The Impact of Eleaxcaftor/Tezacaftor/Ivacaftor on Sinus Disease, Olfaction, and the Sinusonal Microbiome in Patients with Cystic Fibrosis

Lauren M. Cook, BS^1,  W. Jared Martin, BA^1, Yasine Mirmozaffari, BS^1, Ezer H. Benaim, MD^1, Jackson R. Vuncannon, MD¹,Cristine Klatt-Cromwell, MD¹,Charles S. Ebert, Jr, MD, MPH^1, Brian D. Thorp, MD^1,

Brent A. Senior, MD^1, Adam J. Kimple, MD, PhD¹

1. Division of Rhinology, Allergy, and Endoscopic Skull Base Surgery, Department of Otolaryngology-Head & Neck Surgery, UNC School of Medicine, Chapel Hill, North Carolina

OPEN ACCESS

PUBLISHED: 30 January 2024

CITATION: COOK, Lauren M. et al. The Impact of Elexacaftor/Tezacaftor/Ivacaftor on Sinus Disease, Olfaction, and the Sinonasal Microbiome in Patients with Cystic Fibrosis. Medical Research Archives, [S.l.], v. 13, n. 1, jan. 2025.  Available at: <https://esmed.org/MRA/mra/article/view/6242>. 

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v13i1.6242

ISSN 2375-1924

 

ABSTRACT

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective triple modulator therapy that has significantly reduced morbidity and mortality in patients with cystic fibrosis. Beyond pulmonary improvements, ETI’s impact on sinus disease, olfactory function, and the sinonasal microbiome is just beginning to be understood. We present a contemporary review of sinonasal changes in patients with cystic fibrosis after ETI initiation.

 

Methods: We conducted a literature review using PubMed and Google Scholar. Articles about ETI’s impact on sinonasal disease and symptoms in patients with cystic fibrosis published in English from 2019 to August 2024 were eligible for inclusion. Studies were selected based on their contribution to understanding changes in sinus disease severity, sinonasal quality of life, olfactory function, and the sinonasal microbiome in patients with cystic fibrosis after starting ETI.

 

Results: An initial query yielded 41 articles. After screening abstracts, 23 articles were chosen for further review. A total of 19 articles met full inclusion and exclusion criteria. Evidence suggests ETI significantly improves sinus disease in patients with cystic fibrosis, with clinical, radiographical, and quality of life improvements observed within days to months and persisting for up to two years. Studies on olfactory changes showed mixed results, with persistent dysfunction demonstrated on psychophysical tests despite subjective improvements. ETI also alters the sinonasal microbiota, by reducing pathogenic bacteria and total bacterial load, though the clinical implications remain under investigation.

 

Conclusions: ETI therapy markedly improves both objective evidence of sinus disease and sinonasal quality of life in patients with cystic fibrosis. Despite some improvements in olfactory dysfunction, objective tests consistently report refractory impairment post-ETI. Changes in the sinonasal microbiome are evident, but dysbiosis remains a concern. Further research is needed to clarify the long-term effects of ETI on olfactory dysfunction and the sinonasal microbiome, especially in younger populations.

 

Background

 

1.1 OVERVIEW

Cystic fibrosis (CF) is a rare, autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Advances in care have led to the development of CFTR modulators, and most recently elexacaftor/tezacaftor/ivacaftor (ETI) a highly effective triple modulator therapy. While ETI has greatly improved outcomes, most studies have focused on the pulmonary benefits. This article will provide an overview of ETI’s impact on sinus disease, olfaction, and the sinonasal microbiome.

 

1.2 CYSTIC FIBROSIS AND ELEXACAFTOR/TEZACAFTOR/IVACAFTOR

CF affects an estimated 89,900–100,000 people globally. Over 2000 mutations in CFTR have been identified, with the F508del variant present in ~85% of U.S. patients with CF. Until the early 2010s, CF care focused on slowing lung disease progression (the most frequent cause of mortality and morbidity) with inhaled and systemic antibiotics, physiotherapy, and inhaled medications to improve mucus clearance. In 2012, CFTR modulators were introduced, offering targeted therapies to improve protein folding and intracellular trafficking.

