Ultrastructural abnormalities of respiratory cilia: a 25-year experience.
Abstract: * Context.--Ciliary dyskinesia is a rare, but significant, cause of chronic respiratory infections, and transmission electron microscopy is a critical adjunct to making the diagnosis.

Objective.--To investigate a single institution's experience with patients demonstrating abnormal ciliary ultrastructure.

Design.--Retrospective clinicopathologic review of 278 bronchial or nasal turbinate brushings or biopsies from 1983 through 2007.

Results.--There were 12 women and 9 men (mean age, 19.6 years; range, 1-54 years) with abnormal ciliary ultrastructure. Clinical history was unavailable in 3 patients, 15 (83%) of 18 patients presented with chronic or recurrent upper respiratory infections, and 3 (17%) presented with infertility. Seven (39%) of 18 patients had findings of Kartagener syndrome with situs inversus, dextrocardia, and bronchiectasis. Truncation or absence of inner or outer dynein arms occurred in 15 (71%) of 21 cases, and 5 (24%) revealed transposition defects with displacement of the central microtubules and peripheral doublets in 9 + 0 and 8 + 1 patterns. Radial spoke defects with microtubular disarray occurred in 4 (19%) of 21 cases. Compound cilia with multiple axonemes within a single outer sheath and supernumerary microtubules each occurred in 2 (10%) of the cases. Random ciliary orientation was also found in 2 (10%) of the cases, and dense granular basal body inclusions occurred in 1 case (5%). Multiple abnormalities occurred in 6 (29%) of the 21 cases.

Conclusions.--Most patients presented with chronic respiratory tract infections or infertility. Dynein arm defects, transposition defects, and radial spoke defects were the most commonly encountered abnormal findings. Less-frequent abnormal findings included compound cilia, supernumerary microtubules, and dense granular basal body inclusions.
Article Type: Report
Subject: Respiratory tract infections (Development and progression)
Cilia and ciliary motion (Properties)
Transmission electron microscopes (Usage)
Clinical pathology (Research)
Authors: Plesec, Thomas P.
Ruiz, Angela
McMahon, James T.
Prayson, Richard A.
Pub Date: 11/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: Nov, 2008 Source Volume: 132 Source Issue: 11
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230246867
Full Text: Ciliated cells are found lining various body cavities, such as the respiratory tract, the ventricles in the central nervous system, the ductuli efferentes, the fallopian tubes, and the retina. Defects in ciliary anatomy can, therefore, lead to an array of diseases, such as chronic respiratory infections, hydrocephalus, infertility, and blindness. Normal ciliary ultrastructure was initially described by Afzelius in 1959 and consists of 9 peripheral microtubule doublets surrounding a central pair of microtubule singlets (Figure 1). (1) Each doublet has inner and outer dynein arms, which are able to "walk" along the adjacent microtubular doublet, bending the cilium. Radial spokes between the doublets and a central sheath provide structural support. (2) Similar microtubular structures are also present in spermatozoal flagella, and the absence of one or both dynein arms in patients with immotile spermatozoa was first reported in 1975. (1) These patients were also diagnosed with Kartagener syndrome, characterized by the classic triad of sinusitis, bronchiectasis, and situs inversus. Since then, numerous other ciliary structural defects have been described and implicated as causes of ciliarelated disease. These include absence of radial spokes with microtubular disarray, absence of the central pair of microtubules (with or without transposition of one of the outer pairs of microtubules to the center position, socalled 9 + 0 or 8 + 1 defects), absence of the central sheath, supernumerary doublets, absence of the axoneme, elongated cilia, and random ciliary orientation, among others. (1,2)

Several series (3-6) since 2000 have reported on patients with ciliary dyskinesia, often focusing on clinical presentations and outcomes. This study sought to add to the literature by reviewing one institution's experience with ciliary biopsy and brushing specimens, specifically focusing on the clinicopathologic features of cases with ultrastructurally abnormal cilia.

