Research review
The role of impaired esophageal and gastric motility in end-stage lung diseases and after lung transplantation

https://doi.org/10.1016/j.jss.2013.09.023Get rights and content

Abstract

Today, many questions persist regarding the causal relationship of gastroesophageal reflux disease (GERD) to promote aspiration and its potential to induce both pulmonary and allograft failure. Current hypotheses, which have identified GERD as a nonimmune risk factor in inducing pulmonary and allograft failure, center on the role of GERD-induced aspiration of gastroduodenal contents. Risk factors of GERD, such as impaired esophageal and gastric motility, may indirectly play a role in the aspiration process. In fact, although impaired esophageal and gastric motility is not independently a cause of lung deterioration or allograft failure, they may cause and or exacerbate GERD. This report seeks to review present research on impaired esophageal and gastric motility in end-stage lung disease to characterize prevalence, etiology, pathophysiology, and current treatment options within this special patient population.

Introduction

Lung transplantation becomes an eventuality in most patients with end-stage lung diseases (ESLDs). Because the failure of lung transplantation is largely determined by the development of bronchiolitis obliterans syndrome (BOS), a disease process whose pathophysiology is largely unknown, finding modifiable risk factors able to avoid or retard its development and progression has been of significant importance. Recent literature on this subject has demonstrated a significant prevalence of gastroesophageal reflux disease (GERD) in various types of ESLDs, including idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and connective tissue disorders (CTDs), such as scleroderma [1], [2], [3], [4]. Research has also attempted to elucidate the association between GERD and BOS after lung transplantation and has not only shown a very convincing connection between the development of GERD and the progression of BOS, but it has equally shown that effective management of GERD with laparoscopic antireflux surgery (LARS) can decrease the incidence of BOS [5], [6], [7].

Although the association between GERD and progression of BOS has been adequately proven in the literature, the pathophysiology linking the two disease processes is not well understood or accepted. Theories have proposed that along with immunologic factors, nonimmune factors, such as GERD-induced aspiration, could induce pulmonary and allograft failure. According to these theories, continuous exposure to gastroduodenal substances, such as pepsin and bile acids, is more likely to be correlated with the development of BOS [5], [8]. Therefore, GERD is thought to play a crucial role in aspiration-mediated lung injury both before and after lung transplant. Risk factors for GERD, such as impaired esophageal and gastric motility, may indirectly affect the aspiration process. In fact, although impaired esophageal and gastric motility is not independently a cause of lung deterioration or and allograft failure, they may cause and or exacerbate GERD (Fig. 1).

This report seeks to review present research on impaired esophageal and gastric motility in ESLD, and after lung transplantation to characterize prevalence, etiology, pathophysiology, and current treatment options. By integrating the research performed at our institution with a detailed review of the relevant literature, we have sought to shed more light on the role of such risk factors for GERD in ESLDs and after lung transplantation.

The introduction of sophisticated diagnostic technologies, such as high-resolution manometry (HRM) and multichannel pH-impedance testing, has allowed clinicians to document subtle motility pattern disturbances along with nonacidic reflux events previously undetectable or indistinguishable from GERD [9], [10]. With increasing availability and incorporation of such diagnostic testing, abnormalities in patients with ESLDs and lung transplantation have been better recognized (Fig. 2, Fig. 3, Fig. 4). For example, although the high prevalence of abnormal gastroesophageal reflux in patients with IPF has been clearly and extensively documented in the literature, recent studies have incorporated new diagnostic testing for esophageal motility and GERD in this patient population [11]. A recent prospective study conducted by Rhagu et al. in 2006 reported that 87% of 65 IPF patients had abnormal reflux determined by the use of 24-h pH monitoring, which was thought to be an underestimate because 65% of the patients were on antireflux medication [1]. However, despite the increased prevalence of GERD in patients with IPF, the contribution of abnormalities of esophageal peristalsis and the lower esophageal sphincter (LES) on the development of GERD in these patients is less clear and may reflect patient selection in different lung transplant centers or study methodology. For instance, colleagues at the University of California, San Francisco, evaluated 109 patients with ESLD awaiting lung transplantation and found a high prevalence of a hypotensive LES (55%) and impaired esophageal peristalsis (47%) among patients with GERD. Patients with IPF, however, comprised only 25% of the patient population [12]. Another follow-up study on 35 patients with GERD (15 patients before and 20 patients after transplantation) showed that impaired esophageal peristalsis was frequent (it was present in 10 of 15 patients before transplantation and in 15 of 20 patients after transplantation), although only five and four patients had IPF before and after transplantation, respectively [13].

