Olfactory Function in Cystic Fibrosis: Outcome Measures, Olfactory Dysfunction Prevalence and the Impact of Management-A Systematic Review and Meta-Analysis.

BACKGROUND: Olfactory dysfunction (OD) is an increasingly recognized but under-investigated comorbidity of cystic fibrosis (CF). Its prevalence, assessment methods, and response to CF-directed treatment, including highly effective modulator therapy (HEMT) remains incompletely characterized. METHODS: We conducted a PRISMA 2020-compliant systematic review (PROSPERO: CRD420251060317) with a database search from inception to December 2025. Studies were eligible if they included participants with confirmed CF and reported an explicit olfactory outcome. Two reviewers independently screened titles and abstracts; full-text screening and Joanna Briggs Institute critical appraisal were initially completed by one reviewer, with a second-reviewer re-check of a random subset. Narrative synthesis was the primary method. An exploratory random-effects prevalence meta-analysis was pre-specified. Sensitivity analyses and exploratory meta-regression by OD case definition and assessment method, and adult/pediatric subgroup analysis were performed. RESULTS: Twenty-nine publications representing 21 unique study populations were included, and 15 distinct assessment instruments were identified. Exploratory meta-analysis pooled OD prevalence (all assessment methods) was 51.9% (95% CI: 29.1-74.3%; PI 0.0%-100%; I2 = 98.2%). In the psychophysical-only sensitivity analysis, pooled prevalence was 58.6% (95% CI: 41.6-74.6%; I2 = 92.0%), with it being significantly higher (p < 0.0001) in adults 76.4% (95% CI: 66.5-85.1%; n = 319) than in children (27.3% (95% CI: 9.8-48.7% n = 118). The pooled Sniffin' Sticks Test score was 26.5 (95% CI: 22.0-31.0; 95% PI: 17.7-35.4; n = 127), placing the cohort within the hyposmic range. The pooled total SNOT-22 score was 35.8 (95% CI: 27.6-44.1; 95% PI: 10.2-61.4), reflecting substantial overall sinonasal and HRQoL burden. The pooled Lund-Mackay score was 13.5 (95% CI: 11.1-15.9), indicating moderate-to-severe radiological sinonasal disease burden. HEMT consistently improved radiological markers of sinonasal disease, but patient-reported HRQoL improvement was variable and did not reach statistical significance in most studies. No included study demonstrated a statistically significant improvement in psychophysical olfactory performance after HEMT, and olfactory minimum clinically important difference was not reached where reported. CONCLUSIONS: OD is an important comorbidity of CF affecting an estimated 51.9% of people with CF overall, with higher rates in adults than children. Pooled prevalence varies materially by OD case definition and assessment method. Multidimensional psychophysical testing should be considered the reference functional assessment, complemented by olfaction-specific patient-reported outcome measures. HEMT does not appear to restore psychophysical olfactory function in the available studies, supporting continued objective olfactory screening in the modulator era. Prospective longitudinal studies commencing in childhood are needed.