1. Primary Ciliary Dyskinesia Assoc. Prof. Bulent KARADAG Marmara Uni. Faculty of Medicine Div. of Pediatric Pulmonology ISTANBUL-TURKEY

3. Primary Ciliary Dyskinesia (PCD) Associated with abnormal ciliary structure and function Results in retention of mucus and bacteria in the respiratory tract Leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility.

4. PCD Diagnosis of PCD:requires the presence of the characteristic clinical phenotype + specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function. Management remains uncertain and evidence is limited Important to follow-up these patients with an adequate and shared care system to prevent future lung damage.

5. PCD Ciliary dysfunction -polycystic liver and kidney disease, biliary atresia, CNS abnormalities (retinopathy,hydrocephalus. Bush A, Arch Dis Child 2007;92:1136.

6. Epidemiology and natural history Prevalence: Very difficult to estimate accurately. TORGERSEN (Acta Radiol 1947) Radiological study involving approximately a third of the Norwegian population. Situs inversus 1:8,000, 10% had bronchiectasis. PCD 1:40,000. Underestimation (standard CXRs insensitive for BE, and younger patients do not have BE)

7. Epidemiology and natural history AFZELIUS [Int J Dev Biol 2006;50:571] Sweden, 1:22,000, 1976–1990 True prevalence 1:10,000. Broad range of clinical severity Many milder cases remain undiagnosed, Up to 13% of BE ( more common in N. African than in European patients [Verra F, ERJ 1991].

8. PCD Incidence: 1/15.000-60.000 40-50 % Kartagener Syndrome (Situs inversus, BE, Sinusitis) O’Callaghan C, Thorax 2007;62:656.

10. Epidemiology and natural history Mean age at diagnosis: COREN (Acta Paediatr 2002) 4.4 yrs (6 yrs for those without situs inversus) Range of severity of symptoms ?? Natural history ??? Influenced by treatment ????

11. Epidemiology and natural history Long-term outcome (NOONE AJRCCM 2004) Cross-sectional study 1994–2002 78 subjects with PCD (including 31 children). BE in 61% of the children and 98% of the adults. Differs from adult CF patients in the USA, mean annual loss of FEV1 was reported to be 0.8% vs. 3.6%.

12. Epidemiology and natural history HELLINCKX (Eur J Pediatr 1998;1998;157:422) Stable longterm progression of lung function during childhood, adolescents seemed to fare worse. Adult patients were chronically infected with P. aeruginosa, 13 (27%) out of 47 adult patients had very severe disease Different studies might be due to different inclusion criteria and patient selection. Large multicentric representative cohort studies required.

13. Epidemiology and natural history Age at diagnosis, age at initiation of specific treatment affects outcome. ELLERMAN A (ERJ 1997) 24 patients with PCD for 2–16 yrs Lower lung function in those patients entering the cohort as adults compared to children. Therapy offers considerable benefit. Dataset small and heterogeneous ??

16. Genetics Genetically heterogeneous disorder, AR Outer dynein arm….DNAI1, DNAI2, DNAH5, DNAH11, TXNDC3 Central microtubule pair..RSPH9, RSPH4A 28 % DNAH5 7.5 % DNAI1

17. Genetics and Inheritance

19. Clinical Aspects History of lower airway disease, Chronic wet-sounding cough Wheeze or shortness of breath. Chronic rhinitis Ear symptoms (recurrent otitis media) Diagnosis -frequently delayed Positive family history of PCD -10%

20. Clinical Aspects History Early diagnosis- Important BE on diagnosis seen only in >4 yrs of age children (Coren ME, Acta Paediatr 2002) Situs inversus totalis Cerebral ventriculomegaly Siblings of probands

21. PCD History (Symptoms begin on the 1st day of life) Nasal polyps Early diagnosis: may prevent the development of BE. may important for QoL and life expectancy. Bush A, Arch Dis Child 2002;87:363-365.

