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Background: Existing measures of frailty developed in community dwelling older adults may misclassify frailty in lung transplant candidates. We aimed to develop a novel frailty scale for lung transplantation with improved performance characteristics., Methods: We measured the short physical performance battery (SPPB), fried frailty phenotype (FFP), Body Composition, and serum Biomarkers representative of putative frailty mechanisms. We applied a 4-step established approach (identify frailty domain variable bivariate associations with the outcome of waitlist delisting or death; build models sequentially incorporating variables from each frailty domain cluster; retain variables that improved model performance ability by c-statistic or AIC) to develop 3 candidate "Lung Transplant Frailty Scale (LT-FS)" measures: 1 incorporating readily available clinical data; 1 adding muscle mass, and 1 adding muscle mass and research-grade Biomarkers. We compared construct and predictive validity of LT-FS models to the SPPB and FFP by ANOVA, ANCOVA, and Cox proportional-hazard modeling., Results: In 342 lung transplant candidates, LT-FS models exhibited superior construct and predictive validity compared to the SPPB and FFP. The addition of muscle mass and Biomarkers improved model performance. Frailty by all measures was associated with waitlist disability, poorer HRQL, and waitlist delisting/death. LT-FS models exhibited stronger associations with waitlist delisting/death than SPPB or FFP (C-statistic range: 0.73-0.78 vs. 0.57 and 0.55 for SPPB and FFP, respectively). Compared to SPPB and FFP, LT-FS models were generally more strongly associated with delisting/death and improved delisting/death net reclassification, with greater improvements with increasing LT-FS model complexity (range: 0.11-0.34). For example, LT-FS-Body Composition hazard ratio for delisting/death: 6.0 (95%CI: 2.5, 14.2), SPPB HR: 2.5 (95%CI: 1.1, 5.8), FFP HR: 4.3 (95%CI: 1.8, 10.1). Pre-transplant LT-FS frailty, but not SPPB or FFP, was associated with mortality after transplant., Conclusions: The LT-FS is a disease-specific physical frailty measure with face and construct validity that has superior predictive validity over established measures., (Copyright © 2023 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Heterogeneous frailty pathobiology might explain the inconsistent associations observed between frailty and lung transplant outcomes. A Subphenotype analysis could refine frailty measurement. In a 3-center pilot cohort study, we measured frailty by the Short Physical Performance Battery, body composition, and serum biomarkers reflecting causes of frailty. We applied latent class modeling for these baseline data. Next, we tested class construct validity with disability, waitlist delisting/death, and early postoperative complications. Among 422 lung transplant candidates, 2 class model fit the best (P = .01). Compared with Subphenotype 1 (n = 333), Subphenotype 2 (n = 89) was characterized by systemic and innate inflammation (higher IL-6, CRP, PTX3, TNF-R1, and IL-1RA); mitochondrial stress (higher GDF-15 and FGF-21); sarcopenia; malnutrition; and lower hemoglobin and walk distance. Subphenotype 2 had a worse disability and higher risk of waitlist delisting or death (hazards ratio: 4.0; 95% confidence interval: 1.8-9.1). Of the total cohort, 257 underwent transplant (Subphenotype 1: 196; Subphenotype 2: 61). Subphenotype 2 had a higher need for take back to the operating room (48% vs 28%; P = .005) and longer posttransplant hospital length of stay (21 days [interquartile range: 14-33] vs 18 days [14-28]; P = .04). Subphenotype 2 trended toward fewer ventilator-free days, needing more postoperative extracorporeal membrane oxygenation and dialysis, and higher need for discharge to rehabilitation facilities (P ≤ .20). In this early phase study, we identified biological frailty Subphenotypes in lung transplant candidates. A hyperinflammatory, sarcopenic Subphenotype seems to be associated with worse clinical outcomes., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

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., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Rationale: Obesity is associated with an increased risk of pulmonary hypertension (PH); however, regional adipose tissue deposition is heterogeneous with distinct cardiovascular phenotypes. Objectives: To determine the association of body mass index (BMI) and thoracic visceral and subcutaneous adipose tissue areas (VAT and SAT, respectively) with PH in patients with advanced lung disease referred for lung transplantation. Methods: We studied patients undergoing evaluation for lung transplantation at three centers from the Lung Transplant Body Composition Study. PH was defined as mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥3 Wood units. VAT and SAT were measured on chest computed tomography and normalized to height squared. Results: One hundred thirty-seven (34%) of 399 patients included in our study had PH. Doubling of thoracic VAT was associated with significantly lower pulmonary vascular resistance (β, -0.24; 95% confidence interval [95% CI], -0.46 to -0.02; P  = 0.04), higher pulmonary arterial wedge pressure (β, 0.79; 95% CI, 0.32 to 1.26; P  = 0.001), and decreased risk of PH (relative risk, 0.86; 95% CI, 0.74 to 0.99; P  = 0.04) after multivariate adjustment. Vaspin levels were higher in patients without PH (median, 101.8 vs. 92.0 pg/ml; P  < 0.001) but did not mediate the association between VAT and the risk of PH. SAT and BMI were not independently associated with risk of PH. Conclusions: Lower thoracic VAT was associated with a higher risk of PH in patients with advanced lung disease undergoing evaluation for lung transplantation. The role of adipokines in the pulmonary vascular disease remains to be evaluated.

