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Background Previous studies have demonstrated an association between pretransplantation renal dysfunction (PRD) and increased mortality after lung transplantation (LT). The purpose of this study was to determine whether PRD impacts survival after LT in patients with cystic fibrosis (CF). Methods We queried the United Network for Organ Sharing (UNOS) database to identify all adult (≥18 years) recipients with CF who underwent isolated LT from May 4, 2005 to December 31, 2014. We separated recipients into those with and those without PRD (glomerular filtration rate [GFR] ≤60 mL/min). We excluded patients who required dialysis before transplantation. Kaplan-Meier analysis was used to assess unadjusted survival differences. Cox proportional hazards modeling was then performed across 26 variables to assess the risk-adjusted impact of PRD on 1-, 3-, and 5-year mortality. Results Isolated LT was performed on 1,830 patients with CF; 17 patients were excluded because of pretransplantation dialysis. Eighty-two of 1,813 patients (4.5%) had PRD (GFR ≤60 mL/min). Kaplan-Meier analysis revealed no survival differences between PRD and non-PRD groups at 1 year (85.3% versus 89.5%; log-rank p = 0.23), 3 years (71.0% versus 72.5%; p = 0.57), or 5 years (63.3% versus 59.8%; p = 0.95). After risk adjustment, PRD was not independently associated with an increased hazard for mortality at 1 year (hazard ratio [HR], 1.38 [95% confidence interval [CI], 0.74–2.58]; p = 0.31), 3 years (HR, 1.44 [95% CI, 0.92–2.24]; p = 0.11), or 5 years (HR, 1.30 [95% CI, 0.86–1.94]; p = 0.29). Conclusions Although PRD has historically served as a relative contraindication to LT, our study is the first to suggest that among CF recipients, PRD was not associated with increased hazard for mortality out to 5 years after LT. [ABSTRACT FROM AUTHOR]

Background: A higher predicted total lung capacity (pTLC)-ratio (=pTLC donor/pTLC recipient), suggestive of oversized allografts, is associated with improved survival after lung transplantation. It is unknown whether the pTLC-ratio has a different association with survival in bilateral (BLT) versus single lung transplantation (SLT). Methods: The pTLC-ratio was calculated for all adult patients in the United Network of Organ Sharing lung transplant (LTx) registry who underwent first-time LTx in the post lung allocation score era, between May 2005 and April 2010. The LTx recipients were stratified according to procedure (BLT vs SLT). Risk of death at 1 year after LTx was analyzed using Kaplan-Meier survival and Cox proportional hazards models. Results: In the 4,520 BLT patients, each 0.1 increase in pTLC-ratio conferred a 7% decrease in the hazard for death at 1 year (p < 0.001) in univariate analysis. This association remained significant after controlling for diagnosis, comorbidities, acuity, donor, and transplant factors (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.88 to 0.98, p = 0.01). Additional adjustment by a propensity score to account for biases to oversizing showed similar results (HR 0.94, 95% CI 0.90 to 0.99, p = 0.018). In the 2,477 SLT patients, each 0.1 increase in pTLC-ratio conveyed a 6% decrease in the hazard for death at 1 year (p = 0.002) in univariate analysis, which did not persist in the multivariate model (HR 1.00, p = 0.8). Conclusions: A higher pTLC-ratio, suggestive of an oversized allograft, is associated with improved survival after lung transplantation. This association is primarily evident in BLT patients. [Copyright &y& Elsevier]

Background: Whether center volume influences outcomes in lung transplantation is unknown. We reviewed United Network for Organ Sharing data to examine the effect of center volume on short-term mortality. Methods: We reviewed United Network for Organ Sharing data (1998 through 2007) to identify 10,496 first-time adult lung transplantation recipients at 79 centers. Centers were stratified by quartiles of mean annual volume. Risk of 30-day mortality and 1- and 5-year mortality (censored for 30-day death) were assessed by multivariable Cox proportional hazards regression. Results: Mean center volume ranged from less than 1 to 58.2 (median, 9.4 cases/year; volume quartiles: 0 to 2.1, 2.2 to 9.4, 9.5 to 19.9, and 20 to 58.2 cases). Each 1 case/year decrease led to a 2% increase in 30-day mortality (hazard ratio, 1.02; 95% confidence interval, 1.01 to 1.02; p < 0.001). Centers of lowest quartile (performing ≤2.1 lung transplantations/year) had a 30-day cumulative mortality of 9.6% or 89% increase in the risk of death (hazard ratio, 1.89; 95% confidence interval, 1.01 to 3.44; p = 0.05) compared with the highest quartile centers despite fewer idiopathic pulmonary fibrosis patients (15.6% versus 25.8%; p < 0.001) and younger age (40.9 versus 51.5 years; p < 0.001). Low-volume centers had double the risk of 30-day censored 1-year mortality (hazard ratio, 1.95; 95% confidence interval, 1.30 to 2.92; p = 0.001). High-volume centers (≥20 lung transplantations/year) had the lowest 30-day mortality (4.1%). Conclusions: We provide an initial examination of the relationship of volume and lung allocation score to outcomes for lung transplantation. Low center volume is associated with increased short-term and cumulative mortality despite fewer idiopathic pulmonary fibrosis patients and younger patients. [Copyright &y& Elsevier]

