FROM LYON TO LUNG TRANSPLANT, TAKE 2.0: PRE-TRANSPLANT REFLUX SEVERITY WITH ADJUNCTIVE IMPEDANCE DATA PREDICTS CHRONIC REJECTION AND MORTALITY AFTER LUNG TRANSPLANT

Background: Gastroesophageal reflux disease has been associated with poor lung transplant outcomes, through a putative mechanism of reflux-induced aspiration leading to recurrent allograft injury. However, the optimal diagnostic and classification protocol to identify those at risk for reflux-related allograft rejection remains debated. The recent Lyon consensus 2.0 (LC2.0) provides updated guidance to assess evidence of reflux for escalation of anti-reflux therapy, although its role in lung transplant patients is unclear. Establishing criteria specific to this population may guide clinical management and improve transplant outcomes.
Aim: To evaluate the predictive value of reflux testing using LC2.0 framework for lung transplant outcomes and to develop/validate a classification scheme specific to this population.
Methods: This was a retrospective cohort study of lung transplant recipients who underwent pre-transplant impedance-pH off PPI at a tertiary care center, with chronic lung allograft dysfunction (CLAD) and all-cause mortality as the primary and secondary outcomes, respectively. CLAD was defined clinically and histologically per ISHLT criteria. Time-to-event analysis using Cox proportional hazards was utilized. Subjects not meeting the outcomes were censored at anti-reflux surgery, death (CLAD only) or last clinic visit. Fisher’s exact test (binary variables) and student’s t-test (continuous variables) were performed to assess for differences between reflux cohorts.
Results: 184 subjects (58% men, mean age: 58, 37% IPF, mean follow-up: 4.4 years) were included, with 71 (38%) experiencing CLAD and 68 (37%) deaths. Subjects were classified by LC2.0 criteria into reflux cohorts by acid exposure time (AET): conclusive (AET>6%), inconclusive (AET 4-6%), and no reflux (AET<4%). Patients with AET 4-6% were further stratified by the adjunctive criterion total reflux episodes (TRE) >80 (Table 1). Cox regression analysis demonstrated that AET>6% (HR 2.30, p=0.01) and AET 4-6% with TRE >80 (HR 3.00, p=0.05), but not AET 4-6% with TRE <80, predicted increased risk of CLAD compared to AET <4% (Table 2). On secondary analysis, AET>6% (HR 2.69, p=0.004) was also associated with increased mortality, with AET 4-6% with TRE >80 also showing a similar trend.
Conclusion: Conclusive reflux (AET>6%) per LC2.0 and inconclusive reflux (AET 4-6%) with elevated TRE (>80) predicted increased risks of CLAD and mortality in lung transplant patients. Reflux monitoring that includes impedance is relevant in this population, by stratifying those with inconclusive reflux based on AET alone to determine those at higher risk for poor outcomes. Our study supports a practical and standardized clinical classification (Figure 1) to identify lung transplant patients at risk for reflex-related complications, who may benefit from more aggressive reflux management to enhance outcomes.