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Background: Few tools exist for early identification of patients at risk for chronic lung allograft dysfunction (CLAD). We previously showed hyaluronan (HA), a matrix molecule that regulates lung inflammation and fibrosis, accumulates in bronchoalveolar lavage fluid (BALF) and blood in CLAD. We aimed to determine if early posttransplant HA elevations inform CLAD risk., Methods: HA was quantified in 3080 BALF and 1323 blood samples collected over the first posttransplant year in 743 adult lung recipients at 5 centers. The relationship between BALF or blood HA and CLAD was assessed using Cox models with a time-dependent binary covariate for "elevated" HA. Potential thresholds for elevated HA were examined using a grid search between the 50th and 85th percentile. The optimal threshold was identified using fit statistics, and the association between the selected threshold and CLAD was internally validated through iterative resampling. A multivariable Cox model using the selected threshold was performed to evaluate the association of elevated HA with CLAD considering other factors that may influence CLAD risk., Results: BALF HA levels >19.1ng/mL (65th percentile), had the largest hazard ratio for CLAD (HR 1.70, 95% CI 1.25-1.31; p<0.001), optimized fit statistics, and demonstrated robust reproducibility. In a multivariable model, the occurrence of BALF HA >19.1 ng/mL in the first posttransplant year conferred a 66% increase in the hazards for CLAD (adjusted HR 1.66, 95% CI 1.19-2.32; p=0.003). Blood HA was not significantly associated with CLAD., Conclusions: We identified and validated a precise threshold for BALF HA in the first posttransplant year that distinguishes patients at increased CLAD risk., (Copyright © 2024. Published by Elsevier Inc.)

Background: Poor agreement among lung transplant pathologists has been reported in the assessment of rejection. In addition to acute rejection (AR) and lymphocytic bronchiolitis (LB), acute lung injury (ALI) and organizing pneumonia (OP) were recently identified as histopathologic risk factors for chronic lung allograft dysfunction (CLAD). Therefore, maximizing inter-rater reliability (IRR) for identifying these histopathologic risk factors is important to guide individual patient care and to support incorporating them in inclusion criteria for clinical trials in lung transplantation., Methods: Nine pathologists across eight North American lung transplant centers were surveyed for practices in the assessment of lung transplant transbronchial biopsies. We conducted seven diagnostic alignment sessions with pathologists discussing histomorphologic features of CLAD high-risk histopathology. Then, each pathologist blindly scored 75 digitized slides. Fleiss' kappa, accounting for agreement across numerous observers, was used to determine IRR across all raters for presence of any high-risk finding and each individual entity., Results: IRR (95% confidence intervals) and % agreement for any high-risk finding (AR, LB, ALI and/or OP) and each individual finding is as follows: Any Finding, k = 0.578 (0.487, 0.668), 78.9%; AR, k = 0.582 (0.481, 0.651), 79.1%; LB, k = 0.683 (0.585, 0.764), 83.5%; ALI, k = 0.418 (0.312, 0.494), 70.9%; OP, k = 0.621 (0.560, 0.714), 81.0%., Conclusions: After pre-study diagnostic alignment sessions, a multi-center group of lung transplant pathologists seeking to identify histopathology high-risk for CLAD achieved good IRR., (Copyright © 2024 International Society for the Heart and Lung Transplantation. All rights reserved.)

