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Chronic Rhinosinusitis with Nasal Polyposis in People with Cystic Fibrosis

1
Department of Head and Neck Surgery, University of California, Los Angeles, CA 90095, USA
2
Departments of Medicine and Pediatrics, National Jewish Health, Denver, CO 80206, USA
*
Author to whom correspondence should be addressed.
Sinusitis 2023, 7(2), 27-37; https://doi.org/10.3390/sinusitis7020004
Submission received: 16 May 2023 / Revised: 9 August 2023 / Accepted: 28 October 2023 / Published: 31 October 2023
(This article belongs to the Special Issue Frontiers in Chronic Rhinosinusitis with Nasal Polyposis)

Abstract

:
Cystic fibrosis (CF) is an autosomal recessive disorder that results in deranged ion transport and affects multiple organ systems, including the upper and lower respiratory tracts. People with CF (PwCF) often develop chronic rhinosinusitis (CRS) with or without nasal polyposis. CRS can significantly decrease quality of life for PwCF and can lead to more frequent pulmonary exacerbations. The management of CRS in PwCF is different from that in individuals without CF. Novel therapies have emerged in the last several years that have drastically altered the progression of both pulmonary and sinonasal disease in people with CF. It is critical for providers who manage CF-related CRS to understand the unique characteristics and challenges that coincide with this disease process. This review article aims to provide readers with an overview of the pathophysiology of CF and to summarize best practice strategies for the management of CF-related CRS.

1. Cystic Fibrosis: Background and Overview

Cystic fibrosis (CF) is an autosomal recessive disorder that is most common among individuals of northern European descent, yet affects people of all ethnic and racial backgrounds [1]. CF is caused by variants in the CF transmembrane conductance regulator (CFTR) gene, which encodes a complex chloride channel and regulatory protein that is expressed on the surface of epithelial cells that line the respiratory tract and exocrine glands [2,3]. CF causing variants result in deranged ion transport across multiple organ systems, including the upper airway, lower airway, and gastrointestinal system [4,5,6]. Research efforts have traditionally focused on improving lung function, as pulmonary disease is the predominant cause of early mortality among people with CF (PwCF) [7]. However, as treatment options have improved and life expectancy has increased for PwCF, a new emphasis has been placed on improving quality of life (QOL), which includes managing the sinonasal manifestations of CF [8,9]. Furthermore, in line with the unified airway theory, the paranasal sinuses may serve as a reservoir for pulmonary infections [10,11,12,13]. Thus, treating sinonasal disease is an important factor in optimizing pulmonary status in PwCF.
The upper airway manifestations of CF result from an abnormal electrolyte concentration in nasal secretions, leading to reduced water content and inspissated mucus [14,15]. The hyperviscosity of nasal secretions and impaired mucociliary clearance predisposes PwCF to develop chronic bacterial infections and inflammation, which can then lead to chronic rhinosinusitis (CRS) with or without nasal polyposis [8,15,16,17]. Although the majority of PwCF are identified through newborn screening, some individuals are not diagnosed with CF until much later in life. Consequently, evaluation for CF should be considered in adult patients with CRS and a history of pulmonary infections.
Nearly all adults with CF have radiologic or endoscopic findings of sinus inflammation; however, only a minority report typical symptoms of CRS [3,15,18,19,20,21]. Because of minimal reporting, CF-related CRS (CF-CRS) is thought to be underdiagnosed and undertreated, although awareness of this disease complication is increasing [18]. At present, there are no universally accepted diagnostic criteria for CF-CRS; however, patient-reported symptoms and objective findings on nasal endoscopy or imaging are frequently utilized to make the diagnosis [22,23].
Olfactory dysfunction (OD) is one of the hallmark features of CRS and is estimated to occur in up to 80% of non-CF individuals with CRS [24]. Among PwCF, the prevalence of OD is estimated at 63% to 94% [4,25,26]. The mechanism of OD among PwCF is not fully understood but is likely associated with chronic, lifelong inflammation near the olfactory apparatus in the superior nasal cavity. OD may be related to inflammation of the olfactory cleft, nasal polyps, chronic infections, and/or prior functional endoscopic sinus surgery (FESS) [27]. PwCF often do not report subjective olfactory impairment when queried, which is frequently discordant with their objective olfactory testing results [4,27]. This discordance may be due to a response shift or inadvertent deprioritization of olfactory-related QOL, as the global symptom burden PwCF endure is high; however, further investigation on this topic is needed [27,28].

