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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.

BACKGROUND: Acute and chronic forms of lung allograft injury are associated with specific respiratory pathogens. Donor-derived cell free DNA (ddcfDNA) has been shown to be elevated with acute lung allograft injury and predictive of long-term outcomes. We examined the %ddcfDNA values at times of microbial isolation from bronchoalveolar lavage (BAL). METHODS: Two hundred and six BAL samples from 51 Lung Transplant Recipients (LTRs) with concurrently available plasma %ddcfDNA were analyzed along with microbiology and histopathology. Microbial species were grouped into bacterial, fungal, and viral and “higher risk” and “lower risk” cohorts based on historical association with downstream allograft dysfunction. Analyses were performed to determine pathogen category association with %ddcfDNA, independent of inter-subject variability. RESULTS: Presence of microbial isolates in BAL was not associated with elevated %ddcfDNA compared to samples without isolates. However, “higher risk” bacterial and viral microbes showed greater %ddcfDNA values than lower risk species (1.19% vs. 0.65%, p < 0.01), independent of inter-subject variability. Histopathologic abnormalities concurrent with pathogen isolation were associated with higher %ddcfDNA compared to isolation episodes with normal histopathology (medians 1.23% and 0.66%, p = 0.05). Assessments showed no evidence of correlation between histopathology or bronchoscopy indication and presence of higher risk vs. lower risk pathogens. CONCLUSION: %ddcfDNA is higher among cases of microbial isolation with concurrent abnormal histopathology and with isolation of higher risk pathogens known to increase risk of allograft dysfunction. Future studies should assess if %ddcfDNA can be used to stratify pathogens for risk of CLAD and identify pathogen associated injury prior to histopathology.

Background 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. Methods 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. Results 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). Conclusion Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.

Background 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. Methods 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. Results 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 Conclusion 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.

Background Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure. Methods This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis. Findings avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%–9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6–19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable. Interpretation Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. Fund National Institutes of Health.

BACKGROUND: 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 it’s 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. METHODS: 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 (AUROC) of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection. RESULTS: 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 AUROC for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of 90% of these events were coincident to clinical complications missed by histopathology. CONCLUSIONS: 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.

Background Primary Graft Dysfunction (PGD) is a risk factor for Chronic Lung Allograft Dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD. Methods This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3 and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not. Results On post-transplant day 3, %ddcfDNA was higher in PGD than in non PGD patients (median (IQR): 12.2% (8.2, 22.0) vs 8.5% (5.6, 13.2) p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p=0.009). PGD patients who developed CLAD showed ∼2 times higher %ddcfDNA levels than patients who did not develop CLAD (median (IQR): 22.4% (11.8, 27.6) vs. 9.9% (6.7, 14.9), p = 0.007). Conclusion PGD patients demonstrated increased early post-transplant allograft injury, as measured by %ddcfDNA, in comparison to non PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone.

Lung transplantation is a widely accepted treatment to manage the advanced stages of many lung diseases that have failed to respond to all other therapeutic interventions. There have been ever-expanding indications for lung transplantation as a treatment for lung disease. The International Society for Heart and Lung Transplantation (ISHLT) updated guidelines for candidate selection in 2014. This document was published to serve as a guide in selecting appropriate candidates for lung transplantation. Ideal candidates for lung transplantation are those with near-end stage disease, limited life expectancy due to their lung disease, and who experience significant loss in quality of life. At the same time, candidates should be free of significant comorbidities that might negatively impact successful transplantation. Despite well thought out published guidelines for candidate selection, many controversial issues surrounding selection of lung transplant candidates remain. This review will focus on some of the more common controversial issues and explain how most centers approach these issues when choosing candidates for lung transplantation.

Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted.We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity.Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination.A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination.The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

Pulmonary hypertension from pulmonary arterial hypertension or parenchymal lung disease is associated with an increased risk for primary graft dysfunction after lung transplantation.We evaluated the clinical determinants of severe primary graft dysfunction in pulmonary hypertension and developed and validated a prognostic model.We conducted a retrospective cohort study of patients in the multicenter Lung Transplant Outcomes Group with pulmonary hypertension at transplant listing. Severe primary graft dysfunction was defined as PaIn the explanatory model of 826 patients with pulmonary hypertension, donor tobacco smoke exposure, higher recipient body mass index, female sex, listing mean pulmonary artery pressure, right atrial pressure and creatinine at transplant, cardiopulmonary bypass use, transfusion volume, and reperfusion fraction of inspired oxygen were associated with primary graft dysfunction. Donor obesity was associated with a lower risk for primary graft dysfunction. Using a 20% threshold for elevated risk, the prognostic model had good negative predictive value in both derivation and validation cohorts (89.1% [95% confidence interval, 85.3-92.8] and 83.3% [95% confidence interval, 78.5-88.2], respectively), but low positive predictive value.Several recipient, donor, and operative characteristics were associated with severe primary graft dysfunction in patients with pulmonary hypertension, including several risk factors not identified in the overall transplant population. A prognostic model with donor and recipient clinical risk factors alone had low positive predictive value, but high negative predictive value, to rule out high risk for primary graft dysfunction.

