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Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Clinical care of children with primary ciliarydyskinesia

Jane S. Lucas, Mikkel Christian Alanin, Samuel Collins, Amanda Harris, HelleKrogh Johansen, Kim G Nielsen, Jean Francois Papon, Phil Robinson & WoolfT. Walker

To cite this article: Jane S. Lucas, Mikkel Christian Alanin, Samuel Collins, Amanda Harris, HelleKrogh Johansen, Kim G Nielsen, Jean Francois Papon, Phil Robinson & Woolf T. Walker (2017)Clinical care of children with primary ciliary dyskinesia, Expert Review of Respiratory Medicine,11:10, 779-790, DOI: 10.1080/17476348.2017.1360770

To link to this article: https://doi.org/10.1080/17476348.2017.1360770

Accepted author version posted online: 26Jul 2017.Published online: 02 Aug 2017.

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REVIEW

Clinical care of children with primary ciliary dyskinesiaJane S. Lucasa, Mikkel Christian Alaninb, Samuel Collinsa, Amanda Harrisa, Helle Krogh Johansenc,d, Kim G Nielsene,Jean Francois Paponf, Phil Robinsong and Woolf T. Walkera

aPrimary Ciliary Dyskinesia Centre, NIHR Biomedical Research Centre, University of Southampton and University Hospital Southampton,Southampton, United Kingdom; bDepartment of Otorhinolaryngology – Head and Neck Surgery, University Hospital Rigshospitalet, Copenhagen,Denmark; cDepartment of Clinical Microbiology, Afsnit 9301, University Hospital Rigshospitalet, Copenhagen, Denmark; dDepartment of ClinicalMedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; eDanish PCD & chILD Centre, CF CentreCopenhagen Paediatric Pulmonary Service, ERN Accredited for PCD and CF Health Care, Department of Paediatrics and Adolescent Medicine,Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; fAPHP, Bicetre University Hospital, ENT Department, Universite Paris-Sud,Faculté de Médecine, Le Kremlin-Bicetre, France; gPCD Service, Department of Respiratory and Sleep Medicine, Royal Children’s Hospital,Melbourne, Australia

ABSTRACTIntroduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disorder, usually inherited as anautosomal recessive condition but X-linked inheritance is also described. Abnormal ciliary function inchildhood leads to neonatal respiratory distress in term infants, persistent wet cough, bronchiectasis,chronic rhinosinusitis, and hearing impairment; approximately 50% of patients have situs inversus. Thereis a paucity of evidence for treating PCD, hence consensus guidelines are predominantly influenced byknowledge from cystic fibrosis (CF). Extrapolation of evidence from other diseases is inappropriate sincedifferences in pathophysiology, morbidity and prognosis risk treatment failure and lack of adherence.Areas covered: Review authors searched PubMed and Cochrane databases for publications relating tomanagement of children with PCD. Because of the paucity of data, we emphasise the need for well-designed clinical trials with PCD patients rather than reliance on evidence from other diseases.Expert commentary: The evidence for treatment of PCD is poor, and management is often extra-polated from studies of patients with CF or chronic rhinosinusitis. However, much work is underway toimprove the situation and international consortia and networks are conducting well-designed projectsto inform the management of children with PCD.

ARTICLE HISTORYReceived 4 June 2017Accepted 25 July 2017

KEYWORDSPrimary ciliary dyskinesia;PCD; kartagener; therapy;management; microbiology;transition; rare diseases;review

1. Introduction

Primary ciliary dyskinesia (PCD) is a genetically and clinicallyheterogeneous disorder, usually inherited as an autosomalrecessive condition [1]. Abnormal ciliary function leads toslow onset neonatal respiratory distress in term infants, persis-tent wet cough, bronchiectasis, chronic rhinosinusitis (CRS),fertility issues, and conductive hearing impairment. A littleless than 50% of patients have situs inversus and congenitalheart disease has been reported to occur in 5% of children [2].While there is little data relating to the long-term outcomesfor patients with PCD, it is evident that disease progression ishighly variable, with some patients maintaining reasonablygood lung function and quality of life (QOL) into later adult-hood, while others have worse outcomes leading to respira-tory failure and lung transplantation [3–5].

The prevalence of PCD is not clearly established, but it isestimated to affect approximately 1:10,000 Europeans [1], with asignificantly higher incidence in populations with closed geneticpools [6]. A European survey of PCD specialists found that only asmall fraction of expected PCD patients had been diagnosed [7],and an international survey of patients reported that 37% ofpatients had visited a doctor with PCD related symptoms morethan 40 times before being referred for testing [8]. The reasons for

underdiagnosis are multifactorial. Pediatricians rarely see a case,and their awareness of PCD is therefore limited. Symptoms arenonspecific, and only patients with situs inversus, a rare conditionin the general population, are diagnosed at an earlier age [7].There is no gold standard diagnostic test and diagnosis thereforedepends on a combination of tests including nasal nitric oxide(NO), high-speed video microscopy, transmission electron micro-scopy, genetic testing, and immunofluorescence staining of ciliaryproteins [9]. These diagnostic tests are highly specialized andpatients often need to travel considerable distances to attend adiagnostic center.