2. Chronic Rhinosinusitis with Nasal Polyposis in People with Cystic Fibrosis

CRS is a heterogeneous process that consists of multiple phenotypes and endotypes. CRS with nasal polyposis (CRSwNP) is one of the main phenotypes of CRS and makes up approximately 30% of cases in non-CF individuals (Figure 1) [29]. CRSwNP in people without CF (Pw/oCF) typically presents between 40 and 60 years of age and is usually bilateral in nature [29,30]. The prevalence of nasal polyposis among adults with CF has been estimated at 32% to 44% [31,32,33,34], while the prevalence in pediatric patients is approximately 45% to 57% [3,35,36,37]. Additionally, the prevalence of CRSwNP among pediatric patients with CF increases with age—nasal polyposis has been diagnosed in 18% of patients younger than six years and 45% of adolescents [37]. Modest differences in prevalence rates across age are likely due to variation in sampling in different cohorts.
Although the endoscopic and radiologic appearance of nasal polyps is often similar among PwCF and Pw/oCF, different mechanisms are involved in the development of these inflammatory lesions in these two populations. Endotypes refer to distinct immunologic pathways that lead to CRS. In general, CRSwNP is considered a type 2 eosinophilic inflammatory response [38]. However, recent studies have demonstrated that endotypes may vary based on race and geographic location. For instance, Pw/oCF with CRSwNP who identify as white are more likely to have eosinophilic-predominance, while those who identify as Asian are more likely to show neutrophilic inflammation [38,39,40]. Such differences are likely a result of variation in genetic ancestry that impact immune response to stimuli. Although studies on endotypes in nasal polyps in PwCF are limited, CF-CRS is commonly associated with neutrophilic inflammation [41,42,43]. The pathogenesis of CF-CRSwNP is not well understood; however, research has identified associations between the presence of nasal polyposis and factors such as pulmonary colonization with Pseudomonas aeruginosa and severe CFTR variants [44,45].