(A consensus report from The Pulmonary Council of the International Society for Heart and Lung Transplantation) [Copyright &y& Elsevier]

Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of chronic lung allograft dysfunction (CLAD) or death. This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated with these conditions. EMI developed in 16% of patients at a median 343.5 (IQR: 177.3–535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.78, 95% CI: 1.26–6.22, p = 0.012). The risk remained consistent for the Primary EMI subgroup (HR: 2.34, 95% CI 1.18–4.85, p = 0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC = 0.856, 95% CI = 0.805–0.908, p < 0.001). Episodes of EMI in lung transplant recipients are often isolated and may not be detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The association between organizing pneumonia (OP) after lung transplantation with the development of acute rejection (AR) remains undefined. In addition, molecular allograft injury, as measured by donor-derived cell-free DNA (dd-cfDNA), during episodes of OP and its relationship to episodes of AR, chronic lung allograft dysfunction (CLAD), or death is unknown. This multicenter, prospective cohort study collected serial plasma samples from 188 lung transplant recipients for dd-cfDNA at the time of bronchoscopy with biopsy. Multivariable Cox regression was used to analyze the association between OP with the development of AR (antibody-mediated rejection (AMR) and acute cellular rejection (ACR)), CLAD, and death. Multivariable models were performed to test the association of dd-cfDNA at OP with the risk of AR, CLAD, or death. In multivariable analysis, OP was associated with increased risk of AMR (hazard ratio (HR) = 2.26, 95% confidence interval (CI) 1.04-4.92, p = 0.040) but not ACR (HR = 1.29, 95% CI: 0.66-2.5, p = 0.45) or the composite outcome of CLAD or death (HR = 0.88, 95% CI, 0.47-1.65, p = 0.69). Median levels of dd-cfDNA were higher in OP compared to stable controls (1.33% vs 0.43%, p = 0.0006). Multivariable analysis demonstrated that levels of dd-cfDNA at diagnosis of OP were associated with increased risk of both AMR (HR = 1.29, 95% CI 1.03-1.62, p = 0.030) and death (HR = 1.16, 95% CI, 1.02-1.31, p = 0.026). OP is independently associated with an increased risk of AMR but not CLAD or death. The degree of molecular allograft injury at the diagnosis of OP may further predict the risk of AMR and death. [ABSTRACT FROM AUTHOR]

Despite advances in perioperative and post-operative management, lung transplant recipients with select pre transplant risk factors have been shown to experience worse post-transplant outcomes in comparison to those without such risk factors. Among these variables, previous studies have shown that select markers of poor nutritional status prior to transplant, such as low body mass index (BMI) and hypoalbuminemia, have been associated with increased post-transplant mortality. In a past issue of the journal, Chamogeorgakis el al. examine a comprehensive battery markers previously associated with malnutrition to determine their impact on outcomes after lung transplantation. The authors find that hypoalbuminemia is associated with worse survival, but does not appear to affect the risk of post-transplant infections. This article reviews the study presented by Chamogeorgakis et al. to discuss how it furthers our understanding of the impact of nutritional status on transplant-related outcomes and consider areas for future investigation. [Copyright &y& Elsevier]

