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Disorders of Ciliary Motility
Disorders of Ciliary Motility MARK J. COWAN, MD; MARK T. GLADWIN, MD; JAMES H. SHELHAMER, MD
ABSTRACT: Clearance of mucus and other debris from the airways is achieved by 3 main mechanisms: mucociliary activity, coughing, and alveolar clearance. Disorders of ciliary structure or function results in impaired clearance, and result in chronic sinopulmonary disease manifested as chronic sinusitis, otitis media, nasal polyposis, and ultimately bronchiectasis. In addition, situs inversus, dextrocardia, and infertility can be associated with dysfunctional ciliary activity. The term primary ciliary dyskinesia has been proposed for the spectrum of these diseases. The term Kartagener syndrome applies to this syndrome when accompanied by infertility and dextrocardia or situs inversus. The more common types of ciliary dysmotility syndromes are characterized by
missing dynein arms, central microtubule pairs, inner sheath, radial spokes, or nexin links. In addition to structural defects within the cilia, disordered ciliary beating and disordered ciliary arrays on epithelial cell surfaces have been described in this syndrome. Treatment includes rigorous lung physiotherapy, prophylactic and organism-specific antibiotics, and immunization against common pulmonary pathogens. Late stages of the disease may require surgical intervention for bronchiectasis or lung transplant for end-stage lung disease. KEY INDEXING TERMS: Kartagener syndrome; Primary ciliary dyskinesia; Cilia; Bronchiectasis. [Am J Med Sci 2001;321(1):3–10.]
C
(with transposition of 1 of the outer pairs of microtubules to the center position)12; absence of outer, inner, or both dynein arms; and absence of the central sheath.13
ase reports of patients with sinusitis, bronchiectasis, and dextrocardia have existed since 1901.1,2 In 1933, M. Kartagener presented a series of 4 patients with this triad of abnormalities, subsequently termed Kartagener syndrome (KS).3 Afzelius first described the ultrastructural anatomy of cilia, beginning with sperm tails in 1959.4 Camner noted the occurrence of chronic respiratory tract disease and absence of mucociliary clearance in the airways of 2 men with immotile spermatozoa.5 That same year, Afzelius and others applied electron microscopic techniques to patients with KS, showing that immotile spermatozoa from patients with KS lacked 1 or both of the dynein arms on the outer microtubules of their cilia.6,7 Male infertility was thus associated with KS, and an important observation had been made that suggested the cause of the syndrome. Soon after, dynein arm ciliary defects were noted in respiratory tract epithelial cells in patients with KS, and these were associated with decreased mucociliary clearance and absent ciliary and sperm motility.8,9 This led to the proposal that the syndrome be named “immotile cilia syndrome.”10 Since that time, other structural ciliary defects have been identified. These include absence of radial spokes11; absence of the central pair of microtubules
From the Department of Critical Care Medicine, National Institutes of Health, Bethesda, Maryland. Correspondence: Mark J. Cowan, M.D., Department of Critical Care Medicine, National Institutes of Health, 10 Center Drive, Building 10/7D43, Bethesda, MD 20892-1662 (E-mail: mc123@ nih.gov). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
By the mid-1980s, it was clear that there is a subgroup of patients who have ciliary activity but do not have effective mucous clearance.14 For example, in 1990, Rutland et al reported a case in which each individual cilium was morphologically normal, but adjacent cilia were oriented randomly instead of in an ordered array. This arrangement does not allow for effective propulsion of mucous along the mucosal surface and results in chronic bronchiectasis.15 Additional observations on the familial pattern of this syndrome of ciliary dyskinesia, beginning with the elevated incidence of the syndrome with consanguinity16,17 and culminating with a study of the inheritance of the syndrome in 46 patients from 36 families,18 have led to the proposal that the syndrome be named primary ciliary dyskinesia (PCD).14 The term PCD denotes all congenital abnormalities of ciliary function, whereas the term KS is reserved for the subgroup of patients with PCD and situs inversus. Normal Mucociliary Transport Clearance of mucus and other debris from the airways is achieved by 3 main mechanisms: mucociliary activity, coughing, and alveolar clearance. Similar mechanisms operate in the upper airway to achieve clearance from the sinuses and nasal passageways. Much of the clearance of the pulmonary 3
Disorders of Ciliary Motility
epithelium from the larynx to the 16th bronchial division is dependent upon ciliary activity.19,20 Ciliated cells cover the mucosal pseudostratified columnar epithelium. Each ciliated cell projects approximately 200 cilia into the airway. These cilia vary in length from 5 to 7 m in the trachea, to 2 to 3 m in the seventh generation of airways. Their diameter is 0.25 to 0.33 m.21 Normal mucociliary function requires an adequate quantity of mucus with appropriate rheological qualities, as well as properly formed and functioning cilia. Mucus clearance rates within the respiratory tract are 4.5 to 7 mm/min in the nasal mucosa,14 and 3.8 to 4.7 mm/ min in the large airways.11 Overall, most debris is normally cleared from the ciliated airways in 6 to 24 hours.22 Normal ciliary beating effects this clearance. This ciliary beat pattern is composed of 3 events. There is the effective stroke, which actually propels the mucous forward. There is then a recovery phase of short duration before the recovery stroke, where the cilium is moved to its start position, but without effective mucous transport in the opposite direction. This cycle occurs at 11 to 16 Hz.21 All of this requires structurally normal cilia with functioning structural and regulatory proteins. Normal Ciliary Ultrastructure and Function There are more than 200 proteins and polypeptides involved in ciliary formation and structure.23 The majority of these are components of a specific axonemal structure that can be visualized by electron microscopy (eg, the microtubule). There are many other proteins that are critically important for ciliary assembly (eg, tubulin-␥), and initiation, orientation, and control of ciliary activity. A comprehensive review of ciliary structure and function is presented in reference 24, and is summarized below. Axonemes, the core of respiratory cilia and sperm tails, are composed of long microtubules, extending from the cytoplasm to the ciliary tip. Microtubules are structured in 3 forms: singlets, doublets, and triplets, and are composed of polymers of tubulin. Tubulin-␣ and - are globular proteins of approximately 450 residues with a diameter of 4 nm. Tubulin-␣ and tubulin- form a heterodimer, 8 nm in length. These heterodimers polymerize in a head-totail fashion to form a protofilament. Microtubules are composed of rings of protofilaments. The number of protofilaments in each type of microtubule is characteristic: 13 in a singlet, 23 in a doublet, and 33 in a triplet (Figure 1). Standard nomenclature of microtubules gives the name A to the microtubule with a complete ring of 13 protofilaments. B and C denote attached microtubules with incomplete rings of 10 protofilaments each. Each mammalian cilium is anchored to a basal body in the cytoplasm near the plasma membrane. 4
Figure 1. Ultrastructural anatomy of the normal cilium. (Adapted from Rutland J, Iongh RU. Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 1990;323:1681– 4. Copyright © 1990 Massachusetts Medical Society; and Lodesh H, Baltimore D, Berk A, Zipursky SL, Matsudaira P, Darnell J. Microtubules and intermediate filaments. In: Molecular cell biology, 3rd ed. New York: W.H. Freeman & Co.; 1995. p. 1051–122. Used with permission from Massachusetts Medical Society.
