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Bronchiolitis obliterans syndrome (BOS) is a form of chronic lung allograft dysfunction that affects a majority of lung transplant recipients and is the principal factor limiting long-term transplant survival. BOS is characterized by progressive airflow obstruction unexplained by acute rejection, infection, or other coexistent condition. Although BOS is a proven useful clinical syndrome that identifies patients at increased risk for death, its clinical course and underlying causative factors are now recognized to be increasingly heterogeneous. Regardless of the clinical history, the primary pathologic correlate of BOS is bronchiolitis obliterans, a condition of intraluminal airway fibrosis. This article highlights the body of developing research illustrating the mechanisms by which BOS is mediated, including alloimmune reactivity, the emerging roles of humoral and autoimmunity, activation of innate immune cells, and response to nonimmune-related allograft insults, such as infection and aspiration. In addition, we underscore emerging clinical implications and promising future translational research directions that have the potential to advance our knowledge and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Posttransplant lymphoproliferative disorder (PTLD) is a relatively infrequent but devastating complication that occurs after solid-organ transplantation. Although the optimal treatment for this condition is unknown, rituximab, a murine/human chimeric monoclonal antibody, has shown promise in the treatment of PTLD. In this report, we define the incidence, clinical features at presentation, and response to treatment of all cases of PTLD observed at our institution over a 10-year period, including four patients who received treatment with rituximab.Methods: A review of all patients who underwent lung or heart-lung transplant at Duke University from 1992 to 2002 was performed (n = 400), and demographic and clinical outcome data were extracted.Results: PTLD was observed in 10 of 400 patients (2.5%). Patients who acquired PTLD were predominantly > 55 years old (8 of 10 patients) and with a native disease of COPD (7 of 10 patients). Diagnosis of PTLD was made a median of 343 days after transplant. The type of transplant and Epstein-Barr virus (EBV) status prior to transplant did not appear to influence the risk for PTLD. Patients presented with thoracic organ involvement (7 of 10 patients), extrapulmonary disease (2 of 10 patients), or both (1 of 10 patients). Histologic subtypes included polymorphic B cell (n = 4), monomorphic B cell (n = 3), B cell without further classification (n = 2), and anaplastic T cell (n = 1). Only one patient responded to reduced immunosuppression alone. Patients treated with surgery or radiation (n = 2) or rituximab (n = 4) had favorable responses to therapy. Both patients treated with chemotherapy died related to complications of treatment and PTLD.Conclusions: Presentation and histologic appearance of PTLD varies considerably among lung transplant recipients. PTLD was more frequent among older patients with COPD, regardless of pretransplant EBV serology. Rituximab appears effective as a first-line therapy for PTLD, but additional studies are needed in order to define its efficacy and side effect profile in this population of patients. [ABSTRACT FROM AUTHOR]

Study Objectives: Lung transplantation continues to be limited by the development of chronic allograft dysfunction in the form of bronchiolitis obliterans syndrome (BOS). The effect of a transplant operation on patients with BOS has not been well-studied, but patients who undergo double-lung transplantation have better long-term survival. We hypothesized that double-lung transplantation leads to decreased rates of BOS.Methods: A retrospective review of all lung transplant recipients at our institution, surviving for > 6 months after undergoing their transplant operation. Demographic data, information on other factors leading to the development of BOS, survival information, and data on the presence and timing of BOS were collected.Results: BOS occurred in 41.3% of the recipients (93 of 225 patients) at a median time of 4.2 years. Single-lung transplantation was associated with increased rates of BOS compared to double-lung transplantation (49.3% vs 31.7%, respectively; p = 0.007), at the time of the analysis. Single-lung and double-lung transplant recipients had different baseline characteristics, but after controlling for these factors the type of transplant remained a significant predictor of the length of time to the onset of BOS in a multivariable proportional hazard model.Conclusions: Double-lung transplantation is associated with a reduced risk for BOS in our study population. A multicenter study with complete BOS information on all patients with a single pretransplant diagnosis would be useful to confirm the above findings. Further research is needed to determine how the type of transplant contributes to the risk for BOS. [ABSTRACT FROM AUTHOR]

This retrospective, single-center study was conducted to assess the response of native idiopathic pulmonary fibrosis (IPF) lungs to a potent cyclosporine-based immunosuppressive regimen in single-lung transplantation recipients. The study included IPF patients who had undergone single-lung transplantation and had chest CT scans before and after transplantation. Five patients underwent single-lung transplantation for IPF between April 1992 and January 2001, and met entry criteria. All patients were placed on an immunosuppressive regimen consisting of prednisone, azathioprine, and cyclosporine. In two of the five patients, ground glass attenuation in the native IPF lung improved post-transplantation. However, fibrotic changes progressed in all five patients. In patients with advanced IPF, a potent cyclosporine-based immunosuppressive regimen is not likely to have an effect on the progression of the disease. [ABSTRACT FROM AUTHOR]

Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis. [ABSTRACT FROM AUTHOR]

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of death among lung transplant recipients. Eosinophils, effector cells of type 2 immunity, are implicated in the pathobiology of many lung diseases, and prior studies suggest their presence associates with acute rejection or CLAD after lung transplantation., Research Question: Does histologic allograft injury or respiratory microbiology correlate with the presence of eosinophils in BAL fluid (BALF)? Does early posttransplant BALF eosinophilia associate with future CLAD development, including after adjustment for other known risk factors?, Study Design and Methods: We analyzed BALF cell count, microbiology, and biopsy data from a multicenter cohort of 531 lung recipients with 2,592 bronchoscopies over the first posttransplant year. Generalized estimating equation models were used to examine the correlation of allograft histology or BALF microbiology with the presence of BALF eosinophils. Multivariable Cox regression was used to determine the association between ≥ 1% BALF eosinophils in the first posttransplant year and definite CLAD. Expression of eosinophil-relevant genes was quantified in CLAD and transplant control tissues., Results: The odds of BALF eosinophils being present was significantly higher at the time of acute rejection and nonrejection lung injury histologies and during pulmonary fungal detection. Early posttransplant ≥ 1% BALF eosinophils significantly and independently increased the risk for definite CLAD development (adjusted hazard ratio, 2.04; P = .009). Tissue expression of eotaxins, IL-13-related genes, and the epithelial-derived cytokines IL-33 and thymic stromal lymphoprotein were significantly increased in CLAD., Interpretation: BALF eosinophilia was an independent predictor of future CLAD risk across a multicenter lung recipient cohort. Additionally, type 2 inflammatory signals were induced in established CLAD. These data underscore the need for mechanistic and clinical studies to clarify the role of type 2 pathway-specific interventions in CLAD prevention or treatment., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a rare and serious condition that is associated with high health-care resource use. The goal of this study was to estimate hospital-related resource use and costs by using a national, prospective registry of patients who were diagnosed with IPF or who had their diagnosis confirmed at the enrolling center in the past 6 months in the United States., Methods: Participants enrolled between June 5, 2014, and April 12, 2016, in the ongoing Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry were included (N = 300). Time to first hospitalization was analyzed by using Kaplan-Meier methods. Annualized costs were estimated for hospitalizations, ICU admissions, and ED visits., Results: At enrollment, most participants were male (75%), white (95%), commercially insured (64%), smokers (68%), had an FVC between 50% and 80% predicted (66%), and received antifibrotic drugs (55%). During the first 12 months of follow-up, participants averaged 0.11 ED visit, 0.42 hospitalization, 0.08 ICU admission, 2.18 hospital days, and 0.45 ICU day. Probability of hospitalization was 18% and 30% at 6 and 12 months, respectively, and was highest for those with FVC < 50% predicted/diffusing lung capacity for carbon monoxide < 30% predicted. Mean annual costs (95% CI) for ICU admission and inpatient care were $10,098 ($4,732-$16,662) and $13,975 ($8,482-$20,918), respectively, per patient., Conclusions: IPF is associated with a substantial economic burden incurred by patients requiring hospital care. Future research in IPF should focus on improving clinical outcomes while reducing cost of care in hospitals., Trial Registry: ClinicalTrials.gov; No.: NCT01915511; URL: www.clinicaltrials.gov., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Limited data are available on the association between clinically measured disease severity markers and quality of life (QOL) in idiopathic pulmonary fibrosis (IPF). The study examined the associations between objective disease severity metrics and QOL in a contemporary IPF population., Methods: This study evaluated baseline data from patients enrolled in the multicenter, US-based Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry between June 2014 and July 2018. Disease severity metrics included FVC % predicted, diffusing capacity for carbon monoxide (Dlco) % predicted, supplemental oxygen use with activity, supplemental oxygen use at rest, and two summary scores (the Gender-Age-Lung Physiology index, based on gender, age, and % predicted values for Dlco and FVC; and the Composite Physiologic Index, based on % predicted values for Dlco, FVC, and FEV 1 ). Multivariable adjusted regression models were used to examine cross-sectional associations between each severity measure and St. George's Respiratory Questionnaire (SGRQ) total score., Results: Among 829 patients with complete SGRQ data, the median (interquartile range) SGRQ score at enrollment was 40 (26-53), with higher scores indicating worse QOL. Modest SGRQ impairments were observed with increasing Gender-Age-Lung Physiology score (2.9 [1.8-4.0] per 1-point increase] and with increasing Composite Physiologic Index scores (3.0 [2.4-3.6] per 5-point increase). Substantial SGRQ impairments were observed for oxygen use with activity (15.6 [12.9-18.2]), oxygen use at rest (16.2 [13.0-19.4]), and decreasing Dlco (5.0 [4.0-6.1] per 10% decrease in % predicted)., Conclusions: Objective measures of disease severity, including severity scores, physiologic parameters, and supplemental oxygen use, are associated with worse QOL in patients with IPF., Trial Registry: ClinicalTrials.gov; No.: NCT01915511; URL: www.clinicaltrials.gov., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary fibrosis (PF) is the most common disease indication for lung transplantation. Our recent work implicated an excess of rare genetic variants in the telomere-related genes TERT, RTEL1, and PARN in PF disease risk. The impact of such variants on posttransplant outcomes is uncertain. The objective of this study was to determine if patients with these PF-associated variants have altered rates of posttransplant acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival., Methods: The study cohort consisted of 262 PF lung transplant recipients previously genetically characterized by whole exome sequencing. Thirty-one patients (11.8%) had variants in TERT, RTEL1, or PARN, whereas 231 (88.2%) did not. Multivariate Cox proportional hazards models adjusted for relevant clinical variables were used to assess the outcomes of death and CLAD. The AR burden was quantified and compared over the first posttransplant year., Results: Patients with PF with disease-associated variants in TERT, RTEL1, or PARN had a significantly higher risk of death (adjusted hazard ratio [HR], 1.82; 95% CI, 1.07-3.08; P = .03) and CLAD (adjusted HR, 2.88; 95% CI, 1.42-5.87; P = .004) than patients without these variants. There was no difference in AR burden or rates of grade 3 primary graft dysfunction between the two groups., Conclusions: Rare variants in the telomere-related genes TERT, RTEL1, or PARN are associated with poor posttransplant outcomes among PF lung transplant recipients. Further research is needed to understand the biological mechanisms by which telomere-related variants increase the risk for death and CLAD., (Published by Elsevier Inc.)