Background: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making., Methods: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination., Results: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort., Conclusion: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung transplant recipients. Club cell secretory protein (CCSP), produced by airway club cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant allograft injury and determine if early posttransplant BALF CCSP reductions indicate later CLAD risk., Methods: We quantified CCSP and total protein in 1606 BALF samples collected over the first posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating equation models were used to examine the correlation of allograft histology or infection events with protein-normalized BALF CCSP. We performed multivariable Cox regression to determine the association between a time-dependent binary indicator of normalized BALF CCSP level below the median in the first posttransplant year and development of probable CLAD., Results: Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding to histological allograft injury as compared with healthy samples. Patients who experienced any occurrence of a normalized BALF CCSP level below the median over the first posttransplant year had a significant increase in probable CLAD risk independent of other factors previously linked to CLAD (adjusted hazard ratio 1.95; p = 0.035)., Conclusions: We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk; supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification. Additionally, our finding that low CCSP associates with future CLAD underscores a role for club cell injury in CLAD pathobiology., Competing Interests: Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose., (Copyright © 2023 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Lung transplantation is increasingly performed in recipients aged ≥65 years. However, the risk factors for mortality specific to this population have not been well studied. In lung transplant recipients aged ≥65 years, we sought to determine post-transplant survival and clinical factors associated with post-transplant mortality., Methods: We investigated 5,815 adult lung transplants recipients aged ≥65 years in the Scientific Registry of Transplant Recipients. Mortality was defined as a composite of recipient death or retransplantation. The Kaplan-Meier method was used to estimate the median time to mortality. Univariable and multivariable Cox proportional hazards regression models were used to examine the association between time to mortality and 23 donor, recipient, or center characteristics., Results: Median survival in lung transplant recipients aged ≥65 years was 4.41 years (95% CI: 4.21-4.60 years) and significantly worsened by increasing age strata. In the multivariable model, increasing recipient age strata, creatinine level, bilirubin level, hospitalization at the time of transplantation, single lung transplant operation, steroid use at the time of transplantation, donor diabetes, and cytomegalovirus mismatch were independently associated with increased mortality., Conclusions: Among the 8 risk factors we identified, 5 factors are readily available, which can be used to optimize post-transplant survival by informing risk during candidate selection of patients aged ≥65 years. Furthermore, bilateral lung transplantation may confer improved survival in comparison with single lung transplantation. Our results support that after careful consideration of risk factors, lung transplantation can provide life-extending benefits in individuals aged ≥65 years., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: MicroRNAs (miRNAs) are small non-coding RNAs of ∼22 nucleotides that play a crucial role in post-transcriptional regulation of gene expression. Dysregulation of miRNA expression has been shown during microbial infections. We sought to identify miRNAs that distinguish invasive aspergillosis (IA) from non-IA in lung transplant recipients (LTRs)., Methods: We used NanoString nCounter Human miRNA, version 3, panel to measure miRNAs in bronchoalveolar lavage (BAL) samples from LTRs with Aspergillus colonization (ASP group) (n = 10), those with Aspergillus colonization and chronic lung allograft dysfunction (CLAD) (ASPCLAD group) (n = 7), those with IA without CLAD (IA group) (n = 10), those who developed IA with CLAD (IACLAD group) (n = 9), and control patients (controls) (n = 9). The miRNA profile was compared using the permutation test of 100,000 trials for each of the comparisons. We used mirDIP to obtain their gene targets and pathDIP to determine the pathway enrichment., Results: We performed pairwise comparisons between patient groups to identify differentially expressed miRNAs. A total of 5 miRNAs were found to be specific to IA, including 4 (miR-145-5p, miR-424-5p, miR-99b-5p, and miR-4488) that were upregulated and the pair (miR-4454 + miR-7975) that was downregulated in IA group vs controls. The expression change for these miRNAs was specific to patients with IA; they were not significantly differentiated between IACLAD and IA groups. Signaling pathways associated with an immunologic response to IA were found to be significantly enriched., Conclusions: We report a set of 5 differentially expressed miRNAs in the BAL of LTRs with IA that might help in the development of diagnostic and prognostic tools for IA in LTRs. However, further investigation is needed in a larger