P. Marco Fisichella

The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation.

BACKGROUNDnThe goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF).nnnMETHODSnBetween September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF.nnnRESULTSnWe found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes.nnnCONCLUSIONnThis study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.

Gastroesophageal reflux disease after lung transplantation: pathophysiology and implications for treatment.

BACKGROUNDnGastroesophageal reflux disease (GERD) is thought to be a risk factor for the development or progression of chronic rejection after lung transplantation. However, the prevalence of GERD and its risk factors, including esophageal dysmotility, hiatal hernia and delayed gastric emptying after lung transplantation, are still unknown. In addition, the prevalence of Barretts esophagus, a known complication of GERD, has not been determined in these patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients.nnnMETHODSnThirty-five consecutive patients underwent a combination of esophageal function testing, upper endoscopy, barium swallow, and gastric emptying scan after lung transplantation.nnnRESULTSnIn this patient population, the prevalence of GERD was 51% and 22% in those who had been retransplanted. Of patients with GERD,36% had ineffective esophageal motility (IEM), compared with 6% of patients without GERD (P = .037). No patient demonstrated hiatal hernia on barium swallow. The prevalence of delayed gastric emptying was 36%. The prevalence of biopsy-confirmed Barretts esophagus was 12%.nnnCONCLUSIONnOur study shows that, after lung transplantation, more than half of patients had GERD, and that GERD was more common after retransplantation. IEM and delayed gastric emptying are frequent in patients with GERD. Hiatal hernia is rare. The prevalence of Barretts esophagus is not negligible. We conclude that GERD is highly prevalent after lung transplantation, and that delayed gastric emptying and Barretts esophagus should always be suspected after lung transplantation because they are common risks factors and complications of GERD.

Laparoscopic Antireflux Surgery for Gastroesophageal Reflux Disease After Lung Transplantation

BACKGROUNDnAlthough gastroesophageal reflux disease (GERD) is highly prevalent in lung transplantation, the pathophysiology of GERD in these patients is unknown. We hypothesize that the pathophysiology of GERD after lung transplantation differs from that of a control population, and that the 30-d morbidity and mortality of laparoscopic antireflux surgery (LARS) are equivalent in both populations.nnnMETHODSnWe retrospectively compared the pathophysiology of GERD and the 30-d morbidity and mortality of 29 consecutive lung transplant patients with 23 consecutive patients without lung transplantation (control group), all of whom had LARS for GERD between November 2008 and May 2010.nnnRESULTSnBoth groups had a similar prevalence of endoscopic esophagitis and Barretts esophagus , comparable manometric profiles, and similar prevalence of abnormal peristalsis. However, hiatal hernia was more common in controls than in lung transplant patients (57% versus 24%; P = 0.04). Lung transplant patients had a higher prevalence and severity of proximal GERD (65% versus 33%; P = 0.04). The 30-d morbidity and mortality following LARS were similar in both groups regardless of the higher surgical risk of lung transplants (median ASA class: 3 versus 2 for controls, P < 0.001).nnnCONCLUSIONSnThese results show that despite similar manometric profiles, lung transplant patients are more prone to proximal reflux than the general population with GERD; the prevalence of endoscopic esophagitis and Barretts esophagus is the same in both groups of patients; a hiatal hernia is uncommon after lung transplantation; and the morbidity and mortality of LARS are the same for lung transplant patients as the general population with GERD.

Gastroesophageal reflux disease in lung transplant patients with cystic fibrosis

BACKGROUNDnGastroesophageal reflux disease (GERD) in lung transplant patients is being increasingly investigated because of its reported association with chronic rejection. However, information concerning the characteristics of GERD in cystic fibrosis (CF) patients is scarce.nnnMETHODSnWe compared esophageal pH monitoring, manometry, gastric emptying studies, and barium swallow of 10 lung transplant patients with CF with those of 78 lung transplant patients with other end-stage pulmonary diseases.nnnRESULTSnIn lung transplant patients with CF, the prevalence of GERD was 90% (vs 54% controls, P = .04), of whom 70% had proximal reflux (vs 29% controls, P = .02).nnnCONCLUSIONSnLung transplant patients with CF have a significantly higher prevalence and proximal extent of GERD than do other lung transplant recipients. These data suggest that CF patients in particular should be routinely screened for GERD after transplantation to identify those who may benefit from antireflux surgery, especially given the risks of GERD-related aspiration and chronic allograft injury.

