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Original Research: COPD |

Spirometric and Gas Transfer Discordance in α1-Antitrypsin Deficiency03B11-Antitrypsin Deficiency and COPD Progression: Patient Characteristics and Progression FREE TO VIEW

Helen Ward, MBChB; Alice M. Turner, PhD; Robert A. Stockley, MD, DSc
Author and Funding Information

From the Department of Respiratory Medicine (Dr Ward), New Cross Hospital, Wolverhampton; Queen Elizabeth Hospital Research Laboratories (Dr Turner), Birmingham; and Lung Function and Sleep Department (Prof Stockley), University Hospital Birmingham NHS Foundation Trust, Birmingham, England.

Correspondence to: Robert A. Stockley, MD, DSc, ADAPT project, Lung Function and Sleep Department, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2WB, England; e-mail: r.a.stockley@uhb.nhs.uk


Funding/Support: The Antitrypsin Deficiency Assessment and Program for Treatment (ADAPT) project is funded by an unrestricted educational grant from Grifols SA, including Dr Ward’s time as a clinical research fellow.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(6):1316-1324. doi:10.1378/chest.13-1886
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Background:  Phenotypic differences in physiologic, radiologic, and clinical characteristics are increasingly recognized in COPD. The factors associated with α1-antitrypsin deficiency (A1AD) physiologic phenotypes and how they progress with time have yet to be explained.

Methods:  The study comprised 530 patients with the homozygote Z variant (PiZZ) A1AD; 255 patients had ≥ 3 years of data for longitudinal analysis. Patients were categorized into four groups using lower limits of normal for the carbon monoxide transfer coefficient (Kco) and postbronchodilator FEV1/FVC ratio. Group comparisons were undertaken for demographic, clinical, physiologic, health status, survival, and CT scan data.

Results:  Groups with normal lung function or isolated gas transfer defect had the lowest smoking history, least emphysema, and best health status. The group with airflow obstruction (AO) alone had a greater smoking history, more emphysema, and worse health status compared with the normal group. The group with combined AO and gas transfer defect was the worst. The group with AO alone had a faster subsequent decline in Kco than the normal group (P = .002) and the group with both AO and reduced gas transfer (P < .001) and was more likely to change groups with time (62% moved to group B). Lower baseline Kco and male sex predicted 89% of the movement to the group with both physiologic abnormalities.

Conclusions:  There are distinct physiologic phenotypes in A1AD with differing demographic features that relate to progression.

Figures in this Article

COPD is a group of conditions characterized by irreversible airflow obstruction (AO). There is increasing awareness of phenotypic differences in physiologic, radiologic, and clinical characteristics that occur in varying proportions in this heterogeneous disease. These phenotypes may reflect different underlying pathologic processes, contrasting prognoses, and management strategies. Identifying phenotypes will improve the understanding of COPD and may facilitate specific management regimens. Valid phenotypes should provide prognostic information and have predictive value for the patient1 with support from mortality analysis.

α1-Antitrypsin deficiency (A1AD) is the most recognized genetic susceptibility factor for COPD. It is an autosomal codominant disorder that affects around one in 2,000 whites in Northern Europe and predisposes the development of early-onset emphysema.2 The most common, clinically relevant deficiency type is the homozygote Z variant (PiZZ), associated with a critically low serum concentration of α1-antitrypsin and, classically, basal pan acinar emphysema.

Previous studies from our group have related A1AD phenotypes to emphysema distribution and physiology. Parr et al3 showed that the carbon monoxide transfer coefficient (Kco) related better to upper-zone emphysema and FEV1 to lower-zone emphysema. Holme and Stockley4 explored this by assessing a small number of age-matched patients with isolated FEV1 or Kco abnormality defined as < 80% predicted for age and sex. The data confirmed that isolated FEV1 abnormality linked with a more basal emphysema distribution and isolated Kco abnormality with a more apical distribution. However, the small number of subjects precluded determining whether the patterns change with time and any demographic association. The aim of the current study was to explore factors that might predict or be associated with physiologic phenotypes and to assess progression over time to determine whether or how these phenotypes might change.