cohort to validate the findings., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids-putative markers of gastric microaspiration-and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery., Methods: We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay., Results: At 3 months after transplantation, TCA, IL-1β, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery., Conclusions: Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Chronic lung allograft dysfunction (CLAD), including the phenotypes of bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (R-CLAD), represents the leading cause of late death after lung transplantation. Little is known, however, regarding the natural history or prognostic significance of pulmonary function changes after the onset of these conditions. We examined changes in forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) over the first 18 months after CLAD. We also sought to determine whether lung function changes occurring early after CLAD impact longer term outcomes., Methods: We performed a retrospective analysis of 216 bilateral lung recipients with CLAD, which included those with R-CLAD (n = 65) or BOS (n = 151). The course of FEV 1 and FVC after CLAD was described. Cox proportional hazards models were used to evaluate the impact of a ≥10% decline in FEV 1 or FVC within the first 6 months of CLAD on graft loss after that time., Results: Lung recipients with CLAD, whether BOS or R-CLAD, had the largest decreases in FEV 1 and FVC within the first 6 months after onset. Moreover, a decline in FEV 1 or FVC of ≥10% within the first 6 months after CLAD was associated with a significantly increased hazard for graft loss after that time (hazard ratio [HR] = 3.17, 95% confidence interval [CI] 1.56 to 6.42, p = 0.001, and HR = 2.80, 95% CI 1.66 to 4.70, p ≤ 0.001, respectively), an effect observed in both BOS and R-CLAD patients., Conclusions: Early physiologic changes after CLAD were independently associated with graft loss. This suggests lung function changes after CLAD, specifically a ≥10% decline in FEV 1 or FVC, could be a surrogate measure of graft survival., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Patients with greater adiposity before lung transplantation are at an increased risk for worse post-transplant outcomes. Few studies have addressed whether pre-transplant weight loss mitigates this risk. In this study we examined the association between pre-transplant weight loss and post-transplant clinical outcomes., Methods: We conducted a retrospective cohort study of patients who received a lung transplant at the Duke University Hospital from May 1, 2005 to April 30, 2015. The sample included adult transplant recipients with restrictive, obstructive, and vascular diseases. Cox proportional hazards models were used to examine mortality and chronic lung allograft dysfunction (CLAD)-free survival, and negative binomial regression analyses were used to examine length of stay (LOS). Weight loss was assessed from change in body mass index (BMI)., Results: The cohort consisted of 810 patients. Initially, 403 (50%) were overweight and 109 (13%) were obese by BMI criteria. Greater pre-transplant weight loss was associated with dose-response improvements in survival (hazard ratio [HR] 0.83 [0.72 to 0.97], p = 0.018), with modest (0% to 3%, HR 0.91), moderate (7% to 10%, HR 0.83), and high (>15%, HR 0.71) levels of weight loss conferring longer survival, independent of initial weight (p = 0.533 for interaction). Weight loss was also associated with improved CLAD-free survival (HR 0.84 [0.71 to 0.99], p = 0.034) and shorter LOS (b = ‒0.17, p < 0.001)., Conclusions: Weight loss before transplantation was associated with improved short- and long-term clinical outcomes, independent of initial weight. Survival improved proportionally to percentage of weight lost. The mechanisms by which weight loss improve clinical outcomes warrant further exploration., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion., Methods: We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD)., Results: There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects., Conclusions: Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Methods for direct measurement of glomerular filtration rate (GFR) are expensive and inconsistently applied across transplant centers. The Modified Diet in Renal Disease (MDRD) equation is commonly used for GFR estimation, but is inaccurate for GFRs >60 ml/min per 1.73 m(2). The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) and Wright equations have shown improved predictive capabilities in some patient populations. We compared these equations to determine which one correlates best with direct GFR measurement in lung transplant candidates., Methods: We conducted a retrospective cohort analysis of 274 lung transplant recipients. Pre-operative GFR was measured directly using a radionuclide GFR assay. Results from the MDRD, CKDEPI, Wright, and Cockroft-Gault equations were compared with direct measurement. Findings were validated using logistic regression models and receiver operating characteristic (ROC) analyses in looking at GFR as a predictor of mortality and renal function outcomes post-transplant., Results: Assessed against the radionuclide GFR measurement, CKDEPI provided the most consistent results, with low values for bias (0.78), relative standard error (0.03) and mean absolute percentage error (15.02). Greater deviation from