Background: Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA 1 ) pathway is implicated in IPF etiology. Safety and efficacy of BMS-986020, a high-affinity LPA 1 antagonist, was assessed vs placebo in a phase 2 study in patients with IPF., Methods: IM136003 was a phase 2, parallel-arm, multicenter, randomized, double-blind, placebo-controlled trial. Adults with IPF (FVC, 45%-90%; diffusing capacity for carbon monoxide, 30%-80%) were randomized to receive placebo or 600 mg BMS-986020 (once daily [qd] or bid) for 26 weeks. The primary end point was rate of change in FVC from baseline to week 26., Results: Of 143 randomized patients, 108 completed the 26-week dosing phase. Thirty-five patients discontinued prematurely. Patient baseline characteristics were similar between treatment groups (placebo: n = 47; 600 mg qd: n = 48; 600 mg bid: n = 48). Patients treated with BMS-986020 bid experienced a significantly slower rate of decline in FVC vs placebo (-0.042 L; 95% CI, -0.106 to -0.022 vs -0.134 L; 95% CI, -0.201 to -0.068, respectively; P = .049). Dose-related elevations in hepatic enzymes were observed in both BMS-986020 treatment groups. The study was terminated early because of three cases of cholecystitis that were determined to be related to BMS-986020 after unblinding., Conclusions: BMS-986020 600 mg bid treatment for 26 weeks vs placebo significantly slowed the rate of FVC decline. Both regimens of BMS-986020 were associated with elevations in hepatic enzymes., Trial Registry: ClinicalTrials.gov; No.: NCT01766817; URL: www.clinicaltrials.gov., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neurobehavioral functioning is widely recognized as being an important consideration in lung transplant candidates, but little is known about whether these factors are related to clinical outcomes. The present study examined the relationship of neurobehavioral functioning, including measures of executive function and memory, depression, and anxiety, to long-term survival among lung transplant recipients., Methods: The sample was drawn from 201 patients who underwent transplantation at Duke University and Washington University who participated in a dual-site clinical trial investigating medical and psychosocial outcomes in transplant candidates with end-stage lung disease. All patients completed the Beck Depression Inventory-II (BDI-II) and Spielberger State-Trait Anxiety Inventory at baseline and again after 12 weeks, while a subset of 86 patients from Duke University also completed neurocognitive testing. Patients were followed for survival up to 12 years after completing baseline assessments., Results: One hundred eleven patients died over a mean follow-up of 10.8 years (SD=0.8). Baseline depression, anxiety, and neurocognitive function were examined as predictors of posttransplant survival, controlling for age, 6-min walk distance, FEV, and native disease; education and cardiovascular risk factors were also included in the model for neurocognition. Lower executive function (hazard ratio [HR]=1.09, P=.012) and memory performance (HR=1.11, P=.030) were independently associated with greater mortality following lung transplant. Although pretransplant depression and anxiety were not predictive of mortality, patients who scored>13 on the BDI-II at baseline and after 3 months pretransplant had greater mortality (HR=1.85 [95% CI, 1.04, 3.28], P=.036)., Conclusions: Neurobehavioral functioning, including persistently elevated depressive symptoms and lower neurocognitive performance, was associated with reduced survival after lung transplantation., Trial Registry: ClinicalTrials.gov; No.: NCT00113139; URL: www.clinicaltrials.gov.