3. Management of Nasal Polyps in People with Cystic Fibrosis

Until recently, treatments for PwCF were primarily focused on treating the end-organ manifestations of CF [46]. For CF-CRS, management has typically involved a combination of topical and systemic medical therapies followed by sinus surgery for medically refractory disease (Table 1) [13,18].
Several topical therapies exist to treat CF-CRS with or without nasal polyposis. Dornase-alpha is an effective pulmonary and sinonasal treatment that selectively cleaves extracellular DNA that is produced through the degradation of neutrophils [47,48,49]. This medication results in decreased viscosity of secretions and improved mucociliary clearance. Nasally inhaled dornase-alpha results in improved sinonasal symptoms; however, its impact on pulmonary function and radiographic and endoscopic findings of CRS is variable [48,50,51]. The use of intranasal dornase-alpha does not appear to significantly affect the presence or size of nasal polyps in CF-CRS [50].
Nasal saline irrigations (NSI) are another common treatment for CRS in both PwCF and Pw/oCF. A randomized controlled trial demonstrated that both hypertonic and isotonic saline led to small improvements in sinonasal symptom burden assessed via the 22-Item SinoNasal Outcome Test among PwCF, although this was not specific to CF-CRSwNP [52]. There is no evidence showing that NSI alone improves nasal polyps; however, clearing the paranasal sinuses of retained mucus and pathogens may help decrease inflammation along the sinonasal mucosa [53].
Topical corticosteroids can be helpful in treating CF-CRS, especially in patients with nasal polyposis [18]. A randomized controlled trial showed a reduction in nasal polyps but no change in symptom score among patients treated twice daily with topical betamethasone for six weeks [54]. Another study found that nasally inhaled beclomethasone resulted in improvement in nasal obstructive symptoms among PwCF-CRS without nasal polyposis and resulted in a reduction in nasal polyps among CF-CRSwNP [55].
Topical antibiotics have also shown promising results in the treatment of CF-CRS, specifically with regard to patient-reported outcomes and need for revision sinus surgery [56,57,58]. Two randomized controlled trials on CF-CRS demonstrated improved patient-reported outcome measures after treatment with topical tobramycin [56,58]. However, these studies were not specifically designed to examine the effect on nasal polyposis.
In addition to topical therapies, there is a role for systemic medications in the treatment of CF-CRS. Oral antibiotics are a mainstay of treatment in this population, as PwCF suffer from recurrent infections of the respiratory tract [13]. Oral corticosteroids are often used for short-term management of CRSwNP in Pw/oCF; however, data on their use in CF-CRSwNP are limited [8,13]. The Cystic Fibrosis Foundation recommends against the routine use of chronic systemic corticosteroids for CF-CRS [18]. It is possible that PwCF with CRSwNP may benefit from short-term systemic corticosteroids in certain cases; however, oral corticosteroids must be used with caution in PwCF, as there is a high prevalence of CF-related diabetes [13,53].
For individuals with medically refractory disease, FESS continues to have an important role in treating CF-CRSwNP. Individuals who remain symptomatic after appropriate medical therapy are candidates for FESS. Multiple studies have demonstrated that FESS leads to improved sinonasal symptoms and QOL [59,60,61,62]. Compared to Pw/oCF, FESS in PwCF may be more extensive given the need for larger drainage pathways to facilitate clearance of tenacious mucus and instillation of topical medications after surgery. Specifically, maxillary mega-antrostomy (also known as endoscopic medial maxillectomy), Draf 3 frontal sinusotomy, and sphenoid nasalization can be used to facilitate drainage of the sinus cavities [18]. Individuals with CF-CRSwNP should be counseled that nasal polyps are likely to recur because poor mucociliary clearance remains even after surgical intervention [53]. These individuals may require multiple surgical procedures over their lives. Surgery and medical therapies should be used in conjunction to improve individuals’ QOL.

