help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on September 13, 2007, doi:10.1164/rccm.200703-489OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200703-489OCv1
176/12/1215    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Parr, D. G.
Right arrow Articles by Stockley, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Parr, D. G.
Right arrow Articles by Stockley, R. A.
American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 1215-1221, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200703-489OC

Original Article

Prevalence and Impact of Bronchiectasis in {alpha}1-Antitrypsin Deficiency

David G. Parr1,2, Peter G. Guest3, John H. Reynolds4, Lee J. Dowson5 and Robert A. Stockley2

1 Department of Respiratory Medicine, University Hospitals of Coventry and Warwickshire, Coventry; 2 Lung Investigation Unit and 3 Department of Radiology, University Hospital, Birmingham; 4 Department of Radiology, Birmingham Heartlands Hospital, Birmingham; and 5 Department of Respiratory Medicine, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom

Correspondence and requests for reprints should be addressed to David G. Parr, M.D., Department of Respiratory Medicine, University Hospitals of Coventry and Warwickshire, Coventry CV2 2DX, UK. E-mail: david.parr{at}uhcw.nhs.uk


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: {alpha}1-Antitrypsin (AAT) deficiency is associated with increased risk of chronic obstructive pulmonary disease (COPD), in particular emphysema, but airway disease is less well described.

Objectives: To assess the prevalence of airways disease in subjects with AAT deficiency and to identify the relationship between radiological airway abnormalities and clinical phenotype.

Methods: We characterized the computed tomographic phenotype of 74 subjects (PiZ), using visual scoring of airway disease and densitometric assessment of emphysema. Computed tomographic measurements were related to physiology, health status (St. George's Respiratory Questionnaire), and emphysema severity, and the relative impact of airway disease and emphysema severity on health status and airflow obstruction was compared by stepwise regression.

Measurements and Main Results: Bronchiectatic changes were seen in 70 subjects, and a subgroup with a bronchiectasis-predominant phenotype was identified. Clinically significant bronchiectasis (radiologic bronchiectasis in 4 or more bronchopulmonary segments together with symptoms of regular sputum production) occurred in 20 subjects (27%). AAT-deficient index cases had higher airway disease scores (P < 0.05), more severe emphysema (P < 0.001), and greater impairment of physiology (P < 0.001) and health status (P < 0.05) than nonindex cases. Airway disease scores correlated with health status, and bronchial wall thickening correlated with FEV1. Regression analysis indicated that emphysema severity had the strongest associations for health status (r = 0.505, P < 0.001) and FEV1 (r = 0.699, P < 0.001), but the addition of airway disease score improved the regression models (r = 0.596, P = 0.002 and r = 0.783, P < 0.001, respectively).

Conclusions: Emphysema is the predominant component of COPD in AAT deficiency, but the prevalence and impact of airway disease are greater than currently recognized. Consequently, future therapeutic strategies in AAT deficiency should also target this component of COPD.

Key Words: chronic obstructive pulmonary disease • emphysema • bronchiectasis • computed tomography • {alpha}1-antitryspin deficiency



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Bronchiectasis is recognized in {alpha}1-antitrypsin (AAT) deficiency but data are limited concerning the frequency and type of bronchiectasis, as well as the clinical and physiologic manifestations.

What This Study Adds to the Field
Emphysema is the predominant component of COPD in AAT deficiency, but the prevalence and impact of airway disease are greater than currently recognized. Consequently, future therapeutic strategies in AAT deficiency should also target this component of COPD.

 
{alpha}1-Antitrypsin (AAT) deficiency was first described more than 40 years ago, following the observation of an absent band on the electrophoretic strip obtained from a patient in Malmo, Sweden (1). Four of the first six electrophoretic strips that were identified as lacking this plasma protein were observed to have originated from subjects with emphysema (1, 2), and this led to recognition of the clinical syndrome associated with the deficiency of AAT (3).

The classic description of "pure" emphysema in subjects with AAT deficiency has gradually been replaced by an understanding that the associated lung disease is heterogeneous, and the clinical phenotype variable. A significant proportion of patients have airway reactivity with wheezing (4–6), and approximately 40% of patients with AAT deficiency have chronic cough and sputum expectoration (7). The presence of bronchiectasis is recognized, but, because studies of the incidence are limited (4, 8–10), it is recognized that further data are needed to evaluate the frequency and type of bronchiectasis, and to assess the clinical and physiologic manifestations (11).

