Effects of donor smoking history on early post-transplant lung function measured by oscillometry.

Introduction: Prior studies assessing outcomes of lung transplants from cigarette-smoking donors found mixed results. Oscillometry, a non-invasive test of respiratory impedance, detects changes in lung function of smokers prior to diagnosis of COPD, and identifies spirometrically silent episodes of rejection post-transplant. We hypothesise that oscillometry could identify abnormalities in recipients of smoking donor lungs and discriminate from non-smoking donors. Methods: This prospective single-center cohort study analysed 233 double-lung recipients. Oscillometry was performed alongside routine conventional pulmonary function tests (PFT) post-transplant. Multivariable regression models were constructed to compare oscillometry and conventional PFT parameters between recipients of lungs from smoking vs non-smoking donors. Results: The analysis included 109 patients who received lungs from non-smokers and 124 from smokers. Multivariable analysis identified significant differences between recipients of smoking and non-smoking lungs in the oscillometric measurements R5-19, X5, AX, R5z and X5z, but no differences in %predicted FEV1, FEV1/FVC, %predicted TLC or %predicted DLCO. An analysis of the smoking group also demonstrated associations between increasing smoke exposure, quantified in pack years, and all the oscillometry parameters, but not the conventional PFT parameters. Conclusion: An interaction was identified between donor-recipient sex match and the effect of smoking. The association between donor smoking and oscillometry outcomes was significant predominantly in the female donor/female recipient group.

Clinical implications of frailty assessed in hospitalized patients with acute-exacerbation of interstitial lung disease.

BACKGROUND: Approximately 50% of patients with interstitial lung disease (ILD) experience frailty, which remains unexplored in acute exacerbations of ILD (AE-ILD). A better understanding may help with prognostication and resource planning. We evaluated the association of frailty with clinical characteristics, physical function, hospital outcomes, and post-AE-ILD recovery. METHODS: Retrospective cohort study of AE-ILD patients (01/2015-10/2019) with frailty (proportion ≥0.25) on a 30-item cumulative-deficits index. Frail and non-frail patients were compared for pre- and post-hospitalization clinical characteristics, adjusted for age, sex, and ILD diagnosis. One-year mortality, considering transplantation as a competing risk, was analysed adjusting for age, frailty, and Charlson Comorbidity Index (CCI). RESULTS: 89 AE-ILD patients were admitted (median: 67 years, 63% idiopathic pulmonary fibrosis). 31 were frail, which was associated with older age, greater CCI, lower 6-min walk distance, and decreased independence pre-hospitalization. Frail patients had more major complications (32% vs 10%, p = .01) and required more multidisciplinary support during hospitalization. Frailty was not associated with 1-year mortality (HR: 0.97, 95%CI: [0.45-2.10]) factoring transplantation as a competing risk. CONCLUSIONS: Frailty was associated with reduced exercise capacity, increased comorbidities and hospital complications. Identifying frailty may highlight those requiring additional multidisciplinary support, but further study is needed to explore whether frailty is modifiable with AE-ILD.

Airway pepsinogen A4 identifies lung transplant recipients with microaspiration and predicts chronic lung allograft dysfunction.

BACKGROUND: Aspiration is a known risk factor for adverse outcomes post-lung transplantation. Airway bile acids are the gold-standard biomarker of aspiration; however, they are released into the duodenum and likely reflect concurrent gastrointestinal dysmotility. Previous studies investigating total airway pepsin have found conflicting results on its relationship with adverse outcomes post-lung transplantation. These studies measured total pepsin and pepsinogen in the airways. Certain pepsinogens are constitutively expressed in the lungs, while others, such as pepsinogen A4 (PGA4), are not. We sought to evaluate the utility of measuring airway PGA4 as a biomarker of aspiration and predictor of adverse outcomes in lung transplant recipients (LTRs) early post-transplant. METHODS: Expression of PGA4 was compared to other pepsinogens in lung tissue. Total pepsin and PGA4 were measured in large airway bronchial washings and compared to preexisting markers of aspiration. Two independent cohorts of LTRs were used to assess the relationship between airway PGA4 and chronic lung allograft dysfunction (CLAD). Changes to airway PGA4 after antireflux surgery were assessed in a third cohort of LTRs. RESULTS: PGA4 was expressed in healthy human stomach but not lung. Airway PGA4, but not total pepsin, was associated with aspiration. Airway PGA4 was associated with an increased risk of CLAD in two independent cohorts of LTRs. Antireflux surgery was associated with reduced airway PGA4. CONCLUSIONS: Airway PGA4 is a marker of aspiration that predicts CLAD in LTRs. Measuring PGA4 at surveillance bronchoscopies can help triage high-risk LTRs for anti-reflux surgery.

