Implications of High Sensitivity Troponin Levels After Lung Transplantation.

Trends in high-sensitivity cardiac troponin I (hs-cTnI) after lung transplant (LT) and its clinical value are not well stablished. This study aimed to determine kinetics of hs-cTnI after LT, factors impacting hs-cTnI and clinical outcomes. LT recipients from 2015 to 2017 at Toronto General Hospital were included. Hs-cTnI levels were collected at 0-24 h, 24-48 h and 48-72 h after LT. The primary outcome was invasive mechanical ventilation (IMV) >3 days. 206 patients received a LT (median age 58, 35.4% women; 79.6% double LT). All patients but one fulfilled the criteria for postoperative myocardial infarction (median peak hs-cTnI = 4,820 ng/mL). Peak hs-cTnI correlated with right ventricular dysfunction, >1 red blood cell transfusions, bilateral LT, use of EVLP, kidney function at admission and time on CPB or VA-ECMO. IMV>3 days occurred in 91 (44.2%) patients, and peak hs-cTnI was higher in these patients (3,823 vs. 6,429 ng/mL, p < 0.001 after adjustment). Peak hs-cTnI was higher among patients with had atrial arrhythmias or died during admission. No patients underwent revascularization. In summary, peak hs-TnI is determined by recipient comorbidities and perioperative factors, and not by coronary artery disease. Hs-cTnI captures patients at higher risk for prolonged IMV, atrial arrhythmias and in-hospital death.

Association between cytomegalovirus viremia and long-term outcomes in lung transplant recipients.

Although cytomegalovirus (CMV) viremia/DNAemia has been associated with reduced survival after lung transplantation, its association with chronic lung allograft dysfunction (CLAD) and its phenotypes is unclear. We hypothesized that, in a modern era of CMV prophylaxis, CMV DNAemia would still remain associated with death, but also represent a risk factor for CLAD and specifically restrictive allograft syndrome (RAS)/mixed phenotype. This was a single-center retrospective cohort study of all consecutive adult, first, bilateral-/single-lung transplants done between 2010-2016, consisting of 668 patients. Risks for death/retransplantation, CLAD, or RAS/mixed, were assessed by adjusted cause-specific Cox proportional-hazards models. CMV viral load (VL) was primarily modeled as a categorical variable: undetectable, detectable to 999, 1000 to 9999, and ≥10 000 IU/mL. In multivariable models, CMV VL was significantly associated with death/retransplantation (≥10 000 IU/mL: HR = 2.65 [1.78-3.94]; P < .01), but was not associated with CLAD, whereas CMV serostatus mismatch was (D+R-: HR = 2.04 [1.30-3.21]; P < .01). CMV VL was not associated with RAS/mixed in univariable analysis. Secondary analyses with a 7-level categorical or 4-level ordinal CMV VL confirmed similar results. In conclusion, CMV DNAemia is a significant risk factor for death/retransplantation, but not for CLAD or RAS/mixed. CMV serostatus mismatch may have an impact on CLAD through a pathway independent of DNAemia.

Intra-subject variability in oscillometry correlates with acute rejection and CLAD post-lung transplant.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death post-lung transplantation, with acute cellular rejection (ACR) being the biggest contributing risk factor. Although patients are routinely monitored with spirometry, FEV1 is stable or improving in most ACR episodes. In contrast, oscillometry is highly sensitive to respiratory mechanics and shown to track graft injury associated with ACR and its improvement following treatment. We hypothesize that intra-subject variability in oscillometry measurements correlates with ACR and risk of CLAD. Methods: Of 289 bilateral lung recipients enrolled for oscillometry prior to laboratory-based spirometry between December 2017 and March 2020, 230 had ≥ 3 months and 175 had ≥ 6 months of follow-up. While 37 patients developed CLAD, only 29 had oscillometry at time of CLAD onset and were included for analysis. These 29 CLAD patients were time-matched with 129 CLAD-free recipients. We performed multivariable regression to investigate the associations between variance in spirometry/oscillometry and the A-score, a cumulative index of ACR, as our predictor of primary interest. Conditional logistic regression models were built to investigate associations with CLAD. Results: Multivariable regression showed that the A-score was positively associated with the variance in oscillometry measurements. Conditional logistic regression models revealed that higher variance in the oscillometry metrics of ventilatory inhomogeneity, X5, AX, and R5-19, was independently associated with increased risk of CLAD (p < 0.05); no association was found for variance in %predicted FEV1. Conclusion: Oscillometry tracks graft injury and recovery post-transplant. Monitoring with oscillometry could facilitate earlier identification of graft injury, prompting investigation to identify treatable causes and decrease the risk of CLAD.