As with other ‘orphan diseases’, the evidence base for ther-apeutics and management is lacking, hence consensus guide-lines are generally based on clinical trials involving patientswith cystic fibrosis (CF) and small observational studies in PCD[10,11]. Extrapolation of evidence from other diseases is regret-table since differences in pathophysiology, morbidity, andprognosis might lead to treatment failure, lack of adherence,and side effects. Moreover, we need to consider the heteroge-neous nature of PCD; therapies that work in some patientsmight not work in all. In this review, we discuss current manage-ment strategies for children with PCD emphasizing the urgentneed for methodologically sound, randomized clinical trials to

CONTACT Jane S. Lucas jlucas1@soton.ac.uk Southampton University Hospital, Tremona Road, Southampton SO16 6YD, UK

EXPERT REVIEW OF RESPIRATORY MEDICINE, 2017VOL. 11, NO. 10, 779–790https://doi.org/10.1080/17476348.2017.1360770

© 2017 Informa UK Limited, trading as Taylor & Francis Group

enhance the evidence base for treatment. Since the manage-ment of PCD is predominantly based on experience frompatients with CF, we discuss similarities and differencesbetween these diseases throughout the review. The manuscriptis not a systematic review but provides the authors’ expertknowledge of the disease area; in preparation for the review,we searched PubMed and Cochrane data bases for publicationsrelating to management of children with PCD.

2. Pathophysiology of PCD and CF

PCD is characterized by a failure of mucociliary clearance(MCC) and is usually inherited in an autosomal recessive pat-tern, with X-linked inheritance also reported. Biallelic muta-tions in >35 cilia-related genes have been proven to causePCD (listed in [12]); these genes only account for ≈65% ofcases, so many more genes have yet to be discovered [12]. Themutations lead to abnormal ciliary beating which is usuallybut not always associated with abnormal ciliary ultrastructureseen by transmission electron microscopy. The dysfunctionalcilia prevent efficient MCC [13,14].

CF is also an autosomal recessive disorder which leads toimpaired MCC, but the underlying pathophysiology differsfrom PCD. CF is the result of mutations in one gene causingdysfunction of only one protein, the cystic fibrosis transmem-brane conductance regulator (CFTR). Despite the identificationof over 2000 mutations in the CFTR gene, at least one copy ofthe commonest mutation (p.Phe508del) is found in over 90%of CF patients in the UK. CF therefore contrasts markedly withPCD where a number of genes are causative and each of thegenes may carry a large number of different mutations. Therewill therefore be a much higher degree of heterogeneitybetween PCD patients than CF patients. The net result ofCFTR dysfunction is abnormal chloride efflux from the epithe-lial cell with associated abnormalities in sodium influx anddefects in bicarbonate transport [15–17]. However, abnormalCFTR also appears to have intracellular effects that result inimpaired mucociliary transport and defects in innate immu-nity [18].

Although inflammation in CF airways may be present frombirth [19], CF patients have preserved MCC in early life [20].This is in contrast to PCD where MCC is a primary defect,absent from birth. It has been suggested that MCC becomesimpaired in CF only after a ‘2nd hit’ [20]. Using piglet models ofCF, particle clearance was shown to be identical to wild-typeairways at baseline but following cholinergic mucus stimula-tion, the mucus strands remained abnormally tethered to thesubmucosal glands and prevented clearance [21,22]. ImpairedMCC in CF can therefore start following infection orinflammation.

Studies directly comparing CF and PCD are limited. Mucusfrom CF and PCD patients was compared by Bush et al. whofound that IL-8 concentrations were significantly higher in PCDpatients, but with no differences in physical or transport prop-erties of the mucus [23]. This is contrary to the idea that CFmucus viscosity accounts for more severe airway inflammationand failure of MCC, instead supporting the theory mentionedabove that it is abnormal tethering of mucus to the epitheliumthat may inhibit airway clearance in CF. Ratjen et al. compared

inflammation in CF and PCD sputum from children withrespiratory exacerbations. Neutrophils were more abundant,with higher neutrophil elastase activity in PCD than CF spu-tum. Interestingly, this was responsive to oral antibiotic treat-ment in PCD but not in CF [24].

It is also known that nasal NO levels differ in the PCD andCF airways. While CF patients have lower nasal NO levels thanhealthy subjects, this is still much higher than that seen in PCD[25]. The causes and downstream effect of this difference inNO is not entirely clear, but might result in differing responseto infection/inflammation in the airways of PCD and CFpatients.

3. Management of children with PCD

There is no cure for PCD and management therefore aims tooptimize health, social, and psychological well-being whilepreventing progression of lung damage. There have beenfew clinical trials in PCD and management is empiricallybased on other diseases such as CF and CRS. Consensus guide-lines are based on the experience of specialist centers inEurope and North America [10,11]. Patients should be lookedafter in specialist PCD centers by a multidisciplinary teamwhich includes as a minimum a pediatric pulmonologist, anear nose and throat (ENT) doctor, and respiratory physiothera-pists [9,10]. In this review, we will discuss pulmonary manage-ment, which is based on airway clearance and treatment ofinfections, and ENT management of rhinosinusitis and eardisease. We then review the options for monitoring diseasein children with PCD. We will also discuss the role of a transi-tion program to prepare the child and family for transfer toadult services.

3.1. Lower airway clearance therapy

Since impaired MCC is the fundamental problem in patientswith PCD, therapies to facilitate mucus clearance from theairways are central to reducing stasis of secretions, occurrenceof infections, atelectasis, inflammation and progressive lungdisease. A respiratory physiotherapist should tailor the airwayclearance technique to the individual, taking into considera-tion the age of the child, patient preference, ability, mucusproperties, and disease severity. Regular review by a phy-siotherapist will allow the technique to be adapted as needed,for example, transition from parent delivery of treatment toindependent methods, change of techniques where adher-ence is an issue. Airway clearance is usually recommendedtwice daily with increased sessions during exacerbations; thiscan be a significant burden to families [26,27] and poor com-pliance can be an issue. Unlike CF, impaired MCC is presentfrom birth. With newborn screening, CF patients are usuallydiagnosed before MCC has been discussed, and it has beenquestioned whether airway clearance should be started inasymptomatic infants at diagnosis [28]. In contrast, PCDpatients are usually symptomatic from birth [29], are oftenreferred for diagnostic testing late, and the diagnostic processcan be protracted [7,8]; therefore, airway clearance therapyshould undoubtedly be started as soon as a diagnosis of PCDis thought likely.