The 2022 Banff Meeting Lung Report.

The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

Extending the age criteria of lung transplant donors to 70+ years old does not significantly affect recipient survival.

OBJECTIVES: To determine the impact of older donor age (70+ years) on long-term survival and freedom from chronic lung allograft dysfunction in lung transplant (LTx) recipients. METHODS: A retrospective single-center study was performed on all LTx recipients from 2002 to 2017 and a modern subgroup from 2013 to 2017. Recipients were stratified into 4 groups based on donor lung age (<18, 18-55, 56-69, ≥70 years). Donor and recipient characteristics were compared using χ2 tests for differences in proportions and analysis of variance for differences in means. Univariable and multivariable Cox regression was used to describe differences in long-term survival and freedom from chronic lung allograft dysfunction. RESULTS: Between 2002 and 2017, 1600 LTx were performed, 98 of which were performed from donors aged 70 years or older. Recipients of 70+ years donor lungs were significantly older with a mean age of 55.5 ± 12.9 years old (P = .001) and had more Status 3 (urgent) recipients (37.4%, P = .002). After multivariable regression, there were no significant differences in survival or freedom from chronic lung allograft dysfunction between the 4 strata of recipients. CONCLUSIONS: Lung transplantation using donors 70 years old or older can be considered when all other parameters suggest excellent donor lung function without compromising short- or long-term outcomes.

Identification of regional variation in gene expression and inflammatory proteins in donor lung tissue and ex vivo lung perfusate.

OBJECTIVE: Diagnosing lung injury is a challenge in lung transplantation. It has been unclear if a single biopsy specimen is truly representative of the entire organ. Our objective was to investigate lung inflammatory biomarkers using human lung tissue biopsies and ex vivo lung perfusion perfusate. METHODS: Eight human donor lungs declined for transplantation were air inflated, flash frozen, and partitioned from apex to base. Biopsies were then sampled throughout the lung. Perfusate was sampled from 4 lung lobes in 8 additional donor lungs subjected to ex vivo lung perfusion. The levels of interleukin-6, interleukin-8, interleukin-10, and interleukin-1ß were measured using quantitative reverse transcription polymerase chain reaction from lung biopsies and enzyme-linked immunosorbent assay from ex vivo lung perfusion perfusate. RESULTS: The median intra-biopsy equal-variance P value was .50 for messenger RNA biomarkers in tissue biopsies. The median intra-biopsy coefficient of variance was 18%. In donors with no apparent focal injuries, the biopsies in each donor showed no difference in various lung slices, with a coefficient of variance of 20%. The exception was biopsies from the lingula and injured focal areas that demonstrated larger differences. Cytokines in ex vivo lung perfusion perfusate showed minimal variation among different lobes (coefficient of variance = 4.9%). CONCLUSIONS: Cytokine gene expression in lung biopsies was consistent, and the biopsy analysis reflects the whole lung, except when specimens were collected from the lingula or an area of focal injury. Ex vivo lung perfusion perfusate also provides a representative measurement of lung inflammation from the draining lobe. These results will reassure clinicians that a lung biopsy or an ex vivo lung perfusion perfusate sample can be used to inform donor lung selection.

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection.

BACKGROUND: Patients who present to an emergency department (ED) with respiratory symptoms are often conservatively triaged in favour of hospitalisation. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalisation in order to improve the precision of clinical decision making in the ED. METHODS: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from EDs in an international multicentre study: Canada (n=310), Italy (n=131) and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed coronavirus disease 2019 (COVID-19) patients (n=245). An inflammatory profile was determined using a rapid, 50-min, biomarker panel (RALI-Dx (Rapid Acute Lung Injury Diagnostic)), which measures interleukin (IL)-6, IL-8, IL-10, soluble tumour necrosis factor receptor 1 (sTNFR1) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1). RESULTS: RALI-Dx biomarkers were significantly elevated in patients who required hospitalisation across all three sites. A machine learning algorithm that was applied to predict hospitalisation using RALI-Dx biomarkers had a mean±sd area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy) and 86±3% (Brazil). Model performance was 82±3% for COVID-19 patients and 87±7% for patients with a confirmed pneumonia diagnosis. CONCLUSIONS: The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions, and represents an important diagnostic adjunct to advance ED decision-making protocols.

Lung Allograft Microbiome Association with Gastroesophageal Reflux, Inflammation, and Allograft Dysfunction.