radionuclide GFR was observed for all other equations. Pearson's correlation between radionuclide and calculated GFR was significant for all equations. Regression and ROC analyses revealed equivalent utility of the radionuclide assay and GFR equations for predicting post-transplant acute kidney injury and chronic kidney disease (p < 0.05)., Conclusions: In patients being evaluated for lung transplantation, CKDEPI correlates closely with direct radionuclide GFR measurement and equivalently predicts post-operative renal outcomes. Transplant centers could consider replacing or supplementing direct GFR measurement with less expensive, more convenient estimation by using the CKDEPI equation., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research., Methods: Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality., Results: PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each)., Conclusions: Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The optimal approach to cytomegalovirus (CMV) prevention after lung transplantation is controversial. We recently completed a prospective, randomized, placebo-controlled study of CMV prevention in lung transplantation that demonstrated the short-term efficacy and safety of extending valganciclovir prophylaxis to 12 months vs 3 months of therapy. In the current analysis, we monitored a single-center subset of patients enrolled in the CMV prevention trial to determine if extended prophylaxis conferred a sustained long-term benefit and to assess its hematologic safety., Methods: The sub-analysis included 38 randomized patients from Duke University Medical Center. All patients underwent consistent serial serum CMV monitoring and surveillance bronchoscopies. CMV was defined by viremia (≥ 500 CMV DNA copies/ml) or pneumonitis. The safety assessment included a review of all complete blood counts obtained from transplant onward., Results: During a mean follow-up of 3.9 years in each group, extended-course compared with short-course prophylaxis provided a sustained protective benefit with a lifetime CMV incidence of 12% vs 55%, respectively (hazard ratio, 0.13; 95% confidence interval, 0.03-0.61; p = 0.009), an effect that persisted after adjustment for clinical risk factors. Patients in each group underwent a comparable number of peripheral blood draws and bronchoscopies. Post-transplant white blood cell, neutrophil, and platelet counts were similar between each treatment group during the course of follow-up., Conclusion: Extending valganciclovir prophylaxis to 12 months provides a durable long-term CMV protective benefit compared with short-course therapy, without increasing adverse hematologic effects., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) and allograft rejection after lung transplant are parallel immunologic processes that lead to significant morbidity and mortality. Our murine model of pulmonary GVHD after inhaled lipopolysaccharide (LPS) suggests that innate immune activation potentiates pulmonary transplant-related alloimmunity. We hypothesized that the chemokine (C-X-C motif) receptor 3 (CXCR3) receptor is necessary for the development of LPS-induced pulmonary GVHD., Methods: Recipient mice underwent allogeneic or syngeneic HCT, followed by inhaled LPS. CXCR3 inhibition was performed by using CXCR3-knockout donors or by systemic anti-CXCR3 antibody blockade. Pulmonary histopathology, cellular sub-populations, cytokine proteins, and transcripts were analyzed., Results: Compared with the lungs of LPS-unexposed and syngeneic controls, lungs of LPS-exposed allogeneic HCT mice demonstrated prominent lymphocytic peri-vascular and peri-bronchiolar infiltrates. This pathology was associated with increased CD4(+) and CD8(+) T cells as well as an increase in CXCR3 expression on T cells, a 2-fold upregulation of CXCR3 transcript, and a 4-fold increase in its ligand CXCL10/Interferon gamma-induced protein 10 kDa (IP-10). CXCR3 inhibition using gene-knockout strategy or antibody blockade did not change the severity of pulmonary pathology, with a mean pathology score of 6.5 for sufficient vs 6.5 for knockout (p = 1.00) and a mean score of 6.8 for antibody blockade vs 7.4 for control (p = 0.46). CXCR3 inhibition did not prevent CD3 infiltration or prevent production of interleukin-12p40 or significantly change other Th1, Th2, or Th17 cytokines in the lung., Conclusions: In the setting of allogeneic HCT, innate immune activation by LPS potentiates pulmonary GVHD through CXCR3-independent mechanisms. Clinical strategies focused on inhibition of CXCR3 may prove insufficient to ameliorate transplant-related lung disease., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by the JC virus that occurs in the setting of immunosuppression. A 38-year-old female lung transplant recipient at our institution received treatment for episodes of acute rejection with steroids, anti-thymocyte globulin and alemtuzumab, in addition to maintenance immunosuppression. She was diagnosed with PML 13 months after the last episode of rejection, for which she had received alemtuzumab. Despite attempted treatment with cidofovir followed by mirtazapine, PML progressed, and she ultimately died of an acute pulmonary infection and respiratory failure. We provide a detailed clinical and radiographic description of PML in a lung transplant patient and highlight its potential relationship to intensive immunosuppression, as the disease developed in the setting of markedly reduced CD4 counts.