Pulmonary antibody-mediated rejection (AMR) consensus criteria categorize AMR by diagnostic certainty. This study aims to define the clinical features and associated outcomes of these recently defined AMR categories. Adjudication committees reviewed clinical data of 335 lung transplant recipients to define clinical or subclinical AMR based on the presence of allograft dysfunction, and the primary endpoints, time from transplant to allograft failure, a composite endpoint of chronic lung allograft dysfunction and/or death. Clinical AMR was subcategorized based on diagnostic certainty as definite, probable or possible AMR if 4, 3, or 2 characteristic features were present, respectively. Allograft injury was assessed via plasma donor-derived cell-free DNA (ddcfDNA). Risk of allograft failure and allograft injury was compared for AMR categories using regression models. Over the 38.5 months follow-up, 28.7% of subjects developed clinical AMR (n = 96), 18.5% developed subclinical AMR (n = 62) or 58.3% were no AMR (n = 177). Clinical AMR showed higher risk of allograft failure and ddcfDNA levels compared to subclinical or no AMR. Clinical AMR included definite/probable (n = 21) or possible AMR (n = 75). These subcategories showed similar clinical characteristics, ddcfDNA levels, and risk of allograft failure. However, definite/probable AMR showed greater measures of AMR severity, including degree of allograft dysfunction and risk of death compared to possible AMR. Clinical AMR showed greater risk of allograft failure than subclinical AMR or no AMR. Subcategorization of clinical AMR based on diagnostic certainty correlated with AMR severity and risk of death, but not with the risk of allograft failure. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate outcomes in people with cystic fibrosis (CF) who underwent lung transplant (LT) at a transplant center with an accredited Cystic Fibrosis Care Center (CFCC) in the United States. We reviewed the Scientific Registry of Transplant Recipients for all adult patients with CF who received a first-time LT from 2005 to 2018. The primary outcome was graft failure. Unadjusted Kaplan-Meier analysis and adjusted multilevel Cox proportional hazards models were used to evaluate outcomes in CF patients undergoing lung transplantation at a CFCC. 2,573 patients with CF underwent a first time LT during the study period. Of the 68 lung transplantation centers, 50 were CFCCs (73.5%). After adjustment for potential confounders, patients who underwent lung transplantation at a hospital with an accredited CFCC had a 33% reduction in risk of death or re-transplantation compared to those transplanted at a hospital without an accredited CFCC (HR: 0.67, 95% CI: 0.56-0.82, p < 0.001). People with CF who undergo LT at a transplant center with a CFCC have improved graft survival and decreased need for re-transplantation compared to those who undergo LT at a non-CFCC, independent of volume. [ABSTRACT FROM AUTHOR]

Background: Respiratory RNA viruses are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRS); however, the immune mechanisms that regulate airway obliteration remain incompletely understood. Methods: Using the mouse heterotopic tracheal transplant model of obliterative airway disease (OAD), we studied the role of double-stranded (ds)RNA using polyinosinic:polycytidylic acid (poly[I:C]), a synthetic analog of viral dsRNA, in abrogating airway allograft tolerance established with donor-specific transfusion (DST) and anti-CD154 monoclonal antibody therapy. Results: Wild-type (WT) B6 recipients of accepted BALB/c airway grafts demonstrated significantly reduced intragraft CD8+ T cells, with markedly impaired allospecific interferon (INF)-γ and tumor necrosis factor-α secretion, uncoupled from an activated phenotype, and evidence of proliferation. Administration of poly(I:C) to DST/anti-CD154–treated recipients restored OAD pathology and CD8+ alloeffector responses to levels observed in untreated mice. However, B6 type I IFN receptor-deficient (IFN-αβR–/–) recipients were resistant to the abrogation of tolerance mediated by poly(I:C) and did not develop CD8+ alloeffector responses or OAD. Further, adoptive transfers of WT CD8+ T cells or CD11c+ dendritic cells alone into B6 IFNαβR–/– recipients treated with poly(I:C) and DST/anti-CD154 were incapable of abrogating airway graft tolerance. Conclusions: Together, these data indicate abrogation of DST/anti-CD154–induced airway allograft tolerance via dsRNA requires type-I IFN responsiveness for mouse airway obliteration. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic factors such as education, health insurance, and race are known to affect health outcomes. The United Network for Organ Sharing (UNOS) database provides a large cohort of lung transplant (LTx) recipients in which to evaluate the effect of insurance on survival. Methods: We retrospectively reviewed UNOS data for 11,385 adult primary LTx patients (1998–2008). Patients were stratified by insurance (private/self-pay, Medicare, Medicaid, and other type). All-cause mortality was examined with Cox proportional hazard regression incorporating 14 variables. The Kaplan-Meier method was used to model survival after LTx. Results: Of 11,385 recipients, 7,100 (62.4%) had private insurance/self-pay; 2,966 (26.1%) had Medicare; 815 (7.2%) had Medicaid; and 504 (4.4%) had other type insurance. During the study, 4,943 patients (43.4%) died. Medicare and Medicaid patients had 7.0% and 8.1% lower 10-year survival than did private insurance/self-pay patients, respectively. Insurance did not affect 30-day, 90-day, or 1-year survival. Medicare and Medicaid patients had decreased survival at 3 years and longer. In multivariable analyses, Medicare (hazard ratio, 1.10; 95% confidence interval, 1.03–1.19) and Medicaid (hazard ratio, 1.29; 95% confidence interval, 1.15–1.45) significantly increased risk of death. When deaths in the first year were excluded, survival differences persisted. Conclusions: This study represents the largest cohort evaluating the effect of insurance on post-LTx survival. Medicare and Medicaid patients have worse survival after LTx compared with private insurance/self-paying patients. [ABSTRACT FROM AUTHOR]

