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BackgroundWe sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation.MethodsPatients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders.ResultsA total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p=.0002), median LAS (38.0-47.7 p=.009) and the use of ECMO salvage for PGD (5.7%-20.9%, p=.007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p=.0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p=.66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p=.0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]).ConclusionsPGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.

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.

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 ECMO is increasingly used for bridging and salvage therapies in lung transplantation, with favorable short-term results. Mid- to long-term outcomes of ECMO use for bridging and salvage are incompletely understood, as is effect on PGD risk; therefore, we sought to define the effects of these strategies on mortality and PGD. Methods The Lung Transplant Outcomes Group study is a multi-center prospective cohort study designed to identify risk factors for PGD and mortality. Patients were enrolled from August 2011 to June 2018. The effect of pre-operative (bridging) and post-operative (salvage) ECMO on Grade 3 PGD incidence and long-term survival were assessed using time-to-event analyses adjusted for center. Results 1,537 subjects were enrolled with a 17.0% incidence of PGD on day 3 and an 18.9% mortality overall. PGD was associated with mortality (p=0.0001, Fig. 1a). ECMO bridging and salvage strategies increased over time (Fig. 1b). 138 (9%) subjects had bridging ECMO and 275 (17.9%) had salvage ECMO. PGD was associated with bridging strategies (p=0.001). PGD incidence in bridged patients (50.7%) exceeded non-bridged (42.2%). Bridging was not associated with mortality overall (p=0.70, Fig. 1c); however, if PGD developed after transplant using a bridging strategy, there was a significant increase in mortality (HR 1.8 [1.3; 2.61]; p=0.0007). About 45% of patients bridged with ECMO required salvage after transplant. ECMO use for salvage was highly associated with mortality (HR 2.1 [1.6; 2.8]; p Conclusion Use of the ISHLT Revised definition identifies Grade 3 PGD as highly associated with mortality in the ECMO bridging and salvage era. ECMO use is increasing for both bridging and salvage strategies. ECMO bridging strategies do not seem to increase mortality in lung transplant patients unless Grade 3 PGD subsequently develops. ECMO salvage after transplant is associated with increased risk of mortality; however, it is likely used only in the severest cases, thus indication bias is likely present.

Purpose Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies highlight the role of donor smoking in poor post-transplant outcomes. We therefore aimed to identify clinical risk factors for PGD after lung transplantation, more accurately assess the impact of donor smoking, and develop an accurate, generalizable PGD prediction model. Methods We performed a 10-center prospective cohort study of patients in the Lung Transplant Outcomes Group from 2012-2018. PGD was defined as grade 3 PGD at 48 or 72 hours after lung reperfusion. We defined donor smoking history by clinical documentation, UNOS-reported donor smoking, or donor cotinine >9 mg/ml from urine collected at organ procurement. Building on our prior PGD prediction models, multivariable logistic regression was used to identify PGD risk factors and develop regularized predictive models with a simple user interface (R shiny). Results Of 1180 patients, 26% developed PGD and 633 (53%) received an organ from a previously smoking donor. The PGD predictive model included novel predictors of center and donor distance plus recipient age, lung allocation score (LAS), body mass index, pulmonary artery pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor distance; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The predictive model offers decision making benefit in the PGD risk range of 0.15-0.5. Donor smoking was associated with increased risk of PGD but not patient mortality (Figure 1). Conclusion We developed a clinically applicable PGD predictive algorithm based on modern lung transplant practices to aid in transplant decision making, post-transplant care, and to facilitate development of enriched PGD treatment trials. Donor smoking is a risk factor for PGD development but is not associated with increased mortality, potentially because of a lower risk phenotype of PGD occurring in smoking donor recipients.

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.

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

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.

