Correlation of Presentation and Pathologic Condition in Primary Ciliary Dyskinesia

Objectives  To better characterize primary ciliary dyskinesia (PCD) and improve the diagnosis of this uncommon disorder.

Study Design and Setting  We retrospectively reviewed the records of 118 patients with ciliary biopsy or brushing specimens examined at Yale University School of Medicine from 1991 to 2001.

Results  Sinonasal, middle ear, and pulmonary infections were more common in patients with PCD-positive biopsy results than in those with negative results. In addition, PCD caused by random ciliary orientation presented similarly to PCD caused by other ultrastructural defects.

Conclusions  Patients who present with cough alone are highly unlikely to have PCD (χ² test, 24.85; P<.001). In contrast, patients who present with multiple manifestations are highly likely to have PCD (χ² test, 22.2; P<.001). This information may assist the clinician in the diagnosis of PCD.

PRIMARY CILIARY dyskinesia (PCD) is an autosomal recessive disorder that affects approximately 1 in 16 000 live births. Of affected individuals, 50% have the Kartagener syndrome triad of bronchiectasis, sinusitis, and situs inversus. A typical cilium has 9 circumferential microtubular doublets and 2 central tubules surrounded by a sheath (Figure 1). Peripheral doublets are connected to one another by nexin links and to the central sheath by radial spokes. Defects may involve any part of the structure. Random ciliary orientation (Figure 2) in the absence of other cilia defects was first reported in 1990 by Rutland and de Iongh.¹ In contrast to PCD, viral infection and chronic inflammation involve only a subset of the cilia and are transient.^2,3

Several studies have suggested hallmark traits of PCD.^4-7 The most commonly reported manifestations include cough, sinusitis, otitis media, and bronchiectasis. These findings may mimic other conditions such as severe allergies, cystic fibrosis, and hypogammaglobulinemia. Buchdahl et al⁸ suggested that all children with unexplained chronic respiratory disease, particularly if starting in the perinatal period, should be investigated for PCD. However, Mierau et al⁹ found only 1 case of PCD in over 100 biopsy specimens. We provide a large series of patients with PCD and correlate clinical presentation with electron microscopic findings.

Between 1991 and 2000, 180 ciliary biopsy or brushing specimens from different patients were examined for PCD under electron microscopy by the Department of Pathology at Yale University School of Medicine. Patients were included in the study if a complete history was available from the referring clinician and if the pathologist deemed the specimen adequate for diagnosis. One hundred eighteen patients met these criteria. In addition, specimens examined prior to 1991 were excluded because random ciliary orientation was a poorly known entity and PCD may have been underdiagnosed.

Clinical manifestations were placed into the following categories: sinonasal (sinusitis and rhinitis); middle ear (otitis media and mastoiditis); pulmonary (bronchitis, bronchiectasis, pneumonia and asthma); cough; and combinations of the above categories. Grouping of manifestations facilitates comparison because they represent ciliary compromise in the same region. The diagnosis of cough was used if no specific pulmonary process could be identified. Other less common signs or symptoms were not assessed in this study.

Specimens were obtained by nasal or tracheal biopsy or brushing, fixed in 2.5% glutaraldehyde, and were assessed for compound cilia, central and peripheral microtubule defects, numbers of inner and outer dynein arms per cilium, and ciliary orientation. Ciliary orientation was determined to be random if a deviation of 52° or more from the mean angle was measured, as specified by Rutland and de Iongh.¹ We used χ² analysis to determine the statistical significance of correlations between clinical findings and ultrastructural pathologic condition.

Ages ranged from 2 weeks to 48 years, with most patients in the pediatric population. The number of male and female patients was roughly equal, and 73 patients had a PCD-positive biopsy result (positive group). Various ciliary defects were encountered including missing dynein arms, absent cilia, abnormal length, radial spoke and nexin link defects, microtubular transposition, compound cilia, and random ciliary orientation. The PCD-negative biopsy results (negative group) included 21 cases of chronic inflammation and 24 cases of normal ciliary architecture.

To delineate the presentation of random ciliary orientation alone, we divided the patients with PCD into 3 pathologic groups: random ciliary orientation alone (13 patients), random ciliary orientation with other ultrastructural defects (39 patients), and ultrastructural defects with the cilia in proper orientation (21 patients). Table 1 illustrates the similarity of presentation in all 3 groups.

Table 2 shows the difference in presentation between the positive vs negative group. Higher percentages of sinonasal, middle ear, and pulmonary processes were seen in the positive group compared with the negative group. In fact, the percentage of patients with multiple manifestations was markedly higher in the positive group than in the negative group and was highly significant (χ² test, 22.2; P<.001). Also, the percentage of patients who presented only with chronic cough was markedly higher in the negative group than in the positive group and was highly significant (χ² test, 24.85; P<.001). Only 4 (5%) of 73 patients presented with isolated cough in the positive group compared with 20 (44%) of 45 patients in the negative group.

Respiratory tract disease, such as sinusitis, otitis media, and bronchitis, have long been associated with PCD. However, most studies have been small and few have characterized the incidence of such manifestations. To our knowledge, the present study includes the largest series of patients in the literature and demonstrates statistical significance in correlating the presence or absence disease based on certain clinical manifestations.

Sturgess and Turner⁴ studied clinical features in patients with PCD. Virtually all had cough (97.1%) and sinusitis (94.1%). Otitis media (76.5%), bronchiectasis (58.8%), and situs inversus (55.9%) were also common. Greenstone et al⁵ reported that sinonasal symptoms were the most common in a series of 30 patients with PCD, followed by respiratory disease, otitis media, and cough. Barranco et al⁶ believed that diagnostic criteria should include sinusitis and bronchiectasis because other findings were present to the same degree in the absence of PCD.

Buchdahl et al⁸ studied 167 children with chronic respiratory tract problems. They found 18 cases of abnormal ciliary function. All had lower respiratory tract disease, and most had upper respiratory tract problems as well. Respiratory symptoms in the perinatal period were present in all children with PCD compared with only 25% in those with normal cilia.

Rutland and de Iongh¹ first demonstrated random ciliary orientation as a cause of PCD in 1990. Rayner et al¹⁰ corroborated this a few years later in a series of 11 patients. Both studies showed that these patients experience pan-respiratory disease to the same degree as patients with specific defects in the cilia.

Our findings mirror those of previous studies. We found pan-respiratory disease to be highly associated with and a good predictor of PCD. As in other studies, we found sinonasal disease to be the most common, with middle ear and pulmonary disorders also highly prevalent. In addition, we found that the presence of chronic cough without other findings to be an excellent negative predictor of PCD. Finally, our 13 patients with only random ciliary orientation presented similarly to patients with other defects. This information may be useful to clinicians confronted with recurrent respiratory tract disease of unclear cause.

In conclusion, the presence of multiple clinical manifestations (sinonasal, otitis media, and/or pulmonary) is a good predictor of PCD. Patients who present with cough alone are unlikely to have PCD. Our data show that random ciliary orientation alone has a similar clinical presentation to that of other defects.

Accepted for publication May 3, 2002.

Corresponding author and reprints: David E. Karas, MD, 800 Howard Ave, New Haven, CT 06520.