22. PCD 89 PCD patients, HRCT of the lungs, available in 26 patients, Peribronchial thickening 25 patients, BE 20 patients Middle and the lingular lobes Jain K. Clin Radiol. 2007;62(10):986-93.

23. PRIMARY CILIARY DYSKINESIA (PCD) (6.3 %)

25. Clinical Aspects Neonatal respiratory distress (75%) Chronic productive cough, bronchiectasis Severe upper airway disease Immotile sperm Ectopic pregnancy

26. PCD

27. Diagnostic Testing Diagnostic analysis – difficult Secondary ciliary defects ? Screening tests - Nasal NO measurement Very low NO

28. Upper airway NO levels- lower in PCD (n=21) than in the healthy children (n=60) (97 vs 664, p<0.0001). Lower airway NO levels- reduced (2.17 vs 5.94 ppb, p<0.0001). Some overlap

31. Galdo AM, An Pediatr (Barc) 2010

32. Diagnostic Testing Screening tests Saccharin test A microtablet of saccharin is placed on the inferior turbinate Difficult to perform and unreliable in children aged <12 yrs. Diskinetically beating cilia can be missed

33. Diagnostic Testing Screening tests Nasal NO - >5 yrs Saccharin test- Should not be used in children.

34. Diagnostic Testing Obtaining a sample of ciliate cells Nasal brushing Free of an acute upper respiratory tract infection for 4–6 weeks. Bronchoscopic samples Bronchoscopic brush or forceps

43. Diagnostic Testing Ciliary beat pattern and frequency analysis Digital high-speed video camera 500 frames/sec Low beat frequency 10-15 % pattern abnormalities

46. Diagnostic Testing Electron microscopy Important, specialist knowledge is required Ultrastructural defects can be missed using EM

47. Diagnostic Testing Cell culture JORISSEN [Acta Otorhinolaryngol Bel 2000) Highly specialised method Analysis of dynein protein localisation Detection and intracellular localisation of DNAH5 by immunofluorescence microscopy Genetic analysis Not recommended as a part of initial diagnostic testing

49. Respiratory Treatment AIM Improve mucociliary and cough clearance leading to reduction in recurrent infections and Improvement in health related quality of life

50. Respiratory Treatment No randomised trials All treatment recommendations are based on a very low level evidence, or extrapolated from CF guidelines. Be ready to discontinue therapies that are not working. Aggressive treatment of infections Airway clearance by CPT and physical exercise. Center (10–15 patients)

51. Respiratory Treatment Antibiotics Regular (>3-monthly) culture of sputum or cough swabs H.influenzae, S.aureus, S.pneumoniae No evidence to recommend the use of prophylactic oral antibiotics If repeated courses of oral antibiotics are required, prophylaxis should be considered.

53. Respiratory Treatment Antibiotics 3-monthly IV therapies should be considered in patients who are not doing well. No controlled trials If P. aeruginosa is isolated, nebulised antipseudomonal antibiotics are considered, but evidence not sufficient

54. Respiratory Treatment Regular bronchodilator use Nebulised rhDNase Some patients show an improvement Nebulised normal or hypertonic saline N-acetylcysteine – not useful CPT

55. Diagnostic and therapeutic approaches for a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required to improve these recommendations on diagnostic and treatment approaches in this disease.

56. 223 centres in 26 countries, of which 194 cared for PCD patients 90% of centres based their diagnosis on a nasal or bronchial mucosal biopsy Nasal nitric oxide 46% Treatments varied widely between countries, and between centres within a country.

57. 57% male 44% situs inversus. Median age at diagnosis 5.3 years, lower in children with situs inversus (3.5 vs. 5.8 yrs, p<0.001).

63. SUMMARY Great need for more diagnostic awareness Great need for evidence based treatment Follow up in tertiary centres Great need for coordination among centres to enable accordancy Need for “Centres of excellence”