780 J. S. LUCAS ET AL.

A range of airway clearance interventions are availableincluding breathing techniques, manual techniques, posi-tioning, positive expiratory pressure (PEP) adjuncts, andoscillatory-PEP [30]. Combinations of techniques are oftenused, for example a combination of active cycle of breath-ing technique (ACBT) can be used in combination with anoscillatory-PEP device. ACBT aims to improve ventilationthroughout the airways and mobilize mucus from smallerto large airways from where it can be expectorated. PEPaims to open airways, improving ventilation of small air-ways, while the oscillatory device causes vibrations in theairway which are thought to improve mucus flow andenhance clearance. A recent systematic review found onlyone clinical study which compared different airway clear-ance techniques in PCD patients [30]. A randomized cross-over design was used to compare high frequency chest walloscillation (vest therapy) for 5 days at home, with posturaldrainage percussion and vibrations performed by a phy-siotherapist for 5 days in a hospital setting [31]. Both groupshad improved lung function but there was no significantdifference between techniques.

A number of nebulized treatments have been shown toassist mucus clearance in patients with CF. As alreadydiscussed, the pathologies underlying PCD and CF aredifferent, and treatments to alter the properties of mucusand its clearance may not be similarly effective. For exam-ple, recombinant human DNase (rhDNase) lyses neutrophilDNA which originates mainly from decaying neutrophils atsites of airway inflammation. There is good evidence for itsuse in CF [32], but the support for use in PCD is limited toa few case reports [33,34]. Importantly, a large study ofpatients with non-CF bronchiectasis showed faster declinein FEV1 and more frequent exacerbations in patients whoreceived rhDNase in comparison to those treated withplacebo [35]. Until a well-designed study is undertaken inPCD, the role of rhDNase is therefore unclear and notgenerally recommended.

Osmotic agents such as hypertonic saline are also usedin CF to assist with mucus clearance as an adjunct toairways clearance therapy. Recently, the first randomizedclinical trial in PCD [36] explored the effect of hypertonicsaline on the QOL of 22 adults in a double-blind crossovertrial. At the time of the trial, there was no disease-specificQOL measure and results were therefore based on the StGeorge’s Respiratory questionnaire (SGRQ) which was notdesigned for patients with PCD. The study showed nosignificant effect of hypertonic saline on SGRQ score.However, the study population was small particularlygiven the nonspecific outcome measure, and larger studiesare required using outcome measures which are validatedin PCD [26,37,38].

Two studies have suggested that aerobic fitness might bereduced in children with PCD [39,40]. Since exercise is goodfor general well-being and might assist bronchodilation [41], itis important to encourage PCD patients to exercise regularly.However, there is no evidence that exercise adequately clearsairway secretions of PCD patients and it should be used in

combination with, not as an alternative to, airway clearancetherapies.

3.2. Management of airway infections

We will firstly review what is known about the microbiology ofthe PCD airway and will then discuss management strategies.

Haemophilus influenzae is the most frequently isolatedpathogen from the airways of PCD patients [5,42–44]. It infects40–80% of PCD patients annually [42], while Streptococcuspneumoniae, Moraxella catarrhalis, Staphylococcus aureus,Achromobacter xylosoxidans, and Burkholderia spp are less pre-valent [42,43]. Nontuberculous mycobacteria may be culturedin up to 10% of PCD patients [5,45]. In cross-sectional studies,Pseudomonas aeruginosa has been isolated in approximately10% of PCD patients [5,43,45]. Recent studies have foundincreasing prevalence of P. aeruginosa with age and domi-nance in adults [3,42]. Data is limited but increasing bacterialdiversity with age has been reported [42]. A strong age-depen-dent bacteriology also occurs in CF, but in contrast to PCD, thebacterial diversity decreases with age [46].

The reported prevalence of chronic infection with P. aeru-ginosa varies in PCD with reports ranging from 5% to 39%[4,42,43,47]. This might partly reflect the lack of consensusabout the definition of chronic infection for PCD; the LeedsCriteria are widely used to define chronic infection in CF, and aconsensus approach is also warranted for PCD to aid guide-lines on strategies for antibiotic therapy and for comparingand designing clinical studies. According to the 2013European Cystic Fibrosis patient registry approximately 33%of patients with CF are chronically infected with P. aeruginosa[48]. PCD patients colonized or infected with P. aeruginosahave poorer pulmonary function than other PCD patients[4,47], indicating that it is a major pathogen not only in CFbut also in PCD.

Patients with CF can house a bacterial reservoir in their sinusesand concordant bacteriology in the upper and lower airway isfrequent [49–51]. Furthermore, lung re-colonization from thesinuses is frequently observed in lung-transplanted CF patients[52,53]. CRS is almost universal in PCD and bacterial sinusitis hasbeen reported in 88% of PCD patients with CRS [54]. PCD sinusescan house a variety of pathogens, although P. aeruginosa is thedominant pathogen presumably also functioning as a bacterialreservoir leading to lung colonization and infection [54,55].

Recently it was shown that 10 out of 12 (83%) PCD patientskept the same P. aeruginosa clone type for a prolonged period,similar to findings in CF patients [56–59]. To acquire moreknowledge about persistence and adaptation of pathogenicmicroorganism in PCD, more frequent sampling of sputum isneeded, for example, every second month [59]. In a retro-spective longitudinal study, it was reported that chronicP. aeruginosa infection was cleared for at least 1 year in 29out of 42 patients (69%) [42]. This finding raises importantquestions of whether eradication had really been successful:was the quality of the sputum samples optimal, was the rateof sputum sampling too sparse, or were PCD patients reallyable to clear persistent infections?