The purpose of the current study was to address these pertinent issues. Some of the results of these studies have been reported previously in the form of an abstract (12, 13).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Seventy-four subjects with severe AAT deficiency (PiZ phenotype) were selected from among those who had attended our center between 1995 and 2002, and who had undergone clinical and radiologic assessment (see below) leading to a complete dataset. All subjects were assessed in a stable clinical state, and the AAT concentration and phenotype were confirmed as described previously (14). The study was approved by the local ethics committee and all subjects gave written informed consent.

Lung Function Testing
Lung function testing was performed according to the British Thoracic Society/Association of Respiratory Technicians and Physiologists guidelines (15) as described previously (14), and results were expressed as a percentage of predicted values (16).

Health Status
Health status was assessed using the St. George's Respiratory Questionnaire (SGRQ) (17), which was administered before the performance of lung function testing and with the patient well rested.

During this assessment, details relating to cough, sputum production, and sputum characteristics were obtained by direct questioning and from diary cards (18). Each patient was questioned about exacerbations, as defined by Anthonisen and coworkers (19), including information on frequency, duration, and the number of years over which the exacerbations had occurred.

Computed Tomography
Computed tomographic (CT) images were acquired with a General Electric ProSpeed scanner (General Electric Medical Systems, Milwaukee, WI), using a high-resolution protocol (120 kVp [kilovolt peak], 200 mA · s, 1-mm collimation, "bone" reconstruction algorithm). All imaging was obtained without injection of contrast material and with the subject in full inspiration, in the supine position. CT images were independently viewed on the CT console, employing standard settings for window width and level (20), by two radiologists (P.J.G. and J.R.), who were blinded to all other patient details. The presence and type of emphysema were assessed on the basis of accepted criteria (21), and airway disease was scored in each of six lobes (the lingula was regarded as a separate lobe), using a modification of a visual scoring system that has been demonstrated to be reproducible (22). The presence and extent of bronchiectasis were scored, on the basis of established CT criteria (23, 24), as follows:

Type: Grade 0 = no bronchiectasis, grade 1 = tubular bronchiectasis, grade 2 = varicose bronchiectasis, grade 3 = cystic bronchiectasis
Extent: Grade 0 = no disease, grade 1 = localized bronchiectasis affecting one or part of one bronchopulmonary segment, grade 2 = bronchiectasis affecting more than one bronchopulmonary segment
Severity of bronchial dilatation was assessed relative to the adjacent pulmonary artery as follows: Grade 0 = no bronchiectasis, grade 1 = 100 to 200% arterial diameter, grade 2 = more than 200% arterial diameter
Bronchial wall thickness (BWT) was quantified relative to the adjacent pulmonary artery as follows; grade 0 = none, grade 1 = less than 50% arterial diameter, grade 2 = greater than 50% arterial diameter

Airway disease scores for the type, extent, and severity of bronchiectasis were summed to give a bronchiectasis score that reflected just bronchial dilatation (ADSB), and the values for BWT were expressed separately to give an individual BWT score (ADSBWT) that reflected just airway wall thickening. ADSB and ADSBWT were summed to give a total airway disease score (ADSTOTAL). In addition, the distribution of airway disease was assessed using differential scores for the upper and lower lung regions that were calculated as follows: upper lung = (right upper lobe + left upper lobe + right middle lobe + lingula)/2 and lower lung = right lower lobe + left lower lobe.

Densitometric indices (voxel index at –950 Hounsfield units [VI-950]) were calculated for upper zone (UZ) (level of the aortic arch) and lower zone (LZ) (level of the inferior pulmonary veins) images by a single operator (D.G.P.), using Pulmo-CMS software (MEDIS Medical Imaging Systems BV, Leiden, The Netherlands) as described previously (25).

Individuals were grouped into quartiles, according to ADSTOTAL, as follows: 0–9, 10–19, 20–29, and >30.

Statistical Analysis
Data were analyzed with the Statistical Package for the Social Sciences (SPSS), version 11.5 (SPSS, Inc., Chicago, IL). Subject characteristics were described using descriptive statistics and expressed as means (±SD). Comparisons across groups were undertaken using unpaired t tests. Distribution of airway disease was assessed by comparison of the lower lung score with the upper lung score, using a paired t test. Analysis of the relationship between total airway disease score (ADSTOTAL) quartiles and emphysema was performed by analysis of variance. Univariate linear regression analysis was performed to identify whether CT parameters related to health status indices and physiology, and forward stepwise regression analysis, were performed to evaluate whether the assessment of airway disease by visual scoring would provide additive value to the densitometric quantification of emphysema in the prediction of health status and FEV1. A P value of less than 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subject Characteristics
All subjects were white, with a mean age of 50.6 years (SD, 9.2 yr). The majority of subjects (56 of 74) were index cases (defined as individuals diagnosed with {alpha}1-antitrypsin deficiency after presentation with lung disease) and males outnumbered females (53 to 21). Four subjects were smoking at the time of assessment and 54 subjects had been cigarette smokers, with a mean exposure of 16.9 pack-years. The mean (SD) values of the whole group for the physiological indices, expressed as a percentage of predicted values, were as follows: FEV1, 57.9 (34.1); FVC, 99.9 (19.9); residual volume, 136.6 (54.8); total lung capacity, 116.3 (22.8); diffusing capacity of the lung for CO (DLCO) by the single-breath carbon monoxide method and corrected for effective alveolar volume (DLCO/VA), 71.4 (25.0).