This structure is composed of 9 triplets of microtubules (as well as other proteins) that continue out of the basal body and into the cilium to form the outer 9 doublets of microtubules in a cilium. At a poorly understood structure called the transition zone, each of the 9 triplet microtubules becomes a doublet. In addition, a central pair of singlet microtubules is formed within the center of the ring of doublets to form the axoneme. The structure of each cilium is characteristic (Figure 1). There is a central pair of typical singlet microtubules, surrounded by 9 pairs of doublets (9 ⫹ 2 pattern). The entire structure is surrounded by a plasma membrane. The axoneme is held together by 4 sets of protein cross-links. A fibrous inner sheath surrounds the central pair of microtubules. The central microtubules are held together by a “ladder” of bridges. Each doublet outer microtubule is held to the adjacent outer doublet microtubule by nexin links. Finally, a series of spokes radiate from the central pair to each A microtubule in the outer ring. January 2001 Volume 321 Number 1
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Table 1. Ciliary Ultrastructural Abnormalities in Primary Ciliary Dyskinesia Absence of inner and outer dynein arms.13 Absence of most dynein arms.25 Absence of outer dynein arms.13 Abnormal dynein arms.26 Absence of inner dynein arms.27 Absence of radial spokes.11 Absence of central microtubules and/or central sheath.13 Absence of nexin links.13 Supernumerary doublets.28 Axoneme absence with a ciliary membrane.29 Complete lack of cilia.30 Elongated cilia.31 Randomly oriented normal cilia.15 Normal ciliary morphology.32
The A microtubules of the outer ring have several associated structures. These are termed inner and outer dynein arms, and are multimers of high-, intermediate-, and low-molecular-mass proteins. The dynein heavy chain possesses ATPase activity and is a 4500-residue amino acid molecule with a molecular weight of 540 kDa. The intermediate and small proteins probably regulate association of dynein with microtubules. Ciliary motility has been shown to occur via ATP hydrolysis by dynein heavy chains, which results in a sliding of the A microtubule relative to the B microtubule. This results in bending of the cilia away from the microtubules that have been deformed. Microtubule pairs on the opposite side of the cilium mediate bending in the other direction. The outer arm dyneins speed the active sliding of the outer doublets but do not produce the bending. The bending occurs at the inner dynein arms. All these factors result in 2 different stroke motions for the cilia: a forward, effective stroke, and a reverse, recovery stroke, thus allowing effective propulsion.24 Pathogenesis of Primary Ciliary Diskinesia Given our knowledge of the inner structure of cilia, it comes as no surprise that defects in most of the visible structures of the cilium result in defective ciliary activity and human disease. A list of the known defects of cilia found in PCD is presented in Table 1 and depicted in Figure 2. Most of these defects will likely relate to mutations in 1 or more of the proteins involved in ciliary genesis or structure. However, the specific genomic mutations remain undefined, and it is known that some environmental insults can also result in defective ciliary transport with altered ciliary morphology (discussed below). Clinical Presentation PCD is generally considered to be an autosomal recessive disorder; however, examples of other geTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 2. Described abnormalities in ciliary structure. See text for details. (Adapted from Sturgess J, Chao J, Wong J, Aspin N, Turner JAP. Cilia with defective radial spokes. N Engl J Med 1979;300:53– 6 and Sturgess J, Chao J, Turner JAP. Transposition of ciliary microtubules. N Engl J Med 1980;303:318. Afzelius BA, Eliasson R. Flagellar mutants in man. J Ultrastruct Res 1979;69:43.
netic patterns abound. One report of an unaffected mother with 5 children with PCD from 3 different biological fathers suggests an X-linked or autosomal dominant mode of inheritance.33 Other reports describe patterns consistent with X-linked, autosomal dominant, and autosomal dominant with incomplete penetrance.33 The prevalence of KS and PCD derive from mass 5
6
2 /2 (100%)
4 /7 (57%) 3 /3 (100%)
/3 (66%) /2 (100%) /2 (100%)
/10 (90%)
10 /10 (100%) 10 /10 (100%) 9 7 /7 (100%) 7 /7 (100%) 3 /3 (100%) 3 /3 (100%) 3 /3 (100%) 2 2 /2 (100%) 1 /2 (50%) 2 /2 (100%) 2 2 /2 (100%) 2 /2 (100%) 2 /10 (40%) /7 (57%) /3 (33%) /2 (0%) /2 (0%) 4 4 1 0 0 /7 /1 /2 /1 /1
b
a
Not evaluated in all patients. Situs totals in 14 of 27 (52%).
3 6 1 1 1 10 28.2 (18–51) 7 33.3 (28–40) 3 18.7 (11–23) 2 17.5 (15,20) 2 20.5 (19,22)
(.9–16)18 /14 (.1–26)15 /15 (.3–54)11 /16 32 7.6 30 11.1 27 20.2
13 /32 (41%) 15 /30 (50%) 16 /27 (59%)b
27 /27 (100%)a
20 /32 (63%) 27 /30 (90%) 13 /30 (43%) 5 /5 (100%)a 26 /27 (96%) 15 /27 (56%)
25 /34 (74%) 9 /34 (26%) 33 /34 (97%) 20 /34 (59%) 26 /34 (76%) 19 /34 (56%) 9 /34 (26%) 32 /34 (94%) (.5–75)18 /16 34 16.3
Sturgess and Turner (1984)41 Escalier et al (1982)27 Nadel et al (1985)42 Pedersen and Stafanger (1983)43 Rossman et al (1980)44 Eliasson et al (1977)10 Sturgess et al (1979)11 Antonelli et al (1983)28 Sturgess et al (1980)12
Otitis media Bronchiectasis Bronchitis Nasal polyps Sinusitis Clubbing Situs Sex M/F Mean age (range) n
Table 2. Clinical Features of Patients with KS in Published Series
radiographic screenings and clinical observations in the pre-electron microscopy era. The Adult Health Study in Hiroshima and Nagasaki involved complete physical examinations and selected radiographic and laboratory tests of 16,566 persons. Four cases of dextrocardia were detected, all with minimal history of radiation exposure, for a prevalence of 1 per 4,100. Bronchiectasis was present in 1 of these 4 patients.34 Earlier studies of hospitalized patients or mass radiographic surveys of large population bases consistently demonstrate prevalence rates of 1:7,000 to 1:13,000, with bronchiectasis occurring in 16 to 23% of cases.35– 40 Pathologic diagnosis of PCD was not made in these studies and many of the cases of bronchiectasis were probably caused by other entities, such as tuberculosis. Nevertheless, an approximate estimate of the prevalence of KS, based on these data, is 1:30,000 to 1:40,000. If 50% of cases of PCD had situs inversus, one could argue that the incidence of PCD would be 1:15,000 to 1:20,000. It deserves emphasis that these data are speculative at best, because PCD is underdiagnosed and our understanding of the disease derives from case series alone. Clinical characteristics of PCD, such as age at presentation, presence of situs inversus, and severity of symptoms, are similarly biased by the inherent difficulty in diagnosing the illness. Appreciating this caveat, clinical features from selected case series and reports (in which a pathologic diagnosis was established) are presented in Table 2. A number of recurrent patterns are observed at the time of diagnosis. PCD is primarily a pediatric disease that is often not diagnosed until a later age. Although the average age of presentation is 16 years, in most cases, the patient has suffered nasal stuffiness and heavy sputum production since early childhood. One report describes a neonate with heavy mucous production at the time of delivery and respiratory distress at 30 minutes of age.45 In this particular case, the observation of dextrocardia led to suspicion and confirmation of KS. Chronically impaired mucociliary clearance leads to severe sinopulmonary disease characterized by chronic sinusitis and otitis media with hearing impairment, nasal polyps, and ultimately bronchiectasis. Patients frequently present with a history of surgeries including sinus surgery (mastoidectomy, turbinectomy, ethmoidectomy, etc), adenotonsillectomy, nasal polypectomy, and lobectomy. The course of PCD is chronic and indolent, with a better prognosis than other causes of bronchiectasis, such as cystic fibrosis. Severe acute inflammatory events, such as pneumonia, are uncommon. In PCD, structural and functional abnormalities of the axoneme in respiratory cilia are usually accompanied by similar abnormalities in that of the sperm tail.41 Although male patients with PCD usually have normal ejaculate volume and sperm
Reduced hearing