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Management of airway infection in PCD including surveil-lance, prophylaxis, segregation, and treatment is currentlywithout any evidence and is based on expert opinions, oftenextrapolated from experience with CF [10,11]. Consensusguidelines recommend surveillance cultures of expectoratedsputum or oropharyngeal cough swabs 2–4 times a year[10,11]. The impact of sampling frequency of respiratory tractcultures is currently unresolved in CF [60,61] and there is noevidence in PCD, but it inevitably influences likelihood ofdetection of new pathogens, load of therapy, and the abilityto differentiate chronic and non-chronic infection. More fre-quent sampling will undoubtedly increase the detection ofpathogens. The 2013 Infection Control Guideline for CF recom-mendation is quarterly lower airway sample cultures, or morefrequently if clinically indicated [60]. While the current infor-mation for PCD is based on weak and inconsistent data setsfrom few centers, it seems reasonable to follow guidancefrom CF.

Minimizing exposure to respiratory pathogens and otherinfections is probably important, whether this relates to hos-pitalization, visits to the pulmonary outpatient clinic, or daycare settings in infancy and early childhood. Patients with PCDshould receive pneumococcal immunization as part of thenormal immunization program and annual influenza vaccine[10,11]. Recommendations on the use of prophylactic oralantibiotics are disputable, but they are used in some centersand further discussed below. Chronic prophylactic therapywith azithromycin has been previously investigated in CF[62,63] and non-CF bronchiectasis [64,65] showing positiveeffect and is currently under prospective investigation by theBESTCILIA consortium [66].

In a small study of 12 patients from a clinic of 125 (10%)PCD patients, cross-infection with P. aeruginosa was notobserved, but this does not prove that cross-infection is nota risk in PCD [58]. Larger multicenter studies with more fre-quent sampling might improve the evidence for cross-infec-tion and help determine whether strict segregation iswarranted.

Eradication strategies following positive cultures are cur-rently based on expert opinions [10,11]. Although the need forantibiotic treatment for patients with simultaneous symptomsof infection and positive cultures for respiratory pathogens isnot contentious, indications for treatment modalities such aschronic suppressive oral or inhaled antibiotics, or treatmentbased on positive cultures without simultaneous sign ofexacerbation or disease progression are by no means certain.

Furthermore, treatment of respiratory infections reflectsexperience from CF without accounting for possible differ-ences in side-effect profiles between patient groups withrespect to specific antibiotic drugs and dosages used.Recommended doses for CF are often substantially higherthan those recommended in other diseases with the risk ofimposing toxic effects to PCD patients. Given the abovemen-tioned premises, it is unclear whether the management of PCDcan be transferred directly from CF. P. aeruginosa can establishpersistent lung infections in PCD exhibiting exactly the samepattern as in CF lung infections [58]. Adaptive mutationsoptimize pathogen fitness by modification of virulence factorsrequired for survival in both CF and PCD patients [57,58,67]. In

PCD patients P. aeruginosa isolated from the lungs showedconvergent evolution in eight genes like P. aeruginosa isolatedfrom CF patients, for example, related to antibiotic resistance,quorum sensing, motility, type III secretion, and mucoidity.Therefore, until further evidence is available, it seems logicalto follow the same guidelines for management, that is, sur-veillance, segregation, and treatment as in CF, with modifica-tions to the dose of antibiotics. However, if there wereevidence to support that infections in PCD are more easilyeradicated than CF, a less aggressive approach to infectionprevention and control could be justified. Well-designed epi-demiological studies and randomized trials are needed toexamine this further.

3.3. Additional treatments of the lower airway

A number of additional treatments including bronchodilators,inhaled corticosteroids, mannitol, and N-acetylcysteine aresometimes used in patients without evidence [68]. Thesetreatments, which are generally used based on experiencefrom CF and non-CF bronchiectasis, have recently beendiscussed in a comprehensive review by Polineni [69]. In theopinion of the authors of our manuscript, given the lack ofevidence for any treatments in PCD, it is reasonable to trialthese treatments in individual cases following assessment by apediatric pulmonologist, with careful review of response totreatment.

Similarly, evidence for surgical intervention is limited to asmall retrospective, case-control study of five adults whounderwent lobectomy and seven who did not have surgery[70]. Patients who had undergone surgery had worse lungfunction, but it is not possible to say whether this was causedby the surgery, or whether it prompted surgical intervention.Lung transplantation is an option in patients with end stagedisease and has been performed in a number of patients.Transplantation will require advanced planning particularly inpatients with situs abnormalities.

3.4. Management of sinonasal disease

Sinonasal disease is ubiquitous in patients with PCD, mostlyrepresented by CRS. CRS is a hallmark of PCD, affecting ≥70%of patients [4,71–74]. Symptoms include nasal obstruction,decreased sense of smell, pain, coughing, and nasaldischarge. CRS can be very debilitating, affecting QOL[26,38]. Abnormal sinus development, hypo- or aplasia, isfound in >50% of adult patients with PCD [75]. Nasal polyps(NP) are prevalent in up to 50% of adult PCD patients [4] andmay appear in childhood [47,54].

Currently, CRS management in PCD focuses on relievingsymptoms. Therapeutic strategies are inspired from CRS treat-ment in the general population and CF. These include sinona-sal irrigation with saline, topical nasal steroids, and antibiotics.Anecdotally, sinonasal irrigation with iso- or hypertonic salineis a beneficial and safe method for assisting upper airwayclearance in PCD, as it is in the general population [76,77].Nasal irrigation can remove stagnant mucus and it is inexpen-sive, well tolerated, and practical [76–78].