The first 530 patients with PiZZ and complete baseline data to 2008 who attended the Antitrypsin Deficiency Assessment and Program for Treatment (ADAPT) project were included in a cross-sectional study. The longitudinal study included 255 patients with at least 3 years of follow-up (four data points). Patients were reviewed at least 6 weeks after any exacerbation and underwent full pulmonary function tests (PFTs) using British Thoracic Society and the Association of Respiratory Technicians and Physiologists guidelines,5 blood gas sampling, quantitative CT imaging (where possible), health status assessment (St. George’s Respiratory Questionnaire [SGRQ]), and breathlessness assessment (modified Medical Research Council dyspnea score). For a subgroup of patients, mean exacerbation frequency per year was defined using the Anthonisen criteria.6 Although subjects were entered into the ADAPT project at differing stages of their disease, their survival was defined from the date of their first PFTs until the censor date of January 7, 2012, or date of death if that occurred earlier. The South Birmingham Ethics Committee approved this study (LREC No. 3359), and written informed consent was obtained from all patients.

Spirometry was measured pre- and postnebulized salbutamol (5 mg) and ipratropium bromide (500 μg) treatment using a wedge bellows spirometer (CareFusion Corp), lung volume was measured by body plethysmography, and gas transfer was measured using the single-breath carbon monoxide method.7 Predicted values were determined using Miller regression equations8 except for lung volumes, for which the European Community of Coal and Steel equations9 were used. Abnormality of physiologic data was determined using the standardized residual (SR) to define the lower limit of normal (−1.645 SR) as recommended by American Thoracic Society and European Respiratory Society10: SR values = (observed result − predicted result) / residual SD for the prediction equation.11 Reversibility was defined as > 200 mL and > 12% increase defined from the predicted FEV1.12,13

High-resolution CT scan was available for 92% of the patients (n = 489). All scans were assessed by experienced radiologists, and emphysema was noted using recognized criteria.14 For 300 of the patients, this was undertaken in our department using a protocol to determine the voxel index (VI) at a density threshold of −910 Hounsfield units at the level of the inferior pulmonary veins for the lower zones (lower-zone density of −910 Hounsfield units [LZ910]) and the level of the aortic arch for upper zones (upper-zone density of −910 Hounsfield units [UZ910]), as described previously.3

Subjects were classified into physiologic groups using the lower limit of normal for postbronchodilator FEV1/FVC and Kco (Fig 1). The group with normal FEV1/FVC and Kco was labeled N; the group with both tests returning abnormal results was labeled B; the group with abnormal FEV1/FVC alone was labeled F; and the group with abnormal Kco alone was labeled K. Index cases refer to patients identified following presentation with symptoms, and nonindex cases refer to individuals identified through family screening.

Figure Jump LinkFigure 1. Definition of the physiologic groups and number of subjects in each. Kco = carbon monoxide transfer coefficient.Grahic Jump Location

Statistical analysis was performed using PASW Statistics, v.18 (IBM). Nonparametric data were compared using the Mann-Whitney U test and a t test for parametric data. The Pearson χ2 test was used to compare distribution of data between groups. A P value ≤ .05 was accepted as significant with Bonferroni correction for multiple comparisons. Changes in FEV1 and Kco were calculated for the patients with ≥ 3 yearly annual follow-up using linear regression. Multivariate logistic regression analysis was performed to identify variables that predicted movement between subgroups.

Demographic details of the 530 subjects are shown in Tables 1 and 2. The distribution of baseline FEV1/FVC SR and Kco SR for each subject is illustrated in Figure 2.

Table Graphic Jump Location
Table 1 —Baseline Characteristics

Data given as mean (SEM).

a 

Note all demographic data for female patients are less than that of male patients in the study (P < .001), except BMI and age.

Table Graphic Jump Location
Table 2 —Baseline Physiologic Indexes for Male and Female Patients

Data given as mean (SEM). Kco = carbon monoxide transfer coefficient; RV = residual volume; SR = standardized residual; TLC = total lung capacity; Tlco = carbon monoxide transfer factor.

a 

All female physiologic data expressed as SR are lower (P ≤ .001) except for FVC, RV/TLC, and Kco.