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counts, only 0 to 30% of the sperm are motile, with no progressive motility.10,11 Sterility is the rule, although there are case reports of offspring from men with PCD.10,46 Women with PCD have borne children but fertility is reduced, owing to the altered function of fallopian tube cilia.41 Chest radiographs are abnormal in most patients. In a series of 30 patients with PCD, 97% had hyperinflation, 90% had bronchial wall thickening, 63% had segmental volume loss or consolidation, and 43% had segmental bronchiectasis (confirmed by bronchography in half).42 Bronchograms reveal saccular and cylindrical bronchiectasis in most, and 2 of 30 patients had cystic bronchiectasis with air-fluid levels. Parenchymal abnormalities are common (66%) in the middle lobe. Interestingly, 2 patients with situs inversus totalis had this abnormality in the left middle lobe. Although radiographic abnormalities were universal in the previous study, others report normal examinations in a minority (30%), even with serial radiographs.43 Pedersen and Stafanger note that radiographic infiltrates are associated with a deterioration in clinical condition, but are not usually accompanied by clinical signs of pneumonia.43 Pulmonary function testing reveals a mild-to-severe obstructive ventilatory impairment, sometimes associated with air trapping.10,41,43 Mixed obstructive and restrictive abnormalities are also appreciated. Unfortunately, most reports do not describe smoking history. Diagnosis PCD should be considered in the pediatric or adult patient with chronic and intractable sinopulmonary infections. However, other sinopulmonary syndromes, such as cystic fibrosis, common variable immunodeficiency, and Wegener granulomatosis, are either more common or more readily diagnosed than PCD. Unless the patient has associated situs inversus, these alternate causes should be explored before an extensive work-up for PCD. Figure 3 presents a proposed algorithm for the evaluation of suspected PCD. Complete evaluation of PCD includes a thorough clinical evaluation, including the exclusion of other sinopulmonary disorders, ciliary motion analysis, mucociliary transport studies (the saccharin test and whole lung clearance of 99mTc aerosol of human albumin), and confirmation of the diagnosis by electron microscopy of ciliated epithelium from the nasal or bronchial mucosa. Most authors recommend initial screening with ciliary motion analysis and mucociliary transport; if these are positive, examine ciliary ultrastructure by electron microscopy Ciliary motion analysis comprises quantification of ciliary beat frequency and observation of ciliary motion waveform. Because cilia normally beat at 12 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 3. An approach to the evaluation of patients with chronic sinopulmonary disease.
to 14 Hz, this measurement requires either high speed film, high speed video, laser, stroboscopic, or photoelectric systems. A video system with slowand stop-motion capabilities allows for determination of both frequency and waveform.47 A cytology brush is used to scrape the nasal mucosa between the inferior turbinate and lateral nasal wall. The cells are washed off the brush into 2 mL of culture media, transferred to slides, and incubated for study at 37°C.47,48 Patients with PCD have a reduced ciliary beat frequency (mean of approximately 8 Hz) and dyskinetic waveforms characterized by uncoordinated, vibrational, rotary, or diminished movements, rather than the normal back-and-forth bending movement.47–50 Normal, coordinated ciliary beating moves a ladder of mucus from the nasal turbinates posteriorly into the nasopharynx and from the bronchi upward into the oral pharynx. Saccharine placed on the anterior end of the inferior nasal turbinate is carried posteriorly until it reaches the tongue and is tasted. It takes 10 to 20 minutes for a normal person to taste the sweet saccharine and more than 60 minutes for patients with PCD. Patients with cystic fibrosis and bronchiectasis have mean nasal clearance times of 30 minutes.49 This test is simple to perform, inexpensive, and sensitive for the diagnosis 7
Disorders of Ciliary Motility
of PCD; unfortunately, it is not highly specific and should be used only as a screening test.47,49,51 Mucociliary transport can also be assessed by clearance of radioisotope. 99mTc-labeled albumin is placed on the inferior turbinate and viewed by scintigraphy. The droplet will not move in patients with PCD.47 Alternatively, radiolabeled albumin in a saline aerosol is inhaled and whole lung clearance evaluated by scintillation camera. The albumin forms aggregates in the large airways and rates of clearance are quantified with the patient in the supine position. In patients with PCD, the mean tracheal transport rate is zero, whereas in unaffected siblings, it is 3.8 to 4.7 mm/min.11 In a similar technique, 99mTc-labeled Teflon particles are inhaled and clearance is measured over 2 hours. Healthy nonsmokers retain only 29 to 42% of the isotope, whereas patients with PCD have 73 to 99% retention10 Interestingly, coughing will effectively remove the particles and must be avoided during the study. Patients with bronchitis, bronchiectasis from other causes, and chronic obstructive lung disease will also have impaired clearance, which limits the specificity of the study.52,53 In the patient with abnormal ciliary motion and impaired mucociliary clearance, a detailed study of the axonemal ultrastructure, with transmission electron microscope (TEM), is helpful in establishing the diagnosis of PCD. Ciliated epithelium is obtained by scraping the nasal mucosa at the level of the inferior turbinate. This tissue is attached to lens paper, fixed with 2.5% glutaraldehyde, and processed for TEM, as described elsewhere.47,54,55 Tracheal or bronchial epithelium obtained by bronchoscopy and sperm may also be examined. A number of caveats concerning TEM interpretation must be stressed. Importantly, samples must be taken at least 10 weeks after upper respiratory viral illness because central or peripheral axonemal additions and deletions occur after these infections. Dyneinarm or radial-spoke deficiencies, transpositions, and compound cilia were not observed after viral infection.56 Other authors have described abnormalities in ciliary orientation during respiratory infection,57 and compounding of nasal epithelial cilia after exposure to sulfur dioxide.58 Rigorous quantitative determination of the number of inner and outer dynein arms, nexin links, radial spokes, orientation of the ciliary beating axis, abnormal microtubule configuration, and compound cilia should identify patients with PCD.55–57,59 However, cases of PCD with normal ciliary ultrastructure have been described.55,57 Treatment and Prognosis Treatment for PCD is the same as that for bronchiectasis from other causes: antibiotics, lung physiotherapy, and vaccination against influenza viruses, Streptococcus pneumoniae, and Haemophilus 8
influenzae. Few studies have examined the impact of antibiotics and lung physiotherapy on objective outcomes in PCD. Pedersen and Stafanger43 followed peak expiratory flow rate and forced vital capacity in 22 patients during treatment with prophylactic antibiotics and lung physiotherapy. Peak expiratory flow rate increased from 64% of predicted normal to 82% and forced vital capacity increased from 79% to 92%, over a median follow-up period of 3.5 years. Patients had fewer bronchitic exacerbations with this prophylactic therapy. However, forced expiratory volume in 1 second did not change and a control group improved without prophylactic therapy. Once bronchiectasis develops, symptomatic relief is achieved with culture-directed antibiotic therapy. H influenzae is the most frequently isolated organism (58% of positive cultures) followed by S pneumoniae (21%), Staphylococcus aureus (19%), Pseudomonas aeruginosa (14%), Escherichia coli (10%), and other Streptococcus species (1%).43 Antibiotics can be given in cycles, continuously, or only during exacerbations; trials to establish a superior strategy are lacking. Although surgical therapy for chronic sinusitis is often indicated, lobectomy for intractable bronchiectasis is rarely needed in the antibiotic era and must be considered on a case-by-case basis. Lung transplantation has been performed for end-stage disease and the technical difficulties posed by the anastomosis of normal lung and inverted recipient bronchi are described elsewhere.60,61 Patients with PCD are less ill than patients with cystic fibrosis and are less often colonized with P aeruginosa. Only 3 of the 27 patients followed by Pedersen and Stafanger43 had disabling lung disease and a full half of the patients were able to appreciate a normal life. Life expectancy can be normal depending on the severity of bronchiectasis.62,63 It is to be hoped that prevention or delay of the progression of bronchiectasis with targeted antibiotic therapy and aggressive medical care will improve the life expectancy further, as it has for patients with cystic fibrosis.25–32,44 References 1. Oeri R. Bronchiectasis in situs inversus. Frankfurter Zeitschrift fur Pathologie 1901;3:393– 8. 2. Siewert AK. Ueber einem Fall von Bronchiektasie bei einem Patienten mit Situs inversus viscerum. Berl Klin Wchnschr 1904;41:139. 3. Kartagener M. Zur Pathologie der Bronchiektasien: Bronchiektasien bei Situs viscerum inversus. Beitr Klin Tuberk 1933;83:489 –501. 4. Afzelius B. Electron microscopy of the sperm tail: Results obtained with a new fixative. J Biophysic Biochem 1959;5: 269 –78. 5. Camner P, Mossberg B, Afzelius BA. Evidence for congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects. Am Rev Respir Dis 1975;112:807–9.
