Onset Of Bronchiolitis Obliterans Syndrome Research Articles

Periostin in Bronchiolitis Obliterans Syndrome after Lung Transplant.

The utility of measuring serum periostin levels for predicting the occurrence of bronchiolitis obliterans syndrome (BOS) after lung transplantation remains underexplored. We analyzed differentially expressed genes (DEGs) between initially transplanted lung tissue and lung tissue with BOS from four patients. Periostin levels were assessed in 97 patients who had undergone lung transplantation 1 year post-transplantation and at the onset of BOS. The association between periostin levels and BOS, as well as their correlation with the decline in forced expiratory volume in one second (FEV1), was evaluated. Periostin levels in the BOS group were significantly higher than those in the control group (p < 0.001) and the stable group (p < 0.001). Periostin levels at the onset of BOS were significantly higher than those 1 year post-transplantation in the BOS group (p < 0.001). The serum periostin levels at the time of BOS diagnosis showed a positive correlation with the reduction in FEV1 (%) (r = 0.745, p < 0.001). The increase in the serum periostin levels at the time of BOS diagnosis compared with those 1 year post-transplantation was positively correlated with reduction in FEV1 (%) (r = 0.753, p < 0.001). Thus, serum periostin levels may serve as biomarkers for predicting a decline in lung function in patients with BOS after lung transplantation.

Prognostic Value of Chest CT Findings at BOS Diagnosis in Lung Transplant Recipients.

Bronchiolitis obliterans syndrome (BOS) after lung transplantation is characterized by fibrotic small airway remodeling, recognizable on high-resolution computed tomography (HRCT). We studied the prognostic value of key HRCT features at BOS diagnosis after lung transplantation. The presence and severity of bronchiectasis, mucous plugging, peribronchial thickening, parenchymal anomalies, and air trapping, summarized in a total severity score, were assessed using a simplified Brody II scoring system on HRCT at BOS diagnosis, in a cohort of 106 bilateral lung transplant recipients transplanted between January 2004 and January 2016. Obtained scores were subsequently evaluated regarding post-BOS graft survival, spirometric parameters, and preceding airway infections. A high total Brody II severity score at BOS diagnosis (P = 0.046) and high subscores for mucous plugging (P = 0.0018), peribronchial thickening (P = 0.0004), or parenchymal involvement (P = 0.0121) are related to worse graft survival. A high total Brody II score was associated with a shorter time to BOS onset (P = 0.0058), lower forced expiratory volume in 1 s (P = 0.0006) forced vital capacity (0.0418), more preceding airway infections (P = 0.004), specifically with Pseudomonas aeruginosa (P = 0.002), and increased airway inflammation (P = 0.032). HRCT findings at BOS diagnosis after lung transplantation provide additional information regarding its underlying pathophysiology and for future prognosis of graft survival.

Markers of Bronchiolitis Obliterans Syndrome after Lung Transplant: Between Old Knowledge and Future Perspective.

Bronchiolitis obliterans syndrome (BOS) is the most common form of CLAD and is characterized by airflow limitation and an obstructive spirometric pattern without high-resolution computed tomography (HRCT) evidence of parenchymal opacities. Computed tomography and microCT analysis show abundant small airway obstruction, starting from the fifth generation of airway branching and affecting up to 40-70% of airways. The pathogenesis of BOS remains unclear. It is a multifactorial syndrome that leads to pathological tissue changes and clinical manifestations. Because BOS is associated with the worst long-term survival in LTx patients, many studies are focused on the early identification of BOS. Markers may be useful for diagnosis and for understanding the molecular and immunological mechanisms involved in the onset of BOS. Diagnostic and predictive markers of BOS have also been investigated in various biological materials, such as blood, BAL, lung tissue and extracellular vesicles. The aim of this review was to evaluate the scientific literature on markers of BOS after lung transplant. We performed a systematic review to find all available data on potential prognostic and diagnostic markers of BOS.