Purpose Extracorporeal Membrane Oxygenation (ECMO) is a lifesaving procedure in lung transplant recipients with severe primary graft dysfunction (PGD). There is limited information regarding the impact of post-op ECMO on lung allograft function. Circulating donor-derived cell-free DNA (dd-cf-DNA) has emerged as a potential biomarker of lung allograft injury. The goal of our study is to compare the dynamic dd-cf-DNA changes in patients that required ECMO support with changes in lung transplant patients that did not require ECMO. Methods Peri-transplant (pre-transplant and days 1, 3, 7 and 10, 14, 30, 60, 90 post-transplantation) plasma samples from lung transplant recipients (LTRs)of the Genomic Research Alliance for Transplantation (GRAfT) were analyzed for dd-cf-dDNA by next generation sequencing. After matching for gender, type of transplant (single versus double), and underlying diagnosis, the dd-cf-DNA levels and 3 month post-transplant lung function was compared among patients who required (n=9) and did not require (n=45) ECMO post-operatively. Results The dd-cf-DNA levels were similar between patients with PGD that required ECMO compared to non ECMO patients. The dd-cf-DNA levels for both ECMO patients and their matched controls were decreased by day 10 (Figure 1). The figure illustrates dd-cf-DNA trends for 2 matched cases (ECMO) and 10 controls (not ECMO), showing high initial post-transplant dd-cf-DNA levels followed by an exponential decay. There was no difference between lung function (FEV1) at 3 months between the ECMO patients and their matched controls (p=0.27)-Figure 2. Conclusion This report suggests that despite a higher risk for postoperative mortality, patients with severe primary graft failure requiring ECMO had similar cfDNA dynamics and lung function at 3-months post-transplant.

Purpose Clinical outcomes remain extremely poor for children with cystic fibrosis undergoing lung transplantation. Since 1961, the Cystic Fibrosis Foundation has maintained a network of accredited Cystic Fibrosis Care Centers (CFCC) designated to deliver specialized, multidisciplinary care for people with cystic fibrosis (CF). While this integrated clinical approach is thought to be beneficial in patients undergoing transplantation, it remains unknown whether lung transplantation at a CFCC is associated with improved long-term outcomes among children with CF. Methods We used the Scientific Registry of Transplant Recipients to identify all children (age Results We included 336 children with CF who underwent lung transplantation during the study period. Of these patients, 229 (68%) were transplanted at CFCCs. During a median follow-up time of 2.5 person-years, 35 (10%) children experienced graft failure or underwent retransplantation, and 7 (2%) children were lost to follow-up. In our multivariable Cox proportional hazards model, there was no significant difference in graft survival (HR 1.13, 95% CI 0.82-1.56) or overall survival (HR 1.10, 95% CI 0.77-1.57). Conclusion In children with CF, lung transplantation at a designated CFCC was not associated with a significant improvement in overall or graft survival. While treatment at a CFCC may not be associated with improved survival after pediatric lung transplantation, specialized care at a CFCC may result in improvements in other aspects of care which could not be assessed in this analysis.

Patients requiring desensitization prior to renal transplantation are at risk for developing severe antibody-mediated rejection (AMR) refractory to treatment with plasmapheresis and intravenous immunoglobulin (PP/IVIg). We have previously reported success at graft salvage, long-term graft survival and protection against transplant glomerulopathy with the use of eculizumab and splenectomy in addition to PP/IVIg. Splenectomy may be an important component of this combination therapy and is itself associated with a marked reduction in donor-specific antibody (DSA) production. However, splenectomy represents a major operation, and some patients with severe AMR have comorbid conditions that substantially increase their risk of complications during and after surgery. In an effort to spare recipients the morbidity of a second operation, we used splenic irradiation in lieu of splenectomy in two incompatible live donor kidney transplant recipients with severe AMR in addition to PP/IVIg, rituximab and eculizumab. This novel approach to the treatment of severe AMR was associated with allograft salvage, excellent graft function and no short- or medium-term adverse effects of the radiation therapy. One-year surveillance biopsies did not show transplant glomerulopathy (tg) on light microscopy, but microcirculation inflammation and tg were present on electron microscopy.