ETI, marketed as Trikafta and Kaftrio, is the most effective CFTR modulator. Approved by the U.S. Food and Drug Administration (FDA) in 2019 for patients aged 12 and older with at least one F508del allele, its indications have since expanded to children as young as two. Elexacaftor and tezacaftor increase functional CFTR protein at the cell surface, while ivacaftor enhances activity, improving anion transport across the membrane. Additionally, ETI has since been studied and approved for patients with at least one copy of over 170 rare CFTR mutations that have demonstrated responsiveness, further expanding eligibility. ETI has significantly reduced CF-related morbidity and mortality, leading to fewer acute pulmonary exacerbations, improved lung function (e.g., forced expiratory volume in one second [FEV1]), increased body mass index (BMI), increased life expectancy, and improved quality of life. Although most studies have focused on pulmonary outcomes since the introduction of ETI, CF is a multisystem disease. Consequently, research into ETI’s effects on sinonasal symptoms has progressed. For a comprehensive review of the pulmonary improvements following ETI initiation, see Ong et al. (JAMA 2023).

 

1.3 SINUS DISEASE IN CYSTIC FIBROSIS

Chronic rhinosinusitis (CRS) is defined by persistent inflammation of the sinonasal mucosa for 12 weeks or more. Diagnosis requires evidence of disease on endoscopy or imaging and symptoms (e.g., nasal congestion, anterior or posterior nasal drainage, facial pain or pressure, reduced sense of smell). In CF, defective ion transport leads to thickened secretions that overwhelm mucociliary clearance, mucus stasis, persistent infections, and mucosal inflammation. Nearly all patients with CF exhibit sinonasal inflammation and infection on imaging or endoscopy (CF-CRS). Otolaryngologists evaluate sinus disease using endoscopic and radiographic scoring systems (Table 1).

 

1.4 SINONASAL QUALITY OF LIFE IN PATIENTS WITH SINUS DISEASE

Patient reported outcome measures are important for assessing and monitoring sinonasal quality of life (QoL), i.e., the impact of sinonasal conditions on a patient’s overall well-being and daily functioning. Surveys such as the 22-item sinonasal outcome test (SNOT-22) capture symptom burden and have been validated in large cohorts of patients, including those with CF. Recent work has identified the minimal clinically important difference (MCID) for SNOT-22 scores in cystic fibrosis, further enhancing its clinical utility. Table 2 outlines common instruments used to evaluate sinonasal quality of life.

 

Table 1: Objective Scoring Systems for the Assessment of Sinus Disease

---

Table 2: Common Patient Reported Outcome Measures to Evaluate Sinonasal Quality of Life

1.5 OLFACTORY DYSFUNCTION IN CYSTIC FIBROSIS

Patients with CF are more likely to have olfactory dysfunction (OD) than age-matched controls.
While up to 75% of patients report normal smell, objective tests show 60–95% have some degree of impairment.
OD impacts quality of life, safety (e.g., reduced ability to detect hazards like smoke), and BMI.
Assessment methods include subjective tools, such as olfactory quality of life surveys, and objective tests like the Sniffin’ Sticks Identification Test, a validated psychophysical instrument (Table 3).

---

Table 3: Assessment Methods to Evaluate Olfactory Dysfunction

---

2. Methods

A literature review was conducted to evaluate the effects of elexacaftor/tezacaftor/ivacaftor (ETI) in sinus disease and sinonasal quality of life, olfactory function, and the sinonasal microbiome in patients with cystic fibrosis.
PubMed, MEDLINE, and Google Scholar databases were searched for articles published between January 2019 and August 2024.

Search terms used (various combinations):
“elexacaftor,” “tezacaftor,” “ivacaftor,” “CFTR modulator(s),” “cystic fibrosis,” “sinonasal microbiome,” “olfaction,” “olfactory dysfunction,” “olfactory impairment,” “ETI,” “HEMT,” “olfaction,” “microbiome,” “chronic rhinosinusitis,” “sinus disease,” and “quality of life.”