4. The Impact of Highly Effective Modulator Therapy on Sinusitis and Nasal Polyps

Unlike the aforementioned medications that treat the downstream effects of CFTR dysfunction, highly effective CFTR modulator therapy (HEMT) partially reverses the underlying CFTR defect by impacting the CFTR protein. Since the discovery of the CFTR gene in 1989, over 2000 variants in the gene have been identified [63,64]. Each of these gene variants is associated with a specific class, which describes the type of CFTR protein defect incurred by a given variant [64]. Knowledge of the various types of CFTR defects has allowed for the development of targeted therapies.
CFTR modulators consist of potentiators and correctors. Potentiators augment gating of the channel, while correctors improve the processing and trafficking of CFTR, resulting in chloride channel presence at the surface of epithelial cells [65,66]. In 2011, ivacaftor, a CFTR potentiator, became the first CFTR modulator to be approved for PwCF with the G551D mutation [67]. While this medication was highly effective for a small percentage of PwCF, the majority of PwCF were not variant-eligible to take this medication. Since then, additional modulators and combinations of medications have been developed and approved by regulatory bodies for PwCF. The most recent HEMT to be approved was elexacaftor-tezacaftor-ivacaftor (ETI), which is a three-drug combination of two correctors and one potentiator that has been shown to significantly improve lung function, nutritional outcomes, and overall QOL among individuals with at least one copy of F508del, the most common CFTR variant [65,68,69]. Based on in vitro response of additional variants, the approved use of ETI has subsequently been expanded [70].
More recent studies have shown that ETI is efficacious in treating CF-CRS. Specifically, ETI has been shown to significantly improve patient-reported sinonasal outcomes, reduce sinus opacification on computed tomography (CT) scans, and reduce nasal polyp burden on nasal endoscopy (Figure 2) [71,72,73]. In contrast to these improvements CRS severity, treatment with ETI did not lead to improvement in olfactory dysfunction among PwCF—specifically, CT opacification of the olfactory cleft and Smell Identification Test (SIT) scores did not improve [27]. It is possible that earlier intervention with HEMT may improve or prevent olfactory dysfunction; additional studies are needed to investigate this theory.
Given the extrapulmonary benefits of HEMT, the utility of this medication in the post-lung transplantation setting is an area of ongoing research. A study by Benninger et al. found that of the nine adult PwCF who were initiated on ETI after lung transplantation, eight (88.9%) had improvement in subjective sinonasal symptoms [74]. A study by Hayes et al. found that three of five pediatric patients (60%) treated with HEMT after lung transplantation reported improvement in CRS-related symptoms [75]. A multi-institutional study found that among CF lung transplant recipients, the most common reason for ETI initiation in the post-transplant setting was sinonasal disease (68%) [76]. Although HEMT may be helpful in managing the extrapulmonary manifestations of CF after lung transplantation, the initial clinical trials on HEMT excluded transplant recipients; thus, providers need to be aware of the risks, specifically the potential for drug–drug interactions with CFTR modulators and transplant medications [75]. Furthermore, the use of HEMT represents a significant paradigm shift for the management of CF-CRS, and as such, use of the aforementioned conventional therapies is likely to change over time.

5. Unique Considerations for Managing Chronic Rhinosinusitis in the Pediatric Population

The diagnosis and treatment of CRS in children and adolescents with CF is nuanced and differs somewhat from that of the adult population. Compared to adults, pediatric patients may not be as well-equipped to express their concerns and often report minimal sinonasal symptoms, despite significant sinonasal disease on imaging studies [77,78]. Additionally, CT imaging is useful in evaluating sinonasal disease burden; however, this imaging modality exposes individuals to radiation. CT imaging should be used judiciously in all individuals, including children [79]. Magnetic resonance imaging, which does not expose individuals to ionizing radiation, may also be considered [80].
In both children and adults, medical management is the first line treatment for CF-CRS. In addition to the local and systemic therapies that treat the end-organ manifestations of CF-CRS, HEMT has been shown to improve CRS outcomes in PwCF. However, not all PwCF are candidates for HEMT—eligibility depends on age, genotype, and the absence of other co-morbidities such as end-stage liver disease. ETI was recently approved for use in children with eligible variants ≥ 2 years of age and ivacaftor alone was approved for use in infants with eligible variants as young as one month of age [81,82]. Future studies in young children, such as those being done in conjunction with the Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function in Infants and Young Children (BEGIN, NCT04509050), will be crucial for understanding how HEMT impacts sinonasal outcomes when initiated early in life.
If sinonasal symptoms and inflammation persist despite appropriate medical therapy, FESS is a treatment option. FESS has been shown to be safe in the pediatric population and studies have demonstrated that surgery leads to decreased sinonasal symptoms and improved QOL in both adults and children with CF [83,84,85]. FESS in the pediatric population is unique. The paranasal sinuses are incompletely formed at birth and continue to develop throughout childhood, though sinus hypoplasia remains common in the CF population. As such, all sinus cavities are often not fully pneumatized in children and adolescents, particularly in those with CF. Underpneumatization of the sinuses alters surgical planning and may limit the extent of FESS. Prior studies in animal models have raised concerns about midface development in pediatric patients undergoing FESS [86,87]. However, two studies in human subjects found no significant impact on facial development in children who underwent FESS [88,89]. Taken together, this information suggests that surgery can be considered in carefully selected pediatric patients with CF-CRS with refractory disease. Some authors propose waiting until a child is older to embark on surgery [89].
The postoperative management after ESS in children with CF can be challenging, as many pediatric patients are unable to tolerate in-office debridements. Because of this limitation, many physicians have advocated for a second-look debridement procedure a few weeks after the initial surgery. A study by Helmen et al. found that second-look debridements did not impact rates of sinonasal exacerbations or need for revision ESS; however, patients who underwent debridement in the operating room did experience a longer time interval until their first pulmonary exacerbation compared to those who did not undergo debridement (113.9 versus 47.4 days) [90]. Data on the optimal treatments for CF-CRS in the pediatric population are limited, and more robust studies on this topic are needed.

