Managing upper respiratory tract complications of primary ciliary dyskinesia in children

CURRENTOPINION Managing upper respiratory tract complications ofprimary ciliary dyskinesia in children

Raewyn Campbell

Purpose of reviewPrimary ciliary dyskinesia (PCD) is a rare and heterogeneous disease that is often misdiagnosed ordiagnosed late with more advanced sequelae. PCD primarily effects the respiratory tract, yet most researchfocuses on the lower respiratory tract manifestations, most of which is derived from research on cysticfibrosis. Little is known about the management of the upper respiratory tract sequelae of PCD. This reviewsummarizes the available evidence for the management of otologic and sinonasal manifestations of PCD.

Recent findingsThe natural history of otitis media with effusion and hearing loss in PCD appears to fluctuate into adulthoodand does not resolve by the age of 9 years, regardless of treatment, as previously assumed. Ventilationtube insertion improves hearing in PCD, but may lead to a higher rate of otorrhoea when compared withthe general population. Sinonasal disease in PCD is poorly studied; however, it appears that patients withchronic rhinosinusitis (CRS) may benefit from long-term macrolide therapy and endoscopic sinus surgery(ESS) in recalcitrant disease. Therapies targeted at improving mucociliary clearance have not been testedspecifically in PCD. Pharmacogenetic therapy is currently under investigation to target the primary defect inPCD.

SummaryOtologic sequeale in PCD should undergo lifelong evaluation and monitoring and ventilation tube insertionshould be considered to avoid complications of chronic hearing loss. Sinonasal disease benefits frommacrolide therapy and ESS. Randomized controlled trials of treatment efficacy of the upper respiratory tractmanifestations of PCD are lacking.

Keywordschronic rhinosinusitis, Kartagener’s syndrome, otitis media with effusion, primary ciliary dyskinesia, ventilationtubes

INTRODUCTIONPrimary ciliary dyskinesia (PCD) is a rare, autosomalrecessive, heterogeneous group of disorders of ciliaryultrastructure with variable penetrance [1–3] caus-ing chronic airways disease presenting in childhood[4]. PCD is characterized by cilia that beat moreslowly than normal, or with abnormal beat patterns,that result in impaired mucociliary clearance(MCC). PCD affects both sexes equally, has an inci-dence varying from one in 4100 to one in 40000births [2,4–6] and is relatively more common innorth Africa and Europe [7]. A positive familyhistory is noted in approximately 10% of cases[8]. Kartagener’s syndrome is a subgroup of thesechildren with a triad of sinusitis, bronchiectasis andsitus inversus and affects approximately 50% of PCDpatients [9].

Common complications of PCD can be classifiedascentral,upper respiratory tract (sinonasal,otologic),

lower respiratory tract, cardiovascular and reproduc-tive (infertility, subfertility or recurrent ectopic preg-nancy). PCD may also be associated with asplenia orpolysplenia [10,11], polycystic kidney or liver disease[12–14], biliary atresia [12,13], oesophageal disease[15] and oral–facial–digital syndrome type 1 [16].

Managing the complications of PCD is wroughtwith difficulties for many reasons. PCD is a hetero-geneous disease and, therefore, is often misdiag-nosed or diagnosed late (mean age at diagnosis

Department of Otorhinolaryngology, Prince of Wales Hospital, Sydney,New South Wales, Australia

Correspondence to Dr Raewyn Campbell, G BMed (Hons), BAppSc(Phsio), Grad Dip (Ex Sp Sc), c/o Prince of Wales Hospital, High St,Randwick, NSW, 2031, Australia. Tel: +61 2 9382 2222;fax: +61 2 9382 0422; e-mail: [email protected]

Curr Opin Allergy Clin Immunol 2012, 12:32–38

DOI:10.1097/ACI.0b013e32834eccc6

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REVIEW

mailto:[email protected]

8.71–13.4 years [17&&,18&]), permitting progressionof potentially preventable complications [19,20] orpresentation of the disease at amore advanced stage.Delayed diagnosis has been shown to negativelyimpact the outcome [21]. The natural history ofthe disease is also not well documented and, there-fore, provides the clinician with a dilemma regard-ing the timing of intervention and theaggressiveness of any treatment. To date, manage-ment strategies for PCD in children have mostlyderived from those intended for cystic fibrosis(CF), a disease with a very different pathogenesis[19].

There are currently no therapeutic modalitiesthat correct the inherited disorder of cilial dystmo-tility in PCD. This review will focus on the manage-ment of those complications associated with theupper respiratory tract in PCD, specifically, otologicand sinonasal complications.

OTOLOGICOtologic complications of PCD include recurrentacute otitis media, otitis media with effusion(OME), chronic otitis media and conductive hearingloss [17&&]. These have been shown to be morefrequent in children with cilial axonemal defectsinvolving the central complex compared withdefects of outer or inner dynein arms [17&&]. Centralcomplex abnormalities have been noted to be lesscommon, but are associated with more severe lowerrespiratory tract disease [22]. Interestingly, only twocases of cholesteatoma in patients with PCD havebeen documented [17&&,23]. This may be a con-sequence of the disease itself or due to the highrate of ventilation tube insertion in this patientpopulation.

The management of otologic disease in childrenwith PCD aims to improve hearing and prevent thepossible sequelae of long-term hearing loss such asimpairments to cognition, speech and languagedevelopment. Treatment also aims to prevent otherpotential sequelae such as tympanic membrane ate-lectasis and retraction pockets and ossicular chainerosion or necrosis.