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6. Afzelius BA, Eliasson R, Johnsen O, et al. Lack of dynein arms in immotile human spermatoza. J Cell Biol 1975;66: 225–32. 7. Pedersen H, Rebbe H. Absence of arms in the axoneme of immobile human spermatozoa. Biol Reprod 1975;12:541– 4. 8. Afzelius BA. A human syndrome caused by immotile cilia. Science 1976;183:317–9. 9. Pedersen J, Mygind N. Absence of axonemal arms in nasal mucosa cilia in Kartagener’s syndrome [letter]. Nature 1976; 262:494 –5. 10. Eliasson R, Mossberg B, Camner P, et al. The immotilecilia syndrome: A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N Engl J Med 1977;297:1– 6. 11. Sturgess J, Chao J, Wong J, et al. Cilia with defective radial spokes. N Engl J Med 1979;300:53– 6. 12. Sturgess J, Chao J, Turner JAP. Transposition of ciliary microtubules. N Engl J Med 1980;303:318. 13. Afzelius BA, Eliasson R. Flagellar mutants in man. J Ultrastruct Res 1979;69:43. 14. Van der Baan S, Veerman AJP, Wulffraat N, et al. Primary ciliary dyskinesia: ciliary activity. Acta Otolaryngol 1986;102:274 – 81. 15. Rutland J, Iongh RU. Random ciliary orientation: A cause of respiratory tract disease. N Engl J Med 1990;323:1681– 4. 16. Cockayne EA. The genetics of transposition of the viscera. Q J Med 1938;31:479 –93. 17. Torgersen J. Genic factors in visceral asymmetry and in the development and pathologic changes of lungs, heart and abdominal organs. Arch Pathol 1949;47:566 –93. 18. Sturgess JM, Thompson MW, Czegledy-Nagy E, et al. Genetic aspects of immotile cilia syndrome. Am J Med Genet 1986;25:149 – 60. 19. Weibel ER. Morphometry of the human lung. Berlin: Springer-Verlag; 1963. 20. Pavia D. Lung mucociliary clearance. In: Clarke SW, Pavia D, editors. Aerosols and the lung: clinical and experimental aspects. London: Butterworth; 1984. p. 127. 21. Clarke SW. Rationale of airway clearance. Eur Respir J 1989;2(Suppl 7):599s– 604s. 22. Pavia D, Bateman JRM, Clarke SW. Deposition and clearance of inhaled particles. Bull Eur Physiopathol Respir 1980; 16:335. 23. Afzelius BA. The immotile-cilia syndrome: a microtubuleassociated defect. CRC Crit Rev Biochem 1985;19:63– 81. 24. Lodesh H, Baltimore D, Berk A, et al. Microtubules and intermediate filaments. In: Molecular Cell Biology, 3rd ed. New York: W.H. Freeman & Co.; 1995. p. 1051–122. 25. White BL, Catlin FI, Stenback WA, et al. The immotile cilia syndrome: one cause of persistent upper respiratory tract infection. Int J Pediatr Otorhinolaryngol 1980;2:337– 46. 26. Woodring JH, Royer JM, McDonagh D. Kartagenener’s syndrome. JAMA 1982;247:2814 – 6. 27. Escalier D, Jouannet P, David G. Abnormalities of the ciliary axonemal complex in children: an ultrastructural and kinetic study in a series of 34 cases. Biol Cell 1982;44:271– 82. 28. Antonelli M, Modesti A, Quattrucci S, et al. Supernumerary microtubules in the cilia of two siblings causing “immotile cilia syndrome.” Eur J Respir Dis 1983;64:607–12. 29. Baccetti B, Burrini AG, Pallini V. Spermatozoa and cilia lacking axoneme in an infertile man. Andrologia 1980;12: 525–32. 30. Jahrsdoerfer R, Feldman PS, Rubel EW, et al. Otitis media and the immotile cilia syndrome. Laryngoscope 1979; 89:769 –78.
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31. Afzelius BA, Gargani G, Romano C. Abnormal length of cilia as a cause of defective mucociliary clearance. Eur J Resp Dis 1985;66:173– 80. 32. Hendry WF, Whitfield HN, Stansfeld AG, et al. Defects in Young’s syndrome and Kartagener’s syndrome. Lancet 1978; ii:1152. 33. Narayan D, Krishnan SN, Upender M, et al. Unusual inheritance of primary ciliary dyskinesia (Kartagener’s syndrome). J Med Genet 1994;31:493– 6. 34. Katsuhara K, Kawamoto S, Wakabayashi T, et al. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest 1972;61:56 – 61. 35. Adams R, Churchill ED. Situs inversus, sinusitis, bronchiectasis. J Thorac Surg 1937;7:206. 36. Torgersen J. Genetic factors in asymmetry and in the development and pathological changes of lungs, heart, and abdominal organs. Arch Path 1949;47:566 –93. 37. Olsen AM. Bronchiectasis and dextrocardia: observations on etiology of bronchiectasis. Am Rev Tuberc 1943;47:435. 38. Lowe CR, McKeown T. An investigation of dextrocardia with and without transposition of abdominal viscera, with a report of a case in one monozygotic twin. Ann Eugen 1954; 18:267. 39. Gould DM. Nontuberculous lesions found in mass x-ray surveys. JAMA 1945;753:127. 40. Caplan SM. Dextrocardia with situs inversus. Report of eight cases with a review of the literature on dextrocardia. Navy Med Bull 1946;46:1011. 41. Sturgess JM, Turner JA. Ultrastructural pathology of cilia in the immotile cilia syndrome. Perspect Pediatr Pathol 1984; 8:133– 61. 42. Nadel HR, Stringer DA, Levinson H, et al. The immotile cilia syndrome: Radiologic manifestations. Radiology 1985; 154:651–5. 43. Pedersen M, Stafanger G. Bronchopulmonary symptoms in primary ciliary dyskinesia. A clinical study of 27 patients. Eur J Respir Dis 1983;64:118 –28. 44. Rossman CM, Forrest JB, Ruffin RE, et al. Immotile cilia syndrome in persons with and without Kartagener’s syndrome. Am Rev Respir Dis 1980;121:1011– 6. 45. Losa M, Ghelfi D, Hof E. Kartagener syndrome: an uncommon cause of neonatal respiratory distress? Eur J Pediatr 1995;154:236 – 8. 46. Rott HD. Kartagener’s syndrome and the syndrome of immotile cilia. Hum Genet 1979;46:249 – 61. 47. Rossman CM, Newhouse MT. Primary ciliary dyskinesia: evaluation and management. Pediatr Pulmonol 1988;5:36 – 50. 48. Rutland J, Cole PJ. Non-invasive sampling of nasal cilia for measurement of beat frequency and study of ultrastructure. Lancet 1980;ii:564 –5. 49. Rutland J, Cole PJ. Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis. Thorax 1981;36:654 – 8. 50. Rossman CM, Forrest JB, Lee RM, et al. The dyskinetic cilia syndrome. Ciliary motility in immotile cilia syndrome. Chest 1980;78:580 –2. 51. Stanley P, MacWilliam L, Greenstone M, et al. Efficacy of a saccharin test for screening to detect abnormal mucociliary clearance. Br J Dis Chest 1984;78:62–5. 52. Camner P, Mossberg B, Philipson K. Tracheobronchial clearance and chronic obstructive lung disease. Scan J Respir Dis 1973;54:272– 81. 53. Lourenco RV, Loddenkemper R, Carton RW. Patterns of distribution and clearance of aerosols in patients with bronchiectasis. Am Rev Respir Dis 1972;106:857– 66.