Figure Jump LinkFigure 2. Scattergraph illustrating FEV1/FVC SR and KcoSR for each subject. SR = standardized residual. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

The FEV1/FVC SR for the cohort had a bimodal distribution (Fig 3), while Kco was normally distributed. Groups N and K (normal FEV1/FVC results) were grouped together and compared with groups F and B (abnormal FEV1/FVC results). Those with abnormal FEV1/FVC results had a greater smoking history than those in whom the results were normal (median pack-years, 18.00; interquartile ranges, 7.20-27.00, 0.00, and 0.00-8.00, respectively; P < .001), included a higher proportion of ever smokers and fewer never smokers (86% vs 46% and 14% vs 54%, respectively; P < .001), consisted of more men (63% vs 37%, P < .001) and more index cases (88% vs 31%, P < .001), were older (mean age [± SEM], 51.7 ± 0.46 vs 44.1 ± 1.59; P < .001), and had more basal emphysema assessed as the ratio of LZ910 to UZ910 VI (13.88 ± 0.86 vs 2.25 ± 1.08, respectively; P < .001).

Figure Jump LinkFigure 3. Distribution for all the subjects (N = 530) of FEV1/FVC SR (median, −7.10; interquartile range, −8.7 to −4.6) and KcoSR (mean [±SEM], −1.85 ± 0.06). See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Variables That Characterize Each Physiologic Phenotype
Group N:

These patients had PFT findings in the normal range (Table 3), including Pao2. The majority (64.4%) of the patients were women, which is an overrepresentation of the UK population (51% women15) and also higher than in groups F (P = .046) and B (P < .001) (Table 4).

Table Graphic Jump Location
Table 3 —Physiologic Indexes for Each of the Four Groups

Data given as mean (SEM) or median with interquartile ranges for nonparametric data. Percentages are rounded up to the nearest whole number. See Table 2 legend for expansion of abbreviations.

a 

Kco and FEV1 decline are represented only by subjects with longitudinal lung function data available for ≥ 3 y.

Table Graphic Jump Location
Table 4 —Demographics and Other Clinical Indexes for Each of the Four Groups

Data given as mean (SEM), median (interquartile range) for nonparametric data, or as a proportion of the group, rounded up to the nearest whole number. HU = Hounsfield units; SGRQ = St. George’s Respiratory Questionnaire; VI = voxel index.

Group N patients were younger (on average) than those in groups F and B (P < .001), and the majority were nonindex cases. There was a minimal smoking history in group N, and this was less than that of patients in groups B and F (P < .001) and the United Kingdom in general.16 The mean BMI of group N was comparable to F, a third being obese (BMI > 30), as in the UK population (26% adults aged > 16 years17). Group N had the least quantified emphysema (P < .001) and prevalence of visible emphysema (17.6%) compared with the other groups, and a lower UZ910 VI than groups F and B (P ≤ .004).Group N also had a worse health status than a healthy population.18 It was, however, better than groups F and B (P < .001).

Group K:

These patients had low gas transfer (Table 3), and 50.0% were women (Table 4). The majority (62.5%) were index cases with minimal smoking history (like group N). The average BMI was 23.3 ± 1.21, with no patient defined as obese. The prevalence of visible emphysema (50.0%) and amount was comparable to group N, and the group also had a worse health status than a healthy population.18

Group F:

Group F had AO with gas transfer in the normal range, though lower than that of group N (P < .001) (Table 3). The mean residual volume (RV) to total lung capacity (TLC) ratio was within the normal range, but was above the normal range in 20.7% of patients in group F, indicating significant gas trapping. The average Po2 was just below the normal range and lower than that of group N (P < .001). All lung function in patients in group F was better than that of group B (P ≤ .001), one-half of the patients were women, and most (84.0%) were index cases (Table 4). Smoking history was greater than for group N (P < .001) but less than that of group B (P < .007); 21.3% of the patients in group F were obese (comparable to Group N).

Group F had more emphysema than group N (P < .001) but less than group B (P < .001). Health status was also worse than that of group N (P < .001), though better than that of group B (P = .003).

Group B:

Group B had the worst physiology and lower Po2 than groups N and K (P < .001), and respiratory failure was present in 9.6% of patients. Group B had the lowest proportion of female patients, comprised mainly index patients (Table 4), had the greatest smoking history (P ≤ .042 vs other groups), and had more underweight patients than group F (P = .009).

Patients in group B had the highest visual evidence of emphysema (80.3%) and LZ910 VIs compared with all other groups (P ≤ .001 for both), a higher UZ910 VI than groups N and F (P < .001), and a worse total SGRQ score than groups N and F (P ≤ .003) but not group K (P = .055). Dyspnea score was also greater than for all other groups (P ≤ .001).