Background: The Lung Allocation Score (LAS) dramatically changed organ allocation in lung transplantation. The impact of this change on patient outcomes is unknown. The purpose of the study was to examine early mortality after lung transplantation under the LAS system. Methods: All patients undergoing first-time lung transplantation during the period from May 1, 2005 through April 30, 2008 were included in the study. The cohort was divided into quintiles by LAS. A high-risk group (LAS >46) was comprised of the highest quintile, Quintile 5, and a low-risk group (LAS ≤46) included the lower quintiles, Quintiles 1 through 4. A time-to-event analysis was performed for risk of death after transplantation using Kaplan–Meier survival and Cox proportional hazards models. Results: There were 4,346 patients who underwent lung transplantation during the study period. Patients in the high-risk group (LAS >46) were more likely to have idiopathic pulmonary fibrosis (IPF; 52.9% vs 23.8%, p < 0.001) and diabetes (25.8% vs 16.8%, p < 0.001) and to require mechanical ventilatory support (15.4% vs 2.2%, p < 0.001) at the time of transplant as compared with patients in the low-risk group. One-year survival using the Kaplan–Meier product limit estimator was significantly worse in the high-risk group (75% vs 83%, p < 0.001 by log-rank test). Patients in the high-risk group were also found to have increased risk of death (hazard ratio 1.46, 95% confidence interval 1.24 to 1.73) compared with the low-risk group. Conclusions: Overall 1-year survival under the new LAS system appears to be similar to that in historic reports. However, risk of death was significantly increased among patients with LAS >46. [Copyright &y& Elsevier]

Background: Previous studies have shown that mucociliary clearance (MCC) is diminished after lung transplantation. However, it is unknown how early this deficit occurs after transplantation, or whether the abnormality can be improved by pharmacologic means. We hypothesized that impairment of MCC is evident soon after lung transplantation and that the defect in MCC can be improved by inhaled β2-adrenergic receptor agonists. Methods: MCC and cough clearance (CC) were quantified in seven patients at 76 ± 48 days (mean ± standard deviation) after lung transplantation (baseline visit) and again 1 week later after an acute inhalation of albuterol. MCC was also determined once in four healthy subjects. To measure MCC, volunteers inhaled 99m-technetium-sulfur colloid aerosol, followed by gamma-camera imaging of their lungs for 76 minutes. Results: Baseline MCC was significantly reduced in transplant patients, compared with healthy subjects, averaging 8.9 ± 7.3% and 20.9 ± 15.1%, respectively (p = 0.05). CC was not affected by transplantation. Acute inhalation of albuterol significantly improved MCC in transplant patients (31.9 ± 21.9%) compared with baseline values (p < 0.05). Conclusions: MCC is diminished within a few months after transplantation. However, the response to albuterol suggests that the deficit is not static and can be improved with inhalation of a β2-adrenergic receptor agonist. [Copyright &y& Elsevier]

We report a rare case of mediastinal mass caused by Aspergillus fumigatus in a lung transplant recipient. The patient presented 9 months after bilateral lung transplantation for cystic fibrosis with intermittent fevers and new onset atrial fibrillation/flutter caused by a 7-cm mediastinal mass invading the left atrium. The mass was resected, and a prolonged course of voriconazole and caspofungin was given, which resulted in a complete clinical response. Despite long-term suppressive therapy with voriconazole, a relapse occurred 16 months after the initial diagnosis. This case highlights the challenges in the prevention and treatment of invasive aspergillosis in lung transplant recipients. [Copyright &y& Elsevier]

