TY - JOUR
T1 - Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection
AU - Weigt, S. Samuel
AU - Wang, Xiaoyan
AU - Palchevskiy, Vyacheslav
AU - Li, Xinmin
AU - Patel, N.
AU - Ross, David J.
AU - Reynolds, John
AU - Shah, Pali D.
AU - Danziger-Isakov, Lara A.
AU - Sweet, Stuart C.
AU - Singer, Lianne G.
AU - Budev, M.
AU - Palmer, S.
AU - Belperio, John A.
N1 - Funding Information:
Bronchoalveolar lavage (BAL) is routinely performed concurrently with TBBX to rule out infection. As compared with TBBX, BAL is safer and samples a relatively large area of the lung. We hypothesized that gene expression in the BAL cell pellet (CP) could replace TBBX for the diagnosis of ACR and improve risk stratification for progression to CLAD. Participants in this study provided written informed consent for enrollment in the University of California, Los Angeles (UCLA) lung transplant outcomes registry and biorepository approved by the UCLA institutional review board. This study was sponsored by a Clinical Trials in Organ Transplant ancillary studies grant.
Publisher Copyright:
© 2019 International Society for Heart and Lung Transplantation
PY - 2019/8
Y1 - 2019/8
N2 - BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD. METHODS: We performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC). RESULTS: Differential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell–mediated cytotoxicity, and cytokine–cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29–4.53). CONCLUSIONS: BAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD.
AB - BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD. METHODS: We performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC). RESULTS: Differential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell–mediated cytotoxicity, and cytokine–cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29–4.53). CONCLUSIONS: BAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD.
KW - Acute cellular rejection
KW - Lung transplant
KW - bronchoalveolar lavage
KW - gene expression
KW - genomic classifier
KW - transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85065829733&partnerID=8YFLogxK
U2 - 10.1016/j.healun.2019.05.001
DO - 10.1016/j.healun.2019.05.001
M3 - Article
C2 - 31122726
AN - SCOPUS:85065829733
SN - 1053-2498
VL - 38
SP - 845
EP - 855
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 8
ER -