Primary ciliary dyskinesia

Sep 09 2015

Primary Ciliary Dyskinesia (PCD) is a heterogeneous group of genetic respiratory disorders, usually autosomal recessive, whose frequency is estimated at 1/16,000 (1). The structural and functional abnormalities of the respiratory ciliated cells alter the mucociliary clearance thus resulting in debilitating chronic upper and lower respiratory infections that are difficult to treat. In half of the cases, the disorder is associated with situs inversus, thus constituting Kartagener’s syndrome.

  • KEY POINTS +

    PCDs are genetically heterogeneous rare respiratory disorders.

    The diagnosis should be considered when there are severe chronic infections of the superior and inferior airways or recurrent respiratory infections (especially in the presence of situs inversus), inexplicable neonatal respiratory distress, family history of PCD or parental consanguinity. The diagnosis is based on established diagnostic criteria.

    Early diagnosis and aggressive treatment improve the prognosis.

  • PATHOPHYSIOLOGY +

    Structure and function of cilia

    Ciliated epithelium line the conduction airways from the nose to the terminal bronchioles and act as the respiratory system’s first line of defense. Motile cilia are also present in the genital tracts.

    These cilia, about 200 per cell, are ultra-specialized cellular extensions (approximately 6 µm long and 0.25 µm wide). Their coordinated movement ensures mucus clearance from the inferior airways all the way to the large bronchial trunks where the cough reflex finally expels the secretions.

    The axoneme (internal cytoskeleton of the cilia) is the framework of ciliary movement. It is comprised of 9 peripheral microtubule doublets (A and B subunits) which are attached to the central complex (a pair of central microtubules surrounded with a sheath) by radial spokes and are linked together by nexin bonds. The activation of the dynein arms allow the cilia and flagella to beat as the peripheral microtubules slide against each another. The internal and external dynein arms (IDA and EDA) are complex proteins attached to the A subunit at regular intervals.

    dcp_physio
    Cross-section of cilia by electron microscopy
    dcp_physio
    Diagram of ciliary structure

    Ciliary ultrastructural defects

    A common defect in PCD is the absence of external dynein arms which can be either isolated (30%) or associated with an absence of internal arms (30%). The isolated absence of internal dynein arms may also be observed, but is less common (15%). However, all of the axonemal structures, particularly the central microtubules (15%), may be completely or partially altered.

    It is important to note that defects in the dynein arms generally involve all of the cilia whereas in cases of central complex defects, normal cilia are still present.

    Kartagener syndrome is not always associated with ciliary defects: in 10% of cases, the cilia are normal.

    cil_normal
    Cil normal
    cil_abs_bras_dyn_ext
    Cil sans bras de dynéine externes
    cil_abs_bras_dyn_ext
    Cil sans bras de dynéine internes
    avec désorganisation
  • CLINICAL PRESENTATION : WHEN SHOULD THE DIAGNOSIS BE CONSIDERED? +

    The association of chronic or repeated infections of the superior and inferior airways is what should bring up the diagnosis of PCD.

    Respiratory symptoms are not specific; they include the early onset of chronic lower respiratory infections that are not seasonal. These include bronchitis, pneumopathies (particularly of the middle lobe), congestion with a thick productive cough, or atypical asthma. Neonatal respiratory distress, unexplained by premature birth, a materno-fetal infection, or a delay in reabsorption of the amniotic liquid has been observed in over 50 % of the cases. These cases are sometimes accompanied by ventilation trouble and show atelectasis on the thoracic x-ray. The prognosis is generally favorable.

    Associated ENT symptoms include the early onset of a chronic rhinite, repeated otitis, otitis media with effusion, acute otitis with otorrhoea, or bouts of rhinosinusitus at times associated with nasal polyposis.
    Rhinorrhoea and serous membrane otitis occur in 95 – 100% of children with PCD.

    The presence of situs inversus, whether complete or incomplete, is an element that should bring up the diagnosis. About 50% of patients who have PCD exhibit situs inversus (therefore constituting Kartagener syndrome), but only a quarter of patients who exhibit situs invesus have PCD.

    Fertility problems in adult subjects are often observed. Men may be sterile due to immobile spermatozoides. The diagnosis may be considered for women who present ectopic pregnancies or a hypofertility requiring medical assistance to conceive.

    Associated syndroms may exist, linking PCD with renal polykystose, hydrocephalie, biliary atresia, or pigmentary retintite.

  • DIAGNOSTIC APPROACH +

    Ruling out other diagnoses

    The diagnostic approach requires the healthcare professional to first rule out the principal differential diagnoses such as cystic fibrosis (by sweat tests and genetic study), immune deficiency, gastro-oesophageal reflux, or inhalation pathology.

    Tests necessary for the diagnosis

    Study of the respiratory cilia
    The study of respiratory cilia includes both the evaluation of their structure as well as their function, notably of ciliary beat frequency and of mucociliary clearance, through electron microscopy.

    Ciliary studies are performed on ciliated cells that are taken through a biopsy during a bronchoscopy or through nasal brushing when there is no acute secondary infection. A systematic antibiotic treatment 10 days prior to the biopsy is recommended.

    The ciliary beat frequency (CBF) is preferably measured by nasal brushing. The normal rate of CBF is between 10 and 14 Hz.

    Mucociliary clearance can be evaluated in vivo by different techniques. The simplest test is the saccharine test in which a saccharine particle is placed in the nasal cavity of the patient, normally causing the perception of a sweet taste after 10 to 30 minutes. Isotopic techniques can also be used. The mucociliary clearance rate is around 5 to 8 mm/min (up to 33 mm/min is normal). These tests require patient cooperation and can not be considered for children before the age of 8-10 years old.