Prevalence of Emphysema and Bronchiectasis
Results of the visual assessment of emphysema and bronchiectasis subtypes from the baseline scans by the individual radiologists are shown in Table 1. Panlobular emphysema was visualized in the majority of subjects and interobserver agreement was high (57 vs. 55). The presence of additional centrilobular emphysema was identified in at least 20 of these individuals, but there was less concordance between the radiologists in classifying centrilobular emphysema (33 vs. 20). Densitometric assessment of the upper and lower zone images indicated that the majority of individuals had more severe emphysema in the lower lung region. The mean (SD) VI-950 was 15.8 (13.4) in the upper zone and 25.3 (15.4) in the lower zone.


View this table:
[in this window]
[in a new window]

  		TABLE 1. SEVERITY AND EXTENT OF BRONCHIECTASIS SUBTYPE ASSESSED FROM HIGH-RESOLUTION COMPUTED TOMGRAPHIC IMAGES BY TWO INDEPENDENT RADIOLOGISTS

 
The individual and averaged bronchiectasis scores are shown in Table 2, and the interobserver correlation for ADSTOTAL was r = 0.840, P < 0.001. In the majority of cases, bronchiectasis was either tubular or tubulo-varicose, and cystic morphology was present only in a minority of patients (Table 1).


View this table:
[in this window]
[in a new window]

  		TABLE 2. INDIVIDUAL AND MEAN AIRWAY DISEASE SCORES ASSESSED ON THE BASIS OF VISUAL INSPECTION OF HIGH-RESOLUTION COMPUTED TOMOGRAPHIC IMAGES BY TWO INDEPENDENT RADIOLOGISTS

 
On average, airway changes affected more than three lobes, and the distribution mirrored that of emphysema, with significantly more airway disease in the lower lobes compared with the upper and middle (lingula) lobes (Figure 1). Fifty-seven subjects had bronchiectatic changes affecting four or more bronchopulmonary segments, and 20 of these subjects also reported sputum production at least twice per day, on at least 4 days per week.


Figure 1
View larger version (5K):
[in this window]
[in a new window]

  		Figure 1. Distribution of emphysema and airway disease. Paired differences are calculated from the indices of the upper zone minus the lower zone, so that predominant basal disease distribution is represented by negative numbers. All values for the paired differences are statistically significant (P < 0.001). ADSB = airway disease score – bronchiectasis; ADSBWT = airway disease score – bronchial wall thickening; ADSTOTAL = airway disease score – total; VI-950 = voxel index at 950 Hounsfield units.

 
Subjects with greater bronchiectasis severity had more severe emphysema (P < 0.001), but the subgroup of subjects with the highest bronchiectasis score (ADSTOTAL > 30, n = 6) had significantly less emphysema than the two groups with moderate bronchiectasis (ADSTOTAL = 10–19, n = 38; and ADSTOTAL = 20–29, n = 15) (P < 0.001) (Figures 2 and 3). All three subjects who were reported to have changes of cystic bronchiectasis were in the group with the highest airway disease score.


Figure 2
View larger version (6K):
[in this window]
[in a new window]

  		Figure 2. The relationship between ADSTOTAL, divided into quartiles, and voxel index (–950 Hounsfield units [HU]) for the lower zone images. Emphysema severity was related to bronchiectasis score (P < 0.001). The subgroup with a bronchiectasis-predominant phenotype (group IV) had the highest ADSTOTAL score but had significantly less emphysema than groups II and III (P < 0.001). VI-950 = voxel index at 950 HU; ADSTOTAL = airway disease score – total.

 

Figure 3
View larger version (72K):
[in this window]
[in a new window]

  		Figure 3. Top: Lower zone image (at the level of the inferior pulmonary veins) from a subject with severe cystic bronchiectasis and mild emphysema. Bottom: Quantitative analysis of emphysema, with the low-density voxels highlighted in pink (Pulmo-CMS; Medis Medical Imaging Systems).