9
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54. Rossman CM, Lee RMKW, Forrest JB, et al. Nasal ciliary ultrastructure and function in patients with primary ciliary dyskinesia compared with that in normal subjects and in subjects with various respiratory diseases. Am Rev Respir Dis 1984;129:161–7. 55. Nielsen MH, Pedersen M, Christensen B, et al. Blind quantitative electron microscopy of cilia from patients with primary ciliary dyskinesia and from normal subjects. Eur J Respir Dis 1983;64:19 –30. 56. Carson JL, Collier AM, Hu SCS. Acquired ciliary defects in nasal epithelium of children with acute viral upper respiratory infections. N Engl J Med 1985;312:463– 8. 57. Van Der Ban S, Bezemer PD, Veerman AJP, et al. Primary ciliary dyskinesia: quantitative investigation of the ciliary ultrastructure with statistical analysis. Ann Otol Rhinol Laryngol 1987;96:264 –72. 58. Carson JL, Collier AM, Hu SC, et al. The appearance of compound cilia in the nasal mucosa of normal human sub-
10
59.
60.
61.
62.
63.
jects following acute, in vivo exposure to sulfur dioxide. Environ Res 1987;42:155– 65. Teknos TN, Metson R, Chasse T, et al. New developments in the diagnosis of Kartagener’s syndrome. Otolaryngol Head Neck Surg 1997;116:68 –74. Macchiarini P, Chapelier A, Vouhe P, et al. Double lung transplantation in situs inversus with Kartagener’s syndrome. J Thorac Cardiovasc Surg 1994;108:86 –91. Graeter T, Schafers HJ, Wahlers T, et al. Lung transplantation in Kartagener’s syndrome. J Heart Lung Transplant 1994;13:724 – 6. Kollberg H, Mossberg B, Afzelius B, et al. Cystic fibrosis compared with the immotile-cilia syndrome. A study of mucociliary clearance, ciliary ultrastructure, clinical picture and ventilatory function. Scand J Respir Dis 1978;59:297–306. Rossman CM, Newhouse MT. Primary ciliary dyskinesia: Evaluation and management. Pediatr Pulmonol 1988;5:36 – 50.
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ABSTRACT: Clearance of mucus and other debris from the airways is achieved by 3 main mechanisms: mucociliary activity, coughing, and alveolar clearance. Disorders of ciliary structure or function results in impaired clearance, and result in chronic sinopulmonary disease manifested as chronic sinusitis, otitis media, nasal polyposis, and ultimately bronchiectasis. In addition, situs inversus, dextrocardia, and infertility can be associated with dysfunctional ciliary activity. The term primary ciliary dyskinesia has been proposed for the spectrum of these diseases. The term Kartagener syndrome applies to this syndrome when accompanied by infertility and dextrocardia or situs inversus. The more common types of ciliary dysmotility syndromes are characterized by
missing dynein arms, central microtubule pairs, inner sheath, radial spokes, or nexin links. In addition to structural defects within the cilia, disordered ciliary beating and disordered ciliary arrays on epithelial cell surfaces have been described in this syndrome. Treatment includes rigorous lung physiotherapy, prophylactic and organism-specific antibiotics, and immunization against common pulmonary pathogens. Late stages of the disease may require surgical intervention for bronchiectasis or lung transplant for end-stage lung disease. KEY INDEXING TERMS: Kartagener syndrome; Primary ciliary dyskinesia; Cilia; Bronchiectasis. [Am J Med Sci 2001;321(1):3–10.]
C
(with transposition of 1 of the outer pairs of microtubules to the center position)12; absence of outer, inner, or both dynein arms; and absence of the central sheath.13
ase reports of patients with sinusitis, bronchiectasis, and dextrocardia have existed since 1901.1,2 In 1933, M. Kartagener presented a series of 4 patients with this triad of abnormalities, subsequently termed Kartagener syndrome (KS).3 Afzelius first described the ultrastructural anatomy of cilia, beginning with sperm tails in 1959.4 Camner noted the occurrence of chronic respiratory tract disease and absence of mucociliary clearance in the airways of 2 men with immotile spermatozoa.5 That same year, Afzelius and others applied electron microscopic techniques to patients with KS, showing that immotile spermatozoa from patients with KS lacked 1 or both of the dynein arms on the outer microtubules of their cilia.6,7 Male infertility was thus associated with KS, and an important observation had been made that suggested the cause of the syndrome. Soon after, dynein arm ciliary defects were noted in respiratory tract epithelial cells in patients with KS, and these were associated with decreased mucociliary clearance and absent ciliary and sperm motility.8,9 This led to the proposal that the syndrome be named “immotile cilia syndrome.”10 Since that time, other structural ciliary defects have been identified. These include absence of radial spokes11; absence of the central pair of microtubules
From the Department of Critical Care Medicine, National Institutes of Health, Bethesda, Maryland. Correspondence: Mark J. Cowan, M.D., Department of Critical Care Medicine, National Institutes of Health, 10 Center Drive, Building 10/7D43, Bethesda, MD 20892-1662 (E-mail: mc123@ nih.gov). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
By the mid-1980s, it was clear that there is a subgroup of patients who have ciliary activity but do not have effective mucous clearance.14 For example, in 1990, Rutland et al reported a case in which each individual cilium was morphologically normal, but adjacent cilia were oriented randomly instead of in an ordered array. This arrangement does not allow for effective propulsion of mucous along the mucosal surface and results in chronic bronchiectasis.15 Additional observations on the familial pattern of this syndrome of ciliary dyskinesia, beginning with the elevated incidence of the syndrome with consanguinity16,17 and culminating with a study of the inheritance of the syndrome in 46 patients from 36 families,18 have led to the proposal that the syndrome be named primary ciliary dyskinesia (PCD).14 The term PCD denotes all congenital abnormalities of ciliary function, whereas the term KS is reserved for the subgroup of patients with PCD and situs inversus. Normal Mucociliary Transport Clearance of mucus and other debris from the airways is achieved by 3 main mechanisms: mucociliary activity, coughing, and alveolar clearance. Similar mechanisms operate in the upper airway to achieve clearance from the sinuses and nasal passageways. Much of the clearance of the pulmonary 3
Disorders of Ciliary Motility
epithelium from the larynx to the 16th bronchial division is dependent upon ciliary activity.19,20 Ciliated cells cover the mucosal pseudostratified columnar epithelium. Each ciliated cell projects approximately 200 cilia into the airway. These cilia vary in length from 5 to 7 m in the trachea, to 2 to 3 m in the seventh generation of airways. Their diameter is 0.25 to 0.33 m.21 Normal mucociliary function requires an adequate quantity of mucus with appropriate rheological qualities, as well as properly formed and functioning cilia. Mucus clearance rates within the respiratory tract are 4.5 to 7 mm/min in the nasal mucosa,14 and 3.8 to 4.7 mm/ min in the large airways.11 Overall, most debris is normally cleared from the ciliated airways in 6 to 24 hours.22 Normal ciliary beating effects this clearance. This ciliary beat pattern is composed of 3 events. There is the effective stroke, which actually propels the mucous forward. There is then a recovery phase of short duration before the recovery stroke, where the cilium is moved to its start position, but without effective mucous transport in the opposite direction. This cycle occurs at 11 to 16 Hz.21 All of this requires structurally normal cilia with functioning structural and regulatory proteins. Normal Ciliary Ultrastructure and Function There are more than 200 proteins and polypeptides involved in ciliary formation and structure.23 The majority of these are components of a specific axonemal structure that can be visualized by electron microscopy (eg, the microtubule). There are many other proteins that are critically important for ciliary assembly (eg, tubulin-␥), and initiation, orientation, and control of ciliary activity. A comprehensive review of ciliary structure and function is presented in reference 24, and is summarized below. Axonemes, the core of respiratory cilia and sperm tails, are composed of long microtubules, extending from the cytoplasm to the ciliary tip. Microtubules are structured in 3 forms: singlets, doublets, and triplets, and are composed of polymers of tubulin. Tubulin-␣ and - are globular proteins of approximately 450 residues with a diameter of 4 nm. Tubulin-␣ and tubulin- form a heterodimer, 8 nm in length. These heterodimers polymerize in a head-totail fashion to form a protofilament. Microtubules are composed of rings of protofilaments. The number of protofilaments in each type of microtubule is characteristic: 13 in a singlet, 23 in a doublet, and 33 in a triplet (Figure 1). Standard nomenclature of microtubules gives the name A to the microtubule with a complete ring of 13 protofilaments. B and C denote attached microtubules with incomplete rings of 10 protofilaments each. Each mammalian cilium is anchored to a basal body in the cytoplasm near the plasma membrane. 4
Figure 1. Ultrastructural anatomy of the normal cilium. (Adapted from Rutland J, Iongh RU. Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 1990;323:1681– 4. Copyright © 1990 Massachusetts Medical Society; and Lodesh H, Baltimore D, Berk A, Zipursky SL, Matsudaira P, Darnell J. Microtubules and intermediate filaments. In: Molecular cell biology, 3rd ed. New York: W.H. Freeman & Co.; 1995. p. 1051–122. Used with permission from Massachusetts Medical Society.
