing FVC in patients with ESLD. In addition, there have been studies that suggest an improvement of FVC following minimally invasive antireflux surgery and an improvement in the pulmonary destruction in some patients with ESLD .

GERD and IPF

A number of studies have demonstrated the role of GERD relationship in patients with IPF. Tobin et al. describe 17 patients with biopsy-proven IPF that demonstrated increased esophageal acid exposure as measured through dual-sensor, ambulatory esophageal pH monitoring. This acid exposure was significantly greater than eight control patients with ILD other than IPF. Four of the 17 patients studied had typical symptoms of reflux. The authors concluded that patients with IPF have a high prevalence of increased esophageal acid exposure. Gastroesophageal reflux in these patients typically occurs at night and extends into the proximal esophagus. They also surmised that acid reflux may be a contributing factor in the pathophysiology of IPF [3]. The same group evaluated 65 patients with IPF that underwent both 24-hour pH monitoring and esophageal manometry. They showed that 87% of IPF patients had abnormal acid exposure. Seventy-six percent of this study group had abnormal distal acid exposure, and 63% had proximal abnormal esophageal acid exposure. Despite the high percentage of acid exposure measured by pH monitoring, only 47% experienced classic GERD symptoms. Esophageal manometry in these patients with IPF showed normal peristaltic activity [4]. This study did not show a clear relationship of abnormal esophageal peristalsis and IPF. Other studies have been less clear about the role of abnormal peristalsis in patients with IPF. Sweet et al. evaluated 109 patients awaiting lung transplant . Fifty-five percent of these patients had hypotensive lower esophageal sphincter, and 47% demonstrated impaired esophageal peristalsis. Only 25% of these patients had a diagnosis of IPF [5].

GERD and Connective Tissue Disorders

Despite these equivocal studies, there remains a concern among clinicians about the contribution of abnormal esophageal peristalsis to ESLD . This is very apparent in patients with connective tissue disorders such as scleroderma. In these patients, the smooth muscle of the esophagus atrophies resulting in weak muscular contraction and replacement of the esophageal muscle wall with fibrosis. This fibrosis occurs in the mid and distal portion of the esophagus while preserving the striated muscle of the upper esophagus [6]. Diagnosis of esophageal dysfunction in these patients is based on esophageal manometry depicting the low-amplitude peristaltic waves in the lower two-third of the esophagus. This eventually may lead to aperistalsis with reduced lower esophageal sphincter pressure [7]. The reflux and often silent aspiration may contribute to the lung disease seen in these patients. Because of the pulmonary effects related to patients with connective tissue disorders, this may become a relative contraindication for lung transplantation in some centers .

GERD in Cystic Fibrosis

In patients with cystic fibrosis (CF) , it has been suggested that the progression of bronchiectasis is related to the degree of their reflux. To evaluate the presence of duodenogastric reflux in patients with CF, Hallberg et al. studied 10 patients with CF and compared them to 7 health volunteers; all patients had normal migrating motor complexes. All participants underwent gastroduodenal manometry and intragastric perfusion for evaluation of bilirubin and bile acids. Eight CF patients had higher gastric bilirubin levels and five CF patients had bile acid regurgitation. These findings demonstrated that CF patients had an increased incidence of duodenogastric reflux when compared to healthy patients [8]. To determine if the presence of bile acids in sputum of CF patients correlated with their severity of disease, Pauwels et al. obtained sputum from 41 CF patients. The sputum was tested for bile acids and neutrophil elastase. Spirometry and BMI were also assessed at the time of sputum collection. This demonstrated that more than half of the patients with CF had bile acids present in their sputum, suggesting aspiration of duodenogastric contents. This aspiration was associated with increased airway inflammation, the degree of lung function impairment, as well as the need for antibiotics [9].

GERD After Lung Transplant

Several studies have demonstrated the association of chronic lung allograft dysfunction with gastroesophageal reflux and increased acid exposure to the allograft. This may be due to changes in the anatomy of chest in patients after lung transplant . The etiology may also be related to undiagnosed GERD in patients with ESLD prior to their transplant. In addition, nonacidic reflux has been suggested as another nonimmunologic mechanism for chronic lung allograft dysfunction, as seen in patients with cystic fibrosis. One study of a subset of patients undergoing transplantation estimated the incidence of pretransplant GERD at 35% and the incidence of posttransplant GERD to be 65% [10].

The course of the esophagus through the thoracic cavity is important in its relationship to post-lung transplant CLAD . As the esophagus courses through the thoracic inlet, it deviates to the left and then approaches midline in the mid chest cavity around the level of the carina of the trachea. The esophagus remains along the thoracic vertebra bodies and then deviates to the left as it passes through the esophageal hiatus of the diaphragm.

