Bronchoalveolar lavage cytokine-based risk stratification of minimal acute rejection in clinically stable lung transplant recipients
Section snippets
Study design
This was a single-center, retrospective cohort study based on prospectively collected BAL samples. The study was approved by the Institutional Research Ethics Board (Approval number 15-9531-AE). The study population consisted of all adult, bilateral, first lung transplant recipients at Toronto General Hospital who underwent a lung transplant operation between January 1, 2010, and December 31, 2016, and had a minimum of 2 post-transplant forced expiratory volume in 1 second (FEV1) measurements.
Statistical analysis
Demographic characteristics were assessed as counts and percentages for categorical variables and as standard measures (median and interquartile range) for continuous variables. For the primary analysis, univariable and multivariable Cox Proportional Hazards models were used for evaluating the association of BAL protein levels with time from first CSA1R to CLAD or death/retransplant. For time to CLAD analyses, patients who died without CLAD were censored at their date of death. For time to
Study population and patient characteristics
Of all adult, bilateral, first lung transplant recipients who underwent a transplant operation between January 1, 2010, and December 31, 2016, 104 patients with clinically stable first A1 ACR, not preceded by ≥A1 ACR, were included in the pool of potential participants for the primary analysis (Figure 1). After excluding 29 patients (concurrent infection, missing BAL samples, or biopsy obtained after CLAD diagnosis), we identified 75 patients with a first CSA1R, occurring at a median time of 98
Discussion
In this unique cohort of patients with a first, clinically stable, untreated, minimal AR, at a median time of 3 months post-transplant, we were able to identify a protein signature associated with progression to CLAD or death/retransplant. Using a hypothesis-driven approach, we identified 7 individual biomarkers associated with subsequent CLAD and 12 associated with subsequent death. Five of these markers (IL10, PTX 3, S100A8, TNF-R1, and MCP1/CCL2) demonstrated a strong predictive capacity for
Authors' contributions
TM conceived the research concept, supervised the project, oversaw data analysis, and made critical revisions to the manuscript. LL designed and supervised the study, analyzed the data, and wrote the manuscript. EH performed all statistical analyses and made critical revisions to the manuscript. LL, MA, WK, JT, RG collected and organized the clinical data and revised the final manuscript. LL, SH, KZ organized samples for analysis, and together with KB, SM carried out the multiplex assay and
Disclosure statement
The authors of this manuscript have no conflicts of interest to disclose.
The authors would like to thank the Toronto Lung Transplant Program Biobank team for helping with sample collection and retrieval.
This research was supported in part by a grant from The Canadian Institutes of Health Research (#149094, to TM and SJ), a grant from The Physicians’ Services Inc. Foundation (#17–22, to LL and TM), and by a Cystic Fibrosis Canada grant (#12787, to LL).
Reference (59)
- et al.
The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: multiorgan transplantation
J Heart Lung Transplant
(2018) - et al.
Risk factors for bronchiolitis obliterans: a systematic review of recent publications
J Heart Lung Transplant
(2002) - et al.
Acute cellular rejection is a risk factor for bronchiolitis obliterans syndrome independent of post-transplant baseline FEV1
J Heart Lung Transplant
(2009) - et al.
The registry of the international society for heart and lung transplantation: thirty-fourth adult lung and heart-lung transplantation report-2017; focus theme: allograft ischemic time
J Heart Lung Transplant
(2017) - et al.
Spirometrically significant acute rejection increases the risk for BOS and death after lung transplantation
Am J Transplant
(2012) - et al.
Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection
J Heart Lung Transplant
(2007) - et al.
Surveillance bronchoscopy in lung transplant recipients: risk versus benefit
J Heart Lung Transplant
(2008) - et al.
The impact of first untreated subclinical minimal acute rejection on risk for chronic lung allograft dysfunction or death after lung transplantation
Am J Transplant
(2020) - et al.
Significance of a solitary perivascular mononuclear infiltrate in lung allograft recipients with mild acute cellular rejection
J Heart Lung Transplant
(2005) - et al.
Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans syndrome
Am J Transplant
(2005)