Rationale: It remains unclear how gastroesophageal reflux disease (GERD) affects allograft microbial community composition in lung transplant recipients and its impact on lung allograft inflammation and function. Objectives: Our objective was to compare the allograft microbiota in lung transplant recipients with or without clinically diagnosed GERD in the first year after transplant and assess associations between GERD, allograft microbiota, inflammation, and acute and chronic lung allograft dysfunction (ALAD and CLAD). Methods: A total of 268 BAL samples were collected from 75 lung transplant recipients at a single transplant center every 3 months after transplant for 1 year. Ten transplant recipients from a separate transplant center provided samples before and after antireflux Nissen fundoplication surgery. Microbial community composition and density were measured using 16S ribosomal RNA gene sequencing and quantitative polymerase chain reaction, respectively, and inflammatory markers and bile acids were quantified. Measurements and Main Results: We observed a range of allograft community composition with three discernible types (labeled community state types [CSTs] 1-3). Transplant recipients with GERD were more likely to have CST1, characterized by high bacterial density and relative abundance of the oropharyngeal colonizing genera Prevotella and Veillonella. GERD was associated with more frequent transitions to CST1. CST1 was associated with lower inflammatory cytokine concentrations than pathogen-dominated CST3 across the range of microbial densities observed. Cox proportional hazard models revealed associations between CST3 and the development of ALAD/CLAD. Nissen fundoplication decreased bacterial load and proinflammatory cytokines. Conclusions: GERD was associated with a high bacterial density, Prevotella- and Veillonella-dominated CST1. CST3, but not CST1 or GERD, was associated with inflammation and early development of ALAD and CLAD. Nissen fundoplication was associated with a reduction in microbial density in BAL fluid samples, especially the CST1-specific genus, Prevotella.

Engineered mesenchymal stromal cell therapy during human lung ex vivo lung perfusion is compromised by acidic lung microenvironment.

Ex vivo lung perfusion (EVLP) is an excellent platform to apply novel therapeutics, such as gene and cell therapies, before lung transplantation. We investigated the concept of human donor lung engineering during EVLP by combining gene and cell therapies. Premodified cryopreserved mesenchymal stromal cells with augmented anti-inflammatory interleukin-10 production (MSCIL-10) were administered during EVLP to human lungs that had various degrees of underlying lung injury. Cryopreserved MSCIL-10 had excellent viability, and they immediately and efficiently elevated perfusate and lung tissue IL-10 levels during EVLP. However, MSCIL-10 function was compromised by the poor metabolic conditions present in the most damaged lungs. Similarly, exposing cultured MSCIL-10 to poor metabolic, and especially acidic, conditions decreased their IL-10 production. In conclusion, we found that "off-the-shelf" MSCIL-10 therapy of human lungs during EVLP is safe and feasible, and results in rapid IL-10 elevation, and that the acidic target-tissue microenvironment may compromise the efficacy of cell-based therapies.

Recipient bone marrow-derived IL-17 receptor A-positive cells drive allograft fibrosis in a mouse intrapulmonary tracheal transplantation model.

IL-17A is implicated in the pathogenesis of chronic lung allograft dysfunction, which limits survival after lung transplantation. While many cells express the IL-17 receptor A (IL-17RA) which is the main receptor for IL-17A, the cellular targets of IL-17A in development of post-transplant fibrosis are unknown. The purpose of this study was to determine whether IL-17RA expression by donor or recipient structural or bone marrow (BM) cells is required for the development of allograft fibrosis in a mouse intrapulmonary tracheal transplantation (IPTT) model. BM chimeras were generated using C57BL/6 and IL-17RA-knockout mice. After engraftment, allogeneic IPTTs were performed using the chimeric and BALB/c mice as donors or recipients. This allowed us to assess the effect of IL-17RA deficiency in recipient BM, recipient structural, donor BM, or donor structural compartments separately. Tracheal grafts, the surrounding lung, and mediastinal lymph nodes were assessed 28 days after IPTT. Only recipient BM IL-17RA deficiency resulted in attenuation of tracheal graft obliteration. In the setting of recipient BM IL-17RA deficiency, T cells and neutrophils were decreased in mediastinal lymph nodes. Additionally, recipient BM IL-17RA deficiency was associated with increased B220+PNAd+ lymphoid aggregates, consistent with tertiary lymphoid organs, in proximity to the tracheal allograft. In this IPTT model, recipient BM-derived cells appear to be the primary targets of IL-17RA signaling during fibrotic obliteration of the tracheal allograft.