Acute rejection, which includes antibody-mediated rejection and acute cellular rejection, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance transbronchial biopsies to detect and treat acute rejection before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high interobserver variability. We tested the performance of percent donor-derived cell-free DNA (%ddcfDNA), a non-invasive blood test, to detect acute rejection. This multicenter cohort study monitored 148 lung transplant subjects over a median of 19.6 months. We collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data was collected to adjudicate for acute rejection. The primary analysis consisted of computing the area-under-the-receiver-operating-characteristic-curve of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection. ddcfDNA levels were high after transplant surgery and decayed logarithmically. With acute rejection, ddcfDNA levels rose six-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA area-under-the-receiver-operating-characteristic-curve for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of <0.5% and <1.0% showed a negative predictive value of 96% and 90% for acute rejection, respectively. Histopathology detected one-third of episodes with ddcfDNA levels ≥1.0%, even though >90% of these events were coincident to clinical complications missed by histopathology. This study demonstrates that %ddcfDNA reliably detects acute rejection and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury. [ABSTRACT FROM AUTHOR]

Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients. We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF. A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008). Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD. [ABSTRACT FROM AUTHOR]

Background The lung allocation score (LAS) has changed organ allocation for lung transplantation in the United States. Previous investigations of transplant recipients reported an association between high LAS and an increased risk of death after lung transplantation. We hypothesize that a high LAS predicts survival in lung transplant recipients with cystic fibrosis (CF) in the United Network for Organ Sharing Scientific Registry of Transplant Recipients database. Methods A cohort study was conducted of 1,437 U.S. adult lung transplant recipients with CF from May 1, 2005, through December 31, 2012. The cohort was divided into a high-risk group and a low-risk group based on LAS. Survival data were examined using Kaplan-Meier estimates and Cox proportional hazard models to compare survival. The primary outcome was adjusted survival at 1 year after lung transplantation. Results The high-risk group of 318 patients with a median LAS of 69.6 (interquartile range 56.3–87.2) was compared with a low-risk group of 1,119 patients with a median LAS of 38.8 (interquartile range 36.3–42.3). Patients in the high-risk group had a 41% increased relative risk of cumulative mortality at 1 year after transplantation compared with the low-risk group (16.1% vs 12.0%). After adjustment for known predictors of mortality, the risk of death at 1 year after transplantation remained elevated (hazard ratio = 1.41; 95% confidence interval = 1.00–2.01). The high-risk group had worse survival at 90 days and 2 years after lung transplantation. Conclusions High LAS are associated with worse survival in lung transplant recipients with CF. [ABSTRACT FROM AUTHOR]

Background Exhaled nitric oxide (FeNO), a marker of airway inflammation, is often elevated in lung transplant recipients (LTxRs) with acute rejection or infection. Isolated measurements in the setting of bronchiolitis obliterans syndrome have been variable. We sought to assess the utility of serial FeNO in predicting chronic allograft dysfunction or the presence of acute rejection or infection. Methods Eighty-six LTxRs underwent 325 serial FeNO measurements at an expiratory flow rate of 50 ml/s. The change in FeNO (ΔFeNO) between two measurements obtained during a stable state (ΔFeNO-SS) was compared with ΔFeNO, where the first measurement was taken during a stable state and the second during an unstable state (defined as a subsequent decline in FEV 1 > 10% over 3 months [ΔFeNO-SU]) or an acute complication (acute rejection, lymphocytic bronchiolitis or acute infection [ΔFeNO-SAC]). The median follow-up time after the baseline FeNO was 10 (range 3 to 25) months. Results ΔFeNO-SS in 117 FeNO pairs was similar to ΔFeNO-SU in 26 pairs (2.1 ± 3 ppb vs 2.3 ± 4 ppb; p = 0.2). ΔFeNO-SAC in 17 pairs was markedly increased (27 ± 20 ppb; p < 0.001 vs ΔFeNO-SS). The area under the receiver-operating characteristic curve for ΔFeNO in detecting an acute complication was 0.93 ( p < 0.001). By applying a cut-off of >10 ppb, the sensitivity and specificity was 82% and 100%, respectively, with positive and negative predictive values of 100% and 97.5%. Conclusions Changes in FeNO may serve as a useful adjunct in the detection of acute complications after lung transplantation. In this limited analysis, ΔFeNO was not predictive of a subsequent decline in allograft function. [ABSTRACT FROM AUTHOR]