The severity of hearing loss due to otologicdisease in PCD is variable ranging from mild tomoderately severe [9,23–25]. The limited data doc-umenting the natural history of hearing loss due toOME in PCD indicate hearing loss is fluctuant andprolonged into adulthood [17&&,18&,24,26–28]. Thishas an impact for counselling children with PCDand their families, as these children are unlikely tooutgrow the condition and will require long-term management.

Medical treatment options for otologic compli-cations of PCD in children include antibiotics, auto-inflation devices such as the Otovent (InvotecInternational Inc., Jacksonville, Florida, USA) andhearing aids. Surgical options include myringotomywith or without the insertion of ventilation tubes,possibly combined with adenoidectomy. Researchshows an improvement in hearing, and/or areduction in OME duration [29–33] and a lowerincidence of cholesteatoma formation [34] afterventilation tube insertion in the general population.The impact of ventilation tubes for chronic OME onlanguage development is somewhat controversial[29,30,35–39].

It is thought that in PCD, ventilation tube inser-tion alters the middle ear–nasopharyngeal pressurerelationship, allowing drainage of middle earsecretions via the Eustachian/pharyngotympanictube, despite the abnormal mucociliary transportsystem [40]. Ventilation tubes also increase the oxy-gen tension in the middle ear which may reduce thehigher number of secretory cells found in themiddleear mucosa in OME andmay also reduce the biofilmload [41].

Otorrhoea is the most common complication ofventilation tube insertion [42] and has been notedto have a profoundly negative impact on quality oflife (QOL) [43]. Otorrhoea postventilation tubeinsertion was traditionally thought to be morefrequent and/or severe in children with PCD[8,9,24,36]. Thus, it has become protocol in manycentres around the world to avoid ventilation tubeinsertion in these children for fear of chronic otor-rhoea [19,44]. The cause of this association isunknown; however, contributing factors specificto PCD may include recurrent/chronic upper respir-atory tract infections and soiling of the middle earthrough contamination from the nasopharynx [45],

KEY POINTS

! Otitis media with effusion (OME) is nearly ubiquitous inprimary ciliary dyskinesia (PCD) and, contrary tocommonly held beliefs, continues into adulthood.

! The incidence of postventilation tube otorrhoea inchildren with PCD and OME is not necessarily higherthan that of the general population undergoingventilation tube insertion.

! There is a paucity of research in the management ofthe sinonasal manifestations of PCD, most of whichdraw their recommendations from research intocystic fibrosis.

! Evidence supports the use of long-term macrolidetherapy and endoscopic sinus surgery for medicallyrecalcitrant chronic rhinosinusitis in PCD.

Managing upper respiratory tract complications of PCD Campbell

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the immature immune system of the children at thetime of ventilation tube insertion (commonly underthe age of 2 years) [46], the viscous nature of themiddle ear fluid present at the time of insertion andbiofilms. Haemophilus influenzae, Pseudomonas aeru-ginosa, Staphylococcus aureus and Streptococcus pneu-moniae, which readily form biofilms, are commonlyfound in the respiratory tract of children with PCD[1,19,47–49].

However, a review of the management of OMEin PCD noted that the incidence of postventilationtube otorrhoea in children with PCD (50%) wascomparable to that of the general population (26–83%) [50]. Aggressive and targeted treatment ofpotential biofilms preventilation, intraventilationand postventilation tube insertion in children withPCD and improved control of respiratory tractinfections may further contribute to minimizingpostoperative otorrhoea. These measures mayinclude perioperative and postoperative ototopicalciprofloxacin [51] and systemic culture-directedantibiotics that attain high intracellular concen-trations such as macrolides, ketolides, quinolones[52] or azithromycin [53], meticulous intraoperativehaemostasis [54], intraoperative isotonic salineirrigation [55], the use of the Nd:YAG laser todisrupt biofilms on ventilation tubes [56], the useof biofilm-resistant, longer term ventilation tubesand/or concurrent adenoidectomy to reduce naso-pharyngeal colonization and/or Eustachian tubeobstruction.

Finally, transtympanic pulmonary surfactant isan emerging therapy in the treatment of OME andhas been successfully trialed in guinea pigs [57].

SINONASALChronic rhinosinusitis (CRS) is common in childrenwith PCD [58&]. Symptoms include rhinorrhoea,nasal obstruction, facial pain or pressure and hypo-smia [19,59,60] and nasal polyposis. Subsequently,CRS results in aplastic or hypoplastic fontal, sphe-noid and, occasionally, maxillary sinuses [19,61&].The cause of hypoplastic sinuses in PCD is mostlikely secondary to chronic infection, inflam-mation, failure of the nasal mucosal epithelium toinvade into surrounding tissue (see below) and pre-mature ossification of surrounding cartilage [62,63].Bilateral ethmoid sinus mucoceles have beendescribed in children with PCD [64].

PCD patients may suffer from hydocephalus[12–14,19,65,66] due to immotile cilia in the mem-branous lining of the cerebral ventricles and thecentral canal of the spinal cord. This may causechronic headache which may mistakenly be attrib-uted to sinus disease.

Effective management of sinonasal disease inPCD has been shown to improve both otologicand pulmonary function [67], yet research intomanagement strategies for sinonasal disease issparse in PCD. The majority of the research focuseson the pulmonary disease and is derived fromCF data.

Management of sinonasal disease in PCDinvolves both medical and surgical strategies.Medical strategies predominantly focus on improv-ing MCC or inflammation and include intranasal[3,58&] and systemic steroids [3], inhaled aerosolizedantibiotics, long-term macrolide therapy and,occasionally, anticholinergic medications [19,68].Emerging medical therapies that modify mucusviscosity and mobility include L-arginine, nebulizeddornase a, b-adrenergic agonists, topical hypertonicsaline, mannitol and uridine-50-triphosphate (UTP).