Pepsin concentrations are elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis after lung transplantation

BACKGROUNDnAspiration of gastroesophageal refluxate has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the progression of bronchiolitis obliterans syndrome after lung transplantation. The goals of the present study were to identify lung transplant patients at the greatest risk of aspiration and to investigate the causative factors.nnnMATERIALS AND METHODSnFrom September 2009 to November 2011, 252 bronchoalveolar lavage fluid (BALF) samples were collected from 100 lung transplant patients. The BALF pepsin concentrations and the results of transbronchial biopsy, esophageal function testing, barium swallow, and gastric emptying scan were compared among those with the most common end-stage lung diseases requiring lung transplantation: IPF, chronic obstructive pulmonary disease, cystic fibrosis, and α1-antitrypsin deficiency.nnnRESULTSnPatients with IPF had higher BALF pepsin concentrations and a greater frequency of acute rejection than those with α1-antitrypsin deficiency, cystic fibrosis, or chronic obstructive pulmonary disease (P = 0.037). Moreover, the BALF pepsin concentrations correlated negatively with a lower esophageal sphincter pressure and distal esophageal amplitude; negatively with distal esophageal amplitude and positively with total esophageal acid time, longest reflux episode, and DeMeester score in those with chronic obstructive pulmonary disease; and negatively with the upright acid clearance time in those with IPF.nnnCONCLUSIONSnOur results suggest that patients with IPF after lung transplantation are at increased risk of aspiration and a greater frequency of acute rejection episodes, and that the risk factors for aspiration might be different among those with the most common end-stage lung diseases who have undergone lung transplantation. These results support the role of evaluating the BALF for markers of aspiration in assessing lung transplant patients as candidates for antireflux surgery.

Aspiration, Localized Pulmonary Inflammation, and Predictors of Early-Onset Bronchiolitis Obliterans Syndrome after Lung Transplantation

BACKGROUNDnWe hypothesized that immune mediator concentrations in the bronchoalveolar fluid (BALF) are predictive of bronchiolitis obliterans syndrome (BOS) and demonstrate specific patterns of dysregulation, depending on the presence of acute cellular rejection, BOS, aspiration, and timing of lung transplantation.nnnSTUDY DESIGNnWe prospectively collected 257 BALF samples from 105 lung transplant recipients. The BALF samples were assessed for absolute and differential white blood cell counts and 34xa0proteins implicated in pulmonary immunity, inflammation, fibrosis, and aspiration.nnnRESULTSnThere were elevated BALF concentrations of interleukin (IL)-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-α, and myeloperoxidase, and reduced concentrations of α1-antitrypsin, which were predictive of early-onset BOS. Patients with BOS had an increased percentage of BALF lymphocytes and neutrophils, with a reduced percentage of macrophages (p < 0.05). The BALF concentrations of IL-1β; IL-8; interferon-γ-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; neutrophil elastase; and pepsin were higher in patients with BOS (p < 0.05). Among those with BOS, BALF concentrations of IL-1RA; IL-8; eotaxin; interferon-γ-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; myeloperoxidase; and neutrophil elastase were positively correlated with time since transplantation (p < 0.01). Those with worse grades of acute cellular rejection had an increased percentage of lymphocytes in their BALF (pxa0< 0.0001) and reduced BALF concentrations of IL-1β, IL-7, IL-9, IL-12, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, and vascular endothelial growth factor (p ≤ 0.001). Patients with aspiration based on detectable pepsin had increased percentage of neutrophils (p < 0.001) and reduced BALF concentrations of IL-12 (p < 0.001).nnnCONCLUSIONSnThe BALF levels of IL-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-α, myeloperoxidase, and α1-antitrypsin at 6 to 12 months after lung transplantation are predictive of early-onset BOS, and those with BOS and aspiration have an augmented chemotactic and inflammatory balance of pulmonary leukocytes and immune mediators. These data justify the surgical prevention of aspiration and argue for the refinement of antirejection regimens.

