Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

Primary ciliary dyskinesia is a heterogeneous group of inherited disorders characterized by a structural and generalized abnormality of cilia which renders them immotile or dysmotile. Propulsion of sperm and mucus clearance from the respiratory tract and middle ear are impaired. The most common clinical expressions of this condition are chronic upper and lower airway disease and male infertility. In 1902, Siewert described a person with situs inversus and bronchiectasis. He could draw no connection between these two signs, however. Kartagener, in 1933, was the first to recognize a clinical syndrome of situs inversus totalis, bronchiectasis, and chronic sinusitis. Then in 1960, Arge described the association of situs inversus, respiratory disease, and male sterility, but could not explain the association. The pathogenesis of primary ciliary dyskinesia began to come to light in 1975, when Afzelius, Pederson and others described the absence of dynein arms in the tails of immotile sperm. Camner, Mossberg, and Afzelius soon reported the presence of non-functioning cilia in the respiratory tract of two subjects with chronic pulmonary disease. A year later, Afzelius coined the term "immotile cilia syndrome", which remains prevalent in the literature. However, given that cilia are "dysmotile," but not "immotile," in many cases, many authors prefer the term primary ciliary dyskinesia (PCD). Afzelius and others presented evidence that a genetic defect of the gene(s) for dynein, leading to a congenital lack of dynein arms in cilia and sperm tails, was responsible for both the respiratory and fertility problems. They further hypothesized that the lack of ciliary movement in embryonal tissues resulted in random organ rotation, which would result in 50% of PCD patients having situs inversus. Indeed, roughly 50% of PCD patients do have situs inversus, though many authors refute the role of embryonic cilia in organ rotation. These 50% of PCD patients who have situs inversus have Kartagener's syndrome, by definition.

Since the original description of a lack of dynein arms, cilia from many PCD patients have been studied. Defects of all of the axonemal structures, alone or in combination, have been identified in association with PCD. Also, overly long and overly short cilia have been identified, as well as congenitally absent cilia, and cilia that are normal in appearance but randomly oriented. Finally, normal ciliary ultrastructure has been described in a patient with the clinical picture of Kartagener's syndrome. Lack of dynein arms remains the most common defect identified, and the one classically associated with PCD. Some of the described ciliary abnormalities have been documented to result from infections, allergies, and chemical treatments. These include clumping of several axonemes into a giant compound cilium, and the presence of too many or too few microtubules. These findings, therefore, cannot be considered diagnostic of PCD.

PCD has an estimated prevalence of 1 in 16,000 live births. Kartagener's syndrome, the triad of situs inversus, bronchiectasis, and chronic sinusitis, therefore has a prevalence of roughly 1 in 32,000 births. It is important to note that situs inversus occurs without Kartagener's syndrome; only 1/4 to 1/5 of patients with situs inversus also have bronchiectasis and sinusitis. PCD has no geographic, racial, or sexual predilection. PCD is inherited as an autosomal recessive trait. Heterozygotes have normal ciliary function and no clinical features of PCD. The axoneme contains 200 different proteins, and defects in genes coding for any one of these products could conceivably be responsible for PCD. Indeed, the fact that multiple ciliary defects have been identified in different cases of PCD suggests that the syndrome is genetically heterogeneous.

Although PCD is ultrastructurally - and hence genetically - heterogeneous, the disorder is remarkably consistent in its clinical profile. Respiratory tract disease can usually be traced back to very early childhood - sometimes to the date of birth. Chronic cough with mucoid sputum is common, as is a history of atelectasis and pneumonia. Bronchiectasis is an acquired sequela of PCD, probably never present at birth. It develops during childhood and adolescence, and affects primarily the dependent parts of the lung. In contrast, bronchiectasis from cystic fibrosis tends to affect primarily the upper lobes of the lungs. Chronic bronchitis and reactive airway disease are common. Lung function by spirometry may be normal, or may show an obstructive pattern.