 
Relationship between Airway Disease and Clinical Characteristics
Index status.
Index cases had more severe airway disease and emphysema than did nonindex cases (defined as individuals diagnosed with {alpha}1-antitrypsin deficiency after family screening of an index case) (Table 3), but disease severity was not influenced by sex.


View this table:
[in this window]
[in a new window]

  		TABLE 3. COMPARISON OF INDICES OF DISEASE SEVERITY IN INDEX AND NONINDEX CASES

 
Predictive value of sputum production.
Thirty-four subjects (46%) reported that they usually produced sputum, but this symptom was not predictive of ADS, emphysema severity, impairment in physiology, or health status. A subgroup of 23 subjects (31%) reported frequent sputum production (on at least two occasions each day, for at least 4 d/wk). These subjects had significantly higher airway disease scores, a greater number of exacerbations over the preceding 5 years, and greater impairment of health status than those subjects with infrequent or no sputum production (Table 4). There were no significant differences between these groups for age, sex, or smoking history.


View this table:
[in this window]
[in a new window]

  		TABLE 4. COMPARISON OF INDICES OF DISEASE SEVERITY BETWEEN SUBJECTS WITH FREQUENT SPUTUM PRODUCTION AND SUBJECTS WITH INFREQUENT OR NO SPUTUM PRODUCTION

 
The volume of sputum production and sputum color derived from the diary card (17) were positively correlated (r = 0.534, P < 0.001). Sputum volume correlated with ADS and health status, and sputum color correlated with ADS but not with health status (see Table E1 in the online supplement). There was no relationship between sputum characteristics and smoking history, physiology, or emphysema severity, but there was a relationship between the number of years of sputum production and the number of pack-years of cigarette smoking (r = 0.437, P = 0.004).

Exacerbations.
Episodes of increased sputum production lasting more than 3 weeks were reported by 31 subjects (41%) and the mean (SE) total number of exacerbations over the preceding 5 years was 8.71 (1.38). These episodes were associated with more severe emphysema and greater impairment in health status, but there was no association between prolonged exacerbations and ADS (see Table E2).

Relationship between CT scores, physiology, and health status.
Health status correlated with both airway disease scores and emphysema severity (Table 5). Physiologic indices correlated with emphysema severity, but the only correlation with airway disease score was between ADSBWT index and impairment of airflow.


View this table:
[in this window]
[in a new window]

  		TABLE 5. CORRELATION BETWEEN HEALTH STATUS AND COMPUTED TOMOGRAPHY INDICES

 
Relative Impact of Emphysema and Airway Disease on Health Status and FEV1
The relative contribution of emphysema and airway disease to clinical phenotype was assessed by forward regression analysis. Health status (SGRQ Total) and FEV1 (% predicted) were selected as dependent variables, and CT variables (UZ VI, LZ VI, ADSBWT, ADSB, and ADSTOTAL) were selected as predictors. The strongest predictor for both variables was the severity of emphysema in the lower lung (LZ VI-950), but airway disease scores were statistically significant independent predictors (Table 6).


View this table:
[in this window]
[in a new window]

  		TABLE 6. REGRESSION ANALYSES OF HEALTH STATUS AND FEV1 ON COMPUTED TOMOGRAPHY PREDICTORS

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It is well recognized that AAT deficiency is associated with the early development of emphysema, but only a limited number of studies have assessed the association between AAT deficiency and bronchiectasis. Airway disease, including bronchiectasis and changes in the airway walls, has been identified in subjects with AAT deficiency, but these studies have been small case series and largely limited to general radiographic description (8–10). Cylindrical bronchiectasis has been described at autopsy (26), and there are isolated case reports that have suggested a putative association between bronchiectasis and AAT deficiency in the absence of emphysema (27, 28). However, the findings of these studies contrast with those of a larger study of subjects with bronchiectasis that found the prevalence of AAT deficiency to be similar to that of the general population (29). The authors concluded that AAT deficiency was not associated with an increased risk of developing bronchiectasis.