This structure is composed of 9 triplets of microtubules (as well as other proteins) that continue out of the basal body and into the cilium to form the outer 9 doublets of microtubules in a cilium. At a poorly understood structure called the transition zone, each of the 9 triplet microtubules becomes a doublet. In addition, a central pair of singlet microtubules is formed within the center of the ring of doublets to form the axoneme. The structure of each cilium is characteristic (Figure 1). There is a central pair of typical singlet microtubules, surrounded by 9 pairs of doublets (9 ⫹ 2 pattern). The entire structure is surrounded by a plasma membrane. The axoneme is held together by 4 sets of protein cross-links. A fibrous inner sheath surrounds the central pair of microtubules. The central microtubules are held together by a “ladder” of bridges. Each doublet outer microtubule is held to the adjacent outer doublet microtubule by nexin links. Finally, a series of spokes radiate from the central pair to each A microtubule in the outer ring. January 2001 Volume 321 Number 1
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Table 1. Ciliary Ultrastructural Abnormalities in Primary Ciliary Dyskinesia Absence of inner and outer dynein arms.13 Absence of most dynein arms.25 Absence of outer dynein arms.13 Abnormal dynein arms.26 Absence of inner dynein arms.27 Absence of radial spokes.11 Absence of central microtubules and/or central sheath.13 Absence of nexin links.13 Supernumerary doublets.28 Axoneme absence with a ciliary membrane.29 Complete lack of cilia.30 Elongated cilia.31 Randomly oriented normal cilia.15 Normal ciliary morphology.32
The A microtubules of the outer ring have several associated structures. These are termed inner and outer dynein arms, and are multimers of high-, intermediate-, and low-molecular-mass proteins. The dynein heavy chain possesses ATPase activity and is a 4500-residue amino acid molecule with a molecular weight of 540 kDa. The intermediate and small proteins probably regulate association of dynein with microtubules. Ciliary motility has been shown to occur via ATP hydrolysis by dynein heavy chains, which results in a sliding of the A microtubule relative to the B microtubule. This results in bending of the cilia away from the microtubules that have been deformed. Microtubule pairs on the opposite side of the cilium mediate bending in the other direction. The outer arm dyneins speed the active sliding of the outer doublets but do not produce the bending. The bending occurs at the inner dynein arms. All these factors result in 2 different stroke motions for the cilia: a forward, effective stroke, and a reverse, recovery stroke, thus allowing effective propulsion.24 Pathogenesis of Primary Ciliary Diskinesia Given our knowledge of the inner structure of cilia, it comes as no surprise that defects in most of the visible structures of the cilium result in defective ciliary activity and human disease. A list of the known defects of cilia found in PCD is presented in Table 1 and depicted in Figure 2. Most of these defects will likely relate to mutations in 1 or more of the proteins involved in ciliary genesis or structure. However, the specific genomic mutations remain undefined, and it is known that some environmental insults can also result in defective ciliary transport with altered ciliary morphology (discussed below). Clinical Presentation PCD is generally considered to be an autosomal recessive disorder; however, examples of other geTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 2. Described abnormalities in ciliary structure. See text for details. (Adapted from Sturgess J, Chao J, Wong J, Aspin N, Turner JAP. Cilia with defective radial spokes. N Engl J Med 1979;300:53– 6 and Sturgess J, Chao J, Turner JAP. Transposition of ciliary microtubules. N Engl J Med 1980;303:318. Afzelius BA, Eliasson R. Flagellar mutants in man. J Ultrastruct Res 1979;69:43.
netic patterns abound. One report of an unaffected mother with 5 children with PCD from 3 different biological fathers suggests an X-linked or autosomal dominant mode of inheritance.33 Other reports describe patterns consistent with X-linked, autosomal dominant, and autosomal dominant with incomplete penetrance.33 The prevalence of KS and PCD derive from mass 5
6
2 /2 (100%)
4 /7 (57%) 3 /3 (100%)
/3 (66%) /2 (100%) /2 (100%)
/10 (90%)
10 /10 (100%) 10 /10 (100%) 9 7 /7 (100%) 7 /7 (100%) 3 /3 (100%) 3 /3 (100%) 3 /3 (100%) 2 2 /2 (100%) 1 /2 (50%) 2 /2 (100%) 2 2 /2 (100%) 2 /2 (100%) 2 /10 (40%) /7 (57%) /3 (33%) /2 (0%) /2 (0%) 4 4 1 0 0 /7 /1 /2 /1 /1
b
a
Not evaluated in all patients. Situs totals in 14 of 27 (52%).
