Describing the ear, nose, and throat symptom burden in a cohort of Australian patients with primary ciliary dyskinesia

Introduction

Primary ciliary dyskinesia (PCD) is a rare, autosomal-recessive disorder of ciliary motility, characterised by chronic rhinosinusitis (CRS), chronic otitis media with effusion (ChOME), and recurrent lower respiratory tract infections that eventually lead to bronchiectasis (1). PCD has an estimated prevalence of 1–13% in adults with bronchiectasis (2). Approximately half of PCD patients have “situs inversus”, commonly known as “Kartagener’s syndrome”, and up to 17% have congenital heart disease (3). Traditionally considered a mild disease, Halbeisen et al. (4) demonstrated that children and adolescents with PCD have a similar reduction in lung function as those with cystic fibrosis (CF). The estimated prevalence of PCD is 1:10,000 (1), however, this may be higher in certain populations such as those with high rates of consanguinity (5).

Few randomised controlled trials have been published to support specific pharmacotherapeutic treatments for PCD. These therapies include N-acetylcysteine (NAC) (6), salbutamol (7), inhaled hypertonic saline (8), azithromycin maintenance therapy (9), antibiotic eradication therapy for early pseudomonas aeruginosa infection (PsA) (10), and idrevloride (11). While Stafanger et al. (6) were able to demonstrate improvement in pulmonary function tests with oral NAC in their CF patients, no effect was seen in the PCD group. Similarly, Koh et al. (7) found no statistically significant changes in forced expiratory volume in one second (FEV1) or bronchial responsiveness using salbutamol. Although Paff et al. (8) did demonstrate a small improvement in quality-of-life scores using inhaled hypertonic saline, this did not reach statistical significance. This may have been due to the study not reaching the target sample size, thus not being adequately powered. A more recently published systematic review by Zhang et al. reiterates these findings, citing the limited and inconsistent results surrounding hypertonic saline use in PCD (12). In the Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial, Kobbernagel et al. (9) found that azithromycin maintenance therapy for 6 months halved the rate of respiratory exacerbations, from a mean of 1.62 in the placebo group to 0.75 in the azithromycin group. The BESTCILIA trial was the first randomised controlled trial to demonstrate a definitive and substantial symptomatic improvement due to specific pharmacotherapeutic treatment for PCD. Notably, the REPEAT (13) trial is currently underway and aims to build on the results of the BESTCILIA trial, assessing whether combination therapy with azithromycin and erdosteine further reduces exacerbations in PCD.

More recently, a retrospective medical records audit conducted by Gatt et al. (10) demonstrated that antibiotic eradication therapy should be considered in all children with PCD who have early PsA infection, as the cumulative success rate of this approach was 97% in their study population. The CLEAN-PCD (11) was a Phase 2, placebo controlled, crossover trial in which Ringshausen et al. investigated the efficacy of idrevloride, a nebulised epithelial sodium channel inhibitor (ENaC), in combination with hypertonic saline, on lung function and quality of life in PCD patients. They found a significant improvement in lung function in the treatment group receiving idrevloride and hypertonic saline, however, this did not lead to an improvement in quality-of-life measurements. The findings of the CLEAN-PCD trial, while promising, elucidate the ever-present need for further evidence in PCD treatment approaches.

Regarding the specific investigation of sinonasal disease outcomes, the EPIC-PCD study (14) is an ongoing prospective, observational, multinational cohort study aiming to characterise ENT disease in patients with PCD and its relationship with lung pathology. This international cohort continues to generate data allowing for more detailed characterisation of ENT disease in PCD patients, notably Goutaki et al. published the largest study describing otologic disease in PCD (15), and Lam et al. investigated the frequency and severity of several sinonasal features (16).

Evidently, while significant promising research continues to be produced, there remains a scarcity of published data available to guide the clinical management of PCD. Treatment approaches vary widely internationally and have typically been inferred from similar, more common conditions such as CF and other causes of bronchiectasis (17). This is despite differences in pathology and disease characteristics, such as radiologic distribution of bronchiectasis in PCD (primarily in the middle and lower lobes) and CF (primarily in the upper lobes) (18). Furthermore, several studies have demonstrated certain pharmacotherapies to be effective in CF, and yet have no benefit, or indeed may cause harm, in PCD cohorts. O’Donnell et al. (19) and Wills et al. (20) conducted two separate studies that pertinently illustrate this point, in elucidating that while aerosolised rhDNase improves lung function in CF patients, its use may be harmful in non-CF bronchiectasis.