6. Future Directions in the Management of Cystic Fibrosis-Related Chronic Rhinosinusitis with Nasal Polyposis

CF is a complex disease that affects multiple organs; therefore, PwCF should be treated by multidisciplinary care teams that include otolaryngologists with experience managing this challenging disease process. Additionally, research teams comprised of experts from a broad range of specialties are helpful to ensure all aspects of this disease are investigated.
An active area of research Involves understanding the role of biologic therapies for the treatment of CRSwNP in Pw/oCF. There are currently three monoclonal antibodies that are approved in the United States for the treatment of CRSwNP, all of which target the type 2 immune pathway. At this time, none of the biologic medications are approved for use in PwCF. Additionally, since the majority of PwCF have neutrophilic polyps, it is unlikely that the current biologic medications would be of benefit in this population. However, studies have also demonstrated that CF-CRSwNP is a heterogeneous entity, and often involves eosinophilic infiltrates [91]. Thus, the immune pathways implicated in CF-CRSwNP are not fully understood, and future research should investigate whether there is a role for the use of biologic medications in treating this disease.
Personalized medicine involves understanding the unique characteristics of each individual and their disease process. Prior studies have failed to demonstrate a reliable correlation between subjective and objective measures of CF-CRS; thus, it is important for providers to consider all measures of sinonasal disease severity when managing CF-CRS [92,93]. Additionally, it is important for providers to be mindful of the impact that an individual’s treatment burden can have on their QOL. One study found that the average person with CF spends 108 min per day on CF treatment activities [94]. Providers should consider the challenges associated with specific treatment regimens and discuss these factors with PwCF in their care. Although treatment options for PwCF have drastically improved in the last decade, there is still much progress to be made to optimize quality and quantity of life in this population. Furthermore, HEMT is not available for all PwCF; for those individuals who are ineligible or intolerant of HEMT, novel therapeutic options to treat CRS are needed.

Author Contributions

Conceptualization, J.E.M., J.L.T.-C. and D.M.B.; methodology, J.E.M., J.L.T.-C. and D.M.B.; validation, J.E.M., J.L.T.-C. and D.M.B.; formal analysis, J.E.M., J.L.T.-C. and D.M.B.; investigation, J.E.M., J.L.T.-C. and D.M.B.; resources, J.E.M., J.L.T.-C. and D.M.B.; data curation, J.E.M., J.L.T.-C. and D.M.B.; writing—original draft preparation, J.E.M.; writing—review and editing, J.E.M., J.L.T.-C. and D.M.B.; visualization, J.E.M., J.L.T.-C. and D.M.B.; supervision, J.L.T.-C. and D.M.B.; project administration, J.E.M., J.L.T.-C. and D.M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

