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”