The current detailed study of a large cohort of subjects with AAT deficiency (PiZ phenotype) has identified a high prevalence of radiologic bronchiectasis that has previously been unrecognized. A wide spectrum of disease severity was observed that, in general, reflects the severity of emphysema, although there would also appear to be a distinct phenotype in which severe bronchiectasis coexists with relatively mild emphysema. The commonest morphologic type is tubular bronchiectasis, but, in the group of subjects with a bronchiectasis-predominant phenotype, cystic changes were identified (Figure 3). It is important to acknowledge that the radiographic demonstration of airway disease in the current study does not equate, in all subjects, with a diagnosis of bronchiectasis as applied in routine clinical practice. Previous descriptive radiologic studies that have identified a high prevalence of airway disease arbitrarily defined "clinically relevant bronchiectasis" to be present when more than one lobe was affected (9). In the current study, we attempted to identify the prevalence of disease that might be considered clinically relevant by practicing pulmonologists, and the criteria that were applied were symptoms of regular sputum production in association with bronchial dilatation in at least four bronchopulmonary segments. Twenty subjects fulfilled these criteria, representing 27% of the study population. This estimate is similar to previous data in comparable U.K. patient populations with chronic obstructive pulmonary disease (COPD) (30, 31) and supports the validity of the methodology in the current study, but it is acknowledged that the prevalence of bronchiectasis may differ in other populations because of varied genetic and environmental factors. In addition, it is acknowledged that we were unable to perform further extensive investigations in the study population that would have identified alternative or additional conditions that are known to predispose to bronchiectasis, such as cystic fibrosis. Consequently, it cannot be certain that the reported incidence of bronchiectasis in this cohort represents the influence of {alpha}1-antitrypsin deficiency alone, although previous studies in unselected populations of patients with bronchiectasis suggest that the incidence of identifiable causes is low (32).

Previous reports have suggested an association between emphysema and bronchiectasis (29, 33), and a causal link has been postulated (29). The application of semiquantitative assessment in the current study has allowed this association to be more clearly defined, and although the implications remain unclear, it is likely that individual susceptibility to the development of COPD determines the severity of both airway disease and emphysema. This concept is supported by the finding that both emphysema and airway disease severity are greater in index than nonindex cases, although it is acknowledged that the higher mean age of the subjects in the index group will have contributed to this difference. In addition, Cuvelier and colleagues demonstrated that in the presence of emphysema, bronchiectasis is associated with an abnormal distribution of AAT alleles, whereas in those subjects without emphysema no such association was evident (29).

An alternative explanation is that the association between emphysema and bronchiectasis may reflect a regional interaction between the underlying pathogenic processes. In the 14 patients studied by King and coworkers (9), the prevalence of bronchiectasis was greater in lobes in which the emphysema score was higher. The current study similarly indicated a concordant distribution of airway disease and emphysema with greater severity demonstrated in the lower lung. This concordance may reflect the influence of a field effect on a common pathogenic mechanism or may indicate that there is an interaction between the inflammatory processes that are considered to be causative in each condition. Bronchiectasis may be a consequence of emphysema, as previously suggested (29), but the reverse mechanism is equally plausible. Indeed, we have demonstrated that markers of inflammation in sputum relate to subsequent progression of emphysema, which would suggest that disease in the proximal airways does relate to accompanying parenchymal destruction (34). Further studies are needed to confirm and explore this potential relationship.

The prevalence of radiologic bronchiectasis in the current study was unexpectedly high and, consequently, it was of concern that the methodology may have generated data that were not representative of the clinical condition. However, it is recognized that high-resolution computed tomographic (HRCT) imaging is sensitive for detecting morphologic changes within the lung (35), and previous studies using either semiquantitative visual scoring systems (21, 22) or custom software programs (35) have validated its use in the assessment of airways. In addition, morphologic HRCT parameters have been linked with clinical activity in nondeficient subjects with bronchiectasis (37). In the current study, the morphologic features of airway disease that were visible on HRCT were shown to relate to clinical phenotype in subjects with AAT deficiency, and it is therefore likely that the scoring system used was valid. Approximately one-half of the subjects reported productive cough on a regular basis, consistent with previous estimates (7), and those subjects with frequent production of sputum were found to have more extensive bronchiectasis and bronchial wall thickening than were subjects with infrequent sputum production. Furthermore, the group of subjects with more severe bronchiectasis and more frequent sputum production had greater impairment in health status despite similar severity of emphysema and physiological impairment. It is surprising that exacerbations were related to emphysema severity but not to bronchiectasis severity, and this contrasts with the findings of a study in nondeficient individuals that related exacerbation frequency to bronchial wall thickening (37). This difference may reflect a much greater prevalence and impact of emphysema in subjects with AAT deficiency, but other studies in nondeficient subjects have also failed to identify a relationship between HRCT features of bronchiectasis and exacerbation frequency (38).