Rhinitis with mostly thin discharge is almost universally present, accompanied by nasal polyposis in about 30% of patients. Chronic ethmoid and maxillary sinusitis are almost universally seen; the frontal sinuses are usually hypoplastic. Chronic secretory otitis media with conductive hearing loss is a nearly universal feature in childhood as well. Sensorineural hearing loss has not been identified with PCD. About 10 percent of patients, however, do complain of postural instability. Common colds are usually no more severe in PCD patients than in normal patients; when no acute infection is present, ESR and immunoglobulin levels are usually normal. There is no correlation between the severity of upper and lower respiratory tract disease in PCD patients. Digital clubbing is seen only in older patients with bronchiectasis. It is less severe than that seen in CF. Male infertility is the rule, with rare exceptions. Sperm count is normal, but sperm are immotile or dysmotile. Increased female infertility has not been conclusively documented; ovum transport is apparently more dependent on muscular contraction of the fallopian tubes than on ciliary beating. Defective leukocyte migration has been reported in PCD, apparently secondary to cytoplasmic microtubule defects. This leukocyte problem has not been shown to have significant bearing on the clinical course. Hydrocephalus has been seen in cases of PCD. If PCD is the cause, the hydrocephalus might result from impaired ependymal ciliary clearance of CSF. Some PCD patients complain of persistent dull headaches, even during periods free from sinusitis. As noted above, roughly 50% of PCD patients have situs inversus, and therefore have Kartagener's syndrome. The inversion is usually total, though it can occasionally be partial. Usually no other congenital malformations of the heart or other organs are seen with PCD. Isolated dextrocardia is not associated with PCD. In the absence of situs inversus, the most important historical fact is the onset of symptoms shortly after birth. The rest of the clinical picture may be very hard to distinguish from that of severe allergies, hypogammaglobulinemia, or CF. Symptoms of immune deficiency appear after the third month of life, when maternal immunoglobulins are no longer circulating. Unusual infections and other features will eventually make this diagnosis evident. Patients with CF generally have failure to thrive, salty sweat, and history of bronchiolitis and bronchitis. The severe allergy sufferer may have a virtually identical clinical picture. Family history of PCD is very helpful, but the diagnosis may require examination of ciliary ultrastructure. Another condition, reported in adults, is Young's syndrome. It is characterized by bronchiectasis, sinusitis, and obstructive azoospermia. Ciliary ultrastructure and function are normal in Young's syndrome, as well as in CF, hypogammaglobulinemia, and allergic diathesis.

Measurements of airway mucociliary clearance may be valuable screening tools for excluding PCD, since absent mucociliary clearance is a hallmark of the syndrome. Several techniques have been described; my personal favorite is the placement of a few saccharin particles in the nose, and measurement of the time between placement and the first detection of a sweet taste by the patient. While not at all specific or quantitative, it is highly sensitive. Normal transport time is quite variable, but a sweet taste is usually detected within 15 minutes. Absence of sweet taste for greater than 60 minutes after particle placement is consistent with PCD. This test is impractical in young children, as it requires cooperation. Other tests include inhalation and tracking of radiolabelled particles, and placement of various insoluble dyes and small particles in the nose, which can later be visualized in the oropharynx. Particle inhalation and tracking is too expensive and complicated for practical use as a screening test. Placement of particles and / or insoluble dyes in the nose has some advantages over saccharin, one of which is increased feasibility in young children because of the lack of need of cooperation.

To confirm the diagnosis, biopsy of respiratory mucosa or microscopic examination of sperm is required. Sperm exam is easily performed in adolescent and adult males, but is not possible in young children and females. Ideally, biopsy specimens should be obtained from two sites, to confirm the generality of any defect. The nose can be an unreliable source in chronic rhinosinusitis, due to ciliary denundation and epithelial metaplasia. However, nasal biopsy is much more convenient and inexpensive, as it requires no anesthetic. A cytology brush can be gently scraped on the inferior or middle turbinate, or in the mainstem bronchus or trachea in the case of bronchoscopy. Bleeding should be avoided, as the presence of blood in the specimen impairs light microscopic exam for motility. Most pathologists discourage the use of decongestants or local anesthetic, for fear of impairing ciliary motility. Once obtained, the specimens should be left undisturbed on the cytology brush, and the brush tips cut off and placed in saline. More than one specimen should be obtained; one can be placed in saline, for light microscopy, and one in 2.5% glutaraldehyde, for electron microscopy. Specimens must be rushed to the pathologist within 30 minutes for examination of ciliary motility.