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

CMV remains an important opportunistic pathogen in solid organ and hematopoietic cell transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor+/recipient−; D+R−) are at high risk for active CMV infection and increased mortality; however, the immune correlates of viral control remain incompletely understood. We prospectively studied 27 D+R− LTRs during primary CMV infection to determine whether acute CD4+ T cell parameters differentiated the capacity for viral control during early chronic infection. Unexpectedly, the T-box transcription factor, T-bet, was expressed at low levels in CD4+ compared with CD8+ T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65–specific proliferation and CD4+T-bet+ induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multifunction. Furthermore, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with phosphoprotein 65 Ag and combined exogenous IL-2 and IL-12. Acute CD4+ T cell CMV–specific proliferative and effector responses were highly IL-12–dependent in blocking studies. In addition, we generated monocyte-derived dendritic cells using PBMC obtained during primary infection from relapsers and observed impaired monocyte-derived dendritic cell differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared with controls, suggesting an APC defect during acute CMV viremia. Taken together, these data show an important role for CMV-specific CD4+ effector responses in differentiating the capacity of high-risk LTRs to establish durable immune control during early chronic infection and provide evidence for IL-12 as a key factor driving these responses.

Purpose Patients who undergo repeat lung transplantation (LT) are at high risk for perioperative complications. The complexity of their care requires specialized multidisciplinary collaboration, particularly among people with cystic fibrosis (CF). Since 1961, the Cystic Fibrosis Foundation has established a network of accredited Cystic Fibrosis Care Centers (CFCCs) dedicated to the treatment of people with CF, including LT. We hypothesize that patients undergoing repeat lung transplantation at CFCCs will have improved postoperative outcomes compared to those at non-CFCC centers. Methods Using the Scientific Registry of Transplant Recipients, we identified adults with cystic fibrosis who received a repeat LT at a CFCC between 2005 and 2018. We compared clinical, demographic, and donor characteristics between groups. We then used multivariable Cox proportional hazards modeling to compare graft survival (defined as freedom from death, graft failure, or further retransplantation) in people with CF treated at CFCCs and non-CFCC centers during the study period. Results Our cohort included 303 people with CF who underwent repeat LT from 2005-2018. Median age at repeat transplantation was 30 years (SD 8) and 50% were male. During 877 person-years of observation, 159 (53%) patients died, 7 (2%) underwent another transplant, and 4 (1%) were lost to follow-up. In a multivariable model, graft survival was significantly improved at CFCC centers compared to non-CFCCs (adjusted HR 0.62, 95% CI 0.42-0.94). Median survival was 4.2 years among people treated at CFCCs and 2.8 years among those treated at non-CFCCs. Conclusion In people with CF, repeat LT at CFCCs is associated with improved graft and overall survival compared to repeat LT at non-CFCCs. Treatment at a CFCC provides specialized, multidisciplinary care for people with CF and can lead to improved outcomes even among high acuity patient subgroups.

Purpose Since 1961 the Cystic Fibrosis Foundation has designated certain institutions devoted to treating cystic fibrosis (CF) as Cystic Fibrosis Care Centers (CFCC). Little is known about the benefits of undergoing lung transplantation (LT) at a transplant center with an accredited CFCC. The purpose of this study was to evaluate outcomes in people with CF who undergo LT at a transplant center with an accredited CFCC. Methods We reviewed the Scientific Registry of Transplant Recipients for all adult (18 and older) patients with CF who received a first-time LT from 2005 to present. The primary exposure was whether a patient received LT at a designated CFCC. The primary outcome was death or re-transplantation within ten years of LT. Kaplan-Meier analysis and multivariate Cox proportional hazards regression were used to assess outcomes. Results From January 2005 to February 2019, 2,887 patients with CF underwent LT. Of the cohort, there were 1,403 (49%) females. The mean (SD) age at transplant was 32.0 (9.9) years. Out of 72 centers in the US performing LT, 53 (74%) were CFCCs, and most patients (88%) were transplanted at a CFCC. A total of 1,009 (35%) patients died over the study period, and 158 (6%) patients underwent a second transplant. The most common cause of death was infection (n=209, 21%). On adjusted Cox modeling, patients transplanted at a CFCC had a 36% reduced risk of death or re-transplantation compared to those transplanted at a non-CFCC (HR: 0.64, 95% CI: 0.54-0.75, p Conclusion People with CF who undergo LT at a CFCC have improved survival and longer freedom from re-transplantation compared to those transplanted at non-CFCCs. These patients suffering from CF likely have greater access to specialized CF care at CFCCs which may contribute to improved post-transplant survival.

