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Predictive Biomarkers for Bronchiolitis Obliterans
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The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Results: The top genes associated with CLAD reflected de-differentiation (expression loss), injury (expression gain), and inflammation in both TBBs and 3BMBs. These associations were stronger in 3BMBs. Pathway analysis using the top genes also suggested parenchymal de-differentiation (e.g. loss of transcriptional regulation and mitochondrial function in TBBs) and inflammatory pathway activation, particularly in 3BMBs (Table 1). Gene sets previously annotated in atrophy-scarring, including immunoglobulin transcripts (plasma cells), were elevated in CLAD in TBBs and 3BMBs, but 3BMBs also showed more inflammation-related changes (e.g. interferon gamma effects). Conclusion: Molecular changes associated with CLAD were apparent in TBBs and especially in 3BMBs, and indicate that CLAD is a combination of atrophy/scarring, function loss, and, particularly in 3BMBs, inflammation. Molecular assessment of 3BMBs is a particularly promising opportunity to dissect CLAD biology and potentially gain insight into the BOS variant. ClinicalTrials.gov: NCT02812290
15 Chest CT Has Prognostic Value at BOS Diagnosis after Lung Transplantation A. Van Herck,1 A. Sacreas,1 T. Heigl,1 J. Kaes,1 A. Vanstapel,1 S.E. Verleden,1 B.M. Vanaudenaerde,1 W. De Wever,2 G.M. Verleden,1 and R. Vos.1 1Lung Transplant Unit, Department of Chronic Diseases, Metabolism & Ageing, University of Leuven, Leuven, Belgium; and the 2Department of Radiology, University Hospitals Leuven, Leuven, Belgium.
14 Predictive Biomarkers for Bronchiolitis Obliterans V. Kaza,1 C. Zhu,1 L. Feng,1 A. Reddy,2 C. Lacelle,3 L. Terada,1 M. Manish,1 S. Bollineni,1 A. Banga,1 F. Torres,1 J. Mullins,1 and Q. Li.4 1UT SW Med Ctr, Dallas, TX; 2Southwest Pulmonary Associates, Dallas, TX; 3 UT Southwestern Medical Center, Dallas, TX; and the 4Ut SW Med Ctr, Dallas, TX. Purpose: Chronic Allograft Dysfunction (CLAD) with Bronchiolitis obliterans (BOS) phenotype is a major limitation for long term survival after lung transplantation (LT). Predictive biomarkers for BOS are unavailable. Purpose of our study was to establish a tractable system to evaluate the effects of pre-transplant antibodies to self-antigens (AutoAbs) and to examine specific patterns that correlate with BOS. Methods: Serum samples collected pre-transplant and stored in HLA lab were retreived after IRB approval. Pre-existing AutoAbs in sera were measured using a multiplexed protein array bearing 375 auto antigens developed by Microarray core lab. Microarray data was analyzed using GLMNET in R package. Machine learning program was used to select panel of AutoAbs with best predictive value for BOS. Survival analysis was done using Kaplan-Meier estimation or cox proportional hazards model. Results: 41 recipients who met inclusion criteria were grouped into low BOS (BOS grade 0 and 1, n=20) and high BOS (BOS grade 2, 3; n=21). Survival analysis showed worse survival in patients with higher BOS grade (figure 1A). 75 AutoAbs were significantly higher in high BOS compared to low BOS in pre transplant samples (figure 1B). Top 5 significantly elevated AutoAbs in high BOS were: anti-peptidyl arginine deiminases, anti-endothelial cell extract, anti-MPO, anti beta 2 glycoprotein 1 and anti-ribosomal phosphoprotein1. Using the machine learning program, 15 AutoAbs (figure 1C)were selected for best prediction of BOS with area under curve 0.91, CI (95%) 0.83-0.99. Sensitivity of prediction with the panel is 90% and specificity 85% (figure 1D). Conclusion: Our study points to a panel of 15 AutoAb that can predict BOS before LT. Novel findings reported in our study are being confirmed in a replication cohort. Prediction models with a panel of AutoAb can significantly transform management of LT recipients for improved survival.
