L.E. Leard

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.

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation

RATIONALE Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Antireflux surgery for patients with end-stage lung disease before and after lung transplantation

BackgroundGastroesophageal reflux disease (GERD) is prevalent among patients with end-stage lung disease (ESLD). This disease can lead to microaspiration and may be a risk factor for lung damage before and after transplantation. A fundoplication is the best way to stop reflux, but little is known about the safety of elective antireflux surgery for patients with ESLD. This study aimed to report the safety of laparoscopic fundoplication for patients with ESLD and GERD before or after lung transplantation.MethodsBetween January 1997 and January 2007, 305 patients were listed for lung transplantation, and 189 patients underwent the procedure. In 2003, routine esophageal studies were added to the pretransplantation evaluation. After the authors’ initial experience, gastric emptying studies were added as well.ResultsA total of 35 patients with GERD or delayed gastric emptying were referred for surgical intervention. A laparoscopic fundoplication was performed for 32 patients (27 total and 5 partial). For three patients, a pyloroplasty also was performed. Two patients had a pyloroplasty without fundoplication. Of the 35 operations, 15 were performed before and 20 after transplantation. Gastric emptying of solids or liquids was delayed in 12 (92%) of 13 posttransplantation studies and 3 (60%) of 5 pretransplantation studies. All operations were completed laparoscopically, and 33 patients recovered uneventfully (94%). The median hospital length of stay was 2 days (range, 1–34 days) for the patients admitted to undergo elective operations. Hospitalization was not prolonged for the three patients who had fundoplications immediately after transplantation.ConclusionsThe results of this study show that laparoscopic antireflux surgery can be performed safely by an experienced multidisciplinary team for selected patients with ESLD before or after lung transplantation, and that gastric emptying is frequently abnormal and should be objectively measured in ESLD patients.

The impact of pretransplant mechanical ventilation on short- and long-term survival after lung transplantation.

Lung transplantation in mechanically ventilated (MV) patients has been associated with decreased posttransplant survival. Under the Lung Allocation Score (LAS) system, patients at greatest risk of death on the waiting list, particularly those requiring MV, are prioritized for lung allocation. We evaluated whether pretransplant MV is associated with poorer posttransplant survival in the LAS era. Using a national registry, we analyzed all adults undergoing lung transplantation in the United States from 2005 to 2010. Propensity scoring identified nonventilated matched referents for 419 subjects requiring MV at the time of transplantation. Survival was evaluated using Kaplan–Meier methods. Risk of death was estimated by hazard ratios employing time‐dependent covariates. We found that pretransplant MV was associated with decreased overall survival after lung transplantation. In the first 6 months posttransplant, ventilated subjects had a twofold higher risk of death compared to nonventilated subjects. However, after 6 months posttransplant, survival did not differ by MV status. We also found that pretransplant MV was not associated with decreased survival in noncystic fibrosis obstructive lung diseases. These results suggest that under the LAS, pretransplant MV is associated with poorer short‐term survival posttransplant. Notably, the increased risk of death appears to be strongest the early posttransplant period and limited to certain pretransplant diagnoses.

A Thematic Analysis of Quality of Life in Lung Transplant: The Existing Evidence and Implications for Future Directions

Health‐related quality of life (HRQL) has been assessed in various lung transplantation (LT) investigations but never analyzed systematically across multiple studies. We addressed this knowledge gap through a systematic literature review. We searched the PubMed, CINAHL and PsychInfo databases for publications from January 1, 1983 to December 31, 2011. We performed a thematic analysis of published studies of HRQL in LT. Using a comparative, consensus‐based approach, we identified themes that consistently emerged from the data, classifying each study according to primary and secondary thematic categories as well as by study design. Of 749 publications initially identified, 73 remained after exclusions. Seven core themes emerged: (1) Determinants of HRQL; (2) Psychosocial factors in HRQL; (3) Pre‐ and posttransplant HRQL comparisons; (4) Long‐term longitudinal HRQL studies; (5) HRQL effects of therapies and interventions; (6) HRQL instrument validation and methodology; (7) HRQL prediction of clinical outcomes. Overall, LT significantly and substantially improves HRQL, predominantly in domains related to physical health and functioning. The existing literature demonstrates substantial heterogeneity in methodology and approach; relatively few studies assessed HRQL longitudinally within the same persons. Opportunity for future study lies in validating existing and potential novel HRQL instruments and further elucidating the determinants of HRQL through longitudinal multidimensional investigation.

