(414) Longitudinal analysis of early life bronchoalveolar fluid identifies immune mediators associated with bronchiectasis risk in children with CF

Background: In cystic fibrosis (CF), immunoinflammatory dysfunction is a critical contributor to lung tissue damage, including progressive development ofbronchiectasis (Bx). We investigated whether immune mediators in a longitudinal sample set from early and late preschool subjects with CF associated with Bx development.

Methods: Stored bronchoalveolar lavage (BALF) fluid collected annually from 14 subjects from 0.5-5 years were analyzed to quantify soluble immune mediators. Twenty immune mediators were measured using a high-sensitivity chemiluminescent assay (U-PLEX; Meso Scale Diagnostics) well-suited to pediatric BALF samples. Based on chest CT scans taken at the age of 9, samples were categorized as Bx- or Bx+. Samples were grouped between ages 0.5, 1, and 2 years as early preschool (3 time points), and at ages 3, 4, and 5 (3 time points) as late preschool. The Mann-Whitney test was conducted to identify differences between groups, using the Benjamini, Krieger, and Yekutielimethodto control the false discovery rate.

Results: In early preschool timepoints, BALF showed increased CCL2 (p= 0.0006), CXCL8 (IL-8) (p= 0.002), IL-1beta (p= 0.001) and M-CSF (p= 0.0006) in Bx+ subjects compared to Bx-. In late preschool timepoints, the same four mediators CCL2 (p= 0.0002), CXCL8 (p= 0.00002), IL-1beta (p= 0.0005) and M-CSF (p= 0.00001), as well as TNFalpha (p= 0.0005) were also elevated in Bx+ subjects compared to Bx-. Interestingly, immune mediator concentrations in BALF did not differ between early and late preschool timepoints for either Bx+ or Bx- groups.

Conclusions: We identified elevated levels of multiple immune mediators in early and late preschool BALF samples from pediatric CF subjects who eventually developed Bx. These data validate previous association of Bx development with CXCL8/IL-8 and IL-1beta (incriminating epithelial cells and neutrophils) and also identify CCL2, and M-CSF, suggesting a role for monocytes/macrophages. These data also suggest that alterations in the immunoinflammatory microenvironment established at early preschool ages are maintained through late preschool, both for patients who develop Bx and those who do not. Thus, early imbalance in immune regulation in CF lungs may reliably predict later structural damage. With further validation in independent cohorts, measurement of these markers early in life may help predict the risk of future development of bronchiectasis and tailor treatments for preschool subjects with CF.





Acknowledgements: Support: NHMRC SYNERGY Award APP1183640.

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