Exploring fibroblast activation protein as an early biomarker in chronic lung allograft dysfunction

QUESTION: Chronic lung allograft dysfunction (CLAD) is the leading cause of late graft failure after lung transplantation. Fibroblast activation protein (FAP) is selectively upregulated in activated fibroblasts under fibrotic conditions. We asked whether FAP expression is increased in CLAD and whether it can serve as an early diagnostic marker. MATERIALS AND METHODS: We performed single-cell RNA sequencing on two murine orthotopic lung transplant models (C57BL/6→C57BL/10 and BALB/c→C57BL/6) and human lung tissue from five controls and five patients with CLAD. We quantified FAP expression by immunohistochemistry in transbronchial biopsies from 240 lung transplant recipients (62 with CLAD and 178 without CLAD). Receiver-operating characteristic curves determined an optimal FAP-positive area threshold. Kaplan-Meier analysis and Cox proportional hazards models assessed the association between FAP positivity and CLAD. RESULTS: In both murine and human single-cell data, FAP expression was confined to pathogenic fibroblast subsets and was significantly elevated in CLAD. In the clinical cohort, a threshold of 10.8% FAP-positive area discriminated chronic dysfunction with an area under the curve of 0.78 (95% CI 0.72-0.85), sensitivity of 65% and specificity of 84%. FAP positivity predicted shorter CLAD-free survival (p<0.0001) and overall survival (p=0.03). The hazard ratio for CLAD was 5.23 (95% CI 3.11-8.82; p<0.001), remaining significant after multivariable adjustment (hazard ratio 5.43, 95% CI 3.22-9.16; p<0.001). ANSWER: FAP expression is elevated in CLAD and is associated with subsequent CLAD and survival. Tissue FAP may enable early risk stratification and inform clinical surveillance; however, given its moderate discrimination, prospective validation in multicentre cohorts is warranted.