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Topical steroids have a well-documented positive effect inthe general CRS patients [76,77], and it may be reasonable tobelieve that administration can also reduce mucosal inflam-mation and polyps in PCD. However, topical steroids have noclear effect on CF patients with NP, presumably becauseairway inflammation in CF is dominated by neutrophils [79]and this is also the case in PCD [23,24].

Management of sinonasal exacerbation is based on antimi-crobial therapy which can be guided by middle meatus cul-ture. Prophylactic antibiotics (either local or oral) for long-termsinonasal therapy have not been evaluated in PCD. However,therapy with macrolides is effective in treating CRS without NPin the general population [76] and is potentially beneficial intreating PCD patients with CRS as well.

Endoscopic sinus surgery (ESS) can ventilate and drain thesinuses and is a well-established CRS treatment, improvingQOL in patients with CRS including CF where medical therapyhas failed [76,77]. Only a few studies have evaluated thepotential benefits of CRS treatment with ESS in PCD andthey consistently show subjective benefit [54,80,81].Importantly, recent studies suggest that the sinuses may func-tion as a bacterial reservoir causing repeated lower airwayinfection and advocate that ESS can eradicate pathogenicsinus bacteria and thereby protect the lower airways [54,55].

3.5. Management of otologic disease

Conversely to CF, otologic manifestations are frequent in PCD,affecting up to 100% of children <12 years of age [73,82–85].The natural history of otologic disease tends to improve withage [82,86,87]. The cardinal otologic features include recurrentacute otitis media (AOM), otitis media with effusion (OME),and chronic otitis media [73,82,84,87]. Cholesteatoma hasbeen documented in a few patients with PCD [85,87,88].Both recurrent AOM and persistent OME appear between 2and 3 years but, unlike the general population, they continueuntil the age of 6–8 years and commonly persist in adulthood[82,87,89]. A moderate conductive hearing loss is reported inPCD patients with OME, mainly before 12 years [82] which mayimpair speech acquisition.

The management of otologic disease in children with PCDis extrapolated from studies of the general population sinceinterestingly otologic problems in CF are very infrequent. Itaims to improve hearing and prevent possible sequel such asdelayed speech acquisition, tympanic membrane atelectasisand retraction pockets.

Conservative treatment includes courses of oral antibioticsin case of recurrent AOM [73]. The choice of antibiotics isguided by the prevalence of bacteria in AOM, focusing onStreptococcus pyogenes, S. aureus, S. pneumoniae, H. influenzae,and M. catarrhalis. In cases of recalcitrant acute otitis, a myr-ingostomy is considered in order to obtain middle ear fluid forculture. Continuous alternating antibiotics have not been spe-cifically studied, but it does not appear to prevent complica-tions of AOM [87].

In the general population, insertion of ventilation tubes(VTs), possibly combined with adenoidectomy, is indicatedfor restoration of hearing in children with persistent bilateralOME and prevention of further middle ear infections in

children suffering from recurrent AOM [90]. In PCD children,the use of VT is controversial since recurrent mucopurulent eardischarge after insertion is described in 30% of PCD patientswhile it concerns less than 5% of the general pediatric popula-tion [82,87]. The European Respiratory Society ConsensusStatement recommends against placement of VT in patientswith PCD and advises to watch for spontaneous resolution ofOME which may occur in the teenage years [10]. Hearing aidsmay be required in case of hearing loss which is impacting oneducation or speech development.

Antibiotics for ear discharge in children with VT shouldfocus on the most common bacteria causing AOM [91]. Incase of ear discharge occurring after VT insertion, local anti-biotics are usually prescribed but there is no study addressingthis treatment in PCD. In the general pediatric population, arecent Cochrane review found moderate to low-quality evi-dence that antibiotic eardrops (with or without corticosteroid)are more effective than oral antibiotics, corticosteroid ear-drops, and no treatment in children with ear discharge follow-ing VT insertion [90]. Potential ototoxicity of ototopicalantibiotics should be kept in mind; this is a concern in generalwhen prescribing local antibiotics for treatment of ear dis-charge but the risk is higher in PCD as ear discharge mayrequire longer treatment and patient may have preexistingsensorineural hearing loss.

Tympanic membrane perforation and extrusion followingVT insertion is more common in children with PCD than in thegeneral pediatric population [87]. Tympanic membrane per-foration requires myringoplasty once the middle ear is healed.Healing may be partial in PCD and the chances of successfulsurgical outcomes are likely to be lower than in the generalpopulation.

Similarly to CF patients, anesthesia in PCD patients requirestechniques that prevent anesthetic-related morbidity duringthe postoperative period [92]. Meticulous respiratory prepara-tion includes intensive physiotherapy and, if needed, antibio-tics and aerosolized medications. Myringotomy and VTinsertion is a relatively short procedure that does not involvethe airway directly. The postoperative period can be eventfuland merits careful monitoring.

4. Monitoring of disease in children with PCD

Clinical outcome measures should give the clinician orresearcher insight into the patient’s current disease statusand how this has changed from the previous assessment.There are a wide range of potential outcome measures forPCD patients (Table 1) the relevance of which will depend onthe setting they are measured, that is, research study or clinic,and the frequency and practicality of undertaking the mea-surement. Here we consider several of these in more depth.We will consider monitoring of lung function, structural lungdisease, ENT, and QOL in children with PCD.

4.1. Monitoring lung function

Spirometry, and in particular forced expiratory volume in 1 s(FEV1), is routinely used in clinically practice for monitoringPCD patients, as it is widely available and quick to perform.

