ON-PPI ASSESSMENT OF REFLUX-RELATED REJECTION RISK IN LUNG TRANSPLANT: NOVEL CRITERIA INSPIRED BY LYON 2.0

Background: Increased reflux detected on ambulatory reflux monitoring has been associated with poor lung transplant outcomes, though prior studies have relied on testing performed off proton pump inhibitor (PPI) therapy. The recent Lyon consensus 2.0 (LC2.0) introduced definitions for pathologic reflux with on-PPI testing. However, the relevance of these criteria for extraesophageal reflux, and lung transplantation outcomes in particular, is unknown.
Aim: To assess the value of on-PPI testing criteria of LC2.0 on lung transplant outcomes, and to develop a novel definition of reflux on PPI to predict lung transplant rejection.
Methods: This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant impedance-pH on twice daily PPI at a tertiary care center. Per LC2.0, subjects with acid exposure time (AET) >4% was classified as conclusive reflux, while AET 1-4% and <1% were deemed inconclusive and evidence against reflux, respectively. Total reflux episodes (TRE) on impedance were categorized at <40, 40-80 and >80 episodes. The primary outcome was acute cellular rejection (ACR) defined histologically per ISHLT criteria. Time-to-event analysis using Cox proportional hazards was applied adjusting for potential confounders, with censoring for antireflux surgery, death, or last clinic visit if outcome was not reached.
Results: 40 subjects (55% men, mean age: 56, 50% IPF, mean follow-up: 4.9 years) were included, with 15 (37%) developing ACR. Multivariable Cox regression analyses showed that AET>4% (HR 7.42, p=0.05), but not AET 1-4% (HR 2.07, p=0.26), predicted shorter time to ACR compared to AET<1%. On the other hand, TRE>80 was not significantly associated with ACR risk (HR 2.63, p=0.42), likely due to few patients with TRE>80 on PPI. We, therefore, combined the TRE 40-80 and >80 groups to establish a new adjunctive criterion of TRE>40. On subgroup analysis of the inconclusive AET 1-4% cohort, those with TRE>40 had significantly increased risk of ACR (HR 6.88, p=0.006), while no patient with TRE<40 developed ACR. A composite marker of pathologic reflux on PPI (AET>4% or AET 1-4% with TRE>40) independently predicted increased ACR, after controlling for potential confounders (Table 1).
Conclusion: Impedance-pH performed on PPI showing AET >4% or AET 1-4% with TRE>40 independently predicted ACR among lung transplant patients. An LC2.0-inspired classification in lung transplant may identify patients for escalation of antireflux therapy to optimize lung allograft outcomes (Figure 1). This further highlights the role of impedance in stratifying patients with inconclusive reflux by AET alone, and underscores its importance in the evaluation of lung transplant patients. Furthermore, AET <1% or TRE<40 represent evidence against pathologic reflux and potential treatment targets for PPI therapy to reduce transplant rejection risk.