Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis.

OBJECTIVES: The 22-question SinoNasal Outcome Test (SNOT-22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT-22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT-22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF). METHODS: Prospective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT-22 scores were obtained at baseline and after 3-6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution-based methods were used to assess internal consistency and calculate the MCID of the SNOT-22. RESULTS: A total of 184 PwCF participated with mean baseline SNOT-22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre- and post-HEMT data reported improvement in SNOT-22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT-22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02-1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14-18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39-20.11) were associated with greater SNOT-22 improvement. The mean MCID calculated via distribution-based methods was 8.5. CONCLUSION: Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT-22 in PwCF is 8.5 points, similar to non-CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT-22 has strong internal consistency in PwCF. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Patient perspectives on chronic rhinosinusitis in cystic fibrosis: Symptom prioritization in the era of highly effective modulator therapy.

BACKGROUND: Chronic rhinosinusitis (CRS) is common in people with cystic fibrosis (PwCF). Rhinologic symptom prioritization and areas that influence CRS treatment choices, including pursuing endoscopic sinus surgery (ESS), remain understudied. METHODS: Adult PwCF + CRS were enrolled at eight centers into a prospective, observational study (2019-2023). Participants were administered the 22-SinoNasal Outcome Test (SNOT-22) survey and a modified SNOT-22 instrument examining symptom importance. We determined importance rankings for individual symptoms and SNOT-22 symptom importance subdomains in two sets of subgroups-those pursuing ESS versus continuing medical management (CMT), and those on elexacaftor/tezacaftor/ivacaftor (ETI) versus not on ETI. RESULTS: Among 69 participants, the highest priorities were nasal congestion (n = 48, 69.6% important), post-nasal discharge (32, 46.4%), facial pain (29, 43.3%), waking up tired (27, 39.1%), and fatigue (26, 37.7%). Those electing surgery (n = 23) prioritized sleep and psychological dysfunction symptoms compared to those pursuing CMT (n = 49) (sleep median score = 19.0 [interquartile range: 12.0, 25.0] vs. 4.5 [0.0, 12.8]; p < 0.0001; psychological = 17.0 [7.0, 26.0] vs. 7.0 [0.0, 15.8]; p = 0.002). ETI users had comparable SNOT-22 total symptom importance scores to non-ETI users (p = 0.14). Non-ETI users (n = 34) showed a trend toward prioritizing sleep symptoms compared to ETI users (n = 35) (13.0 [2.8, 22.3] vs. 6.0 [2.0, 17.0]; p = 0.055). CONCLUSIONS: Nasal congestion and post-nasal discharge were top priorities reported by PwCF + CRS. Those electing surgery prioritized sleep and psychological symptoms, highlighting their importance in pre-operative discussions. Non-ETI users' prioritization of sleep improvement may highlight their unique disease impact and therapeutic needs; however, additional investigation is required.

Factors that predict pursuing sinus surgery in the era of highly effective modulator therapy.

BACKGROUND: Comorbid chronic rhinosinusitis (CRS) remains unresolved for many people with cystic fibrosis (PwCF). While highly effective modulator therapy improves quality-of-life and symptom severity, the impact of this intervention and other factors associated with pursuing endoscopic sinus surgery (ESS) remains understudied. METHODS: Adult PwCF + CRS were enrolled into a prospective, observational, multi-institutional study. Participants completed validated outcome measures to evaluate respiratory symptom severity, depression, headache, and sleep quality, as well as nasal endoscopy, sinus computed tomography (CT), and olfactory testing. Bivariate comparisons and regression modeling evaluated treatment cofactors, disease characteristics, and outcome measures associated with pursuing ESS. RESULTS: Sixty PwCF were analyzed, including 24 (40%) who elected ESS. Pursuing ESS was associated with worse SinoNasal Outcome Test (SNOT-22) total, rhinologic, psychological, and sleep dysfunction domain scores; worse Patient Health Questionnaire-9-Revised depression scores; worse Pittsburgh Sleep Quality Index total scores; worse weight, role, emotion, and eating domain scores on the Cystic Fibrosis Questionnaire-Revised; more severe disease on nasal endoscopy; and lack of modulator therapy (all p < 0.050). Multivariable regression identified that worse SNOT-22 total score was associated with electing ESS (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.16, p = 0.015) and elexacaftor/tezacaftor/ivacaftor (ETI) treatment (OR 0.04, 95% CI 0.004-0.34, p = 0.004) was associated with pursing medical therapy. CONCLUSIONS: Worse sinonasal symptom burden, lack of ETI treatment, sleep quality, depression, and nasal endoscopy scores were associated with electing ESS, while lung disease severity and sinus CT scores were not. ETI use was associated with lower odds of pursuing ESS independent of sinonasal symptom burden.

Decreases in Rhinology Care Utilization by People with Cystic Fibrosis on Highly Effective Modulator Therapy.

