Impact of intrinsic and extrinsic risk factors on early-onset lung disease in cystic fibrosis.

Background: Although respiratory pathology is known to develop in young children with cystic fibrosis (CF), the determinants of early-onset lung disease have not been elucidated.

Objective: We aimed to determine the impact of potential intrinsic and extrinsic risk factors during the first 3 years of life, testing the hypothesis that both contribute significantly to early-onset CF lung disease.

Design: We studied 104 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and evaluated comprehensively to 36 months of age. Lung disease manifestations were quantified with a new scoring system known as CFELD for Cystic Fibrosis Early-onset Lung Disease. The variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were determined and categorized. Whole genome sequencing was performed on each subject and the data transformed to polygenic risk scores (PRS) that aggregate variants associated with lung function. Extrinsic factors included socioeconomic status (SES) indicators and environmental experiences such as exposures to smoking, pets, and daycare.

Results: We found by univariate analysis that CFTR genotype and genetic modifiers aggregated by the PRS method were significantly associated with early-onset CF lung disease. Ordinal logistic regression analysis demonstrated that high and stable SES (maternal education ≥community college, stable 2-parent home, and not receiving Medicaid) and better growth (weight-for-age and height-for-age z-scores) reduced risks, while exposure to smoking and daycare ≥20 h/week increased the risk of CFELD severity.

Conclusions: Extrinsic, modifiable determinants are influential early and potentially as important as the intrinsic risk factors in the onset of CF lung disease.