The multidisciplinary treatment approach in PCD aims to slow disease progression, improve symptom burden and minimise exacerbations. Routine therapies include facilitating airway clearance of secretions through chest physiotherapy, mucolytics, and hypertonic saline, and the use of antibiotics to treat respiratory exacerbations (17). Maintenance therapy with azithromycin is increasingly used in PCD, and was popular even before the results of the BESTCILIA trial were published (9). This is largely due to its proven efficacy in CF and non-CF bronchiectasis (21,22). Non-respiratory symptoms are managed on an organ-specific basis. CRS has a significant impact on quality of life (23). While symptom severity is variable, CRS most commonly causes nasal congestion, anosmia, persistent purulent secretions, and may be a source of exacerbations of lower respiratory tract disease (24,25). Common treatment approaches include saline sinus irrigations, topical intranasal corticosteroids, and systemic and topical antibiotics (24). ChOME is often associated with prolonged or intermittent conductive hearing loss and recurrent middle ear infections (26). ChOME may be managed conservatively, with hearing aids and antibiotics, or with insertion of middle ear ventilation tubes (26).

The ear, nose, and throat (ENT) manifestations of PCD typically occur early in life, are variable but persistent, and significantly affect quality of life. Early diagnosis allows for intervention prior to irreversible lung damage, minimises symptom burden, and delays disease progression (27). There is a need for multidisciplinary care and evidence-based treatments for all patients with PCD. International research collaborations such as the BEAT-PCD (28) and EPIC-PCD (14) projects, the iPCD cohort (29), and the international PCD registry (30), are of cardinal importance to provide ongoing data allowing for longitudinal classification of PCD symptoms. Yet currently there are few published studies on the progression of ENT symptoms with treatment. Despite almost all PCD patients having sinonasal or otologic complications. This study aimed to contribute toward verifying the efficacy of multidisciplinary PCD management, by demonstrating a discernible improvement in the ENT symptom burden in a cohort of Australian patients treated at CRGH in Sydney. The Concord Hospital Multidisciplinary PCD clinic is Australia’s national reference centre for both diagnosis and management of adults and children with PCD. We present this article in accordance with the STROBE reporting checklist (available at https://www.theajo.com/article/view/10.21037/ajo-24-6/rc).

Methods

Study design and setting

This study was a single site, retrospective medical records audit using the CRGH PCD patient database to assess a cohort of Australian patients with PCD who attended the CRGH PCD multidisciplinary clinic from January 2015 to January 2022. We described changes in this cohort’s ENT symptom burden over their treatment period by analysing mean nasal nitric oxide levels, cilial beat frequency at time of diagnosis, dynein arm deficiencies, SNOT-22 scores, and pure-tone audiometry.

Participants

Patients were eligible for inclusion in this study if they had a confirmed diagnosis of PCD, were aged 6 years or older, were a patient undergoing treatment for PCD at the CRGH PCD multidisciplinary clinic from the time period spanning 2015 to 2022, had demonstrated follow-up after any major interventions, and had recorded at least one SNOT-22 questionnaire to allow for quantification of their ENT symptom burden. The entirety of the CRGH PCD patient database was assessed for eligibility for inclusion in this study.

Variables

Primary outcomes of this study were changes in SNOT-22 overall scores as well as the five established individual domain scores (rhinologic, extra-nasal rhinologic, ear/facial, psychological, sleep), and pure-tone audiometry results over time. The 22 questions of the SNOT-22 were categorised into these five domains according to previously published guidelines (31,32). The SNOT-22 is a validated patient-reported measure of outcome, which was developed to help quantify the severity of CRS symptoms and their impact on quality of life (33). Regarding audiograms, the mean of air conduction thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz were calculated for each ear. Secondary outcomes involved characterisation of our cohort according to the following variables and PCD-related diagnostic measurements: sex, age, ethnicity, mean room temperature ciliary beat frequency at time of diagnosis, mean nasal nitric oxide levels measured throughout the treatment period, and ciliary ultrastructural defects on transmission electron microscopy (involving the dynein arms or microtubules).

Data measurement

The CRGH PCD patient database exists partly as non-digital data stored in a locked filing cabinet of the secured Concord Respiratory Department, and partly as digital data stored (de-identified) on REDCap. This study accessed this database for the purposes of data collection from the period 2015 to 2022, including both non-digital and digital data formats.