Inclusion criteria:

• Articles published in English

• Research involving patients with cystic fibrosis treated with ETI

• Articles addressing chronic rhinosinusitis, sinonasal quality of life, olfactory dysfunction, and the microbiota of the upper respiratory tract.

Exclusion criteria:

• Non-peer-reviewed articles

• Studies lacking specific sinonasal findings

• Studies using non-original cohorts

• Case reports

• Abstracts accepted to conference presentations without accompanying articles.

---

3. Analysis of Findings

3.1 Article Selection

The initial query yielded 41 eligible articles. After screening abstracts, 23 articles met the initial inclusion criteria

After review by two independent researchers and applying full inclusion and exclusion criteria, 19 articles were selected for final synthesis. A total of 4 articles were excluded from analysis for failing to meet full predetermined inclusion and exclusion criteria (e.g., non-original cohort, reviews, case studies).

The data were organized into four primary focus areas:

1. Changes in sinonasal QoL

2. Objective (radiographic and endoscopic) evidence of disease

3. Changes in olfaction

4. Changes in sinonasal microbiome after ETI initiation

For studies with overlapping focus areas, one was arbitrarily chosen. If multiple focus areas were discussed, the study was repeated in discrete tables with applicable findings.

Tables 4, 5, 6, and 7 are organized by article (first author and year), cohort size, data collection timepoints, instrument(s) used, and notable findings.

 

3.2 The Impact of ETI on Sinonasal Quality of Life Outcome Measures

Several studies have documented the benefits of elexacaftor/tezacaftor/ivacaftor (ETI) and other CFTR modulators on sinonasal quality of life in patients with cystic fibrosis (PwCF).

Five studies were selected for inclusion in Table 4 and for discussion.

In 2021, DiMango et al. published the first prospective cohort study of patients with CF on ETI, reporting a clinically significant improvement in Sino-Nasal Outcome Test 22 (SNOT-22) scores after three to six months of treatment.

Studies have shown that patients homozygous for F508del and with higher baseline SNOT-22 scores experience the most significant improvements with ETI. Tham, Li et al. recently conducted a meta-analysis of seven prospective and two retrospective studies (249 PwCF), showing significant improvements in SNOT-22 scores after ETI treatment.

Clinically significant improvements in sinonasal quality of life have also been reported as early as one week after treatment initiation. Additionally, Shakir et al. reported a statistically and clinically significant improvement in SNOT-22 scores after six months of ETI in a longitudinal cohort study of 32 patients.

Collectively, these studies demonstrate a consistent and clinically significant improvement in sinonasal quality of life after ETI initiation, particularly among patients with higher baseline disease burdens.

---

Table 4: Studies on Sinonasal Quality-of-Life before and after ETI Initiation

Article	Cohort	Timepoints	Instrument	Findings
Bode (2023)	n = 43 n = 20 (control group)	Mean of 9.3 (2–16) months after ETI initiation	SNOT-22	– SNOT-22 improved from mean of 32.7 to mean of 15.7 (p < 0.0001) post-ETI – Children showed lower SNOT-22 scores than adults – SNOT-22 score improved from 9.4 to 2.2 (p = 0.25)
Allgood (2023)	n = 22	Baseline Days 14, 28, 42, 56, 70, and 84 after ETI initiation	SNOT-22	– Baseline mean of 21.7, which improved to 13.8 at the 12-week (84 day) time point – Largest drop in mean SNOT-22 score from baseline to day 14
Minzoni (2024)	n = 45	Baseline 12 months after ETI initiation	SNOT-22	– Mean SNOT-22 reduced from 53.9 to 22.8 (p < 0.001) – Subgroup analysis showed a statistically significant greater reduction in scores among post-ESS patients (-19.6 vs -35.8, p = 0.015)
Tervo (2023)	n = 41	Baseline 3 months after ETI initiation	CFQR SNOT-22	– SNOT-22 and CFQR scores significantly improved in cohort after ETI (p < 0.0001)

 