Background Donor-to-recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC) ratio (donor pTLC/recipient pTLC). We aimed to determine whether the pTLC ratio is associated with the risk of primary graft dysfunction (PGD) after bilateral LTx (BLT). Methods We calculated the pTLC ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between March 2002 to December 2010. Patients were stratified by pTLC ratio >1.0 (“oversized”) and pTLC ratio ≤1.0 (“undersized”). PGD was defined as any ISHLT Grade 3 PGD (PGD3) within 72 hours of reperfusion. We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size-matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories. Results In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, 0.45-0.85, p = 0.003). In a multivariate model accounting for center-effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38 to 0.88, p = 0.01). The risk-adjusted point estimate was similar for the non-COPD diagnosis groups (OR 0.52, 95% CI 0.32 to 0.86, p = 0.01); however, there was no detected association within the COPD group (OR 0.72, 95% CI 0.29 to 1.78, p = 0.5). Conclusion Oversized allografts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients. [ABSTRACT FROM AUTHOR]

Background: Oversizing the lung allograft, as estimated by a donor-to-recipient predicted total lung capacity (pTLC) ratio > 1.0, was associated with improved long-term survival after lung transplantation (LTx) but could be associated with increased post-operative complications and higher resource utilization. Methods: The prospectively maintained LTx database at The Johns Hopkins Hospital was retrospectively reviewed for bilateral LTx patients in the post-Lung Allocation Score (LAS) era. Patients were grouped by pTLC ratio ≤ 1.0 (undersized) or > 1.0 (oversized). Post-operative complications and hospital charges were analyzed. Results: The pTLC ratio was available for 70 patients: 31 were undersized and 39 oversized. Undersized patients had a higher LAS (40.4 vs 35.8, p = 0.009), were more often in the intensive care unit (ICU) pre-LTx (35% vs 10%, p = 0.01), and had a higher occurrence of primary graft dysfunction (PGD; 25% vs 5%, p = 0.013) and tracheostomy (32% vs 10%, p = 0.02), longer index hospitalizations (20 [interquartile range (IQR), 10–46] vs 16 [IQR, 12–25] days, p = 0.048), and higher index hospitalization charges ($176,247 [IQR, $137,646–$284,012] vs $158,492 [IQR, $136,250–$191,301], p = 0.04). After adjusting for LAS and pre-LTx ICU stay, a lower pTLC ratio remained associated with higher hospital charges (p = 0.049). Airway complications were more frequent and severe in undersized patients. Conclusion: Oversized allografts were not associated with an increase in post-LTx complications. However, LTx recipients of undersized allografts were more likely to experience PGD, tracheostomy, and had higher resource utilization. Higher acuity in the undersized group might explain these findings; however, multivariate models suggest an independent association between undersizing, PGD, and resource utilization. [Copyright &y& Elsevier]

Background: The RIFLE criteria (risk, injury, failure, loss, end stage) are new consensus definitions for acute kidney injury (AKI) associated with increased mortality; however, they have not been applied in lung transplantation (LTx). Using the RIFLE criteria, we examined the effect of AKI on outcomes and cost in LTx. Methods: We retrospectively reviewed all LTx patients at our institution since the lung allocation score (LAS) system was initiated (May 2005–August 2010). Using the Modification of Diet in Renal Disease formula, we assigned appropriate RIFLE class (R, I, F) comparing baseline creatinine to peak levels in the first 7 days after LTx. Generalized linear models assessed the effect of AKI on in-hospital and 1-year mortality. Hospital charges were used to examine the financial effect of AKI. Results: During the study, 106 LTx were performed. Excluding patients bridged to LTx with extracorporeal membrane oxygenation, 84 (86%) lived 1 year. Median LAS was 37.1 (interquartile range, 34.1–45.2). RIFLE status was I or F in 39 (36.7%), and 14 (13.2%) required renal replacement therapy (RRT). After adjusting for LAS, RIFLE-F had an increased relative rate (RR) of in-hospital mortality (RR, 4.76, 95% confidence interval [CI], 1.65–13.7, p = 0.004) and 1-year mortality (RR, 3.17, 95% CI 1.55–6.49, p = 0.002). RIFLE-R and I were not associated with higher in-hospital or 1-year mortality. Post-operative RRT was associated with increased in-hospital (RR, 28.2; 95% CI, 6.18–128.1; p < 0.001) and 1-year mortality (RR, 4.97; 95% CI, 1.54–16.0; p < 0.001). AKI patients had higher median hospital charges of $168,146 vs $143,551 for no AKI (p = 0.02). Conclusions: This study shows high rates of AKI using the new RIFLE criteria in LTx. RIFLE-F is associated with higher in-hospital and 1-year mortality. Less severe degrees of AKI are not associated with increased mortality. The financial burden associated with AKI is significant. [Copyright &y& Elsevier]