Pulmonary epithelial markers in phenotypes of chronic lung allograft dysfunction.

BACKGROUND: Airway epithelial injury is thought to be a key event in the pathogenesis of chronic lung allograft dysfunction (CLAD). We investigated whether markers of epithelial activity and injury in bronchoalveolar lavage fluid (BAL) correlate with CLAD diagnosis and major CLAD phenotypes: bronchiolitis obliterans syndrome (BOS) vs restrictive allograft syndrome (RAS)-related phenotypes (including RAS, mixed phenotype, and all other patients with RAS-like opacities). METHODS: CLAD status and phenotypes were retrospectively determined in a cohort of all consecutive adult, first, bilateral lung transplants performed 2010-2015, with available BAL samples. All patients with RAS-related phenotypes were included and 1:1 matched with BOS patients based on the time from transplant to CLAD-onset. Subjects who were CLAD-free for a minimum of 3 years post-transplant were 1:1 matched to CLAD patients and included as controls. Proteins that maintain the barrier function of the airway epithelial mucosa (club cell secretory protein, surfactant protein-D and epithelial mucins: MUC1, MUC5AC, MUC5B, MUC16), as well as epithelial cell death markers (M30&M65 representing epithelial cell apoptosis and overall death, respectively), were measured in BAL obtained within 6-months post CLAD onset using a double-sandwich ELISA or a multiplex bead assay. Protein levels were compared using Mann-Whitney-U-test. Association between protein levels and graft survival was assessed using Cox proportional hazards models, adjusted for CMV serology mismatch status and CLAD phenotype. RESULTS: Fifty-four CLAD (27 BOS, 11 RAS, 7 mixed, 9 others with RAS-like opacities) patients and 23 CLAD-free controls were included. Median BAL levels were significantly higher in patients with CLAD compared to CLAD-free controls for M30 (124.5 vs 88.7 U/L), MUC1 (6.8 vs 3.2 pg/mL), and MUC16 (121.0 vs 30.1 pg/mL). When comparing CLAD phenotypes, M30 was significantly higher in patients with RAS-related phenotypes than BOS (160.9 vs 114.6 U/L). In multivariable models, higher M30 and MUC5B levels were associated with decreased allograft survival after CLAD onset independent of phenotype (p < 0.05 for all). CONCLUSIONS: Airway epithelial mucins and cell death markers are enhanced in the BAL of patients with CLAD and can assist in differentiating between CLAD phenotypes and post-CLAD outcomes. Abnormal airway mucin expression and epithelial cell death may be involved in the pathogenesis of CLAD, and therefore their detection may aid in future selection of targeted therapies.

Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-ß1 (transforming growth factor-ß1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2, in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.

Donor and recipient human leukocyte antigen-G polymorphisms modulate the risk of adverse immunologic events following lung transplantation.

The long-term benefits of lung transplantation (LTx) are limited by pathogenic alloimmune responses that drive injury, inflammation, and chronic dysfunction. Human leukocyte antigen-G (HLA-G) plays a key role in the modulation of these pathways. This study assesses the impact of the HLA-G genotype on immunologic risk and survival following LTx. This retrospective cohort study included 289 bilateral LTx. Recipient and donor HLA-G genotypes were analyzed to identify associations with de novo donor-specific antibodies, acute rejection, chronic lung allograft dysfunction, and allograft survival. We further assessed these associations, both individually and in paired analysis, based on a grouped haplotype classification of HLA-G expression. Donor HLA-G single nucleotide polymorphisms were associated with allograft injury, the onset of chronic lung allograft dysfunction following injury, and allograft survival. Recipient HLA-G single nucleotide polymorphisms were associated with allograft injury, cellular rejection, and donor-specific antibody formation. "Low HLA-G expression" donor haplotypes were associated with impaired allograft survival, as were "low HLA-G expression" donor-recipient haplotype pairs. This study provides compelling evidence for the role of HLA-G in modulating immunologic risk after LTx. Our results highlight the importance of both donor and recipient HLA-G genotypes on the overall risk profile and underscore the lasting influence of donor genotype on lung transplant outcomes.