Up to 30% of people with PCD have nasal poly-posis [69,70]. Steroids have been described as effec-tive in 50% of the patients with PCD and nasalpolyposis; however, there are no clinical researchdata to support this statement [3]. The cytokineprofile in nasal polypsosis in PCD has never beenstudied; however, the mucus in CF is similar to thatin PCD [71]. The cytokine profile of polyps in CF hasbeen noted to differ from themost common types ofCRS with polyposis (CRSwNP). In CF, the polypsdemonstrate a TH1-dominant inflammatory processwith increased IL-8 and myeloperoxidase (MPO)levels [72&&] and have been described as neutro-philic. This difference would bring into questionthe effectiveness of steroids in the management ofCRSwNP in CF and PCD [73,74].

Antimicrobial therapy is frequently used forinfective exacerbations of respiratory disease or asmaintenance therapy in those with more severedisease. Inhaled tobramycin reduces the density ofPseudomonas in non-CF bronchiectasis; however, aslight reduction in FEV1 is also demonstrated [75–77]. The impact of tobramycin on sinonasal diseasein PCD has not been studied.

Apart form their antibacterial properties, macro-lides also possess anti-inflammatory and immune-mediating properties. Macrolides inhibit neutrophilmigration and oxidative burst [78,79] and accelerateneutrophil apoptosis [80,81], modify cytokinerelease [82–84], inhibit destructive enzyme releaseby P. aeruginosa [85], alter biofilm structure [86],improve mucociliary transport [87–89], reduce gob-let cell hypersecretion [90] and improve mucousviscoelasticity [91]. Case reports have demonstratedimproved pulmonary and sinonasal disease in fourpatients with PCD treated with prolongedmacrolidetherapy [92&,93,94]; however, no improvement inpulmonary function was noted in eight patients

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with Kartagener’s syndrome treated with clariithro-mycin or erythromycin [95]. These differences maybe due to variations in dose and duration of treat-ment and also in disease severity.

Exhaled nasal nitric oxide is significantlyreduced in PCD [44,96–99] and may be includedin the diagnostic criteria for the disease. The cause ofthis is unknown; however, it may be due todecreased or defective nitric oxide formation [99].Nitric oxide has been shown to affect cilial beatfrequency (CBF) and MCC [100], to improve pul-monary ventilation–perfusion matching [101,102],and is bacteriostatic to S. aureus [103]. A significantinverse relation between exhaled nasal nitric oxideand hypoplasia/aplasia of the paranasal sinuses hasbeen noted in PCD patients but not in secondaryciliary dyskinesia [61&]. It is hypothesized that thismay be due to a failure of the nasal mucosal epi-thelium in PCD to invade into the surroundingtissue combined with impaired nasal ventilationand chronic infection [61&]. L-Arginine, the substrateof nitric oxide synthase, has been shown to increasenasal and exhaled nitric oxide concentrations inPCD patients, yet its levels remained significantlylower than that in normal controls and had noimpact on pulmonary function [99]. However,Loukides et al. [104] demonstrated increased CBFand MCC after nebulized L-arginine in patients withPCD in a double-blind randomized controlled trial.The impact on sinonasal disease is not known.

Manuka honey has antibiofilm activity and isactive against S. aureus and P. aeruginosa [105,106]and, therefore, may be of benefit in the medicallyrecalcitrant CRS that is so common in PCD.

Increased DNA has been found in the sputum innon-CF bronchiectasis [107]. Nebulized dornase a,recombinant DNase, cleaves DNA released by neu-trophils in sputum and reduces viscosity. It has beenshown to improve quality of life in patients with CFwhen compared with normal saline [108&&]. Twocase reports have described improved pulmonaryfunction [109,110] and gastrointestinal symptoms[110] in childrenwith PCD after recombinant DNasetherapy. Its effect on CRS in PCD has not beeninvestigated.

b-Adrenergic agonists enhance in-vitro CBF[111,112] and may improve mucus hydration[113]; however, the impact on dyskinetic cilia isunknown. Due to the lack of data evaluating theeffect of b-agonists in sinonasal disease in PCD, andthe failure of these agents to achieve bronchodila-tion in PCD, their clinical utility in this disease isdoubtful.

Hypertonic saline also improves mucushydration and may also stimulate prostaglandinE2 production which increases CBF [3]. Hypertonic

saline improves MCC [114] and lung function in CF[115]. Another hyperosmolar agent, inhaled man-nitol, has been shown to improve MCC in peoplewith bronchiectasis [116]. Neither of these agentshas been studied in PCD.

UTP improves chloride ion transport, goblet celldegranulation and CBF, improving mucociliaryclearance [117,118]. Noone et al. [118] demon-strated an improvement in whole-lung clearanceduring coughing in patients with PCD; however,the effect of UTP on sinonasal disease has notbeen evaluated.

Endoscopic sinus surgery (ESS) is often requiredafter failed medical management in PCD[25,67,119,120]. The aim of ESS is to establishdependent drainage of the sinuses and to improveaccess for regular toilet and for topical medications.No randomized controlled trials exist which evalu-ate ESS in the management of sinonasal disease inPCD; however, ESS has been shown to improvesinonasal symptoms and also improve otologicand lower respiratory tract symptoms in three chil-dren with PCD [67]. Conversely, ESS did notimprove pulmonary function [121,122] nor hadany impact on microbial pathogens in a retrospec-tive review of 41 children with CF [122]. ESS may,however, reduce hospital admissions for 6 monthspostoperatively in children with CF [123]. Sinussurgery should be considered in PCDwhen imaging,symptoms and clinical examination are consistentin confirmingmedically recalcitrant disease burden.

