Motile cilia have a highly ordered ultrastructure with a canonical 9 + 2 microtubule-based organization (Wallmeier et al., 2020). Multiple motile cilia lining the cell surface of different tissues beat in a coordinated slow backward and fast forward stroke in order to clean the airways. The upper airways also comprise the nose, paranasal sinuses, and middle ears. Primary ciliary dyskinesia (PCD; ORPHA:244) is a rare genetic disorder affecting the function of motile cilia (Mirra et al., 2017). This results in impaired mucociliary clearance and a wide spectrum of clinical symptoms and manifestations in various organ systems (Werner et al., 2015; Paff et al., 2021). To date, pathogenic variants in more than 50 genes are related to PCD (Wallmeier et al., 2020). The severity and course of the disease differ based on the genotypes (Paff et al., 2021). Some of these ciliary defects cause ultrastructural changes that are detectable by transmission electron microscopy (TEM), whereas others do not (Shoemark et al., 2020). Therefore, the diagnostics of PCD are complex, and several tests, including measurement of nasal nitric oxide, high-speed video microscopy of vital ciliated epithelial cells (i.e., collected by nasal brushes), immunofluorescence analyses, TEM, and genetic analyses, are needed (Lucas et al., 2017a).

There is no cure for PCD, and its management focuses on symptomatic treatment (Paff et al., 2021). As good clinical evidence is missing, the management of PCD is often adopted to experiences in the more frequent and well-investigated respiratory disease cystic fibrosis (CF) (Lucas et al., 2017b; Marthin et al., 2021). Both diseases show an impaired mucociliary clearance leading to bacterial colonization, recurring/chronic infections, and progressive changes of the upper and lower airways (i.e., bronchiectasis) (Marthin et al., 2021). However, the pathophysiology is different, and some highly effective therapies in CF, such as inhalation of recombinant human dornase alfa, do not benefit individuals with PCD (Paff et al., 2021).

The majority of individuals with PCD suffer from symptoms related to the paranasal sinuses, and half of these patients fulfil the formal criteria for chronic rhinosinusitis (CRS) (Sommer et al., 2011; Bhatt et al., 2019). Zawawi et al. demonstrated that nasal congestion (83%) and nasal discharge (77%) were the most frequent upper airway symptoms in a cohort of children with PCD and that sinonasal disease can lead to a decrease in health-related quality of life (Zawawi et al., 2021). Pifferi et al. investigated the sense of smell in individuals with PCD and showed an inverse correlation between loss of smell and radiologic grading of CRS. In the cohort, sense of smell was reduced in PCD individuals with abnormal ciliary ultrastructure compared to PCD individuals with normal ultrastructure due to pathogenic variants in DNAH11 (Pifferi et al., 2018). However, data on CRS in individuals with PCD remain limited, including detailed genotype–phenotype correlation.

In this study, we investigated the impact of CRS in a large cohort of individuals with genetically confirmed PCD on health-related quality of life (HrQoL), and we graded CRS severity based on radiologic imaging and the Lund–Mackay scoring system. We grouped PCD individuals based on genetic defects that are predicted to cause either (near) normal or abnormal ciliary ultrastructure for genotype–phenotype correlation.

Reports on CRS in individuals with PCD are scarce. Here, we investigated the clinical phenotype of the upper airways with a focus on the paranasal sinuses in a large cohort of 58 individuals with genetically confirmed PCD. Our cohort comprised PCD individuals with disease-causing variants in 22 different genes illustrating the high genetic heterogeneity of PCD (Wallmeier et al., 2020; Pennekamp et al., 2023). We investigated the impact of CRS based on radiologic imaging and the Lund–Mackay scoring system (LMS) and health-related quality of life (HrQoL) to grade CRS severity.

In this study, we decided not to modify LMS for the absence of sinuses compared to other investigations (Pifferi et al., 2011; Berkhout et al., 2016). The modification would increase the total scores in case of sinus aplasia, implicating a higher disease severity. However, aplastic sinuses cannot become inflamed, and a modification of LMS would therefore distort the results. In addition, available sinus imaging showed a moderate-to-severe grade of opacification of sinuses, as indicated by a mean LMS of 10.3. An LMS of four or higher in adolescents and five or higher in children is considered pathologic and highly predictive for the diagnosis of CRS if applied using a CT scan (Fokkens et al., 2020). Our cohort was evaluated by both CT and MRI. Based on previous literature, Lund–Mackay scores based on MRI scans do not overestimate sinus opacification (Lin and Bhattacharyya, 2009). This is supported by our findings. When comparing CT and MRI scans in this cohort, there was no difference in LMS between these groups (CT 10.4 ± 4.3, MRI 9.9 ± 3.6, p = 0.74). Thus, MRI can be used for future studies in order to reduce the radiation exposure.