Background: Lung transplant survival is limited by the development of bronchiolitis obliterans syndrome (BOS). The strongest risk factor for BOS is acute rejection (AR). We have previously shown that rabbit anti-thymocyte globulin (RATG) induction therapy is associated with a decrease in early AR. Thus, we hypothesized that RATG induction would translate to reduced BOS and improved long-term graft survival., Methods: Forty-four lung recipients were prospectively randomized to receive conventional immunosuppression with RATG induction (RATG group) or conventional immunosuppression alone (control group). End-points included graft survival, early and total acute rejection, BOS and treatment complications., Results: There was no difference in graft survival between the groups at 8 years (RATG: 36%; control: 23%; p = 0.48). The RATG group had fewer early rejections compared with the control group (5% vs 41%; p = 0.01). However, the overall rejection incidence did not differ (RATG: 62%; control: 68%; p = 0.52). There was a trend toward a delay in BOS onset among RATG subjects compared with control subjects (2,376 days vs 1,108 days; log rank, p = 0.15). There was no difference in the incidence of infections, but the RATG group had a higher rate of malignancies., Conclusions: Our results suggest that alternative approaches to anti-thymocyte induction should be pursued to reduce BOS and prolong allograft survival.

Background: Cytomegalovirus (CMV) disease is a major cause of morbidity and mortality after lung transplantation despite ganciclovir prophylaxis. The emergence of ganciclovir-resistant CMV in lung transplant patients has been reported, although the optimal strategy for the management of these infections remains uncertain. A review of the results of glanciclovir susceptibility testing in lung transplant recipients was performed., Methods: We found 54% (113 of 210) of lung transplant patients developed CMV infection over a 4-year study period with ganciclovir-resistant CMV infection occurring in >5% of patients (6 of 113). The demographic and clinical characteristics of patients who developed ganciclovir-resistant vs -sensitive CMV infection were similar, although 50% (3 of 6) patients who developed resistance were CMV mismatched (D(+)/R(-) serology). All patients' CMV isolates had mutations in the UL97 gene. In addition, the 3 mismatch patients also had CMV with mutations in the UL54 gene., Results: Treatment with a combination of foscarnet and ganciclovir or foscarnet alone for ganciclovir-resistant infection led to a significant reduction in virologic load in all patients (p = 0.03), although transient increases in viremia were observed in some patients early after treatment. Renal function worsened after treatment, but overall it was not significantly different from pre-treatment values (p = 0.07)., Conclusions: Single or combination therapy with foscarnet is effective for treatment of ganciclovir-resistant isolates and excessive concern regarding toxicity should not preclude consideration of these treatments when clinically indicated.

