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Original Research |
1 Division of Pulmonary and Critical Care Medicine, University of North
Carolina, Chapel Hill, NC.
2 Present address; Division of Pulmonary Medicine, M. D. Anderson Cancer Center,
1400 Holcombe Blvd., Unit 403, Houston, TX 77030-4009.
3 Division of Pediatric Pulmonology, University of North Carolina, Chapel Hill,
NC.
4 Department of Radiology, University of North Carolina at Chapel Hill, Chapel
Hill, NC.
Received July 24, 2006;
accepted after revision October 11, 2006.
Address correspondence to M. P. Kennedy
(kennedy{at}mdanderson.org).
Abstract
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MATERIALS AND METHODS. High-resolution CT studies were available for 45 PCD patients from 42 families with ranges of age and disease severity. The images were assessed for severity and distribution of bronchiectasis, peribronchial thickening, mucous plugging, and other findings. A bronchiectasis severity score was calculated. CT findings were correlated with phenotypic findings, including situs type, ciliary ultrastructural defect, nasal level of nitric oxide, forced expiratory volume in 1 second, and microbiologic findings in the airways.
RESULTS. Twenty-nine adults (mean age, 42 ± 15 years; age range, 21-73 years) and 16 children (mean age, 8 ± 4 years; age range, 1-14 years) were included; 26 (58%) of the patients were women or girls. Situs inversus totalis (38%) or heterotaxy (18%) was identified in 56% of the patients. A high (9%) prevalence of pectus excavatum was identified. High-resolution CT of all of the adult and 56% of the pediatric patients showed bronchiectasis in a predominantly middle and lower lobe distribution. The right middle lobe was most commonly involved. Bronchiectasis severity score correlated with older age and worse pulmonary function.
CONCLUSION. High-resolution CT shows that pulmonary disease related to PCD predominantly involves the middle and lower lobes of the lungs. In adults, high-resolution CT findings negative for bronchiectasis may have a role in excluding the diagnosis of PCD. Correlation of severity of disease on high-resolution CT with patient phenotype gives further insight into the diversity and natural history of PCD.
Keywords: airway • chest • high-resolution CT • lung • lung diseases
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Morbidity in PCD is predominantly related to chronic suppurative airway disease secondary to chronic infection [1]. Although the progression of pulmonary disease is slower in PCD than in cystic fibrosis (a genetic disorder also leading to defective airway mucociliary clearance with common clinical and radiographic features), a significant percentage (as high as 25% in one series) of patients may experience respiratory failure as defined by hypoxemia, or a forced expiratory volume in 1 second (FEV1) less than 40% of the predicted value [1, 5]. The current diagnostic test of choice is electron microscopic ultrastructural analysis of respiratory cilia in samples of nasal or airway mucosa acquired with minimally invasive techniques. Most PCD patients have defects in the outer or inner dynein arms that lead to lack of or dysfunctional ciliary motility [1].
Structural changes in the lung visualized with CT may correlate with histologic findings in a number of chronic airway diseases, including asthma, chronic obstructive pulmonary disease, and bronchiectasis [6-8]. The CT findings in cystic fibrosis are well established and can serve as a guide for the radiographic evaluation of PCD. High-resolution CT has been used to track the natural history of airway disease in cystic fibrosis, to evaluate and manage pulmonary exacerbations, and to measure outcomes in clinical research [9-13]. In cystic fibrosis, changes on high-resolution CT may be present before abnormalities in pulmonary function test results are detected [13]. The realizations that results of pulmonary function tests may be underestimates of the presence of lung disease and that more sensitive outcome surrogates are needed in clinical trials and the development of safer and more effective CT techniques are expanding the utility of CT in the diagnosis of cystic fibrosis and other chronic pulmonary diseases [14].
The utility of high-resolution CT in a cohort of PCD patients with wide ranges of age and disease severity has not been established. We analyzed all chest high-resolution CT studies available for a cohort of patients with well-characterized PCD to identify the pattern of high-resolution CT changes associated with PCD, to examine the usefulness of high-resolution CT in identifying complications of the disease, and to examine the correlation between findings on high-resolution CT and other phenotypic parameters.
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High-Resolution CT Analysis
High-resolution CT scans were reviewed by a board-certified thoracic
radiologist who was blinded to clinical information. Situs type was
identified. Situs solitus was defined as normal thoracoabdominal asymmetry and
situs inversus totalis as mirror image reversal. Markers of heterotaxy (situs
ambiguus) were documented, including cardiac, splenic, hepatic, vascular, and
pulmonary anatomic abnormalities. All data pertaining to lobar distribution
were presented as anatomic site (e.g., the anatomic right middle lobe is on
the left in a patient with situs inversus totalis). Other defects documented
were pectus excavatum and kyphoscoliosis. If pectus excavatum was identified,
the Haller index (ratio of maximal internal transverse diameter of the chest
divided by the minimal anteroposterior diameter at the same level) was
calculated [15].
