81717861 diskinezia-ciliară-primară
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81717861 diskinezia-ciliară-primară
- 2. Noțiune • Diskinezia ciliară primară este o maladie congenitală determinată de defecte specifice în ultrastructura cililor, asociate cu deficiență de motilitate ciliară și clearance mucociliar. • Transmitere genetică : AR, AD, XL • Incidență: 1:15.000 – 1:20.000 • Vîrsta medie de adresare: 4 ani
- 3. Fiziologie • Epiteliu ce conține celule ciliate : – Tractul respirator, sinusurile paranazale, urechea medie – Celulele ependimale în encefal – Tubele Fallope • Flagelii (structură asemeni cililor, cu aceleași caracteristici fundamentale ale motilității): – Cozile spermatozoizilor
- 4. • Frecvența bătăilor cililor este mai rapidă în căile aeriene proximale decît în cele distale (~12 bătăi/sec. în nas și trahee vs. 8 bătăi/sec. în bronhiole) și este mai rapidă la copii decît la adulți (frecvența bătăilor ciliare în nas e aproape de 13 bătăi per sec. la copii vs. 11.5 bătăi per sec. la adulți) • Transportul mucociliar normal are viteza de circa 20-30mm/min.
- 7. Etiopatogenie • Mutații în genele ce codifică dyneina: DNAH5 (γ lanțul greu) și DNAI1 (lanțul intermediar IC78) -> • Dyneina defectă -> • clearance ineficient al secrețiilor de mucus și particolelor inhalate -> • Recurente sau persistente : rinită, sinusită, otită medie, bronșită, bronșiectazie. • Defecte de lateralizare (situs ambiguus, situs inversus) • Infertilitate masculină, hipofertilitate feminină.
- 11. Istoric • 1930, Kartagener sdr. – triada (situs inversus, sinuzită cronică, bronșiectazie) • Sdr. cililor imotili • Diskinezie ciliară primară vs secundară (IRVA, toxine)
- 12. Anamneză • tuse cronică, productivă • combinație de infecții respiratorii cronice și recurente, icluzînd : rinită, sinuzită, otită medie, bronșită, pneumonie. • Tahipnee, tuse, hipoxemie în perioada neonatală, adesea atribuite pneumoniei neo- natale sau pneumonitei prin aspirație. • Istoric familial de DCP
- 13. Clinic • Frecvent (>60% pacienți) – Detresă respiratorie în perioada neonatală – Tuse cronică productivă – Pneumonie recurentă – Obstrucția căilor respiratorii – Rinită cronică și ronoree – Otită medie cronică – Sinuzită cronică – Sterilitate masculină • Obișnuit (20-60% pacienți) – Situs inversus – Polipi nazali – Pierderea auzului din cauza conductibilității – Perforație cronică a membranei timpanice – Hippocratism digital (adesea mai mult la adulți decît la copii) DD cu fibroza cistică
- 14. Infecții ale cailor resp.inf. • Tuse cronică productivă (spută mucoidă sau purulentă), predominant dimineața • Date fizicale: raluri umede care pot dispărea după o tuse forțată; uneori hiperinflația toracelui • Haemophilus influenzae, Staphylococcus aureus, Streptococcus viridans, și Streptococcus pneumoniae. • Pseudomonas aeruginosa
- 15. Situs inversus totalis • 50% din pacienții cu DCP • Tipic, toate viscerele abdominale și toracice sunt transpoziționate (i.e. situs inversus totalis) • Cea mai acceptată ipoteză e că rotația normală a viscerelor în ontogeneză depinde de funcționalitatea cililor embrionali. În dereglarea motilității ciliare – rotația organelor ține de oportunitate – 50% normală, 50% dextrorotație sau situs inversus, proces denumit “randomizarea asimetriei corporale stînga-dreapta”
- 16. arg – discul embrionar pr – stria primitivă
- 17. Alte modificări • Hidrocefalie (pacienți unitari) • Migrarea deficitară a leucocitelor (alterarea microtubulilor citoplasmatici)
- 18. • Diagnosticul de certitudine de Diskinezie Ciliară Primară necesită demonstrarea anomaliei de motilitate și ultrastructură cililor.
