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

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.     

Laparoscopic antireflux surgery in the lung transplant population

BACKGROUND: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. METHODS: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. RESULTS: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). CONCLUSIONS: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.     

Chronic Aspiration of Gastric Fluid Induces the Development of Obliterative Bronchiolitis in Rat Lung Transplants

Long-term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY-to-F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL-1α, IL-1β, IL-6, IL-10, TNF-α and TGF-β in BAL and of IL-1α, IL-4 and GM-CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration-related injuries might improve outcomes in clinical lung transplantation.     

The diagnostic value of gastroesophageal reflux disease (GERD) symptoms and detection of pepsin and bile acids in bronchoalveolar lavage fluid and exhaled breath condensate for identifying lung transplantation patients with GERD-induced aspiration

Background

Gastroesophageal reflux disease (GERD) is thought to lead to aspiration and bronchiolitis obliterans syndrome after lung transplantation. Unfortunately, the identification of patients with GERD who aspirate still lacks clear diagnostic indicators. The authors hypothesized that symptoms of GERD and detection of pepsin and bile acids in the bronchoalveolar lavage fluid (BAL) and exhaled breath condensate (EBC) are effective for identifying lung transplantation patients with GERD-induced aspiration.

Methods

From November 2009 to November 2010, 85 lung transplantation patients undergoing surveillance bronchoscopy were prospectively enrolled. For these patients, self-reported symptoms of GERD were correlated with levels of pepsin and bile acids in BAL and EBC and with GERD status assessed by 24-h pH monitoring. The sensitivity and specificity of pepsin and bile acids in BAL and EBC also were compared with the presence of GERD in 24-h pH monitoring.

Results

The typical symptoms of GERD (heartburn and regurgitation) had modest sensitivity and specificity for detecting GERD and aspiration. The atypical symptoms of GERD (aspiration and bronchitis) showed better identification of aspiration as measured by detection of pepsin and bile acids in BAL. The sensitivity and specificity of pepsin in BAL compared with GERD by 24-h pH monitoring were respectively 60 and 45 %, whereas the sensitivity and specificity of bile acids in BAL were 67 and 80 %.

Conclusions

These data indicate that the measurement of pepsin and bile acids in BAL can provide additional data for identifying lung transplantation patients at risk for GERD-induced aspiration compared with symptoms or 24-h pH monitoring alone. These results support a diagnostic role for detecting markers of aspiration in BAL, but this must be validated in larger studies.     

Gastroesophageal reflux disease in lung transplant recipients

BACKGROUND: Chronic allograft dysfunction after lung transplantation contributes to poor long-term survival. A link between gastric aspiration and post-transplant lung dysfunction has been suggested, but little is known about the significance of gastroesophageal reflux disease (GERD) after lung transplantation. METHODS: A retrospective study was performed to determine the prevalence of GERD in lung transplant recipients. Patients who underwent lung transplantation at Duke University, survived at least 6 months and had post-transplant 24-h pH studies were included in the analysis. Antireflux medications were discontinued prior to the pH study. Demographic data, pH study date and results, FEV1 at the time of the pH study, confirmed acute rejection episodes, and current medications were collected. The FEV1 ratio was calculated at the time of pH study (current FEV1/best post-transplant FEV1). RESULTS: Forty-three patients met entry criteria. Studies were performed at a median of 558 d post-transplant. Thirty of forty-three (69.8%) patients tested had abnormal total acid contact times (normal: <5%). The mean acid contact times for all patients were 10% total, 11.8% upright and 7.9% supine. A negative correlation was found between total or upright acid reflux and FEV1 ratio at the time of studies (-0.341 and -0.419; p = 0.025 and p = 0.005, respectively). The effect of acid reflux on FEV1 ratio remained significant after multivariable analysis. CONCLUSIONS: There is a high prevalence of GERD among selected lung transplant recipients who had pH studies performed and its presence is associated with worse pulmonary function. Future studies are needed to assess whether GERD contributes to the pathogenesis of bronchiolitis obliterans syndrome (BOS).     

Symptomatic gastroesophageal reflux disease after lung transplantation

Purpose  

Gastroesophageal reflux disease (GERD) is associated with allograft dysfunction after lung transplantation (LTX). We attempted to identify outcomes in LTX recipients with clinical evidence of GERD.     