High-resolution CT images were assessed for severity of bronchiectasis in each lobe. A score of 0 indicated no bronchiectasis; 1, mild bronchiectasis (bronchial dilatation two times the diameter of the accompanying blood vessel); 2, moderate bronchiectasis (bronchial dilatation two to three times vessel diameter); 3, severe bronchiectasis (bronchial dilatation more than three times vessel diameter). An overall bronchiectasis severity score for all six lobes (score range, 0-18) was calculated. The distribution of bronchiectasis was classified in each lobe as central (proximal 50% of lung parenchyma), peripheral (distal 50% of lung parenchyma), or diffuse. If lobectomy had been performed, a severity score of 3 was assigned to the missing lobe by arbitrary definition, and distribution was presumed diffuse. The presence or absence of peribronchial thickening and mucous plugging for each lobe was recorded.
Correlation of Severity of Bronchiectasis with Phenotypic and Other Parameters
The situs type, ciliary ultrastructural defect, nasal nitric oxide level,
most recent FEV1 value, presence of mutations in DNAI1 or
DNAH5
[16-21],
and presence or absence of Pseudomonas aeruginosa were analyzed as
previously described [1].
Testing for correlation was performed by simple linear regression with the
high-resolution CT bronchiectasis scores. Data were recorded as mean ±
1 SEM. Linear regression analysis was performed with the statistical program
Stata (Stata).
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Bronchiectasis
High-resolution CT showed bronchiectasis in all of the adults and 56% of
the children (Table 2, Figs.
1,
2A,
2B,
2C,
3,
4,
5 and
6A,
6B). The right middle lobe was
the most common lobe to manifest bronchiectasis in both adult (93%) and
pediatric patients (38%) (Fig.
1). Upper lobe bronchiectasis was present in only one pediatric
patient. Figure 2A shows the
typical lobar distribution of bronchiectasis in PCD. Widespread bronchiectasis
(five or more lobes) was present in eight (27%) of the adults and one (6%) of
the children. Overall severity score was 5 ± 1 (range, 1-15) in adults
and 1.5 ± 0.5 (range, 0-6) in children
(Fig. 1). Bronchiectasis
severity score correlated with older age at high-resolution CT (p =
0.004) (Fig. 6A) and worse lung
function as reflected by FEV1 (p = 0.0001)
(Fig. 6B) and with the presence
of mucoid P. aeruginosa (n = 12, p = 0.002). As
assessed by linear regression, bronchiectasis severity score did not correlate
with the presence of smooth P. aeruginosa, situs type, nasal nitric
oxide level, or the presence of ciliary ultrastructural defect.
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The distribution of bronchiectasis was central (42%) or diffuse (53%). No patient was found to have peripheral bronchiectasis alone. Peribronchial thickening in all six lobes was identified in one of seven pediatric patients without bronchiectasis. In the subset of patients who underwent only conventional CT (n = 10, five adults), severity score was 5.8 ± 2.3 (range, 3-6) in adults (five with bronchiectasis) and 0.8 ± 0.3 (range, 0-3) in children (two with bronchiectasis).
Situs Abnormalities
Situs solitus was present in 44%, situs inversus in 38%, and heterotaxy in
18% of the adults (Table 2).
Heterotaxic subgroups included situs inversus with congenital heart disease
(n =2), polysplenia with cardiovascular anomalies (n =2;
n = 1, congenital heart disease)
(Fig. 4), polysplenia alone
(n = 2), asplenia with vascular anomalies (n = 1), and
abdominal situs inversus with polysplenia (n = 1). Overall, three
(6.6%) of the 45 PCD patients had congenital heart disease and five (11%) had
polysplenia. Pectus excavatum was identified in four (9%) of the patients
(Fig. 5). Haller index score
(mean, 3.26; range 3-3.44) was consistent with the diagnosis of pectus
excavatum. Normal Haller index score varies with age and sex, but a Haller
index score greater than 3.25 often necessitates corrective surgery
[15]. Two patients with PCD
and pectus excavatum had heterotaxy: one, situs inversus, and the other, situs
solitus.
