PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is a chronic, multi-organ process characterized by inspissated secretions that adversely impact the upper and lower airway, gastrointestinal tract, and other organ systems. Chronic rhinosinusitis (CRS) is a prevalent and clinically impactful disease complication in individuals with CF. CRS is detrimental to quality of life, impairs pulmonary status and worsens overall disease state. Olfactory dysfunction is a key feature of CRS, further worsens quality of life, and is associated with depression and nutritional alterations. These comorbidities are significantly understudied in young children with CF (YCwCF). Highly effective CF transmembrane conductance regulator modulator therapy (HEMT) improves pulmonary health and certain extra- pulmonary domains for adults with CF. Previous research showed that adults with CF have substantial improvement in CRS after HEMT initiation. However, prior work demonstrated that adults treated with HEMT did not have improvements in olfactory dysfunction or have complete resolution of sinus disease. Given that airway inflammation and infection are present for a short time in young children (before starting HEMT), we anticipate that initiating therapy at an early age will lead to substantial improvement in CRS and olfactory dysfunction. The goals of this study are to characterize CRS and olfactory dysfunction in YCwCF and test the hypothesis that these comorbidities improve with HEMT. This prospective, observational, multi-center study will pair with a prospective, observational, multi-center study of outcomes in YCwCF that will investigate changes in other domains (pulmonary, microbiological, endocrine, and gastrointestinal) following initiation of HEMT. In this study, CRS and olfactory dysfunction will be evaluated using validated, age-appropriate, objective and subjective, non- invasive outcome measures. A treatment group will be comprised of YCwCF who initiate HEMT. A control group will be comprised of YCwCF who do not initiate HEMT. Both groups will be followed for two years and the groups will be age-matched. Analysis will use mixed-effect models for longitudinal data to compare outcomes between groups and incorporate propensity scoring. Specific Aim 1 will characterize CRS and olfactory dysfunction in YCwCF. Specific Aim 2 will test the hypothesis that HEMT improves CRS in YCwCF utilizing sinus magnetic resonance imaging opacification and sinonasal symptom burden. Specific Aim 3 will test the hypothesis that HEMT improves olfactory dysfunction in YCwCF using olfactory bulb volume, quantitative olfactory function, olfactory cleft opacification, and olfactory-specific quality of life. Findings from this research will inform strategies that will lead to greater overall health status and improved quality of life. Results will highlight the importance of complication evaluation and management early in life.