The predictive value of pulmonary function test before transplantation for chronic pulmonary graft-versus-host-disease after allogeneic hematopoietic stem cell transplantation

BackgroundPulmonary chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a devastating complication and often diagnosed at a late stage when lung dysfunction is irreversible. Identifying patients before transplant who are at risk may offer improved strategies to decrease the mortality. Bronchiolitis obliterans syndrome (BOS) is the typical manifestation of pulmonary cGVHD, which is clinically diagnosed by pulmonary function test (PFT). This study aimed to evaluate the predictive value of PFT pre-HSCT for BOS.MethodsA single center cohort of 923 allo-HSCT recipients was analyzed, including 15 patients who developed pulmonary cGVHD. Kaplan–Meier method was used to analyze the 3 year progression free survival and 3 year overall survival (OS). A Cox regression model was applied for univariate and multivariate models.ResultsThe 3 year cumulative incidence of pulmonary cGVHD was 2.04% (95% CI 1.00–3.08%). According to the cut-off values determined by receiver operator characteristic curve, higher ratio of forced expiratory volume during one second to forced vital capacity (FEV1/FVC) pre-HSCT was correlated to a lower incidence of pulmonary cGVHD [0.91% (95% CI 0.01–1.81%) vs. 3.61% (95% CI 1.30–5.92%), P < 0.01], and so as peak expiratory flow to predictive value (PEF/pred) [0.72% (95% CI 0–1.54%) vs. 3.74% (95% CI 1.47–6.01%), P < 0.01]. Multivariate analysis showed that FEV1/FVC (HR = 3.383, P = 0.047) and PEF/pred (HR = 4.426, P = 0.027) were independent risk factors for onset of BOS. Higher FEV1/FVC and PEF/pred level were related to a significantly decreased 3 year non-relapse mortality. The 3 year OS was superior in patients with higher PEF/pred [78.17% (95% CI 74.50–81.84%) vs. 71.14% (95% CI 66.08–76.20%), P = 0.01], while FEV1/FVC did not show significance difference.ConclusionOur results suggested that PFT parameters such as PEF/pred and FEV1/FVC could be predictors for pulmonary cGVHD and even transplant outcomes before HSCT.

Bronchial artery revascularization in lung transplantation: a systematic review and meta-analysis.

BackgroundBronchial artery revascularization (BAR) during lung transplantation has been hypothesized to improve early tracheal healing and delay the onset of bronchiolitis obliterans syndrome (BOS). We aimed to assess the outcomes of BAR after lung transplantation.MethodsElectronic search in Ovid Medline, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Scopus, and Cochrane Controlled Trials Register (CCTR) databases was performed to identify all relevant studies published about lung transplantation with BAR. Studies discussing lung transplantation utilizing BAR were included while those without outcome data such as BOS and survival were excluded. Cohort-level data were extracted and pooled for analysis. A binary outcome meta-analysis of proportions with logit transformation was conducted. Newcastle-Ottawa scale was used for risk of bias assessment.ResultsSeven studies were selected for the analysis comprising 143 patients. Mean patient age was 47 (95% CI: 40–55) years. Sixty-one percent (48–72%) were male. Seventy-three percent (65–79%) of patients underwent double lung transplant while 27% (21–25%) underwent single lung transplant. In patients with postoperative angiography, successful BAR was demonstrated in 93% (82–97%) of all assessed conduits. The 30-day/in-hospital mortality was 6% (3–11%). Seventy-nine percent (63–89%) of patients were free from rejection at three months. Eighty-three percent (29–98%) of patients were free from signs of airway ischemia at three and six months. Pooled survival at one year and five years was 87% (78–92%) and 71% (46–87%), respectively, with a mean follow-up time of 21 (3–38) months. Pooled freedom from bronchiolitis obliterans was 86% (77–91%) at two years.ConclusionsWhile this systematic review and meta-analysis is limited by the available surgeons, institutions, and papers discussing a highly specialized technique, it does show that BAR is a viable technique to minimize BOS and early anastomotic intervention following lung transplantation.