MATERIALS AND METHODS

After receiving institutional review board approval, results of transmission electron microscopy (TEM) performed on respiratory cilia of patients from 1983 through 2007 were retrospectively reviewed. The study group consisted of those cases with ultrastructurally abnormal cilia. Specimens consisted of bronchial or nasal turbinate brushings. Motility was assessed by evaluation of saline wet-mount preparations for assessment of wave patterns. In specimens demonstrating absent ciliary motility, cell viability was assessed by trypan blue dye exclusion. Tissue submitted for ultrastructural evaluation was fixed in 3.75% glutaraldehyde, 6% sucrose, and buffered with 0.1M cacodylate at pH 7.2 to 7.4. Postfixation used 1% osmium tetroxide and 0.1M cacodylate at pH 7.2 to 7.4. Tannic acid was not used. Forty- to sixty-nanometer sections were cut and stained in uranyl acetate and lead citrate. Surgical pathology reports were reviewed to classify the ultrastructural ciliary defects. At the time of diagnosis, at least 50 cross sections were examined, similar to other reports in the literature. (7-10) The retrospective nature of this series precluded precise quantification of the ciliary defects, given the possibility of selection bias in the preserved photomicrographs. However, upon review of the TEM photomicrographs, a semiquantitative analysis was performed. Those defects that occurred in a minority of ciliary cross sections (approximately <20%) were ruled out as an etiology of primary ciliary dyskinesia (PCD) because these defect frequencies are often seen in healthy patients or in secondary processes.8,11-15

[FIGURE 1 OMITTED]

Clinical presentation and demographic information were obtained for those patients with abnormal TEM findings via medical record review. The diagnosis of PCD requires assimilation of clinical, radiologic, laboratory, and pathologic data. (3,16,17) Therefore, the determination of the presence or absence of PCD was based on that chart review and the clinical teams' final determination.

RESULTS

Ciliary brushing results from 278 patients were reviewed. Of those, 128 (46%) were excluded because they lacked TEM studies after the motility study findings were normal or, rarely, because the specimens were inadequate. The remaining 150 (54%) of 278 specimens underwent electron microscopic examination, with or without motility studies, and 14% (21/150) were found to have abnormal ciliary structure.

The clinicopathologic features of the 21 patients with abnormal TEM findings are summarized in Table 1. The group consisted of 12 women and 9 men (mean age, 19.6 years; range 1-54 years). In 3 (14%) of the 21 patients, clinical information was unavailable. Of the remaining 18 patients, 15 (83%) presented with chronic or recurrent upper respiratory infections. Three (17%) of the 18 patients presented with infertility, 1 of whom had infertility as the sole complaint. Seven (39%) of the 18 patients had findings consistent with Kartagener syndrome, with situs inversus, dextrocardia, and bronchiectasis. Fourteen (78%) of the 18 patients with available clinical history were found to have PCD, whereas only 1 (6%) of the 18 patients was documented to have acquired or secondary ciliary dyskinesia (SCD).

Fresh tissue studies demonstrated absent or weak ciliary motility in viable epithelial cells in 14 (67%) of 21 cases. Two additional cases had viable epithelial cells that demonstrated abnormal motility: one with rapid ciliary activity and metachronous wave patterns with focal immotility and premature ending of the wave motion, and the other with demonstrated activity but no identifiable metachronicity. Three cases (14%) showed normal ciliary motility with metachronic wave patterns. Ciliary motility studies were not performed in 2 patients.

Table 2 lists the various cilia ultrastructural abnormalities and correlates those abnormalities with the presence or absence of documented PCD. Most cases of PCD involved dynein arm defects (10/14; 71%). Other defects associated with documented PCD included transposition defects (2/14; 14%), abnormal ciliary orientation (1/14; 7%), and radial spoke defects (1/14;7%). When abnormalities were encountered only rarely or infrequently (<20%), they were excluded as an etiology for the PCD. Cases with only rare or infrequent ultrastructural abnormalities included transposition defects (n = 2), supernumerary microtubules (n = 2), radial spoke defects (n = 1), compound cilia (n = 1), and basal body inclusions (n = 1).

Truncation or absence of inner or outer dynein arms was the most frequently encountered ultrastructural abnormality, occurring in 71% (15/21; Figure 2, A) of the cases. The abnormality was the sole defect in all but 1 case, which showed radial spoke defects and compound cilia. Follow-up evaluation in that case, 4 months later, revealed normal ciliary motility and completely normal cilia ultrastructure, findings consistent with acquired defects.

Cilia in 5 (24%) of the 21 cases revealed displacement of the central microtubules and peripheral doublets in 9 + 0 and 8 + 1 patterns (Figure 2, B). The resultant axoneme was seen in an 8 + 1 pattern, if a doublet was displaced to the center--the so-called transposition defect--and in a 9 + 0 arrangement, if no displacement occurred. Three cases with transposition defects also revealed other abnormalities, including supernumerary microtubules and radial spoke defects in one case, radial spoke defects and compound cilia in another, and random ciliary orientation in the third.