Postoperatively, nasal irrigation with surfac-tants, such as 1% baby shampoo, has been shownto inhibit Pseudomonas biofilm formation inpatients with CRS [124] and, therefore, may be ofbenefit in PCD.

Finally, pharmacogenetic therapy is currentlyunder investigation to target the primary defect inPCD [125]; however, it may be prolonged in evol-ution due to the genetic heterogeneity of PCD. Ingeneral, avoidance of environmental contaminants,such as cigarette smoke and adherence to an immu-nization schedule should also be considered in allPCD patients [3,19].

CONCLUSIONPCD is a heterogeneous disease which is often diag-nosed late and, therefore, with more advanced dis-ease manifestations. The management of upperrespiratory tract complications is controversial dueto a paucity of research, the majority of which isderived from research in CF, a pathophysiologicallydistinct disease entity.

As there are no therapeutic strategies currentlyavailable that directly target the cilial dysfunction in



PCD, current management bypasses the cilial dys-function and aims to improvemucociliary clearanceand prevent infectious exacerbations of the diseaseand the ensuing complications [125].

OME persists into adulthood in PCD and, there-fore, should be closely monitored for specific oto-logic sequelae as well as complications of hearingloss such as speech and language delay. Options forthe management of otologic complications includehearing aids, systemic antibiotics and insertion ofventilation tubes using meticulous surgical tech-nique, intraoperative saline irrigation, ototopicalantibiotics and adenoidectomy. Emerging tech-niques to disrupt biofilms such as transtympanicpulmonary surfactant and laser warrant furtherinvestigation.

Sinonasal disease is prevalent in PCD, yet poorlystudied. It may result in aplastic or hypoplasticfontal and sphenoid sinuses and may also exacer-bate pulmonary and otologic disease. There is someevidence to support the use of prolonged macrolidetherapy and ESS for recalcitrant sinonasal disease.Emerging therapies may incorporate those currentlyunder investigation in CF such as L-arginine, nebu-lized dornase a, topical hypertonic saline, mannitoland UTP.

No current treatment exists that targets theprimary genetic defect in PCD; however, pharma-cogenetic therapy is currently under investigation.

Large, randomized controlled trials are requiredto adequately investigate the management of PCDin the hope of early diagnosis and haltingdisease progression.

Acknowledgements

None.

Conflicts of interest

This study was not funded and the author had no conflictof interest regarding this article.

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:& of special interest&& of outstanding interestAdditional references related to this topic can also be found in the CurrentWorld Literature section in this issue (pp. 92–93).

1. Long SS, Pickering LK, Prober G. Long: principles and practice of pediatricinfectious diseases. 2nd ed. Philadelphia: Churchill Livingstone; 2003.

2. Kumar V, Abbas A, Fausto N, et al. Pathologic basis of disease. 7th ed.Philadelphia: Elsevier Saunders; 2005.

3. Yoo Y, Koh YY. Current treatment of primary ciliary dyskinesia conditions.Expert Opin Pharmacother 2004; 5:369–377.

4. Behrman RE, Kliegman RM, Jenson HB. Nelson textbook of pediatrics. 17thed. Philadelphia: Saunders; 2004.

5. Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients withcomplete X-linked phenotype combining primary ciliary dyskinesia andretinitis pigmentosa. J Med Genet 2006; 43:326–333.

6. Katsuhara K, Kawamoto S, Wakabayashi T, et al. Situs inversus totalis andKartagener’s syndrome in a Japanese population. Chest 1972; 61:56–61.

7. Verra F, Escudier E, Bignon J, et al. Inherited factors in diffuse bronchiectasisin the adult: a prospective study. Eur Respir J 1991; 4:937–944.

8. Coren ME, Meeks M, Morrison I, et al. Primary ciliary dyskinesia: age atdiagnosis and symptom history. Acta Paediatr 2002; 91:667–669.

9. Hadfield PJ, Rowe-Jones JM, Bush A, Mackay IS. Treatment of otitis mediawith effusion in children with primary ciliary dyskinesia. Clin Otolaryngol AlliedSci 1997; 22:302–306.

10. Brueckner M. Cilia propel the embryo in the right direction. Am J Med Genet2001; 101:339–344.

11. Raman R, Al-Ali SY, Poole CA, et al. Isomerism of the right atrial appendages:clinical, anatomical and microscopic study of a long surviving case withasplenia and ciliary abnormalities. Clin Anat 2003; 16:269–276.

12. Bush A, Chodhari R, Collins N, et al. Primary ciliary dyskinesia: current stateof the art. Arch Dis Child 2007; 92:1136–1140.

13. Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging classof human genetic disorders. Annu Rev Genomics Hum Genet 2006; 7:125–148.

14. Bisgrove BW, Yost HJ. The roles of cilia in developmental disorders anddisease. Development 2006; 133:4131–4143.

15. Gemou Engesaeth V,Warner JO, Bush A. New associations of primary ciliarydyskinesia syndrome. Pediatr Pulmonol 1993; 16:9–12.

16. Budny B, Chen W, Omran H, et al. A novel X-linked recessive mentalretardation syndrome comprising macrocephaly and ciliary dysfunction isallelic to oral-facial-digital type 1 syndrome. Hum Genet 2006; 120:171–178.

17.&&

Pruliere-Escabasse V, Coste A, Chauvin P, et al.Otologic features in childrenwith primary ciliary dyskinesia. Arch Otolaryngol Head Neck Surg 2010;136:1121–1126.