3.3 The Impact of ETI on Objective Measures of Sinus Disease

Multiple studies have demonstrated objective improvements in sinus disease after ETI initiation.
Han et al. observed a reduction in the frequency of rhinology clinic visits and nasal cultures obtained.
Bode et al. noted improvements in endoscopic exams in 5 out of 8 patients within one year of ETI initiation.
Stapleton et al. noted significant improvement in polyps, crusting, and inflammation on endoscopic exams, with a reduction in sinus disease severity seen in over thirty patients.
Minzoni et al. documented significant improvements across multiple parameters, reflecting a comprehensive improvement in sinonasal outcomes at the one-year mark post-ETI initiation.
These findings highlight ETI’s role in improving markers of sinus disease, including endoscopic findings and healthcare utilization indices.

---

Table 5: Studies on Objective Evidence of Sinus Disease Before and After ETI Initiation

Table: Minzoni (2024)

---

3.4 The Impact of ETI on Olfactory Dysfunction

Studies on the effect of ETI therapy on olfactory dysfunction (OD) in patients with cystic fibrosis have focused predominantly on adults and yielded mixed conclusions. Five studies were identified with outcome measures evaluating OD (Table 6). Subjective olfactory quality of life scores show statistically significant improvements but are not always clinically relevant.

Miller et al. contributed to understanding of smell loss in patients with CF by noting a MCID of 3.7 on the QOD. Findings suggest that persistent olfactory impairment following ETI treatment may result from irreversible olfactory neuron loss in the setting of chronic inflammation.

The importance of objective, psychophysical testing for evaluating OD in patients with cystic fibrosis is emphasized. Further studies, especially involving pediatric patients, are needed to assess the effects of early ETI initiation. Notably, although ETI has proven benefits in sinonasal-related quality of life, it does not appear to enhance olfactory-related quality of life metrics.

---

Table 6: Studies on Olfactory Function Before and After ETI Initiation

3.5 The Impact of ETI on the Sinonasal Microbiome

The initiation of ETI has been shown to significantly alter the sinonasal microbiome, leading to notable shifts in bacterial populations and highlighting the interconnectedness of sinonasal and pulmonary health in cystic fibrosis.

Zemke et al. demonstrated that ETI initiation is associated with notable changes in the sinonasal microbiome, including:

• A reduction in the abundance of pathogenic bacteria, particularly Pseudomonas aeruginosa

• An increase in bacteria associated with healthy sinonasal environments, such as Moraxella

Additionally, they noted that existing evidence shows patients with CF may be colonized with a greater proportion of Staphylococcus spp. in the sinuses compared to the lungs.

Armbruster et al. corroborated these findings, showing a reduction in the relative abundance of P. aeruginosa after ETI initiation, although the same clonal populations persisted. This persistence indicates that while ETI reduces bacterial load, it may not fully eradicate pathogenic strains. This underscores the need for continued otolaryngologic care and suggests that the nasal cavity and sinuses could serve as alternative sites to monitor respiratory microbes, population diversity, and disease status.

Another study found that ETI led to a significant reduction in Pseudomonas spp., with Staphylococcus spp. (including methicillin-resistant Staphylococcus aureus) becoming the dominant organisms in the cohort of patients. Hilliam et al. found that Pseudomonas spp. levels in the sinuses dropped sharply after ETI initiation but rebounded over time, with data extending up to two years post-ETI.

This finding mirrors what has previously been shown in lower respiratory studies, again reinforcing the similarities between pulmonary and sinonasal microbiome studies. Future directions could explore sinonasal microbiome changes beyond two years of ETI treatment, assess whether ETI reduces the need for antibiotics in treating chronic sinus disease, and examine the potential of adjunctive therapies to further address sinonasal dysbiosis in cystic fibrosis.

---

Table 7: Studies on the Sinonasal Microbiome Before and After ETI Initiation

Table: Studies on Sinonasal Microbiome (Additional)

---

4. Conclusions

4.1 ETI’s Impact on Sinus Disease in Patients with Cystic Fibrosis

ETI initiation is associated with significant improvements in sinus disease, as reflected by numerous studies reporting clinically meaningful improvements in sinonasal quality of life scores.