To further clarify the role of abnormal esophageal motility in patient with IPF, a study jointly conducted at our institution and University of Chicago attempted to bring to light this point by using HRM, barium swallow, 24-h pH monitoring, and upper endoscopy to characterize patterns of esophageal motility, reflux, and clinical presentations in 22 IPF patients compared with 80 control group patients with GERD only. Interestingly, patients with and without IPF had similar profiles in terms of pH monitoring, esophageal motility, and LES function but were 40% less likely to present with typical symptoms, had a higher incidence of hypotensive upper esophageal sphincter, demonstrated shorter durations of proximal and distal esophageal amplitudes on HRM, and had significantly slower acid clearance and more frequent proximal reflux in the supine position when compared with the control group [14]. Data from our Center confirmed these findings and showed no difference in manometric findings in IPF patients compared with those with other ESLDs, as opposed to patients without GERD and no pulmonary involvement as in the joint study [15]. These findings taken together may have specific pathophysiological implications, which will be discussed in depth later.

A relatively new area of research has also begun evaluating these concerns in patients with CF before lung transplantation. The studies performed in this patient population are relevant as they introduce and establish the concept of aspiration of duodenogastric contents, which is aspiration of refluxed bile from the duodenum, and the transient LES relaxation (TLESR) episodes as potential pathophysiological mechanisms of GERD. In patients with CF, impaired esophageal and gastric motility has been shown to be a significant contributor to the severity of bronchiectasis, the need for lung transplantation, and the subsequent development of BOS, as revealed by a recent prospective study conducted by Pauwels et al. Esophageal reflux and gastric motility were studied in 53 patients with CF using 13C-octanoic acid breath tests to examine gastric emptying, whereas multichannel pH-impedance testing and combined impedance pH–Bilitec monitoring was used to determine reflux patterns. Decreased gastric emptying (DGE) was identified in one third of patients (t1/2 > 75 min). This study also demonstrated a very high correlation between DGE and duodenogastricesophageal reflux, which was quantified in terms of bile reflux [16]. A follow-up study by the same authors examined sputum for the presence of bile in patients with CF, asthma, and chronic cough. Of these patients, bile was present in 13% of healthy subjects, 14% of patients with chronic cough, 28% of asthmatic patients, and 56% of patients with CF [8]. These results not only demonstrated evidence of duodenogastric aspiration but also suggested a positive correlation between the severity of the lung deterioration and the presence of aspiration and impaired motility. Using HRM, Pauwels et al. also quantified the prevalence of impaired esophageal motility in 12 patients with CF, five of which were reported with either absent or otherwise “failed” esophageal peristalsis. Pauwels et al. also noted that TLESR episodes in patients with CF may play a significant pathophysiological role as TLESR was more likely to correlate with distal and proximal reflux than in healthy subjects [8].

The association of impaired esophageal motility and CTDs is more striking than in all other ESLDs, because CTDs, such as scleroderma, directly affect the function of the esophagus, and therefore a causative factor is easy to identify in the pathogenesis of GERD in these patients. In fact, lung deterioration and impaired esophageal motility are so prevalent in these patients that lung transplant in some centers is a relative contraindication, as they have significantly increased risk of allograft dysfunction after lung transplantation because of GERD-induced aspiration. To give a sense of the prevalence of impaired esophageal motility in this patient population, a retrospective review of 26 patients with CTD referred for lung transplantation demonstrated that 78% had impaired or absent peristalsis [17]. More specifically, a follow up from the same Center showed that esophageal peristalsis was maintained in all patients with CTD and GERD, whereas peristalsis was absent in half of patients with ESLD [3].

