Age-Linked Neutrophilic Inflammation Signatures Associate with Disease Severity in Primary Ciliary Dyskinesia 2309093

Abstract

Abstract Introduction 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. Funding Source Research Centers in Minority Institutions (RCMI) Center for Research Resources Grant and the Molecular and Genomics Core (#U54MD007579), PR-INBRE Developmental Research Project Program (DRPP) (#5P20GM103475-21), Graham Grant. Topic Categories Immune Mechanisms of Human Disease (HUM)