Introduction
Primary ciliary dyskinesia (PCD) is a rare, incurable, genetic disorder of ciliary structure and function.1 It is progressive in nature and characterised by ineffective mucus clearance from the airways resulting in recurrent or chronic respiratory infections. The lower airway infections and accompanying inflammation can result in bronchiectasis,2 leading eventually to respiratory failure and premature mortality.1 Recurrent upper airway infections causing persistent sino-ear-nasal disorders and hearing impairment are the most common early clinical manifestations of PCD.1 Despite the serious nature of PCD, there are large unmet needs in both its diagnosis and management.3 4
In addition to optimising general respiratory health (eg, vaccinations, enhancing nutrition, avoiding inhaled toxicants),2 current therapy for people with PCD seeks to improve mucociliary clearance and reduce infection and tissue injury from airway inflammation.1 5 However, current interventions used in PCD are without a strong evidence base and are generally extrapolated from studies and clinical experience gained from treating people with cystic fibrosis (CF) and other causes of bronchiectasis.1 2 5 These treatments in PCD include antibiotics for managing and preventing acute exacerbations,6 7 hypertonic saline (a mucolytic agent) in selected patients8 9and airway clearance therapies to ameliorate the deleterious effects of ciliary dysfunction on the lung.1
Reducing acute respiratory exacerbations in PCD is important as these episodes impair quality-of-life (QoL) and can lead to chronic infection, bronchiectasis and a decline in lung function.10 11 Recently, several RCTs have demonstrated that oral macrolides (mainly azithromycin) can significantly reduce exacerbations in people with bronchiectasis.12 13 A meta-analysis of nine randomised controlled trials (RCTs) involving 572 patients with non-CF bronchiectasis found that adults (risk ratio (RR)=1.66, 95% CI 1.37 to 2.02) and children (RR=5.03, 95% CI 2.02 to 12.50) receiving placebo were at significantly greater risk of exacerbations than those taking long-term (>3 months) macrolides.12 Nevertheless, data specific to people with PCD14 are needed, especially as azithromycin use by clinicians is highly variable.15 Moreover, not all people with PCD have bronchiectasis, and none of the RCTs of azithromycin in bronchiectasis have informed cost-effectiveness analyses.
The sole RCT that examined oral azithromycin (250 or 500 mg three times per week) enrolled 90 people with PCD,14 having planned to recruit 125 people.16 The participants’ mean age was 18.9 (SD=8.9) years in the azithromycin group and 19.7 (SD=10.8) years in the placebo group.14 We believe that although this RCT14 is important and showed that azithromycin more than halved the exacerbation rate in the active treatment group (RR=0.45, 95% CI 0.26 to 0.78), it has limited clinically applicability. There were just 26 (29%) participants aged ≤12 years and the trial drugs were only administered over a 6-month period. These limitations are relevant, as managing children with bronchiectasis differs in several aspects to adults,2 17 while longer-term RCTs (>12 months) in CF18 and bronchiectasis7 found the maximum effect of azithromycin extended beyond the 6-month period.7 Moreover, in clinical practice, azithromycin is usually prescribed for much longer durations, often years.15 Thus, further RCTs using azithromycin in people with PCD are required to inform clinical practice and health policies.
Our RCT plan includes assessing the risk/benefit of long-term antibiotics by measuring antimicrobial resistance (AMR) as clinical benefits arising from azithromycin must be balanced against possible adverse effects. Although nasopharyngeal cultures do not reliably predict lower airway bacteria,19 they provide good data on post-treatment AMR in colonising respiratory bacterial pathogens.6 7 We have identified previously that poor adherence (<70%) and living in remote communities are risk factors for AMR development in Australian First Nations children.20 However, these data need repeating in a different cohort, setting (urban centres) and clinical profile (PCD with or without bronchiectasis). Furthermore, azithromycin AMR in First Nations children should be contextualised, since in remote Australian communities, azithromycin is second only to amoxicillin as the most prescribed antibiotic and is used widely to treat skin, respiratory and genitourinary infections.21 Because of its long half-life, we will assess AMR in respiratory bacterial pathogens 3 months after ceasing azithromycin.