Radial spoke defects were evidenced by microtubule disarray or displacement (not absence) of the central singlet pair, and these defects involved 4 (19%) of the 21 cases (Figure 2, C). Three contained additional abnormalities of cilia. Two cases showed transposition defects, and 2 cases revealed compound cilia. A single case with radial spoke defects demonstrated supernumerary microtubules, whereas another showed absent dynein arms.

Random ciliary orientation was seen in 2 (10%) of the 21 cases (Figure 2, D): one had transposition defects, and the other had dense granular basal body inclusions along with supernumerary microtubules. Compound cilia (Figure 3, A), which consisted of multiple axonemes within a single outer sheath, occurred in 2 (10%) of the cases. The TEM showed each had multiple other abnormalities of the cilia, including radial spoke defects in both, as well as transposition defects and absent dynein arms in 1 each. Supernumerary microtubules (Figure 3, B) occurred in 2 (10%) of the cases, each with defects, including transposition defects and radial spoke defects in 1 and dense granular basal body inclusions in another (Figure 3, C). Multiple abnormalities were observed in 6 (29%) of the 21 cases.

COMMENT

Abnormal cilia are a common occurrence in human bronchial epithelium; 4% to 10% of cilia in healthy patients can reveal ultrastructural abnormalities. (8,13,14) In chronic respiratory disease, the percentage of abnormal cilia can increase to 20%. (8,11-15) McDowell et al (11) reported that 97% (30/31) of the patients with various neoplastic and nonneoplastic diseases had abnormal ciliary ultrastructure. However, the abnormalities were rare in all specimens, with most of the cilia examined revealing normal ultra structure. Al-Rawi et al (15) found that 87% (20/23) of the patients with severe chronic sinusitis had ultrastructural defects, including compound cilia, microtubule defects, and dynein arm defects. Although not precisely quantified, the abnormalities were typically found in a minority of the cilia. Therefore, authorities have concluded that patients with acquired ciliary abnormalities have only a minority of cilia with ultrastructural defects, whereas patients with PCD have defects in most, or all, cilia. (13,15,18,19)

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Secondary ciliary dyskinesia refers to ciliary abnormalities caused by environmental factors, such as viral or bacterial infections or other sources of chronic mucosal inflammation. Distinguishing PCD from SCD by light microscopy or electron microscopy can be quite difficult but is important because SCD is potentially reversible.2 Perhaps the most definitive laboratory method for distinguishing PCD from SCD was described by Jorissen et al.20 Ciliated cells were biopsied and stimulated to undergo ciliogenesis in culture. After ciliogenesis, the cultured cilia from all patients with SCD had coordinated ciliary activity, whereas none of the cilia from patients with PCD did. The major drawbacks are that the test takes up to 6 weeks and is performed by only a few centers.

In truth, few ultrastructural defects are specific for either PCD or SCD. Possible exceptions include the absence of dynein arms and the high percentage of eccentric or absent central pairs, defects generally thought to be specific for PCD. (2,20) However, not all patients with PCD have disease characterized by the absence of dynein arms or by absent central pairs, and numerous other defects have been described. Even normal ultrastructural findings have been reported, (20) and 25% of patients with PCD may have nonclassic findings.20,21 Although groups have attempted to standardize criteria for the diagnosis of PCD by TEM, (7,14,22) none have been universally accepted. The causes of this lack of standardization are multifaceted. Primary ciliary dyskinesia is quite rare, with an estimated incidence of 1:15000; it has many clinical manifestations and mimics; and it lacks a universally agreed upon, sensitive, and specific diagnostic test. (17) Transmission electron microscopy has been heralded as the gold standard, but again, standard diagnostic criteria for the diagnosis are lacking. The multitude of ultrastructural defects reportedly associated with PCD (12 according to Afzelius)2 and the rarity of the disease make standardization of TEM interpretation difficult, if not impossible. Even false-positive and false-negative rates have never been reported for TEM. (16) In the absence of ciliary culture, documenting the persistence of the ultrastructural defects over time may provide added specificity to the diagnosis of PCD. (12,14)