Primary graft dysfunction (PGD) is acute lung injury within 72 hours of lung transplantation. We hypothesized that cell-free hemoglobin (CFH) contributes to PGD by increasing lung microvascular permeability and tested this in patients, ex vivo human lungs, and cultured human lung microvascular endothelial cells. In a nested case control study of 40 patients with severe PGD at 72 hours and 80 matched controls without PGD, elevated preoperative CFH was independently associated with increased PGD risk (odds ratio [OR] 2.75, 95%CI, 1.23–6.16, P = 0.014). The effect of CFH on PGD was magnified by reperfusion fraction of inspired oxygen (FiO2) ≥ 0.40 (OR 3.41, P = 0.031). Isolated perfused human lungs exposed to intravascular CFH (100 mg/dl) developed increased vascular permeability as measured by lung weight (CFH 14.4% vs. control 0.65%, P = 0.047) and extravasation of Evans blue–labeled albumin dye (EBD) into the airspace (P = 0.027). CFH (1 mg/dl) also increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers (hPMVECs). Hyperoxia (FiO2 = 0.95) increased human lung and hPMVEC permeability compared with normoxia (FiO2 = 0.21). Treatment with acetaminophen (15 μg/ml), a specific hemoprotein reductant, prevented CFH-dependent permeability in human lungs (P = 0.046) and hPMVECs (P = 0.037). In summary, CFH may mediate PGD through oxidative effects on microvascular permeability, which are augmented by hyperoxia and abrogated by acetaminophen.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP

Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. Therefore, we conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom. Patients with CF who underwent lung or heart–lung transplantation in the United States or United Kingdom between January 1, 2000 and December 31, 2011 were included. The primary outcome was all-cause mortality. Kaplan–Meier analysis and Cox proportional hazards regression evaluated the effect of healthcare system and insurance on mortality after LTx. 2,307 US LTx recipients and 451 individuals in the United Kingdom were included. 894 (38.8%) US LTx recipients had publically funded Medicare/Medicaid insurance. US private insurance and UK patients had improved median predicted survival compared with US Medicare/Medicaid recipients (p

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.

CMV remains an important opportunistic pathogen in solid organ transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor+/recipient−; D+R−) are at high-risk for active CMV infection and increased mortality, however the immune correlates of viral control remain incompletely understood. We prospectively studied 23 D+R− LTRs during primary CMV infection to determine whether acute CD8+ T cell parameters differentiated the capacity for viral control in early chronic infection. T-box transcription factors expression patterns of T-bet > Eomesodermin (Eomes) differentiated LTR controllers from viremic relapsers and reciprocally correlated with granzyme B loading, and CMV phosphoprotein 65 (pp65)–specific CD8+IFN-γ+ and CD107a+ frequencies. LTR relapsers demonstrated reduced CD8+Ki67+ cells ex vivo and substantially impaired CD8+pp65-specific in vitro proliferative responses at 6 d, with concomitantly lower pp65-specific CD4+IL-2+ frequencies, as compared with LTR controllers. However, CMV-specific in vitro proliferative responses could be significantly rescued, most effectively with pp65 Ag and exogenous IL-2, resulting in an increased T-bet:Eomes balance, and enhanced effector function. Using class I CMV tetramers, we observed similar frequencies between relapsers and controllers, although reduced T-bet:Eomes balance in tetramer+ cells from relapsers, along with impaired CD8+ effector responses to tetramer-peptide restimulation. Taken together, these data show impaired CMV-specific CD8+ effector responses is not for complete lack of CMV-specific cells but rather underscores the importance of the T-bet:Eomes balance, with CMV-specific proliferation a key factor driving early T-bet expression and effector function in CD8+ T cells during primary infection and differentiating the capacity of high-risk LTRs to establish immune control during early chronic infection.

Background Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. Methods We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR + LTRs. Results Compared with ACR, AMR episodes ( n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs −0.6 liter, p 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. Conclusion Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

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.

Human polyomavirus-7-associated rash and pruritus (PVARP) is a chronic superficial viral skin infection, which primarily impacts immunocompromised individuals. We report on a case of PVARP in a lung transplant recipient. Our patient developed symptoms 13 years after being on his immunosuppressive regimen, with an insidious course of progressive gray lichenification with marked islands of sparing and quality of life-altering pruritus. Treatment for PVARP is not established; however, topical cidofovir combined with immunomodulation may offer sustained therapeutic benefit.

Lung transplantation (LT) for treatment for end stage lung disease is becoming increasingly available, and can improve survival and quality of life for some patients. Because of limited availability of donor organs and because of limited post-transplant survival of recipients, appropriate selection of candidates is invariably important. Since the revision of the 2006 international guidelines for selection of lung-transplant recipients, new literature has continued to improve our understanding of the effect of non-pulmonary comorbidities on disease-specific prognosis. By applying this new understanding to evaluation of potential lung-transplant recipients, we can best ensure optimum allocation of the limited resource of donor organs to recipients that are most likely to benefit from LT. This article will review the most recent literature on lung transplant candidate selection to provide an updated framework for optimum allocation of this limited resource.