Strongyloides hyper-infection in a lung transplant recipient: Case report and review of the literature.

CASE PRESENTATION: A 63-year-old man with a left single lung transplant for end-stage combined restrictive and obstructive lung disease developed persistent pulmonary infiltrates and recurrent gram-negative bacteremia post-transplant. Bronchoalveolar lavage fluid revealed a nematode on Papanicolau staining compatible with Strongyloides stercoralis larvae on day 50 post-transplant. Although Strongyloides serology performed post-transplant was negative, a retrospective review of the medical record revealed marked peripheral blood eosinophilia on several occasions before transplantation. Despite reduction in immunosuppression and treatment with albendazole and ivermectin, the patient developed another episode of Escherichia coli bacteremia. He died 3 months post-transplant from pulmonary and neurological complications. DIAGNOSIS: Strongyloides hyper-infection. DISCUSSION: Strongyloides hyper-infection syndrome is known to occur in immunocompromised patients, but it has only been reported once in a lung transplant recipient. This case illustrates the importance of screening for parasitic infections before transplantation in patients with marked eosinophilia, especially among immigrants from countries in which Strongyloides is endemic. Hyper-infection syndrome may appear years after infection in the context of immunosuppression or immunodeficiency. This case also highlights the association between Strongyloides hyper-infection and bacteremia with enteric organisms.

PRÉSENTATION DU CAS: Un homme de 63 ans ayant subi une transplantation du poumon gauche à cause d'une pneumopathie en phase terminale à la fois restrictive et obstructive a développé des infiltrats pulmonaires persistants et une bactériémie à Gram négatif récurrente après la transplantation. À la coloration de Papanicolau, le liquide du lavage bronchoalvéolaire a révélé un nématode compatible avec des larves de Strongyloides stercoralis le cinquantième jour après la transplantation. Même si la sérologie du Strongyloides effectuée après la transplantation était négative, une analyse rétrospective de son dossier médical a révélé une éosinophilie sanguine périphérique marquée à plusieurs occasions avant la transplantation. Malgré la diminution de l'immunodépression et un traitement à l'albendazole et à l'ivermectine, le patient a contracté une nouvelle bactériémie à Escherichia coli. Il est décédé de complications pulmonaires et neurologiques trois mois après la transplantation. DIAGNOSTIC: Hyperinfestation à Strongyloides. DISCUSSION: On sait que le syndrome d'hyperinfestation à Strongyloides se déclare chez des patients immunodéprimés, mais il n'a été signalé qu'une fois chez un transplanté du poumon. Ce cas démontre l'importance du dépistage d'infections parasitaires avant la transplantation chez des patients atteints d'éosinophilie marquée, notamment chez des immigrants de pays où le Strongyloides est endémique. Le syndrome d'hyperinfestation peut se manifester des années après l'infection en cas d'immunodépression ou d'immunodéficience. Ce cas fait également ressortir l'association entre l'hyperinfestation à Strongyloides et la bactériémie causée par des organismes entériques.

The Association Between Extravascular Lung Water and Critical Care Outcomes Following Bilateral Lung Transplantation.