Dynein arm defects are considered the most frequent ultrastructural abnormality of cilia, comprising from 50% to greater than 80% of all abnormalities. (6,14,22-25) Of the patients studied in this series, 71% (15/21) demonstrated absent or truncated dynein arms, 10 of whom had documented PCD. The inner and outer dynein arms serve as the motor apparatus for the bending of cilia.26 Peripheral microtubule doublets contain both the inner and outer dynein arms, and dynein arm defects are characterized by complete absence or shortening of one or both of the arms. The defects are considered by most to be congenital in nature and inherited in an autosomal recessive manner. (25) Two genes have been documented to cause dynein arm defects, accounting for up to 38% of PCD cases. (25) The DNAI1 gene, located on bands 9p13 to 9p21, encodes a component protein of the outer dynein arm. These patients often present with PCD, randomization of right/left body symmetry, and infertility. (23,25) The second gene, DNAH5, is located on chromosome arm 5p, and mutations have been associated with outer dynein arm absence or shortening and right/left asymmetry. (23,25,27) A mutation to DNAH11 on band 7p21 was initially described in one patient with PCD, and situs inversus and has been validated in a kindred of 6, interestingly, with normal ciliary ultrastructural findings. (21,28)

Twenty-four percent of the patients demonstrated transposition defects, 2 of whom had documented PCD. These defects are thought to comprise roughly 10% of ciliary abnormalities. (23) The normal ciliary axoneme arrangement consists of a pair of central microtubule singlets surrounded by 9 microtubule doublets, the 9 + 2 arrangement. The transposition defect results from absence of the central singlet pair, causing a 9 + 0 arrangement to the axoneme. Often, 1 of the 9 peripheral doublets is translocated to the center of the axoneme, causing an 8 + 1 arrangement. (29) To date, there are no genes known to cause the transposition defect.

Nineteen percent of patients with ultrastructural ciliary abnormalities exhibited radial spoke defects, 1 of whom had documented PCD. According to reports, radial spoke defects are thought to account for about 6% of defects. (23) Radial spokes are proteins that provide structural support and tethering to the central pair through connections between each microtubule pair and the central sheath. Absence of the radial spokes causes displacement without loss of the central pair and is readily recognized by TEM. (30) Again, no specific genetic causes have been found so far.

A variety of other abnormalities were seen less frequently in this series. Compound cilia were seen in 2 cases and are thought to be secondary defects. (26) They are evidenced by multiple axonemes within one outer sheath. Supernumerary microtubules also occurred in 2 patients and have been reported as a cause of PCD. (31) Supernumerary microtubules consist of extra microtubules, beyond the normal 9 + 2 arrangement. Abnormal or random ciliary orientation with normal individual ciliary ultrastructural findings were also identified in 2 patients, 1 of whom had documented PCD. To effectively clear mucus via coordinated movement, cilia need to be oriented in a similar plane. Random ciliary orientation as a cause of PCD was first reported in 1990 (32) and has since been challenged by Jorissen and Willems (24) who found that ciliary disorientation as the sole ultrastructural abnormality was eliminated after ciliogenesis in culture.

Our series provides further evidence that absent dynein arms are the most common ciliary abnormality in patients with PCD. Other less-frequent defects associated with PCD include transposition, radial spokes, and abnormal cilia orientation. The other abnormalities encountered in this series were rare and were never the sole defect in patients with documented PCD. Although standardized pathologic criteria for the diagnosis of PCD are lacking, this series provides further evidence that frequent dynein arm, transposition, radial spoke, and orientation defects are associated with the disease.

Accepted for publication April 23, 2008.

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(18.) Ehouman A, Pinchon MC, Escudier E, Bernaudin JF. Ultrastructural abnormalities of respiratory cilia: descriptive and quantitative study of respiratory mucosa in a series of 33 patients. Virchows Arch B Cell Pathol InclMol Pathol. 1985; 48:87-95.

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(27.) Olbrich H, Haffner K, Kispert A, et al. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet. 2002; 30:143-144.

(28.) Bartoloni L, Blouin JL, Pan Y, et al. Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc Natl Acad Sci USA. 2002;99:10282 10286.

(29.) Sturgess JM, Chao J, Turner JAP. Transposition of ciliary microtubules: another cause of impaired ciliary motility. N Engl J Med. 1980;303:31 8-322.

(30.) Sturgess JM, Chao J, Wong J, Aspin N, Turner JA. Cilia with defective radial spokes: a cause of human respiratory disease. N Engl J Med. 1979;300:53-56.

(31.) Antonelli M, Modesti A, Quattrucci S, de Angelis M. Supernumerary microtubules in the cilia of two siblings causing "immotile cilia syndrome." Eur J Respir Dis. 1983;64:607-612.

(32.) Rutland J, de longh RU. Random ciliary orientation: a cause of respiratory tract disease. New Engl J Med. 1990;323:1681-1 684.