This study is the first to correlate age and type of ciliary defect in PCD with thecharacteristics of the otologic features of the disease.18.&

Sommer JU, Schafer K, Omran H, et al. ENT manifestations in patients withprimary ciliary dyskinesia: prevalence and significance of otorhinolaryngolo-gic co-morbidities. Eur Arch Otorhinolaryngol 2011; 268:383–388.

This study highlights the delayed diagnosis in children with PCD and the pre-valence of upper respiratory tract symptoms and encourages an increasedawareness of PCD among ENT specialists.19. Barbato A, Frischer T, Kuehni CE, et al. Primary ciliary dyskinesia: a con-

sensus statement on diagnostic and treatment approaches in children. EurRespir J 2009; 34:1264–1276.

20. O’Callaghan C, Chilvers M, Hogg C, et al. Diagnosing primary ciliarydyskinesia. Thorax 2007; 62:656–657.

21. Ellerman A, Bisgaard H. Longitudinal study of lung function in a cohort ofprimary ciliary dyskinesia. Eur Respir J 1997; 10:2376–2379.

22. Tamalet A, Clement A, Roudot-Thoraval F, et al. Abnormal central complex isa marker of severity in the presence of partial ciliary defect. Pediatrics 2001;108:E86.

23. El-Sayed Y, Al-Sarhani A, Al-Essa AR. Otological manifestations of primaryciliary dyskinesia. Clin Otolaryngol Allied Sci 1997; 22:266–270.

24. van der Baan S. Primary ciliary dyskinesia and the middle ear. Laryngoscope1991; 101:751–754.

25. Mygind N, Pedersen M. Nose-, sinus- and ear-symptoms in 27 patients withprimary ciliary dyskinesia. Eur J Respir Dis Suppl 1983; 127:96–101.

26. Majithia A, Fong J, Hariri M, Harcourt J. Hearing outcomes in children withprimary ciliary dyskinesia: a longitudinal study. Int J Pediatr Otorhinolaryngol2005; 69:1061–1064.

27. Ernstson S, Afzelius BA, Mossberg B. Otologic manifestations of theimmotile cilia syndrome. Acta Otolaryngol (Stockh) 1984; 97:83–92.

28. Turner JA, Corkey C, Lee JVC, et al. Clinical expressions of immotile ciliasyndrome. Pediatrics 1981; 67:805–810.

29. Lous J, Burton LJ, Felding JU, et al. Grommets (ventilation tubes) for hearingloss associated with otitis media with effusion in children. Cochrane Data-base Syst Rev 2005:CD001801.

30. Rovers MM, Black N, Browning GG, et al. Grommets in otitis media witheffusion: an individual patient data meta-analysis. Arch Dis Childhood 2005;90:480–485.

31. MRC Multicentre Otitis Media Study Group. Speech reception in noise: anindicator of benefit from otitis media with effusion surgery. Clin Otolaryngol2004; 29:497–504.

32. MRC Multicentre Otitis Media Study Group. The role of ventilation tubestatus in the hearing levels in children managed for bilateral persistent otitismedia with effusion. Clin Otolarygol 2003; 28:146–153.

33. Diacova S, McDonald TJ. A comparison of outcomes following tympanost-omy tube placement or conservative measures for management of otitismedia with effusion. Ear Nose Throat J 2007; 86:552–554.

34. Welch D, Dawes P. No negative outcomes of childhoodmiddle ear disease inadulthood. Laryngoscope 2007; 117:466–469.

35. Simpson SA, Thomas CL, van der Linden MK, et al. Identification of childrenin the first four years of life for early treatment for otitis media with effusion.Cochrane Database Syst Rev 2007; (1):CD004163.

36. Bennett KE, Haggard MP, Silva PA, Stewart IA. Behaviour and develop-mental effects of otitis media with effusion into the teens. Arch Dis Child2001; 85:91–95.



37. Gravel JS, Wallace IF. Language, speech and educational outcomes of otitismedia. J Otolaryngol 1998; 27 (Suppl 2):17–25.

38. Minter KR, Roberts JE, Hooper SR, et al. Early childhood otitis media inrelation to children’s attention-related behaviour in the first six years of life.Pediatrics 2001; 107:1037–1042.

39. Rosenfeld RM, Bhaya MH, Bower CM, et al. Impact of tympanostomy tubeson child quality of life. Arch Otolaryngol Head Neck Surg 2000; 126:585–592.

40. Sade J. Ciliary activity and middle ear clearance. Arch Otolaryngol 1967;86:128–135.

41. Greenstone M, Rutman A, Dewar A, et al. Primary ciliary dyskinesia: cyto-logical and clinical features. Q J Med 1988; 67:405–430.

42. Vaile L, Williamson T, Waddell A, Taylor G. Interventions for ear dischargeassociated with grommets (ventilation tubes). Cochrane Database Syst Rev2006; (2):CD001933.

43. Debruyne F, Degroote M. One-year follow-up after tympanostomy tubeinsertion for recurrent acute otitis media. ORL J Otorhinolaryngol Relat Spec1993; 55:226–229.

44. Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis andstandards of care. Eur Respir J 1998; 12:982–988.

45. Samuelson A, Freijd A, Rynnel-Dagoo B. Treatment failure in otitis-pronechildren with prophylactic tympanostomy tubes is correlated with nasophar-yngeal Haemophilus influenzae colonization. Acta Otolaryngol 1991;111:1090–1096.

46. Ingels K, Rovers MM, van der Wilt GJ, Zielhuis GA. Ventilation tubes ininfants increase the risk of otorrhoea and antibiotic usage. B-ENT 2005; 1:173–176.