Background: Ex vivo lung perfusion (EVLP) allows for a reassessment of lung grafts initially deemed unsuitable for transplantation, increasing the available donor pool; however, this requires a pre- and post-EVLP period of cold ischemic time (CIT). Paucity of data exists on how the sequence of cold normothermic-cold preservations affect outcomes., Methods: A total of 110 patients were retrospectively analyzed. Duration of 3 preservation phases was measured: cold pre-EVLP, EVLP, and cold post-EVLP. The donor and recipient clinical data were collected. Primary graft dysfunction (PGD) and survival were monitored. Risk of mortality or PGD was calculated using Cox proportional hazards and logistic regression models to adjust for baseline characteristics., Results: Using the highest quartile, patients were stratified into extended vs non-extended pre-EVLP (<264 vs ≥264 minutes) and post-EVLP (<287 vs ≥287 minutes) CIT. The rates of 1-year mortality (8.4% vs 29.6%, p = 0.013), PGD 2-3 (20.5% vs 52%, p = 0.002), and PGD 3 (8.4% vs 29.6%, p = 0.005) at 72 hours were increased in the extended post-EVLP CIT group. After adjusting for baseline risk factors, the extended group remained an independent predictor of PGD ≥2 (odd ratio: 6.18, 95% CI: 1.88-20.3, p = 0.003) and PGD 3 (odd ratio: 20.4, 95% CI: 2.56-161.9, p = 0.004) at 72 hours and 1-year mortality (hazard ratio: 17.9, 95% CI: 3.36-95.3, p = 0.001). Cold pre-EVLP was not a significant predictor of primary outcomes., Conclusions: Extended cold post-EVLP preservation is associated with a risk for PGD and 1-year mortality. Pre-EVLP CIT does not increase mortality or high-grade PGD. These findings from a multicenter trial should caution on the implementation of extended cold preservation after EVLP., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI -20 to -8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI -21 to -10). CT imaging may improve candidate risk stratification., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown., Methods: We performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height. 2 We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD., Results: A total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD., Conclusions: Subcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Frailty is a state of decreased physiologic reserve associated with poor outcomes before and after lung transplantation. Obesity, particularly central obesity characterized by excess proinflammatory visceral adipose tissue (VAT), is associated with incident frailty in middle-aged and older adults. The association between VAT and frailty in advanced lung disease, however, is unknown. In two, nonoverlapping multicenter cohorts of adults listed for lung transplantation, we measured VAT area on bioelectrical impedance assay (BIA) in one cohort and cross-sectional VAT and subcutaneous adipose tissue (SAT) areas on abdominal computed tomography (CT) in the other. We identified a nonlinear relationship between greater VAT by BIA and frailty. In fully adjusted piecewise regression models, every 20 cm 2 increase in VAT area was associated with 50% increased odds of frailty in subjects with high VAT (95% CI 1.2-1.9, P < .001), and 10% decreased odds of frailty (95% CI 0.7-1.04, P = .12) in subjects with low VAT. Compared to frail subjects with low VAT, those with high VAT were more likely to have low grip strength and less likely to have weight loss, suggesting that mechanisms of frailty may differ by VAT. Further investigation of mechanisms linking VAT and frailty may identify new targets for prevention and treatment., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: Surfactant proteins A and D are important molecules involved in lung allograft innate immunity. Genetic polymorphisms of surfactant proteins A and D are associated with various lung diseases. In this study, surfactant protein A and D expression responses were investigated during pharmacogenetics upon methylprednisolone treatment as observed during lung transplantation., Methods: A human cell line (NCI-H441) and precision-cut lung slices from 16 human donors were incubated with methylprednisolone, and surfactant protein A1, surfactant protein A2, and surfactant protein D messenger RNA and surfactant protein A protein expression were assayed. Surfactant protein A1, A2, and D polymorphisms and surfactant protein A gene and protein expressions were determined., Results: In NCI-H441 cells, methylprednisolone treatment at 10 -5  M and 10 -6  M reduced surfactant protein A1 and surfactant protein A2 messenger RNA and surfactant protein A protein expression (P < .05). A pharmacogenetic relationship was observed in human donor precision-cut lung slices between the surfactant protein A2 (1A x ) variants: Surfactant protein A1, A2, and D messenger RNA expression were greater for 1A 0 versus 1A 1 (P < .05); surfactant protein A1/surfactant protein A2 genotype 6A 2 6A 2 /1A 0 1A 0 (n = 5) showed greater surfactant protein A1, A2, and D messenger RNA expression and surfactant protein A protein expression compared with the other surfactant protein A1/surfactant protein A2 genotypes (n = 11) (P < .05)., Conclusions: The surfactant protein A genotype and methylprednisolone stimuli influence donor lung surfactant protein A and D expression. Lungs carrying the surfactant protein A2 variant 1A 0 have a greater expression of surfactant protein A when treated with methylprednisolone. Surfactant protein A polymorphisms could be used to personalize immunosuppressive regimens., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Solid organ transplantation disrupts virus-host relationships, potentially resulting in viral transfer from donor to recipient, reactivation of latent viruses, and new viral infections. Viral transfer, colonization, and reactivation are typically monitored using assays for specific viruses, leaving the behavior of full viral populations (the "virome") understudied. Here we sought to investigate the temporal behavior of viruses from donor lungs and transplant recipients comprehensively. We interrogated the bronchoalveolar lavage and blood viromes during the peritransplant period and 6-16 months posttransplant in 13 donor-recipient pairs using shotgun metagenomic sequencing. Anelloviridae, ubiquitous human commensal viruses, were the most abundant human viruses identified. Herpesviruses, parvoviruses, polyomaviruses, and bacteriophages were also detected. Anelloviridae populations were complex, with some donor organs and hosts harboring multiple contemporaneous lineages. We identified transfer of Anelloviridae lineages from donor organ to recipient serum in 4 of 7 cases that could be queried, and immigration of lineages from recipient serum into the allograft in 6 of 10 such cases. Thus, metagenomic analyses revealed that viral populations move between graft and host in both directions, showing that organ transplantation involves implantation of both the allograft and commensal viral communities., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Tissue-resident memory T cells (T RM ) maintain immunity in diverse sites as determined in mouse models, whereas their establishment and role in human tissues have been difficult to assess. Here, we investigated human lung T RM generation, maintenance, and function in airway samples obtained longitudinally from human leukocyte antigen (HLA)-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of T RM signature markers including CD69, CD103, and CD49a, whereas lung-infiltrating recipient T cells gradually acquire T RM phenotypes over months in vivo. Single-cell transcriptome profiling of airway T cells reveals that donor T cells comprise two T RM -like subsets with varying levels of expression of T RM -associated genes, whereas recipient T cells comprised non-T RM and similar T RM -like subpopulations, suggesting de novo T RM generation. Transplant recipients exhibiting higher frequencies of persisting donor T RM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared with recipients with low donor T RM persistence, suggesting that monitoring T RM dynamics could be clinically informative. Together, our results provide spatial and temporal insights into how human T RM develop, function, persist, and affect tissue integrity within the complexities of lung transplantation., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Rationale: Bilateral lung transplantation is widely used to treat chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), on the basis of an expectation of improved survival after transplantation. Yet, waiting list mortality is higher while awaiting bilateral transplantation. The net effect of procedure preference on overall survival is unknown., Objectives: To determine whether an unrestricted procedure preference is associated with improved overall outcomes after listing for lung transplantation., Methods: We performed a retrospective cohort study of 12,155 adults with COPD or ILD listed for lung transplantation in the United States between May 4, 2005, and December 31, 2014. We defined a "restricted" procedure preference as listing for "bilateral transplantation only" and an "unrestricted" procedure preference as listing for any combination of bilateral or single lung transplantation. We used a composite "intention-to-treat" primary outcome that included events both before and after transplantation, defined as the number of days between listing and death, removal from the list for clinical deterioration, or retransplantation., Results: In adjusted analyses, an unrestricted procedure preference was associated with a 3% lower rate of the primary intention-to-treat outcome in COPD (adjusted hazard ratio [aHR], 0.97; 95% confidence interval [CI], 0.89-1.07) and a 1% higher rate in ILD (aHR, 1.01; 95% CI, 0.94-1.08). There was no convincing evidence that these associations varied by age, disease severity, or the use of mechanical support. Among those with ILD and concomitant severe pulmonary hypertension, an unrestricted preference was associated with a 17% increased rate of the primary outcome (aHR, 1.17; 95% CI, 0.99-1.39). An unrestricted preference was consistently associated with lower rates of death or removal from the list for clinical deterioration and with higher rates of transplantation. Graft failure rates were similar among those listed with restricted and unrestricted preferences., Conclusion: When considering outcomes both before and after transplantation, we found no evidence that patients with COPD or ILD benefit from listing for bilateral lung transplantation compared with listing for a more liberal procedure preference. An unrestricted listing strategy for suitable candidates may increase the number of transplants performed without impacting overall survival.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in adults with systemic autoimmune rheumatic diseases (ARDs). The aim of this study was to determine whether adults with ARDs and PAH on right-sided heart catheterization (ARD-PAH) have increased mortality following lung transplantation compared with those with PAH not due to an ARD., Methods: We conducted a retrospective cohort study of 93 adults with ARD-PAH and 222 adults with PAH who underwent lung transplantation in the USA between 4 May 2005 and 9 March 2015 using data from the United Network for Organ Sharing. We examined associations between diagnosis and survival after lung transplantation using stratified Cox models adjusted for potential confounding recipient factors., Results: Among adults undergoing lung transplantation in the USA, we did not detect a difference in the multivariable-adjusted mortality rate between those with ARD-PAH and those with PAH [hazard ratio 0.75 (95% CI 0.47, 1.19)]., Conclusion: The presence of an ARD was not associated with increased mortality after lung transplantation in adults with PAH.