Various techniques have been described for visualizing and characterizing ciliary motion. Oscillometry, phase contrast photometry, and recently, computerized microphotometry have been employed to calculate ciliary beat frequency and to rate motility quality and pattern. Electron microscopy should include longitudinal and transverse sections through many axonemes. Grouped sections can be inspected for proper orientation; the axis of orientation of adjacent cilia should not vary by greater than 25 degrees, on average.

Making the diagnosis is important so that genetic counseling can be provided to families, at-risk siblings can be identified, infertility counseling can be provided for male patients, and so that a coherent lifetime treatment plan can be developed. Afzelius argues, and many authors would agree, that electron microscopy is not technically necessary from a clinical standpoint; the diagnosis can be made with the proper history and light microscopic documentation of ciliary dyskinesia.

Treatment of PCD is symptomatic, and is directed against upper and lower respiratory tract complications. If situs inversus is present, it is readily diagnosed by X-ray, and needs no treatment. Antimicrobials are useful in suppressing bacterial colonization and recurrent infection; they need to be administered frequently. New infections need to be identified and treated early. The choice of drugs is based on cultured organisms. PCD patients frequently grow non-typable H. Flu from their respiratory secretions. With time, they become colonized with Staph aureus and Pseudomonas auruginosa. Bronchodiliators are useful in curbing airway reactivity. Physiotherapy and postural drainage are often important adjuncts, and, if started early in life, can sometimes prevent or delay development of bronchiectasis and atelectasis. Surgical resection of ectatic pulmonary segments should only be performed in the face of refractory recurrent pneumonia directly related to the ectatic site. Abstinence from smoking is a vital health factor. Tympanostomy is almost universally required in young PCD patients with recurrent otitis - sometimes multiple times. Endoscopic sinus surgery may be repeatedly necessary, but conservatism is a virtue, since spontaneous remission is common in adult life.

The development of antibiotics has brought the life expectancy of the PCD patient close to or within the normal range, although infant mortality is probably increased. Most PCD patients seem to lead an active life, often with long periods of clinical stability.

In conclusion, primary ciliary dyskinesia is a genetically heterogeneous, recessively inherited defect of ciliary motility, which leads to chronic upper and lower respiratory tract pathology, middle ear disease, and male infertility, along with situs inversus in 50% of cases. Although PCD is uncommon, the otolaryngologist should entertain this diagnosis in any patient with lifelong history of sinus, ear, and respiratory problems. The differential includes CF, immune deficiency, and allergic diathesis. Tests of mucociliary transport can be used to rule out disease, but definitive diagnosis requires mucosal or exam of sperm. Treatment is primarily symptomatic. A degree of surgical conservatism is warranted, since symptoms often improve in adult life. With proper medical care and abstinence from smoking, the prognosis for primary ciliary dyskinesia is quite good.

A 7 1/2-month-old Latin American male was transferred to the Texas Children's Hospital with chronic lung disease, failure to thrive, and newly diagnosed cystic fibrosis. He had been previously hospitalized for one and a half months, where he had required intubation for two weeks for pneumonia and respiratory failure. The patient was a former 34-week premature infant, with past medical history significant for intubation on the tenth day of life for respiratory failure. He had been intubated for one month at that time, and had developed bronchopulmonary dysplasia. He was noted during that stay to have situs inversus totalis.

During his stay at TCH he received two weeks of intravenous antibiotics for pneumonia, along with vigorous pulmonary toilet and nutritional support. The otolaryngology service was consulted to investigate the possibility of Kartagener's syndrome. Left mainstem bronchial brush biopsy was performed under general anesthesia, and light microscopic examination of the specimen revealed immotile cilia. Electron microscopy showed normal ciliary ultrastructure. The patient's pulmonary and nutritional status slowly improved, and he was discharged home after a one-month stay.

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