Patients with higher baseline (worse) SNOT-22 scores and those with homozygous F508del genotypes seem to experience the most pronounced benefits. Additionally, evidence supports that ETI improves the clinical appearance and severity of sinus disease.

More broadly, ETI initiation was associated with fewer clinic visits and nasal cultures obtained in an observational study, suggesting improvements in sinus disease severity in a particular cohort. Combining ETI with sinus surgery shows promise, particularly in cases of refractory sinus disease and post-lung transplantation, though larger studies are needed to further characterize these benefits.

Pediatric and adolescent populations appear to be underrepresented in current studies on the impact of ETI on sinonasal disease, olfactory dysfunction, and the sinonasal microbiome.

---

4.2 ETI’s Impact on Olfactory Dysfunction in Patients with Cystic Fibrosis

Studies on the impact of ETI on olfactory dysfunction in cystic fibrosis have shown mixed results. Subjective olfactory quality of life scores often indicate improvements in perceived olfactory function and olfactory-related quality of life after ETI initiation; however, studies with psychophysical olfactory tests generally show little to no improvement post-ETI.

This suggests that olfactory dysfunction may persist due to irreversible damage to olfactory neurons, emphasizing the need for continued research on the pathophysiology of smell loss in patients with cystic fibrosis and the potential benefits of earlier ETI initiation.

---

4.3 ETI’s Impact on the Sinonasal Microbiome in Patients with Cystic Fibrosis

Research on the sinonasal microbiome before and after ETI has shown significant shifts in bacterial loads and diversity. ETI initiation is associated with a reduction in pathogenic bacteria and an increase in beneficial populations.

Despite reductions in total bacterial load, the persistence of the same strains of P. aeruginosa suggests that ETI does not fully eliminate native pathogenic strains. Staphylococcus spp. tend to become more dominant after ETI initiation, mirroring previous pulmonary microbiome findings.

Future research may explore the long-term effects of ETI on sinonasal microbiome stability, its impact on antibiotic use, and overall management of sinus disease in patients with cystic fibrosis.

 

Conflicts of Interest Statement:

The authors have no conflicts of interest to disclose.

Funding Statement:

The NIDCD branch of the NIH supported research in this publication under award number T32 DC005360 (E.H.B). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

 

REFERENCES

 

1. Ong T, Ramsey BW. Cystic Fibrosis: A Review. JAMA. 2023;329(21):1859-1871.
doi:10.1001/jama.2023.8120

2. Regard L, Martin C, Da Silva J, Burgel PR. CFTR Modulators: Current Status and Evolving Knowledge. Semin Respir Crit Care Med. 2023; 44(2):186-195. doi:10.1055/s-0042-1758851

3. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. New England Journal of Medicine. 2019;381(19):1809-1819. doi:10.1056/NEJMoa1908639

4. Ferreira FC, Buarque CD, Lopes-Pacheco M. Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor. Molecules. 2024;29(4):821. doi:10.3390/molecules29040821

5. Burgel PR, Durieu I, Chiron R, et al. Rapid Improvement after Starting Elexacaftor–Tezacaftor– Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease. Am J Respir Crit Care Med. 2021;204(1):64-73. doi:10.1164/rccm.202011-4153OC

6. Dreano E, Burgel PR, Hatton A, et al. Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription. Eur Respir J. 2023;62(4):2300110. doi:10.1183/13993003.00110-2023

7. Zemanick ET, Taylor-Cousar JL, Davies J, et al. A Phase 3 Open-Label Study of Elexacaftor/ Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele. Am J Respir Crit Care Med. 2021;203 (12):1522-1532. doi:10.1164/rccm.202102-0509OC

8. Nichols DP, Morgan SJ, Skalland M, et al. Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist. J Clin Invest. 2023;133(10). doi:10.1172/JCI167957

9. McNally P, Lester K, Stone G, et al. Improvement in Lung Clearance Index and Chest Computed Tomography Scores with Elexacaftor/ Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older – The RECOVER Trial. Am J Respir Crit Care Med. 2023; 208(9):917-929. doi:10.1164/rccm.202308-1317OC

10. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019;394(10212):1940-1948. doi:10.1016/S0140-6736(19)32597-8

11. International consensus statement on allergy and rhinology: rhinosinusitis 2021 – Orlandi – 2021 – International Forum of Allergy & Rhinology – Wiley Online Library. Accessed November 9, 2024. https://onlinelibrary.wiley.com/doi/10.1002/alr.22741

12. Mainz JG, Koitschev A. Pathogenesis and Management of Nasal Polyposis in Cystic Fibrosis. Curr Allergy Asthma Rep. 2012;12(2):163-174. doi:10.1007/s11882-012-0250-y

13. Kang SH, Dalcin P de TR, Piltcher OB, Migliavacca R de O. Chronic rhinosinusitis and nasal polyposis in cystic fibrosis: update on diagnosis and treatment. J Bras Pneumol. 2015;41(1):65-76. doi:10.1590/S1806-37132015000100009

14. Le C, McCrary HC, Chang E. Cystic Fibrosis Sinusitis. Adv Otorhinolaryngol. 2016;79:29-37. doi:10.1159/000444959

15. Ting F, Hopkins C. Outcome Measures in Chronic Rhinosinusitis. Curr Otorhinolaryngol Rep. 2018;6(3):271-275. doi:10.1007/s40136-018-0215-3

16. Chen T, Chidarala S, Young G, et al. Association of Sinonasal Computed Tomography Scores to Patient-Reported Outcome Measures: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 2023;168(4):628-634. doi:10.1177/01945998221114078

17. Beswick DM, Liu CM, Overdevest JB, et al. Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis. Laryngoscope. 2024;134(9):3965-3973. doi:10.1002/lary.31438

18. Lindig J, Steger C, Beiersdorf N, et al. Smell in cystic fibrosis. Eur Arch Otorhinolaryngol. 2013;
270(3):915-921. doi:10.1007/s00405-012-2124-2

19. Miller JE, Liu CM, Zemanick ET, et al. Olfactory loss in people with cystic fibrosis: Community perceptions and impact. Journal of Cystic Fibrosis. 2023;0(0). doi:10.1016/j.jcf.2023.11.006

20. Di Lullo AM, Iacotucci P, Comegna M, et al. Cystic Fibrosis: The Sense of Smell. Am J Rhinol Allergy. 2020;34(1):35-42. doi:10.1177/1945892419870450

21. Bacon DR, Stapleton A, Goralski JL, et al. Olfaction Before and After Initiation of Elexacaftor-Tezacaftor-Ivacaftor in a Cystic Fibrosis Cohort. Int Forum Allergy Rhinol. 2022;12(2):223-226. doi:10.1002/alr.22891

22. Miller JE, Taylor-Cousar JL, Overdevest JB, et al. 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. International Forum of Allergy & Rhinology. 2024;14(6):1079-1087.
doi:10.1002/alr.23312

23. DiMango E, Overdevest J, Keating C, Francis SF, Dansky D, Gudis D. Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis. Journal of Cystic Fibrosis. 2021; 20(3):460-463. doi:10.1016/j.jcf.2020.07.002

24. Tham T, Li FA, Schneider JR, et al. Functional and radiological sinonasal outcomes of CFTR modulators for sinus disease in cystic fibrosis: A meta-analysis. International Forum of Allergy & Rhinology. n/a(n/a). doi:10.1002/alr.23439

25. Stapleton AL, Kimple AJ, Goralski JL, et al. Elexacaftor-Tezacaftor- Ivacaftor improves sinonasal outcomes in cystic fibrosis. J Cyst Fibros. 2022;21 (5):792-799. doi:10.1016/j.jcf.2022.03.002

26. Shakir S, Echevarria C, Doe S, Brodlie M, Ward C, Bourke SJ. Elexacaftor-Tezacaftor-Ivacaftor improve Gastro-Oesophageal reflux and Sinonasal symptoms in advanced cystic fibrosis. J Cyst Fibros. 2022;21(5):807-810. doi:10.1016/j.jcf.2022.06.003

