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).

Cell-Free DNA Maps Tissue Injury and Correlates with Disease Severity in Lung Transplant Candidates.

Rationale: Plasma cell-free DNA levels correlate with disease severity in many conditions. Pretransplant cell-free DNA may risk stratify lung transplant candidates for post-transplant complications. Objectives: To evaluate if pretransplant cell-free DNA levels and tissue sources identify patients at high risk of primary graft dysfunction and other pre- and post-transplant outcomes. Methods: This multicenter, prospective cohort study recruited 186 lung transplant candidates. Pretransplant plasma samples were collected to measure cell-free DNA. Bisulfite sequencing was performed to identify the tissue sources of cell-free DNA. Multivariable regression models determined the association between cell-free DNA levels and the primary outcome of primary graft dysfunction and other transplant outcomes, including Lung Allocation Score, chronic lung allograft dysfunction, and death. Measurements and Main Results: Transplant candidates had twofold greater cell-free DNA levels than healthy control patients (median [interquartile range], 23.7 ng/ml [15.1-35.6] vs. 12.9 ng/ml [9.9-18.4]; P < 0.0001), primarily originating from inflammatory innate immune cells. Cell-free DNA levels and tissue sources differed by native lung disease category and correlated with the Lung Allocation Score (P < 0.001). High pretransplant cell-free DNA increased the risk of primary graft dysfunction (odds ratio, 1.60; 95% confidence interval [CI], 1.09-2.46; P = 0.0220), and death (hazard ratio, 1.43; 95% CI, 1.07-1.92; P = 0.0171) but not chronic lung allograft dysfunction (hazard ratio, 1.37; 95% CI, 0.97-1.94; P = 0.0767). Conclusions: Lung transplant candidates demonstrate a heightened degree of tissue injury with elevated cell-free DNA, primarily originating from innate immune cells. Pretransplant plasma cell-free DNA levels predict post-transplant complications.

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).

Elevated cell-free DNA in respiratory viral infection and associated lung allograft dysfunction.

Respiratory viral infection (RVI) in lung transplant recipients (LTRs) is a risk for chronic lung allograft dysfunction (CLAD). We hypothesize that donor-derived cell-free DNA (%ddcfDNA), at the time of RVI predicts CLAD progression. We followed 39 LTRs with RVI enrolled in the Genomic Research Alliance for Transplantation for 1 year. Plasma %ddcfDNA was measured by shotgun sequencing, with high %ddcfDNA as ≥1% within 7 days of RVI. We examined %ddcfDNA, spirometry, and a composite (progression/failure) of CLAD stage progression, re-transplant, and death from respiratory failure. Fifty-nine RVI episodes, 38 low and 21 high %ddcfDNA were analyzed. High %ddcfDNA subjects had a greater median %FEV1 decline at RVI (-13.83 vs. -1.83, p = .007), day 90 (-7.97 vs. 0.91, p = .04), and 365 (-20.05 vs. 1.09, p = .047), compared to those with low %ddcfDNA and experienced greater progression/failure within 365 days (52.4% vs. 21.6%, p = .01). Elevated %ddcfDNA at RVI was associated with an increased risk of progression/failure adjusting for symptoms and days post-transplant (HR = 1.11, p = .04). No difference in %FEV1 decline was seen at any time point when RVIs were grouped by histopathology result at RVI. %ddcfDNA delineates LTRs with RVI who will recover lung function and who will experience sustained decline, a utility not seen with histopathology.

Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant.

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.

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.

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.

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.

T-bet:Eomes balance, effector function, and proliferation of cytomegalovirus-specific CD8+ T cells during primary infection differentiates the capacity for durable immune control.

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

Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.

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.

Lung transplantation in telomerase mutation carriers with pulmonary fibrosis.

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the U.S.A., Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients.

Clinical risk factors for primary graft dysfunction after lung transplantation.

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).

Domperidone for delayed gastric emptying in lung transplant recipients with and without gastroesophageal reflux.

Evidence demonstrates a link between gastroesophageal reflux disease and chronic allograft dysfunction in lung transplant recipients. Delayed gastric emptying plays an important role in the occurrence of gastroesophageal reflux disease, with limited therapeutic options available for treatment. This retrospective observational study reports the use of domperidone in the management of delayed gastric emptying in lung transplant recipients. All patients who underwent lung transplant at our institution from 2007 to 2011 were reviewed and patients who were treated with domperidone were identified. Clinical symptoms and results of gastric emptying studies before and after initiation of domperidone were documented. QTc intervals were compared from before to after domperidone treatment at 3 months and at 1 year. Weight and dose-normalized calcineurin inhibitor troughs were evaluated before and 2 weeks after domperidone treatment was started. Of 82 patients, 24% (n = 20) had documented delayed gastric emptying and 35% (n = 29) had documented gastroesophageal reflux disease. Twelve of the 20 patients with delayed gastric emptying started treatment with domperidone. All patients responded symptomatically and 6 patients with gastric emptying studies before and after domperidone had documented improvement. No adverse effects were observed in any patients treated with domperidone. Results indicate that domperidone can be used safely and may improve symptoms related to delayed gastric emptying in lung transplant recipients.

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.

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.

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.

Variation in PTX3 is associated with primary graft dysfunction after lung transplantation.

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.

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.

Supranormal expiratory airflow after bilateral lung transplantation is associated with improved survival.

RATIONALE: flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern). OBJECTIVES: characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival. METHODS: we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50) > 1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern. MEASUREMENTS AND MAIN RESULTS: the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009). CONCLUSIONS: the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests potential therapeutic approaches to improve outcomes in BLT/HLT patients.