Primary Ciliary Dyskinesia

Bruce K. Rubin, MEngr, MD, MBA, FRCPC, FAAP

Introduction/Etiology/Epidemiology

•Primary ciliary dyskinesia (PCD) is a disorder that affects motile cilia in the airways, the female reproductive tract (fallopian tubes), the flagella of spermatozoa, and, in some patients, cilia in the ventricular aqueducts in the brain.

•PCD occurs in approximately 1 in 16,000 live births.

•PCD is usually inherited as an autosomal recessive disorder. As of this writing, 33 distinct genetic defects have been identified that lead to abnormal function of the ciliary axoneme. It is estimated that known genetic defects account for approximately two-thirds of reported cases of PCD.

•Motion of embryonic nodal cilia leads to normal visceral asymmetry, and absence of this normal motion results in a lack of definitive patterning, with just under half of patients having normal visceral placement (situs solitus).

•A similar proportion of patients have mirror image arrangement (situs inversus).

•Heterotaxy (situs ambiguus) occurs in approximately 12% of patients with PCD.

•Absence of ciliary beating leads to accumulation of infected secretions within the airway, eventually producing bronchiectasis but also leading to recurrent otitis media.

•Normal ciliary beating is thought to facilitate clearance of fluid from the lungs at birth, with most newborns who have PCD demonstrating respiratory distress.

•Normal flagellar beating is necessary for propelling the fertilized egg into the uterus and for normal spermatic motion.

History

•In 1904, the association between situs inversus and recurrent lung infections was described, and in 1936, Kartagener reported 4 patients with male infertility, situs inversus, and bronchiectasis.

•When abnormalities of ciliary axoneme structure were noted in 1976, the term immotile cilia syndrome was proposed for this disorder.

Clinical Features

•Failure to clear airway secretions leads to recurrent otitis media, chronic cough, and recurrent pneumonia, eventually leading to bronchiectasis.

•Although cystic fibrosis (CF) and PCD both result in abnormal mucociliary clearance, PCD has unique clinical features that distinguish it from CF.

—Very few newborns with CF have respiratory distress, but approximately 80% of term neonates with PCD have tachypnea, transient hypoxemia, and respiratory distress in association with poor clearance of lung liquid.

—Also distinct from CF, children with PCD almost always have recurrent severe otitis media, often with purulent drainage from ruptured tympanic membranes.

•Similar to CF, patients with PCD have persistent sinusitis and chronic wet cough, and most eventually develop bronchiectasis.

—Pseudomonas lung infection is a late finding in patients with PCD, and it usually represents bronchiectatic changes.

•Because the structure of the spermatic flagella is similar to that of the ciliary axoneme, most men with PCD are infertile because of lack of spermatic motion. Women have decreased fertility and are at risk for tubal pregnancies because of poor transport of the fertilized egg down the fallopian tube and into the uterus.

—Unexplained neonatal respiratory distress can persist for several days in term infants (although they commonly do not need supplemental oxygen).

—The patient may have early-onset, year-round wet cough.

—The patient may have early-onset, year-round nasal congestion.

—The patient may have laterality defects.

•The sensitivity and specificity of these 4 criteria indicate that they can

be used to identify at-risk children and direct decisions regarding further diagnostic testing.

•Further diagnostic testing includes

—Nasal nitric oxide (NO) measurement

▪Because of defective NO synthase, NO production is profoundly decreased in the noses of patients with PCD, and its measurement is both sensitive and specific.

▪Testing is currently limited to cooperative children, typically 5 years of age and older, and can usually be performed only at PCD specialty centers. Nasal NO measurement requires special expertise and equipment that differ from those used for the more common measurement of exhaled NO performed for evaluation of lower-airway inflammation in asthma.

▪Many patients with PCD will have poor ciliary motility when fresh brushings of airway cells are examined under a phase-contrast microscope, and many will have characteristic abnormalities, particularly of the motility apparatus in the ciliary axoneme that consists of dynein arms and the 9 microtubule doublets.

▪However, obtaining biopsy specimens is uncomfortable for the patient and requires special expertise to harvest the epithelium from the nose or the airway and expertise in preparing these specimens for examination with transmission electron microscopy (TEM) or for phase-contrast microscopy evaluation. Furthermore, even in expert hands, the diagnostic reliability of the interpretation of these studies is variable.

•Several companies provide commercial genetic testing for a panel of abnormalities associated with PCD. As of this publication, approximately 65% of patients with PCD can be identified with genetic testing, including some with structurally normal cilia at TEM. Genetic testing for PCD has high positive predictive value but limited sensitivity (similar to that of microscopy). Most PCD centers now use nasal NO as the initial screen, followed by genetic testing as the initial evaluation.

Management

•When possible, patients should be comanaged by their primary care physician and a comprehensive PCD center capable of full diagnostic testing, close monitoring for complications, and access to clinical trials of new therapies. The development of registries in the United States, Europe, Japan, and Israel will facilitate the evaluation of proposed PCD therapies, as these may differ from CF therapy.

•The management of PCD includes avoiding airway irritants, such as tobacco smoke, and using antibiotics and airway clearance maneuvers to delay the development of bronchiectasis. This is similar to the use of antibiotics and airway clearance in patients with CF.

•Routine immunizations, including influenza and pneumococcal immuni-

zations, may help prevent respiratory infections.

•Early and frequent use of antibiotics for ear infections allows most patients to avoid the insertion of tympanostomy tubes with subsequent hearing loss. However, some otolaryngologists recommend the early placement of tympanostomy tubes.

•Although often used, there is no clinical evidence regarding the use of hypertonic saline, dornase alfa, or N-acetylcysteine aerosol therapy. There is some evidence that the use of medications such as expectorants and cough suppressants may worsen disease.

•There is evidence that the chronic use of low-dose macrolide antibiotics (eg, azithromycin and clarithromycin) may ameliorate mucus hypersecretion and inflammation in patients with PCD, similar to CF and non-CF bronchiectasis therapy.

•Surgical intervention may be needed for congenital heart disease and severe gastroesophageal reflux.

Expected Outcomes/Prognosis

•Conductive hearing loss due to persistent otitis media with effusion is common. Hearing abnormalities often improve in adolescence, but in some cases, they continue into adulthood.

•The rate of development of bronchiectasis is variable, but lung disease in childhood is typically not as severe as is seen in CF. Nonetheless, while management is directed against the prevention of bronchiectasis, it typically develops over time, and complications of suppurative lung disease, including respiratory failure, are seen as patients get older.

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