Background: Fear of transmission of donor organisms that may result in recipient pneumonia has a negative impact on donor lung utilization. We reviewed our experience with routine donor bronchial aspiration and culture at the time of transplantation to study the impact of donor bronchial organisms on the development of recipient post–lung transplant pneumonia (PTP) and other outcomes. Methods: We reviewed 80 consecutive single and bilateral lung transplants (SLTs and BLTs) from August 1998 to August 2001. Pediatric recipients and those not surviving >3 days were excluded. All donors met standard criteria for donor acceptance. All recipients received broad-spectrum antibiotics pending the results of final operating room cultures. PTP required clinical evidence (fever, leukocytosis and hypoxia), radiologic evidence (infiltrate), and culture confirmation during initial hospitalization or within 30 days. Results: Sixty-four donors for 71 recipients (39 SLTs, 32 BLTs) comprised the study population. Organisms were grown from 57 (89%) donors and 46 were polymicrobial. A total of 149 organisms were cultured consisting of 21 different species, with Staphylococcus (n = 35) and Streptococcus (n = 33) being the most common. PTP was seen in 31 (41%) recipients, with Pseudomonas species (n = 13) the most prevalent. Of the 71 donor–recipient pairs, 2 had both donor and recipient with no growth and PTP. The donor organisms had a sensitivity of 0.75 with a low specificity of 0.04 and were negatively correlated with development of PTP. PTP was an independent predictor of overall mortality. Conclusions: The presence of donor organisms does not predict PTP. Therefore, donor acceptance criteria need to be re-examined. [Copyright &y& Elsevier]

Introduction: Secondary pulmonary hypertension (SPH), defined as a mean pulmonary artery pressure (PAM) greater than 25 mm Hg, complicates end-stage lung diseases of varying etiology. Although previous studies have suggested that SPH does not adversely affect outcome, no study has assessed the impact of the degree of SPH. Methods: A retrospective review of the lung transplant database was used to identify patients who underwent either single-lung (SLT) or bilateral lung transplantation (BLT) complicated by SPH. SPH patients were stratified into low SPH (PAM = 30–40 mm Hg) and high SPH (PAM ≥ 40 mm Hg). Each group was further sub-categorized into SLT or BLT. Patients with a heart–lung transplant or primary pulmonary hypertension were excluded. Recipients without pulmonary hypertension transplanted over the same time were used as controls. Data are reported as controls vs low SPH vs high SPH. Results: One hundred-four patients received lung transplants between August 1998 and March 2003. There were 45 patients (18 men and 27 women) with SPH. Of these, 28 patients had low SPH, and 17 patients had high SPH. Forty-two patients (18 men and 24 women) without PH were the controls. There were no significant differences between groups except pre-operative oxygen dependence (81% vs 100% vs 94%, respectively) and use of CPB (28.6% vs 57.1% vs 64.7%, respectively). Pao 2–Pao 2 gradients and Pao 2/Fio 2 ratios were significantly worse in the high SPH group (116.2 vs 132.9 vs 186.3; p &#60; 0.006) and (277.8 vs 234.3 vs 214.4; p &#60; 0.026) respectively. There was no statistical difference in length of mechanical ventilation or duration of intensive care unit stay between groups. PAMs were significantly different pre-operatively (22.2 ± 0.8 vs 34.0 ± 0.6 vs 47.8 ± 2.0; p &#60; 0.001) and post-operatively (20.9 ± 1.1 vs 23.7 ± 1.3 vs 24.8 ± 2.1; p &#60; 0.001). There were no operative deaths. There were 3 early deaths in the control group, 1 in the low SPH group, and 3 in the high SPH group, none were related to pulmonary hypertension. Actuarial survival at 12, 24, and 48 months was not significantly different among the groups nor between SLT or BLT with SPH. Conclusion: Although SPH increases the risk of reperfusion injury; survival is equivalent with mild or moderate pulmonary hypertension. Either SLT or BLT may be used in patients with SPH without compromising outcome. This has the added benefit of expanding the donor pool. [Copyright &y& Elsevier]

