Small airway brush gene expression predicts chronic lung allograft dysfunction and mortality

Area of Science:

• Pulmonary Medicine
• Transplant Immunology
• Molecular Diagnostics

Background:

• Chronic lung allograft dysfunction (CLAD) significantly impacts lung transplant recipient survival.
• Current diagnostic methods for CLAD detect substantial lung damage after disease onset.
• Early identification of CLAD risk and prediction of graft failure are critical unmet needs.

Purpose of the Study:

• To investigate small airway gene expression patterns for early CLAD risk identification.
• To develop a gene expression signature that predicts subsequent graft failure in lung transplant recipients.

Main Methods:

• A derivation cohort of 156 small airway brushes from CLAD cases and controls was used to identify candidate genes.
• Genes associated with CLAD and graft failure were selected, forming the Airway Inflammation 2 (AI2) gene set.
• An independent validation cohort assessed the AI2 score's diagnostic and prognostic performance using receiver operating characteristic (ROC) analysis.

Main Results:

• The AI2 gene score identified CLAD before clinical diagnosis and in early/late post-CLAD stages (AUC 0.69-0.88).
• The AI2 score's association with CLAD was independent of microbiology, CLAD stage, or subtype.
• The AI2 score accurately predicted time to graft failure and retransplant-free survival in both derivation and validation cohorts (p ≤ 0.03).

Conclusions:

• The developed airway inflammation gene score (AI2) is a promising biomarker for CLAD development and progression.
• This score associates with lung allograft failure and mortality post-transplant.
• Further research into molecular heterogeneity of airway inflammation may enable targeted therapies for CLAD.