Background: The impact of panresistant bacteria, other than Burkholderia cepacia, on the survival after lung transplantation in patients with cystic fibrosis (CF) remains controversial., Methods: To determine the impact of panresistant bacteria in CF patients on survival after lung transplantation a retrospective multicenter study was performed. All lung transplant recipients with a pre-transplant diagnosis of CF, at the University of Toronto (n = 53) and Duke University (n = 50), were included. Patients were included in the panresistant group if at least one specimen isolated from their respiratory secretions grew bacteria resistant or intermediate to all classes of antibiotics tested. Patients with sensitive or resistant B cepacia were excluded because of its adverse impact upon post-transplant survival., Results: Forty-five of 103 (43.7%) patients harbored panresistant bacteria (43 had Pseudomonas aeruginosa, 1 had Stenotrophomonas maltophilia, and 1 had Achromobacter xylosoxidans). According to log-rank test, there was decreased survival in patients with panresistant bacteria compared to patients with sensitive bacteria (survival: 91.1 +/- 4.2% vs 98.3 +/- 1.7% at 3 months; 88.6 +/- 4.8% vs 96.6 +/- 2.4% at 1 year; 63.2 +/- 8.6% vs 90.7 +/- 4.0% at 3 years; 58.3 +/- 9.2% vs 85.6 +/- 5.2% at 5 years; p = 0.016). The results did not differ significantly between the two centers. Both groups had similar or better survival than CF patients as reported by the United Network of Organ Sharing (UNOS) registry (1-year, 86.0%; 3 years, 65.4%; 5 years, 49.6%)., Conclusions: Patients with CF harboring panresistant bacteria have slightly decreased survival, but their survival is comparable to the results published by the UNOS registry.

Background: Cytokine polymorphisms are inconsistently associated with transplant rejection and other adverse outcomes. To address this controversy, we evaluated cytokine single nucleotide polymorphisms (SNPs) in a lung transplant cohort., Methods: All patients who underwent lung transplantation from 1993 to 1998 and had post-transplant survival of at least 6 months were included in the initial analysis. Subjects were genotyped for: TNF-alpha -308 G/A; IFN-gamma +874 A/T; TGF-beta1 +869 T/C and +915 G/C; IL-10 -1082 A/G, -819 C/T and -592 C/A; and IL-6 -174 G/C. End-points were onset of broncholitis obliterans syndrome (BOS) and survival., Results: In the cohort, 78 subjects, with an overall mean +/- SE survival 2,339 +/- 117 days, had no correlation between onset of BOS1, BOS2 or survival with TNF-alpha, IFN-gamma, TGF-beta1 or IL-10 gene polymorphisms. However, IL-6 polymorphisms GG or GC were associated with an earlier onset of BOS1 (p = 0.039), BOS2 (p = 0.021), and decreased overall post-transplant survival (p = 0.038). A second cohort of more recent lung transplant recipients did not validate an association between IL-6 polymorphisms and earlier onset of BOS1 (p = 0.70), BOS2 (p = 0.54) or overall post-transplant survival (p = 0.25)., Conclusions: Polymorphisms of TNF-alpha, IFN-gamma, TGF-beta1, IL-10 and IL-6 do not appear to influence the onset of BOS or graft survival in recipients.

Background: Lung transplantation is a commonly employed therapy in the treatment of patients with advanced lung diseases related to tobacco use. Little is known about the long-term incidence or risk factors for primary lung cancer after lung transplantation. To determine the frequency, clinical features and risk factors for primary bronchogenic malignancy after lung transplantation, we designed a matched cohort study of single and bilateral lung transplant recipients with extended follow-up., Methods: We retrospectively reviewed the records of 262 lung transplant recipients who survived > or =90 days post-transplant and assessed for the development of primary lung cancer. One hundred thirty-one consecutive single-lung transplant (SLTx) recipients were matched to 131 consecutive bilateral lung transplant (BLTx) recipients by native disease. Risk factors for lung cancer development were derived using univariate and multivariate proportional hazards models., Results: Of the SLTx recipients, 6.9% developed primary lung cancer after transplantation as compared with 0% of the BLTx recipients (p = 0.002), after a mean of 52 months. Histologically, non-small-cell cancers were present in the native lung, which led to death in 67% (6 of 9) of the patients despite treatment. Significant risk factors for the development of primary lung cancer were increasing age (p = 0.004), >60-pack-year smoking history (p = 0.03), and SLTx as compared with BLTx (p < 0.001)., Conclusions: Single-lung transplant confers a significantly elevated risk of developing primary post-transplant lung cancer as compared with BLTx in patients with comparable native disease, age and tobacco history.