Lung transplantation in patients with connective tissue disorders and esophageal dysmotility.

Lung and esophageal dysfunction are common in patients with connective tissue disease (CTD). Recent reports have suggested a link between pathologic gastroesophageal reflux and bronchiolitis obliterans syndrome (BOS) after lung transplant. Because patients with CTD have a high incidence of esophageal dysmotility and reflux, this group may be at increased risk of allograft dysfunction after lung transplantation. Little is known about antireflux surgery in these patients. Our aims were to describe: (i) the esophageal motility and reflux profile of patients with CTD referred for lung transplantation; and (ii) the safety and outcomes of laparoscopic fundoplication in this group. A retrospective review of 26 patients with CTD referred for lung transplantation between July 2003 and June 2007 at a single center. Esophageal studies included manometry and ambulatory 24-h pH monitoring. Twenty-three patients had esophageal manometry and ambulatory 24-h pH monitoring. Nineteen patients (83%) had pathologic distal reflux and 7 (30%) also had pathologic proximal reflux. Eighteen patients (78%) had impaired or absent peristalsis. Eleven of 26 patients underwent lung transplantation. Ten patients are alive at a median follow-up of 26 months (range 3-45) and one has bronchiolitis obliterans syndrome-1. Six patients had a laparoscopic fundoplication, 1 before transplantation and 5 after. All fundoplication patients are alive at median follow-up of 25 months (range 19-45). In conclusion, esophageal dysmotility and reflux are common in CTD patients referred for lung transplant. For this group, laparoscopic fundoplication is safe in experienced hands.

Mesothelial cell proliferation and apoptosis

Abstract:  Mesothelial cells line the pleural and peritoneal surfaces, where under normal conditions they proliferate and undergo cell death at a slow rate, thereby maintaining a constant number of cells. These tightly regulated processes are disrupted in malignancy. By developing a better understanding of the mechanisms that regulate cell proliferation and apoptosis in mesothelial and mesothelioma cells, we may be able to develop more effective therapeutic agents that target specific steps in these pathways to induce apoptosis more efficiently. This paper reviews our current knowledge of the signaling pathways involved in the regulation of mesothelial cell proliferation and apoptosis. The latest advancements in identifying proteins that play key roles in the resistance to apoptosis are highlighted.

Clinical outcomes of lung transplant recipients with telomerase mutations

BACKGROUND Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations. METHODS Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations. RESULTS The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive. CONCLUSIONS The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations.

Rhinovirus and other respiratory viruses exert different effects on lung allograft function that are not mediated through acute rejection

Community acquired respiratory virus (CARV) infections in lung transplant recipients (LTR) have been associated with adverse outcomes, including acute rejection (AR) and decline in allograft function, in some but not in all studies.

Progression of native lung fibrosis in lung transplant recipients with idiopathic pulmonary fibrosis.

BACKGROUND Single lung transplant recipients with idiopathic pulmonary fibrosis provide an opportunity to study fibrosis in the native lung over time in the setting of pronounced immunosuppression. Lung transplant patients are treated with a regimen of steroids, an antiproliferative agent and a calcineurin inhibitor. This represents a much greater immunosuppression regime than the typical treatment for IPF. To determine whether this regimen of high dose immunosuppression would arrest the progression of fibrosis, the high-resolution chest CT scans (HRCTs) of these patients were reviewed. METHODS HRCTs of 21 patients who underwent single lung transplant for IPF between 1/96 and 1/06 were reviewed. Scans were evaluated by two readers at 6 months intervals, beginning within 1-2 months after transplant. Two calculations were made on the native lung: total volume and percentage of lung affected by fibrosis. Baseline pulmonary function test data was correlated with the immediate post-transplant CT. Patients were followed for an average of 35 months after transplant. RESULTS The mean total volume of the native lung just after transplant was 1120cc. This decreased to 875cc by 2 years and 691cc by 4 years after transplant, representing an average decline of 10.8%/year. Initially, 52% of the native lung was affected by fibrosis compared to 92% at 4 years. Excluding scans with 100% of the lung affected by fibrosis, percentage fibrosis increased 11% per year. CONCLUSION Fibrotic disease within the native lung progresses rapidly in single lung transplant recipients with IPF despite prolonged high dose immunosuppression.