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.

Rationale: 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., Objectives: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity., Methods: 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., Measurements and Main Results: 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., Conclusions: 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.

Despite the importance of pretransplantation outcomes, 1-year posttransplantation survival is typically considered the primary metric of lung transplant center performance in the United States. We designed a novel lung transplant center performance metric that incorporates both pre- and posttransplantation survival time. We performed an ecologic study of 12 187 lung transplant candidates listed at 56 U.S. lung transplant centers between 2006 and 2012. We calculated an "intention-to-treat" survival (ITTS) metric as the percentage of waiting list candidates surviving at least 1 year after transplantation. The median center-level 1-year posttransplantation survival rate was 84.1%, and the median center-level ITTS was 66.9% (mean absolute difference 19.6%, 95% limits of agreement 4.3 to 35.1%). All but 10 centers had ITTS values that were significantly lower than 1-year posttransplantation survival rates. Observed ITTS was significantly lower than expected ITTS for 7 centers. These data show that one third of lung transplant candidates do not survive 1 year after transplantation, and that 12% of centers have lower than expected ITTS. An "intention-to-treat" survival metric may provide a more realistic expectation of patient outcomes at transplant centers and may be of value to transplant centers and policymakers., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Rationale: Pulmonary hypertension from pulmonary arterial hypertension or parenchymal lung disease is associated with an increased risk for primary graft dysfunction after lung transplantation., Objective: We evaluated the clinical determinants of severe primary graft dysfunction in pulmonary hypertension and developed and validated a prognostic model., Methods: 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 Pa O 2 /Fi O 2 ≤200 with allograft infiltrates at 48 or 72 hours after transplantation. Donor, recipient, and operative characteristics were evaluated in a multivariable explanatory model. A prognostic model derived using donor and recipient characteristics was then validated in a separate cohort., Results: In 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., Conclusions: 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.

Background: Frail lung transplant candidates are more likely to be delisted or die without receiving a transplant. Further knowledge of what frailty represents in this population will assist in developing interventions to prevent frailty from developing. We set out to determine whether frail lung transplant candidates have reduced exercise capacity independent of disease severity and diagnosis., Methods: Sixty-eight adult lung transplant candidates underwent cardiopulmonary exercise testing (CPET) and a frailty assessment (Fried's Frailty Phenotype (FFP)). Primary outcomes were peak workload and peak aerobic capacity (V˙O 2 ). We used linear regression to adjust for age, gender, diagnosis, and lung allocation score (LAS)., Results: The mean ± SD age was 57 ± 11 years, 51% were women, 57% had interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had cystic fibrosis, and the mean LAS was 40.2 (range 19.2-94.5). In adjusted models, peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V˙O 2 decreased by 1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V˙O 2 was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to non-frail participants. Frailty accounted for 16% of the variance (R 2 ) of watts and 19% of the variance of V˙O 2 in adjusted models., Conclusion: Frailty contributes to reduced exercise capacity among lung transplant candidates independent of disease severity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rationale: Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood., Objectives: To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation., Methods: Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined., Measurements and Main Results: Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2-year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40., Conclusions: A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy.