Mycobacterial infections are increasingly recognized in cystic fibrosis (CF) patients before transplant; however, knowledge about the clinical significance or spectrum of infections observed with mycobacterial infections in lung transplant recipients is still evolving. Herein, we report a case of infection with Mycobacterium abscessus in a CF lung transplant recipient. Despite aggressive treatment before and peri-operatively with anti-mycobacterial therapy, the patient developed skin and soft tissue infection of the incision and of bilateral breast implants, eventually leading to disseminated pulmonary infection and death. This report highlights the potential for M abscessus to cause post-transplant disease in CF patients undergoing lung transplant, despite peri-operative anti-mycobacterial therapy. Thus, pre-transplant colonization with M abscessus should be viewed as a strong relative, if not absolute, contraindication to lung transplantation. The combination of the virulent pre-transplant pathogen M abscessus and foreign bodies in the chest likely acted synergistically to contribute to the unfortunate outcome in this patient.

Background: Cytomegalovirus (CMV) is the most important opportunistic pathogen in lung transplant recipients and is associated with direct and indirect morbidity. Infection or disease with CMV is often diagnosed through detection of the virus in the blood, culture of bronchoalveolar lavage fluid, or histologic examination of lung tissue obtained on transbronchial biopsy. Endobronchial lesions involving the virus have received little attention, however., Methods: We reviewed the records of 76 endobronchial biopsies obtained at our institution from January 1999 through October 2004 and performed a detailed examination of the specimens and clinical histories for all patients with biopsy evidence of bronchial CMV infection., Results: We identified three patients with endobronchial CMV infection, manifested in each case as an endobronchial polyp. On histologic examination of the endobronchial biopsy specimens, cells with cytopathic effects characteristic or suggestive of CMV infection were present in two cases, and immunohistochemical staining confirmed the presence of CMV in all three. All patients were clinically well with normal chest X-rays before biopsy. Two of three patients had multiple subsequent episodes of CMV disease., Conclusions: To our knowledge, this is the first report of endobronchial polypoid CMV disease in lung transplant recipients. Our results suggest that biopsy of endobronchial lesions in pulmonary allografts should be pursued to establish a definitive etiology.

Innate immunity represents the first line of defense against microbial invasion. Recent studies have determined that a group of germline-encoded receptors, termed Toll-like receptors (TLRs), are critical for recognizing foreign motifs on microbial organisms and initiating innate responses. An exciting area of research has recently linked activation of TLRs on antigen-presenting cells (APCs) to effective antigen presentation and activation of naive T cells. Most studies have shown that TLR-dependent immune function leads to T-helper 1 (TH1) immunity, although evidence also supports that TH2 immune responses may be initiated by TLR signaling in certain contexts. In either case, innate immune signaling via TLRs leads to a productive adaptive immune response. In contrast to studies in purely infectious models, emerging data from experimental and clinical studies have provided evidence that TLR immune function is important in acute allograft rejection. Specifically, MyD88, an important TLR signal adaptor, was found to be critical for the rejection of minor-mismatched skin allografts, and important for alloimmune priming and TH1 immunity against fully allogeneic skin grafts. Furthermore, a clinical study has shown that recipients with TLR 4 polymorphisms associated with endotoxin hyporesponsiveness manifest reduce acute lung allograft rejection. Collectively, these studies demonstrate that innate immunity is important for alloimmunity. Future therapeutic modalities that target innate rather than adaptive immune mechanisms represent a promising avenue for future studies in thoracic organ transplantation.