Purpose: Long-term survival after lung transplantation (LTx) is hampered by chronic lung allograft dysfunction, with bronchiolitis obliterans syndrome (BOS) as its most common phenotype. Bronchiectasis (BRECT), hyperinflation and airtrapping are considered the key features of BOS on chest CT. We investigated whether chest CT and key features have prognostic value at BOS diagnosis in patients with established BOS after LTx. Methods: Double LTx recipients transplanted between 2004-2015 with a survival of >90 days (n=668) who developed BOS (n=118) were included. BOS was defined as a persistent FEV₁ decline of ≥20%, in absence of other conditions explaining FEV₁ decline, restrictive pulmonary function tests or persistent infiltrates. Chest CT was scored at BOS diagnosis by a radiologist experienced in LTx imaging with an adapted Brody score (1 score for the whole lung) and subscores (BRECT score, hyperinflation score, mucous plugging score, peribronchial thickening score and parenchyma score). Post-BOS survival of patients with a score higher than the median was compared with post-BOS survival of patients with a score lower than the median. Results: Patients with a higher adapted Brody score (n=38), demonstrated worse survival compared to patients with a lower adapted Brody score (n=52, p=0.019) (figure). Additionally, patients with a higher mucous plugging score (n=19), peribronchial thickening score (n=32) and parenchyma score (n=70), had worse survival compared to patients with lower mucous plugging score (n=99, p=0.0003), peribronchial thickening score (n=86, p=0.0046) and lower parenchyma score (n=48, p=0.016). In contradiction,
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Results: The top genes associated with CLAD reflected de-differentiation (expression loss), injury (expression gain), and inflammation in both TBBs and 3BMBs. These associations were stronger in 3BMBs. Pathway analysis using the top genes also suggested parenchymal de-differentiation (e.g. loss of transcriptional regulation and mitochondrial function in TBBs) and inflammatory pathway activation, particularly in 3BMBs (Table 1). Gene sets previously annotated in atrophy-scarring, including immunoglobulin transcripts (plasma cells), were elevated in CLAD in TBBs and 3BMBs, but 3BMBs also showed more inflammation-related changes (e.g. interferon gamma effects). Conclusion: Molecular changes associated with CLAD were apparent in TBBs and especially in 3BMBs, and indicate that CLAD is a combination of atrophy/scarring, function loss, and, particularly in 3BMBs, inflammation. Molecular assessment of 3BMBs is a particularly promising opportunity to dissect CLAD biology and potentially gain insight into the BOS variant. ClinicalTrials.gov: NCT02812290
15 Chest CT Has Prognostic Value at BOS Diagnosis after Lung Transplantation A. Van Herck,1 A. Sacreas,1 T. Heigl,1 J. Kaes,1 A. Vanstapel,1 S.E. Verleden,1 B.M. Vanaudenaerde,1 W. De Wever,2 G.M. Verleden,1 and R. Vos.1 1Lung Transplant Unit, Department of Chronic Diseases, Metabolism & Ageing, University of Leuven, Leuven, Belgium; and the 2Department of Radiology, University Hospitals Leuven, Leuven, Belgium.
14 Predictive Biomarkers for Bronchiolitis Obliterans V. Kaza,1 C. Zhu,1 L. Feng,1 A. Reddy,2 C. Lacelle,3 L. Terada,1 M. Manish,1 S. Bollineni,1 A. Banga,1 F. Torres,1 J. Mullins,1 and Q. Li.4 1UT SW Med Ctr, Dallas, TX; 2Southwest Pulmonary Associates, Dallas, TX; 3 UT Southwestern Medical Center, Dallas, TX; and the 4Ut SW Med Ctr, Dallas, TX. Purpose: Chronic Allograft Dysfunction (CLAD) with Bronchiolitis obliterans (BOS) phenotype is a major limitation for long term survival after lung transplantation (LT). Predictive biomarkers for BOS are unavailable. Purpose of our study was to establish a tractable system to evaluate the effects of pre-transplant antibodies to self-antigens (AutoAbs) and to examine specific patterns that correlate with BOS. Methods: Serum samples collected pre-transplant and stored in HLA lab were retreived after IRB approval. Pre-existing AutoAbs in sera were measured using a multiplexed protein array bearing 375 auto antigens developed by Microarray core lab. Microarray data was analyzed using GLMNET in R package. Machine learning program was used to select panel of AutoAbs with best predictive value for BOS. Survival analysis was done using Kaplan-Meier estimation or cox proportional hazards model. Results: 41 recipients who met inclusion criteria were grouped into low BOS (BOS grade 0 and 1, n=20) and high BOS (BOS grade 2, 3; n=21). Survival analysis showed worse survival in patients with higher BOS grade (figure 1A). 75 AutoAbs were significantly higher in high BOS compared to low BOS in pre transplant samples (figure 1B). Top 5 significantly elevated AutoAbs in high BOS were: anti-peptidyl arginine deiminases, anti-endothelial cell extract, anti-MPO, anti beta 2 glycoprotein 1 and anti-ribosomal phosphoprotein1. Using the machine learning program, 15 AutoAbs (figure 1C)were selected for best prediction of BOS with area under curve 0.91, CI (95%) 0.83-0.99. Sensitivity of prediction with the panel is 90% and specificity 85% (figure 1D). Conclusion: Our study points to a panel of 15 AutoAb that can predict BOS before LT. Novel findings reported in our study are being confirmed in a replication cohort. Prediction models with a panel of AutoAb can significantly transform management of LT recipients for improved survival.
Purpose: Long-term survival after lung transplantation (LTx) is hampered by chronic lung allograft dysfunction, with bronchiolitis obliterans syndrome (BOS) as its most common phenotype. Bronchiectasis (BRECT), hyperinflation and airtrapping are considered the key features of BOS on chest CT. We investigated whether chest CT and key features have prognostic value at BOS diagnosis in patients with established BOS after LTx. Methods: Double LTx recipients transplanted between 2004-2015 with a survival of >90 days (n=668) who developed BOS (n=118) were included. BOS was defined as a persistent FEV₁ decline of ≥20%, in absence of other conditions explaining FEV₁ decline, restrictive pulmonary function tests or persistent infiltrates. Chest CT was scored at BOS diagnosis by a radiologist experienced in LTx imaging with an adapted Brody score (1 score for the whole lung) and subscores (BRECT score, hyperinflation score, mucous plugging score, peribronchial thickening score and parenchyma score). Post-BOS survival of patients with a score higher than the median was compared with post-BOS survival of patients with a score lower than the median. Results: Patients with a higher adapted Brody score (n=38), demonstrated worse survival compared to patients with a lower adapted Brody score (n=52, p=0.019) (figure). Additionally, patients with a higher mucous plugging score (n=19), peribronchial thickening score (n=32) and parenchyma score (n=70), had worse survival compared to patients with lower mucous plugging score (n=99, p=0.0003), peribronchial thickening score (n=86, p=0.0046) and lower parenchyma score (n=48, p=0.016). In contradiction,