47. Nawasreh OO, Al-Wedyan IA. Prophylactic ciprofloxacin drops after tympa-nostomy tube insertion. Saudi Med J 2004; 25:38–40.

48. Corkey CW, Levison H, Turner JA. The immotile cilia syndrome. A longitudinalsurvey. Am Rev Respir Dis 1981; 124:544–548.

49. Hellinckx J, Demedts M, De Boeck K. Primary ciliary dyskinesia: evolution ofpulmonary function. Eur J Pediatr 1998; 157:422–426.

50. Campbell RG, Birman CS, Morgan L. Management of otitis media witheffusion in children with primary ciliary dyskinesia: a literature review. Int JPediatr Otorhinolaryngol 2009; 73:1630–1638.

51. Macfayden CA, Acuin JM, Gamble C. Systemic antibiotics versus topicaltreatments for chronically discharging ears with underlying eardrum perfora-tions. Cochrane Database Syst Rev 2006:CD005608. doi: 10.1002/14651858.CD005608.

52. Bouchet V, Hood DW, Li J, et al. Host-derived sialic acid is incorporated intoHaemophilus influenzae lipopolysaccharide and is a major virulence factor inexperimental otitis media. Proc Natl Acad Sci U S A 2003; 100:8898–8903.

53. Malaty J, Antonelli PJ. Effect of blood and mucus on tympanostomy tubebiofilm formation. Laryngoscope 2008; 118:867–870.

54. Kocaturk S, Yardimci S, Yildirim A, Incesulu A. Preventive therapy for post-operative purulent otorrhea after ventilation tube insertion. Am J Otolaryngol2005; 26:123–127.

55. Krespi YP, Stoodley P, Hall-Stoodley L. Laser disruption of biofilm. Laryngo-scope 2008; 118:1168–1173.

56. Ma ZX, Chen XH, Li M, et al. Histo-morphological changes of Eustachiantube of guinea pigs with effusion after being treated by pulmonary surfactant.Chung Hua Erh Pi Yen Hou Ko Tsa Chih 2003; 38:445–447.

57. Williamson IG, Dunleavey J, Bain J, Robinson D. The natural history of otitismedia with effusion: a three-year study of the incidence and prevalence ofabnormal tympanograms in four South West Hampshire infant schools. JLaryngol Otol 1994; 108:930–934.

58.&

Woodbury K, Ferguson BJ. Recalcitrant chronic rhinosinusitis: investigationand management. Curr Opin Otolaryngol Head Neck Surg 2011; 19:1–5.

This article evaluates alternative diagnoses for recalcitrant CRS and provides anupdate on treatment options for difficult CRS.59. Leigh MW. Primary ciliary dyskinesia. Semin Respir Crit Care Med 2003;

24:653–662.60. Min YG, Shin JS, Choi SH, et al. Primary ciliary dyskinesia: ultrastructural

defects and clinical features. Rhinology 1995; 33:189–193.61.&

Pifferi M, Bush A, Caramella D, et al. Agenesis of paranasal sinuses and nasalnitric oxide in primary ciliary dyskinesia. Eur Respir J 2011; 37:566–571.

This study reports on an inverse correlation between frontal and sphenoidal sinushypoplasia/aplasia and nasal nitric oxide levels in PCD and suggests the finding ofaplasia/hypoplasia of these sinuses should prompt exclusion of PCD.62. Sato I, Sunohara M, Mikami A, et al. Immunocytochemical study of the maxilla

and maxillary sinus during human fetal development. Okajimas Folia Anat Jpn1998; 75:205–216.

63. Ellington JK, Elhofy A, Bost KL, et al. Involvement of mitogen-activated proteinkinase pathways in Staphylococcus aureus invasion of normal osteoblasts.Infect Immun 2001; 69:5235–5242.

64. Berlucchi M, Maroldi R, Aga A, et al. Ethmoid mucocele: a new feature ofprimary ciliary dyskinesia. Pediatr Pulmonol 2010; 45:197–201.

65. Greenstone MA, Jones RW, Dewar A, et al. Hydrocephalus and primaryciliary dyskinesia. Arch Dis Child 1984; 59:481.

66. Picco P, Leveratto L, Cama A, et al. Immotile cilia syndrome associated withhydrocephalus and precocious puberty: a case report. Eur J Pediatr Surg1993; 3 (Suppl 1):20.

67. Parsons DS, Greene BA. A treatment for primary ciliary dyskinesia: efficacyof functional endoscopic sinus surgery. Laryngoscope 1993; 103:1269–1272.

68. Hassan JA, Saadiah S, Roslan H, Zainudin B. Bronchodilator response toinhaled beta-2 agonist and anticholinergic drugs in patients with bronch-iectasis. Respirology 1999; 4:423–426.

69. Garg A, Wadhera R, Gulati SP, et al. Primary ciliary dyskinesia: an under-diagnosed entity. J Assoc Phys India 2010; 58:704–706.

70. Schidlow DV. Primary ciliary dyskinesia (the immotile cilia syndrome). AnnAllergy 1994; 73:457–469.

71. Bush A, Payne D, Pike S, et al. Mucus properties in children with primaryciliary dyskinesia. Comparison with cystic fibrosis. Chest 2006; 129:118–123.

72.&&

DeMarcantonio MA, Han J. Nasal polyps: pathogenesis and treatmentimplications. Otolaryngol Clin North Am 2011; 44:685–695.