Other Radiographic Findings
Twelve adults (27% of all patients) had undergone lobectomy. The mean age
at lobectomy was 17 years (range, 3-38 years). One, two, and three lobes were
removed in six, five, and one patient, respectively (19 lobes total). The
right middle and left lower lobes were removed most often (26% each). In seven
of these patients, the indication for lobectomy was not available. The
indication was recurrent pneumonia in a bronchiectatic lobe with or without
hemoptysis in the other five patients.
Other findings are highlighted in Table 2. Mucous plugging evident on high-resolution CT was present more commonly in adults than in children (35% vs 13%). In all but one adult, mucous plugging was identified in bronchiectatic lobes only. Emphysema was identified in three (10%) of the adults. Distribution was lower lobe predominant, and two patients were former smokers. Calcium deposition was identified in six patients (Fig. 5). Distribution involved bronchiectatic airways, both peribronchial and endobronchial, in five patients. In one patient, calcium deposition was identified in two focal right upper lobe nodules.
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Bronchiectasis was a consistent finding in all adults with PCD in this cohort. The distribution of bronchiectasis in PCD is predominantly the middle and lower lobes of the lung. The distribution of bronchiectasis in individual lobes was central or diffuse; isolated peripheral bronchiectasis was not identified. Upper lobe involvement alone was identified in only one pediatric patient. These observations may be useful to clinicians evaluating patients with a possible diagnosis of PCD. On the basis of the observation that all 29 adults had bronchiectasis on high-resolution CT, an adult patient without bronchiectasis on CT is unlikely to have PCD. The data also suggest that the diagnosis of PCD is less likely in any adult or pediatric patient with upper-lobe-predominant bronchiectasis, in contrast to bronchiectasis related to cystic fibrosis.
Because this study was a retrospective review, selection bias might have been present. Although the cohort of patients was collected at random, and high-resolution CT was performed for clinical indications, high-resolution CT is not considered mandatory in the diagnostic evaluation of PCD. It therefore is probable that patients with severe disease are more likely to undergo high-resolution CT and might have been overrepresented in this study. The high prevalence of P. aerugionsa infection among adults and children and the frequent history of lobectomy are consistent with this theory. However, the severity of lung disease reflected by FEV1 in this cohort of 45 PCD patients with CT images available was not different from the findings for adults and pediatric patients (n = 78) in our previously described larger series [1].
Our findings are consistent with those of previous radiographic studies of PCD in which radiographic manifestations of chronic airway disease progressing from bronchial wall thickening to bronchiectasis were identified [1, 22, 23]. Bronchiectasis was identified in 40-80% of patients; however, two of those studies included only patients 20 years and younger. The anatomic distribution of bronchiectasis in PCD identified on high-resolution CT also was similar to that described in reports of studies [1, 22, 23] in which middle-lobe-predominant disease was identified. This finding is in contrast to that for cystic fibrosis, in which disease predominates in the upper lobes or is diffuse throughout both lungs [9-14, 24, 25]. The central or diffuse distribution of bronchiectasis, however, was not a distinguishing feature of cystic fibrosis [11].
The usefulness of CT to differentiate idiopathic bronchiectasis and bronchiectasis caused by specific diseases has been examined in a number of studies. The results suggest that although patterns of radiographic findings can be applied to different diseases, CT alone should not be used to diagnose the cause of bronchiectasis in individual patients [25-27]. One of these studies [27] included 18 pediatric patients with PCD with disease predominating in the middle and lower lobes. Despite identifying one patient with PCD and upper lobe bronchiectasis alone, we conclude that a pattern of middle and lower lobar distribution of bronchiectasis is associated with PCD.
As expected from the underlying pathophysiologic characteristics of PCD, severity of bronchiectasis correlated with severity of pulmonary function as reflected by FEV1 and age at CT. Because of the chronic failure of mucociliary defense in PCD, both the number of lobes involved and the severity of bronchiectasis increase as age progresses.
A number of outliers in our study may reflect the heterogeneity of PCD lung disease. This study, however, was cross-sectional and not longitudinal. The presence of mucoid P. aeruginosa was associated with more severe bronchiectasis on high-resolution CT, although the numbers were small. The presence of mucoid P. aeruginosa is a poor prognostic factor in cystic fibrosis, and we [1, 28] have previously found that it may be associated with older age of patients with PCD. Thus, chronic failure of the ciliary apparatus in PCD appears to be associated with acquisition of mucoid P. aeruginosa, albeit at an older age than in cystic fibrosis. In contrast, correlation between bronchiectasis severity score and the presence of smooth P. aeruginosa, situs type, ciliary ultrastructural defect, and nasal nitric oxide level were tested without identifying a relation. Situs subtype appears to be a random phenomenon. Therefore, it is not surprising that a correlation between situs abnormalities and bronchiectasis severity score was not identified [1, 3].