During the course of lung transplant , the esophagus, vagus nerve, or esophageal collaterals may be injured anywhere along the path of the intrathoracic esophagus. This may occur at the thoracic inlet as the esophagus is entering the chest. In patients who have had previous pneumothoraces, there may be dense adhesions in the area leading to a challenging dissection. This can result in potential injury to the recurrent laryngeal nerves or proximal vagal nerves resulting in upper esophageal sphincter dysfunction or vocal cord paralysis. In patients with infectious components related to their ESLD , such as in patients with CF, there are typically large lymph nodes and bronchial arterial collaterals, especially around the mid portion of the esophagus as it passes near the carina. Dissection in this area may lead to further injury of the vagus nerve or collaterals. There may be incidental ligation of the nerve or arterial collaterals of the esophagus as hemostasis from lung transplant is occurring. If the patient is undergoing a repeat lung transplant, there may be injury anywhere along the esophagus because of dense adhesions. Injury to the vagus nerve and its branches may result in either esophageal or gastric dysfunction. This can lead to either esophageal or gastric dysmotility and resultant reflux [11]. This has been further characterized by Reid et al., who presented their initial findings of complications in 11 heart lung transplants . The authors identified five recipients who developed chronic aspiration. This was evident by these recipients having a chronic cough and either delayed gastric emptying or esophageal dysmotility. Imaging studies supporting this were either a nuclear study or a barium meal. Three of these patients had esophageal manometry performed demonstrating decreased primary peristalsis or diminished amplitude of the primary peristaltic wave. At the time of evaluation, these five patients had evidence of bronchiectasis. Three of these patients were identified to have obliterative bronchiolitis. Most of the five patients who improved after medical therapy were instituted to inhibit reflux. The authors believed the etiology of this cohort of patients was due to injury of the vagus nerve during the course of the heart–lung transplant [12]. This initial report has been confirmed by other studies suggesting that post-thoracic transplant patients experience esophageal or gastric dysmotility due to a possible injury to the vagus nerves or its branches during the conduct of the transplant [13, 14]. Another etiology of CLAD after lung transplant may be related to bile salts. Bile acid aspiration has been associated with biomarkers of injury following lung transplantation. This suggests a possible etiology for lung allograft injury suggesting a possible pathway due to nonacid reflux [15].

Taken together, a combination of one or several of these issues contribute to the further progression of the lung destruction in patients with ESLD . During the workup and evaluation of these patients, these physiologic issues must be taken into account in the studies performed.

Because of the above concerns, these patients should be considered for anti-reflux surgery. The evaluation should include evaluation of acid exposure in these patients. Esophageal manometry is also important in determining the degree of esophageal dysmotility present in this patient population. Gastric motility studies should be included in these patients to assist in optimum management. Imaging studies of the chest including CT scans will assist in evaluating anatomic issues contributing to these patients’ GERD.

The data is sparse regarding optimum timing of intervention in these patients. In addition, there is limited data regarding the effectiveness of medical and surgical therapy for management of these patients reflux disease .

ARS Before Lung Transplant

There is a growing trend that GERD plays a role in either the etiology and/or progression of idiopathic pulmonary fibrosis. The 5-year survival in these patients ranges from 5 to 15%. There have been several case series that have found an association between early surgical management of GERD and a decrease in the clinical pulmonary manifestations of IPF. A phase 2 randomized controlled trial was performed that compared surgical management of gastroesophageal reflux disease with laparoscopic anti-reflux surgery versus best medical management of GERD in patients with idiopathic pulmonary fibrosis. This was a 1:1 randomization process, randomizing 58 patients. The primary end-point was changes in FVC and reduction of clinical symptoms related to the patients IPF, including acute exacerbation, respiratory related hospitalization, and death. The study did demonstrate feasibility of minimally invasive anti-reflux surgery performed in these patients, but it did not reach its primary endpoints. Despite having a decrease in FVC, respiratory-related hospitalization, and death, this was not statically significant [16].

Still the question remains as to when is the best timing of anti-reflux surgery for patients in the perioperative period surrounding lung transplantation . To avoid the issues surrounding CLAD , Linden et al. evaluated the risk and physiologic effects of laparoscopic fundoplication in patients on the lung transplant list. Of the 149 patients that were on the lung transplant list at the time of their study, 19 were found to have reflux as identified by symptoms, pH studies, and esophageal manometry. What was identified was that the patients that underwent fundoplication had no decrease in lung function, stability of their exercise capacity, and stability of their oxygen requirements. The control patients had a statistically significant deterioration in oxygen requirement [17].

Evaluation of these patients for anti-reflux surgery should occur during the initial evaluation for lung transplantation , if not prior. The evaluation should include standard preoperative assessment, including symptom questionnaire, barium swallow, pH probe, and esophageal manometry. This will provide the clinician with determination of severity of symptoms and lifestyle limitations. The barium swallow will assist in assessing esophageal and gastric-emptying anatomic evaluation of the patient’s upper GI tract. A pH probe will assist in determining the severity of reflux, and manometry studies will assist in the evaluation esophageal function. Test results can help determine feasibility of transplant in the future and preoperating planning for anti-reflux procedure. To minimize morbidity and mortality in this patient population, minimally invasive approaches to the anti-reflux procedure should be performed .

ARS After Lung Transplantation

The medical management for patients who develop CLAD after lung transplant is challenging. The use of azithromycin has been suggested as a treatment modality for CLAD because of medication’s anti-inflammatory action and pro-motility qualities. Studies have demonstrated that azithromycin does decrease the bile concentration in BAL aspirates and decreases the number of reflux events in CLAD patients; the study did not find any evidence to support the role of the drug at decreasing the progression of CLAD induced by aspiration [18, 19].

Several studies have demonstrated that the effectiveness of early anti-reflux surgery decreases the frequency of nonimmune CLAD [20].

Currently, the most successful management of GERD in patients following lung transplant is an anti-reflux operation. Davis et al. evaluated 128 post-lung transplant patients using ambulatory 24-hour esophageal pH probe. Surgical fundoplication was performed in 43 of these patients of which 26 had BOS. After fundoplication, 3 patients had improvement in the BOS scores, while 13 patients had reversal of their BOS such that they no longer met criteria. There was also a 24% improvement in lung function after fundoplication. This study clearly demonstrated anti-reflux surgery in patients after lung transplant improves lung function and can improve criteria related to BOS [21].