    Classic techniques of electron microscopy are used to examen the ciliary ultrastructure. The quantitative analysis of the ciliary ultrastructure is based on the study of at least 30 cross-sections of axonemes from several ciliated cells. The results are expressed in a quantitative (% of abnormal cilia/ number of total cilia studied) and qualitative manner (by specifying the type of dominant abnormality; unique or polymorphous). In normal subjects, up to 15% of cilia can present ultrastructural abnormalities.

    The ultrastructural study is done if the functional studies of the cilia are abnormal and/or if there is a clinical indicator.

    Azote (NO) measurement
    Measuring nasal nitric oxide (NO) flow rate is particularly interesting in this pathology because there is a drastic reduction in nasal NO output in patients with PCD. This reduction seems quite characteristic when it is less than 100 ppm. In certain pathologies like asthma or respiratory infections, the flow rate of NO is elevated. Even though the NO flow rate in cystic fibrosis is reduced, it is still significantly higher than in patients with a ciliary disorder.

    Genetic analysis

    PCD are genetically heterogeneous: several genes can be at the origin of the same ultrastructural abnormality. The disorder is usually inherited in an autosomal recessive manner. For this reason, populations with a strong degree of consanguinity have a higher frequency of individuals affected.

    dcp_genes

    Other exams

    Thoracic imagery
    Bronchial dilations are frequent and can appear early (appearing in 70% of children with PCD around the age of 10 years old). They are most often segmentary occurring predominantly at the bases. The exact topography and extension of the bronchial dilations are illustrated by a high resolution scanner. There is no connection between the severity of the dilation shown on the x-ray and gender, the presence of situs inversus, or the type of ultrastructural abnormality. There is, however, a connection between the extension of the bronchial dilations and the degree to which the respiratory function is affected.

    Functional respiratory exploration
    Respiratory function is often altered, with an obstructive syndrome most often irreversible after bronchodilatators. The presence of hypoxia indicates the severity of the illness.

    Bacteriological studies of respiratory biopsies
    Bacterial infections of the bronchial tree are frequently found to include Haemophilus influenza and/or Staphylococcus aureus. A Pseudomnas aeruginosa infection may be documented later on.

  • TREATMENT +

    Treatments are purely symptomatic. However, it has been shown that the prognosis depends on timely diagnosis and treatment.

    Healthcare providers must take into account the patient’s surroundings, the importance of a smoke-free environment, and the necessity to properly vaccinate these children (Pneumocoque, Parainfluenza, as well as the classic vaccinations).

    Treatment is essentially based on chest physiotherapy and all other bronchial drainage techniques. The technique that is currently approved is bronchial drainage by way of expiratory flux acceleration.

    Antiobiotic therapy is the most efficient means to fight against bacterial infections. It is most often sequential, adapted to the bacteriological results of the the child. In fact, no study has shown that continual alternated antiobiotherapy is more effective than sequential antiobiotherapy. Pseudomonas aeruginosa infections are treated in the same way as cystic fibrosis.

    Inhaled treatments using bronchodilators may be suggested if the results of functional respiratory explorations show improvement in the ventilatory parameters. Long term benefits of glucocorticoids have never been evaluated, but their use to diminish chronic bronchial inflammation is recommended.

    The treatment of PCD requires a joint follow-up with an ENT for a treatment adapted to the affected upper respiratory area. This treament includes, but is not limited to nasal irrigation twice a day as well as audiometric monitoring. The use of a ventilator in this context is not necessary.

  • 1


(1) Ciliary defects and genetics of primary ciliary dyskinesia. Escudier E, Duquesnoy P, Papon JF, Amselem S. Paediatr Respir Rev. 2009 Jun;10(2):51-4. Epub 2009 Apr 18.

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PNDS DPI DCP

Déclarations publiques d’intérêts

PNDS Dyskinésies ciliaires primitives de l'enfant

Prénom, NomDéclaration publique d'intérêts
Aline TamaletConsulter
Chiara SileoConsulter
Dominique GirardonConsulter
Hubert Ducou le PointeConsulter
Estelle EscudierConsulter
Guillaume ThouveninConsulter
Harriet CorvolConsulter
Isabelle CizeauConsulter
Isabelle HonoréConsulter
Isabelle PinConsulter
Jean-Christophe DubusConsulter
Jocelyne DerelleConsulter
Justin MichelConsulter
Katia BessaciConsulter
Laurence BassinetConsulter
Marc KoskasConsulter
Marie LegendreConsulter
Marie-Pierre RevelConsulter
Meriem RahmaniConsulter
Muriel LebourgeoisConsulter
Nicole BeydonConsulter
Pierre-Régis BurgelConsulter
Stéphanie WaninConsulter
Véronique HoudouinConsulter

PNDS DPI PID

Déclarations publiques d’intérêts

PNDS Pneumopathies interstitielles diffuses de l’enfant

Prénom, NomDéclaration publique d'intérêts
Rola Abou TaamConsulter
Serge AmselemConsulter
Tiphaine BihouéeConsulter
Céline BinetConsulter
Laureline BertelootConsulter
Déborah BlochConsulter
Michèle BouléConsulter
Aurélie ClavelConsulter
Annick ClementConsulter
Aurore CoulombConsulter
Pierrick CrosConsulter
Jacques de BlicConsulter
Jean-Christophe DubusConsulter
Hubert Ducou le PointeConsulter
Ralph EpaudConsulter
Michaël FayonConsulter
Laurent GouyaConsulter
Alice HadchouelConsulter
Véronique HoudouinConsulter
Marie LegendreConsulter
Nadia NathanConsulter
Meriem RahmaniConsulter
Philipe ReixConsulter
Jean-Luc RittiéConsulter
Chiara SileoConsulter
Aurélie TatopoulosConsulter
Caroline ThumerelleConsulter