Retrospective Analysis of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

Objective: To explore the incidence, clinical features,risk factors and survival prognosis of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) by using large samples form a single center.Provide a prerequisite for improving the early diagnosis of BOS after allo-HSCT.Methods: We retrospectively investigated the case data of 802 patients who underwent allo-HSCT in our institute in petiod of January 1, 2015 to December 31, 2019 and survived more than 100 days. Adopt a multidisciplinary discussion method in the Department of Hematology, Respiratory and Radiology,according to the 2014 National Institutes of Health (NIH) ,diagnose and assess the severity of patiencts with BOS.Describe the clinical characteristics of BOS, and then analyze the risk factors and survival prognosis.Result: Among the 802 patients，46 patients（5.74%), 26males and 20 females with a median age of 32 years was diagnosed BOS.The median time to first appearance of respiratory symptoms was 13.5 months after transplantation, and the median time to diagnosis was 14.4 months.The cumulative incidence rate for 1- year, 2- year, and 5 -year after allo-HSCT is 3.7%, 6.5%, and 8.4%,while the cumulative incidence rate for patients already diagnosed with cGVHD is 7.5%、12.4% and 15.0% . Univariate analysis showed several risk factors associated with the onset of BOS,including the presence of preoperative or postoperative pneumonia,free of ATG ,use of DLI,peripheral blood stem cell transplantation, occurrence of GVHD and the severity and number of these episodes .And multivariate analysis denotes :free of ATG ,use of DLI,and number of organs affected by cGVHD were the variables correlated with increased incidences of BOS. At the onset of BOS, FEV1, FEV1%pred, FEV1/FVC ,FEV1/FVC %pred were significantly lower than those before transplantation. Compare before and after onset, the average decrease rate of FEV1 is 0.17L/month, while FEV1%pred is 5.15%/month.We also recorded the last follow-up lung function to evaluate the treatment efficacy : after treatment, the average FEV1 was 2.46L, the average of FEV1%pred was 36.61%, the average of FEV1/FVC was 45.80%, and the average of FEV1/FVC%pred was 56.36%, before and after treatment., FEV1%pred has no statistical difference (P=0.455).Not only that, there was no statistical difference in the treatment effect among different severity of BOS.The median follow-up time after the diagnosis of BOS was 19 months, and there was no statistical difference in the survival rate between the BOS and non-BOS groups at the end of the follow-up. The analysis result shows that early-onset BOS is a independent risk factors for poor survival time of BOS.Compare BOS with other non-infectious lung complications,the severity of BOS and cGVHD involving extrapulmonary organs are statistically different.Conclusion: BOS is a serious refractory complication after allo-HSCT.Early detection of potential patients with BOS is very difficult , and because most of the BOS patients did not respond to the therapy well, eventually lead to the irreversibility of deterioration of PFT. Compared with other non-infectious lung complications, strong association with severe cGVHD and deterioration of lung function characterized by obstructive ventilation disorder，etc.It suggests that the clinical need to deepen the recognition of BOS, continue to explore the early diagnosis method of BOS , more importantly , strive to give effective treatment at the early stage to improve the prognosis.KEYWORDS Bronchiolitis obliterans Allogeneic hematopoietic stem cell transplantation Risk factors Non-infectious pulmonary complications DisclosuresNo relevant conflicts of interest to declare.

Characterization of localized macrophages in bronchiolitis obliterans after allogeneic hematopoietic cell transplantation

Bronchiolitis obliterans syndrome (BOS) remains one of the most devastating manifestations of chronic graft-versus-host disease in hematopoietic cell transplantation (HCT). Recent findings of BOS after lung transplantation indicate that donor (lung)-derived lung-resident macrophages contribute to BOS, suggesting that differences in the origin of immune cells and localized antigen-presenting cells cause the onset of BOS. We identified the phenotype and origin of infiltrating macrophages using immunohistochemistry and fluorescence in situ hybridization in eight sex-mismatched HCT recipients who underwent lung transplantation for BOS after HCT. Most of the infiltrating macrophages appeared to be derived from donor (hematopoietic) cells in patients who developed BOS following HCT. Macrophages observed in the early-stage region of BOS were positive for cluster of differentiation (CD)68 and inducible nitric oxide synthase (iNOS) and negative for CD163 and CD206, suggesting an M1 phenotype. In the late-stage region, macrophages were negative for CD68 and iNOS in all patients, but also positive for CD163 and CD206 in some patients. Donor-derived M1-macrophages may be involved in the pathogenesis of the early-stage region of BOS. In addition, some macrophages in the late-stage region showed M2 polarization that might be involved in fibrosis.