Background: There is significant heterogeneity within the primary graft dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung dysfunction and patterns of resolution., Methods: Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death., Results: Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent dysfunction (class 1), (2) complete resolution of dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P &lt; .001)., Conclusions: There are distinct phenotypes of resolution of dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of graft dysfunction.

Background: Long-term survival after lung transplant is limited by the development of chronic and progressive airflow obstruction, a condition known as bronchiolitis obliterans syndrome (BOS). While prior studies strongly implicate cellular rejection as a strong risk factor for BOS, less is known about the clinical significance of human leukocyte antigen (HLA) antibodies and donor HLA-specific antibodies in long-term outcomes., Methods: A single-center cohort of 441 lung transplant recipients, spanning a 10-year period, was prospectively screened for HLA antibodies after transplant using flow cytometry-based methods. The prevalence of and predictors for HLA antibodies were determined. The impact of HLA antibodies on survival after transplant and the development of BOS were determined using Cox models., Results: Of the 441 recipients, 139 (32%) had detectable antibodies to HLA. Of these 139, 54 (39%) developed antibodies specific to donor HLA. The detection of posttransplant HLA antibodies was associated with BOS (HR, 1.54; P=.04) and death (HR, 1.53; P=.02) in multivariable models. The detection of donor-specific HLA antibodies was associated with death (HR, 2.42; P<.0001). The detection of posttransplant HLA antibodies was associated with pretransplant HLA-antibody detection, platelet transfusions, and the development of BOS and cytomegalovirus pneumonitis., Conclusions: Approximately one-third of lung transplant recipients have detectable HLA antibodies, which are associated with a worse prognosis regarding graft function and patient survival.

Background: Quality of life (QOL) is an important but understudied outcome after lung transplantation. Previous cross-sectional, single-center studies suggest improved QOL, but few prior longitudinal multicenter data exist regarding the effect of transplantation on the patient’s QOL., Methods: We hypothesized that lung transplantation confers a 1-year QOL benefit in both physical and psychologic well-being; we further hypothesized that the magnitude of benefit would vary by sex, native disease, age, or type of transplant operation. To test these hypotheses, we conducted a secondary analysis using QOL data prospectively and serially measured with the Medical Outcomes Study 36-Item Short-Form Health Survey, version 2 (SF-36) in a multicenter cytomegalovirus prevention clinical trial. Linear mixed-effects models were used to assess the impact of transplantation on the recipient’s QOL., Results: Over the first year after lung transplantation, the SF-36 Physical Component Score significantly increased an average of 10.9 points from baseline levels (P < .0001). A positive benefit was observed for all native diseases; however, the magnitude varied slightly by native disease (P = .04) but not by sex (P = .35), age (P = .06), or transplant type (P = .30). In contrast, the SF-36 Mental Component Score did not change from baseline (P = .36) and remained well below population norms., Conclusions: Our results demonstrate that lung transplantation confers clinically important QOL benefits in physical domains but not in psychologic well-being. A better understanding of the barriers to psychologic well-being after transplant is critical to enhancing the benefits of lung transplantation.

Background: Serum levels of surfactant protein D (SP-D) have been suggested as reflecting epithelial damage in acute lung injury, COPD, and idiopathic pulmonary fibrosis (IPF). However, little is known about SP-D levels in the setting of lung transplantation., Methods: We examined plasma SP-D levels in 104 subjects from a prospective, multicenter cohort study of lung allograft recipients. Plasma SP-D was measured by enzyme-linked immunosorbent assay prior to transplant and daily for 3 days after transplant., Results: Subjects undergoing transplant for IPF had higher baseline SP-D levels (median, 325 ng/mL) compared with subjects with cystic fibrosis, COPD, and pulmonary hypertension (median, 100, 80, and 82 ng/mL, respectively; P = .0001). Among subjects with IPF undergoing bilateral transplant, SP-D levels declined rapidly postoperatively. In contrast, SP-D levels in subjects undergoing single lung transplant for IPF remained significantly higher than those of bilateral allograft recipients. Among subjects undergoing single lung transplant for IPF, the development of primary graft dysfunction (PGD) was associated with a subsequent rise in SP-D levels, whereas SP-D levels in IPF subjects undergoing bilateral transplant declined, even in the presence of grade 3 PGD. Importantly, single lung allograft recipients without PGD had higher postoperative SP-D levels than bilateral allograft recipients with PGD., Conclusions: Subjects undergoing lung transplant for IPF have significantly higher baseline plasma SP-D levels compared with those with other diagnoses. Plasma SP-D is likely a biomarker of the air-blood barrier integrity in the native IPF lung, but may be less useful as a biomarker of PGD after transplant.