Gastric pacing for severe gastroparesis in a heart-lung transplant recipient.

Gastroparesis is a serious complication of lung and heart-lung transplantation that can lead to malnutrition, gastroesophageal reflux, aspiration pneumonia and deteriorating lung function. Some patients with severe gastroparesis have symptoms that are refractory to dietary modifications and gastric promotility agents and require surgery. We describe the successful use of gastric pacing for the management of intractable gastroparesis, malnutrition and recurrent aspiration in a heart-lung allograft recipient. Lung transplant recipients with severe gastroparesis may benefit from gastric pacing.     

Feasibility of laparoscopic Nissen fundoplication after pediatric lung or heart�Clung transplantation: should this be the standard?

Background  

Five-year graft survival in the pediatric lung transplant (LTxp) population is less than 50%, with obliterative bronchiolitis (OB) the leading cause of death at 1, 3, and 5 years post-transplant. Bronchiolitis obliterans syndrome (BOS), defined using spirometry values, is the clinical surrogate for the histological diagnosis of obliterative bronchiolitis. Surgical correction of documented gastroesophageal reflux disease (GERD) has been proposed as a means to potentially delay the onset of BOS and prolong allograft survival in adults before or after lung transplantation but only one such study exists in children. We have examined the safety and possible benefits of laparoscopic antireflux surgery in pediatric patients following lung (LTxp) and heart–lung transplantation (HLTxp).     

Antireflux surgery in the setting of lung transplantation: strategies for treating gastroesophageal reflux disease in a high-risk population

In lung transplant recipients, GERD is associated with increased incidence of acute rejection, earlier onset of chronic rejection, and higher mortality. Surgical treatment of GERD in lung recipients seems to prevent early allograft dysfunction and improve overall survival. A total (360 degrees) fundoplication is shown to be a safe and effective method for treating GERD in lung transplant recipients and is the authors' procedure of choice, in most cases, for this high-risk patient population. The principal goal should be to minimize reflux of enteric contents that may lead to micro- or macroaspiration events in this complicated group of patients. Perioperative care should involve a multidisciplinary approach, including physicians and other health care providers familiar with the complexities of lung transplant recipients.     

The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation

OBJECTIVE: To determine the prevalence and proximal extent of gastroesophageal reflux (GERD) in patients awaiting lung transplantation. BACKGROUND: GERD has been postulated to contribute to accelerated graft failure in patients who have had lung transplantations. However, the prevalence of reflux symptoms, esophageal motility abnormalities, and proximal esophageal reflux among patients with end-stage lung disease awaiting lung transplantation are unknown. METHODS: A total of 109 patients with end-stage lung disease awaiting lung transplantation underwent symptomatic assessment, esophageal manometry, and esophageal pH monitoring (using a probe with 2 sensors located 5 and 20 cm above the lower esophageal sphincter). RESULTS: Reflux symptoms were not predictive of the presence of reflux (sensitivity, 67%; specificity, 26%). Esophageal manometry showed a high prevalence of a hypotensive lower esophageal sphincter (55%) and impaired esophageal peristalsis (47%) among patients with reflux. Distal reflux was present in 68% of patients and proximal reflux was present in 37% of patients. CONCLUSIONS: These data show that in patients with end-stage lung disease: 1) symptoms were insensitive and nonspecific for diagnosing reflux; 2) esophageal motility was frequently abnormal; 3) 68% of patients had GERD; 4) in 50% of the patients with GERD, acid refluxed into the proximal esophagus. We conclude that patients with end-stage lung disease should be screened with pH monitoring for GERD.     

Usefulness of pH monitoring in predicting the survival status of patients with scleroderma awaiting lung transplantation

Background

Patients with scleroderma and end-stage lung disease (ESLD) have a very high prevalence of gastroesophageal reflux disease (GERD). Because GERD has been associated with aspiration in those with ESLD, and because those with scleroderma are particularly prone to develop severe GERD, there is some concern that GERD may contribute to shorten survival in patients with scleroderma awaiting lung transplantation. Therefore, we hypothesized that esophageal pH monitoring could predict survival of those with scleroderma and ESLD awaiting lung transplantation and that the severity of reflux can impact survival.

