Two‐Year Impact of Highly Effective Modulator Therapy on Olfactory Dysfunction

Olfactory dysfunction (OD) impacts quality of life (QOL) of individuals with chronic rhinosinusitis (CRS), a common comorbidity among people with cystic fibrosis (PwCF).1, 2 Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator that improves health, pulmonary, and CRS outcomes, and extends life expectancy.3-5 Despite these benefits, OD in adults and older adolescents with CF did not improve after ETI initiation.5-8 The long-term effects of ETI on OD remain understudied, prompting research about the potential for restoring olfactory function after extended treatments of ETI.6 As an extension of prior work, this prospective, observational study aimed to investigate the impact of 2 years of ETI on olfactory status in CF-related CRS (CF-CRS).6 Adults with CF-CRS who initiated ETI for clinical purposes were enrolled at National Jewish Health from August 2019–October 2020 and had F508del/F508del or F508del/minimal function variants.6, 9, 10 Institutional Review Board approval and written informed consent were obtained. Three olfactory outcome measures were utilized: 40-question Smell Identification Test (SIT), Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS), and olfactory cleft opacification (%OCO) assessed through sinus CT imaging. The QOD-NS is comprised of 17 statements, scored from 0 to 3, with higher scores reflecting worse olfactory-specific QOL. The SIT is graded on a scale of 0 to 40, with lower scores representing worse odor identification. %OCO quantifies opacification as the percentage of olfactory cleft volume with CT attenuation greater than −500 Hounsfield Units. Data collection occurred at three time points: baseline (prior to ETI initiation), 6 months, and 24 months after ETI initiation. Outcomes across time points were analyzed using multivariable linear mixed effects models, following an intention-to-treat approach with adjustments for multiple comparisons.6, 10 The models incorporated covariates such as visit, prior modulator use, sinus surgery history, age, nasal polyps, and CF-related diabetes (CFRD). A random intercept term for participant was included to account for correlation in responses from the same individual. Thirty adults with CF were enrolled, with 28 and 26 who completed 6-month and 24-month follow-up appointments, respectively. Mean age was 35.6 years and 60.0% were female.9 At baseline, the mean ± standard deviation (SD) SIT score was 30.6 ± 6.7, and after 6 and 24 months of ETI, SIT scores worsened by −2.0 (p = 0.02) and − 1.8 (p = 0.04), respectively (Table I). The mean ± SD QOD-NS score at baseline was 5.5 ± 6.7 and improved by −2.3 (p = 0.003) and −1.8 (p = 0.02) after 6 and 24 months of ETI, respectively. The mean ± SD %OCO score at baseline was 65.9 ± 9.4, with no change after 6 and 24 months of ETI (all p > 0.05). All outcome measures were unchanged between 6 and 24 months of ETI. Olfactory outcomes after ETI were not impacted by prior modulator use, sinus surgery history, age, nasal polyp status, or CFRD. This prospective study investigated the impact of 24 months of ETI on olfactory status in PwCF as an extension of prior work.6 %OCO remained stable and SIT scores modestly worsened but did not surpass the minimal clinically important difference (MCID) of 4.11 These findings suggest that despite highly effective therapy that improves CRS and other disease manifestations of CF, OD in adults with CF appears to be irreversible. We theorize this is due to chronic inflammation near the olfactory apparatus starting near birth.12 Olfactory loss also impacts patients with other mucociliary diseases, such as those with primarily ciliary dyskinesia.13, 14 Because OD among adults with CF appears to be refractory to improvement with ETI, future studies should evaluate if early intervention improves OD. Despite modest worsening odor identification, QOD-NS scores statistically improved after 24 months of treatment with ETI, supporting the nuanced and multifactorial relationship between olfaction and QOL. However, mean QOD improvements for the cohort did not exceed the MCID for PwCF (3.7), consistent with previous research.6, 15, 16 Tervo et al. reported that patient-reported olfactory impairment improved with ETI but emphasized that this measure of olfactory impairment was not an independent mediator of improved QOL.16 Odor threshold and discrimination, not originally included in this investigation to minimize study burden, may offer additional insights into olfactory status in this population. The extended 24-month duration of this study complements our prior 6-month investigation and highlights nuances that emerge with a longer duration of ETI. Although OD in adults with CF did not improve in a clinically relevant manner, QOD-NS scores improved with 24 months of ETI. In other CF manifestations, such as CFRD, modulators may have positive effects beyond the initial 6-month period, emphasizing the importance of long-term follow-up to understand the full therapeutic impact of ETI.17 Limitations of this study include a single institution setting and a modest cohort size, acknowledging the potential for Type 2 errors in associations with olfactory outcomes and covariates.5 OD in adults with CF did not improve in a clinically relevant manner after 2 years of ETI. Further study into mechanisms of olfactory loss in PwCF and the impact of early intervention on preventing or improving OD is warranted.