Purpose: Overweight and underweight conditions are considered relative contraindications to lung transplantation due to their association with excess mortality. Yet, recent work suggests that body mass index (BMI) does not accurately reflect adipose tissue mass in adults with advanced lung diseases. Alternative and more accurate measures of adiposity are needed. Chest fat estimation by routine computed tomography (CT) imaging may therefore be important for identifying high-risk lung transplant candidates. In this paper, an approach to chest fat quantification and quality assessment based on a recently formulated concept of standardized anatomic space (SAS) is presented. The goal of the paper is to seek answers to several key questions related to chest fat quantity and quality assessment based on a single slice CT (whether in the chest, abdomen, or thigh) versus a volumetric CT, which have not been addressed in the literature., Methods: Unenhanced chest CT image data sets from 40 adult lung transplant candidates (age 58 ± 12 yrs and BMI 26.4 ± 4.3 kg/m2), 16 with chronic obstructive pulmonary disease (COPD), 16 with idiopathic pulmonary fibrosis (IPF), and the remainder with other conditions were analyzed together with a single slice acquired for each patient at the L5 vertebral level and mid-thigh level. The thoracic body region and the interface between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in the chest were consistently defined in all patients and delineated using Live Wire tools. The SAT and VAT components of chest were then segmented guided by this interface. The SAS approach was used to identify the corresponding anatomic slices in each chest CT study, and SAT and VAT areas in each slice as well as their whole volumes were quantified. Similarly, the SAT and VAT components were segmented in the abdomen and thigh slices. Key parameters of the attenuation (Hounsfield unit (HU) distributions) were determined from each chest slice and from the whole chest volume separately for SAT and VAT components. The same parameters were also computed from the single abdominal and thigh slices. The ability of the slice at each anatomic location in the chest (and abdomen and thigh) to act as a marker of the measures derived from the whole chest volume was assessed via Pearson correlation coefficient (PCC) analysis., Results: The SAS approach correctly identified slice locations in different subjects in terms of vertebral levels. PCC between chest fat volume and chest slice fat area was maximal at the T8 level for SAT (0.97) and at the T7 level for VAT (0.86), and was modest between chest fat volume and abdominal slice fat area for SAT and VAT (0.73 and 0.75, respectively). However, correlation was weak for chest fat volume and thigh slice fat area for SAT and VAT (0.52 and 0.37, respectively), and for chest fat volume for SAT and VAT and BMI (0.65 and 0.28, respectively). These same single slice locations with maximal PCC were found for SAT and VAT within both COPD and IPF groups. Most of the attenuation properties derived from the whole chest volume and single best chest slice for VAT (but not for SAT) were significantly different between COPD and IPF groups., Conclusions: This study demonstrates a new way of optimally selecting slices whose measurements may be used as markers of similar measurements made on the whole chest volume. The results suggest that one or two slices imaged at T7 and T8 vertebral levels may be enough to estimate reliably the total SAT and VAT components of chest fat and the quality of chest fat as determined by attenuation distributions in the entire chest volume., Competing Interests: The authors have declared that no competing interests exist.