Purpose The primary driver of poor outcomes in the early stages of lung transplantation is primary graft dysfunction (PGD). Patients with cystic fibrosis (CF) have unique physiology and demographics compared to other lung transplant recipients. Therefore, we sought to identify risk factors for PGD in the CF patient population undergoing lung transplantation. Methods We utilized clinical data on lung transplant recipients with CF and their donors from the Lung Transplant Outcomes Group cohort, a multi-center prospective cohort study of PGD pathogenesis. The primary outcome was grade 3 PGD within the first 72 hours after transplantation. Potential covariates were identified in univariate analysis and assessed for collinearity. Independent PGD risk factors were identified using multivariate logistic regression. A sensitivity analysis was performed using grade 3 PGD 48 to 72 hours after transplantation. Results We identified 195 patients with CF who received lung transplants between August 2014 and June 2018 across ten centers. Grade 3 PGD developed in 80 subjects (41%). Risk factors for PGD in CF patients based on the multivariable model were white donor race (odds ratio [OR]: 2.6, 95% confidence interval [CI]: 1.4-5.1), any positive panel reactive antibodies (PRA) (OR: 2.2, 95% CI: 1.0-4.7), recipient female gender (OR: 2.1, 95% CI: 1.1-3.9), intraoperative cardiopulmonary bypass use (OR: 2.2, 95% CI: 1.2-4.2), increasing lung allocation score (LAS) (OR: 1.2 per 10 point increase in LAS, 95% CI: 1.0-1.4), and ECMO (extracorporeal membrane oxygenation) bridge to transplant (OR: 2.7, 95% CI: 1.1-6.7). LAS and ECMO were assessed in separate models due to their collinearity. Mean pulmonary artery pressure at the time of transplant was included as a potential confounder. Similar findings were seen in a more severe phenotype of PGD that developed 48 to 72 hours after transplant. Conclusion The CF population is often considered to be at low risk of PGD, however we observed a relatively high rate of PGD in this study. Any positive PRA, female recipient gender, intraoperative bypass, increasing LAS, and ECMO are PGD risk factors that have been identified non-CF transplant populations. We validated these risk factors in recipients with CF. White donor race is a novel risk factor that has not been previously identified in lung transplant recipients with another primary diagnosis.

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.

Rationale:Thereceptorforadvancedglycationendproducts(RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. Objectives:TotesttheassociationofsolubleRAGE(sRAGE)levelswith PGD in a prospective, multicenter cohort study. Methods: We measured plasma levels of sRAGE at 6 and 24 hours afterallograftreperfusion in317 lungtransplantrecipientsatseven centers. The primary outcome was grade 3 PGD (PaO2 /FIO2 , 200 with alveolar infiltrates) within the first 72 hours after transplantation. Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P 5 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P , 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P 5 0.003) and 24 hours (P , 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman’s r 5 0.39, P 5 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P 5 0.02). Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

Platelet activation with subsequent neutrophilic adherence to the vasculature initiates ischemia-reperfusion injury. We hypothesized that higher plasma P-selectin levels reflecting platelet activation would therefore be associated with primary graft dysfunction (PGD) after lung transplantation.In a prospective, multicenter cohort study of 376 patients who had undergone lung transplantation between 2002 and 2007, we measured soluble P-selectin levels before lung transplantation and at 6 and 24 h after lung reperfusion in 20 patients with grade III PGD (Pao(2)/fraction of inspired oxygen,200 mm Hg [with alveolar infiltrates seen on chest radiographs]) at 72 h after transplantation and 61 control subjects without PGD.Higher postoperative soluble P-selectin levels were associated with an increased risk of PGD at 72 h after transplantation (odds ratio [OR] per 1 natural log increase in soluble P-selectin at 6 h after lung allograft reperfusion, 3.5; 95% confidence interval [CI], 1.01 to 11.8; p = 0.048) and at 24 h after lung allograft reperfusion (OR, 4.8; 95% CI, 1.4 to 16.1; p = 0.01). Higher preoperative mean pulmonary artery pressure and the use of cardiopulmonary bypass were also associated with an increased risk of PGD.Higher postoperative soluble P-selectin levels were associated with an increased risk of PGD at 72 h following lung transplantation.