Background: Idiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF., Methods: We performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables., Results: The mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship., Conclusions: Higher mPAP in patients with IPF is associated with the development of PGD.

Background: Despite the frequent occurrence of pleural effusions in lung transplant recipients, little is known about early posttransplant pleural space infections. We sought to determine the predictors and clinical significance of pleural infection in this population., Methods: We analyzed 455 consecutive lung transplant recipients and identified patients who had undergone sampling of pleural fluid within 90 days posttransplant. A case-control analysis was performed to determine the characteristics that predict infection and the impact of infection on posttransplant survival., Results: Pleural effusions undergoing drainage occurred in 27% of recipients (124 of 455 recipients). Ninety-six percent of effusions were exudative. Pleural space infection occurred in 27% of patients (34 of 124 patients) with effusions. The incidence of infection did not differ significantly by native lung disease or type of transplant operation. Fungal pathogens accounted for > 60% of the infections; Candida albicans was the predominant organism found. Bacterial etiologies were present in 25% of cases. Infected pleural effusions had elevated lactate dehydrogenase levels (p = 0.036) and markedly increased neutrophil levels in the pleural space (p < 0.0001) compared to noninfected effusions. A pleural neutrophil percentage of > 21% provides a sensitivity of 70% and a specificity of 79% for correctly identifying an infection. Patients with pleural space infection had a diminished 1-year survival rate compared to those without infection (67% vs 87%, respectively; p = 0.002)., Conclusion: Pleural infection with fungal or bacterial pathogens commonly complicates lung transplantation, and an elevated neutrophil level in the pleural fluid is the most sensitive and specific indicator of infection.

This review examines psychosocial issues among lung transplant patients from the time of assessment through the posttransplant period. Although psychological factors are recognized as being important in the transplant evaluation, no standard approach to psychological assessment currently exists. Lung transplant candidates often experience high levels of psychological distress while awaiting transplant, and both pretransplant and posttransplant psychological functioning have been found to predict posttransplant quality of life, adherence to treatment, and, in some cases, medical outcomes. Given the limited long-term survival following transplantation, improving psychosocial functioning is essential for enhancing outcomes among lung transplant recipients. This review summarizes the extant literature on the psychosocial factors in lung transplantation and highlights several innovative efforts to improve psychological outcomes in this challenging patient population.

Rationale: The main hindrance to long-term success of lung transplantation is bronchiolitis obliterans syndrome (BOS), generally thought to be a manifestation of chronic allograft rejection. BOS is associated histologically with epithelial injury, bronchocentric mononuclear inflammation, and fibrosis of small airways known as bronchiolitis obliterans (BO). Few studies have directly compared clinical, radiographic, and histologic findings of BOS and BO, particularly in the era of improved immunosuppression and infection prophylaxis. Patients undergoing pulmonary retransplantation for BOS provide a unique opportunity to investigate these relationships., Methods: All patients who underwent pulmonary retransplantation for BOS from 1992 to 2004 at Duke University Medical Center were reviewed. Pathology findings in explanted lung allografts were compared with clinical, radiographic, and transbronchial biopsy data., Results: Over the 12-year study period, 12 patients underwent pulmonary retransplantation for BOS. The median time to BOS was 517 days (intraquartile range, 396 to 819.8 days). BOS scores prior to retransplantation were 2 in 2 patients and 3 in 10 patients. We developed a semiquantitative scoring system for epithelial, inflammatory, and fibrotic changes in affected airways to permit better comparison between BO and BOS. Somewhat surprisingly, only 50% (6 of 12 patients) had severe fibrotic changes, although all had some degree of epithelial injury, fibrosis, or inflammation centered around the bronchi and bronchioles. Furthermore, pathology findings other than BO were present in most explanted allografts and included cholesterol clefts (n = 4), focal invasive aspergillosis (n = 1), interstitial fibrosis (n = 2), and chronic vascular rejection (n = 1)., Conclusions: In this series of patients with advanced BOS undergoing retransplantation, at least some degree of BO was present in all explanted allografts. However, the degree of epithelial changes, fibrosis, and inflammation present among affected bronchi varied considerably. Furthermore, a wide range of pathologic processes of potential clinical significance were evident in half of the patients. We conclude that significant histologic heterogeneity exists among patients undergoing retransplantation for BOS, potentially contributing to the variability of patient responses to treatment.