Infinitix-BOS Trial: Multi-Center, Randomised, Double-Blind Placebo-Controlled Trial of Nintedanib in Lung Transplant Recipients with Bronchiolitis Obliterans Syndrome (BOS) Grade 0-p and Grade 1-2

Purpose Lung transplantation (TxP) is now a validated treatment of end-stage pulmonary diseases, but long-term survival are still hampered by the development of chronic allograft dysfunction (CLAD) affecting> 50% of patients. Bronchiolitis obliterans syndrome/obliterative bronchiolitis (BOS/OB) is the most common manifestation of CLAD. Survival after onset of BOS is poor ( Methods A phase III clinical randomized trial to assess the efficacy of Nintedanib in LTx recipients with BOS.Inclusion criteria: n=80 LTx recipients with BOS 0p-1-2, with a decline of FEV1> 200ml within the previous year.Primary Objective: to assess Nintedanib efficacy in the reduction of the rate of decline of FEV1 (forced expiratory volume in 1 sec) at a dose of 150 mg twice daily (bid) compared to placebo over 6 months. Secondary Objectives: to assess Nintedanib efficacy and tolerance in the treatment of BOS 0p-1-2, based on the change over 6 months of : 6WT, QOL, BOS grade/graft failure, O2 saturation, KL-6, SPD, VEGF, PDGF parameters, and tolerance. Results The trial was started in December 2019 among 8 french LTx centers (Hopital Foch, Bichat, HEGP/Cochin, Marie-Lannelongue, Marseille, Bordeaux, Strasbourg, and Grenoble), for a total duration of inclusion anticipated at 36 months. On October 15th 2020, 14 patients were already included. Conclusion Infinitix-BOS is the first therapeutic randomized trial testing the efficacy of nintedanib in LTx recipients with BOS. In case of demonstrated effectiveness of Nintedanib, the benefit for LTx patients with BOS seems high in terms of stabilization of lung function and enhancement of survival.

Prevalence of antibodies to lung self-antigens (Kα1 tubulin and collagen V) and donor specific antibodies to HLA in lung transplant recipients and implications for lung transplant outcomes: Single center experience

PurposeFor patients with end stage lung disease, lung transplantation (LT) remains the only definitive treatment option. Long term survival post LT is limited by acute and chronic allograft dysfunction. Antibodies to lung self-antigens Kα1Tubulin and collagen V (autoantibodies) have been implicated in adverse outcomes post LT. The aim of our study was to determine the prevalence of autoantibodies in pre- and post-transplant sera, evaluate the impact on post-transplant outcomes. MethodsIn a prospective observational cohort analysis, 44 patients were enrolled who received LT between 09/01/2014 and 10/31/2015. Pre- and post-transplant sera were analyzed using enzyme-linked immunosorbent assay (ELISA) for the presence of antibodies to collagen I, collagen V, and K-alpha 1 tubulin. The outcome variables are presence of primary graft dysfunction (PGD), cumulative acute cellular rejection (ACR), treatment with pulse steroids for clinical rejection, association with DSA, and onset of Bronchiolitis Obliterans Syndrome (BOS). ResultsIn our cohort, 33 patients (75%) tested positive for the presence of autoantibodies. Pre-transplant autoantibodies were present in 23 patients (70%). Only a small percentage (26%) cleared these antibodies with standard immunosuppression. Some developed de novo post-transplant (n = 10). PGD was observed in 34% of our cohort, however the presence of autoantibodies did not correlate with increase in the incidence or severity of PGD. The prevalence of donor specific antibodies (DSA) in the entire cohort was 73%, with an increased prevalence of DSA noted in the autoantibody positive group (78.7% vs. 54.5%) than in the autoantibody negative group. BOS was observed in 20% of the cohort, with a median time to onset of 291 days' post-transplant. Patients with pre-transplant autoantibodies had a statistically significant decrease in BOS-free survival (p = 0.029 by log-rank test). ConclusionsIn our cohort, we observed a high prevalence of autoantibodies and DSA in lung transplant recipients. Pre-transplant autoantibodies were associated with de novo development of DSA along with a decrease in BOS-free survival. Limitations to our study include the small sample size and single center enrollment, along with limited time for follow-up.