Background: Lung transplantation is an established treatment modality for a number of chronic lung diseases. Long-term survival after lung transplantation is limited by chronic allograft dysfunction, usually manifested by bronchiolitis obliterans syndrome. We describe a case series with upper lobe fibrosis, a novel presentation of chronic allograft dysfunction., Methods: We reviewed lung transplants at the Toronto General Hospital and Duke University Hospital from 1990 to 2002 and identified patients with upper lobe fibrosis., Results: Thirteen of 686 patients (6 women) developed upper lobe fibrosis (Toronto, 9; Duke, 4); 12 of 13 had bilateral transplants. The median age at diagnosis was 42 years (range, 19-70). Primary diagnoses were cystic fibrosis, 6; emphysema, 4; sarcoidosis, 1; and pulmonary fibrosis, 2 patients. Radiographic diagnosis was made at a median of 700 days post-transplant (range, 150-2,920). Pulmonary function tests demonstrated predominantly a progressively worsening restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of obliterative bronchitis, bronchiolitis obliterans obstructive pneumonia, and aspiration. Nine patients died at a median follow-up of 2,310 days (range, 266-3,740), 8 due to respiratory failure., Conclusion: Upper lobe fibrosis is a novel presentation of chronic allograft dysfunction in lung transplant recipients and is differentiated from bronchiolitis obliterans syndrome on the basis of physiologic and radiologic findings.

Background: The presence of antibodies to human leukocyte antigens (HLA) prior to transplantation has been linked to worse post-transplant outcomes in many solid organ transplants. The effect of these antibodies is less clear in lung transplant recipients, although previous studies have suggested an increased incidence of allograft dysfunction., Methods: A retrospective study of all first lung transplant recipients from the University of Toronto (November 1983-July 2001, n = 380) and Duke University (April 1992-June 2000, n = 276) was performed. Demographic data, survival information, and level of last pre-transplant panel reactive antibody (PRA) were collected. PRA level was measured by the complement-dependent cell cytotoxicity assay at both centers. Survival analysis was performed using the Kaplan-Meier method, and groups were compared with the Wilcoxon rank sum test., Results: Of 656 lung transplant recipients, 101 (15.4%) had a PRA greater than 0, 37 (5.6%) had a PRA greater than 10%, and 20 (3.0%) had a PRA greater than 25%. Patients with a PRA greater than 25% had decreased median survival than did the rest of the patients (1.5 vs 5.2 years) and at 1 month (70% vs 90%), 1 year (65% vs 76%), and 5 years (31% vs 50%), respectively (p = 0.006, Wilcoxon's rank sum test) test)., Conclusion: Significant elevation of PRA prior to lung transplantation is associated with worse survival, especially in the early post-transplant period. This may be due to a direct effect of anti-HLA antibodies on the allograft. The effectiveness of treatments such as plasmapheresis and intravenous immunoglobulin prior to transplantation needs to be evaluated.

Intravenous injection of drugs that contain insoluble foreign material can lead to pulmonary embolization of the material and can have devastating results, including pulmonary hypertension and death. Most cases are detected after the onset of extensive, irreversible damage, precluding potentially life-saving intervention, or are detected at autopsy. We report here a case of microcrystalline cellulose embolization in a lung transplant recipient detected at routine transbronchial biopsy, and we describe the circumstances associated with the development of this condition and its clinical outcome.

Background: Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance., Materials and Methods: We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmenger's syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other., Results: After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmenger's syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001)., Conclusions: CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Anastomotic infection is an uncommon but potentially life-threatening complication after lung transplantation. We recently encountered three lung transplant recipients with invasive candidal anastomotic infection. Two patients were admitted with dyspnea and fever, and one asymptomatic infection was detected on surveillance bronchoscopy. All three patients were treated similarly with a combination of intravenous amphotericin B, inhaled amphotericin B, and oral fluconazole. The combination of systemic and inhaled antifungal agents successfully treated all three cases of anastomotic infection.