Methods

We conducted a retrospective analysis of all scleroderma patients referred for lung transplantation who underwent esophageal manometry and pH monitoring since August 2008. We identified 10 patients in whom we calculated and compared the area under the curve for each receiver operating characteristic curve of the following variables: DeMeester score, forced expiratory volume in 1 s (FEV1), %predicted FEV1, forced vital capacity (FVC), %predicted FVC, diffusion capacity for carbon monoxide (DL_co), and %predicted DL_co.

Results

The DeMeester score nominally outperformed FEV₁, FVC, and DL_co. Receiver operating characteristic curve analysis was also used to define the optimal DeMeester score (65.2) in differentiating survival status, as determined by maximizing sensitivity and specificity. Based on this value, we calculated the 1-y survival from the time of the esophageal function testing, which was 100% in seven patients with a DeMeester score of <65.2, and 33% in three patients with a score >65.2 (P = 0.01). The latter patients had greater total time pH < 4, greater time pH < 4 in the supine position, greater total episodes of reflux, and higher prevalence of absent peristalsis. The single survivor with a DeMeester score >70 had also proximal reflux, underwent antireflux surgery, and is alive 1201 d after transplant.

Conclusions

Our study shows that esophageal pH monitoring can predict survival status in patients with scleroderma awaiting lung transplantation and that the severity of reflux can impact the 1-y survival rate. Therefore, esophageal pH monitoring should be considered early in patients with scleroderma and ESLD, as this test could appropriately identify those in whom laparoscopic antireflux surgery should be performed quicker to prevent GERD and its detrimental effects in patients awaiting lung transplantation.     

Histopathological Findings Associated With Gastroesophageal Reflux Disease and Aspiration After Lung Transplantation: Initial Brazilian Single-Center Experience

Background

Gastro-esophageal reflux disease (GERD) and broncho-aspiration (BA) are known to increase the risk for chronic lung allograft dysfunction (CLAD). However, specific lung injury mechanisms are not clearly known. The objective of the study was to describe histopathological findings in surveillance lung transbronchial biopsies that can be correlated with episodes of BA in the lung allograft.

Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts

BACKGROUND: A biologically plausible link between gastro-oesophageal reflux (GOR), aspiration, and lung allograft dysfunction has been suggested, but there is no systematic evidence indicating the presence of gastric contents in the lung. We have tested the hypothesis that pepsin, as a marker of aspiration, is detectable in bronchoalveolar lavage (BAL) fluid of allograft recipients who had not reported symptoms of GOR. METHODS: Standardised 3 x 60 ml surveillance BAL fluid samples from 13 chronologically sequential stable lung allograft recipients without chronic rejection (10 patients treated with a prophylactic proton pump inhibitor) were studied. Lavage supernatants were assayed by an ELISA based on a monospecific goat antibody for pepsin/pepsinogen. Pepsin levels were compared with those from four normal volunteer controls. RESULTS: Pepsin levels were measurable in all allograft recipients, in keeping with gastric aspiration (median 109 ng/ml (range 35-1375)). In the control group the pepsin levels were below the limit of detection. Treatment with a proton pump inhibitor was not correlated with pepsin levels. There was no correlation between BAL fluid neutrophils and pepsin levels. CONCLUSION: These data demonstrate lung epithelial lining fluid concentrations of pepsin in lung allograft recipients which are much higher than blood reference levels, with no detectable pepsin in controls. This provides direct evidence of gastric aspiration, which is potentially injurious to the allograft.     

Gastroesophageal reflux disease and graft failure after lung transplantation

In spite of advances in lung transplantation, the median survival after lung transplant remains less than 5 years, an outcome that is significantly worse than other solid organ transplants. Efforts to understand the unique hurdles faced in lung transplant have revealed gastroesophageal reflux disease (GERD) as a risk factor for ultimate graft failure. The link between GERD and chronic lung rejection parallels the association between GERD and other forms of lung disease such as idiopathic pulmonary fibrosis. Understanding how GERD predisposes to graft failure is an important issue as it may lead to therapies such as surgical correction that aim to lessen the exposure of the pulmonary epithelium to gastric contents. Here, we review the link between GERD and lung disease and discuss the preclinical and clinical studies that are starting to elucidate a mechanism for this association.     