Primary graft dysfunction (PGD) is a form of acute respiratory failure that complicates 30% of bilateral lung transplants. Higher grades of PGD correlate with higher severity of respiratory failure and unfavorable outcomes. Immediate PGD determination posttransplant' however, is not always predictive of PGD over subsequent days or intensive care unit outcomes. We aimed to evaluate whether extravascular lung water index (ELWI) measured immediately post bilateral lung transplant was associated with higher severity of PGD at 72 h and duration of mechanical ventilation. Methods: We conducted a prospective, observational study of bilateral lung transplant patients admitted to the intensive care unit. ELWI measurements were performed at admission, 6, 12, 24, 36, 48, 60, and 72 h following transplant or until extubation. We evaluated the association between admission ELWI and 72-h PGD grade and duration of mechanical ventilation. Results: Across 56 patients enrolled, 268 transpulmonary thermodilution measurements were conducted. At admission, median ELWI increased with PGD grade (grade 1: 9 mL/kg [interquartile range (IQR), 8-11 mL/kg]' grade 2 [10 mL/kg (IQR, 8-12 mL/kg)]' and grade 3 [17 mL/kg (IQR, 14-19 mL/kg); P < 0.001]). Using multivariable Poisson regression analysis adjusting for confounders, admission ELWI elevation was associated with higher severity of PGD at 72 h (incidence rate ratio [IRR], 1.06; 95% confidence interval, 1.01-1.12) and duration of mechanical ventilation (IRR, 1.62; 95% confidence interval, 1.23-2.14). The combination of an ELWI of ≥13 mL/kg and partial pressure of oxygen/fraction of inspired oxygen ≤ 100 within 6 h of admission had high sensitivity (75%) and specificity (100%) for grade 3 PGD at 72 h (area under the curve, 0.95) and performed better than ELWI or partial pressure of oxygen/fraction of inspired oxygen alone. Conclusions: Our exploratory study demonstrates an association between admission ELWI and high grades of PGD at 72 h and longer duration of ventilation. These results provide the impetus to study whether goal-directed ELWI algorithms can improve transplant outcomes.

Phenotyping CLAD after single lung transplant: Limits and prognostic assessment of the 2019 ISHLT classification system.

BACKGROUND: Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) is challenging, due to the native lung contribution to pulmonary function test (PFT). We aimed to assess the applicability and prognostic performance of International Society for Heart and Lung Transplantation (ISHLT) classification in SLTX. METHODS: In this retrospective study of adult, first, SLTX performed 2009-2017, patients with persistent drop in FEV1≥20% were assessed by 2 independent adjudicators to determine CLAD status and phenotype. Interobserver agreement (IOA) was calculated (Cohen's Kappa) for CLAD, phenotype and presence of RAS (resttrictive allograft syndrome)-like opacities (RLO). Association of CLAD phenotypes with time to death or retransplant (ReTx), adjusted for age at SLTX, sex, CMV mismatch and native lung condition, were assessed using Cox proportional hazards models. RESULTS: Of 172 SLTX recipients, 92 experienced a persistent drop in FEV1>20%. Following adjudication, 67 were diagnosed with CLAD. We noted a moderate IOA for CLAD diagnosis (Kappa 0.69) and poor IOA for phenotype adjudication (Kappa 0.52). The final phenotype adjudication was 31 bronchiolitis obliterans syndrome (BOS) (46.3%), 13 RAS (19.4%), 2 mixed (3%), 2 Undefined (3%), and 19 remained Unclassified (28.3%). Using these adjudicated phenotypes, RAS was significantly associated with a higher risk of death/ReTx compared to other groups (HR 2.98, 95%CI [1.39-6.4]). The adjudication of RLO had the best IOA (Kappa 0.73). The presence of RLO was a strong predictor of death or ReTx (HR 2.37, 95%CI [1.2-4.5]), regardless of the final phenotype. CONCLUSIONS: PFT interpretation is challenging in SLTX. A classification essentially relying on imaging, which harbored good IOA, obtained better prognostic performance than a classification using published physiological cut-offs.

Diffusing capacity of the lung for carbon monoxide: association with long-term outcomes after lung transplantation in a 20-year longitudinal study.