To the Editor: Primary graft dysfunction (PGD) is a form of acute lung injury occurring within 72 hours of lung transplantation (1, 2). We have previously demonstrated an increase in early mortality in subjects with PGD (2). Understanding of the mechanisms leading to PGD and early mortality is important in identifying potential therapeutic targets and interventions. The complement system defines a group of plasma and cell membrane proteins that play a key role in innate immunity as well as regulating adaptive immune response. C3a, C4a, and C5a, downstream products of the activated complement cascade, are potent neutrophil and lymphocyte chemoattractants (3–5). In animal models, activation of the complement system during lung ischemia and reperfusion can lead to cellular injury and lung allograft failure (6, 7). Based on the relationship between complement activation and ischemia reperfusion injury in the lung allograft, we hypothesized that plasma levels of C3a, C4a, and C5a would be associated with both PGD and mortality after lung transplantation. We performed a prospective cohort study of 190 lung transplant recipients from 10 centers enrolled between 2008 and 2010 in the Lung Transplant Outcomes Group (LTOG) cohort. We included consecutive subjects who had plasma samples available at the preoperative, 6-hour, and 24-hour time points (see Figure E1 in the online supplement). Clinical and mortality data were collected as described elsewhere (2). Informed consent was obtained from each subject. The Investigational Review Board at each center approved our study. The primary outcome was grade 3 PGD within 72 hours after transplantation, which has demonstrated construct validity for survival (8). Grade 3 PGD at 24 hours was used to evaluate the relationship between concurrent lung injury, and grade 3 PGD at 48 or 72 hours was used to evaluate a severe lung injury phenotype (2). We evaluated all-cause mortality as an additional end point. Plasma C3a, C4a, and C5a concentrations were measured using a commercially available cytometric bead array (BD Biosciences, San Jose, CA) in a manner devised to ensure stability of complement (see online supplement). We evaluated absolute differences in levels between each time point to assess changes during the early transplant period. The association between complement and PGD was determined using Wilcoxon rank sum testing. We used Cox regression to evaluate associations between complement levels and time to death, conditioned on 90-day survival, to exclude bias from the effect of PGD and sepsis on early mortality. We adjusted for recipient, donor, and surgical variables (see online supplement). Of the 190 subjects enrolled, 82 developed PGD (43%) within 72 hours post-transplant, and 33 had PGD at 48 or 72 hours (17%). Demographics of the cohort are in Table E1. There were no differences between subjects enrolled with blood samples at all three time points and other subjects enrolled in LTOG (Table E2). The median change in plasma C5a levels between 6 and 24 hours post transplantation was significantly greater in subjects with PGD than in those without (867 vs. −156 pg/ml, P = 0.01) (Figure 1A). The median change in plasma C4a levels between preoperative and 6 hours was greater in subjects with PGD (72,075 vs. −79,501, P = 0.01) (Figure 1B). There was no significant difference in change in plasma C3a levels between the PGD and non-PGD group at any individual time point (Table E3). In sensitivity analyses, there was no difference in complement levels using grade 3 PGD at 24 hours (Table E4). However, there was a similar relationship between change in plasma C5a levels between 6 and 24 hours (1,164 vs.113, P = 0.24) and change in plasma C4a levels between preoperative and 6 hours (109,654 vs. −8,185, P = 0.04) using grade 3 PGD at 48 or 72 hours. Figure 1. (A) Plasma C5a concentration at each time point in subjects without primary graft dysfunction (PGD) (dashed line) and with grade 3 PGD (solid line). The P value indicates that the difference in C5a concentration (represented by the slope of the line) ... Of 175 patients with available mortality data, 32 died (17%). The change in C5a levels from 6 to 24 hours was associated with an increased risk of death (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.16, 2.83; P = 0.01). C5a levels measured preoperatively and 24 hours after transplantation were also associated with an increased risk of death (HR, 1.64; 95% CI, 1.29, 2.09; P < 0.01; and HR, 1.94; 95% CI, 1.39, 2.72; P < 0.01; respectively). C3a levels measured at 6 hours were associated with an increased risk of death (HR, 1.68; 95% CI, 1.04, 2.71; P = 0.03). There was no association between change in C3a or C4a levels and mortality (Tables E5 and E6). These associations were independent of adjustment for all tested confounders, including PGD (Table 1). Table 1. Association of C3a and C5a at Different Time Points with Mortality Our study demonstrates that early changes in plasma C4a and C5a are associated with PGD, and there is an association between C3a and C5a levels with mortality, independent of PGD. Collectively, these data suggest that systemic complement activation is important in both short- and long-term outcomes after transplantation. The increase in C5a between 6 and 24 hours is associated with both PGD and mortality. This suggests a role for an early systemic complement response in both early and late outcomes. Prior work has implicated complement activation in lung ischemia–reperfusion injury (9). The change in C5a level was observed early after transplant and was not associated with concurrent lung injury (grade 3 at 24 h), indicating it may be driving lung injury and not just a marker of injury. Complement may be important in the pathogenesis PGD by attracting neutrophils and accelerating both the innate and adaptive immune responses within the first 24 hours after injury (10, 11). The association of complement with mortality was independent of PGD. Prior work found an association between C3a, C5a, and obliterative bronchiolitis in a mouse model (12). Our findings in humans suggest a role for complement activation that continues after the early reperfusion period, potentially a signal of chronic immune activation starting in the early post-transplant period and leading to formation of autoantibodies, leading to chronic graft dysfunction and mortality. These findings support the study of blockade of complement activation to improve clinical outcomes after transplantation. Our study had limitations. We were unable to measure complement levels in bronchoalveolar lavage; therefore, we could not link the plasma and lung compartments. The incidence of PGD in this study was 40%, which is higher than previous reports; however, we observed a similar trend in sensitivity analyses using a more restrictive definition of PGD. Finally, we were unable to adjust for center effect given small numbers. In conclusion, our study suggests a role for early, systemic activation of the complement pathway in development of severe PGD and mortality after lung transplantation.

Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) within 72 hours of LTx. PGD is clinically and histologically analogous to the acute respiratory distress syndrome. In patients at risk for or with acute respiratory distress syndrome, lung-protective ventilation strategies (low tidal volume and positive end-expiratory pressure) improve outcomes. There is, however, little information available on mechanical ventilation strategies after LTx.Our aim in this international survey was to describe the current practices of mechanical ventilation immediately after LTx.An electronic survey was sent to the medical and surgical directors of U.S. LTx programs (n = 111) and to members of the Pulmonary Council of the International Society for Heart and Lung Transplantation (n = 470).A total of 149 individuals from 18 countries responded to the questionnaire. The most common modes of ventilation were pressure assist/control (37%) and volume assist/control (35%). Tidal volumes were most often determined by recipient characteristics. Donor characteristics were rarely considered (35%) and were infrequently known by the team managing the ventilator (42%). When presented with a choice of ideal tidal volumes, a majority of respondents selected 6 ml/kg recipient predicted body weight (58%), fewer selected 10 ml/kg (21%), and none selected 15 ml/kg. A majority preferred limiting the fraction of inspired oxygen rather than positive end-expiratory pressure (PEEP) (69% versus 31%, P = 0.006). The median minimum PEEP was 5 cm H2O, and the median maximum PEEP was 11.5 cm H2O. The presence of PGD increased the perceived importance of monitoring plateau pressure to adjust tidal volumes. The median plateau pressure limit perceived as a threshold triggering reduction in tidal volume was 30 cm H2O.Most respondents reported using lung-protective approaches to mechanical ventilation after lung transplantation. Low tidal volumes based on recipient characteristics were frequently chosen. Donor characteristics often were not considered and frequently were not known by the team managing mechanical ventilation after LTx.

Rationale: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. Objectives: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. Methods: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. Measurements and Main Results: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10−5) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5′ promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10−5). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Conclusions: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

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.

OBJECTIVES: Mechanical ventilation tidal volumes are usually set according to an estimate of patient size in millilitres (ml) per kilogram (kg) body weight. We describe the relationship between donor–recipient lung-size mismatch and postoperative mechanical ventilation tidal volumes according to recipient- and donor-predicted body weights in a cohort of bilateral lung transplant patients. METHODS: A most-undersized (10 patients with lowest predicted total lung capacity [pTLC] ratio = pTLC-donor/pTLC-recipient), a most-oversized (10 patients with highest pTLC ratio) and best-matched subset (10 patients with predicted total lung capacity ratio closest to 1.0) were selected within a cohort of 70 patients. All tidal volumes during mechanical ventilation in the first 96 h after bilateral lung transplantation were recorded. Tidal volumes were expressed in ml and ml/kg-recipient-predicted body weights and ml/kgdonor-predicted body weights. RESULTS: Postoperative absolute tidal volumes (in ml) were comparable between subsets of patients with undersized, matched and oversized allografts (552 ± 103 vs 581 ± 107 vs 582 ± 104 ml), and tidal volumes in ml/kg-recipient-predicted body weights were also similar (8.8 ± 1.4 vs 9.3 ± 1.1 vs 9.8 ± 2.1). However, tidal volumes in ml/kg-donor-predicted body weights revealed significant differences between undersized, matched, and oversized subsets (11.4 ± 3.1 vs 9.4 ± 1.2 vs 8.1 ± 2.1, respectively; P< 0.05). Two patients developed primary graft dysfunction grade 3, both in the undersized subset. Four patients in the undersized group underwent tracheotomy (vs none in matched and one in oversized subset). CONCLUSIONS: During mechanical ventilation after bilateral lung transplantation, undersized allografts received relatively higher tidal volumes compared with oversized allografts when the tidal volumes were related to donor-predicted body weights.

