Application of plasma donor-derived cell free DNA for lung allograft rejection diagnosis in lung transplant recipients

Abstract

Background Donor-derived cell-free DNA (dd-cfDNA) has been applied to monitor acute rejection (AR) in kidney and heart transplantation. This study was aimed to investigate the application of dd-cfDNA levels in the diagnosis of AR and chronic lung allograft dysfunction (CLAD) among the lung transplantation recipients (LTRs). Methods One hundred and seventy LTRs were enrolled at the First Affiliated Hospital of Guangzhou Medical University between 1 June 2015 and 30 March 2021. Patients were divided into 4 groups: stable group, AR group, infection group and CLAD group. The level of dd-cfDNA was analyzed using target region sequencing and the performance characteristics of dd-cfDNA for diagnosis of AR and CLAD were determined, respectively. Results Kruskal–Wallis test showed that there were some significant differences in the level of dd-cfDNA (%) among the 4 groups, with p < 0.001. Among them, the level of dd-cfDNA (%) was highest (median 2.17, IQR [1.40–3.82]) in AR group, and higher in CLAD group (median 1.07, IQR [0.98–1.31]), but lower in infection group (median 0.71, IQR [0.57–1.07]) and lowest in stable group (median 0.71, IQR [0.61–0.84]). AUC-ROC curve analysis showed that the threshold of dd-cfDNA for AR was 1.17%, with sensitivity being 89.19% and specificity being 86.47%, and the optimal threshold of 0.89% was determined of CLAD, with sensitivity being 95.00% and specificity of 76.99%. Conclusions Plasma dd-cfDNA could be a useful tool for the assessment of lung allograft rejection, including AR and CLAD, and holds promise as a noninvasive biomarker for “allograft injury” in both acute and chronic rejection following lung transplantation.

Differentiation between lung allograft rejection and infection using donor-derived cell-free DNA and pathogen detection by metagenomic next-generation sequencing

“…Elevated plasma dd-cfDNA levels in the rejection group are consistent with previous findings [ 7 , 11 ]. However, dd-cfDNA levels were also found to be slightly elevated in the infection group, especially in cases of CMV infection.…”

“…In our previous study, we explored plasma dd-cfDNA levels and lung allograft rejection in Chinese LTRs, and our preliminary results suggest that elevated dd-cfDNA levels could be a promising tool for diagnosing rejection in lung transplantation [ 11 ]. Generally, lung allograft rejection should be differentiated from infection, with a negative pathogen result being required.…”

Circulating donor-derived cell-free DNA as a marker for rejection after lung transplantation

“…After a careful review of the titles and abstracts, 304 articles were excluded for duplicate and irrelevance, of which 61 articles were selected for additional screening based on the full text. Finally, a total of 16 studies were included in this systematic review and meta-analysis ( 19 – 34 ).…”

“…A summary of characteristics of the included studies was shown in Tables 1 , Table 2 . Eleven studies were from USA ( 21 , 23 – 28 , 31 – 36 ), 1 study from France ( 20 ), 1 study from Italy ( 22 ), and 1 study from Japan ( 29 ), and two studies from China ( 19 , 30 ). In total, eleven studies measured dd-cfDNA levels in graft rejection ( 19 , 21 , 22 , 25 , 26 , 28 – 30 , 32 , 34 ), 6 studies measured dd-cfDNA levels in ACR ( 23 – 25 , 27 , 31 , 33 ), and 7 studies measured dd-cfDNA levels in AMR ( 21 , 23 – 25 , 31 , 33 , 34 ), respectively.…”

“…Eleven studies were from USA ( 21 , 23 – 28 , 31 – 36 ), 1 study from France ( 20 ), 1 study from Italy ( 22 ), and 1 study from Japan ( 29 ), and two studies from China ( 19 , 30 ). In total, eleven studies measured dd-cfDNA levels in graft rejection ( 19 , 21 , 22 , 25 , 26 , 28 – 30 , 32 , 34 ), 6 studies measured dd-cfDNA levels in ACR ( 23 – 25 , 27 , 31 , 33 ), and 7 studies measured dd-cfDNA levels in AMR ( 21 , 23 – 25 , 31 , 33 , 34 ), respectively. Eleven studies evaluated the diagnostic accuracy of circulating dd-cfDNA in graft rejection ( 19 , 21 – 25 , 27 , 28 , 30 , 33 ), providing AUROC, sensitivity and specificity.…”