Rationale: α1-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.
Bronchiectasis is recognized in α1-antitrypsin (AAT) deficiency but data are limited concerning the frequency and type of bronchiectasis, as well as the clinical and physiologic manifestations.
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.
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).
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 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 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 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.
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.
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 α1-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).
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.
|n||No. of Lobes (mean [SD])||n||No. of Lobes (mean [SD])|
|Any subtype||70||3.7 (1.74)||70||3.7 (1.79)|
|Simple tubular||65||3.9 (1.44)||46||3.4 (1.35)|
|Varicose||4||2.0 (1.73)||22||2.5 (1.69)|
|None||4||Not applicable||4||Not applicable|
|Panlobular emphysema||57||Not assessed||55||Not assessed|
|Centrilobular emphysema||33||Not assessed||20||Not assessed|
| None||13||Not applicable||15||Not applicable|
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).
|ADSBWT||1.62 (0.21)||2.42 (0.20)||0.79 (0.14)||2.02 (0.19)|
|ADSB||14.51 (0.91)||15.10 (1.08)||0.59 (0.64)||14.80 (0.95)|
|ADSTOTAL||16.14 (1.02)||17.51 (1.11)||1.34 (0.61)||16.82 (1.03)|
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.
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.
Index cases had more severe airway disease and emphysema than did nonindex cases (defined as individuals diagnosed with α1-antitrypsin deficiency after family screening of an index case) (Table 3), but disease severity was not influenced by sex.
Index (n = 56)
Nonindex (n = 18)
Difference (mean [95% CI])
|Age, yr||52.55 (1.16)||44.83 (2.11)||7.72 (3.03 to 12.41)||0.002|
|FEV1, % predicted||49.67 (3.75)||83.52 (9.20)||−33.85 (−17.11 to −50.60)||<0.001|
|DlCO/Va, % predicted||66.92 (3.26)||85.21 (5.24)||−18.30 (−5.39 to −31.21)||0.006|
|UZ VI-950||18.12 (1.90)||8.11 (1.62)||10.01 (3.12 to 16.91)||<0.001|
|LZ VI-950||28.56 (1.99)||14.29 (2.82)||14.27 (6.64 to 21.90)||<0.001|
|SGRQ Total||52.67 (2.60)||32.59 (7.12)||20.08 (7.95 to 32.22)||0.002|
|ADSBWT||2.21 (0.23)||1.44 (0.29)||0.76 (0.11 to 1.64)||0.048|
|ADSB||15.90 (0.97)||11.42 (2.38)||4.48 (0.16 to 8.80)||0.042|
|ADSTOTAL||18.10 (1.05)||12.86 (2.51)||5.24 (0.59 to 9.90)||0.028|
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.
Frequent Sputum (n = 23)
Infrequent or No Sputum (n = 51)
Mean Difference (95% CI)
|FEV1, % predicted||51.97 (6.41)||60.58 (4.96)||−8.62 (−25.68 to 8.45)||0.318|
|DlCO/Va, % predicted||68.43 (5.21)||72.69 (3.52)||−4.27 (−16.84 to 8.30)||0.501|
|UZ VI-950||15.25 (2.39)||15.84 (2.02)||−0.59 (−7.35 to 6.18)||0.863|
|LZ VI-950||24.85 (2.58)||25.12 (2.35)||−0.26 (−8.00 to 7.49)||0.947|
|Symptoms||82.61 (2.55)||51.86 (3.50)||30.75 (19.87 to 41.63)||<0.001|
|Activity||67.99 (4.88)||54.56 (4.70)||13.43 (−0.12 to 26.98)||0.052|
|Impacts||49.36 (3.85)||31.31 (3.16)||18.05 (7.39 to 28.71)||0.001|
|Total||60.54 (3.58)||41.82 (3.45)||18.71 (8.78 to 28.66)||<0.001|
|Exacerbations over 5 yr||11.23 (2.12)||5.64 (1.32)||5.59 (0.23 to 10.96)||0.042|
|ADSBWT||2.83 (0.37)||1.65 (0.21)||1.17 (0.39 to 1.95)||0.004|
|ADSB||17.84 (1.79)||13.43 (1.08)||4.42 (0.43 to 8.40)||0.030|
|ADSTOTAL||20.67 (2.04)||15.09 (1.11)||5.59 (1.33 to 9.85)||0.011|
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).
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).
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.
|ADSBWT||0.354 (0.001)||0.373 (0.001)||0.397 (<0.001)||0.393 (<0.001)||−0.531 (<0.001)||−0.399 (<0.001)||−0.181 (0.062)|
|ADSB||0.381 (<0.001)||0.307 (0.004)||0.386 (<0.001)||0.380 (<0.001)||−0.087 (0.229)||−0.086 (0.223)||−0.110 (0.176)|
|ADSTOTAL||0.399 (<0.001)||0.337 (0.002)||0.411 (<0.001)||0.405 (<0.001)||−0.179 (0.063)||−0.153 (0.096)||−0.135 (0.125)|
|UZ VI-950||0.355 (0.001)||0.426 (<0.001)||0.402 (<0.001)||0.433 (<0.001)||−0.493 (<0.001)||−0.067 (0.285)||−0.737 (<0.001)|
|LZ VI-950||0.337 (0.002)||0.557 (<0.001)||0.437 (<0.001)||0.482 (<0.001)||−0.694 (<0.001)||−0.203 (0.043)||−0.663 (<0.001)|
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).
Standardized Coefficient B
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 α1-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.
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