Background: Although atrial fibrillation or flutter (AF) is thought to occur commonly after pulmonary transplantation, little is known about the epidemiology, risk factors, or clinical significance of arrhythmia in this population. The aim of the current study was to determine the incidence, clinical predictors, and associated morbidity of AF after lung transplant., Methods: The records of 200 consecutive adult patients who underwent lung transplantation at a single institution from August 1998 to June 2002 were studied. Multivariate logistic regression analysis was performed to define the predictors for posttransplant AF., Results: Indications for transplant included COPD in 43%, cystic fibrosis in 18%, and idiopathic pulmonary fibrosis (IPF) in 17%. The transplants were bilateral (79%) or single lung (21%). The mean age of the patients was 50 years (range, 19 to 66 years; median, 54 years). Postoperative AF within 14 days of transplant occurred in 78 patients (39%), with a mean onset of 3.8 +/- 3.0 days (+/- SD). Significant predictors of AF were as follows: age >or= 50 years (odds ratio [OR], 2.1; p = 0.01), IPF (OR, 2.3; p = 0.03), existing coronary disease (OR, 2.0; p = 0.009), enlarged left atrium (LA) on echocardiography (OR, 3.9; p = 0.05), and number of postoperative vasopressors (OR, 1.5; p = 0.03). Patients with AF had longer hospital stays (32.4 +/- 60.0 days vs 17.5 +/- 24.1 days, p = 0.04), were more likely to undergo tracheostomy (OR, 3.6; p = 0.0003), and had more in-hospital deaths (OR, 5.7; p = 0.0005) than patients without AF., Conclusions: AF is a frequent complication after lung transplant. Advanced age, IPF, known coronary disease, enlarged LA, and use of postoperative vasopressors increase the risk for developing AF. The development of posttransplant AF is associated with significantly prolonged hospital stay and increased mortality. Prospective studies designed to prevent posttransplant AF are needed to clarify the extent to which AF impacts on posttransplant outcomes.

Introduction: Lung transplantation is an acceptable treatment option for end-stage lung disease. Short-term survival has improved, but lung transplant recipients remain at high risk for a variety of complications that can necessitate care in an ICU. Little is known about the epidemiology, clinical outcomes, and risk factors for survival among lung transplant recipients admitted to the ICU., Methods: All lung transplant recipients at a single institution discharged from the hospital after their transplant and subsequently admitted to the medical ICU (MICU) between March 1, 1999, and February 28, 2001, were included. Patients were followed until death or February 28, 2002. Demographic data collected included transplant type and date, APACHE (acute physiology and chronic health evaluation) III scores, last preadmission and best posttransplant FEV(1) in liters, admitting diagnosis, use of mechanical ventilation, and previous MICU admission., Results: There were 51 patients admitted to the MICU during the study period (73 total admissions). Their demographic data, pretransplant diagnoses, and type of transplant were similar to those of the rest of Duke University Medical Center lung transplant patients. Fifty-three percent (27 of 51 patients) required mechanical ventilation during their first MICU admission. Thirty-seven percent (19 of 51 patients) died during their first MICU admission. Fifty-nine percent (16 of 27 patients) receiving mechanical ventilation died. Patients who died had lower FEV(1) to posttransplant best FEV(1) ratio prior to MICU admission, and also had higher APACHE III scores on MICU admission compared to survivors: FEV(1), 51.3 +/- 21.9% (n = 14) vs 75.5 +/- 20.4% (n = 30) [p = 0.001]; APACHE III score, 77.7 +/- 21.4 (n = 19) vs 60.1 +/- 16.5 (n = 32) [p = 0.002]. Survival rates by Kaplan-Meier analysis at 1 year and 2 years after initial MICU admission were 43.1% and 40.9%, respectively. The longest survivor is currently alive 1,087 days after initial MICU admission., Conclusion: Admission to the MICU is common in lung transplant recipients. MICU care, including mechanical ventilation, is associated with a poor prognosis in lung transplant recipients, but is appropriate for selected patients with good allograft function.

Study Objective: To examine the relationship between psychiatric comorbidity and quality of life in patients awaiting lung transplantation., Setting: Duke University Medical Center/Lung Transplantation Program., Participants: One hundred patients with end-stage pulmonary disease listed for lung transplantation., Measurements and Results: Twenty-five percent (n = 25) of the sample met diagnostic criteria for at least one current mood or anxiety disorder. Controlling for age, gender, ethnicity, percentage of predicted FEV, and lung disease diagnosis, patients with a current psychiatric diagnosis reported poorer general quality of life (p < 0.0001), poorer disease-specific quality of life (p < 0.0001), greater shortness of breath (p = 0.01), more symptoms of psychological distress (p < 0.0001), lower levels of social support (p < 0.0001), and fewer positive health habits (p < 0.04) than their counterparts without a psychiatric diagnosis., Conclusions: Psychiatric comorbidity affects a significant portion of patients awaiting lung transplantation and is associated with decreased health-related quality of life.