The finding of a comparable relationship for ADS and densitometric indices in univariate regression against health status further supports the validity and clinical importance of the reported airway changes, because the role of CT densitometry in the assessment of emphysema in individuals with AAT deficiency is well established. Multiple regression analysis of the SGRQ Total score allowed estimation of the relative importance of these relationships. A stronger model was obtained by combining ADSTOTAL with LZ VI-950, although it is recognized that the strongest association was the severity of emphysema in the lower lung.

In contrast, the relationship between airflow obstruction and CT indices was much stronger for VI than ADS. Although bronchial dilatation (ADSB) and the ADSTOTAL did not relate to any physiologic parameter, bronchial wall thickening (ADSBWT) related to FEV1 impairment (see Table 5) and the combination of ADSBWT with LZ VI-950 produced a stronger model in the stepwise regression of FEV1 (see Table 6). Previous studies in subjects with usual COPD have also found that the combination of emphysema and software-derived airway measurements improves the estimate of physiologic impairment (36, 39), and have demonstrated a comparable relationship to that seen in the current study. In addition, studies in nondeficient individuals have also found that airflow obstruction was not related to the severity of bronchiectasis (38, 39).

There are some limitations to the current study that require further comment. The aim of this observational study was to address the issues identified in the American Thoracic Society/European Respiratory Society statement (11) and, because an exploratory approach was necessary, the use of multiple comparisons was unavoidable. The P values for these comparisons have been included, although the need for reporting in observational studies is recognized to be contentious. Nevertheless, the majority of the relationships that were identified were clinically concordant and highly statistically significant, and therefore adjustment for multiple comparisons was not made. Furthermore, the relationships between emphysema severity, health status, and physiologic impairment, and the importance of index status on the severity of disease, have been identified in previous studies and are widely accepted.

The use of a visual scoring system is understood to be reproducible (37, 40, 41) but inevitably introduced subjectivity to the assessment of airway abnormalities, and this will have increased the variability of the airway indices. Although the two radiologists adhered to the viewing and reporting criteria that had been previously agreed by mutual consent, there were individual case differences in the absolute ADSBWT scores and the classification of bronchiectasis morphology. Nevertheless, the correlation between the scores produced by the two radiologists is strong, which indicates consistency in the assessment of the relative severity of airway abnormalities across the spectrum of disease, and the mean difference in ADSTOTAL is small. Although the variability inherent in the subjective visual scoring method that was used in the current study is greater than that of custom software, the technique can be more easily applied to the global assessment of multiple airways throughout the lung than current automated methods. Nevertheless, it is likely that the use of measurements obtained by custom software analysis would have strengthened the relationships that were demonstrated in the current study and enabled more equitable comparison with the objective measurements used in the assessment of emphysema severity. It is anticipated that improvements in software for airway morphometry will facilitate comprehensive assessment of the airways in future studies.

In conclusion, we have identified a high prevalence of bronchiectasis and bronchial wall thickening in subjects with AAT deficiency and have demonstrated that the morphologic features identified from HRCT images relate to clinical phenotype. These findings indicate the need for further characterization of airway disease in AAT deficiency and suggest that this component of lung disease should be included in future therapeutic strategies in AAT deficiency.


   FOOTNOTES
 
Funding for the ADAPT program is by a noncommercial grant from Talecris Biotherapeutics, and use of the Pulmo-CMS software is supported by European Union funding (grant RNDV.07773).

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200703-489OC on September 13, 2007

Conflict of Interest Statement: D.G.P. received $1,600 in 2004, $3,200 in 2005, and $2,400 in 2006 from Talecris, $600 in 2006 from Roche for consultancy fees, and accepted sponsorship for conference attendance from Boehringer in 2006. P.G.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.H.R. received fees from AstraZeneca for a lecture in 2006. L.J.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.A.S. received $2,000 from GlaxoSmithKline, $1,000 from Schering, $1,000 from Merck Sharp & Dohme, and $1,000 from Boehringer in advisory board fees; $1,000 from Talecris, $1,000 from AstraZeneca, and $1,000 from Roche in lecture fees; $950,000 from Talecris and $120,000 from AstraZeneca in grants; and accepted $5,000 in sponsorship fees to attend meetings from Boehringer from 2004 to 2007.