3 6 1 1 1 10 28.2 (18–51) 7 33.3 (28–40) 3 18.7 (11–23) 2 17.5 (15,20) 2 20.5 (19,22)
(.9–16)18 /14 (.1–26)15 /15 (.3–54)11 /16 32 7.6 30 11.1 27 20.2
13 /32 (41%) 15 /30 (50%) 16 /27 (59%)b
27 /27 (100%)a
20 /32 (63%) 27 /30 (90%) 13 /30 (43%) 5 /5 (100%)a 26 /27 (96%) 15 /27 (56%)
25 /34 (74%) 9 /34 (26%) 33 /34 (97%) 20 /34 (59%) 26 /34 (76%) 19 /34 (56%) 9 /34 (26%) 32 /34 (94%) (.5–75)18 /16 34 16.3
Sturgess and Turner (1984)41 Escalier et al (1982)27 Nadel et al (1985)42 Pedersen and Stafanger (1983)43 Rossman et al (1980)44 Eliasson et al (1977)10 Sturgess et al (1979)11 Antonelli et al (1983)28 Sturgess et al (1980)12
Otitis media Bronchiectasis Bronchitis Nasal polyps Sinusitis Clubbing Situs Sex M/F Mean age (range) n
Table 2. Clinical Features of Patients with KS in Published Series
radiographic screenings and clinical observations in the pre-electron microscopy era. The Adult Health Study in Hiroshima and Nagasaki involved complete physical examinations and selected radiographic and laboratory tests of 16,566 persons. Four cases of dextrocardia were detected, all with minimal history of radiation exposure, for a prevalence of 1 per 4,100. Bronchiectasis was present in 1 of these 4 patients.34 Earlier studies of hospitalized patients or mass radiographic surveys of large population bases consistently demonstrate prevalence rates of 1:7,000 to 1:13,000, with bronchiectasis occurring in 16 to 23% of cases.35– 40 Pathologic diagnosis of PCD was not made in these studies and many of the cases of bronchiectasis were probably caused by other entities, such as tuberculosis. Nevertheless, an approximate estimate of the prevalence of KS, based on these data, is 1:30,000 to 1:40,000. If 50% of cases of PCD had situs inversus, one could argue that the incidence of PCD would be 1:15,000 to 1:20,000. It deserves emphasis that these data are speculative at best, because PCD is underdiagnosed and our understanding of the disease derives from case series alone. Clinical characteristics of PCD, such as age at presentation, presence of situs inversus, and severity of symptoms, are similarly biased by the inherent difficulty in diagnosing the illness. Appreciating this caveat, clinical features from selected case series and reports (in which a pathologic diagnosis was established) are presented in Table 2. A number of recurrent patterns are observed at the time of diagnosis. PCD is primarily a pediatric disease that is often not diagnosed until a later age. Although the average age of presentation is 16 years, in most cases, the patient has suffered nasal stuffiness and heavy sputum production since early childhood. One report describes a neonate with heavy mucous production at the time of delivery and respiratory distress at 30 minutes of age.45 In this particular case, the observation of dextrocardia led to suspicion and confirmation of KS. Chronically impaired mucociliary clearance leads to severe sinopulmonary disease characterized by chronic sinusitis and otitis media with hearing impairment, nasal polyps, and ultimately bronchiectasis. Patients frequently present with a history of surgeries including sinus surgery (mastoidectomy, turbinectomy, ethmoidectomy, etc), adenotonsillectomy, nasal polypectomy, and lobectomy. The course of PCD is chronic and indolent, with a better prognosis than other causes of bronchiectasis, such as cystic fibrosis. Severe acute inflammatory events, such as pneumonia, are uncommon. In PCD, structural and functional abnormalities of the axoneme in respiratory cilia are usually accompanied by similar abnormalities in that of the sperm tail.41 Although male patients with PCD usually have normal ejaculate volume and sperm
Reduced hearing
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counts, only 0 to 30% of the sperm are motile, with no progressive motility.10,11 Sterility is the rule, although there are case reports of offspring from men with PCD.10,46 Women with PCD have borne children but fertility is reduced, owing to the altered function of fallopian tube cilia.41 Chest radiographs are abnormal in most patients. In a series of 30 patients with PCD, 97% had hyperinflation, 90% had bronchial wall thickening, 63% had segmental volume loss or consolidation, and 43% had segmental bronchiectasis (confirmed by bronchography in half).42 Bronchograms reveal saccular and cylindrical bronchiectasis in most, and 2 of 30 patients had cystic bronchiectasis with air-fluid levels. Parenchymal abnormalities are common (66%) in the middle lobe. Interestingly, 2 patients with situs inversus totalis had this abnormality in the left middle lobe. Although radiographic abnormalities were universal in the previous study, others report normal examinations in a minority (30%), even with serial radiographs.43 Pedersen and Stafanger note that radiographic infiltrates are associated with a deterioration in clinical condition, but are not usually accompanied by clinical signs of pneumonia.43 Pulmonary function testing reveals a mild-to-severe obstructive ventilatory impairment, sometimes associated with air trapping.10,41,43 Mixed obstructive and restrictive abnormalities are also appreciated. Unfortunately, most reports do not describe smoking history. Diagnosis PCD should be considered in the pediatric or adult patient with chronic and intractable sinopulmonary infections. However, other sinopulmonary syndromes, such as cystic fibrosis, common variable immunodeficiency, and Wegener granulomatosis, are either more common or more readily diagnosed than PCD. Unless the patient has associated situs inversus, these alternate causes should be explored before an extensive work-up for PCD. Figure 3 presents a proposed algorithm for the evaluation of suspected PCD. Complete evaluation of PCD includes a thorough clinical evaluation, including the exclusion of other sinopulmonary disorders, ciliary motion analysis, mucociliary transport studies (the saccharin test and whole lung clearance of 99mTc aerosol of human albumin), and confirmation of the diagnosis by electron microscopy of ciliated epithelium from the nasal or bronchial mucosa. Most authors recommend initial screening with ciliary motion analysis and mucociliary transport; if these are positive, examine ciliary ultrastructure by electron microscopy Ciliary motion analysis comprises quantification of ciliary beat frequency and observation of ciliary motion waveform. Because cilia normally beat at 12 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 3. An approach to the evaluation of patients with chronic sinopulmonary disease.
to 14 Hz, this measurement requires either high speed film, high speed video, laser, stroboscopic, or photoelectric systems. A video system with slowand stop-motion capabilities allows for determination of both frequency and waveform.47 A cytology brush is used to scrape the nasal mucosa between the inferior turbinate and lateral nasal wall. The cells are washed off the brush into 2 mL of culture media, transferred to slides, and incubated for study at 37°C.47,48 Patients with PCD have a reduced ciliary beat frequency (mean of approximately 8 Hz) and dyskinetic waveforms characterized by uncoordinated, vibrational, rotary, or diminished movements, rather than the normal back-and-forth bending movement.47–50 Normal, coordinated ciliary beating moves a ladder of mucus from the nasal turbinates posteriorly into the nasopharynx and from the bronchi upward into the oral pharynx. Saccharine placed on the anterior end of the inferior nasal turbinate is carried posteriorly until it reaches the tongue and is tasted. It takes 10 to 20 minutes for a normal person to taste the sweet saccharine and more than 60 minutes for patients with PCD. Patients with cystic fibrosis and bronchiectasis have mean nasal clearance times of 30 minutes.49 This test is simple to perform, inexpensive, and sensitive for the diagnosis 7
Disorders of Ciliary Motility
