Lung Volume Reduction Surgery in Patients With Emphysema and α-1 Antitrypsin Deficiency

University of California, San Diego, San Diego, California, United States
The Annals of thoracic surgery (Impact Factor: 3.85). 01/2007; 83(1):241-51. DOI: 10.1016/j.athoracsur.2006.07.080
Source: PubMed
ABSTRACT
The role of lung volume reduction surgery (LVRS) for individuals with alpha-1 antitrypsin (AAT) deficiency is unclear.
To assess the role of LVRS in individuals with severe deficiency of AAT, outcomes within the National Emphysema Treatment Trial were analyzed.
Of 1218 randomized subjects, 16 (1.3%) had severe AAT deficiency (serum level < 80 mg/dL) and a consistent phenotype (when available). Characteristics of these 16 patients include 87.5% male; median serum AAT level, 55.5 mg/dL; age, 66 years; forced expiratory volume in 1 second (FEV1), 27% predicted; and 50% had upper-lobe-predominant emphysema. All 10 subjects randomized to LVRS underwent the procedure. Although the small number of subjects hampered statistical analysis, 2-year mortality was higher with surgery (20% versus 0%) than with medical treatment. Comparison of outcomes between the 10 AAT-deficient and the 554 AAT-replete subjects undergoing LVRS showed a greater increase in exercise capacity at 6 months in replete subjects and a trend toward lower and shorter duration FEV1 rise in deficient individuals.
This study extends to 49 cases the published experience of LVRS in severe AAT deficiency. Although the small number of subjects precludes firm conclusions, trends of lower magnitude and duration of FEV1 rise after surgery in AAT-deficient versus AAT-replete subjects and higher mortality in deficient individuals randomized to surgery versus medical treatment suggest caution in recommending LVRS in AAT deficiency.

Full-text

Available from: Yvonne M Meli, Dec 27, 2013
Lung Volume Reduction Surgery in Patients With
Emphysema and -1 Antitrypsin Deficiency
James K. Stoller, MD, MS, Thomas R. Gildea, MD, Andrew L. Ries, MD, MPH,
Yvonne M. Meli, RN, and Matthew T. Karafa, PhD, for the National Emphysema
Treatment Trial Research Group*
Division of Medicine, Section of Respiratory Therapy; Departments of Pulmonary, Allergy, and Critical Care Medicine; and
Quantitative Health Sciences, The Cleveland Clinic Foundation, Cleveland, Ohio; and University of California, San Diego School
of Medicine, San Diego, California
Background. The role of lung volume reduction sur-
gery (LVRS) for individuals with -1 antitrypsin (AAT)
deficiency is unclear.
Methods. To assess the role of LVRS in individuals
with severe deficiency of AAT, outcomes within the
National Emphysema Treatment Trial were analyzed.
Results. Of 1218 randomized subjects, 16 (1.3%) had
severe AAT deficiency (serum level < 80 mg/dL) and a
consistent phenotype (when available). Characteristics of
these 16 patients include 87.5% male; median serum AAT
level, 55.5 mg/dL; age, 66 years; forced expiratory volume
in 1 second (FEV
1
), 27% predicted; and 50% had upper-
lobe-predominant emphysema. All 10 subjects random-
ized to LVRS underwent the procedure. Although the
small number of subjects hampered statistical analysis,
2-year mortality was higher with surgery (20% versus 0%)
than with medical treatment. Comparison of outcomes
between the 10 AAT-deficient and the 554 AAT-replete
subjects undergoing LVRS showed a greater increase in
exercise capacity at 6 months in replete subjects and a
trend toward lower and shorter duration FEV
1
rise in
deficient individuals.
Conclusions. This study extends to 49 cases the pub-
lished experience of LVRS in severe AAT deficiency. Al-
though the small number of subjects precludes firm con-
clusions, trends of lower magnitude and duration of FEV
1
rise after surgery in AAT-deficient versus AAT-replete
subjects and higher mortality in deficient individuals ran-
domized to surgery versus medical treatment suggest cau-
tion in recommending LVRS in AAT deficiency.
(Ann Thorac Surg 2007;83:241–51)
© 2007 by The Society of Thoracic Surgeons
T
he effects of lung volume reduction surgery (LVRS) in
patients with emphysema have been investigated
extensively, and results from the National Emphysema
Treatment Trial (NETT) have shown benefits of LVRS in
some patients [1, 2]; however, little attention has been
given to the effectiveness of LVRS in emphysema asso-
ciated with severe -1 antitrypsin (AAT) deficiency. In-
deed, some randomized trials of LVRS have explicitly
excluded individuals with AAT deficiency [3].Onthe
other hand, some have speculated that individuals with
panlobular emphysema, minimal smoking histories, and
less small airways disease, such as may be seen with AAT
deficiency, may be likely to benefit from LVRS [4].
To date, findings in the three small observational series
describing 6 [4],12[5], and 21 patients [6] suggest that
LVRS can confer similar [5, 6] or more modest [4] initial
improvements in forced expiratory volume in 1 second
(FEV
1
) and that these benefits are more short-lived in
AAT-deficient individuals than in AAT-replete patients
with chronic obstructive pulmonary disease (COPD) [5, 6].