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Adults with primary graft dysfunction (PGD) after lung transplantation are at increased risk for pulmonary and functional impairment. No prior studies have described the long-term (within 1.5 years of transplant) cardiopulmonary exercise testing (CPET) results in adults with grade 3 PGD. The objective of this study was to compare the functional outcomes of lung transplant patients with and without grade 3 PGD via CPET and six-minute talk tests (6MWD)., Methods: 243 adults underwent lung transplantation between 2003 and 2010, 128 (53%) of whom underwent CPET and 6MWD within 12-18 months of transplantation. The primary measure of exposure was grade 3 PGD at 72 h, however grade 3 PGD within 72 h was also assessed. In addition, the impact of potential confounding variables was explored., Results: Approximately one-third (32%) of the 243 patients experienced grade 3 PGD within 72 h; among these, 15 (6%) had grade 3 PGD at the 72 h time point. There were no differences in CPET or 6MWD between those with and without grade 3 PGD at 72 h despite a longer length of hospital stay and lower pulmonary function. Similar results were seen for patients with and without grade 3 PGD within 72 h, with the exception of a lower heart rate on CPET., Conclusions: Participants with grade 3 PGD are able to achieve functional outcomes comparable to those without PGD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation of bronchoscopic findings, palpation and visual assessment. Central gases may not accurately represent true quality of the lungs. We report our experience using selective pulmonary vein gases to corroborate the subjective judgement., Methods: Starting, January 2012, donor lungs have been assessed by intraoperative bronchoscopy, palpation and visual judgement of lung collapse upon temporary disconnection from ventilator, central gases from the aorta and selective pulmonary vein gases. Partial pressure of oxygen (pO 2 ) <300 mmHg on FiO 2 of 1.0 was considered low. The results of the chest X-ray and last pO 2 in the intensive care unit were also collected. Post-transplant primary graft dysfunction and survival were monitored., Results: To date, 259 consecutive brain-dead donors have been assessed and 157 transplants performed. Last pO 2 in the intensive care unit was poorly correlated with intraoperative central pO 2 (Spearman's rank correlation r s = 0.29). Right inferior pulmonary vein pO 2 was associated (Mann-Whitney, P < 0.001) with findings at bronchoscopy [clean: median pO 2 443 mmHg (25th-75th percentile range 349-512) and purulent: 264 mmHg (178-408)]; palpation [good: 463 mmHg (401-517) and poor: 264 mmHg (158-434)] and visual assessment of lung collapse [good lung collapse: 429 mmHg (320-501) and poor lung collapse: 205 mmHg (118-348)]. Left inferior pulmonary pO 2 was associated (P < 0.001) with findings at bronchoscopy [clean: 419 mmHg (371-504) and purulent: 254 mmHg (206-367)]; palpation [good: 444 mmHg (400-517) and poor 282 mmHg (211-419)] and visual assessment of lung collapse [good: 420 mmHg (349-496) and poor: 246 mmHg (129-330)]. At 72 h, pulmonary graft dysfunction 2 was in 21/157 (13%) and pulmonary graft dysfunction 3 in 17/157 (11%). Ninety-day and 1-year mortalities were 6/157 (4%) and 13/157 (8%), respectively., Conclusions: Selective pulmonary vein gases provide corroborative objective support to the findings at bronchoscopy, palpation and visual assessment. Central gases do not always reflect true function of the lungs, having high false-positive rate towards the individual lower lobe gas exchange. Objective measures of donor lung function may optimize donor surgeon assessment, allowing for low pulmonary graft dysfunction rates and low 90-day and 1-year mortality., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

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

Rationale: Anecdotally, short lung transplant candidates suffer from long waiting times and higher rates of death on the waiting list compared with taller candidates., Objectives: To examine the relationship between lung transplant candidate height and waiting list outcomes., Methods: We conducted a retrospective cohort study of 13,346 adults placed on the lung transplant waiting list in the United States between 2005 and 2011. Multivariable-adjusted competing risk survival models were used to examine associations between candidate height and outcomes of interest. The primary outcome was the time until lung transplantation censored at 1 year., Measurements and Main Results: The unadjusted rate of lung transplantation was 94.5 per 100 person-years among candidates of short stature (<162 cm) and 202.0 per 100 person-years among candidates of average stature (170-176.5 cm). After controlling for potential confounders, short stature was associated with a 34% (95% confidence interval [CI], 29-39%) lower rate of transplantation compared with average stature. Short stature was also associated with a 62% (95% CI, 24-96%) higher rate of death or removal because of clinical deterioration and a 42% (95% CI, 10-85%) higher rate of respiratory failure while awaiting lung transplantation., Conclusions: Short stature is associated with a lower rate of lung transplantation and higher rates of death and respiratory failure while awaiting transplantation. Efforts to ameliorate this disparity could include earlier referral and listing of shorter candidates, surgical downsizing of substantially oversized allografts for shorter candidates, and/or changes to allocation policy that account for candidate height.

Rationale: Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction., Objectives: The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH., Methods: We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N-terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, β-thromboglobulin, and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed., Measurements and Main Results: Sixty-five patients with PAH were enrolled. The mean age was 51 years, and 86% were women. Higher vWF activity, lower high-density lipoprotein cholesterol, and higher thromboxane B2 levels were associated with worse World Health Organization functional class after adjustment for age, sex, and etiology of PAH. Higher NT-pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH, and 6-minute-walk distance., Conclusions: In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT00384865).

Rationale: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation., Objectives: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates., Methods: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively., Measurements and Main Results: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB., Conclusions: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Objective: Many transplant programs are hesitant to offer lung transplantation to patients with systemic sclerosis (SSc) due to concerns about extrapulmonary involvement that might affect survival. The aim of this study was to determine whether adults with SSc have higher 1-year mortality rates after lung transplantation compared to those with interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) not due to SSc., Methods: Using data provided by the United Network for Organ Sharing, we performed a retrospective cohort study of 229 adults with SSc, 201 with PAH, and 3,333 with ILD who underwent lung transplantation in the US between May 4, 2005 and September 14, 2012. We examined associations between diagnosis and 1-year survival after lung transplantation using stratified Cox models adjusted for recipient, donor, and procedure factors., Results: Adults with SSc undergoing lung transplantation in the US had a multivariable-adjusted 48% relative increase in the 1-year mortality rate compared to those with non-SSc-related ILD (hazard ratio 1.48 [95% confidence interval 1.01-2.17]). However, we did not detect a difference in the risk of death at 1 year between those with SSc and those with non-SSc-related PAH (hazard ratio 0.85 [95% confidence interval 0.50-1.44])., Conclusion: A diagnosis of SSc may confer an increased risk of death 1 year following lung transplantation compared to a diagnosis of ILD, but this risk is similar to that of PAH, a widely accepted indication for lung transplantation. Future work should identify modifiable risk factors that can improve transplant outcomes in this population., (© 2015, American College of Rheumatology.)