J.E.M.: None. D.M.B.: Over the last 24 months: Consultant for Garner Health (equity); received grant funding from Cystic Fibrosis Foundation and International Society of Inflammation and Allergy of the Nose; received honorarium from Rockpointe. JLTC: In the last 36 months, J.L.T.-C. has received grants from the CF Foundation related to this work as well as for work unrelated to the manuscript. Unrelated to this work, she has received grants to her institution from Vertex Pharmaceuticals Incorporated, Eloxx, and 4DMT; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design, participation on advisory boards, and speaking engagements; and has served on advisory boards and/or provided clinical trial design consultation for Insmed, 4DMT, and AbbVie. She serves on a DMC for AbbVie. She serves as the adult patient care representative to the CFF Board of Trustees, and on the CF Foundation’s Clinical Research Executive Committee, Clinical Research Advisory Board, Racial Justice Working Group and as immediate past chair of the CF TDN’s Sexual Health, Reproduction and Gender Research Working Group, on the scientific advisory board for Emily’s Entourage, and on the ATS Respiratory Health Awards, Scientific Grant Review and Clinical Problems Assembly Programming Committees. The funders had no role in the writing of the manuscript or in the decision to publish.

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Figure 1. Left nasal cavity endoscopy images from a person with chronic rhinosinusitis with nasal polyposis. Abbreviations: NS = nasal septum; SS = septal spur; NP = nasal polyps; LNW = lateral nasal wall.
Figure 1. Left nasal cavity endoscopy images from a person with chronic rhinosinusitis with nasal polyposis. Abbreviations: NS = nasal septum; SS = septal spur; NP = nasal polyps; LNW = lateral nasal wall.
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Figure 2. Coronal sinus computed tomography images of a person with cystic fibrosis before (A) and after six months (B) of elexacaftor/tezacaftor/ivacaftor treatment. This twice daily oral therapy leads to an improvement (decrease) in sinus opacification.
Figure 2. Coronal sinus computed tomography images of a person with cystic fibrosis before (A) and after six months (B) of elexacaftor/tezacaftor/ivacaftor treatment. This twice daily oral therapy leads to an improvement (decrease) in sinus opacification.
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Table 1. Summary of treatments for cystic fibrosis-related chronic rhinosinusitis and their effects on nasal polyps.
Table 1. Summary of treatments for cystic fibrosis-related chronic rhinosinusitis and their effects on nasal polyps.
Treatment for Cystic Fibrosis-Related Chronic RhinosinusitisMechanismEffect on Nasal Polyps
Local
Therapies
Dornase-alphaCleaves extracellular DNA, resulting in decreased secretion viscosity and improved mucociliary clearance.None
Nasal saline irrigationsClears retained mucus and pathogens from the paranasal sinuses.None
Topical corticosteroidsDecreases inflammation of the sinonasal mucosa.Reduction in polyps
Topical antibioticsTreats bacterial infections, which results in decreased inflammation of the paranasal sinuses.Unknown
Endoscopic sinus surgeryImproves ventilation of the paranasal sinuses, removes polyps, and allows for improved delivery of topical medications postoperatively.Reduction in polyps
Systemic
Therapies
Oral antibioticsTreats bacterial infections of the paranasal sinuses.Unknown
Oral corticosteroidsDecreases inflammation of the sinonasal mucosa.Possible reduction in polyps, although evidence is limited
Highly effective modulator therapySignificantly improves CFTR dysfunction.Reduction in polyps
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Miller, J.E.; Taylor-Cousar, J.L.; Beswick, D.M. Chronic Rhinosinusitis with Nasal Polyposis in People with Cystic Fibrosis. Sinusitis 2023, 7, 27-37. https://doi.org/10.3390/sinusitis7020004

AMA Style

Miller JE, Taylor-Cousar JL, Beswick DM. Chronic Rhinosinusitis with Nasal Polyposis in People with Cystic Fibrosis. Sinusitis. 2023; 7(2):27-37. https://doi.org/10.3390/sinusitis7020004

Chicago/Turabian Style

Miller, Jessa E., Jennifer L. Taylor-Cousar, and Daniel M. Beswick. 2023. "Chronic Rhinosinusitis with Nasal Polyposis in People with Cystic Fibrosis" Sinusitis 7, no. 2: 27-37. https://doi.org/10.3390/sinusitis7020004

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