Pulmonary immune changes early after laparoscopic antireflux surgery in lung transplant patients with gastroesophageal reflux disease

BACKGROUNDnThe biologic mechanisms by which laparoscopic antireflux surgery (LARS) might influence the inflammatory process leading to bronchiolitis obliterans syndrome are unknown. We hypothesized that LARS alters the pulmonary immune profile in lung transplant patients with gastroesophageal reflux disease.nnnMETHODSnIn 8 lung transplant patients with gastroesophageal reflux disease, we quantified and compared the pulmonary leukocyte differential and the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF) 4 weeks before LARS, 4 weeks after LARS, and 12 months after lung transplantation. Freedom from bronchiolitis obliterans syndrome (graded 1-3 according to the International Society of Heart and Lung Transplantation guidelines), forced expiratory volume in 1 second trends, and survival were also examined.nnnRESULTSnAt 4 weeks after LARS, the percentages of neutrophils and lymphocytes in the BALF were reduced (from 6.6% to 2.8%, P = 0.049, and from 10.4% to 2.4%, P = 0.163, respectively). The percentage of macrophages increased (from 74.8% to 94.6%, P = 0.077). Finally, the BALF concentration of myeloperoxide and interleukin-1β tended to decrease (from 2109 to 1033 U/mg, P = 0.063, and from 4.1 to 0 pg/mg protein, P = 0.031, respectively), and the concentrations of interleukin-13 and interferon-γ tended to increase (from 7.6 to 30.4 pg/mg protein, P = 0.078 and from 0 to 159.5 pg/mg protein, P = 0.031, respectively). These trends were typically similar at 12 months after transplantation. At a mean follow-up of 19.7 months, the survival rate was 75% and the freedom from bronchiolitis obliterans syndrome was 75%. Overall, the forced expiratory volume in 1 second remained stable during the first year after transplantation.nnnCONCLUSIONSnOur preliminary study has demonstrated that LARS can restore the physiologic balance of pulmonary leukocyte populations and that the BALF concentration of pro-inflammatory mediators is altered early after LARS. These results suggest that LARS could modulate the pulmonary inflammatory milieu in lung transplant patients with gastroesophageal reflux disease.

The Pulmonary Side of Reflux Disease: from Heartburn to Lung Fibrosis

IntroductionGastroesophageal reflux disease (GERD) is the most prevalent gastrointestinal disorder in the USA. Heartburn is the symptom most commonly associated with this disease, and the highly commercialized medical treatment directed toward relief of this symptom represents a 10-billion-dollar-per-year industry.DiscussionUnfortunately, there is often little awareness that GERD can be potentially a lethal disease as it can cause esophageal cancer. Furthermore, there is even less awareness about the relationship between GERD and respiratory disorders with the potential for severe morbidity and even mortality.

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

IntroductionSeveral 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.MethodsThe purpose of this article is to describe a step-by-step approach to the laparoscopic treatment of GERD in lung transplant patients. We also address specific technical concerns encountered in the surgical management of this high-risk patient population; we provide data on the safety of this operation; and we illustrate the evidence-based rationale for each technical step of the procedure.

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

AbstractBackgroundnGastroesophageal 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.nMethodsFrom 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.ResultsThe 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 45xa0%, whereas the sensitivity and specificity of bile acids in BAL were 67 and 80xa0%.ConclusionsThese 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.