(214) Age-Linked Neutrophilic Inflammation Signatures Associate with Disease Severity in Primary Ciliary Dyskinesia

Introduction/Rationale: Primary ciliary dyskinesia (PCD) is characterized by chronic neutrophil-predominant airway inflammation, yet spirometric measures alone incompletely capture disease heterogeneity and progression. Quantitative inflammatory signatures may help identify biologically meaningful disease phenotypes beyond spirometry alone.

Methods: Plasma samples were collected from genetically confirmed PCD patients at clinical baseline, defined by the absence of acute respiratory exacerbation. Using high-sensitivity NULISA™ proteomic profiling, we quantified ten neutrophil-associated inflammatory and remodeling markers (MPO, CXCL8, S100A9, LCN2, MMP8, MMP9, CCL3, CCL4, CCL20, and CCL2). A composite Neutrophil Inflammation Score (NIS) was defined as the mean z-score of these markers. A Neutrophil-to-Lung Function Index (NLFI) was calculated by normalizing NIS to FEV1 % predicted, integrating inflammatory burden with airway function. Patients were stratified into High- and Low/Moderate-inflammation groups. Associations with age and lung function were examined.

Results: NIS was significantly higher in PCD patients compared with healthy controls (p = 0.0020). Within the PCD cohort, NIS showed no significant association with lung function (FEV₁ % predicted; r = –0.232, p = 0.4244), but demonstrated a significant positive association with age (r = 0.552, p = 0.0438). Patients in the High-inflammation group exhibited markedly reduced lung function compared with the Low/Moderate group (Cohen’s d = –1.25). The NLFI increased across age strata, with the highest values observed in older patients. This shows that with aging and disease progression, neutrophilic inflammation increases while lung function declines.

Conclusion: Quantitative neutrophil-inflammatory profiling showed an age-linked, high-risk inflammatory endotype in PCD that is not apparent from spirometry alone. Integrated inflammatory indices may improve patient stratification and inform current and future studies of neutrophil-targeted therapeutic strategies.