Overall, this sparse available experience invites further
examination of the role of LVRS in patients with emphy-
sema related to AAT deficiency.
In the NETT, 1218 patients were randomized to LVRS or
medical therapy. We sought to address three questions:
1. What is the frequency of severe AAT deficiency
among NETT participants?
2. What were the outcomes among participants with
severe AAT deficiency randomized to LVRS versus
medical therapy?
3. Among subjects undergoing LVRS in NETT, what
were the outcomes in AAT-deficient versus AAT-
replete participants?
Material and Methods
The study protocol was approved by the Institutional
Review Boards of all participating centers, and all sub-
jects granted consent to participate.
The primary outcomes were survival and change in
exercise capacity measured by maximal, incremental,
symptom-limited exercise on a cycle ergometer, both
within 24 months. Secondary outcomes included pulmo-
nary function, symptoms, and quality of life performed as
previously described (Table 1) [1, 2].
Accepted for publication July 28, 2006.
*The NETT credit roster appears in the Appendix.
Address correspondence to Dr Stoller, Department of Pulmonary, Allergy
and Critical Care Medicine–A90, The Cleveland Clinic Foundation, 9500
Euclid Ave, Cleveland, OH 44195; e-mail: stollej@ccf.org.
© 2007 by The Society of Thoracic Surgeons 0003-4975/07/$32.00
Published by Elsevier Inc doi:10.1016/j.athoracsur.2006.07.080
GENERAL THORACIC
Page 1
Subjects were deemed eligible when both the available
AAT phenotype and level were consistent with severe
deficiency (ie, level 80 mg/dL) [7]; when only a pheno-
type was available, eligible phenotypes included PI*ZZ,
PI*Null Null, and PI*Z Null, or others recognized to be
severely deficient [8]. Because only a minority of PI*SZ
have serum levels below the protective threshold value
(80 mg/dL) [9], PI*SZ individuals were only eligible if an
accompanying AAT serum level was less than 80 mg/dL.
The radiographic distribution of emphysema was clas-
sified as either heterogeneous or homogeneous, as deter-
mined by high-resolution computed tomographic (CT)
scans read by radiologists using a visual scoring system.
Patterns of emphysema were (1) predominantly affecting
the upper lobes, (2) predominantly affecting the lower
lobes, (3) diffuse, or (4) predominantly affecting the
superior segments of the lower lobes. The latter three
groups were combined to form a “predominantly non-
upper-lobe disease” category.
As in the primary NETT analysis [2], baseline measure-
ments were those obtained at the visit closest to random-
ization after completion of required pulmonary rehabil-
itation and before randomization to medical treatment or
LVRS.
Bilateral stapled LVRS was performed by median ster-
notomy or by bilateral video-assisted thoracoscopy. The
surgical goal was to resect 20% to 30% of each lung,
targeting the most diseased portions.
Statistical analysis was conducted using the SAS soft-
ware (SAS Institute, Cary, NC). Analysis of groups at
baseline and follow-up was performed using
2
for cate
-
goric features and Wilcoxon rank sum tests for continu-
ous measures. Survival analyses through October 31,
2004 were performed using Kaplan-Meier mortality esti-
mates with the log-rank test. Values of p 0.05 were
considered statistically significant. Comparisons of
changes between AAT-deficient versus AAT-replete sub-
jects were adjusted for multiple comparisons at 6, 12, and
24 months using a Bonferroni correction, resulting in a
significance criterion of p 0.016.
Results
Of the 3775 individuals screened for NETT, 1929 (51.1%)
had serum AAT levels in normal ranges, and 29 (1.5%)
had severe AAT deficiency. Their mean serum AAT level
was 45.8 mg/dL (median, 53.0; quartiles, 24.0, 65.0) and
the phenotypes were PI*SZ in 11, PI*ZZ in 8, PI*Null Null
in 1, and other/unknown in 9.