- 19. Screening • Nu discriminează între DCP și diskinezie ciliară secundară • Testul cu Saccharin (N<60min) • Testul cu coloranți (N<60min) • De elecție : Estimarea NO nazal (În DCP : 10-20% din normă) [N: > 250 ppb] • Testul de clearance pulmonar al radioaerosolului (metodă scintigrafică, rata eliminării PRF inhalat)
- 20. Diagnostic morfologic • Biopsie exfoliativă a epiteliului nasal • Biopsie endoscopică a mucoasei bronșice • Microscopie simplă • Microscopie electronică (Analiza ultrastructurală) • Cultură celulară
- 21. Diagnostic funcțional • Videomicroscopie a epiteliului ciliar proaspăt- prelevat – Analiza frecvenței și modului de bătaie a cililor
- 22. Diagnostic genetic • DNAH5 și DNAI1 • Imunofluorescență
- 23. Diagnostic • Spirografie: tip obstructiv; CEF 25-75% , VEMS 25-75%, ↑Vrezidual. Răspuns variabil la bronhodilatatoare.
- 24. Criterii radiologice • Tipic în lobul mediu și lobul lingular • Frecvente (> 60% pacienți) – Hiperinflație pulmonară – Îngroșarea peretelui bronșic – Atelectazii segmentare – Îngroșarea mucoasei sinusurilor paranazale • Obișnuite (20-60% pacienți) – Situs inversus – Bronșiectazii – Opacifierea sinusurilor paranazale
- 26. Diagnostic diferențial • Diskinezie ciliară secundară • Fibroza chistică • Boala de reflux gastro-esofagian • Aspirație • Imunodeficiență primară
- 27. Tratament • Nespecific, asemeni fibrozei chistice. • Drenaj postural • Exerciții viguroase spre a spori tusea • Bronhidilatatoare (Albuterol) • Vaccin (pneumococic, pertusis, Haemophilus influenzae tip B, antigripal) • Antibioticoterapie în suprainfecții • Polipectomie, Lobectomie
- 28. Pronostic • Progresia afectării pulmonare este variabilă, durata vieții putînd fi normală sau apropiată de cea normală.
Editor's Notes
- One review of 55 patients diagnosed at a tertiary referral centre records the median age at referral to be 4 years.
- Often male patients are sterile because of dysmotile or immotile spermatozoa. Female patients are not sterile, but might be ‘hypofertile’. In familieswith PCD, all affected patients have respiratory symptoms, but only half of the affected siblings have a situs inversus. This is due to randomization of the left–right body asymmetry. In some animal models and population isolates, PCD is not associated with situs inversus.
- The ciliary beat frequency is faster in the proximal airways than in the distal airways (∼12 beats/second in the nose and trachea vs. 8 beats/second in the bronchioles) and is faster in children than in adults (nasal ciliary beat frequency is close to 13 beats/ second in young children vs. 11.5 beats/second in adults) Normal mucociliary transport rates may be as rapid as 20 to 30 mm/min.
- Each normal cilium contains an array of longitudinal microtubules, consisting of nine doublets arranged in an outer circle around a central pair. Ciliary bending results from the longitudinal displacement of adjacent microtubular doublets. FIGURE 63-1. A, Ultrastructure of a normal cilium in cross-section. B, A diagrammatic representation illustrating the major structural components. The nine outer doublet tubules and two central singlet tubules are interconnected by nexin and radial spoke linkages. Outer and inner dynein arms are attached to A subunits of the outer doublets. The plane of ciliary beating is perpendicular to the ciliary axis, determined by the alignment of the central tubules. (A, Courtesy of J.L. Carson. B, From Rutland J, deIongh RU: Random ciliary orientation—a cause of respiratory tract disease. N Engl J Med 1990; 323[24]:1681–1684.)
- FIGURE 63-2. Ciliary orientation determined by the alignment of the central tubules is almost parallel in normal subjects (A), but can be random in patients with primary ciliary dyskinesia (B), resulting in uncoordinated and ineffective ciliary beating. (From Rutland J, deIongh RU: Random ciliary orientation—a cause of respiratory tract disease. N Engl J Med 1990;323[24]: 1681–1684.)