Longterm Effect of Azithromycin in Bronchiolitis Obliterans Syndrome after Lung Transplantation; Post Hoc Analysis of a Randomized Trial

Background: Azithromycin has been shown to stabilize and improve lung function (FEV1) in lung transplantation patients with bronchiolitis obliterans syndrome (BOS). We performed a post hoc analysis to assess the long term effect on FEV1, progression of BOS, and survival in patients initially randomized to placebo or azithromycin. Methods: Forty-eight patients were recruited between November 2006 and December 2010 for the randomized placebo controlled trial. After 3 months all patients received open label azithromycin and were followed up until 6 years after inclusion. FEV1, BOS free progression and overall survival were assessed. Follow-up data from 45 patients was available for analysis, 22 had initially received azithromycin and 23 placebo. Findings: FEV1 in the placebo group improved after open label azithromycin and was comparable to the treatment group by 6 months (FEV1 70% ± 4 vs 72% ±5). FEV1 subsequently decreased in both groups (67% ±4 and 57% ±7 vs 72% ± 5 and 59% NS) after 1 and 5 years. Progression free survival (log-rank test p = 0.40) and overall survival (log-rank test p = 0.28) was not significantly different between the groups. In the open label period survival of patients with early BOS (< median = 2.55 year) was not different than late onset of BOS (log-rank test p = 0.74). Interpretation: Long term treatment with azithromycin slows down the progression of BOS. BOS progression and long term survival were not affected by randomization to the placebo group. Thus performing randomized placebo controlled trials in lung transplantation patients with BOS with a blinded trial duration is feasible, effective and safe. Funding: None. Declaration of Interest: Dr Christiaan Tji-Joong Gan was the recipient of the European Respiratory Society Clinical Fellowship 2015 Ethical Approval: All patients provided written informed consent before randomization. The institutional review board approved the study.

Lobe-wise assessment of lung volume and density distribution in lung transplant patients and value for early detection of bronchiolitis obliterans syndrome

PurposeTo evaluate quantitative computed tomography (CT) measurements of the lung parenchyma in lung transplant (LTx) patients for early detection of the bronchiolitis obliterans syndrome (BOS). Materials and Methods359 CT scans of 122 lung transplant patients were evaluated. Measurements of lung volume and density were performed for the whole lung and separately for each lobe. For longitudinal analysis the difference between the baseline at 6 months after LTx and follow-up examinations was calculated. Patients with and without BOS (matched 1:2) were compared at two different time points, the last examination before the BOS onset and the first examination within one year after BOS onset. Results30 patients developed BOS during the follow-up period. Longitudinal changes in the lung volume and lung density measured on CT differed significantly between those patients with and without early BOS, in particular the difference of the inspiratory and expiratory lung volume (p < 0.001), the ratio of the expiratory and inspiratory lung volume (p < 0.001-p = 0.001) and MLD (p < 0.001-p = 0.001), the volume on expiration (p < 0.001-p = 0.007), the MLD on expiration (p < 0.001-p = 0.007), and the percentiles on expiration (p < 0.001-p = 0.002) with an increase of lung volume and a decrease of lung density. Changes were pronounced in the lower lobes. Before BOS onset, patients with and without future development of BOS showed no significant differences. ConclusionLongitudinal changes of lung volume and lung density measured on CT start markedly at BOS onset with increased lung volume and decreased lung density indicating increased inflation levels. Even though this method may help to diagnose BOS at onset it is not useful as a predictor for BOS before disease onset.