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However, it is effort dependent and therefore generally onlypossible in children over 5 years of age. While predicted valuesare widely available, these are not specific to all ethnic groups,in particular to patients from South Asia in whom the preva-lence of PCD can be high [6,93]. Furthermore, spirometry lackssensitivity in detecting early structural lung disease progres-sion evident on high-resolution computer tomography (HRCT)scan [94], and peripheral airway disease as detected in lungclearance index [95–98]. In the experience of the authors, FEV1can be highly variable in stable PCD patients even on thesame day. This is presumably due to variable obstructioncaused by secretions with cough clearance between first andfollowing attempts. To be meaningful as an outcome withinpatient variability needs to be understood.

Lung clearance index derived from a multiple breath wash-out technique expresses ventilation inhomogeneity. It can beperformed in all ages, as it only requires tidal breathing, andchanges little with age. However, measurements are reliant onthe dispersal of the inhaled gas throughout the lungs and, asit will not enter obstructed areas of the lung, has the potentialto underestimate disease severity. It has been widely studiedin CF patients and has been demonstrated to be more sensi-tive in detecting early disease than FEV1 and correlates betterwith changes on chest HRCT scans [99,100]. However, theliterature on its use in PCD is mixed with some showing acorrelation with FEV1, while others not, and no correlation toHRCT findings [95–98].

4.2. Monitoring structural lung disease

Most PCD clinics undertake routine CXR, annually or every fewyears, as they are readily available, cheap, and involve a mini-mal radiation burden [10,11]. However, CXRs are not sensitivefor early structural changes of disease. Due to concern overthe radiation exposure most centers use HRCT in PCD patientswhen clinically indicated, with few using it routinely. Publishedliterature concerning structural lung disease in both CF andPCD has principally concentrated on changes evident on

HRCT. Data is conflicting whether lung disease is worse in CFthan PCD [101,102]. While all lobes are effected in CF, there isrelative sparing of the upper lobes in patients with PCD [101].Typical changes seen in both diseases include bronchiectasis,peribronchial thickening, mucus plugging, atelectasis, andconsolidation/collapse. Significantly more information in thisarea is available from patients with CF, due in part to theability to detect the condition by newborn screening and theclinical drive to detect and potentially prevent or retard theonset of early lung disease. The desire for periodic assessmentof structural lung disease to aid in this assessment has resultedin qualitative and, more recently, quantitative scoring systemsfor CF lung disease allowing longitudinal assessment ofchanges in structural disease as well as uniformity betweenreviewers [103–105]. Two commonly used scoring systemsderived for assessment of structural CF lung disease, Brodyand Bhalla, were derived by descriptive reviews of structuralchanges seen on HRCT scans from a heterogeneous group ofpatients with CF with subsequent construction of a scoringsystem [103,104]. Refinement of the systems over ensuringyears has led to reliable, validated scoring systems used notonly in clinical care but also as end points for interventiontrials. Probably the most commonly employed scoring systemfor both these end points is the modified Brody score whichentails the scoring of five different parameters: bronchiectasis,mucous plugging, peribronchial thickening, parenchymalchanges of consolidation and ground glass thickening, andfocal air trapping; several reports of structural lung disease inPCD have employed the use of a modified Brody score todescribe and quantitate structural changes [101,102,106].This of course assumes that structural changes in PCD aresimilar if not identical to those seen in CF, and the assumptionhas as yet not been ratified.

Up to 70% of infants with PCD are reported to have evi-dence of neonatal respiratory difficulty despite birth at term.Mullowney et al. previously described the high incidence ofupper lobe disease associated with this presentation [29]; in acase–control study of 46 infants subsequently diagnosed ashaving PCD, 70% of the 23 infants in whom a chest X-ray hadbeen performed showed evidence of lobar collapse – 75% ofwhich occurred in the upper lobes. This high level of upperlobe disease, interestingly in contrast to the relative sparing ofupper lobes in HRCT scans in older children with PCD, isdistinctly different from reports of lung disease at diagnosisin infants with CF detected by new born screening. In a groupof 57 infants with CF detected by newborn screening, Sly et al.reported 80% of HRCT scans at a median age of 3.6 monthshad evidence of structural lung disease including 19% withbronchial dilatation, 45% with bronchial wall thickening, and67% with gas trapping [107]. Lobar collapse was not reported.

Several investigators have described structural changes seenon HRCT scans from older patients with PCD. Jain et al. reviewed26 HRCT scans from children with PCD and found that while thepreviously reported changes seen in CF were also evident in PCD,there was relative sparing of upper lobes from disease, particu-larly bronchiectasis [106]. Overall severity scores assessed usingthe CF derived modified Brody score were highest for the middleand lingular lobes. A further study evaluated the lung disease in20 children and adults with PCD by a modified Brody composite

Table 1. Monitoring children with PCD in clinical practice and for research.

Clinical

● Mortality● Exacerbation rate● Admission rate

Sputum and bronchoalveolar lavage

● Bacteriology and antibiotic resistance● Viruses, fungi, and nontuberculous

mycobacterium culture

Growth

● Height● Weight● Body mass index● Bioelectrical impe-

dance analysis

ENT functions

● Audiogram (age appropriate)● Auditory evoked potentials● Rhinomanometry (after 6 years)● Olfactory tests

Lung function

● Spirometry● Plethysmography● Lung clearance index

Radiology

● Chest X-ray● Chest high-resolution computer tomo-

graphy scan

Questionnaires

● QOL-PCD (age appro-priate version)

● Magnetic resonance imaging● Sinus and ear high resolution computer

tomography scan

784 J. S. LUCAS ET AL.

HRCT scan score to assess the prevalence of the structuralabnormalities [101]. They also attempted to correlate HRCTscan scores with spirometry findings and clinical data.Bronchiectasis was seen in 80% of cases while peribronchialthickening (80%), mucous plugging (75%), and parenchymalchanges (65%) were also seen commonly. Mosaic perfusionwas the least common abnormality and was seen in only 45%of cases. The total HRCT scan score was significantly related toage and lung function including both FEV1 and FVC.