RATIONALE: The diffusing capacity of the lung for carbon monoxide corrected for haemoglobin (D LCOcor) measures gas movement across the alveolar-capillary interface. We hypothesised that D LCOcor is a sensitive measure of injurious allograft processes disrupting this interface. OBJECTIVES: To determine the prognostic significance of the D LCOcor trajectory on chronic lung allograft dysfunction (CLAD) and survival. METHODS: A retrospective analysis was conducted of all bilateral lung transplant recipients at a single centre, between January 1998 and January 2018, with one or more D LCOcor measurements. Low baseline D LCOcor was defined as the failure to achieve a D LCOcor >75% predicted. Drops in D LCOcor were defined as >15% below recent baseline. RESULTS: 1259 out of 1492 lung transplant recipients were included. The median (range) time to peak D LCOcor was 354 (181-737) days and the mean±sd D LCOcor was 80.2±21.2% pred. Multivariable analysis demonstrated that low baseline D LCOcor was significantly associated with death (hazrd ratio (HR) 1.68, 95% CI 1.27-2.20; p<0.001). Low baseline D LCOcor was not independently associated with CLAD after adjustment for low baseline forced expiratory volume in 1 s or forced vital capacity. Any D LCOcor declines ≥15% were significantly associated with death, independent of concurrent spirometric decline. Lower percentage predicted D LCOcor values at CLAD onset were associated with shorter post-CLAD survival (HR 0.75 per 10%-unit change, p<0.01). CONCLUSION: Low baseline D LCOcor and post-transplant declines in D LCOcor were significantly associated with survival, independent of spirometric measurements. We propose that D LCOcor testing may allow identification of a subphenotype of baseline and chronic allograft dysfunction not captured by spirometry. There may be benefit in routine monitoring of D LCOcor after lung transplantation to identify patients at risk of poor outcomes.

Inhibition of Vascular Endothelial Growth Factor Receptors 1 and 2 Attenuates Natural Killer Cell and Innate Immune Responses in an Experimental Model for Obliterative Bronchiolitis.

Obliterative bronchiolitis (OB) after lung transplantation is a nonreversible, life-threatening complication. Herein, the role of vascular endothelial growth factor receptor (Vegfr)-1 and -2 was investigated in the development of obliterative airway disease (OAD), an experimental model for OB. The nonimmunosuppressed recipients underwent transplantation with fully major histocompatibility complex mismatched heterotopic tracheal allografts and received Vegfr1 and -2-specific monoclonal antibodies either alone or in combination, or rat IgG as a control. The treatment with Vegfr1- or -2-blocking antibody significantly decreased intragraft mRNA expression of natural killer cell activation markers early after transplantation. This was followed by reduced infiltration of Cd11b+ cells and Cd4+ T cells as well as down-regulated mRNA expression of proinflammatory chemokines and profibrotic growth factors. However, blocking of both Vegfr1 and -2 was necessary to reduce luminal occlusion. Furthermore, concomitant inhibition of the calcineurin activation pathway almost totally abolished the development of OAD. This study proposes that blocking of Vegf receptors blunted natural killer cell and innate immune responses early after transplantation and attenuated the development of OAD. The results of this study suggest that further studies on the role of Vegfr1 and -2 blocking in development of obliterative airway lesions might be rewarding.

Postoperative Management of Lung Transplant Recipients in the Intensive Care Unit.

The number of lung transplantations is progressively increasing worldwide, providing new challenges to interprofessional teams and the intensive care units. The outcome of lung transplantation recipients is critically affected by a complex interplay of particular pathophysiologic conditions and risk factors, knowledge of which is fundamental to appropriately manage these patients during the early postoperative course. As high-grade evidence-based guidelines are not available, the authors aimed to provide an updated review of the postoperative management of lung transplantation recipients in the intensive care unit, which addresses six main areas: (1) management of mechanical ventilation, (2) fluid and hemodynamic management, (3) immunosuppressive therapies, (4) prevention and management of neurologic complications, (5) antimicrobial therapy, and (6) management of nutritional support and abdominal complications. The integrated care provided by a dedicated multidisciplinary team is key to optimize the complex postoperative management of lung transplantation recipients in the intensive care unit.