Similar investigations documenting the prevalence of GERD and its risk factors in association with lung transplant rejection have been an increasingly important, as GERD is thought to be a modifiable risk factor in the development of BOS and lung allograft failure. In 2010, for instance, we sought to determine the prevalence and extent of GERD, as well as the frequency of risk factors and complications of GERD (namely, impaired esophageal motility, hiatal hernia, DGE, and Barrett esophagus), in lung transplant patients. In 35 consecutive patients, we found that more than half of patients had GERD and that half of these patients had proximal reflux, which was more pronounced when supine with the potential to predispose to aspiration [4]. We also found that 36% of patients with GERD had ineffective esophageal motility compared with 6% of patients without GERD. These patients had decreased distal esophageal amplitude, clearance, and prolonged esophageal transit time on impedance compared with patients without GERD. Moreover, no patient demonstrated hiatal hernia on barium swallow, whereas the prevalence of DGE was 36% and the prevalence of biopsy-confirmed Barrett esophagus was 12%, a non-negligible figure, similar to that of the nontransplant population. The importance of Barrett esophagus in this patient population lies in its potential to progress to esophageal adenocarcinoma, and that this event may be precipitated by the concomitant use of immunosuppressant and immunomodulating agents. Furthermore, the prophylactic use of antireflux medications, routinely prescribed to all lung transplant patients in most centers could not reduce the prevalence of Barrett esophagus that we have observed.

In another study, we further sought to understand the risk factors for aspiration after lung transplantation, especially in those with IPF. We measured the concentration of pepsin in the bronchoalveolar lavage fluid of lung transplant patients, as a means of direct detection of aspiration, and correlated these findings with the results of HRM, pH monitoring, barium swallow, and gastric emptying studies. Our findings indicated that lung transplant patients with IPF were at increased risk for aspiration and had a greater frequency of acute rejection episodes [15]. Importantly, similar to Bandeira et al. [18], we also found no difference in the findings of manometric, barium swallow, or gastric emptying study in IPF patients compared with those with other ESLDs, thus speculating that risk factors for aspiration may be different among those who had undergone transplantation [15]. Other factors, such as an increased transdiaphragmatic gastroesophageal pressure gradient, are thought to play a major role in causing abnormal reflux in patients with ESLD; however, the literature is limited on this topic. Nevertheless, we have hypothesized that increased transdiaphragmatic gastroesophageal pressure gradient could be responsible in exacerbating GERD in a specific situation other than in patients with CF as previously suggested by Pauwels et al. In a study that we conducted to elucidate the higher prevalence of GERD in patients according to the type of transplant they received, we found that patients who had undergone a bilateral lung transplant or re-transplantation had GERD more frequently than those who received a unilateral lung transplant. In addition, we found that proximal reflux, a likely proxy for aspiration, was more frequent and severe in those after bilateral or re-transplantation [19]. As in our study, typical risk factors for GERD seemed less relevant to the development of GERD, and we speculated that an increased transdiaphragmatic gastroesophageal pressure gradient may be involved in the pathogenesis of GERD in this specific situation. We also speculated that iatrogenic vagal nerve disruption, more likely after an extensive dissection in patients with bilateral transplants or re-transplants, could have also played a role in causing GERD. Results from our study supported this hypothesis, as patients with GERD after bilateral or re-transplantation tended to have some indirect evidence of vagal nerve injury, such as a more pronounced delayed gastric emptying, impaired esophageal motility, and delayed esophageal acid clearance, in comparison with those who had received a unilateral lung transplant.

Other centers, such as the Toronto Lung Transplant Program, have extensively studied DGE in the lung transplant population. A large retrospective study by Raviv et al. published in 2012 and conducted by Toronto Lung Transplant Program examined 139 lung transplant patients who had at least one nuclear gastric emptying study for solids within the perioperative or postoperative period [20]. Raviv et al. found that 50% of patients before lung transplant exhibited DGE (t1/2 > 90 min). In patients after lung transplant, this percentage was even higher, with the percentage of patients suffering from DGE at 3 and 12 mo after lung transplantation being 74% and 64%, respectively [20].

In contrast to these findings, a study conducted at our institution in 2012 showed somewhat dissimilar but intriguing results. We compared the data from HRM, dual-sensor pH monitoring, upper endoscopy, barium swallow, and gastric emptying studies performed in 10 patients with CF to those of 78 lung transplant patients without CF, or control group patients. We found that the prevalence of GERD in patients with CF was 90% (versus 54% of control group patients), proximal reflux was present in 70% (versus 29% of control group patients), and the degree of impaired esophageal and gastric motility and frequency of Barrett esophagus were similar among the groups [2]. We speculated therefore that lung transplant patients with CF were more prone to aspiration because of their higher prevalence of GERD and proximal reflux, although these findings let us ponder the pathophysiological mechanism that would cause GERD in these patients.