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

Background: Acute lung injury is characterized by hypercoagulability and impaired fibrinolysis. We hypothesized that lower protein C and higher type 1 plasminogen activator inhibitor (PAI-1) levels in plasma would be associated with primary graft dysfunction (PGD) after lung transplantation. Design: Prospective, multicenter cohort study. Methods: We measured plasma levels of protein C and PAI-1 before lung transplantation and 6, 24, 48, and 72 h after allograft reperfusion in 128 lung transplant recipients at six centers. The primary outcome was grade 3 PGD (PaO2/FiO2 < 200 with alveolar infiltrates) 72 h after transplantation. Biomarker profiles were evaluated using logistic regression and generalized estimating equations. Results: Patients who developed PGD had lower protein C levels 24 h posttransplantation than did patients without PGD (mean ± SD [relative to control]: 64 ± 27 vs. 92 ± 41%, respectively; p = 0.002). Patients with PGD also had PAI-1 levels that were almost double those of patients without PGD at 24 h (213 ± 144 vs. 117 ± 89 ng/ml, respectively; p < 0.001). Throughout the 72-h postoperative period, protein C levels were significantly lower (p = 0.007) and PAI-1 levels were higher (p = 0.026) in subjects with PGD than in others. These differences persisted despite adjustment for potential confounders in multivariate analyses. Higher recipient pulmonary artery pressures, measured immediately pretransplantation, were associated with higher PAI-1 levels and increased risk of PGD. Conclusion: Lower postoperative protein C and higher PAI-1 plasma levels are associated with PGD after lung transplantation. Impaired fibrinolysis and enhanced coagulation may be important in PGD pathogenesis.

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

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.

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

RationalePrimary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.ObjectivesWe sought to identify donor, recipient, and perioperative risk factors for PGD.MethodsWe performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.Measurements and main resultsA total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% increase in FiO2; 95% CI, 1.0-1.2; P = 0.01); single lung transplant (OR, 2; 95% CI, 1.2-3.3; P = 0.008); use of cardiopulmonary bypass (OR, 3.4; 95% CI, 2.2-5.3; P < 0.001); overweight (OR, 1.8; 95% CI, 1.2-2.7; P = 0.01) and obese (OR, 2.3; 95% CI, 1.3-3.9; P = 0.004) recipient body mass index; preoperative sarcoidosis (OR, 2.5; 95% CI, 1.1-5.6; P = 0.03) or pulmonary arterial hypertension (OR, 3.5; 95% CI, 1.6-7.7; P = 0.002); and mean pulmonary artery pressure (OR, 1.3 per 10 mm Hg increase; 95% CI, 1.1-1.5; P < 0.001). PGD was significantly associated with 90-day (relative risk, 4.8; absolute risk increase, 18%; P < 0.001) and 1-year (relative risk, 3; absolute risk increase, 23%; P < 0.001) mortality.ConclusionsWe identified grade 3 PGD risk factors, several of which are potentially modifiable and should be prioritized for future research aimed at preventative strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 00552357).

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

Rationale: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis. Objectives: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD. Methods: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis. Measurements and Main Results: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5′ region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis. Conclusions: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels.

Introduction Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD. Methods We performed a case-control study, nested within the multi-center Lung Transplant Outcomes Group cohort. Plasma angiopoietin-2 levels were measured pre-transplant and 6 and 24 hours post-reperfusion. The primary outcome was development of grade 3 PGD in the first 72 hours. The association of angiopoietin-2 plasma levels and PGD was evaluated using generalized estimating equations (GEE). Results There were 40 PGD subjects and 79 non-PGD subjects included for analysis. Twenty-four PGD subjects (40%) and 47 non-PGD subjects (59%) received a transplant for the diagnosis of idiopathic pulmonary fibrosis (IPF). Among all subjects, GEE modeling identified a significant change in angiopoietin-2 level over time in cases compared to controls (p = 0.03). The association between change in angiopoietin-2 level over the perioperative time period was most significant in patients with a pre-operative diagnosis of IPF (p = 0.02); there was no statistically significant correlation between angiopoietin-2 plasma levels and the development of PGD in the subset of patients transplanted for chronic obstructive pulmonary disease (COPD) (p = 0.9). Conclusions Angiopoietin-2 levels were significantly associated with the development of PGD after lung transplantation. Further studies examining the regulation of endothelial cell permeability in the pathogenesis of PGD are indicated.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation.To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation.We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios.Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass.Obesity is an independent risk factor for primary graft dysfunction after lung transplantation.