BACKGROUND: Many people with cystic fibrosis (PwCF) have chronic rhinosinusitis (CRS). CRS requires additional management beyond that of pulmonary disease and leads to increased utilization of healthcare resources. Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy that has been shown to improve CRS in PwCF. However, the impact of ETI on rhinologic healthcare utilization is understudied. OBJECTIVE: To compare rates of rhinologic healthcare utilization and procedures among PwCF prior to and after initiating ETI therapy. METHODS: A single-center, cohort study investigating adult PwCF was performed in January 2023. Demographics, clinical characteristics, and data related to CF treatment were retrospectively abstracted. Characteristics of the cohort were compared over 2 periods: the 12-months prior to ETI initiation and the 12-months after ETI initiation. Post-ETI data were linearly extrapolated if a subject had not yet completed the full 12 months of ETI. Paired t-testing, Wilcoxon signed rank testing, and regression analysis were performed. RESULTS: Of 126 PwCF, 98 (77.8%) were on ETI therapy and 35 (27.7%) were both on ETI and concurrently followed by the rhinology service (ETI-ENT). Rhinology clinic visits (P = .007) and frequency of obtaining nasal cultures (P = .046) decreased for the ETI-ENT cohort after initiating ETI treatment. There were no significant changes in the number of endoscopic sinus surgeries (P = .452) performed. Beyond ETI use, regression analysis did not identify any factors associated with changes in utilization. CONCLUSION: Aspects of rhinology healthcare utilization by PwCF decreased after initiation of ETI therapy. Additional studies are needed to determine rhinologic healthcare requirements for PwCF who remain on ETI for the long-term and to evaluate larger cohorts of PwCF on ETI.

Determining the minimal clinically important difference for the questionnaire of olfactory disorders in people with cystic fibrosis and factors associated with improvement after highly effective modulator therapy.

INTRODUCTION: Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF). The Questionnaire of Olfactory Disorders (QOD) is a validated instrument that evaluates olfactory-specific quality-of-life. The QOD minimal clinically important difference (MCID) and factors associated with olfactory improvement after elexacaftor/tezacaftor/ivacaftor have not been determined for PwCF. METHODS: Prospective observational data were pooled from three studies that enrolled adult PwCF with chronic rhinosinusitis (CRS). QOD scores and disease characteristics were assessed. To evaluate internal consistency and calculate the QOD MCID, Cronbach's alpha and four distribution-based methods were employed. For participants who enrolled prior to elexacaftor/tezacaftor/ivacaftor, QOD scores were obtained at baseline and after elexacaftor/tezacaftor/ivacaftor initiation. Multivariable regression was used to identify factors associated with QOD improvement. RESULTS: Of 129 PwCF included, 65 had QOD scores before and 3-6 months after starting elexacaftor/tezacaftor/ivacaftor. Mean baseline QOD score was 6.5 ± 7.9. Mean Cronbach's alpha was ≥0.85. The MCID estimates were as follows: Cohen's effect size = 1.6, standard error of measurement = 2.5, ½ baseline standard deviation = 4.0, and minimal detectable change = 6.9. Mean MCID was 3.7. Of those with pre/post elexacaftor/tezacaftor/ivacaftor QOD scores, the mean change in QOD was -1.3 ± 5.4. After elexacaftor/tezacaftor/ivacaftor, QOD improvement surpassed the MCID in 22% of participants (14/65). Worse baseline QOD scores and nasal polyps were associated with improved QOD scores after elexacaftor/tezacaftor/ivacaftor (both p < 0.04). CONCLUSION: The QOD MCID in PwCF was estimated to be 3.7. Elexacaftor/tezacaftor/ivacaftor led to qualitative but not clinically meaningful improvements in QOD score for most PwCF; PwCF with worse baseline QOD scores and nasal polyps improved in a clinically significant manner.

Preliminary evidence for sustained efficacy of CFTR modulator therapy with concomitant rifabutin administration.

The concomitant use of elexacaftor/tezacaftor/ivacaftor (ETI) and strong CYP3A inducers including rifampin and rifabutin is not recommended due to the risk of drug-drug interactions (DDI). This presents a significant challenge to the treatment of non-tuberculous mycobacteria precluding the first line treatment. While rifabutin induces CYP3A activity, its effect appears to be moderate compared to rifampin. In this study, we investigated three cases in which concomitant use of rifabutin and CFTR modulators (ETI or ivacaftor monotherapy) was used, and these cases suggest that addition of rifabutin did not compromise the efficacy of ETI or ivacaftor as evidenced by pulmonary function and sweat chloride testing. A full physiologically based pharmacokinetic model predicted lung concentrations of ETI upon rifabutin coadministration to exceed the half-maximal effective concentrations (EC50) determined from chloride transport in phe508del human bronchial epithelial cells. This study provides preliminary evidence in support of the use of rifabutin in patients receiving ETI.