A Molecular Reappraisal of Quilty Lesions: Insights from Tissue and Circulating Biomarkers in Heart Transplantation.
Academic Article
Overview
abstract
INTRODUCTION: Quilty lesions are characterized by nodular T-lymphocyte infiltrates in the endocardium of transplanted hearts. Their clinical significance is still not fully understood and remains controversial. In this study, we investigate the relationship between Quilty lesions and rejection using tissue-based transcriptomic diagnostics and explore their impact on clinical outcomes. METHODS: This study included consecutive single-organ for-cause endomyocardial biopsies (EMB) undergoing Molecular Microscope Analysis (MMDx) between November 2022-March 2025) and classified into four histology-Quilty groups (R-/Q-, R-/Q+, R+/Q-, R+/Q+). Donor specific antibodies (DSA), circulating biomarkers including donor-derived cell-free DNA (dd-cfDNA), gene-expression profiling (GEP), and MMDx results were compared using generalized estimating equations. The primary outcome was a composite of mortality, graft dysfunction, or need for re-transplantation, evaluated using clustered Cox proportional hazards models with administrative censoring at 2 years. Secondary outcomes included future histologic rejection and persistent dd-cfDNA elevation. Individual components of the primary outcome, along with secondary outcomes and Quilty recurrence, were additionally evaluated. RESULTS: The cohort included 579 EMB from 303 recipients; overall, 62 biopsies (10.7%) demonstrated Quilty lesions, 42 of which occurred in histology-negative samples. Baseline characteristics were similar across groups, although Quilty+ biopsies were more frequently in patients with prior history of treated acute cellular rejection (ACR). Quilty+ samples exhibited higher dd-cfDNA and GEP levels and substantially increased molecular rejection, driven by TCMR (R-/Q- 2.8% vs 11.4% in R+/Q- vs R-/Q+ 16.7% vs R+/Q+ 30.0%; global p<0.001). Among histology-negative biopsies, these associations were even stronger. Quilty+ samples had seven-fold higher odds of TCMR (16.7% vs 2.8%; OR 6.90; 95% CI 2.38-20.96; p <0.001). Transcriptomic analyses revealed a reproducible TCMR-dominant signature with modest ABMR/NK-cell contributions. PET imaging demonstrated lower stress MBF in Quilty+ biopsies (β -0.34 mL/min/g; p=0.06). Over a median 1.53-year follow-up, Quilty positivity was not associated with the composite of death or graft dysfunction (HR 1.12; 95% CI 0.53-2.38), but was associated with the immunologic composite (HR 1.86; 95% CI 1.23-2.80), driven by persistent dd-cfDNA elevation (HR 2.51; 95% CI 1.58-3.97), and strongly predicted future Quilty recurrence (HR 3.60; 95% CI 2.07-6.27). CONCLUSION: Quilty lesions were associated with higher dd-cfDNA levels, elevated GEP, and a TCMR-weighted molecular signature on MMDx. Although Quilty was not linked to increased risks of mortality, subsequent graft dysfunction or histologic rejection, it was associated with persistent dd-cfDNA elevation during follow-up, suggesting a pattern of ongoing low-grade alloimmune activity. These findings are hypothesis-generating and support the need for longitudinal studies to define the role of Quilty lesions in contemporary heart-transplant surveillance.
