Background. In pediatric liver transplantation (pLT), follow-up liver biopsies (fLBs) frequently reveal subclinical histological abnormalities, despite normal liver function tests. Findings, including inflammation, fibrosis, and immune-mediated changes, suggest overlapping alloimmune and autoimmune mechanisms with potential long-term consequences. Methods. We performed a prospective, single-center cohort study at the Vall d’Hebron Barcelona Hospital Campus, including 167 children who underwent 299 liver biopsies (214 protocol, 85 post–immunosuppression modification) from 2018 to 2024. Immunosuppression was adjusted according to a preestablished histology-guided protocol, intensifying therapy in patients with subclinical T cell–mediated rejection (S-TCMR; Banff Rejection Activity Index ≥2) detected in protocol biopsies. Results. S-TCMR was identified in 71 of 214 (33.2%) protocol biopsies, with fibrosis (Ishak ≥2) in 38 (53.5%). Following protocol-driven immunosuppressive intensification, 57 of 71 (80.3%) achieved S-TCMR resolution at 12 mo, with 8 of 12 showing further improvement at 24 mo. Fibrosis regressed by ≥1 Ishak stage in 21 of 38 (55.3%). Autoantibody responders showed superior S-TCMR ( P = 0.006) and fibrosis outcomes ( P = 0.05). Donor-specific antibody–positive patients exhibited lower S-TCMR resolution (odds ratio OR, 3.3; P = 0.1) and a higher risk of persistent fibrosis (OR, 4.8; P = 0.03). Plasma cell–rich S-TCMR (18/71 25.4%) strongly correlated with C4d deposition (5-fold increase) and markedly reduced fibrosis regression (OR, 11.0; P < 0.001), indicating resistance to standard immunosuppression. Conclusions. Histology-guided, protocol-driven immunosuppression intensification effectively reversed most S-TCMR and fibrosis, underscoring the importance of long-term protocol biopsies for individualized therapy in pLT.
Quintero-Bernabeu et al. (2026) studied this question.