Rationale: Obesity and underweight are contraindications to lung transplantation based on their associations with mortality in studies performed before implementation of the lung allocation score (LAS)-based organ allocation system in the United States Objectives: To determine the associations of body mass index (BMI) and plasma leptin levels with survival after lung transplantation., Methods: We used multivariable-adjusted regression models to examine associations between BMI and 1-year mortality in 9,073 adults who underwent lung transplantation in the United States between May 2005 and June 2011, and plasma leptin and mortality in 599 Lung Transplant Outcomes Group study participants. We measured body fat and skeletal muscle mass using whole-body dual X-ray absorptiometry in 142 adult lung transplant candidates., Measurements and Main Results: Adjusted mortality rates were similar among normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9), and class I obese (BMI 30-34.9) transplant recipients. Underweight (BMI < 18.5) was associated with a 35% increased rate of death (95% confidence interval, 10-66%). Class II-III obesity (BMI ≥ 35 kg/m(2)) was associated with a nearly twofold increase in mortality (hazard ratio, 1.9; 95% confidence interval, 1.3-2.8). Higher leptin levels were associated with increased mortality after transplant surgery performed without cardiopulmonary bypass (P for interaction = 0.03). A BMI greater than or equal to 30 kg/m(2) was 26% sensitive and 97% specific for total body fat-defined obesity., Conclusions: A BMI of 30.0-34.9 kg/m(2) is not associated with 1-year mortality after lung transplantation in the LAS era, perhaps because of its low sensitivity for obesity. The association between leptin and mortality suggests the need to validate alternative methods to measure obesity in candidates for lung transplantation. A BMI greater than or equal to 30 kg/m(2) may no longer contraindicate lung transplantation.

Background: We aimed to determine the effects of treatment with intravenous immunoglobulin on bacterial infections in patients with hypogammaglobulinemia (HGG) after lung transplantation., Methods: We performed a randomized, double-blind, placebo-controlled two-period crossover trial of immune globulin intravenous (IVIG), 10% Purified (Gamunex, Bayer, Elkhart, IN) monthly in eleven adults who had undergone lung transplantation more than three months previously. We randomized study participants to three doses of IVIG (or 0.1% albumin solution (placebo)) given four weeks apart followed by a twelve week washout and then three doses of placebo (or IVIG). The primary outcome was the number of bacterial infections within each treatment period., Results: IVIG had no effect on the number of bacterial infections during the treatment period (3 during IVIG and 1 during placebo; odds ratio 3.5, 95% confidence interval 0.4 to 27.6, p = 0.24). There were no effects on other infections, use of antibiotics, or lung function. IVIG significantly increased trough IgG levels at all time points (least square means, 765.3 mg/dl during IVIG and 486.3 mg/dl during placebo, p<0.001). Four serious adverse events (resulting in hospitalization) occurred during the treatment periods (3 during active treatment and 1 during the placebo period, p = 0.37). Chills, flushing, and nausea occurred during one infusion of IVIG., Conclusions: Treatment with IVIG did not reduce the short-term risk of bacterial infection in patients with HGG after lung transplantation. The clinical efficacy of immunoglobulin supplementation in HGG related to lung transplantation over the long term or with recurrent infections is unknown., Trial Registration: Clinicaltrials.gov NCT00115778.

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.

This article summarizes the current literature regarding surgical interventions in pulmonary hypertension, excluding chronic thromboembolic pulmonary hypertension. The article discusses the use of atrial septostomy in patients meeting criteria as well as single, double, and heart-lung transplantation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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