Longitudinal Change

There were 255 subjects with results of four or more complete PFTs over at least 3 years (mean, 5.37 ± 0.13 years). The average changes in FEV1 (mL/y) and Kco (mmol/min/kPa/L/y) are summarized in Table 3. There were no significant differences between the groups for FEV1 decline, although group F had a faster Kco decline than either groups B (P < .001) or N (P = .002). There was no relationship between age and decline in FEV1 or Kco. The average decline in lung function was greater than expected for age, indicated by a mean change of FEV1% predicted per year (−0.56 ± 0.25, −2.34 ± 0.58, −0.61 ± 0.17, and −0.89 ± 0.18 for groups N, K, F, and B, respectively) and Kco % predicted per year (−2.04 ± 0.34, −1.58 ± 0.69, −3.65 ± 0.26, and −1.85 ± 0.25 for groups N, K, F, and B, respectively. During the follow-up, 140 patients died, including six from group N, one from group K, 34 from group F, and 99 from group B (equivalent to 2.0%, 3.0%, 5.7%, and 8.6% of the respective groups per year).

Figure 4 summarizes movement between physiologic groups during follow-up. The majority of group N stayed in group N, but 30.0% of patients moved (four to group F, six to group K, and two to group B). The group with the largest movement was F, where 61.6% of patients moved to group B (n = 45).

Figure Jump LinkFigure 4. Bar chart showing, for each of the patient groups at baseline (horizontal axis), the percentage of subjects who were in each group at the end of the follow-up (mean, 3.87 ± 2.47 y). The number within the bars indicates the percentage of patients who remained in their baseline group.Grahic Jump Location

The 28 patients remaining in group F were compared with the 45 patients who moved to B (Table 5). There was no difference in baseline or follow-up demographics between the two groups, except that most of those who moved from group F to group B were men, and they had more upper-zone emphysema, lower baseline Kco, faster Kco decline, and more AO at baseline and follow-up than those who stayed in group F (Table 5). Female patients who moved from group F to group B had a lower baseline Kco than male patients (−1.29 ± 0.08 and −0.81 ± 0.09, respectively; P = .002), although subsequent decline was greater in male patients (mean [± SEM], −0.071 ± 0.006 and −0.051 ± 0.007 mmol/min/kPa/L/y, respectively; P = .047).

Table Graphic Jump Location
Table 5 —Demographics of Group FFa and FBb

Data given as mean (SEM), or median (interquartile range) for nonparametric data. mMRC = modified Medical Research Council. See Table 2 and 4 legends for expansion of other abbreviations.

a 

Those in group F at baseline and follow-up.

b 

Those in group F at baseline and group B at follow-up.

c 

Percentages are rounded up to the nearest whole number.

d 

P < .05.

e 

P < .01.

f 

P ≤ .001.

g 

P < .005.

Logistic regression showed the independent predictors of movement from group F to group B were baseline Kco and male sex, which together predicted 89.0% of movement. No other variable, including exacerbations, independently predicted movement from group F to group B.

These results are from the largest cohort of untreated patients with A1AD with extensive demographic and follow-up data and demonstrate four distinct physiologic groups based on gas transfer and spirometry. The data show a modal reduction in gas transfer but a bimodal distribution of AO. This suggests that the protease/antiprotease imbalance caused by antitrypsin deficiency leads to general parenchymal disease, while determinants of AO require additional factors accounting for the bimodal distribution of FEV1/FVC. We have shown that if the emphysema is distributed apically rather than basally, the FEV1 is more likely to be normal.3 Alternatively, it may represent a difference in the time course, as gas transfer is an earlier marker of parenchymal damage, whereas spirometry is a later marker of airways physiology.19 This discordance requires further epidemiologic and genetic study.

We classified patients into four distinct groups: N (data in the normal range), K (abnormal gas transfer), F (abnormal spirometry), and B (abnormal spirometry and gas transfer). It is unlikely these four groups represent a single process of progression, for two reasons. First, except for group N, the groups have the same average age; second, there are different demographic features associated with each group. It is possible that other exposures, such as pollution and/or smoking habit, may play some role. For instance, the greater smoking history of group B compared with group F may reflect the balance of parenchymal vs airways disease, and length of exposure may influence those who subsequently move from group F to group B. However, this latter possibility seems unlikely, since almost exclusively the patients recruited to the longitudinal study had stopped smoking by their first visit.