Received in original form March 26, 2007; accepted in final form September 12, 2007


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Laurell CB, Eriksson S. The electrophoretic {alpha}1-globulin pattern of serum in {alpha}1-antitrypsin deficiency. Scand J Clin Lab Invest 1963;15:132–140.[CrossRef]
  2. Eriksson L, Laurell CB. A new abnormal serum globulin {alpha}1-antitrypsin. Acta Chem Scand A 1963;17:150–153.
  3. Eriksson S. Studies in {alpha}1-antitrypsin deficiency. Acta Med Scand Suppl 1965;432:1–85.[Medline]
  4. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:S77–S121.
  5. Black LF, Hyatt RE, Stubbs SE. Mechanism of airflow limitation in chronic obstructive pulmonary disease associated with {alpha}1-antitrypsin deficiency. Am Rev Respir Dis 1972;105:891–899.[Medline]
  6. Makino S, Chosy L, Valdiva E, Reed CE. Emphysema with hereditary {alpha}1-antitrypsin deficiency masquerading as asthma. J Allergy 1970;46:40–48.[CrossRef][Medline]
  7. Tobin MJ, Cook PJ, Hutchison DC. {alpha}1-Antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z: a survey by the British Thoracic Association. Br J Dis Chest 1983;77:14–27.[Medline]
  8. Guest PJ, Hansell DM. High resolution computed tomography (HRCT) in emphysema associated with {alpha}1-antitrypsin deficiency. Clin Radiol 1992;45:260–266.[CrossRef][Medline]
  9. King MA, Stone JA, Diaz PT, Mueller CF, Becker WJ, Gadek JE. {alpha}1-Antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology 1996;199:137–141.[Abstract/Free Full Text]
  10. Shin MS, Ho KJ. Bronchiectasis in patients with {alpha}1-antitrypsin deficiency: a rare occurrence? Chest 1993;104:1384–1386.[CrossRef][Medline]
  11. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with {alpha}1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818–900.[Free Full Text]
  12. Parr DG, Reynolds JH, Stockley RA. Assessment of the prevalence and impact of bronchiectasis in {alpha}1-antitrypsin deficiency [abstract]. Proc Am Thorac Soc 2006;3:A494.[CrossRef]
  13. Parr DG, Reynolds JH, Guest PJ, Bailey D, Sullivan A, Stockley RA. The relationship between inflammation and COPD phenotype and in {alpha}1-antitrypsin deficiency (AATD) [abstract]. Am J Respir Crit Care Med 2007;175:A990.
  14. Dowson LJ, Newall C, Guest PJ, Hill SL, Stockley RA. Exercise capacity predicts health status in {alpha}1-antitrypsin deficiency. Am J Respir Crit Care Med 2001;163:936–941.[Abstract/Free Full Text]
  15. British Thoracic Society. Guidelines for the measurement of respiratory function: recommendations of the British Thoracic Society and the Association of Respiratory Technicians and Physiologists. Respir Med 1994;88:165–194.[Medline]
  16. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows: Report of working party, standardization of lung function tests, European Community for Steel and Coal [official statement of the European Respiratory Society]. Eur Respir J Suppl 1993;16:5–40.[Medline]
  17. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation: the St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321–1327.[Medline]
  18. Woolhouse IS, Hill SL, Stockley RA. Symptom resolution assessed using a patient directed diary card during treatment of acute exacerbations of chronic bronchitis. Thorax 2001;56:947–953.[Abstract/Free Full Text]
  19. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196–204.[Abstract/Free Full Text]
  20. Bankier AA, Fleischmann D, Mallek R, Windisch A, Winkelbauer FW, Kontrus M, Havelec L, Herold CJ, Hubsch P. Bronchial wall thickness: appropriate window settings for thin-section CT and radiologic–anatomic correlation. Radiology 1996;199:831–836.[Abstract/Free Full Text]
  21. Naidich DP. High-resolution computed tomography of cystic lung disease. Semin Roentgenol 1991;26:151–174.[CrossRef][Medline]
  22. Bhalla M, Turcios N, Aponte V, Jenkins M, Leitman BS, McCauley DI, Naidich DP. Cystic fibrosis: scoring system with thin-section CT. Radiology 1991;179:783–788.[Abstract/Free Full Text]
  23. Grenier PA, Beigelman-Aubry C, Fetita C, Preteux F, Brauner MW, Lenoir S. New frontiers in CT imaging of airway disease. Eur Radiol 2002;12:1022–1044.[CrossRef][Medline]
  24. McGuinness G, Naidich DP. CT of airways disease and bronchiectasis. Radiol Clin North Am 2002;40:1–19.[CrossRef][Medline]
