Airway Pepsinogen A4 Identifies Lung Transplant Recipients with Microaspiration and Predicts Chronic Lung Allograft Dysfunction

BACKGROUND: Aspiration is a known risk factor for adverse outcomes post -lung transplantation. Airway bile acids are the gold -standard biomarker of aspiration; however, they are released into the duodenum and likely reflect concurrent gastrointestinal dysmotility. Previous studies investigating total airway pepsin have found conflicting results on its relationship with adverse outcomes post -lung transplantation. These studies measured total pepsin and pepsinogen in the airways. Certain pepsinogens are constitutively expressed in the lungs, while others, such as pepsinogen A4 (PGA4), are not. We sought to evaluate the utility of measuring airway PGA4 as a biomarker of aspiration and predictor of adverse outcomes in lung transplant recipients (LTRs) early post -transplant. METHODS: Expression of PGA4 was compared to other pepsinogens in lung tissue. Total pepsin and PGA4 were measured in large airway bronchial washings and compared to preexisting markers of aspiration. Two independent cohorts of LTRs were used to assess the relationship between airway PGA4 and chronic lung allograft dysfunction (CLAD). Changes to airway PGA4 after antireflux surgery were assessed in a third cohort of LTRs. RESULTS: PGA4 was expressed in healthy human stomach but not lung. Airway PGA4, but not total pepsin, was associated with aspiration. Airway PGA4 was associated with an increased risk of CLAD in two independent cohorts of LTRs. Antireflux surgery was associated with reduced airway PGA4. CONCLUSIONS: Airway PGA4 is a marker of aspiration that predicts CLAD in LTRs. Measuring PGA4 at surveillance bronchoscopies can help triage high -risk LTRs for anti-reflux surgery. J Heart Lung Transplant 2024;43:973-982 (c) 2024 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).