An excellent review and update on the pathogenesis and treatment of nasalpolyposis.73. Robertson JM, Friedman EM, Rubin BK. Nasal and sinus disease in cystic

fibrosis. Paediatr Respir Rev 2008; 9:213–219.74. Claeys S, Van Hoecke H, Holtappels G, et al. Nasal polyps in patients with

and without cystic fibrosis: a differentiation by innate markers and inflam-matory mediators. Clin Exp Allergy 2005; 35:467–472.

75. Barker AF, Couch I, Fiel SB, et al. Tobramycin solution for inhalation reducessputum Pseudomonas aeruginosa density in bronchiectasis. Am J RespirCrit Care Med 2000; 162:481–485.

76. Couch IA. Treatment with tobramycin solution for inhalation in bronchiectasispatients with Pseudomonas aeruginosa. Chest 2001; 120:114–117.

77. Bilton D. Update on noncystic fibrosis bronchiectasis. Curr Opin Pulm Med2008; 14:595–599.

78. Hand WL, Hand DL, King-Thompson NL. Antibiotic inhibition of the respira-tory burst response in human polymorphonuclear leukocytes. AntimicrobAgents Chemother 1990; 34:863–870.

79. Braga PC, Maci S, DalSasso M, et al. Effects of rokitamycin on phagocytosisand release of oxidant radicals of human polymorphonuclear leukocytes.Chemotherapy 1997; 43:190–197.

80. Inamura K, Ohta N, Fukase S, et al. The effects of erythromycin on humanperipheral neutrophil apoptosis. Rhinology 2000; 38:124–129.

81. Aoshiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival byaccelerating apoptosis. Antimicrob Agents Chemother 1995; 39:872–877.

82. MacLeod CM, Hamid QA, Cameron L, et al. Anti-inflammatory activity ofclarithromycin in adults with chronically inflamed sinus mucosa. Adv Ther2001; 18:75–82.

83. Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8 (IL-8) and aninhibitory effect of erythromycin on IL-8 release in the airways of patients withchronic airway diseases. Infect Immun 1994; 62:4145–4152.

84. Suzuki H, Shimomura A, Ikeda K, et al. Inhibitory effect of macrolides oninterleukin- 8 secretion from cultured human nasal epithelial cells. Laryngo-scope 1997; 107 (12 Pt 1):1661–1666.

85. Hirakata Y, Kaku M, Mizukane R, et al. Potential effects of erythromycin onhost defense systems and virulence of Pseudomonas aeruginosa. Antimi-crob Agents Chemother 1992; 36:1922–1927.

86. Wozniak DJ, Keyser R. Effects of subinhibitory concentrations of macrolideantibiotics on Pseudomonas aeruginosa. Chest 2004; 125 (2 Suppl):62S–69S.

87. Nakano T, Ohashi Y, Tanaka A, et al. Roxythromycin reinforces epithelialdefence function in rabbit trachea. Acta Otolaryngol Suppl 1998; 538:233–238.

88. Hamid Q, Cameron L, MacLeod C, et al. Anti-inflammatory activity ofclarithromycin in the treatment of adults with chronically-inflamed sinusmucosa. In: Abstracts of the European Congress of Chemotherapy;2000; Madrid.

89. Nishi K, Mizuguchi M, Tachibana H, et al. Effect of clarithromycin onsymptoms and mucociliary transport in patients with sino-bronchial syn-drome. Nippon Kyobu Shikkan Gakkai Zasshi 1995; 33:1392–1400.

90. Tamaoki J, Takeyama K, Yamawaki I, et al. Lipopolysaccharide-inducedgobletcell hyper-secretion in the guinea pig trachea: inhibition by macrolides.Am J Physiol 1997; 272 (1 Pt 1):L15–L19.

91. Rhee CS, Majima Y, Arima S, et al. Effects of clarithromycin on rheologicalproperties of nasal mucus in patients with chronic sinusitis. Ann Otol RhinolLaryngol 2000; 109:484–487.

92.&

Yoshioka D, Sakamoto N, Ishimatsu Y, et al. Primary ciliary dyskinesia thatresponded to long-term, low-dose clarithromycin. Intern Med 2010;49:1437–1440.

This study is the only study to report on the response of sinonasal symptoms inPCD to macrolide therapy.93. Ishiguro T, Takayanagi N, Hijikata N, et al. Primary ciliary dyskinesia. A case

report and comparison with 4 previous cases. Nihon Kokyuki Gakkai Zasshi2009; 47:242–248.

94. Itoh M, Kishi K, Nakamura H, et al. A case of immotile dyskinetic ciliasyndrome responding to clenbuterol hydrochloride and azithromycin. NihonKokyuki Gakkai Zasshi 2002; 40:617–621.

95. Homma S, Kawabat M, Kishi K, et al. Bronchiolitis in Kartagener’s syndrome.Eur Resp J 1999; 14:1332–1339.



96. Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia: diagnosticand phenotypic features. Am J Respir Crit Care Med 2004; 169:459–467.

97. Karadag B, James AJ, Gultekin E, et al. Nasal and lower airway level of nitricoxide in children with primary ciliary dyskinesia. Eur Respir J 1999; 13:1402–1405.

98. Lundberg JO,Weitzberg E, Nordvall SL, et al. Primarily nasal origin of exhalednitric oxide and absence in Kartagener’s syndrome. Eur Respir J 1994;7:1501–1504.

99. Grasemann H, Gartig SS, Wiesemann HG, et al. Effect of L-arginine infusionon airway NO in cystic fibrosis and primary ciliary dyskinesia syndrome. EurRespir J 1999; 13:114–118.

100. Lindberg S, Cervin A, Runer T. Low levels of nasal nitric oxide(NO) correlateto impaired mucociliary function in the upper airways. Acta Otolaryngol(Stockh) 1997; 117:728–734.

