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Primary Ciliary Dyskinesia

Primary Ciliary Dyskinesia. Assoc. Prof. Bulent KARADAG Marmara Uni. Faculty of Medicine Div. of Pediatric Pulmonology ISTANBUL-TURKEY. Primary Ciliary Dyskinesia (PCD). A ssociated with abnormal ciliary structure and function

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Primary Ciliary Dyskinesia

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

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

  3. 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 islimited • Important to follow-up these patients with an adequate and shared care systemto prevent future lung damage.

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

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

  6. 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 commonin N. African than in European patients [Verra F, ERJ 1991].

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

  8. Epidemiology and natural history • Mean ageat diagnosis: COREN (Acta Paediatr 2002) 4.4 yrs (6 yrs for those without situs inversus) • Range of severity ofsymptoms ?? • Natural history ??? • Influenced by treatment ????

  9. Epidemiology and natural history • Long-termoutcome (NOONE AJRCCM 2004) • Cross-sectionalstudy 1994–2002 • 78 subjects with PCD (including 31 children). • BE in 61% of the childrenand 98% of the adults. • Differsfromadult CF patients in the USA,mean annual loss ofFEV1 was reported to be 0.8% vs. 3.6%.

  10. 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.

  11. Epidemiology and natural history • Age at diagnosis, age at initiation of specific treatmentaffects outcome. • ELLERMAN A(ERJ 1997) • 24patients with PCD for 2–16 yrs • Lower lung functionin those patients entering the cohort as adults compared tochildren. • Therapy offers considerablebenefit. • Dataset small and heterogeneous ??

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

  13. Genetics and Inheritance

  14. Clinical Aspects History of lowerairway disease, Chronic wet-sounding cough Wheeze or shortness of breath. Chronic rhinitis Ear symptoms (recurrentotitis media) Diagnosis -frequently delayed Positive family historyof PCD -10%

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

  16. 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.

  17. 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.

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

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

  20. PCD

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

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

  23. Galdo AM, An Pediatr (Barc) 2010

  24. Diagnostic Testing Screening tests Saccharin test A microtablet ofsaccharin is placed on the inferior turbinate Difficult toperform and unreliable in children aged <12 yrs. Diskinetically beating cilia can be missed

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

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

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

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

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

  30. Respiratory Treatment AIM • Improve mucociliary and cough clearance leading toreduction in recurrent infections and • Improvement in health related quality of life

  31. Respiratory Treatment No randomised trials • All treatment recommendations are based on avery low level evidence, orextrapolated 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)

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