Background: Lung transplant recipients routinely undergo bronchoscopy, during which bronchoalveolar lavage (BAL) fluid and transbronchial biopsies are usually obtained. These specimens are typically sent for microbiology, histopathology and cytopathology testing. Cytopathology testing is expensive, and its diagnostic value is questionable. We hypothesized that cytopathology specimens have no additional diagnostic yield beyond that of microbiology and histopathology testing in the routine care of our lung transplant patients. Methods: We reviewed all bronchoscopies performed on a cohort of patients who underwent lung transplantation between February 1999 and August 2002 at our institution. Demographic data, immunosuppressive therapy and the incidence of opportunistic infections in this cohort of 65 patients were reviewed. To ascertain the diagnostic value of cytopathology testing, microbiology and histopathology results from bronchoalveolar lavage and transbronchial biopsy tests were compared with cytopathology results. Results: Three hundred sixty-six bronchoscopies were reviewed. Microbiologic and histopathology identified 51 cytomegalovirus-, 157 fungus- and 13 mycobacteria-positive specimens as well as respiratory syncitial virus, influenza A and B, enterovirus, actinomyces, Nocardia and mycoplasma. Cytopathology of BAL fluid identified only 3 cytomegalovirus- and 13 fungus-positive specimens. The only unique diagnoses made by cytopathology were 1 case of Aspergillus and 1 unidentifiable fungal element. Conclusions: We conclude that routine cytopathology testing has little additive diagnostic value in bronchoscopic specimens from lung transplant recipients. Cytopathology results did not alter patient management in any of our 366 cases. Centers should consider discontinuing routine use of cytopathology testing of BAL fluid for surveillance or clinically indicated bronchoscopy, because the yield of this expensive test is extremely low in the setting of lung transplantation. [Copyright &y& Elsevier]

Combined heart-lung transplantation has been a proven therapeutic option for patients with end-stage cardiopulmonary disease since 1981. Occasional patients are not candidates to receive both lungs en bloc. We describe such a case and propose indications and a surgical technique and present the limited published experience of combined heart-single-lung transplantation. [ABSTRACT FROM AUTHOR]

We describe 2 patients with neurofibromatosis type 1 (NF1) who underwent lung transplantation. Case 1 reports a patient with NF1 with no complications 5 years after bilateral lung transplantation. Case 2 details a patient with NF1 diagnosed with both post-transplant lymphoproliferative disorder (PTLD) and massive intra-abdominal sarcoma consistent with a malignant nerve sheath tumor 9 months after lung transplantation. There was no clinical evidence of sarcoma preceding or immediately following lung transplant as demonstrated by a normal abdominal sonogram 3 months post-transplantation. Although an increased risk for cancer has been documented in NF1, the rapid malignant degeneration of a neurofibroma following transplantation raises concern about immunosuppression and transplantation candidacy among individuals with NF1. [Copyright &y& Elsevier]

Background: The purpose of this study was to investigate the relationship between donor–recipient height, gender and predicted estimates of total lung capacity (pTLC) mismatches and post-transplant survival. Methods: The lung transplant databases at three programs were reviewed. The pTLC ratios (donor pTLC/recipient pTLC) and height ratios (donor height/recipient height) were calculated retrospectively. Patients were grouped according to pTLC ratio ≤1.0 or >1.0 and height ratio ≤1.0 or >1.0, and according to gender (mis-)matching. A time-to-event analysis was performed for risk of death after transplantation conditional on 30-day survival using Kaplan–Meier survival and Cox proportional hazard models. Results: There were 211 adult bilateral lung transplant recipients who qualified for the analysis. Mean follow-up was comparable for all cohorts (range 2.21 to 3.85 years). In the univariate Cox proportional hazard models, a pTLC ratio >1.0 (HR 0.43, p = 0.002) and a height ratio >1.0 (HR 0.61, p = 0.03) were associated with better survival, and a female-donor-to-male-recipient gender mismatch (F-to-M) was associated with worse survival (HR 2.35, p = 0.01). In the multivariate Cox proportional hazard model accounting for F-to-M gender mismatch and height ratio >1.0, a pTLC ratio >1.0 remained associated with survival (HR 0.38, p = 0.015). However, accounting for a pTLC ratio >1.0, a height ratio of >1.0 and F-to-M mismatch were not associated with survival. Conclusions: A pTLC ratio >1.0 is associated with improved survival after bilateral lung transplantation. The pTLC ratio might better reflect allograft–thorax mismatch than the height ratio, as it also accounts for effects of gender on lung and thoracic volumes. [ABSTRACT FROM AUTHOR]