We simulated the impact of regionalization of isolated heart and lung transplantation within United Network for Organ Sharing (UNOS) regions. Overall, 12 594 orthotopic heart transplantation (OHT) patients across 135 centers and 12 300 orthotopic lung transplantation (OLT) patients across 67 centers were included in the study. An algorithm was constructed that “closed” the lowest volume center in a region and referred its patients to the highest volume center. In the unadjusted analysis, referred patients were assigned the highest volume center's 1-year mortality rate, and the difference in deaths per region before and after closure was computed. An adjusted analysis was performed using multivariable logistic regression using recipient and donor variables. The primary outcome was the potential number of lives saved at 1 year after transplant. In adjusted OHT analysis, 10 lives were saved (95% confidence interval [CI] 9–11) after one center closure and 240 lives were saved (95% CI 209–272) after up to five center closures per region, with the latter resulting in 1624 total patient referrals (13.2% of OHT patients). For OLT, lives saved ranged from 29 (95% CI 26–32) after one center closure per region to 240 (95% CI 224–256) after up to five regional closures, but the latter resulted in 2999 referrals (24.4% of OLT patients). Increased referral distances would severely limit access to care for rural and resource-limited populations.

Lung transplantation can improve survival and quality of life in select patients with end-stage lung disease. Because of the limited availability of donor lungs and limited post-transplant survival of recipients, selection of candidates that are most likely to benefit from transplantation is of utmost importance.Since the revision of 2006 international guidelines for the selection of lung-transplant candidates, new literature has emerged to improve our understanding of disease-specific prognosis and the impact of nonpulmonary comorbidities on post-transplant outcomes. Further published data on the cumulative effect of multiple comorbidities have allowed transplant professionals to better define the high-risk recipient. Applying each of the above principles to the evaluation of potential lung-transplant recipients will allow optimal allocation of donor organs to recipients that are most likely to benefit.This article will review the most recent literature in the field in order to provide an updated framework for the optimal selection of candidates for lung transplantation.

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.

Cytomegalovirus (CMV) remains a significant opportunistic infection in solid organ transplant recipients, particularly lung transplant recipients (LTRs) [1–5]. LTRs have increased susceptibility to CMV infection, perhaps because the lung is a major reservoir for latent virus [6]. As a β-herpesvirus, CMV establishes a state of chronic infection after primary infection, with the risk of reactivation. LTRs mismatched for CMV (donor positive/recipient negative [D+R−]) have the highest risk of active CMV infection and demonstrate increased 1- and 5-year mortality [7]. Active CMV infection is a risk factor for the development of chronic allograft rejection (bronchiolitis obliterans syndrome), a major limiting factor for long-term survival in LTRs [8, 9]. Importantly, CMV viremia early after lung transplantation is strongly associated with the development of bronchiolitis obliterans syndrome in LTRs [10]. Moreover, repeated episodes of relapsing viremia in LTRs are associated with a decreased survival [11]. However, despite the impact of CMV on outcomes in LTRs, prophylaxis, monitoring, and treatment regimens vary widely among institutions and the correlates of protective immunity remain to be fully elucidated. The adaptive immune system, particularly CD8+ T cells, plays a key role in the control of acute viral infections, including CMV infection [12]. However, control of CMV during chronic infection requires ongoing effective immune surveillance to prevent viral relapse in its host [13]. Viral-specific effector CD8+ T cells exert their antiviral activities through the production of type 1 cytokines (eg, interferon γ [IFN-γ] and tumor necrosis factor α [TNF-α]) and cytolytic activity. The differentiation of effector T cells, including CD8+ T cells, is transcriptionally regulated—often by the same transcription factors that mediate their effector function [14]. The T-box transcription factor, T-bet, was first described as being critical for the development of CD4+ T-helper 1 cells in mice [15] and subsequently shown to be important in CD8+ T cells [16–18]. However, although T-bet is critical for the development of effective CD8+ T cells in animal models, little is known about its functional importance in humans. We elsewhere demonstrated the acquisition of de novo primary CMV-specific CD8+ T cell effector responses in D+R− LTRs predominated by IFN-γ production toward the structural protein of phosphoprotein 65 (pp65) [19]. We have subsequently noted relapsing CMV viremia after completion of therapy for primary infection in a subset of these D+R− LTRs during early chronic infection. We therefore hypothesized that LTRs who developed adequate CD8+ effector responses during primary infection would be protected from viral relapse during early chronic CMV infection. Herein, we report our findings of the importance of adequate induction of T-bet and its facilitation of pp65-specific effector responses in CD8+ T cells during human primary CMV infection in viral control during early chronic infection.

