# Prognostic impact of restrictive ventilatory defects in chronic lung allograft dysfunction without restrictive allograft syndrome-like opacities: Stratification of emerging undefined and unclassified phenotypes

## TL;DR

This study finds that restrictive ventilatory defects in non-RLO chronic lung allograft dysfunction are linked to worse survival outcomes, challenging previous assumptions about prognosis.

## Contribution

The study identifies restrictive ventilatory defects and pleural effusion as significant prognostic factors in non-RLO CLAD cases.

## Key findings

- Restrictive ventilatory defects in non-RLO CLAD are significantly associated with increased death risk when accounting for retransplantation.
- Pleural effusion is an independent prognostic factor for worse outcomes in non-RLO CLAD patients.
- Non-RLO CLAD cases with restrictive defects do not follow a favorable BOS-like prognosis.

## Abstract

Chronic lung allograft dysfunction (CLAD) remains a critical factor affecting post-lung transplant prognosis. While RAS-like opacities (RLO) are established as poor prognostic indicators, prognostic stratification of non-RLO CLAD cases, including undefined and unclassified phenotypes per the 2019 International Society for Heart and Lung Transplantation (ISHLT) criteria, remains unexplored.

We retrospectively analyzed 241 bilateral lung transplant recipients between 2005 and 2021. CLAD was diagnosed and classified per the 2019 ISHLT criteria. Non-RLO patients were stratified by restrictive ventilatory defects for survival analysis. Diaphragmatic elevation and pleural effusion were also evaluated as potential causes of restrictive physiology and their prognostic significance.

Of 83 CLAD patients, 61 (73.5%) had no RLO. In multivariable Cox analysis of non-RLO patients, restrictive ventilatory defects showed a trend toward worse outcomes (Hazard ratio [HR]: 2.56, 95% CI: 0.98–6.71; p = 0.055), while obstructive defects showed no association (HR: 0.88, p = 0.785). When accounting for retransplantation as a competing event using Fine-Gray regression, restrictive ventilatory defects were significantly associated with increased cumulative incidence of death (subdistribution HR: 2.96, 95% CI: 1.17–7.51; p = 0.022). Pleural effusion showed a trend toward association with restrictive defects (p = 0.063) and emerged as an independent prognostic factor (HR: 5.06, 95% CI: 1.57–16.27; p = 0.007).

Non-RLO CLAD patients with restrictive ventilatory defects demonstrated significantly increased cumulative incidence of death (retransplantation as a competing risk), challenging the assumption that all non-RLO cases follow a favorable BOS-like prognosis. Pleural effusion was identified as a significant independent prognostic marker.