Prognostic validation of the 2019 ISHLT chronic lung allograft dysfunction states in lung transplant recipients

Background The 2019 ISHLT consensus chronic lung allograft dysfunction (CLAD) definition introduced a standardized classification for CLAD into potential, possible, probable and definite stages, based on the degree and persistence of FEV1 decline. While probable and definite CLAD have been associated with graft loss, the significance of earlier stages remains unclear. Aim This study aimed to validate the 2019 ISHLT CLAD classification system under simulated prospective conditions and to define their prognostic and clinical relevance. Methods In 482 lung allograft recipients with measurable baseline FEV1, CLAD states were assigned longitudinally for 10312 pulmonary function tests according to ISHLT 2019 criteria. Each CLAD state was modeled as a time-dependent covariate to assess mortality risk in multivariable Cox regression analysis. Transitions between CLAD stages were evaluated by Kaplan-Meier and Cox regression models. Results Possible CLAD was the earliest stage independently associated with increased mortality (HR 2.8 95-% confidence interval 1.7–4.5), similar to probable and definite CLAD (HR 3.5 1.8–7.6 and 3.5 2.4–5.2, respectively). Most lung allograft recipients with possible CLAD progressed to probable/definite CLAD, confirming its clinical importance. In contrast, potential CLAD frequently resolved and was not associated with increased mortality, identifying it as early but reversible warning signal. Conclusion Potential CLAD shows uncertain prognostic significance, underscoring the need for biomarkers to identify patients at risk of progression. Possible CLAD is independently linked to increased mortality and defines the earliest actionable stage of chronic allograft dysfunction, for timely intervention.