Bronchiolitis obliterans syndrome susceptibility and the pulmonary microbiome

Lung transplantation outcomes remain complicated by bronchiolitis obliterans syndrome (BOS), a major cause of mortality and retransplantation for patients. A variety of factors linking inflammation and BOS have emerged, meriting further exploration of the microbiome as a source of inflammation. In this analysis, we determined features of the pulmonary microbiome associated with BOS susceptibility. Bronchoalveolar lavage (BAL) samples were collected from 25 patients during standard of care bronchoscopies before BOS onset. Microbial DNA was isolated from BAL fluid and prepared for metagenomics shotgun sequencing. Patient microbiomes were phenotyped using k-means clustering and compared to determine effects on BOS-free survival. Clustering identified 3 microbiome phenotypes: Actinobacteria dominant (AD), mixed, and Proteobacteria dominant. AD microbiomes, distinguished by enrichment with Gram-positive organisms, conferred reduced odds and risks for patients to develop acute rejection and BOS compared with non-AD microbiomes. These findings were independent of treatment models. Microbiome findings were correlated with BAL cell counts and polymorphonuclear cell percentages. In some populations, features of the microbiome may be used to assess BOS susceptibility. Namely, a Gram-positive enriched pulmonary microbiome may predict resilience to BOS.

Machine Learning Algorithms Utilizing Quantitative CT Features May Predict Eventual Onset of Bronchiolitis Obliterans Syndrome After Lung Transplantation

Long-term survival after lung transplantation (LTx) is limited by bronchiolitis obliterans syndrome (BOS), defined as a sustained decline in forced expiratory volume in the first second (FEV1) not explained by other causes. We assessed whether machine learning (ML) utilizing quantitative computed tomography (qCT) metrics can predict eventual development of BOS. Paired inspiratory-expiratory CT scans of 71 patients who underwent LTx were analyzed retrospectively (BOS [n = 41] versus non-BOS [n = 30]), using at least two different time points. The BOS cohort experienced a reduction in FEV1 of >10% compared to baseline FEV1 post LTx. Multifactor analysis correlated declining FEV1 with qCT features linked to acute inflammation or BOS onset. Student t test and ML were applied on baseline qCT features to identify lung transplant patients at baseline that eventually developed BOS. The FEV1 decline in the BOS cohort correlated with an increase in the lung volume (P = .027) and in the central airway volume at functional residual capacity (P = .018), not observed in non-BOS patients, whereas the non-BOS cohort experienced a decrease in the central airway volume at total lung capacity with declining FEV1 (P = .039). Twenty-three baseline qCT parameters could significantly distinguish between non-BOS patients and eventual BOS developers (P < .05), whereas no pulmonary function testing parameters could. Using ML methods (support vector machine), we could identify BOS developers at baseline with an accuracy of 85%, using only three qCT parameters. ML utilizing qCT could discern distinct mechanisms driving FEV1 decline in BOS and non-BOS LTx patients and predict eventual onset of BOS. This approach may become useful to optimize management of LTx patients.

Lung transplantation in cystic fibrosis patients in Israel: The importance of ethnicity and nutritional status.

To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF). We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996 and 2014 at Rabin Medical Center, Israel. Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62%, and 39% at 1, 3, 5, and 10 years, respectively. Better survival correlated with: BMI at 6 months and 1 year after transplantation (P=.002 and P=.003, respectively), ischemic time of less than 300minutes (P=.023), absence of liver disease (P=.012), and Jewish compared to Arab ethnicity (P=.007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75%, and 72% at 1, 3, and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (P=.012, P=.007). Additionally, prolonged time free of BOS correlated with male gender (P=.039), older age (P<.001), absence of liver disease (P=.012), and higher BMI 1 year after transplantation (P<.001). Clinically important determinants for survival include BMI pre- and 1-year post-transplantation and improved freedom from BOS. Arab ethnicity correlated with higher incidence and earlier onset of BOS compared to Jewish ethnicity in Israel.