Introduction: A high prevalence of gastroesophageal reflux (GER) has been reported in lung transplant recipients and is possibly linked to the development of bronchiolitis obliterans syndrome. The etiology of posttransplant GER remains unknown but may occur due to the transplant operation or posttransplant medications, or represent preexisting GER disease. We evaluated these possibilities by studying the nature and severity of GER in a cohort of patients before and after lung transplantation., Methods: Total, upright, and supine acid contact times were recorded in lung transplant recipients who underwent 24-h pH studies before and after transplantation. Patients also underwent esophageal manometry and gastric-emptying studies. Medications for acid suppression and gastric motility were discontinued before testing. Paired comparison between pretransplant and posttransplant results was performed using a paired t test., Results: Twenty-three patients were included in the analysis. The mean age was 51.5 years, and native diseases included emphysema (n = 11), cystic fibrosis (n = 4), pulmonary fibrosis (n = 3), and others (n = 5). Posttransplant studies occurred a median of 100 days after transplantation. After lung transplantation, the total acid contact time increased a mean of 3.7% (p = 0.03) and the supine acid contact time increased a mean of 6.4% (p = 0.019). Thirty-five percent (8 of 23 patients) had abnormal acid contact times before transplant, and 65% (15 of 23 patients) had abnormal acid contact after transplant. Changes in acid contact times were not explained by changes in esophageal or gastric motility. Only 20% (3 of 15 patients) with abnormal posttransplant pH studies were symptomatic., Conclusions: There is a significant increase in GER after lung transplantation, as measured objectively by 24-h pH studies, despite a lack of symptoms in most patients. Further research is needed to determine the physiologic mechanisms of posttransplant GER and its impact on long-term allograft function.

Background: Lung transplantation has become an acceptable treatment option for many end-stage lung diseases. Pulmonary mycetomas are found in patients with end-stage lung diseases, especially sarcoidosis. The clinical course and long-term outcome of these patients after transplantation remains unknown., Methods: We reviewed retrospectively the pathology reports of the explanted lungs from all lung and heart-lung transplantations performed at our institution between January 20, 1992, and June 26, 2000. Patients were included in our study if mycetomas were present on the specimens. Information on transplant date and type, diagnosis, information on antifungal therapy and fungal infections pretransplant and posttransplant, and clinical course after transplantation was recorded., Results: Mycetomas were present in 3.0% of transplant recipients (9 of 303 patients). The underlying pulmonary diagnoses were sarcoidosis (six patients), and emphysema, idiopathic pulmonary fibrosis, and pneumoconiosis (one patient each). Seven patients received bilateral lung transplants, one patient received a heart/lung transplant, and one patient received a single lung transplant. Aspergillus was isolated from culture in five patients pretransplant and from five patients posttransplant. Six patients received treatment with itraconazole, or IV or inhaled amphotericin B prior to transplantation. All patients who survived transplantation received posttransplant antifungal therapy. Four patients died in the first month after transplantation. Two patients died at 17 months and 24 months posttransplant, respectively; one patient received a second transplant 30 months later; and two patients are alive and free from fungal infections 17 months and 18 months, respectively, after transplantation. All of the medium-term survivors received lengthy therapy with inhaled and systemic amphotericin B and itraconazole before and after transplantation., Conclusions: Lung transplant recipients with mycetomas have significantly reduced posttransplant survival. Careful selection of patients and aggressive antifungal therapies before and after transplantation have led to improved outcomes in patients with mycetomas. Additional research is needed to define the best therapeutic strategy for these patients during transplantation.

Background: Long-term mechanical ventilation is considered as a relative or absolute contraindication for lung transplantation by most centers. We report on the results of transplantation in nine patients requiring long-term mechanical ventilation at two lung transplant centers., Methods: The study group (group 1) consisted of nine patients receiving mechanical ventilation who underwent lung transplantation at either Duke University Medical Center or the University of Florida between 1992 and 1997. Patients in group 1 met the following criteria: they underwent exercise therapy with a physical therapist, and they were without panresistant bacterial airway colonization. The study patients that met these criteria spent at least 13 days receiving mechanical ventilation prior to transplantation. The control population (group 2; n = 65) consisted of all patients who underwent transplantation at either center in the calendar year 1997 who were ventilator independent. The 1-year survival rates in each group were calculated by the Kaplan-Meier method. The number of days required for extubation in each group were compared by the nonparametric Wilcoxon rank sum test. The FEV(1) value at 1 year was reported in each group., Results: The 1-year survival rates were 78% and 83% in group 1 and group 2, respectively. The mean number of days required until extubation were 41 days in group 1 and 9 days in group 2 (p < 0.01). The allograft function was comparable in the two groups at 1 year., Conclusions: In a select population of ventilator-dependent patients, the 1-year survival rate is comparable to the standard lung transplant population. However, these ventilator-dependent patients require a significantly longer time until extubation than other transplant recipients.