Each participant’s initial SNOT-22 and audiometry results were taken as their “Baseline”, and if more than one result was recorded over our study time period, then these baseline values were compared to the average of their recorded results following this to highlight a trend in ENT symptom burden. All data was originally collected as part of routine clinical care.

Statistical methods

Because of the rarity of PCD, our sample size was derived from the entirety of the data available, and interpretation of the power of this to uncover findings was based on expert opinion from the coordinating investigator and principal investigator. As this was a retrospective data analysis using already quantified values, there is little role for bias and random error. Yet, these remain pertinent considerations and care was taken in the interpretation of equivocal values via consultation with the coordinating and principal investigators for expert advice. There is certainly a degree of selection bias in using SNOT-22 questionnaires as the only quantifying measurement for ENT symptom burden, as it is reasonable to assume that patients with a greater symptom burden were more likely to fill out these optional data points. Shapiro-Wilk tests for normality were conducted on all datasets, which were accordingly analysed using the Wilcoxon signed-rank test or paired T-tests. All analyses were conducted using Statistical Package for the Social Sciences (SPSS) software for Mac, and graphical displays were generated using GraphPad. A P value of less than 0.05 was considered statistically significant.

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Concord Hospital Research Office, Sydney Local Health District (No. 2021/ETH11876) and individual consent for this retrospective analysis was waived.

Results

The CRGH PCD patient database, from January 2015 to January 2022, was screened for eligibility for inclusion in this study. Sixty-one of the 103 patients were excluded for reasons stated in Figure 1, including not having any recorded SNOT-22 questionnaires, not meeting age requirements, and one patient received a lung transplant with no follow-up SNOT-22 documented. Forty-two patients were deemed eligible for inclusion in this study, of which 18 had only one SNOT-22 available (Group B) and 24 had at least two recorded (Group A). Similarly, 9 patients had only one audiogram available (Group D) and 17 had at least two recorded (Group C). Hence analysis regarding the trend in ENT symptom burden and hearing loss could only be conducted for Groups A and C.

Figure 1 Trial profile. This flowchart describes the process of participant selection. From the available 103 patients assessed for eligibility, 24 patients had two or more recorded SNOT-22 tests (Group A), and 18 patients had one (Group B). Of these, 17 patients had two or more recorded audiograms (Group C), and 9 patients had one (Group D). SNOT, Sino-Nasal Outcome Test.

We described our cohort according to demographic characteristics and several PCD-related diagnostic variables (Table 1). Age was reported using the following categories (6 to 18, 19 to 30, 31 to 40, 41 to 50, 51 to 65 years), and sex was classified dichotomously (male, female). Ethnicity was classified according to the Australian Standard Classification of Cultural and Ethnic Groups (Australian, European, unknown and other—which includes New Zealand Peoples, Micronesian, People of the Americas, Asian, Middle Eastern, African, Melanesian and Papuan, Polynesian). Mean room temperature ciliary beat frequency at time of diagnosis [6.1 Hz; standard deviation (SD): 3.2], mean nasal nitric oxide levels measured throughout the treatment period (79.6 ppb; SD: 69.4), and ciliary ultrastructural defects (involving the dynein arms or microtubules) were also appraised.

Baseline SNOT-22 overall and domain scores for Groups A and B, as well as changes in these values over the study period, are summarised in Table 2. Regarding Group A, statistically significant improvements were observed in SNOT-22 overall (9.0±12.4, P<0.001) and all domain scores (rhinologic: 2.5±4.7, P<0.05; extra-nasal: 1.2±2.7, P<0.05; ear/facial: 1.9±4.1, P<0.05; psychological: 3.4±5.7, P<0.05; sleep: 2.0±4.6, P<0.05).

Figure 2 shows that 71% of these patients experienced an average improvement in their ENT symptom burden, 59% of these exceeded the mean clinically important difference, and 29% did not improve. However, of this group, the average increase in overall symptom score was only 2.5.

Figure 2 Response of patients in Group A. This figure indicates the percentage of patients in Group A who, throughout treatment, saw an overall improvement in their ENT symptoms (blue), experienced an improvement greater than the MCID (brown), or did not experience any changes in their symptom burden (cream). Group A: two or more recorded SNOT-22 tests. MCID, mean clinically important difference; ENT, ear, nose, and throat; SNOT, Sino-Nasal Outcome Test.