We [1] previously identified no relation between ciliary ultrastructural defect and lung function in PCD. Therefore, it was not surprising that there was no correlation between ciliary defect and bronchiectasis severity score. It is also not surprising that nasal nitric oxide level does not correlate with bronchiectasis severity score or lung function, because nasal nitric oxide level is uniformly low in PCD, regardless of pulmonary function [1]. It is unclear why the concentration of nitric oxide is low in PCD. Some authors predict that it may be related to the influence of ciliary function on nitric oxide synthase activity [1].
An unexpected finding was that 12 of 29 adults had undergone lobectomy. The indication for lobectomy was severe bronchiectasis with persistent infection with or without hemoptysis. That lobectomy had been performed was generally found in older patients. The surgery, however, had been performed when the patients were young, during a different era of medical and surgical practice. This observation may lead to overestimation of the prevalence of lobectomy in young adults with PCD. In a previous report [1] of clinical disease in 78 patients, approximately 10% of PCD patients had undergone lobectomy. It is possible that patients with a history of lobectomy are more likely to have severe disease and therefore undergo high-resolution CT. A benefit from lobectomy would not be predicted in PCD given the distribution (73% adults, three or more lobes) of bronchiectasis on high-resolution CT in our cohort. Lobectomy, however, may have a role in individual cases in which morbidity can be related to a focal area of disease. It is uncertain what percentage of these patients had a diagnosis of PCD before lobectomy. This observation highlights the need for more public awareness of PCD and access to specialized diagnostic centers.
Normal thoracoabdominal asymmetry and thus situs solitus were identified in approximately 50% of patients, as previously reported [1, 2, 22, 23]. Situs inversus totalis was identified in 38% of the patients. Severity of disease as reflected by bronchiectasis severity score was not worse in patients with situs inversus totalis. Eight (18%) of the patients had anatomic anomalies consistent with heterotaxia, including congenital heart disease, a previously reported association with PCD [29-32]. In a multicenter analysis of 337 patients, we have recently identified a 6.3% incidence of heterotaxy [33]. Heterotaxy, including congenital heart disease, has also been identified in a murine model of PCD and, like situs inversus totalis, is related to disorganized left-right axis asymmetry caused by embryonic nodal ciliary dysfunction [34].
An association between PCD and pectus excavatum has not been previously identified. The incidence of pectus excavatum in the general population is 0.3%, in comparison with the prevalence of 9% identified in this PCD cohort [35]. A case report of situs inversus totalis and pectus excavatum without a clinical phenotype of PCD has been previously published [36]. The link between pectus excavatum and PCD is uncertain at this point and does not appear to be related to situs type. A diagnosis of PCD should be considered in patients with pectus excavatum with concomitant sinopulmonary disease.
Peribronchial consolidation, mucous plugging, atelectasis, and nonspecific infiltrates have been associated with bronchiectasis [8, 11, 24]. Without follow-up imaging, it is uncertain whether these findings are temporary changes related to infection and inflammation or permanent changes related to airway remodeling and chronic scarring. Longitudinal studies are needed to identify the use of high-resolution CT in the long-term care of patients with PCD.
Emphysematous changes were identified in three patients, two of whom were previous smokers. The distribution of emphysema was the lower lobe in all three of these patients, suggesting an association with PCD-related bronchiectasis. We [37] have previously reported the results of an analysis of airway calcification and calcite lithoptysis in elderly PCD patients and hypothesize that airway calcification is associated with chronic airway inflammation and the retention of infected secretions.
In conclusion, in a subset of patients with PCD, high-resolution CT findings were highlighted in terms of more accurate delineation of the distribution and nature of chronic lung disease secondary to failure of the mucociliary clearance apparatus. These findings may help in the evaluation of patients with a PCD phenotype. In all of the adult patients and more than one half of the pediatric patients in this study, bronchiectasis was evident and was distributed in the middle and lower lobes of the lung. This finding contrasts to the more diffuse disease of cystic fibrosis, which has an upper-lobe predilection. Bronchiectasis severity correlated with worse pulmonary function as reflected by FEV1 and older age at CT. In accordance with the findings in previous reports, approximately 50% of PCD patients had abnormalities of thoracoabdominal asymmetry. Most of these patients had situs inversus totalis, but some had heterotaxy. We identified the association of pectus excavatum and PCD. This assessment of high-resolution CT studies and the correlation of disease severity on high-resolution CT with patient phenotype give further insight into the diversity and natural history of PCD.
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