  25. Parr DG, Stoel BC, Stolk J, Nightingale PG, Stockley RA. Influence of calibration on densitometric studies of emphysema progression using computed tomography. Am J Respir Crit Care Med 2004;170:883–890.[Abstract/Free Full Text]
  26. World Health Organisation. {alpha}1-Antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ 1997;75:397–415.[Medline]
  27. Longstreth GF, Weitzman SA, Browning RJ, Lieberman J. Bronchiectasis and homozygous {alpha}1-antitrypsin deficiency. Chest 1975;67:233–235.[CrossRef][Medline]
  28. Scott JH, Anderson CL, Shankar PS, Stavrides A. {alpha}1-Antitrypsin deficiency with diffuse bronchiectasis and cirrhosis of the liver. Chest 1977;71:535–538.[CrossRef][Medline]
  29. Cuvelier A, Muir JF, Hellot MF, Benhamou D, Martin JP, Benichou J, Sesboue R. Distribution of {alpha}1-antitrypsin alleles in patients with bronchiectasis. Chest 2000;117:415–419.[CrossRef][Medline]
  30. Dowson LJ, Guest PJ, Stockley RA. The relationship of chronic sputum expectoration to physiologic, radiologic, and health status characteristics in {alpha}1-antitrypsin deficiency (PiZ). Chest 2002;122:1247–1255.[CrossRef][Medline]
  31. O'Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000;55:635–642.[Abstract/Free Full Text]
  32. Pasteur MC, Helliwell SM, Houghton SJ, Webb SC, Foweraker JG, Coulden RA, Flower CD, Bilton D, Keogan MT. An investigation into causative factors in bronchiectasis. Am J Respir Crit Care Med 2000;162:1277–1284.[Abstract/Free Full Text]
  33. Loubeyre P, Paret M, Revel D, Wiesendanger T, Brune J. Thin-section CT detection of emphysema associated with bronchiectasis and correlation with pulmonary function tests. Chest 1996;109:360–365.[Medline]
  34. Parr DG, White AJ, Bayley DL, Guest PJ, Stockley RA. Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study. Respir Res 2006;7:136.[CrossRef][Medline]
  35. Kang EY, Miller RR, Muller NL. Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens. Radiology 1995;195:649–654.[Abstract/Free Full Text]
  36. Nakano Y, Muro S, Sakai H, Hirai T, Chin K, Tsukino M, Nishimura K, Itoh H, Pare PD, Hogg JC, et al. Computed tomographic measurements of airway dimensions and emphysema in smokers: correlation with lung function. Am J Respir Crit Care Med 2000;162:1102–1108.[Abstract/Free Full Text]
  37. Ooi GC, Khong PL, Chan-Yeung M, Ho JC, Chan PK, Lee JC, Lam WK, Tsang KW. High-resolution CT quantification of bronchiectasis: clinical and functional correlation. Radiology 2002;225:663–672.[Abstract/Free Full Text]
  38. Patel IS, Vlahos I, Wilkinson TM, Lloyd-Owen SJ, Donaldson GC, Wilks M, Reznek RH, Wedzicha JA. Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:400–407.[Abstract/Free Full Text]
  39. Aziz ZA, Wells AU, Desai SR, Ellis SM, Walker AE, MacDonald S, Hansell DM. Functional impairment in emphysema: contribution of airway abnormalities and distribution of parenchymal disease. AJR Am J Roentgenol 2005;185:1509–1515.[Abstract/Free Full Text]
  40. Roberts HR, Wells AU, Milne DG, Rubens MB, Kolbe J, Cole PJ, Hansell DM. Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests. Thorax 2000;55:198–204.[Abstract/Free Full Text]
  41. Lucidarme O, Grenier P, Coche E, Lenoir S, Aubert B, Beigelman C. Bronchiectasis: comparative assessment with thin-section CT and helical CT. Radiology 1996;200:673–679.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 NEJMHome page
E. K. Silverman and R. A. Sandhaus
Alpha1-Antitrypsin Deficiency
N. Engl. J. Med., June 25, 2009; 360(26): 2749 - 2757.
[Full Text] [PDF]

Home page
 ChestHome page
A. E. O'Donnell
Bronchiectasis
Chest, October 1, 2008; 134(4): 815 - 823.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
E. D. Chan and M. D. Iseman
Significance of Bronchiectasis in Patients with {alpha}1-Antitrypsin Deficiency
Am. J. Respir. Crit. Care Med., July 15, 2008; 178(2): 208 - 208.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. G. Parr, P. G. Guest, J. H. Reynolds, L. J. Dowson, and R. A. Stockley
Significance of Bronchiectasis in Patients with {alpha}1-Antitrypsin Deficiency
Am. J. Respir. Crit. Care Med., July 15, 2008; 178(2): 208 - 209.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200703-489OCv1
176/12/1215    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Parr, D. G.
Right arrow Articles by Stockley, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Parr, D. G.
Right arrow Articles by Stockley, R. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2007 American Thoracic Society