The weighted distribution of ENT symptoms (corrected according to the total potential score for each domain) from each patient’s initial and post-baseline SNOTs over their treatment period, expressed as a percentage of overall score, is summarised in Figure 3. Notably, the greatest burden of disease was found to be derived from rhinologic symptoms and psychological dysfunction, and this was consistent from beginning to end of treatment.

Figure 3 Distribution of ENT symptom burden in Group A. This figure uses two pie charts to demonstrate the distribution of ENT symptom burden in Group A, and how this changed throughout treatment. Blue represents the presence of rhinologic symptoms as a percentage of the total SNOT-22 score. Similarly, grey represents sleep dysfunction, aqua represents psychological dysfunction, cream represents ear/facial symptoms, and brown represents extra-nasal rhinologic symptoms. Group A: two or more recorded SNOT-22 tests. SNOT, Sino-Nasal Outcome Test; ENT, ear, nose, and throat.

Consideration was also given to understand the treatment journey itself and how our patient’s experience of PCD changed from year to year. Figure 4 offers insight to this effect, demonstrating that the greatest improvement in ENT symptoms occurred in the first year of treatment, which was followed by a small rebound increase in symptom burden, and then a relatively sustained improvement from there.

Figure 4 Change in overall SNOT scores in Group A. This figure illustrates how Group A’s SNOT scores changed throughout treatment (green line). The blue vertical dotted line indicates the point at which the authors deemed there were insufficient numbers of available SNOTs to generate a valid trend (highlighted within the grey area). Group A: two or more recorded SNOT-22 tests. SNOT, Sino-Nasal Outcome Test.

Similarly, baseline pure-tone audiometry hearing thresholds for Groups C and D, as well as changes in these values over the study period, are summarised in Table 3. While we did demonstrate a small improvement of 0.7 dB over the period of this study, this value did not achieve statistical significance (P=0.52, SD: 3.1).

Discussion

This study quantified the ENT symptom burden in a cohort of patients with PCD over time, with the goal of demonstrating symptomatic improvement with adherence to optimal management delivered via a multidisciplinary clinic. Although the SNOT-22 is a commonly used tool in the evaluation of CRS, exactly what constitutes a normal score is poorly understood. Farhood et al. (33) conducted a meta-analysis of ten studies which evaluated SNOT-22 scores in non-CRS populations, and found the weighted mean SNOT-22 score was 11±9.4. Our study found baseline SNOT-22 scores of Groups A and B to be 41.9 (SD: 13.7) and 37.4 (SD: 18.5) respectively, emphasising the significant burden of ENT disease suffered by PCD cohorts and the effect of this on quality of life. Our results approximately align with those of Lam et al. (16) who found a median SNOT-22 score of 39 in their population of 57 patients, using the EPIC-PCD cohort. Sommer et al. (34) reinforces this idea in emphasising otolaryngologic symptoms are common in PCD and significantly contribute to general morbidity.

Yet, this study sought not only to demonstrate that PCD patients commonly suffer from CRS, but further that they experience measurable improvements in their symptom burden through adherence to treatment; and that this occurs despite the chronicity and progressive disease course that defines PCD. Interpretation of SNOT-22 score changes involves consideration of the minimal clinically important difference (MCID), which identifies the minimum value change necessary for a patient to perceive a true and worthwhile improvement in their quality of life. Chowdhury et al. demonstrated the MCID for overall SNOT-22 scores in patients with CRS to be 9 for surgical management (35) and 8 for medical therapy (36), while MCID values for rhinologic, extra-nasal rhinologic, ear/facial, psychological dysfunction, and sleep symptom domains were 3.8 to 3.9, 2.4 to 2.5, 3.2 to 3.3, 3.4 to 3.9, and 2.9 respectively. These results suggest that while multidisciplinary management indeed lead to a discernible improvement in overall quality of life in our cohort, this may have been mediated by a global improvement in ENT symptoms without any specific symptom group experiencing a meaningful change. These findings align with those of Chowdhury et al. (36) regarding medical therapy for CRS, wherein they similarly observed SNOT-22 overall scores to exceed the MCID without any domain doing so. However, our study contrasts with the results achieved via endoscopic sinus surgery (35), whereby discernible improvements were seen in rhinologic, psychological dysfunction, and sleep symptom domains. Furthermore, we found that while the vast majority (71%) of patients did improve over the treatment period (Figure 2), 29% of our patients noted an overall increase in their SNOT-22 score of 2.5. Being less than the MCID, we conclude that in this small sub-group treatment stabilised their symptom burden. This finding is in approximate agreement with Behan et al. (37), who conducted a study-specific survey of 365 patients with PCD from 25 countries, and found that 21% of overall surveyed patients reported no improvement in health since their diagnosis of PCD. Emphasising the importance of early diagnosis and initiation of appropriate management, several studies including those conducted by Behan et al. (37) and Pifferi et al. (38) have demonstrated that there is a significant difference in quality of life among patients diagnosed with PCD in childhood compared to adolescence and adulthood. Reinforcing this, lung function has been observed to be worse in PCD patients diagnosed later in life (27).