Chronic bronchitis, mucus hypersecretion and disruption of the mucociliary apparatus are all integral to the vicious cycle (vortex) hypothesis of bronchiectasis2 and also occur in people with PCD5 and chronic obstructive pulmonary disease (COPD).22 Despite the importance of these airway clearance mechanisms, there is only one small published RCT on mucolytics in people with PCD, which failed to identify a clinical benefit for hypertonic saline in 22 adult participants.23
Erdosteine is a novel thiol, synthesised to overcome problems (eg, non-efficacy and toxicity related to increased free thiols in the circulation) observed with other thiols (eg, N-acetylcysteine).22 Erdosteine has four main properties that could moderate the effects of ciliary dysfunction in the lungs (and thus potentially reduce exacerbations) in PCD. These are: (a) a mucolytic, modulating mucus production and increasing mucociliary transport; (b) an antioxidant, with (c) airway anti-inflammatory and (d) bacterial antiadhesion properties.22 24 As these actions target the underlying lung pathogenetic mechanisms in PCD,5 25 it is plausible that regular erdosteine could improve clinical outcomes.
Despite its potential benefit, there are no studies on erdosteine in PCD and only a single open-label RCT of erdosteine for 15-days in 30 elderly bronchiectasis patients that showed small but significant improvements in lung function and sputum volumes.26 Like macrolides, such medications are usually given for prolonged periods and a 15-day study is too short to assess its benefit. Erdosteine is licenced currently in 40 countries, including the UK (orphan drug in the USA,27 but not in Australia.27 RCTs in approximately 500 children aged >1 year with acute respiratory infections showed erdosteine for up to 2 weeks was well tolerated and significantly accelerated cough resolution in two studies28 29 but not in the third.30 Erdosteine has been used for longer-term studies in adults with chronic bronchitis/COPD, and a meta-analysis of individual patient data (n=1046) found it was associated with significant improvements in respiratory symptoms, including cough frequency and intensity, as well as sputum viscosity, when compared with either placebo or other mucolytics.31
Diagnosing PCD is not straightforward. It relies on gene analysis and interpreting cilia biopsy specimens.32–34 However, academic society guidelines provide differing recommendations for confirming a PCD diagnosis, and no single test or combination of tests conclusively excludes PCD in someone exhibiting a strong clinical phenotype.32 33 Importantly, in a recent comparative study, the different algorithms used to diagnose PCD resulted in a discordant diagnosis in 8/54 (15%) patients.35 Furthermore, acquired cilia ultrastructural defects or dyskinesia secondary to respiratory infections4 may be difficult to differentiate from PCD, particularly outside specialised testing centres.32 Consequently, cilia biopsies should only be undertaken at least 4–6 weeks after a viral infection or 2 weeks after full recovery from an illness.1 Unfortunately, this is virtually impossible in settings where recurrent ear and sino-nasal-pulmonary disease are highly prevalent as in Australian First Nations children living in remote communities where at any one time about 20% have chronic suppurative otitis media, up to 80% will be hospitalised during infancy, and as many as 1 in 68 will have a diagnosis of bronchiectasis.7 21 36 To help address these difficulties, a validated, simple diagnostic prediction tool (PICADAR) has been developed (box 1).37 Since current diagnostic methods are substantially limited,32–34 especially for First Nations children who have a high prevalence of bronchiectasis,7 our RCT includes children diagnosed by current traditional methods as well as those with a PICADAR score ≥5 and low nasal nitric oxide (nNO) or clinically suspected of having PCD.
PICADAR score37 is used to predict the likelihood of Primary Ciliary Dyskinesia in patients with chronic respiratory symptoms from early childhood. The features in the score are:
Born full term.
Chest symptoms present in the neonatal period (eg, tachypnoea, pneumonia, cough).
Admission to a neonatal unit.
Presence of a situs abnormality (heterotaxy).
Presence of congenital heart disease.
Presence of persistent perennial rhinitis.
Chronic ear or hearing symptoms.
Our RCT’s primary question is: among children and adults with PCD, can exacerbations be reduced during 12 months of treatment with: (a) oral azithromycin (given three times a week) compared with placebo (equivalent volume) or (b) oral erdosteine (given two times a day) compared with placebo (equivalent volume or capsule)?
Our primary hypothesis is that people with PCD who are prescribed either oral azithromycin or erdosteine for 12 months will have fewer exacerbations than those taking the corresponding placebo.
Our secondary aims are to evaluate the impact of the active treatments on:
PCD-specific QoL and other clinical outcomes (lung function, time-to-next exacerbation, hospitalisations).
Nasopharyngeal carriage of respiratory bacterial pathogens and their AMR to azithromycin.
Additionally, we will collect healthcare-related resource use for use in subsequent economic evaluation of these active treatments.
Our secondary hypotheses are that (a) azithromycin and/or erdosteine improve QoL and (b) azithromycin reduces bacterial carriage of respiratory pathogens, but with increased AMR to the antibiotic. Our additional hypothesis is that these active treatments will be associated with less exacerbation-related less resource use.