Correlation between BAL CXCR3 chemokines and lung allograft histopathologies: A multicenter study.

The histopathologic diagnosis of acute allograft injury is prognostically important in lung transplantation with evidence demonstrating a strong and consistent association between acute rejection (AR), acute lung injury (ALI), and the subsequent development of chronic lung allograft dysfunction (CLAD). The pathogenesis of these allograft injuries, however, remains poorly understood. CXCL9 and CXCL10 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells. We hypothesized that these chemokines are involved in the mononuclear cell recruitment associated with AR and ALI. We further hypothesized that the increased activity of these chemokines could be quantified as increased levels in the bronchoalveolar lavage fluid. In this prospective multicenter study, we evaluate the incidence of histopathologic allograft injury development during the first-year post-transplant and measure bronchoalveolar CXCL9 and CXCL10 levels at the time of the biopsy. In multivariable models, CXCL9 levels were 1.7-fold and 2.1-fold higher during AR and ALI compared with "normal" biopsies without histopathology. Similarly, CXCL10 levels were 1.6-fold and 2.2-fold higher during these histopathologies, respectively. These findings support the association of CXCL9 and CXCL10 with episodes of AR and ALI and provide potential insight into the pathogenesis of these deleterious events.

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.

Eosinophils in transbronchial biopsies: a predictor of chronic lung allograft dysfunction and reduced survival after lung transplantation - a retrospective single-center cohort study.

Long-term outcomes after lung transplantation remain inferior to those of other solid organ groups. The significance of eosinophils detected on transbronchial biopsies (TBBx) after lung transplantation and their relationship to long-term outcomes remain unknown. A retrospective single-center cohort study was performed of patients transplanted between January 01, 2001, and July 31, 2018, who had at least 1 TBBx with evaluable parenchymal tissue. Multivariable Cox proportional hazard models were used to assess the associations between eosinophil detection and: all-cause mortality and Chronic Lung Allograft Dysfunction (CLAD). 8887 TBBx reports from 1440 patients were reviewed for the mention of eosinophils in the pathology report. 112 (7.8%) patients were identified with eosinophils on at least one TBBx. The median (95% CI) survival time for all patients was 8.28 (7.32-9.31) years. Multivariable analysis, adjusted for clinical variables known to affect post-transplant outcomes, showed that the detection of eosinophils was independently associated with an increased risk of death (HR 1.51, 95% CI 1.24-1.85, p < 0.01) and CLAD (HR 1.35, 95% CI 1.07-1.70, P = 0.01). Eosinophils detected in TBBx are associated with an increased risk of CLAD and death. There may be benefit in specifically reporting the presence of eosinophils in TBBx reports and incorporating their presence in clinical decision-making.

Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study.

BACKGROUND: Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNFα trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear. METHODS: Unbiased proteomic analysis of laser-captured and microdissected glomeruli and tubulointerstitium was performed on 30 for-cause kidney biopsy specimens with early AMR, acute cellular rejection (ACR), or acute tubular necrosis (ATN). RESULTS: A total of 107 of 2026 glomerular and 112 of 2399 tubulointerstitial proteins was significantly differentially expressed in AMR versus ACR; 112 of 2026 glomerular and 181 of 2399 tubulointerstitial proteins were significantly dysregulated in AMR versus ATN (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit γ-1 (LAMC1) expression decreased in AMR, as did glomerular nephrin (NPHS1) and receptor-type tyrosine-phosphatase O (PTPRO). The proteomic analysis revealed upregulated galectin-1, which is an immunomodulatory protein linked to the ECM, in AMR glomeruli. Anti-HLA class I antibodies significantly increased cathepsin-V (CTSV) expression and galectin-1 expression and secretion in human glomerular endothelial cells. CTSV had been predicted to cleave ECM proteins in the AMR glomeruli. Glutathione S-transferase ω-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNFα-treated proximal tubular epithelial cells. CONCLUSIONS: Basement membranes are often remodeled in chronic AMR. Proteomic analysis performed on laser-captured and microdissected glomeruli and tubulointerstitium identified early ECM remodeling, which may represent a new therapeutic opportunity.

Bronchoalveolar bile acid and inflammatory markers to identify high-risk lung transplant recipients with reflux and microaspiration.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids-putative markers of gastric microaspiration-and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery. METHODS: We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay. RESULTS: At 3 months after transplantation, TCA, IL-1ß, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery. CONCLUSIONS: Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation.

Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study.