Chronic lung allograft dysfunction phenotype and prognosis by machine learning CT analysis.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the principal cause of graft failure in lung transplant recipients and prognosis depends on CLAD phenotype. We used a machine learning computed tomography (CT) lung texture analysis tool at CLAD diagnosis for phenotyping and prognostication compared with radiologist scoring. METHODS: This retrospective study included all adult first double lung transplant patients (January 2010-December 2015) with CLAD (censored December 2019) and inspiratory CT near CLAD diagnosis. The machine learning tool quantified ground-glass opacity, reticulation, hyperlucent lung and pulmonary vessel volume (PVV). Two radiologists scored for ground-glass opacity, reticulation, consolidation, pleural effusion, air trapping and bronchiectasis. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of machine learning and radiologist for CLAD phenotype. Multivariable Cox proportional hazards regression analysis for allograft survival controlled for age, sex, native lung disease, cytomegalovirus serostatus and CLAD phenotype. RESULTS: 88 patients were included (57 bronchiolitis obliterans syndrome (BOS), 20 restrictive allograft syndrome (RAS)/mixed and 11 unclassified/undefined) with CT a median 9.5 days from CLAD onset. Radiologist and machine learning parameters phenotyped RAS/mixed with PVV as the strongest indicator (area under the curve (AUC) 0.85). Machine learning hyperlucent lung phenotyped BOS using only inspiratory CT (AUC 0.76). Radiologist and machine learning parameters predicted graft failure in the multivariable analysis, best with PVV (hazard ratio 1.23, 95% CI 1.05-1.44; p=0.01). CONCLUSIONS: Machine learning discriminated between CLAD phenotypes on CT. Both radiologist and machine learning scoring were associated with graft failure, independent of CLAD phenotype. PVV, unique to machine learning, was the strongest in phenotyping and prognostication.

Lung transplantation for acute respiratory distress syndrome: a retrospective European cohort study.

BACKGROUND: The published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres. METHODS: We conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of "ARDS/pneumonia" were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed. RESULTS: 55 centres (81%) with a total transplant activity of 12 438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35 years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015-2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977-55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation. CONCLUSIONS: Lung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.

Connective-Tissue Growth Factor Contributes to TGF-ß1-induced Lung Fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and in the lung. Connective-tissue growth factor (CTGF) exacerbates pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we demonstrate upregulation of CTGF in a rat lung fibrosis model induced by an adenovirus vector encoding active TGF-ß1 (AdTGF-ß1). We show that CTGF is also upregulated in patients with idiopathic pulmonary fibrosis. Expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on Days 7 and 14 as well as endothelial cells sorted from fibrotic lungs on Days 14 and 28. These findings suggest contributions of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-ß increases profibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-ß in inducing pulmonary fibrosis. Also, the fibrotic extracellular matrix upregulated CTGF expression, compared with the normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for treatment of pulmonary fibrosis.

Significance of phenotype change after chronic lung allograft dysfunction onset.

Definitions for chronic lung allograft dysfunction (CLAD) phenotypes were recently revised (2019 ISHLT consensus). Post-CLAD onset phenotype transition may occur as a result of change in obstruction, restriction, or RAS-like opacities (RLO). We aimed to assess the prevalence and prognostic implications of these transitions. This was a single-center, retrospective cohort study of bilateral lung transplants performed in 2009-2015. CLAD phenotypes were determined per ISHLT guidelines. CLAD phenotype transition was defined as a sustained change in obstruction, restriction or RLO. We specifically focused on phenotype changes based on RLO emergence. Association of RLO development with time to death or retransplant were assessed using Kaplan-Meier and Cox proportional hazards models. Among 211 patients with CLAD, 47 (22.2%) experienced a phenotype transition. Nineteen patients developed RLO. Development of RLO phenotype after CLAD onset was associated with a shorter time to death/retransplant when considering the entire CLAD patient cohort (HR = 4.00, CI 2.74-5.83, P < 0.001) and also when restricting the analysis to only patients with a Non-RLO phenotype at CLAD onset (HR 9.64, CI 5.52-16.84, P < 0.0001). CLAD phenotype change based on emergence of RAS-like opacities implies a worse outcome. This highlights the clinical importance of imaging follow-up to monitor for phenotype transitions after CLAD onset.

Bronchoalveolar lavage cytokine-based risk stratification of minimal acute rejection in clinically stable lung transplant recipients.