A retrospective study of 10 cases of post-transplant bronchiolitis obliterans

Objective: To analyze the clinical features of bronchiolitis obliterans syndrome (BOS) in patients with allogeneic hematopoietic stem cell transplantation (HSCT). Methods: This retrospective study included patients who underwent allogeneic HSCT from January 1998 to December 2016. The clinical features, radiological manifestations and treatment of clinically proven BOS were reviewed. Results: Of 681 patients who experienced HSCT, 10(1.47%) met the diagnostic criteria. The duration of BOS onset after transplantation was 5-48 months, averaging (18±15) months. Cough and worsening dyspnea were present in most cases, and 9 (90%) of the cases had manifestations of chronic graft versus host disease. Hyperinflation with areas of decreased attenuation and bronchiectasis were present in 7 (70%) cases and air trapping was present during the expiratory phase of imaging. The management of BOS consisted of high dose systemic corticosteroids and immunosuppressive therapy. Patients were treated with bronchodilators if they were symptomatic and during acute exacerbations of respiratory symptoms. In 5 (50%) patients the condition deteriorated and caused death, while in 3 patients the condition was improved. Two patients were lost to follow up. Conclusion: BOS is the most common late noninfectious pulmonary complication following allogeneic HSCT and has a poor prognosis.

1H NMR To Evaluate the Metabolome of Bronchoalveolar Lavage Fluid (BALf) in Bronchiolitis Obliterans Syndrome (BOS): Toward the Development of a New Approach for Biomarker Identification.

This report describes the application of NMR spectroscopy to the profiling of metabolites in bronchoalveolar lavage fluid (BALf) of lung transplant recipients without bronchiolitis obliterans syndrome (BOS) (stable, S, n = 10), and with BOS at different degrees of severity (BOS 0p, n = 10; BOS I, n = 10). Through the fine-tuning of a number of parameters concerning both sample preparation/processing and variations of spectra acquisition modes, an efficient and reproducible protocol was designed for the screening of metabolites in a pulmonary fluid that should reflect the status of airway inflammation/injury. Exploiting the combination of mono- and bidimensional NMR experiments, 38 polar metabolites, including amino acids, Krebs cycle intermediates, mono- and disaccharides, nucleotides, and phospholipid precursors, were unequivocally identified. To determine which signature could be correlated with the onset of BOS, the metabolites' content of the above recipients was analyzed by multivariate (PCA and OPLS-DA) statistical methods. PCA analysis (almost) totally differentiated S from BOS I, and this discrimination was significantly improved by the application of OPLS-DA, whose model was characterized by excellent fit and prediction values (R2 = 0.99 and Q2 = 0.88). The analysis of S vs BOS 0p and of BOS 0p vs BOS I samples showed a clear discrimination of considered cohorts, although with a poorer efficiency compared to those measured for S vs BOS I patients. The data shown in this work assess the suitability of the NMR approach in monitoring different pathological lung conditions.

Low Levels of Exhaled Surfactant Protein A Associated With BOS After Lung Transplantation.

BackgroundThere is no clinically available marker for early detection or monitoring of chronic rejection in the form of bronchiolitis obliterans syndrome (BOS), the main long-term complication after lung transplantation. Sampling and analysis of particles in exhaled air is a valid, noninvasive method for monitoring surfactant protein A (SP-A) and albumin in the distal airways.MethodsWe asked whether differences in composition of exhaled particles can be detected when comparing stable lung transplant recipients (LTRs) (n = 26) with LTRs who develop BOS (n = 7). A comparison between LTRs and a matching group of healthy controls (n = 33) was also conducted. Using a system developed in-house, particles were collected from exhaled air by the principal of inertial impaction before chemical analysis by immunoassays.ResultsSurfactant protein A in exhaled particles and the SP-A/albumin ratio were lower (P = 0.002 and P = 0.0001 respectively) in the BOS group compared to the BOS-free group. LTRs exhaled higher amount of particles (P < 0.0001) and had lower albumin content (P < 0.0001) than healthy controls.ConclusionsWe conclude that low levels of SP-A in exhaled particles are associated with increased risk of BOS in LTRs. The possibility that this noninvasive method can be used to predict BOS onset deserves further study with prospective and longitudinal approaches.