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction.Objectives: To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort.Methods: We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence.Measurements and Main Results: During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06; P ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57; P ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year.Conclusions: We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.

Lung transplantation for cystic fibrosis.

BACKGROUND: The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. We aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time. METHODS: A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan-Meier method and analyzed with log-rank tests. RESULTS: From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF retransplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and retransplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction. CONCLUSIONS: Lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.

Life-threatening bronchiolitis related to electronic cigarette use in a Canadian youth.

BACKGROUND: Although electronic cigarettes (e-cigarettes) were initially marketed as a potential smoking-cessation aid and a safer alternative to smoking, the long-term health effect of e-cigarette use ("vaping") is unknown. Vaping e-liquids expose the user to several potentially harmful chemicals, including diacetyl, a flavouring compound known to cause bronchiolitis obliterans with inhalational exposure ("popcorn worker's lung"). CASE DESCRIPTION: We report the case of a 17-year-old male who presented with intractable cough, progressive dyspnea and malaise after vaping flavoured e-liquids and tetrahydrocannabinol intensively. Initial physical examination showed fever, tachycardia, hypoxemia, and bibasilar inspiratory crackles on lung auscultation. Computed tomography of the chest showed diffuse centrilobular "tree-inbud" nodularity, consistent with acute bronchiolitis. Multiple cultures, including from 2 bronchoalveolar lavage samples, and biopsy stains, were negative for infection. He required intubation, invasive mechanical ventilation and venovenous extracorporeal membrane oxygenation (ECMO) for refractory hypercapnia. The patient's condition improved with high-dose corticosteroids. He was weaned off ECMO and mechanical ventilation, and discharged home after 47 days in hospital. Several months after hospital discharge, his exercise tolerance remained limited and pulmonary function tests showed persistent, fixed airflow obstruction with gas trapping. The patient's clinical picture was suggestive of possible bronchiolitis obliterans, thought to be secondary to inhalation of flavouring agents in the e-liquids, although the exact mechanism of injury and causative agent are unknown. INTERPRETATION: This case of severe acute bronchiolitis, causing near-fatal hypercapnic respiratory failure and chronic airflow obstruction in a previously healthy Canadian youth, may represent vaping-associated bronchiolitis obliterans. This novel pattern of pulmonary disease associated with vaping appears distinct from the type of alveolar injury predominantly reported in the recent outbreak of cases of vaping-associated pulmonary illness in the United States, underscoring the need for further research into all potentially toxic components of e-liquids and tighter regulation of e-cigarettes.

IL-17A Contributes to Lung Fibrosis in a Model of Chronic Pulmonary Graft-versus-host Disease.

BACKGROUND: Chronic pulmonary graft-versus-host disease (cpGVHD) after hematopoietic cell transplant (HCT) manifests as progressive airway and parenchymal lung fibrosis. On the basis of our prior data, mice that undergo allogeneic HCT with Tbet-knockout donors (AlloTbet) have increased lung Th17 cells and IL-17A and develop fibrosis resembling human cpGVHD. The role of IL-17A in posttransplant pulmonary fibrosis remains incompletely understood. We hypothesized that IL-17A is necessary for development of murine cpGVHD in this model. METHODS: AlloTbet mice received weekly intraperitoneal anti-IL-17A or IgG (200 µg/mouse) starting 2 weeks post-HCT and were sacrificed after week 5. Histologic airway and parenchymal fibrosis were semiquantitatively graded in a blinded fashion. Lung cells and proteins were measured by flow cytometry, ELISA, and multicytokine assays. RESULTS: Anti-IL-17A modestly decreased airway and parenchymal lung fibrosis, along with a striking reduction in pulmonary neutrophilia, IL-6, MIP-1α, MIP-1ß, CXCL1, and CXCL5 in AlloTbet mice. Additionally, anti-IL-17A decreased CCL2, inflammatory monocytes and macrophages, and Th17 cells. CONCLUSIONS: In the setting of murine AlloHCT with Tbet donors, IL-17A blockade decreases fibrotic features of cpGVHD. This may be mediated by the observed reduction in neutrophils or specific lung monocyte and macrophage populations or alternatively via a direct effect on fibroblasts. Collectively, our results further suggest that anti-IL-17A strategies could prove useful in preventing alloimmune-driven fibrotic lung diseases.

Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion.

Importance: The mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes. Objective: To assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP. Design, Setting, and Participants: This retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP. Exposure: Donor lungs undergoing EVLP. Main Outcomes and Measures: The incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development. Results: This study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups. Conclusions and Relevance: Since 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.