Thomas P. Plesec, MD; Angela Ruiz, MD; James T. McMahon, PhD; Richard A. Prayson, MD

From the Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland OH 44195 (e-mail: praysor@ccf.org).
Table 1. Clinicopathologic Summary of 21 Patients With Abnormal
Cilia Ultrastructure *

Case   Age,
No.    y/Sex   Clinical Presentation                   PCD

 1      7/F    Recurrent sinusitis, otitis media,      Yes
               situs inversus, dextrocardia
 2      8/M    Recurrent sinusitis, otitis media,      Yes
               pneumonia, situs inversus,
               mesocardia, multiple congenital
               cardiac malformations
 3     25/F    Recurrent upper respiratory tract       Yes
               infections, infertility
 4      8/M    Chronic otitis media, recurrent         Yes
               cough, situs inversus,
               dextrocardia
 5      4/M    Recurrent sinusitis, pneumonia          No f/u
 6     10/F    Chronic sinusitis, recurrent            Yes
               pneumonia, otitis media, bronchiecta-
               sis, situs inversus, dextrocardia
 7     54/M    Data unavailable                        No f/u
 8     13/F    Chronic productive cough, bronchi-      Yes
               ectasis, situs inversus, dextrocardia
 9     53/F    Chronic sinusitis, bronchiectasis       No f/u
10      6/M    Data unavailable                        No f/u
11      5/F    Chronic sinusitis, asthma,              Yes
               bronchiectasis
12     33/M    Infertility                             No f/u
13      7/M    Data unavailable                        No f/u
14     49/F    Chronic sinusitis, bronchiectasis       Yes
               and infertility
15     40/F    Chronic sinusitis and diffuse           Yes
               bronchiectasis
16      7/F    Chronic sinusitis and productive        Yes
               cough, bronchiectasis
17      2/F    Chronic otitis media, sinusitis,        Yes
               and cough
18      1/M    Recurrent otitis media, asthma          Yes
19      7/F    Chronic otitis media, asthma, situs     Yes
               inversus, dextrocardia, seizures
20     46/F    Laryngeal dysfunction                   No
21     26/M    Situs inversus                          Yes

Case   Age,
No.    y/Sex   Ciliary Motility     Ultrastructure

 1      7/F    None                 Absent/truncated dynein arms
 2      8/M    Mostly none;         Absent/truncated dynein arms
               rare jerky
               movement
 3     25/F    Metachronic wave     Transposition defect; abnormal
               pattern with         orientation
               focally absent,
               sluggish
 4      8/M    Rare twitchy         Radial spoke defect; rare
               movement; absent     supernumerary microtubules;
               motility             rare transposition defect
 5      4/M    Normal               Rare supernumerary microtubules;
                                    rare dense granular basal body
                                    inclusions
 6     10/F    None                 Absent/truncated dynein arms
 7     54/M    None                 Transposition defect
 8     13/F    None                 Absent/truncated dynein arms
 9     53/F    None                 Radial spoke defect
10      6/M    Normal               Absent/truncated dynein arms
11      5/F    Focal metachronic    Transposition defect; rare radial
               wave pattern         spoke defect; rare compound cilia
12     33/M    None                 Absent/truncated dynein arms
13      7/M    None                 Absent/truncated dynein arms
14     49/F    Immotile and         Absent/truncated dynein arms
               sluggish
15     40/F    None                 Absent/truncated dynein arms
16      7/F    Present; no          Abnormal orientation; rare
               metachronicity       transposition defect
17      2/F    Absent/sluggish      Absent/truncated dynein arms
18      1/M    Quivering/sluggish   Absent/truncated dynein arms
19      7/F    None                 Absent/truncated dynein arms
20     46/F    Not performed        Absent/truncated dynein arms,
                                    radial spoke defect, compound
                                    cilia
21     26/M    Not performed        Absent/truncated dynein arms

* PCD indicates primary ciliary dyskinesia; f/u, follow-up.

Table 2. Frequency of Specific Cilia Ultrastructure
Abnormalities and Associations With Primary Ciliary
Dyskinesia (PCD) *

                                             Rare/
                                    PCD      Infrequent
Cilia Defect            No. (%)   (n = 14)   Defects

Dynein arm              15 (71)   Yes (10)   0/15
Transposition            5 (24)   Yes (2)    2/5
Radial spoke             4 (19)   Yes (1)    1/4
Abnormal orientation     2 (10)   Yes (1)    0/2
Compound cilia           2 (10)   No         1/2
Supernumerary
  microtubules           2 (10)   No         2/2
Basal body inclusions    1 (5)    No         1/1
Multiple defects         6 (29)   NA         NA

* Cases with rare/infrequent defects occurred in <20% of
cilia cross sections. NA indicates not applicable.
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