Olfactory dysfunction in people with cystic fibrosis with at least one copy of F508del

Olfactory dysfunction (OD) is a core component of chronic rhinosinusitis (CRS) and is common in people with cystic fibrosis (PwCF).1, 2 However, limited research has investigated factors associated with OD in PwCF. Olfaction is commonly evaluated via psychophysical testing.3 Additional methods to augment olfactory assessment include measures of olfactory-specific quality of life (QOL) and olfactory cleft opacification (OCO). OCO has been shown to correlate with olfactory function in individuals with non-CF-CRS. These measures have not been widely used in PwCF. This study sought to prospectively investigate factors associated with OD using psychophysical testing and to evaluate the utility of complementary measures of olfactory status in PwCF. Adults with CRS and CF homozgyous for F508del or heterozgyous for F508del/minimal function mutations were prospectively enrolled from National Jewish Health (NJH) in an observational study from August 2019 to March 2020.4, 5 All subjects provided written informed consent for this Institutional Review Board–approved study. This analysis was conducted using baseline participant data from a study whose primary aim investigated the impact of elexacaftor/tezacaftor/ivacaftor (ETI) on CRS.4 Data in this analysis was collected prior to initiation of ETI. The 40-item Smell Identification Test (SIT; Sensonics Inc.) was used to assess olfaction. Normative cutoff values were applied to SIT scores to dichotomize the cohort into normosmic (total SIT score >35–36) and dysosmic status (total SIT score <35–34).6 The Questionnaire of Olfactory Disorders-Negative Statements (QOD) is a validated, olfactory-specific QOL survey. The olfactory cleft (OC) was segmented from sinus computed tomography (CT) scans obtained at enrollment. OCO was calculated using a threshold of −500 Houndsfeld units (HU) (Fig. S1).5 Sinus CT opacification was assessed via a deep learning algorithm using the same HU threshold and via the Lund-Mackay score.4, 5 Patient and disease factors were evaluated for potential associations with OD using univariable and multivariable logistic regression models. Multivariable models were fit using stepwise selection using a significance level for entry (SLE) of 0.2 and significance level for staying in the model (SLS) of 0.15. Pearson correlations were used to investigate potential associations across SIT score, QOD score, %OCO, 22-item Sino-Nasal Outcome Test (SNOT-22) score, and percent sinus opacification. Two-sided tests using α = 0.05 were used. Analyses were completed using SAS (SAS Institute, Inc.). Overall, 30 participants’ data were analyzed (Table 1). On average, the cohort was hyposmic with mean SIT score 30.6. Using normative thresholds, 19 individuals were dysosmic and 11 people were normosmic. Participants had elevated %OCO; however, most participants did not report abnormal values on the QOD. In univariate analyses, F508 heterozygosity and CF-related diabetes (CFRD) were associated with lower odds of normal olfaction. Nasal polyp status and markers of CRS disease severity were not associated with differential odds of OD. A stepwise selection model based on predetermined SLS and SLE incorporated CFRD, genotype, percent predicted forced expiratory volume in 1 second (ppFEV1), and SNOT-22 score and demonstrated that CFRD and F508 heterozygosity remained associated with differential (worse) odds of normal olfaction (Table 2). SIT scores were correlated with QOD scores and trended toward correlation with %OCO. %OCO was correlated with total sinus opacification on CT. SIT scores were not correlated with SNOT-22 scores or total sinus opacification (Table S1). This study was undertaken to investigate OD in individuals with CF/CRS, which is an understudied area. Findings from this prospective study add to the literature by identifying factors that are associated with worse olfactory status in PwCF with F508del, which aid with prognostication, and by evaluating the use of complementary olfactory measures. Although many PwCF are now eligibile for ETI, OD does not improve after 6 months of therapy, and not all PwCF are eligibile for ETI, including a higher percentage of individuals of racial and ethnic minorities.5, 7 In this study, CFRD was associated with OD. CFRD, which occurs in ∼30% of adults with CF, is a marker of overall CF disease severity and is associated with more frequent pulmonary exacerbations, decreased lung function, worse CRS severity, and shorter lifespan.8, 9 Our findings extend the import of CFRD as a negative prognostic factor to the olfactory domain and are consistent with prior non-olfactory studies. In our findings, F508del heterozygosity was associated with worse olfaction. This finding may result from the fact that PwCF who are homozygous for F508del were eligible for less effective modulator therapy prior to this study, and that long-term modulator therapy had a protective effect on olfaction. Several factors that are traditionally associated with OD in individuals with non-CF-CRS were not associated with OD, including nasal polyp status and CRS severity.10 These data suggest that olfactory impairment in PwCF may have different pathophysiologic components than OD in individuals with non-CF-CRS, and identifies a need for further study of olfaction in PwCF. Results from this study did not demonstrate an association between OD and body mass index. In this study, SIT scores correlated with QOD scores and approached significant correlation with OCO. These complementary measures provide a valuable means of assessing olfactory status in PwCF beyond psychophysical testing. Study findings should be interpreted cautiously. Results may not extend to the approximately 10% of PwCF without F508del. The possibility of type 2 error exists in a study of modest size. No control group was available. Although NJH is the country's largest CF center and includes PwCF from >30 states, individuals were enrolled from a single center. Daniel M. Beswick: Medtronic, prior consultant (ended 2020); Stephen M. Humphries: Boehringer Ingelheim, Parexel and Imidex, consultant not affiliated with this work; David A. Lynch: Parexel, Boehringer Ingelheim, Siemens, Veracyte, consultant, not related to this work; Jennifer L. Taylor-Cousar: received grants from Vertex Pharmaceuticals Incorporated, Gilead, N30, Celtaxsys, Proteostasis, and Bayer; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design, participation on advisory boards, and speaking engagements; has received speaking fees from Celtaxsys; and has served on advisory boards and/or provided consultation for Novartis, Genentech, Gilead, Protalix, Santhera, 4DMT, AbbVie, and Proteostasis; Connor D. Balkissoon, Matthew Strand, Jessa Miller, and Eszter K. Vlada: none. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.