- In some patients with typical clinical manifestations of PCD and ciliary dysmotility, ciliary ultrastructure appears normal, suggesting other defects that affect function but not structure. Isolation and development of probes for the numerous components of cilia or their genes are needed to further define primary defects in cilia and to understand the steps in ciliogenesis that are interrupted to create secondary ciliary defects. DNAH5 (γ heavy chain) and DNAI1 (intermediate chain IC78)
- Middle ear findings may be most helpful in distinguishing PCD from cystic fibrosis or other causes of chronic lung disease.
- According to the most widely accepted hypothesis, normal rotation of viscera depends on functioning embryonic cilia. With disruption of normal ciliary movement, as in PCD, rotation becomes a chance occurrence; 50% have normal rotation and 50% have dextrorotation or situs inversus.38,40,49 This randomness of laterality in PCD has been demonstrated in genetically identical twins with PCD: one with situs solitus and one with situs inversus as well as in dynein knockout mouse models. randomization of the left–right body asymmetry.
- Surface view of embryo of a rabbit. arg. Embryonic disk. pr. Primitive streak.
- Hydrocephalus has been reported in a few patients with PCD and in some knockout mouse models for PCD; ultrastructural and functional defects in ventricular ependymal cilia provide a theoretical basis for this association. Defective leukocyte migration has been reported in a few PCD patients, suggesting that the cytoplasmic microtubules of leukocytes may be altered, but specific defects in neutrophil chemotaxis have not been defined.
- Definitive diagnosis of PCD requires demonstration of abnormal ciliary motility and ultrastructure.
- Measuring nasal NO has become the screening test of choice in specialist centres as it is almost universally lowin PCD. When air is sampled from the nose at a rate of 250 ml/min during a breath hold, an NO level of > 250 ppb will exclude PCD as a diagnosis with almost 97% certainty.31 The reasons for this are not clear and this finding appears paradoxical in a condition where chronic inflammation is invariably present. Because there is some degree of overlap seen with some patients with cystic fibrosis and other bronchiectatic conditions, as well as rhinosinusitus, it is used as a screening test and diagnostic tests must always be undertaken to confirm the diagnosis. There is less experience in babies and small infants, in whom results must be interpreted with caution. Despite these difficulties, the use of this test in paediatric respiratory units has grownextensively.More recently, a group from Copenhagen has used pulmonary radioaerosol clearance techniques (PRMC) to measure mucociliary clearance in the lower airway. This test, which has been performed in children as young as 5, has the advantage of avoiding the possible secondary defects of mucociliary clearance so common in the nose. More data from a second population are needed before this test can be definitely recommended. The role of nasal NO measurement in the diagnostic evaluation has not been defined; however, recent studies suggest that this assay may be a useful screening test for PCD or serve as an adjunctive diagnostic test in individuals with “uncertain” ciliary ultrastructural studies.
- The most frequent genetic defects are mutations of DNAH5 and DNAI1, both of which encode the outer dynein arm (ODA) components of the axoneme. By utilizing specific antibodies, it has been shown that there is specific regional distribution along the axoneme, indicating at least two distinct types of ODA. The use of high-resolution immunoflourescent staining, using specific antibodies, not only offers the potential to further identify the complex ultrastructural defects resulting in PCD, but should also enhance our diagnostic standards.
- Typical findings include decreased flow rates (forced expiratory flow between 25% and 75% of vital capacity [FEF25%–75%] and forced expiratory volume in 1 second [FEV1]), increased residual volume (RV), and increased ratio of residual volume to total lung capacity (RV/TLC). Bronchodilator responsiveness is variable.
- At present, no specific therapeutic modalities are available to correct the ciliary dysfunction. Management should include aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial superinfections. Approaches to enhance mucus clearance in PCD are similar to those used in the management of cystic fibrosis. A number of measures to prevent respiratory tract infection and irritation should be considered. PCD patients should receive routine immunizations that provide protection against a number of respiratory pathogens, including pertussis, measles, and Haemophilus influenzae type b, as well as the pneumococcal vaccine and a yearly influenza virus vaccine. Preventive counseling should include avoidance of exposure to respiratory pathogens, tobacco smoke, and other pollutants and irritants that may damage airway mucosa and stimulate mucus secretion.
- Chronic lung disease with bronchiectasis and some degree of pulmonary disability has been the usual outcome. Progression of lung disease is quite variable, and a number of individuals have experienced a normal or near-normal life span. Little is known about the impact that current symptomatic therapy may have on the course of lung disease.