Group N had physiologic features consistent with a normal population. The majority were nonindex patients with minimal smoking history, consistent with previous literature indicating better physiology in nonindex patients20 and benefits of not smoking.21 However, the group had symptoms and impaired health status that may reflect those who were obese and, as most were women (64%), the tendency to be more aware of symptoms.22 Alternatively, this may also reflect the presence of very early disease while in the normal ranges, as the spirometry was greater and gas transfer was lower than for a healthy population.

Group K patients were slightly older, 50% were women, and they had impaired gas transfer despite normal postbronchodilator spirometry. Smoking history was minimal, although most (63%) were index patients having presented with symptoms. The health status of patients in group K was worse than that of those in group N, consistent with increased symptoms, including cough, phlegm, wheeze, and dyspnea recorded in the SGRQ symptom domain (Table 6). The older age but minimal smoking history suggests this could be the usual progression for some patients (never-smokers) from group N.

Table Graphic Jump Location
Table 6 —SGRQ Characteristics for Each of the Four Groups

Data given as median (interquartile range) unless otherwise indicated. See Table 4 and 5 legends for expansion of abbreviations.

Group F had impaired spirometry and air trapping but normal gas transfer, although the mean (SEM) SR value of −0.72 ± 0.06 suggests some reduction. The group had equal sex distribution, a tendency to be overweight, and greater smoking history than groups N and K. These features suggest smoking has an important effect on spirometry and this, with a significant proportion of overweight subjects (22%) and reduced Pao2, significantly affects health status. Despite the lower than average but “normal” gas transfer, lung densitometry indicated significant lower-zone emphysema and less upper-zone change, consistent with previous data for this physiologic group.4

Group B had the worst health status, mortality, spirometry and air-trapping findings, and gas transfer impairment. The group was predominantly male and had the greatest smoking history, although the average age was similar to that of patients in group F. Group B also had the greatest proportion of underweight subjects (often associated with an emphysema phenotype) and emphysema both in the lower zone and, importantly, in the upper zone.3 The combination of all these factors is likely to be the reason for the greater mortality of this group.

Our data on patients with A1AD have, for the first time to our knowledge, allowed comprehensive assessment of longitudinal change up to 11 years. The average decline in FEV1 was not different among groups, although gas transfer decline was greatest in group F. Changes were greater than expected for age, indicating a real pathologic change, especially for Kco in group F, which has a significant proportion of patients moving to group B.

Patients moving to B were predominantly male, had slightly worse spirometry at baseline and follow-up, and more upper-zone emphysema consistent with a lower baseline Kco.3 Importantly, the subsequent decline in Kco was more rapid in those whose Kco became abnormal (as would be predicted) than those whose gas transfer remained in the normal range.

Brantly et al,23 in a study of patients with A1AD whose lung function declined more rapidly over a shorter period, identified 24 similar patients. They reported the average FEV1 decline was 1.5 times normal (51 ± 82 mL/y), similar to our groups. However, they noted a 10-fold greater-than-normal decline in gas transfer. The reasons for this differing progression of spirometry and gas transfer were unknown, but our current and previous data3 suggest it reflects an increasing distribution of the emphysema to the upper zone, a feature of male patients and time.

The importance of this observation is that spirometry and gas transfer reflect two different, at least in part, interdependent physiologic processes of emphysema and AO. Previous work in A1AD has shown FEV1 decline is dependent on baseline FEV1, with greatest changes seen in patients with moderate AO (FEV1 50%-80% predicted). Kco decline was greatest in patients with more severe AO thought to be a later phenomenon, relating to the extension of emphysema to the upper zones.24 Parr et al25 reported that augmentation therapy in A1AD showed more treatment effects in the basal than the middle and apical lung regions, hypothesizing that differing pathology types and processes of emphysema are important determinants. For instance, a polymorphism of MMP3 has been implicated in gas transfer values in A1AD,26 which preferentially mark apical emphysema3 and may explain the lesser effect of α1-antitrypsin augmentation in this region. Studies of an MMP9 single nucleotide polymorphism shown to influence emphysema distribution in usual COPD27 showed it may have a similar influence in A1AD, but rates of upper-zone emphysema were too low to have adequate power.28 It is important that this issue is resolved, since it may impact the indications or expectations for augmentation therapy in A1AD.