27. Beswick DM, Khatiwada A, Miller JE, et al. Impact of highly effective modulator therapy on chronic rhinosinusitis and health status: 2-year follow-up. J Cyst Fibros. 2024;23(2):214-218.
doi:10.1016/j.jcf.2023.09.013

28. Douglas JE, Civantos AM, Locke TB, et al. Impact of novel CFTR modulator on sinonasal quality of life in adult patients with cystic fibrosis. Int Forum Allergy Rhinol. 2021;11(2):201-203. doi:10.1002/alr.22716

29. Bode S, Rapp H, Lienert N, Appel H, Fabricius D. Effects of CFTR-modulator triple therapy on sinunasal symptoms in children and adults with cystic fibrosis | European Archives of Oto-Rhino-Laryngology. 2023;280.
doi:https://doi.org/10.1007/s00405-023-07859-4

30. Allgood S, Levy R, Bubaris D, Riekert K, Psoter KJ, Lechtzin N. The effect of elexacaftor/ tezacaftor/ivacaftor on non-pulmonary symptoms in adults with cystic fibrosis. Heliyon. 2023;9(9): e20110. doi:10.1016/j.heliyon.2023.e20110

31. Minzoni A, Mazzetti L, Orlando P, et al. Cystic fibrosis-related chronic rhinosinusitis: the key role of a comprehensive evaluation in the era of highly effective modulator therapy. Eur Arch Otorhinolaryngol. Published online August 7, 2024. doi:10.1007/s00405-024-08888-3

32. Tervo JP, DiMango E, Gudis DA, et al. Olfaction, body mass index, and quality of life with cystic fibrosis combination therapy. International Forum of Allergy & Rhinology. 2023;13(12):2165-2171. doi:10.1002/alr.23209

33. Han EJ, Beswick DM, Eshaghian PH, et al. Decreases in Rhinology Care Utilization by People with Cystic Fibrosis on Highly Effective Modulator Therapy. Ann Otol Rhinol Laryngol. 2024;133(3): 340-344. doi:10.1177/00034894231211626

34. Miller JE, Oh E, Khatiwada A, et al. Two-Year Impact of Highly Effective Modulator Therapy on Olfactory Dysfunction. Laryngoscope. 2024; 134(6):2492-2494. doi:10.1002/lary.31447

35. Beswick DM, Humphries SM, Balkissoon CD, et al. Olfactory dysfunction in cystic fibrosis: Impact of CFTR modulator therapy. Journal of Cystic Fibrosis. 2022;21(2):e141-e147. doi:10.1016/j.jcf.2021.09.014

36. Atteih SE, Armbruster CR, Hilliam Y, et al. Effects of highly effective modulator therapy on the dynamics of the respiratory mucosal environment and inflammatory response in cystic fibrosis. Pediatr Pulmonol. 2024;59(5):1266-1273. doi:10.1002/ppul.26898

37. Zemke AC, Hilliam Y, Stapleton AL, et al. Elexacaftor-tezacaftor-ivacaftor decreases pseudomonas abundance in the sinonasal microbiome in cystic fibrosis. Int Forum Allergy Rhinol. 2024;14(5):928-938. doi:10.1002/alr.23288

38. Armbruster CR, Hilliam YK, Zemke AC, et al. Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis. mBio. 2024; 15(5):e0051924. doi:10.1128/mbio.00519-24

39. Hilliam Y, Armbruster CR, Rapsinski GJ, et al. Cystic fibrosis pathogens persist in the upper respiratory tract following initiation of elexacaftor/ tezacaftor/ivacaftor therapy. Microbiol Spectr. 2024; 12(8):e0078724. doi:10.1128/spectrum.00787-24

40. Armbruster CR, Li K, Kiedrowski MR, et al. Low Diversity and Instability of the Sinus Microbiota over Time in Adults with Cystic Fibrosis. Microbiol Spectr. 2022;10(5):e0125122. doi:10.1128/spectrum.01251-22