A study of structural changes onHRCT scans in 20 adolescentswith PCD reported bronchiectasis (70%), mucous plugging(70%), peribronchial thickening (90%), parenchymal abnormal-ities (65%), and hyperinflation (50%) [108]. HRCT scores, using acombined modified Brody and Bhalla scoring system, signifi-cantly increased (i.e. worse disease) with age, and were nega-tively correlated to PaO2, FVC, FEV1, and FEF25-75% longitudinalchanges. Similar findings were described in a study from Israelwhich compared lung function and HRCT changes assessed,again using a Brody score, between children with PCD and twogroups of CF patients, pancreatic sufficient (CF-PS), and pancrea-tic insufficient (CF-PI). The severity of structural lung disease wassimilar for PCD and CF-PS and significantly worse in CF-PI [102].

The desire to avoid the radiation doses associated withHRCT imaging has led some investigators to consider nonra-diation-based imaging techniques such as magnetic reso-nance imaging (MRI) scanning to assess structural changes.Montella et al., in a study of 41 subjects with non-CF chroniclung disease including 14 patients with PCD, found that MRIscanning had good agreement with paired HRCT scans indescribing features of suppurative lung disease includingbronchiectasis and mucous plugging [109]. Further develop-ment of this technique may aid examination of longitudinalchanges over time in PCD as well as being a useful assessmenttool for short-term intervention therapy trials. To date, nostudies have reported the use of hyperpolarizing gas MRI,Helium3 or Xenon, in the assessment of lung disease in PCD.

4.3. Monitoring ENT diseases

An annual ENT evaluation is a minimum for monitoring ear andsinus disease in childrenwith PCD. Considering the high incidenceof hearing impairment in PCD, evaluation of audition is usuallydone at diagnosis and can be repeated annually in case of eardisease. Hearing is measured with open field audiogram and puretone audiogram respectively before and after 6 years. In case ofsensorineural hearing impairment, auditory evoked potentials areuseful to evaluate the auditory nerve functioning. Ear or sinusimaging is not classical part of ENT monitoring of children withPCD. Sinus CT (classical or cone-beamed) is indicated prior toperforming ESS. Nasal function testing (i.e. rhinomanometry andolfactory testing) canbeproposed, especially in case ofNP, in orderto objectively measure nasal congestion and its consequence onolfaction.

4.4. Monitoring health-related QOL

PCD effects the physical, psychological, and social well-being ofpatients and their families [110]. Health-related QOL question-naires allow measurement of the patient’s perceptions of the

impact of their disease. There are a number of generic question-naires which have been used as outcomes measures in PCDpatients, for example, SGRQ and Sino-Nasal Outcome Test(SNOT-22) [110]. Disease-specific outcome measures for CF (CFQ-R) and bronchiectasis (QOL-B) have also been used as outcomemeasure for PCD patients [36,110]. However, these questionnaireswere not designed for use in PCD patients, and have often notbeen validated in the age-groups in which they have been used.PCD-specific QOL questionnaires (QOL-PCD) were therefore devel-oped and validated for children and adults [26,37,38]. QOL-PCDhave been translated into a number of languages and are beingused in a number of studies. In the future, the QOL-PCD will notonly be used as an important outcomemeasure in research of PCDpatients but also in the routine monitoring of their diseaseprogression.

5. Transition of patients from pediatric to adult care

Transition is a gradual process of empowerment that equipsyoung people with the skills and knowledge necessary tomanage their own medical condition in preparation for adultservices. In all chronic conditions a good transition from pedia-tric to adult services is necessary to optimize long-term out-comes of young people [111]. This is particularly important ina rare condition such as PCD where adult specialist servicesare limited and many health-care professionals have not heardof the condition. The lack of a specialist PCD adult service canlead to patients being mismanaged in respiratory services orgeneral practice. In the experience of the authors, young adultpatients report that having left pediatric services they may beadvised to stop physiotherapy between exacerbations, beprescribed vitamins in accordance with CF guidelines, struggleto get sputum microbiological assessment, and struggle to getantibiotics to treat exacerbations.

Ensuring young people have the knowledge to become‘expert patients’ with a good understanding of the manage-ment of PCD and skills to negotiate with physicians may serveto reduce morbidity [111,112]. They should have a goodunderstanding of their condition, their medications, and howto access medical services (e.g. how to get prescriptions andfertility advice). A good transition program should be holistic,not only addressing medical aspects of care but also ‘healthyliving’, careers options, bullying, etc.

Transition can be facilitated by a simple tool; ‘Ready SteadyGo’ is a structured generic transition program which has beenrecommended by the National Institute for Health and CareExcellence UK as an example of good practice [111,113]. Theprogram is used as a framework to guide transition by all fournational PCD centers in England [9], where it has been tailoredto meet the needs of children with PCD. The program beginsaround the age of 11 when children are moving to seniorschool, thereby taking more responsibility for other aspectsof their lives. This allows plenty of time to address all aspectsof daily life, in bite size pieces, while preparing the child andfamily for transfer to adult services at 16–18 years [111].Alongside this, the English Service provides a ‘PCD folder’ foreach child from diagnosis with sections for all aspects of theircare including diagnostic information, Family Support Groupinformation, audiology, cardiac, annual reviews, discharge

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summaries, school, disability living allowance, etc. Thisencourages the family to keep all their child’s information inone place and is a useful resource should the child need to beseen in a non-PCD center. It also ensures that as the youngperson moves to adult services they have a comprehensiverecord of their clinical journey.