Background: Lung transplantation is an effective treatment for patients with advanced lung disease. In the United States, lungs are allocated on the basis of the lung allocation score (LAS), a composite measure of transplantation urgency and utility. Clinical deteriorations result in increases to the LAS; however, whether the trajectory of the LAS has prognostic significance is uncertain., Objective: To determine whether an acute increase in the LAS before lung transplantation is associated with reduced posttransplant survival., Design: Retrospective cohort study of adult lung transplant recipients listed for at least 30 days between 4 May 2005 (LAS implementation) and 31 December 2010 in the United Network for Organ Sharing registry. An acute increase in the LAS was defined as an LAS change (LASΔ) greater than 5 units between the 30 days before and the time of transplantation. Multivariable Cox proportional hazard models were used to examine the relationship between an LASΔ >5 and posttransplant graft survival., Setting: All U.S. lung transplantation centers., Patients: 5749 lung transplant recipients., Measurements: Survival time after lung transplantation., Results: 702 (12.2%) patients experienced an LASΔ >5. These patients had significantly worse posttransplant survival (hazard ratio, 1.31 [95% CI, 1.11 to 1.54]; P = 0.001]) after adjustment for the LAS at transplantation (LAS-T) and other clinical covariates. The effect of an LASΔ >5 was independent of the LAS-T, underlying diagnosis, center volume, or donor characteristics., Limitation: Analysis was based on center-reported data., Conclusion: An acute increase in LAS before transplantation is associated with posttransplant survival after adjustment for LAS-T. Further emphasis on serial assessment of the LAS could improve the ability to offer accurate prediction of survival after transplantation., Primary Funding Source: National Institutes of Health.

Rationale: Primary 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., Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD., Methods: We 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 Results: A 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., Conclusions: We 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).

Monocyte chemotactic protein-1 (MCP-1), also known as "chemokine ligand 2" (CCL2), is a monocyte-attracting chemokine produced in lung epithelial cells. We previously reported an association of increased levels of plasma MCP-1 with primary graft dysfunction (PGD) after lung transplantation in a nested case-control study of extreme phenotypes using a multiplex platform. In this study, we sought to evaluate the role of plasma MCP-1 level as a biomarker across the full spectrum of PGD. We performed a prospective cohort study of 108 lung transplant recipients within the Lung Transplant Outcomes Group cohort. Plasma MCP-1 levels were measured pretransplantation and 6 and 24 hours after transplantation. The primary outcome was development of grade 3 PGD within 72 hours of transplant, with secondary analyses at the 72-hour time point. Multivariable logistic regression was used to evaluate confounding. Thirty subjects (28%) developed PGD. Median MCP-1 measured at 24 hours post-transplant was elevated in subjects with PGD (167.95 vs 103.5 pg/mL, P = .04). MCP-1 levels at 24 hours were associated with increased odds of grade 3 PGD after lung transplantation (odds ratio for each 100 pg/mL, 1.24; 95% confidence interval, 1.00-1.53) and with grade 3 PGD present at the 72-hour time point (odds ratio for each 100 pg/mL, 1.57; 95% confidence interval, 1.18-2.08), independent of confounding variables in multivariable analyses. MCP-1 levels measured preoperatively and 6 hours after transplant were not significantly associated with PGD. Persistent elevations in MCP-1 levels at 24 hours are a biomarker of grade 3 PGD post-transplantation. Monocyte chemotaxis may play a role in the pathogenesis of PGD., (Copyright © 2012 Mosby, Inc. All rights reserved.)

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.

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

Background: Primary graft dysfunction (PGD) frequently complicates lung transplantation in the immediate postoperative period. Both female gender and estradiol modulate the body's response to injury and can influence the rate of alveolar fluid clearance., Objective: We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation., Methods: We measured plasma estradiol levels preoperatively, 6 hours postoperatively, and 24 hours postoperatively in a cohort of 111 lung transplant recipients at 2 institutions., Results: Mean age was 57 years (12.5) and 52% were female. Median postoperative estradiol level was 63.9 pg/mL (interquartile range, 28.8-154.3 pg/mL) in male and 65.1 pg/mL (interquartile range, 28.4-217.2 pg/mL) in female patients. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in male patients (P = 0.001). This association was preserved when accounting for other factors known to be associated with PGD. However, there was no relationship between gender and risk of PGD or between estradiol levels and PGD in females., Conclusion: These findings suggest that there might be different biologic effects of estrogens in males and females, and highlight the importance of considering gender differences in future studies of PGD., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

In 2010, 1770 lung transplant procedures were performed in the USA, yet 2469 new candidates were added to the waiting list the same year. The shortage of suitable donor lungs requires that transplant professionals select patients for lung transplantation only if they are likely to sustain a survival benefit from the procedure. However, 20% of lung transplant recipients die within the first year of transplantation, suggesting that we are failing to identify those at high risk for severe early complications. In this perspective, we review the current guidelines for the selection of lung transplant candidates, which are based largely on expert opinion and small case series. We also propose the study of new extrapulmonary factors, such as frailty and sarcopenia, that might help improve the prediction of complications and early death after lung transplantation, leading to an improved candidate selection process.

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.