101. Rossaint R, Falke KJ, Lopez F, et al. Inhaled nitric oxide for the adultrespiratory distress syndrome. N Engl J Med 1993; 328:399–405.

102. Lundberg JO, Settergren G, Gelinder S, et al. Inhalation of nasally derivednitric oxide modulates pulmonary function in humans. Acta Physiol Scand1996; 158:343–347.

103. Mancinelli RL, McKay CP. Effects of nitric oxide and nitrogen dioxide onbacterial growth. Appl Environ Microbiol 1983; 46:198–202.

104. Loukides S, Kharitonov S, Wodehouse T, et al. Effect of arginine onmucociliary function in primary ciliary dyskinesia. Lancet 1998; 352:371–372.

105. Lusby PE, Coombes AL, Wilkinson JM. Bactericidal activity of differenthoneys against pathogenic bacteria. Arch Med Res 2005; 36:464–467.

106. Alandejani T, Marsan J, Ferris W, et al. Effectiveness of honey on Staphy-lococcus aureus and Pseudomonas aeruginosa biofilms. Otolaryngol HeadNeck Surg 2009; 141:114–118.

107. Potter JL, Spector S, Matthew JW, Lemm J. Studies on pulmonary secretions.3: The nucleic acids in whole pulmonary secretions from patients with cytsicfibrosis, bronchiectasis, and laryngectomy. Am Rev Respir Dis 1969;99:909–916.

108.&&

Mainz JG, Schiller I, Ritschel C, et al. Sinonasal inhalation of dornase alfa inCF: a double-blind placebo-controlled cross-over pilot trial. Auris NasusLarynx 2011; 38:220–227.

This is the first study to evaluate the use of dornas alfa for the treatment of thesinonasal symptoms in CF patients.109. Ten Berge M, Brinkhorst G, Kroon AA, de Jongste JC. Dnase treatment in

primary ciliary dyskinesia: assessment by nocturnal pulse oximetry. PediatrPulmonol 1999; 27:59–61.

110. Desai M, Weller PH, Spencer DA. Clinical benefit from nebulised humanrecombinant Dnase in Kartagener’s syndrome. Pediatr Pulmonol 1995;20:307–308.

111. Phipps RJ, Nadel JA, Davis B. Effect of alpha-adrenergic stimulation onmucus secretion and on ion transport in cat trachea in vitro. Am Rev RespirDis 1920; 121:359–365.

112. Phipps RJ, Williams IP, Richardson PS, et al. Sympathomimetic drugsstimulate the output of secretory glycoproteins from human bronchi in vitro.Clin Sci (Lond) 1982; 63:23–28.

113. Bennett WD. Effect of B-adrenergic agonists on mucociliary clearance. JAllergy Clin Immunol 2002; 110 (6 Suppl):S291–S297.

114. King M, Dasgupta B, Tomkiewicz RP, Brown NE. Rheology of cystic fibrosissputum after in vitro treatment with hypertonic saline alone and in combina-tion with recombinant human deoxyribonuclease I. Am J Respir Crit Care Med1997; 156:173–177.

115. Robinson M, Regnis JA, Bailey DL, et al. Effect of hypertonic saline, amilorideand cough on mucociliary clearance in patients with cystic fibrosis. Am JRespir Crit Care Med 1996; 153:1503–1509.

116. Daviskas E, Anderson SD, Eberl S, et al. Inhalation of dry-powder mannitolincreases mucociliary clearance in patients with bronchiectasis. Am J RespirCrit Care Med 1999; 159:1843–1848.

117. Knowles MR, Clarke LL, Boucher RC. Activation by extracellular nucleotidesof chloride secretion in the airway epithelia of patients with cystic fibrosis. NEngl J Med 1991; 325:533–538.

118. Noone PG, Bennett WD, Regnis JA, et al. Effect of aerosolised uridine-50-triphosphate on airway clearance with cough in patients with primary ciliarydyskinesia. Am J Respir Crit Care Med 1999; 160:144–149.

119. Pedersen H, Rebbe H. Absence of arms in the axoneme of immobile humanspermatozoa. Biol Reprod 1975; 12:541–544.

120. American Academy of Pediatrics. Subcommittee onManagement of SinusitisandCommittee onQuality Improvement Clinical Practice Guideline: manage-ment of sinusitis. Pediatrics 2001; 108:798–808.

121. Jarrett WA, Militsakh O, Anstad M, Manaligod J. Endoscopic sinus surgery incystic fibrosis: effects on pulmonary function and ideal body weight. EarNose Throat J 2004; 83:118–121.

122. Osborn AJ, Leung R, Ratjen F, James AL. Effect of endoscopic sinus surgeryon pulmonary function and microbial pathogens in a pediatric population withcystic fibrosis. Arch Otolaryngol Head Neck Surg 2011; 137:542–547.

123. Rosbe KW, Jones DT, Rahbar R, et al. Endoscopic sinus surgery in cysticfibrosis: do patients benefit from surgery? Int J Pediatr Otorhinolaryngol2001; 61:113–119.

124. Chiu A, Palmer JN, Woodworth BA, et al. Baby shampoo nasal irrigations forthe symptomatic postfunctional endoscopic sinus surgery patient. Am JRhinol 2008; 22:34–37.

125. Amirav I, Cohen-Cymberknoh M, Shoseyov D, Kerem E. Primary ciliarydyskinesia: prospects for new therapies, building on the experience in cysticfibrosis. Paediatr Respir Rev 2009; 10:58–62.



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Managing upper respiratory tract complications of primary ciliary dyskinesia in children