Baseline Lung Allograft Dysfunction After Bilateral Lung Transplantation Is Associated With an Increased Risk of Death: Results From a Multicenter Cohort Study.

Background: A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. Methods: This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. Results: BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; P = 0.15). Conclusions: BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.

Extreme elevations of donor-derived cell-free DNA increases the risk of chronic lung allograft dysfunction and death, even without clinical manifestations of disease.

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

Higher Molecular Injury at Diagnosis of Acute Cellular Rejection Increases the Risk of Lung Allograft Failure: A Clinical Trial.

Rationale: The association of acute cellular rejection (ACR) with chronic lung allograft dysfunction (CLAD) in lung transplant recipients has primarily been described before consensus recommendations incorporating restrictive phenotypes. Furthermore, the association of the degree of molecular allograft injury during ACR with CLAD or death remains undefined. Objectives: To investigate the association of ACR with the risk of CLAD or death and to further investigate if this risk depends on the degree of molecular allograft injury. Methods: This multicenter, prospective cohort study included 188 lung transplant recipients. Subjects underwent serial plasma collections for donor-derived cell-free DNA (dd-cfDNA) at prespecified time points and bronchoscopy. Multivariable Cox proportional-hazards analysis was conducted to analyze the association of ACR with subsequent CLAD or death as well as the association of dd-cfDNA during ACR with risk of CLAD or death. Additional outcomes analyses were performed with episodes of ACR categorized as "high risk" (dd-cfDNA ⩾ 1%) and "low risk" (dd-cfDNA < 1%). Measurements and Main Results: In multivariable analysis, ACR was associated with the composite outcome of CLAD or death (hazard ratio [HR], 2.07 [95% confidence interval (CI), 1.05-4.10]; P = 0.036). Elevated dd-cfDNA ⩾ 1% at ACR diagnosis was independently associated with increased risk of CLAD or death (HR, 3.32; 95% CI, 1.31-8.40; P = 0.012). Patients with high-risk ACR were at increased risk of CLAD or death (HR, 3.13; 95% CI, 1.41-6.93; P = 0.005), whereas patients with low-risk status ACR were not. Conclusions: Patients with ACR are at higher risk of CLAD or death, but this may depend on the degree of underlying allograft injury at the molecular level. Clinical trial registered with www.clinicaltrials.gov (NCT02423070).

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

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

Organizing pneumonia is associated with molecular allograft injury and the development of antibody-mediated rejection.

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

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories.

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

The effect of the cystic fibrosis care center on outcomes after lung transplantation for cystic fibrosis.

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

Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study.

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

Risk of primary graft dysfunction following lung transplantation in selected adults with connective tissue disease-associated interstitial lung disease.

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.

Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation.

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

Selection of Candidates for Lung Transplantation and Controversial Issues.

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

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury.

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.

Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.

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

Impaired Renal Function Should Not Be a Barrier to Transplantation in Patients With Cystic Fibrosis.

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

Clinical Risk Factors and Prognostic Model for Primary Graft Dysfunction after Lung Transplantation in Patients with Pulmonary Hypertension.

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 PaO2/FiO2 ≤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.

IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control.

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

Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients.

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

Serial monitoring of exhaled nitric oxide in lung transplant recipients.

BACKGROUND: Exhaled nitric oxide (FeNO), a marker of airway inflammation, is often elevated in lung transplant recipients (LTxRs) with acute rejection or infection. Isolated measurements in the setting of bronchiolitis obliterans syndrome have been variable. We sought to assess the utility of serial FeNO in predicting chronic allograft dysfunction or the presence of acute rejection or infection. METHODS: Eighty-six LTxRs underwent 325 serial FeNO measurements at an expiratory flow rate of 50 ml/s. The change in FeNO (ΔFeNO) between two measurements obtained during a stable state (ΔFeNO-SS) was compared with ΔFeNO, where the first measurement was taken during a stable state and the second during an unstable state (defined as a subsequent decline in FEV1 > 10% over 3 months [ΔFeNO-SU]) or an acute complication (acute rejection, lymphocytic bronchiolitis or acute infection [ΔFeNO-SAC]). The median follow-up time after the baseline FeNO was 10 (range 3 to 25) months. RESULTS: ΔFeNO-SS in 117 FeNO pairs was similar to ΔFeNO-SU in 26 pairs (2.1 ± 3 ppb vs 2.3 ± 4 ppb; p = 0.2). ΔFeNO-SAC in 17 pairs was markedly increased (27 ± 20 ppb; p < 0.001 vs ΔFeNO-SS). The area under the receiver-operating characteristic curve for ΔFeNO in detecting an acute complication was 0.93 (p < 0.001). By applying a cut-off of >10 ppb, the sensitivity and specificity was 82% and 100%, respectively, with positive and negative predictive values of 100% and 97.5%. CONCLUSIONS: Changes in FeNO may serve as a useful adjunct in the detection of acute complications after lung transplantation. In this limited analysis, ΔFeNO was not predictive of a subsequent decline in allograft function.

Lung size mismatch and primary graft dysfunction after bilateral lung transplantation.

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