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.

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.

This study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary graft dysfunction (PGD) grades with lung injury biomarker profiles and survival.The study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade.PGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation (p0.05 for each). Grade 3 had the highest 30-day (test for trend p0.001) and overall mortality (log rank p0.001), with PGD Grades 1 and 2 demonstrating intermediate risks of mortality. The ability to discriminate both 30-day and overall mortality improved as the time of grading moved away from the time of transplantation (test for trend p0.001).The ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.

Lung transplantation offers potential improvement in survival and improved quality of life in patients with end-stage lung disease. International guidelines for candidate selection have been agreed upon to aid physicians and providers in selecting appropriate candidates for lung transplantation. In recent years the U.S. lung allocation score (LAS) has been developed and implemented in an attempt to both maximize utility of scarce donor organs and provide benefit to those in need of lung transplantation. This has helped in the process of offering transplantation to those with the greatest need and best chance of survival. Appropriate lung transplantation candidates should have life-threatening lung disease but remain otherwise healthy, because significant comorbidities may increase the risk of poor outcomes after transplantation limiting long-term survival. Improved outcomes are seen through early referrals to a specialized center and vigilant evaluation to select the most appropriate candidates for lung transplantation.

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.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.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; p0.001). Centers of lowest quartile (performingor=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%; p0.001) and younger age (40.9 versus 51.5 years; p0.001). 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 (or=20 lung transplantations/year) had the lowest 30-day mortality (4.1%).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.

Background CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV 1 and percent predicted value of FEV 1 with CT scan measures of emphysema and airway disease. Results In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT ( r = −0.28, p = 0.0001) and SRWA ( r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV 1 % predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV 1 % predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema.

Background— Pulmonary hypertension (PH) secondary to left heart failure portends a poor prognosis and is a relative contraindication to heart transplantation at many centers. We tested the hypothesis that when PH persists after adequate left ventricle unloading via recent left ventricular assist device (LVAD) therapy, phosphodiesterase type 5A inhibition would decrease PH in this population. Methods and Results— We performed an open-label clinical trial using control patients not receiving therapy. Between 1999 and 2007, 138 consecutive patients undergoing cardiac transplantation evaluation with advanced left ventricular dysfunction, an elevated pulmonary capillary wedge pressure, and PH (defined by a pulmonary vascular resistance (PVR) >3 Woods Units), were treated with LVAD therapy. Fifty-eight of these patients reduced their pulmonary capillary wedge pressure to a value P P Conclusions— In patients with persistent PH after recent LVAD placement, phosphodiesterase type 5A inhibition in this open-label trial resulted in a significant decrease in PVR when compared with control patients.

Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor+/recipient− (D+R−) individuals. In 15 D+R− LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8+ T cells into the lung airways/allograft was observed, with inversion of the CD4+:CD8+ T cell ratio. De novo CMV-specific CD8+ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4+ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of effector memory CD8+ T cells in the lung airways following primary infection. CMV-tetramer+CD8+ T cells from PBMC were CD45RA− during viremia and transitioned to CD45RA+ following resolution. In contrast, CMV-specific CD8+ effectors in the lung airways/allograft maintained a CD45RA− phenotype during transition from acute into chronic infection. Together, these data reveal differential CMV-specific CD8+ effector frequencies, immunodominance, and polyfunctional cytokine responses predominating in the lung airways/allograft compared with the blood during acute primary infection. Moreover, we show intercompartmental phenotypic differences in CMV-specific memory responses during the transition to chronic infection.

Purpose of reviewLung transplantation has become a widely accepted treatment in the management of a broad spectrum of end-stage lung disease. Appropriate candidates should have severe lung disease associated with a limited life expectancy. Patients should be sick enough that survival without a trans

The past decade has witnessed enormous strides in the treatment of pulmonary arterial hypertension (PAH). Currently available pharmacologic agents are capable of inducing sustained clinical improvements and reducing mortality, particularly for idiopathic PAH (IPAH). However, response is variable, and morbidity and mortality remain unacceptably high in this relatively young population.12 Lung transplantation, therefore, remains an important option in the face of progressive disease.