Gastroesophageal reflux (GER) is increasingly recognized as contributing to a number of pulmonary disorders. The relationship of GER to pulmonary allograft dysfunction after lung transplantation is unknown. In this report, we describe a lung transplant recipient who developed an acute decline in pulmonary function several months after a retransplantation for chronic rejection. A pulmonary workup at that time, including bronchoscopy with biopsy, revealed bronchial inflammation with no allograft rejection or infection. Because of increasing GI symptoms after retransplantation, the patient also underwent additional testing, which revealed severe acid reflux. The treatment of this patient's acid reflux with Nissen fundoplication surgery resulted in a prompt and sustained improvement in his pulmonary function. We suggest that GER should be considered among the potential causes of allograft dysfunction after lung transplantation.

Study Objectives: The efficacy of antithymocyte induction therapy in lung transplantation is controversial, and its use varies from center to center. We hypothesized that rabbit antithymocyte globulin (RATG) induction therapy would decrease acute rejection after lung transplantation, and we designed a single-center, randomized, prospective study to test this hypothesis., Design: A total of 44 single or bilateral adult lung transplant recipients were randomly assigned to receive either RATG induction therapy (dosage, 1.5 mg/kg/d for 3 days) at the time of transplantation, along with conventional immunosuppression (cyclosporine, azathioprine, and prednisone), or conventional immunosuppression alone with no induction therapy., Results: Although a similar number of biopsies were performed in each group, the number of patients experiencing biopsy-proven grade II or greater acute rejection was significantly reduced in the group receiving RATG induction therapy (23% incidence), as compared to the patients treated with conventional immunosuppression alone (55% incidence; p = 0.03). In addition, there was a nonsignificant reduction in the incidence of bronchiolitis obliterans syndrome at the conclusion of the study in patients who received RATG induction (20%), as compared to patients in the control group (38%). The incidence of posttransplant infections and malignancies were similar between the two groups., Conclusion: Induction therapy with RATG significantly reduces the incidence of acute allograft rejection after lung transplantation.

Study Objective: To define the epidemiology, clinical manifestations, and long-term complications of respiratory viral infections in adult lung transplant recipients., Design: Retrospective review of the records of 122 adult lung transplant recipients over a 5-year period at one institution., Results: Ten episodes of infection with respiratory syncytial virus, parainfluenza, influenza, or adenovirus were identified. All patients presented with symptoms of respiratory tract infection. Two patients died acutely and four patients subsequently had development of obliterative bronchiolitis (OB)., Conclusions: These data suggest community respiratory viral infections cause significant morbidity and mortality in lung transplant recipients. Further prospective studies are warranted to clarify the relationship between respiratory viral infection and OB and to define the optimal therapy for these viral infections.

Williams-Campbell syndrome is a rare disorder characterized by a deficiency of cartilage in subsegmental bronchi leading to distal airway collapse and bronchiectasis. We report the first case of lung transplantation in a patient with end-stage lung disease secondary to Williams-Campbell syndrome. Although the patient did not have proximal airway collapse prior to transplantation, his posttransplant course was complicated by the development of bronchomalacia of the right and left mainstem bronchi. The patient experienced recurrent pulmonary infections and died of bacterial pneumonia 1 year after transplantation. Autopsy revealed cartilage deficiency in both right and left mainstem bronchi. A hypothesis may be made that a combination of proximal cartilage deficiency and posttransplant airway ischemia led to the development of bronchomalacia after lung transplantation. Thus, in contrast to previous reports, the cartilage deficiency in Williams-Campbell syndrome can involve both proximal and distal airways. Consequently, bilateral sequential lung transplantation may not be an effective therapeutic option in patients with this syndrome.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension associated with fibrotic occlusion of the smaller pulmonary veins. Although vasodilator therapy is effective in many patients with primary pulmonary hypertension, the role of vasodilators in PVOD is unclear because of concerns about precipitating pulmonary edema. Recently, however, there have been reports of successful therapy with oral vasodilators or intravenous administration of prostacyclin in patients with PVOD. In contrast, a patient with PVOD is described who developed acute pulmonary edema and respiratory failure during low-dose prostacyclin infusion, leading to death. This report suggests that vasodilators, especially prostacyclin, must be used with extreme caution in patients with known PVOD.