Primary graft dysfunction (PGD) is the leading cause of early post-transplant morbidity and mortality after lung transplantation. Clara cell secretory protein (CC16) is produced by the non-ciliated lung epithelium and may serve as a plasma marker of epithelial cell injury. We hypothesized that elevated levels of CC16 would be associated with increased odds of PGD. We performed a prospective cohort study of 104 lung transplant recipients. Median plasma CC16 levels were determined at three time points: pre-transplant and 6 and 24 hours post transplant. The primary outcome was the development of grade 3 PGD within the first 72 hours after transplantation. Multivariable logistic regression was performed to evaluate for confounding by donor and recipient demographics and surgical characteristics. Twenty-nine patients (28%) developed grade 3 PGD within the first 72 hours. The median CC16 level 6 hours after transplant was significantly higher in patients with PGD (13.8 ng/ml (IQR 7.9, 30.4 ng/ml)) than in patients without PGD (8.2 ng/ml (IQR 4.5, 19.1 ng/ml)), p = 0.02. Elevated CC16 levels were associated with increased odds of PGD after lung transplantation. Damage to airway epithelium or altered alveolar permeability as a result of lung ischemia and reperfusion may explain this association.

Primary graft dysfunction (PGD), a form of acute lung injury occurring within 72 h following lung transplantation, is characterized by pulmonary edema and diffuse alveolar damage. We hypothesized that higher concentrations of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) would be associated with the occurrence of PGD. A total of 128 lung transplant recipients among 7 lung transplant centers were enrolled in a multicenter, prospective, cohort study. Blood specimens were collected preoperatively and at 6, 24, 48 and 72 h following lung transplantation. The primary outcome was Grade 3 PGD at 72 h after transplant. Logistic regression and generalized estimating equations (GEE) were used to analyze plasma ICAM-1 and vWF. At each postoperative timepoint, mean plasma ICAM-1 concentrations were higher for patients with PGD versus no PGD. The GEE contrast estimate for the association of plasma ICAM-1 with PGD was 107.5 ng/mL (95% CI 38.7, 176.3), p = 0.002. In the multivariate analyses, this finding was independent of all clinical variables except pulmonary artery pressures prior to transplant. There was no association between plasma vWF levels and PGD. We conclude that higher levels of plasma ICAM-1 are associated with PGD following lung transplantation.

Purpose Free hemoglobin (freeHgb) is a potent oxidant released from red cells in conditions such as sepsis, hemolysis, hemodialysis and cardiopulmonary bypass. We determined whether plasma freeHgb is elevated in lung transplant recipients and whether levels are associated with primary graft dysfunction (PGD). We also tested whether the potential oxidative injury associated with freeHgb is potentiated by high FiO2 at reperfusion. Methods and Materials Patients were lung recipients in the Lung Transplant Outcomes Group cohort and included 40 cases with Grade 3 PGD at 72h after transplant and 80 controls with no PGD, frequency matched for diagnosis (COPD, IPF) and procedure (single, bilateral). Plasma freeHgb was measured pre-op, and at 6 and 24h after reperfusion. PGD status was determined by ISHLT criteria. Results FreeHgb was detectable in 91% of pre-op, 97% of 6h and 85% of 24h samples. Pre-op [median 30 mg/dL (IQR 20-50 )] and 6h [30 (10-80)] levels were similar, but fell at 24h [20 (10-40), p=0.002]. Post-op freeHgb levels were similar between cases and controls although levels were higher in those who underwent cardiopulmonary bypass [80 (40–150) vs 20 (10–40), p Figure ). Conclusions High pre-op levels of plasma freeHgb associate with PGD, particularly when FiO2 is high at reperfusion. FreeHgb may be a mediator of oxidative injury during ischemia reperfusion and high levels of inspired O2 may potentiate this oxidative injury.