Current indications for treatment are based on the presence of moderate disease where FEV1 decline is greatest. Our study shows that using phenotypes determined by spirometry and Kco may identify candidates for augmentation therapy more clearly. For instance, a subgroup with an abnormal FEV1 ratio and faster Kco decline was identified, indicating disease progression independent of FEV1 decline and a different focus for treatment. If emphysema at the lung apex arises from a distinct, pathologic process related to matrix metalloproteinases, augmentation therapy may be less effective in such patients. This possibility clearly warrants further exploration to determine whether the apical distribution of emphysema represents a natural progression related to severity and/or a distinct pathophysiologic phenotype. Prospective studies including quantitative progression in all regions of the lung matched with epidemiologic and genetic data are clearly indicated.

A potential limitation to our study is that patients enter the program at different disease stages. This varies due to the effects of occasional late diagnosis, differences in referral patterns to the UK registry and the approach to family screening. This could influence the baseline demographics, physiologic characteristics, and observed disease progression. Nevertheless, we found distinct phenotypes from which general conclusions can be drawn, especially emphasizing the importance of gas transfer in assessing A1AD.

In summary, we identified distinct physiologic phenotypes in patients with A1AD with differing demographic backgrounds that likely influence the progression of the disease, suggesting underlying epigenetic influences.

Author contributions: Prof Stockley had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Ward: contributed to data analysis, drafted the manuscript, approved the final version of the manuscript, and served as principal author.

Dr Turner: contributed to preparing the database and the data analysis and reviewed and approved the manuscript.

Prof Stockley: contributed to the study concept, supervised the study, and reviewed, edited, and approved the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Ward has received monies for speaking and industry advisory committee activities from Novartis AG, Almirall SA, GlaxoSmithKline plc, and Boehringer Ingelheim GmBH, and has attended respiratory national conferences with the financial support of pharmaceutical companies. Dr Turner has received grant awards from the Medical Research Council, Linde REAL fund, Alpha 1 Foundation, Wellcome Trust, Healthcare Infection Society, and the West Midlands Chest Fund. She has also received honoraria from GlaxoSmithKline plc, AstraZeneca plc, Boehringer Ingelheim GmBH, and Novartis AG, and works with a group that is funded by Grifols SA and CSL Ltd. Prof Stockley has lectured at symposia sponsored by Almirall SA, Boehringer Ingelheim GmBH, GlaxoSmithKline plc, Takeda Pharmaceutical Co Ltd, Novartis AG, CSL Behring LLC, and Grifols SA; has sat on numerous advisory boards for drug design and trial implementation; and has received noncommercial grant funding from AstraZeneca plc, Grifols SA, and CSL Behring LLC.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: We thank David Parr, MD, for critical appraisal of the manuscript, and the ADAPT project and Lung Function Department at University Hospital Birmingham for their support and time collecting the data, and patient support.

A1AD

α1-antitrypsin deficiency

AO

airflow obstruction

Kco

carbon monoxide transfer coefficient

LZ910

lower-zone density of −910 Hounsfield units

PFT

pulmonary function test

RV

residual volume

SGRQ

St. George’s Respiratory Questionnaire

SR

standardized residual

TLC

total lung capacity

UZ910

upper-zone density of −910 Hounsfield units

VI

voxel index

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Dales RE, Mehdizadeh A, Aaron SD, Vandemheen KL, Clinch J. Sex differences in the clinical presentation and management of airflow obstruction. Eur Respir J. 2006;28(2):319-322.
 
Brantly ML, Paul LD, Miller BH, Falk RT, Wu M, Crystal RG. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis. 1988;138(2):327-336.
 
Dawkins PA, Dawkins CL, Wood AM, Nightingale PG, Stockley JA, Stockley RA. Rate of progression of lung function impairment in alpha1-antitrypsin deficiency. Eur Respir J. 2009;33(6):1338-1344.
 
Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency. Respir Res. 2009;10:75.
 