of PCD; unfortunately, it is not highly specific and should be used only as a screening test.47,49,51 Mucociliary transport can also be assessed by clearance of radioisotope. 99mTc-labeled albumin is placed on the inferior turbinate and viewed by scintigraphy. The droplet will not move in patients with PCD.47 Alternatively, radiolabeled albumin in a saline aerosol is inhaled and whole lung clearance evaluated by scintillation camera. The albumin forms aggregates in the large airways and rates of clearance are quantified with the patient in the supine position. In patients with PCD, the mean tracheal transport rate is zero, whereas in unaffected siblings, it is 3.8 to 4.7 mm/min.11 In a similar technique, 99mTc-labeled Teflon particles are inhaled and clearance is measured over 2 hours. Healthy nonsmokers retain only 29 to 42% of the isotope, whereas patients with PCD have 73 to 99% retention10 Interestingly, coughing will effectively remove the particles and must be avoided during the study. Patients with bronchitis, bronchiectasis from other causes, and chronic obstructive lung disease will also have impaired clearance, which limits the specificity of the study.52,53 In the patient with abnormal ciliary motion and impaired mucociliary clearance, a detailed study of the axonemal ultrastructure, with transmission electron microscope (TEM), is helpful in establishing the diagnosis of PCD. Ciliated epithelium is obtained by scraping the nasal mucosa at the level of the inferior turbinate. This tissue is attached to lens paper, fixed with 2.5% glutaraldehyde, and processed for TEM, as described elsewhere.47,54,55 Tracheal or bronchial epithelium obtained by bronchoscopy and sperm may also be examined. A number of caveats concerning TEM interpretation must be stressed. Importantly, samples must be taken at least 10 weeks after upper respiratory viral illness because central or peripheral axonemal additions and deletions occur after these infections. Dyneinarm or radial-spoke deficiencies, transpositions, and compound cilia were not observed after viral infection.56 Other authors have described abnormalities in ciliary orientation during respiratory infection,57 and compounding of nasal epithelial cilia after exposure to sulfur dioxide.58 Rigorous quantitative determination of the number of inner and outer dynein arms, nexin links, radial spokes, orientation of the ciliary beating axis, abnormal microtubule configuration, and compound cilia should identify patients with PCD.55–57,59 However, cases of PCD with normal ciliary ultrastructure have been described.55,57 Treatment and Prognosis Treatment for PCD is the same as that for bronchiectasis from other causes: antibiotics, lung physiotherapy, and vaccination against influenza viruses, Streptococcus pneumoniae, and Haemophilus 8
influenzae. Few studies have examined the impact of antibiotics and lung physiotherapy on objective outcomes in PCD. Pedersen and Stafanger43 followed peak expiratory flow rate and forced vital capacity in 22 patients during treatment with prophylactic antibiotics and lung physiotherapy. Peak expiratory flow rate increased from 64% of predicted normal to 82% and forced vital capacity increased from 79% to 92%, over a median follow-up period of 3.5 years. Patients had fewer bronchitic exacerbations with this prophylactic therapy. However, forced expiratory volume in 1 second did not change and a control group improved without prophylactic therapy. Once bronchiectasis develops, symptomatic relief is achieved with culture-directed antibiotic therapy. H influenzae is the most frequently isolated organism (58% of positive cultures) followed by S pneumoniae (21%), Staphylococcus aureus (19%), Pseudomonas aeruginosa (14%), Escherichia coli (10%), and other Streptococcus species (1%).43 Antibiotics can be given in cycles, continuously, or only during exacerbations; trials to establish a superior strategy are lacking. Although surgical therapy for chronic sinusitis is often indicated, lobectomy for intractable bronchiectasis is rarely needed in the antibiotic era and must be considered on a case-by-case basis. Lung transplantation has been performed for end-stage disease and the technical difficulties posed by the anastomosis of normal lung and inverted recipient bronchi are described elsewhere.60,61 Patients with PCD are less ill than patients with cystic fibrosis and are less often colonized with P aeruginosa. Only 3 of the 27 patients followed by Pedersen and Stafanger43 had disabling lung disease and a full half of the patients were able to appreciate a normal life. Life expectancy can be normal depending on the severity of bronchiectasis.62,63 It is to be hoped that prevention or delay of the progression of bronchiectasis with targeted antibiotic therapy and aggressive medical care will improve the life expectancy further, as it has for patients with cystic fibrosis.25–32,44 References 1. Oeri R. Bronchiectasis in situs inversus. Frankfurter Zeitschrift fur Pathologie 1901;3:393– 8. 2. Siewert AK. Ueber einem Fall von Bronchiektasie bei einem Patienten mit Situs inversus viscerum. Berl Klin Wchnschr 1904;41:139. 3. Kartagener M. Zur Pathologie der Bronchiektasien: Bronchiektasien bei Situs viscerum inversus. Beitr Klin Tuberk 1933;83:489 –501. 4. Afzelius B. Electron microscopy of the sperm tail: Results obtained with a new fixative. J Biophysic Biochem 1959;5: 269 –78. 5. Camner P, Mossberg B, Afzelius BA. Evidence for congenitally nonfunctioning cilia in the tracheobronchial tract in two subjects. Am Rev Respir Dis 1975;112:807–9.
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6. Afzelius BA, Eliasson R, Johnsen O, et al. Lack of dynein arms in immotile human spermatoza. J Cell Biol 1975;66: 225–32. 7. Pedersen H, Rebbe H. Absence of arms in the axoneme of immobile human spermatozoa. Biol Reprod 1975;12:541– 4. 8. Afzelius BA. A human syndrome caused by immotile cilia. Science 1976;183:317–9. 9. Pedersen J, Mygind N. Absence of axonemal arms in nasal mucosa cilia in Kartagener’s syndrome [letter]. Nature 1976; 262:494 –5. 10. Eliasson R, Mossberg B, Camner P, et al. The immotilecilia syndrome: A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility. N Engl J Med 1977;297:1– 6. 11. Sturgess J, Chao J, Wong J, et al. Cilia with defective radial spokes. N Engl J Med 1979;300:53– 6. 12. Sturgess J, Chao J, Turner JAP. Transposition of ciliary microtubules. N Engl J Med 1980;303:318. 13. Afzelius BA, Eliasson R. Flagellar mutants in man. J Ultrastruct Res 1979;69:43. 14. Van der Baan S, Veerman AJP, Wulffraat N, et al. Primary ciliary dyskinesia: ciliary activity. Acta Otolaryngol 1986;102:274 – 81. 15. Rutland J, Iongh RU. Random ciliary orientation: A cause of respiratory tract disease. N Engl J Med 1990;323:1681– 4. 16. Cockayne EA. The genetics of transposition of the viscera. Q J Med 1938;31:479 –93. 17. Torgersen J. Genic factors in visceral asymmetry and in the development and pathologic changes of lungs, heart and abdominal organs. Arch Pathol 1949;47:566 –93. 18. Sturgess JM, Thompson MW, Czegledy-Nagy E, et al. Genetic aspects of immotile cilia syndrome. Am J Med Genet 1986;25:149 – 60. 19. Weibel ER. Morphometry of the human lung. Berlin: Springer-Verlag; 1963. 20. Pavia D. Lung mucociliary clearance. In: Clarke SW, Pavia D, editors. Aerosols and the lung: clinical and experimental aspects. London: Butterworth; 1984. p. 127. 21. Clarke SW. Rationale of airway clearance. Eur Respir J 1989;2(Suppl 7):599s– 604s. 22. Pavia D, Bateman JRM, Clarke SW. Deposition and clearance of inhaled particles. Bull Eur Physiopathol Respir 1980; 16:335. 23. Afzelius BA. The immotile-cilia syndrome: a microtubuleassociated defect. CRC Crit Rev Biochem 1985;19:63– 81. 24. Lodesh H, Baltimore D, Berk A, et al. Microtubules and intermediate filaments. In: Molecular Cell Biology, 3rd ed. New York: W.H. Freeman & Co.; 1995. p. 1051–122. 25. White BL, Catlin FI, Stenback WA, et al. The immotile cilia syndrome: one cause of persistent upper respiratory tract infection. Int J Pediatr Otorhinolaryngol 1980;2:337– 46. 26. Woodring JH, Royer JM, McDonagh D. Kartagenener’s syndrome. JAMA 1982;247:2814 – 6. 27. Escalier D, Jouannet P, David G. Abnormalities of the ciliary axonemal complex in children: an ultrastructural and kinetic study in a series of 34 cases. Biol Cell 1982;44:271– 82. 28. Antonelli M, Modesti A, Quattrucci S, et al. Supernumerary microtubules in the cilia of two siblings causing “immotile cilia syndrome.” Eur J Respir Dis 1983;64:607–12. 29. Baccetti B, Burrini AG, Pallini V. Spermatozoa and cilia lacking axoneme in an infertile man. Andrologia 1980;12: 525–32. 30. Jahrsdoerfer R, Feldman PS, Rubel EW, et al. Otitis media and the immotile cilia syndrome. Laryngoscope 1979; 89:769 –78.
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