While meeting the physical needs of PCD patients is certainly an important clinical goal, this study also emphasises the psychological bearing of living with such a diagnosis. Figure 3 displays the distribution of ENT symptoms in our cohort, and illuminates that the greatest burden of disease from beginning to end of treatment was in both the rhinologic and psychological dysfunction symptom domains. Therefore, this study emphasises the importance of proper wholistic management of PCD that includes consideration of appropriate psychological therapy.

In the BESTCILIA trial, Kobbernagel et al. (9) found that both their azithromycin and placebo groups had baseline hearing thresholds within normal limits (mean air conduction thresholds of less than or equal to 25 dB). While both groups demonstrated improvement in their hearing, neither was able to reach statistical significance. Our study found a similar result, as Groups C and D yielded normal baseline pure-tone thresholds of 19.5 and 19.1 dB respectively. While we did show an improvement in Group C’s hearing over time, this improvement was unable to reach statistical significance. Notably, audiometry remains an essential component of PCD management, as hearing loss can be found in up to 25% of children with PCD (39).

There are various limitations to our study approach. Firstly, the CRGH multidisciplinary clinic updated from SNOT-20 to SNOT-22 questionnaires in 2015, and hence we are only analysing this data. As such, taking our initial measurements from 2015 may not indicate each patient’s true baseline, as many had been treated at the clinic for years previously and thus we may be underestimating their true degree of improvement. Additionally, taking an average of all follow-up SNOT-22 scores ignores the natural relapsing-remitting course of PCD, and symptom flares during exacerbations may thus also result in an understating of improvement.

There is a clear need for early intervention, multidisciplinary care, and evidence-based treatments for all patients with PCD, with available data that clearly demonstrates symptomatic improvement with treatment adherence. This study has contributed to this goal, demonstrating that optimal management of PCD through a multidisciplinary clinic results in a clinically meaningful reduction in ENT symptom burden, as measured through overall SNOT-22 score. We found that the greatest improvement in quality of life occurs early in treatment (Figure 4) and that further sustained improvements are achieved with continued treatment adherence.

Conclusions

Through analysing the SNOT-22 scores and pure-tone audiograms of a cohort of Australian patients with PCD treated at CRGH, this study was able to quantify changes in their ENT symptom burden. Our results confirmed that optimal management in a multidisciplinary clinic reduces CRS symptoms and leads to a discernible improvement in quality of life, and that this is achievable despite the chronic and progressive nature of PCD. This may be mediated by a global improvement in ENT symptoms, without any particular symptom domain experiencing a meaningful change. We hope the results of this study will contribute toward the developing body of research verifying the efficacy of PCD management.

Acknowledgments

The authors appreciate the supports by the University of Sydney. The abstract was accepted for presentation at the 5^th World Bronchiectasis & NTM Conference, held in Prague, Czech Republic, between June 30^th and July 2^nd, 2022.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/10.21037/ajo-24-6/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-24-6/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-24-6/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-24-6/coif). R.G.C. serves as an unpaid editorial board member of Australian Journal of Otolaryngology from January 2019 to December 2024. R.G.C. is expert witness both for Hunter New England Health and Crown Solicitor’s Office South Australia. R.G.C. is on the speakers’ burea for Medtronic, Viatris and GSK. L.C.M. has received ad board consulting fees from ReCODE therapeutics for work in the PCD space. L.C.M. is part of a DSMB for ReCODE therapeutics in the PCD space. L.C.M. is unpaid chair of LFA and an associate editor of Respirology Case Reports. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Concord Hospital Research Office, Sydney Local Health District (No. 2021/ETH11876), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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