Distinct pulmonary pathophysiological mechanisms in COPD, bronchiectasis, and primary immunodeficiency: a multi-omics investigation of disease heterogeneity via sputum and blood profiling

Bronchiectasis (BE), Chronic Obstructive Pulmonary Disease (COPD) and Primary Immunodeficiency (PID) are distinct respiratory conditions that share features such as chronic inflammation, airway obstruction, and recurrent infections. Despite distinct underlying causes, disease manifestations often overlap clinically, complicating diagnosis and treatment. We aimed to characterise shared and disease-specific immune mechanisms in BE, COPD, and PID using a multi-omics approach across blood and sputum. Adults with BE, COPD, PID, and healthy controls underwent serum and sputum protein quantification, sputum proteomics, and transcriptomic profiling of sputum and blood. Neutrophil fractions were included as covariates in transcriptomic analyses. Distinct clinical profiles were observed across disease groups. Serum analyses showed changes in inflammatory and extracellular matrix markers, particularly in BE and COPD. Sputum from BE patients showed elevated inflammatory markers and pathogen burden. Proteomic profiling demonstrated that BE and COPD shared neutrophil-driven inflammatory pathways, while PID exhibited a unique humoral immune signature. Transcriptomic analyses further confirmed neutrophil abundance as a major driver of gene expression variation across disease cohorts. After adjusting for neutrophil fractions, disease-specific differentially expressed genes (DEG) were identified, including OLFML2B, FZD2, and STAB1 in BE, and GPR15, METTL7B, and RNASE1 in COPD. PID samples showed no significant DEGs but enrichment of interferon signalling pathways. CD177 and DEFA3 were overexpressed beyond variation driven by neutrophil abundance, highlighting association with key inflammatory drivers in BE and COPD. This study uses an integrative multi-omics analysis to improve the understanding of disease heterogeneity and distinct inflammatory pathways in BE, COPD and PID.