Prevalence of Cystic Fibrosis Carrier Status in Chronic Rhinosinusitis Without Nasal Polyp

Maintaining regulated mucociliary clearance is critical to the host defense mechanism, which depends on intact epithelial structure, ciliary beating, and the mucoviscous properties of the airway surface liquid (ASL) [1, 2]. The ASL is noticeably influenced by alterations in chloride transport and pH through the cystic fibrosis transmembrane conductance regulator (CFTR), as clearly exemplified in cystic fibrosis (CF) [3]. Mutations in CFTR form thick mucus and accumulate secretions across various organ systems, including the gastrointestinal (GI), reproductive, and respiratory tracts [4]. Individuals with a single CFTR mutation (CF carriers) have 50% of normal CFTR protein function, which is generally considered adequate to maintain health [5]. However, multiple studies have indicated that CF carriers may be at risk for subclinical laboratory abnormalities and a wide range of CF-like phenotypes (e.g., bronchitis, chronic rhinosinusitis (CRS), idiopathic chronic pancreatitis) [5-7]. A recent systematic review showed that the pooled prevalence of CFTR mutations in CRS (without CF) was below 6% (7.89%) in the United States [6, 7]. When approaching the diagnostic workup for recalcitrant CRS, there may be a higher prevalence of CFTR mutations in this CRS subgroup with nonallergic phenotypes. Therefore, this study aims to determine the prevalence of CFTR mutations in CRS patients without nasal polyposis (CRSsNP) at a tertiary care facility.

This study was approved by the Institutional Review Board of the University of Alabama at Birmingham (UAB). For this retrospective case-control study, all CRSsNP patients (≥ 15 years of age) visiting the UAB sinus clinic (D.Y.C., J.W.G., and B.A.W.) were recruited between August 2023 and January 2024 (6 months). Cases were diagnosed with CRSsNP according to the guidelines set forth by the International Consensus Statement on Allergy and Rhinology: rhinosinusitis 2021 [8]. All individuals had symptoms for longer than 12 weeks, with nasal endoscopy or findings of sinonasal mucosal thickening on computed tomography. Those with findings consistent with nasal polyposis/allergic fungal sinusitis or (unilateral) odontogenic sinusitis were excluded from this analysis. All patients were subjected to a screening blood test (Quest Diagnostics Inc. Secaucus, NJ) for > 90% of CF genetic mutations (detecting 32 mutations, including 23 core mutations) during their initial visit. Clinical data, including sinus cultures during these 6 months, were collected. Data were presented as a mean ± standard error. Chi-square test was performed using GraphPad Prism version 10.0 (San Diego, CA). Differences were considered statistically significant at p <  0.05.

Out of 115 patients with CRSsNP (52 males and 63 females; mean age = 53.6 ± 1.6 years, Caucasian: Non-Caucasian = 101:14), 10 (8.7%; 7 males and 3 females; mean age = 55.5 ± 6.8 years; all Caucasian) were heterozygous for at least one of the screened CF mutations, including delta F508, R117H, G542X, and R334W (Table 1). The prevalence of a single CF mutation in Caucasians was even higher (9.9%) in this cohort. The most common mutation was the class 2 mutation (CFTR trafficking defect (little or no CFTR reaching the cell surface), delta F508). A significantly higher prevalence of CF carrier status was observed in culture-positive patients (14.1%) compared to culture-negative patients (1.96%) (p = 0.02). Staphylococcus species were the most cultured in the CF carriers (5/10) and Pseudomonas aeruginosa was identified in one patient. Once the screening test was completed, all patients with positive screening were referred to the UAB CF clinic for further evaluation: GI, pulmonary, endocrine, and nutrition. Then, based on the patient's symptoms and severity of comorbid conditions, triple combination therapy (elexacaftor–tezacaftor–ivacaftor) has been recommended. Three of those 10 patients began triple combination therapy (Patients 1, 2, and 3 in Table 1). Their responses to the treatment are currently being monitored.

The study revealed a notably higher prevalence of CFTR mutations in patients with culture-positive CRSsNP (8.7% overall, 9.9% in Caucasian, 14.1% in culture-positive subsets, and 15.8% in Caucasian & culture-positive subsets), suggesting a potential link between CF carrier status and the development of bacterial sinusitis in non-type 2 CRS subsets. This finding underscores the importance of considering CFTR mutation screening during CRS workup, particularly in cases resistant to standard treatments. Additionally, identifying high-risk patients will aid in selecting CFTR mutation screening in the future.

According to the CF Foundation report, about 1 in 35 Caucasians in the United States are CF carriers, totaling over 10 million people [5, 9]. Studies have demonstrated meaningful consequences of having a single CFTR mutation in the CRS [6, 10]. Carlton et al. reported that CFTR heterozygotes with CRS have notably smaller sinuses compared to those without mutations, which may play a role in impaired mucus clearance and the development of CRS. Although carriers are often asymptomatic, environmental factors such as pollutants or infections, along with genetic modifications, may elevate their risk of developing CF-like phenotypes [5]. Additionally, the recent advancement of highly effective CFTR modulators presents an opportunity to repurpose these drugs for treating CF-like diseases, including CRS, as three of our study patients are already on.

This study has several limitations. First, as a retrospective case-control study, there is an inherent selection bias, particularly given that our tertiary facility is located in the south (higher Caucasians). Second, the study utilized a screening test rather than whole genome sequencing. Due to insurance coverage constraints, none of the patients underwent whole genome sequencing. When such testing becomes more accessible, the prevalence may be higher than the current estimate. Third, we included only CRSsNP subpopulation in this study to offer a distinct perspective on existing literature [6]. Lastly, a prospective multicenter study would facilitate developing and implementing more standardized protocols to address the limitations of a single-center study.

Bradford A. Woodworth is a consultant for Cook Medical and Smith and Nephew. The other authors declare no conflicts of interest.