Diagnosis and management of GERD before and after lung transplantation

The strong association between gastroesophageal reflux disease (GERD) and the development and progression of pulmonary diseases has been suggested, and GERD has been focused on as a potential cause and thus a target for prevention and/or therapy. Because GERD is curable, the proper diagnosis and management of underlying GERD would theoretically improve the outcomes. This article reviews the existing literature and discusses the strategy to manage GERD in patients with end-stage pulmonary diseases before and after lung transplantation.     

Long-term follow-up of living-donor single-lobe lung transplantation for bronchiolitis obliterans in a four-year-old male: improvement of over-sized lung allograft

We report a long-term outcome of extremely oversized lung allograft. A left lower lobe transplantation from an adult donor was performed on a four-year-old recipient after left pneumonectomy. Lobar lung allograft volume was calculated to be approximately 180% of the recipient's predicted left thoracic capacity. Accordingly, the lung allograft was compressed to 47% of its original size immediately after transplantation. Initial postoperative functional recovery of the allograft was excellent despite this severe compression. As the patient grew physically, both his forced expiratory volume in 1 s (FEV(1)) and his left lung volume increased slowly but steadily during an observation period of two years and four months after transplantation.     

Successful lung retransplantation after extended use of extracorporeal membrane oxygenation as a bridge

Redo lung transplantation remains a major clinical challenge and its indication for patients with early allograft dysfunction is difficult to determine. We report a case of potentially fatal early allograft dysfunction owing to possible acute cellular rejection after single lung transplantation in a patient who underwent redo double lung transplantation after successful use of extracorporeal membrane oxygenation as a bridge, which resulted in a successful outcome.     

Pediatric lung transplantation as standard of care

For infants, children, and adolescents with progressive advanced lung disease, lung transplantation represents the ultimate therapy option. Fortunately, outcomes after pediatric lung transplantation have improved in recent years now producing good long‐term outcomes, no less than comparable to adult lung transplantation. The field of pediatric lung transplantation has rapidly advanced; thus, this review aims to update on important issues such as transplant referral and assessment, and extra‐corporal life support as “bridge to transplantation”. In view of the ongoing lack of donor organs limiting the success of pediatric lung transplantation, donor acceptability criteria and surgical options of lung allograft size reduction are discussed. Post‐transplant, immunosuppression is vital for prevention of allograft rejection; however, evidence‐based data on immunosuppression are scarce. Drug‐related side effects are frequent, close therapeutic drug monitoring is highly advised with an individually tailored patient approach. Chronic lung allograft dysfunction (CLAD) remains the Achilles' heel of pediatric lung transplant limiting its long‐term success. Unfortunately, therapy options for CLAD are still restricted. The last option for progressive CLAD would be consideration for lung re‐transplant; however, numbers of pediatric patients undergoing lung re‐transplantation are very small and its success depends highly on the optimal selection of the most suitable candidate.     

Bronchoalveolar lavage in a patient with recurrence of sarcoidosis after lung transplantation.

End-stage pulmonary disease due to sarcoidosis rarely leads to lung transplantation. Once a patient has undergone lung transplantation, sarcoidosis often recurs in the lung allograft. In this case report we show, for the first time, the utility of bronchoalveolar lavage fluid in diagnosing the recurrence of sarcoidosis in the transplanted allograft.     

Laparoscopic Fundoplication with or Without Pyloroplasty in Patients with Gastroesophageal Reflux Disease After Lung Transplantation: How I Do It

Introduction  

Several studies have confirmed that gastroesophageal reflux disease (GERD) in lung transplant patients is a risk factor for the development and progression of bronchiolitis obliterans syndrome (BOS), a form of rejection after lung transplantation. Moreover, numerous reports indicate that surgical correction of GERD may control the decline in lung function characteristic of BOS. Although laparoscopic fundoplication is an accepted treatment option for these patients with GERD, the surgical technique, which often includes a laparoscopic pyloroplasty, has not been standardized.