McAloon CJ, Wood AM, Gough SC, Stockley RA. Matrix metalloprotease polymorphisms are associated with gas transfer in alpha 1 antitrypsin deficiency. Ther Adv Respir Dis. 2009;3(1):23-30.
 
Ito I, Nagai S, Handa T, et al. Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema. Am J Respir Crit Care Med. 2005;172(11):1378-1382.
 
Wood AM, McNab GL, Stockley RA. A polymorphism in the matrix metalloproteinase 9 gene may influence emphysema distribution in AATD. Thorax. 2007;62(suppl III):A29.
 

Figures

Figure Jump LinkFigure 1. Definition of the physiologic groups and number of subjects in each. Kco = carbon monoxide transfer coefficient.Grahic Jump Location
Figure Jump LinkFigure 2. Scattergraph illustrating FEV1/FVC SR and KcoSR for each subject. SR = standardized residual. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3. Distribution for all the subjects (N = 530) of FEV1/FVC SR (median, −7.10; interquartile range, −8.7 to −4.6) and KcoSR (mean [±SEM], −1.85 ± 0.06). See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Bar chart showing, for each of the patient groups at baseline (horizontal axis), the percentage of subjects who were in each group at the end of the follow-up (mean, 3.87 ± 2.47 y). The number within the bars indicates the percentage of patients who remained in their baseline group.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Characteristics

Data given as mean (SEM).

a 

Note all demographic data for female patients are less than that of male patients in the study (P < .001), except BMI and age.

Table Graphic Jump Location
Table 2 —Baseline Physiologic Indexes for Male and Female Patients

Data given as mean (SEM). Kco = carbon monoxide transfer coefficient; RV = residual volume; SR = standardized residual; TLC = total lung capacity; Tlco = carbon monoxide transfer factor.

a 

All female physiologic data expressed as SR are lower (P ≤ .001) except for FVC, RV/TLC, and Kco.

Table Graphic Jump Location
Table 3 —Physiologic Indexes for Each of the Four Groups

Data given as mean (SEM) or median with interquartile ranges for nonparametric data. Percentages are rounded up to the nearest whole number. See Table 2 legend for expansion of abbreviations.

a 

Kco and FEV1 decline are represented only by subjects with longitudinal lung function data available for ≥ 3 y.

Table Graphic Jump Location
Table 4 —Demographics and Other Clinical Indexes for Each of the Four Groups

Data given as mean (SEM), median (interquartile range) for nonparametric data, or as a proportion of the group, rounded up to the nearest whole number. HU = Hounsfield units; SGRQ = St. George’s Respiratory Questionnaire; VI = voxel index.

Table Graphic Jump Location
Table 5 —Demographics of Group FFa and FBb

Data given as mean (SEM), or median (interquartile range) for nonparametric data. mMRC = modified Medical Research Council. See Table 2 and 4 legends for expansion of other abbreviations.

a 

Those in group F at baseline and follow-up.

b 

Those in group F at baseline and group B at follow-up.

c 

Percentages are rounded up to the nearest whole number.

d 

P < .05.

e 

P < .01.

f 

P ≤ .001.

g 

P < .005.

Table Graphic Jump Location
Table 6 —SGRQ Characteristics for Each of the Four Groups

Data given as median (interquartile range) unless otherwise indicated. See Table 4 and 5 legends for expansion of abbreviations.

References

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Brantly ML, Paul LD, Miller BH, Falk RT, Wu M, Crystal RG. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis. 1988;138(2):327-336.
 
Dawkins PA, Dawkins CL, Wood AM, Nightingale PG, Stockley JA, Stockley RA. Rate of progression of lung function impairment in alpha1-antitrypsin deficiency. Eur Respir J. 2009;33(6):1338-1344.
 
Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency. Respir Res. 2009;10:75.
 
McAloon CJ, Wood AM, Gough SC, Stockley RA. Matrix metalloprotease polymorphisms are associated with gas transfer in alpha 1 antitrypsin deficiency. Ther Adv Respir Dis. 2009;3(1):23-30.
 
Ito I, Nagai S, Handa T, et al. Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema. Am J Respir Crit Care Med. 2005;172(11):1378-1382.
 
Wood AM, McNab GL, Stockley RA. A polymorphism in the matrix metalloproteinase 9 gene may influence emphysema distribution in AATD. Thorax. 2007;62(suppl III):A29.
 
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