BACKGROUND: Acute cellular rejection (ACR) remains the most significant risk factor for chronic lung allograft dysfunction (CLAD). While clinically significant or higher-grade (≥A2) ACR is generally treated with augmented immunosuppression (IS), the management of clinically stable grade A1 ACR remains controversial. At our center, patients with clinically stable grade A1 ACR are routinely not treated with augmented IS. While the overall outcomes in this group of patients at our center are equivalent to patients with stable A0 pathology, CLAD and death rates remain overall high. We hypothesized that a distinct cytokine signature at the time of early minimal rejection state would be associated with worse outcomes. Specifically, we aimed to determine whether bronchoalveolar lavage (BAL) biomarkers at the time of first clinically stable grade A1 ACR (CSA1R) are predictive of subsequent CLAD or death. METHODS: Among all adult, bilateral, first lung transplants, performed 2010-2016, transbronchial biopsies obtained within the first-year post-transplant were categorized as clinically stable or unstable based on the presence or absence of ≥10% concurrent drop in forced expiratory volume in 1 second (FEV1). We assessed BAL samples obtained at the time of CSA1R episodes, which were not preceded by another ACR (i.e., first episodes). Twenty-one proteins previously associated with ACR or CLAD were measured in the BAL using a multiplex bead assay. Association between protein levels and subsequent CLAD or death was assessed using Cox Proportional Hazards models, adjusted for relevant peri-transplant clinical covariates. RESULTS: We identified 75 patients with first CSA1R occurring at a median time of 98 days (range 48.5-197) post-transplant. Median time from transplant to CLAD or death was 1247 (756.5-1921.5) and 1641 days (1024.5-2326.5), respectively. In multivariable models, levels of MCP1/CCL2, S100A8, IL10, TNF-receptor 1, and pentraxin 3 (PTX3) were associated with both CLAD development and death (p < 0.05 for all). PTX3 remained significantly associated with both CLAD and death after adjusting for multiple comparisons. CONCLUSION: Our data indicate that a focused BAL protein signature, with PTX3 having the strongest association, may be useful in determining a subset of CSA1R patients at increased risk and may benefit from a more aggressive management strategy.

The Impact of Inadequate ("AX") Transbronchial Biopsies on Post-lung Transplant CLAD or Death.

BACKGROUND: Procuring a good quality transbronchial-biopsy sample is essential for diagnosing acute cellular rejection after lung transplantation (LT). Insufficient transbronchial-biopsy samples are graded "AX." We hypothesized that AX samples may be associated with a higher risk for chronic lung allograft dysfunction (CLAD) or death/retransplant, through a potential anatomic or physiologic underlying pulmonary process or because of undiagnosed acute cellular rejection episodes. METHODS: We conducted a single-center, retrospective, cohort study drawn from all consecutive adult, first, bilateral LT between 1999 and 2015. We reviewed all biopsies obtained within the first year posttransplant and compared outcomes of patients with ≥1 AX to patients with no AX. Association of any AX or percent AX with time to CLAD or death/retransplant was assessed using Cox Proportional Hazards models. RESULTS: The cohort consisted of 809 patients with a median of 6 (interquartile range 5-6) biopsies and 16.7% (interquartile range 0-25) AX samples within the first year posttransplant. Four hundred thirty-nine (54.3%) subjects had ≥1 AX sample obtained within the time period. Median time to CLAD or death/retransplant, from 1 year posttransplant, was 761 (320, 1587) and 1200 (662, 2308) days, respectively. In the multivariable analysis, there was no difference in risk for CLAD (hazard ratio = 1.05, 95% confidence interval, 0.87-1.28, P = 0.60), or death/retransplant (hazard ratio = 1.14, 95% confidence interval, 0.92-1.42, P = 0.24) between patients with ≥1 AX biopsy versus none. Among subjects with ≥1 AX, having >50% AX biopsies was not associated with outcome. CONCLUSIONS: This is the first study to demonstrate that AX biopsies are not associated with an increased risk of CLAD or death/retransplant after LT and may not require to repeat the biopsy.