Impact of Donor Arterial Partial Pressure of Oxygen on Outcomes After Lung Transplantation in Adult Cystic Fibrosis Recipients

Donor PaO2 levels are used for assessing organs for lung transplantation (LTx), but survival implications of PaO2 levels in adult cystic fibrosis (CF) patients receiving LTx are unclear. UNOS registry data spanning 2005-2013 were used to test for associations of donor PaO2 with patient survival and bronchiolitis obliterans syndrome (BOS) in adult (age≥18years) first-time LTx recipients diagnosed with CF. The analysis included 1587 patients, of whom 1420 had complete data for multivariable Cox models. No statistically significant differences among donor PaO2 categories of ≤200, 201-300, 301-400, or >400mmHg were found in univariate survival analysis (log-rank test p=0.290). BOS onset did not significantly differ across donor PaO2 categories (Chi-square p=0.480). Multivariable Cox models of patient survival supported the lack of difference across donor PaO2 categories. Interaction analysis found a modest difference in survival between the two top categories of donor PaO2 when examining patients with body mass index (BMI) in the lowest decile (≤16.5kg/m(2)). Donor PaO2 was not associated with survival or BOS onset in adult CF patients undergoing LTx. Notwithstanding statistically significant interactions between donor PaO2 and BMI, there was no evidence of post-LTx survival risk associated with donor PaO2 below conventional thresholds in any subgroup of adults with CF.

Observational study of lung transplant recipients surviving 20 years

BackgroundLung transplant recipients have reduced long-term survival compared with other solid organ recipients. There is a lack of published data on the characteristics of very long term survivors. MethodsWe describe the demographics, clinical history and post-procedure function of all lung transplant recipients who have survived greater than 20 years at our centre. ResultsAt the time of analysis there were 21 (16.4%) of 128 patients who survived over 20 years. The mean age at transplantation was 31.8 ± 9.9 years. Five of 21 had undergone single-lung, eight double-lung and eight heart-lung transplant procedures. At the last evaluation, mean percentage predicted FEV1 in recipients of single and double lung were 51.3% and 57.9% respectively. By 20 years, 19 (90.5%) patients had developed bronchiolitis obliterans syndrome (BOS) with three (14%) BOS 1, six (29%) BOS 2 and 10 (48%) BOS 3 and two (9.5%) free from BOS. The median time to onset of BOS was 9.7 years (range 1.6–17.9). Of eight patients (38%) who required renal replacement, four (19%) had successfully undergone renal transplantation and four (19%) were on haemodialysis. Only one patient (5%) had symptomatic osteoporosis. Nineteen patients (90%) were treated for hypertension. Five patients (24%) had diabetes, all with an underlying diagnosis of cystic fibrosis and four of them developing diabetes post operatively. ConclusionsIn our experience, 20-year survivors of lung transplantation had a delayed onset of BOS and morbidities due to immunosuppression that can be appropriately managed leading to long-term survival.

Induction Therapy for Lung Transplantation in COPD: Analysis of the UNOS Registry

ABSTRACTAlthough studies demonstrate that induction therapy improves outcomes after lung transplantation, its influence on survival in patients with chronic obstructive pulmonary disease (COPD) is not clear. The United Network for Organ Sharing database was queried to obtain data regarding adult patients with COPD receiving lung transplant between May 2005 and June 2014. Therapies evaluated include anti-thymocyte globulin, anti-lymphocyte globulin, thymoglobulin, basiliximab, and alemtuzumab. Data were categorized based on receiving induction (INDUCED) and no induction (NONE). Kaplan–Meier plots, Cox proportional hazards models of patient survival, and competing-risks regression models for secondary endpoints were utilized. A total of 3,405 patients who underwent lung transplantation for COPD were enrolled with 1,761 (52%) receiving induction therapy. Of INDUCED, 1,146 (65%) received basiliximab, 380 (22%) received alemtuzumab, and 235 (13%) received a polyclonal preparation. The hazard ratio for INDUCED vs. NONE was 0.793 (95% CI = 0.693, 0.909; p = 0.001) in the fully adjusted Cox model. A multivariable competing-risks model also found a protective influence of induction therapy with respect to delayed onset of bronchiolitis obliterans syndrome after transplantation (SHR = 0.801; 95% CI = 0.694, 0.925; p = 0.003). In a cohort of recently transplanted patients with COPD, there appears to be a benefit from contemporary induction agents with no concurrent increase in the risk of death due to infection.