Post-transplant trajectories of the CRP-to-albumin ratio identify a late-emerging high-risk phenotype in interstitial lung disease

BACKGROUND: After bilateral lung transplantation for interstitial lung disease (ILD), most recipients recover well, but some deteriorate over the following years. The C-reactive protein-to-albumin ratio (CAR) combines a marker of systemic inflammation (CRP) with one of nutritional and hepatic-synthetic reserve (albumin); a rising ratio reflects worsening inflammation against falling reserve. We assessed whether tracking CAR over time identifies the subgroup at risk. METHODS: We studied 138 consecutive adult ILD recipients of bilateral lung transplants (Giessen, 2000 to 2026), with a median of 13 paired CRP and albumin measurements each. Using group-based trajectory modelling, we grouped patients by the trajectory of their CAR from the first routine follow-up visit (month 4) to year 5, then related the groups to five-year survival and the Clinical Frailty Scale (CFS). RESULTS: Three CAR trajectories emerged. Most patients were stable-low (39%, CAR near zero throughout) or resolving (38%, initially high then falling). The key group was CAR-rising (23%): at four months these patients were indistinguishable from the best-recovering stable-low group but then climbed steadily over the following years. Five-year survival was 92%, 61% and 69% in the stable-low, rising and resolving groups (log-rank p = 0.029; rising versus stable-low hazard ratio 4.5, 95% CI 1.2 to 17.1). A landmark analysis among patients alive at year 2 confirmed this late risk: 33% of the rising group died over the next three years versus 5% of the stable-low group (p = 0.005). In the pre-specified model, phenotype membership was not predicted by ILD subtype or LAS at listing (likelihood-ratio p = 0.16); pre-transplant CAR itself differed modestly across the groups (p = 0.049) but was not prognostic for survival. The CFS trajectory, scored independently of CRP and albumin, showed the same pattern: groups were equally frail before transplant (p = 0.83) but separated afterwards (p = 0.01 at 4 months, p = 0.001 at 5 years), the adverse groups drifting back toward frailty. CONCLUSIONS: A simple test already measured at every post-transplant visit, the CRP-to-albumin ratio, can be read as a trajectory to identify the ILD recipients who enter an inflammatory and nutritional decline associated with worse five-year survival. These findings are hypothesis-generating, and further work is needed to establish what drives the CAR trajectory before any clinical application. TRIAL REGISTRATION: The analysis draws on two registries: the European IPF Registry and Biobank (eurIPFreg; ClinicalTrials.gov NCT02951416, registered 1 November 2016) and the European ILD Registry and Biobank (eurILDreg; German Clinical Trials Register DRKS00028968, registered 26 July 2022).