6. Expert commentary

The evidence for treatment of PCD is poor, and manage-ment is often extrapolated from studies of patients with CFor CRS. However, much work is underway to improve thesituation. Collaborations between PCD clinicians and scien-tists are strong, and in recent years, a number of majoradvances have been made to improve care of childrenwith PCD. We are now ready for methodologically robustclinical trials to be conducted in PCD patients. Moreover,scientists are actively seeking novel treatments. The firstrandomized clinical trial in PCD was recently published[36], and the first commercially funded clinical trial is inprogress (CLEAN-PCD [114]).

Two recent European Respiratory Society (ERS) task forces,various national and international consortia, EU-FP7-fundedBESTCILIA, and a current international network BEATPCDhave been particularly fruitful for advancing the field. An ERStaskforce (ERS TF 2007–9) provided evidence of the disparity indiagnosis and treatment across Europe [7,68] and published aconsensus statement for the diagnosis and treatment of chil-dren with PCD [10]. A second ERS Task Force (2014–16) pub-lished the first evidence-based guideline for the diagnosis ofPCD [12] and investigated patient perspectives about diagno-sis, treatment, and research [8]. In North America, the PCDFoundation has similarly developed a consensus statement forthe diagnosis and management of patients with PCD [11].BESTCILIA (2012–15) led to the development of a EuropeanPCD registry [115], the international PCD cohort (iPCD) withover 3000 patients [116], a randomized-controlled clinical trialto investigate azithromycin to prevent respiratory exacerba-tions [66] and the development and validation of QOL ques-tionnaires, QOL-PCD [26,37,38,118]. National and internationalconsortia have been particularly successful in advancing ourunderstanding of PCD genetics [9,12,45]. BEAT-PCD (COSTAction BM1407) is an EU-funded network of clinicians andscientists, coordinating research from basic science to clinicalresearch, with the ultimate aim of finding treatments that leadto measurable improvements in long-term outcome ofpatients with PCD [117,119]. An important focus of the net-work is to establish the evidence and gain expert consensusfor the key components to underpin clinical trials which arecurrently missing, for example, definition of a respiratoryexacerbation.

In addition to existing research networks and collabora-tions, PCD will benefit from a new clinical network. InDecember 2016, the European Commission approved23 European Reference Networks (ERNs) for rare diseases,including one for rare respiratory diseases; ERN-LUNG [120].The ERN-LUNG is a network of health-care providers, includinga core group of PCD reference centers dedicated to providing

and promoting excellence in diagnosis and care of patientsacross Europe.

7. Five-year view

Over the coming years, we anticipate that a number of clinicaltrials will contribute to evidence-based guidelines for themanagement of PCD. Importantly, iPCD is positioned to deli-ver epidemiological evidence of practice that might be asso-ciated with better clinical outcomes that can then beexamined in randomized trials. Examples of studies mightinclude evaluation of different airway clearance techniques,effectiveness of nasal steroids, efficacy of VTs, and P. aerugi-nosa eradication studies.

We anticipate significant advances as our understanding ofthe genetics and pathophysiology of PCD grows, and newtechnologies relating to genetics studies and novel therapiesemerge. A number of research groups are searching for noveltherapies including gene therapy. In an ex vivo proof of con-cept study, a DNAh11 mutation was corrected using transcrip-tion activator-like effector nucleases (TALENs) [121]. However,experience of gene therapy in CF has been relatively disap-pointing and would be considerably more complicated in PCDgiven the large number of associated genes. Other noveltreatments such as read-through drugs may prove beneficialand knowledge gained from molecular studies might contri-bute to a personalized medicine approach as is emerging forpatients with CF.

In addition, microbiology and infection prevention andcontrol guidelines will need special attention in relation toPCD. Networks such as BEATPCD are facilitating researchersto share knowledge, samples, and models which will hopefullyexpedite preclinical research. The close collaboration of scien-tists and clinicians should then ease the pipeline to clinicaltrials. With the new ERN-LUNG PCD reference centers, weanticipate that all patients in Europe should have access todiagnostic and care facilities which adhere to ERS Guidelines[12], will be included in the European PCD registry [115], andwill have the opportunity to participate in well-designed clin-ical trials [120].

Key issues

● Lower airway clearance therapy is critical to improvemucus clearance in children with PCD. Given theabsence of evidence for any method, or that a particularmethod is superior, physiotherapists should individua-lise the treatment based on individual need and patientpreference.

● There is no evidence that mucolytics or osmotic agentsimprove mucus clearance. However, case reports sug-gest that patients might benefit, therefore well designedclinical trials are needed.

● There is no evidence for or against cross-infectionbetween patients with PCD, but this is perhaps due tolack of surveillance and poor data. The pathogens infect-ing PCD patients are similar to those implicated in CFand, in the authors’ opinions, in the absence of evidence

786 J. S. LUCAS ET AL.

to the contrary, segregation and other measures to pre-vent cross-infection should align to measures used in CFpatients.

● Studies to assess antimicrobial treatments are urgentlyneeded: pro phylaxis, treatments of exacerbation, treat-ment of asymptomatic cultures and eradication of P.aeruginosa.

● Chronic rhinosinusitis affects most patients with PCD, butevidence for treatments is lacking. Randomised trials areneeded to investigate the effect of nasal rinsing, non-ster-oidal drugs and topical nasal steroids, on the upper airwaysin PCD, as well as studies to investigate the role of surgicalintervention.

● Management of serous otitis media is controversial inPCD, and well-designed studies are needed to deter-mine whether conservative or surgical treatment issuperior.

Funding

This manuscript has not received any funding. All authors are members ofBEAT-PCD (COST Action BM1407).

Declaration of interest

The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.

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