The pneumatization of paranasal sinuses develops during adolescence (Barghouth et al., 2002) and is therefore strictly related to the age of individuals. Hence, we investigated paranasal sinus aplasia only in individuals aged 16 years or older. Increased frequency of aplasia of frontal and sphenoid sinus in PCD was also reported previously (Pifferi et al., 2011; Bequignon et al., 2019a; Bhatt et al., 2019). In our study, the frontal sinus was bilaterally aplastic in 19% of individuals (16 years of age or older), and the sphenoid sinus was aplastic in 9.5% of this cohort. This is more frequent than in the general European population, in whom frontal sinus aplasia occurs in only 5% of individuals (Butaric et al., 2020). We demonstrate that frontal sinus aplasia can occur in different genotypes without being prevalent in distinct genotypes or subgroups. The sample size of the subgroups for individual genes was too small for statistical analysis. Further studies with larger samples are needed to uncover potential genotype–phenotype correlations.

Sinus aplasia is not unique to PCD as individuals with cystic fibrosis (CF) suffering from reduced mucociliary clearance, due to abnormally viscous mucus, show a high prevalence as well (Orlandi and Wiggins, 2009; Berkhout et al., 2016; Kang et al., 2017; Halderman et al., 2019). Thus, our data indicate that clinicians who examine patients with severe CRS and underdeveloped paranasal sinuses should consider a disease with reduced mucociliary clearance and, accordingly, refer them to a center specialized in CF and PCD diagnostics, especially when chronic respiratory symptoms are present.

CRS had a strong clinical impact in our cohort as at least 47% of the individuals with PCD underwent sinus surgery once or multiple times (Table 2). This rate might even be underestimated due to recall bias as many adult participants were included who primarily reported pulmonary symptoms. To reduce this bias, we analyzed the imaging for signs of functional endoscopic sinus surgery (FESS). We found seven additional individuals exhibiting signs of FESS who were not reported in electronic health records. Thus, the majority of the individuals with PCD underwent sinus surgery.

The CRS-related QoL was strongly reduced, as indicated by the mean SNOT-20-GAV score of 35. This is considerably higher than the impact of CRS in the healthy general population (a SNOT-20-GAV of 13 is expected) (Baumann et al., 2008) but comparable to the impact of CRS in individuals with CF (mean SNOT-22 of >30) (Habib et al., 2015; Kang et al., 2017) and the impact of primary CRS (Baumann et al., 2008). Interestingly, some individuals reached even less than 5 points in the questionnaire, emphasizing the broad spectrum of disease severity. For CRS, it has been previously reported that female people show a significant reduction in HrQoL (Fokkens et al., 2020). Therefore, we analyzed our HrQoL-Data for sex-specific differences. We could not show any significant sex-specific differences. However, there was a tendency toward reduced HrQoL in female PCD individuals. Therefore, future studies with larger patient cohorts should address this question again.

We also consider certain limitations to this study. First, HrQoL was evaluated with SNOT-20-GAV rather than the highly regarded SNOT 22 (Fokkens et al., 2020; Albrecht et al., 2021). At the time of the initiation of this investigation, SNOT-20-GAV was the only available validated German translation (Baumann, 2009; Albrecht et al., 2021). Due to the recent implementation of SNOT-22 in German (Albrecht et al., 2021), we aim to use a comparable questionnaire for future meta-analyses.

Here, we further evaluated the upper airway symptoms in the genetically defined PCD cohort by grouping PCD individuals based on genetic defects that are predicted to cause either (near) normal (28%) or abnormal (72%) ciliary ultrastructure. Previous studies have shown that there are differences in diagnostic and clinical findings between PCD with abnormal and PCD with (near) normal ultrastructure (Raidt et al., 2022; Kinghorn et al., 2023). Previously, we have shown that PCD individuals with (near) normal ultrastructure have a higher nasal NO production rate, more residual ciliary activity, and lower frequency of laterality defects (Raidt et al., 2022; Pennekamp et al., 2023). We therefore studied if there are also differences regarding upper airway disease.

Interestingly, our analyses did not find evidence for differences in the CRS disease severity among those PCD subgroups because the HrQoL and LMS scores did not differ significantly (Figures 1, 3). Further subgroup analyses were not performed because of the marked genetic heterogeneity present in our PCD cohort (22 different PCD genes were affected).

Because of the high disease burden of CRS in PCD individuals and the frequent paranasal sinus surgeries, our findings strongly support that PCD individuals should be followed by ENT specialists on a regular basis. Current therapy mainly focuses on secretion management by nasal rinsing, nasal inhalation of hypertonic saline solution, and topical steroids (Bequignon et al., 2019b; Paff et al., 2021). Although FESS in PCD individuals showed a positive effect on HrQoL in a small clinical trial with 24 PCD individuals (Alanin et al., 2017), the rates of recurrence and re-intervention are high, as indicated by this investigation. Therefore, surgical interventions should be considered individually based on patient history, physical examination, and reduction of HrQoL (Werner et al., 2015; Fokkens et al., 2020).

In summary, this is the first study to investigate the disease burden of upper airways in a genetically defined cohort of PCD individuals (n = 58). As demonstrated by the summary of affected genes in Table 1, a challenge in current PCD investigations is the broad spectrum of different affected genes (Wallmeier et al., 2020) resulting in small subgroups for further genotype–phenotype correlations. Therefore, international collaborative efforts such as the ERNLUNG PCD study group aim to collect ENT data in a systematic way using the international PCD registry (Werner et al., 2016).