Download - 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)
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.
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.
PCD
Ciliary dysfunction -polycystic liver and kidney disease, biliary atresia, CNS abnormalities (retinopathy,hydrocephalus.
Bush A, Arch Dis Child 2007;92:1136.
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)
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].
PCD
Incidence: 1/15.000-60.000
40-50 % Kartagener Syndrome
(Situs inversus, BE, Sinusitis)
O’Callaghan C, Thorax 2007;62:656.
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 ????
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%.
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.
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 ??
Genetics
Genetically heterogeneous disorder, AR Outer dynein arm….DNAI1, DNAI2,
DNAH5, DNAH11, TXNDC3 Central microtubule pair..RSPH9, RSPH4A 28 % DNAH5 7.5 % DNAI1
Genetics and Inheritance
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%
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
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.
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.
PRIMARY CILIARY DYSKINESIA (PCD) (6.3 %)
Clinical Aspects
Neonatal respiratory distress (75%)
Chronic productive cough, bronchiectasis
Severe upper airway disease
Immotile sperm
Ectopic pregnancy
PCD
Diagnostic Testing
Diagnostic analysis – difficult
Secondary ciliary defects ?
Screening tests
- Nasal NO measurement
Very low NO
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
Galdo AM, An Pediatr (Barc) 2010
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
Diagnostic Testing
Screening tests
Nasal NO - >5 yrs Saccharin test- Should not be used in
children.
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
Diagnostic Testing
Ciliary beat pattern and frequency analysis
Digital high-speed video camera 500 frames/sec Low beat frequency 10-15 % pattern abnormalities
Diagnostic Testing
Electron microscopy
Important, specialist knowledge is
required
Ultrastructural defects can be missed
using EM
Diagnostic Testing
Cell cultureJORISSEN [Acta Otorhinolaryngol Bel 2000)Highly specialised method Analysis of dynein protein
localisationDetection and intracellular localisation ofDNAH5 by immunofluorescence microscopy Genetic analysisNot recommended as a part of initial
diagnostic testing
Respiratory Treatment
AIM
Improve mucociliary and cough clearance
leading to reduction in recurrent infections
and
Improvement in health related quality of life
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)
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.
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
Respiratory Treatment
Regular bronchodilator use
Nebulised rhDNase
Some patients show an improvement
Nebulised normal or hypertonic saline
N-acetylcysteine – not useful
CPT
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.
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% male44% situs inversus. Median age at diagnosis 5.3 years, lower in children with situs inversus (3.5 vs. 5.8 yrs, p<0.001).
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”