Although extensive literature has documented the presence of GERD as a modifiable risk factor in ESLD, understanding the pathophysiological link between GERD and aspiration—as we have shown—has proven more complicated. On the basis of the evidence discussed, it seems reasonable to speculate that each single risk factor for GERD (e.g., impaired esophageal and gastric motility, TLESR, duodenogastric reflux, or transdiaphragmatic gastroesophageal pressure gradient) may have a different relative pathophysiological weight in patients with different ESLD (e.g., patients with IPF, CF, or scleroderma) at different times in the course of their disease (before and after lung transplant, especially in bilateral, or re-transplant). This concept is important, because, if proven, it may foster further research in trying to individualize the patient's treatment.

Treatment modalities for GERD in patients with ESLD and after lung transplantation are limited. In terms of medical management, azithromycin has gained a lot of attention in this field [21], [22] because of its anti-inflammatory and prokinetic qualities, although its effects on improving impaired motility in the setting of ESLD have been disappointing. Mertens et al. successfully demonstrated that although azithromycin reduced the bile concentration in BAL aspirates and decreased the number of reflux events in BOS patients, they did not find any evidence to support the role of azithromycin in decreasing the progression of BOS induced by aspiration [21], [22]. A recent review of chronic lung rejection syndromes by Sato pointed out that most BOS cases responding to azithromycin treatment corresponded to a specific subtype of BOS mediated by interleukin 8. In contrast, those who did not respond to azithromycin were more likely to have a fibrous subtype of BOS not linked to neutrophilic invasion [23]. This further supports the conclusion by Mertens et al. that the clinical benefit of azithromycin in BOS progression is more likely because of its anti-inflammatory actions rather than its prokinetic qualities.

To date, the most successful management of GERD in patients with ESLD and after lung transplantation is LARS [5], [6], [7]. Data from our Center have shown that the LARS is safe even in high-risk lung transplant patients. In 2011, we analyzed our perioperative morbidity and mortality of LARS in the lung transplant population, compared it with the control group, and found that the morbidity and mortality of LARS in lung transplant and in the control group were equivalent [24]. Interestingly, the additional comparison of the pathophysiological characteristics of GERD between these groups showed that despite comparable impaired esophageal motility, lung transplant patients were more prone to proximal reflux, and thus possibly aspiration, than the general population with GERD [24]. Therefore, these findings would additionally support the concept that not all risk factors for GERD play the same role in all patients.

Although evidence has proven that LARS could improve lung function, its postulated effect on preventing GERD-induced aspiration has been confirmed by our data showing that the detection of pepsin identifies those who aspirate and that patients with LARS had minimal pepsin levels in their bronchoalveolar lavage fluid. Furthermore, we demonstrated that those with GERD who did not have LARS had more pepsin, a quicker progression to BOS (Table), and more episodes of acute rejection, which could lead to chronic rejection (Figs. 5 and 6) [6]. We further speculated that the ability of LARS in preventing GERD-induced aspiration might act at the molecular level by modulating the pulmonary inflammatory milieu [26].

Controversy on the best treatment and its timing still persist as LARS, although safe, remains an invasive procedure. Currently, a phase II National Institute of Health study of laparoscopic fundoplication versus medical treatment with antireflux medication for the treatment of IPF is underway, seeking to determine both its correlation to improved or preserved lung function and its safety profile within this patient population. Future directions will hopefully follow similar footsteps and formally explore the benefits of surgical treatment of GERD in patients suffering from other ESLDs, and lung transplant patients.

Section snippets

Acknowledgment

This work has been supported by funding from the 2011 SAGES Research Grant Award (P. Marco Fisichella, MD) for the study entitled: “A non-invasive test to detect markers of aspiration after lung transplantation.”

The authors would like to thank Dr Maria Picken, MD, PhD for her assistance with the histopathologic illustrations.

References (26)

  • M.G. Hartwig et al.

    Gastroesophageal reflux disease-induced aspiration injury following lung transplantation

    Curr Opin Organ Transplant

    (2012)
  • T. Hoppo et al.

    Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation

    Arch Surg

    (2011)
  • A. Pauwels et al.

    Mechanisms of increased gastroesophageal reflux in patients with cystic fibrosis

    Am J Gastroenterol

    (2012)
  • Cited by (0)

    View full text