Molecular biopsy features associated with baseline lung allograft dysfunction in a multicenter international cohort

Baseline lung allograft dysfunction (BLAD) is a state of abnormally low peak post-transplant lung function, but the mechanisms are poorly understood. In this study, we examined transbronchial biopsy (TBB) gene expression changes associated with BLAD in an international cohort of prospectively enrolled lung transplant recipients.

BLAD status was assessed at 1-year post-transplant and defined as failure to reach normal lung function, as defined by a forced expiratory volume in 1 s and a forced vital capacity > 80% predicted on two consecutive occasions > 3 weeks apart. We used genome-wide microarray measurements in 252 TBBs obtained during the first post-transplant year from 214 double lung transplant recipients to identify top genes and pathogenesis-based transcript sets in BLAD and develop a molecular BLAD classifier.

BLAD at 1-year post-transplant was diagnosed in 41% of patients and was more frequent in patients with interstitial lung disease (ILD) as transplant indication. TBBs from patients with BLAD showed increased transcripts associated with T cell-mediated rejection (TCMR) and cytotoxic T cell burden. BLAD biopsies were more likely to be classified as TCMR archetype - despite no differences in histology - and low surfactant archetype and less likely to be classified as no rejection. A molecular classifier developed to predict BLAD showed modest performance (AUC 0.58), which improved to 0.64 with the inclusion of clinical variables.

TBBs obtained during the first post-transplant year from patients with BLAD exhibit more frequent molecular features of TCMR not detected by histology, suggesting undetected or undertreated rejection may be contributing to poorer post-transplant lung function.