Levels of AAT were available for 711 (27.8%) of the 2557
screened subjects who did not satisfy inclusion criteria
for NETT. Severe AAT deficiency was present in 13
(1.8%) of the 711, leaving 16 individuals (1.3%) with
severe AAT deficiency among the 1218 randomized in
NETT. Their phenotypes were PI*SZ in 7, PI*ZZ in 4,
PI*Null Null in 1, and other/unknown in 4, whose serum
Table 1. Baseline Characteristics of
-1 Antitrypsin Deficient Subjects
a
Feature
Allocated to
b
Total Group
(n 16)
LVRS
(n 10)
Medical Treatment
(n 6)
AAT serum level (mg/dL) 55.5 (36.5, 65.0) 58.5 (55.0, 71.0) 42.5 (35.0, 53.0)
Age (median, range), years 66.3 (50.1, 77.0) 65.8 (55.4, 77.0) 67.5 (50.1, 70.8)
White (%) 100 100 100
Female (%) 2 (12.5) 2 (20) 0 (0)
FEV
1
% predicted (post-bronchodilator)
27.0 (23.0, 32.5) 27.0 (26.0, 32.0) 25.0 (21.0, 33.0)
FEV
1
/FVC (post-bronchodilator)
0.320 (0.272, 0.374) 0.281 (0.243, 0.319) 0.374 (0.322, 0.389)
Maximum exercise capacity (watts) 57.0 (43.5, 75.0) 65.0 (46.0, 78.0) 49.0 (32.0, 70.0)
SGRQ overall score 43.7 (37.5, 52.0) 42.5 (35.0, 54.0) 46.1 (43.5, 50.0)
6-minute walk distance (feet) 1449.0 (1263.5, 1601.0) 1489.5 (1398.0, 1637.0) 1331.0 (1215.0, 1565.0)
Upper lobe predominant emphysema (%) 8 (50) 7 (70) 1 (16.7)
Perfusion ratio 0.385 (0.265, 0.720) 0.310 (0.190, 0.580) 0.650 (0.420, 0.890)
Post-bronchodilator mean TLC (% predicted) 129.5 (121.0, 134.5) 129.5 (121.0, 135.0) 126.5 (120.0, 133.0)
Post-bronchodilator RV (% predicted) 216.0 (183.5, 243.0) 216.0 (180.0, 229.0) 217.5 (187.0, 306.0)
Dlco (% predicted) 29.0 (23.0, 38.0) 26.5 (22.0, 38.0) 31.5 (27.0, 38.0)
Resting, room air
Pao
2
(mm Hg)
61.0 (56.5, 67.5) 64.5 (58.0, 70.0) 57.0 (54.0, 63.0)
Paco
2
(mm Hg)
42.0 (41.0, 43.0) 43.0 (42.0, 43.0) 41.0 (34.0, 42.0)
Quality of Well-Being Scale, 3-day mean score 0.567 (0.471, 0.634) 0.614 (0.498, 0.654) 0.514 (0.454, 0.542)
UCSD Shortness of Breath score 52.0 (38.0, 69.5) 52.0 (37.0, 71.0) 49.0 (39.0, 61.0)
a
Median (quartiles) are shown unless otherwise stated.
b
All comparisons between subjects allocated to LVRS versus medical treatment had p 0.05
except FEV
1
/FVC, where p 0.028.
AAT ⫽␣-1 Antitrypsin; Dlco diffusing capacity of the lung for carbon dioxide; FEV
1
forced expiratory volume in 1 second; FVC forced
vital capacity; LVRS lung volume reduction surgery; RV residual volume; SGRQ St. George’s Respiratory Questionnaire; TLC
total lung capacity; UCSD University of California, San Diego.
242 STOLLER ET AL Ann Thorac Surg
AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS 2007;83:241–51
GENERAL THORACIC
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Table 2. Changes in Outcomes at 6, 12, and 24 Months in
-1 Antitrypsin Deficient Individuals in NETT
6 Months 12 Months 24 Months
LVRS Medical Therapy LVRS Medical Therapy LVRS Medical Therapy
Median
a
[n]
Median
a
[n]
Median
a
[n]
Median
a
[n]
Median
a
[n]
Median
a
[n]
% with change in
exercise
capacity
10 watts
0 (0.0) [8] 0 (0.0) [4] 1 (25.0) [4] 1 (25.0) [4] 2 (33.3) [6] 0 (0.0) [4]
% with decrease
in SGRQ 8 pts
3 (37.5) [8] 0 (0.0) [5] 4 (25.0) [4] 0 (0.0) [5] 1 (16.7) [6] 0 (0.0) [5]
Change in
exercise
capacity (watts)
5.5 (22.5, 0.5) [8] 2.0 (6.5, 5.5) [4] 8.5 (20.5, 3.5) [4] 1.0 (3.0, 15.0) [4] 12.5 (14.0, 11.0) [6] 5.5 (8.0, 3.0)
6-minute walk
distance (feet)
42.0 (86.0, 135.0) [7] 179.0 (213.0, 14.0) [4] 14.0 (358.0, 268.5) [4] 197.0 (210.0, 122.0) [5] 69.0 (292.0, 160.0) [6] 122.0 (246.5, 87.5) [4]
FEV
1
, post-
bronchodilator
(L)
0.080 (0.10, 0.30) [8] 0.095 (0.03, 0.20) [4] 0.045 (0.16, 0.18) [4] 0.060 (0.07, 0.05) [5] 0.020 (0.16, 0.12) [6] 0.040 (0.21, 0.16) [4]
FEV
1
% predicted
3.0 (3.0, 9.5) [8] 2.0 (0.0, 5.5) [4] 0.5 (3.5, 5.0) [4] 2.0 (2.0, 2.0) [5] 0.5 (6.0, 6.0) [6] 1.0 (5.5, 4.5) [4]
FEV
1
by 20%
baseline value
3 (37.5%) [8] 1 (25.0%) [4] 1 (25.0%) [4] 1 [5] 2 (33.3%) [6] 1 (25.0%) [4]
TLC (% predicted) 18.5 (23.0, 10.5) [8] 2.5 (5.0, 0.0) [4] 15.0 (21.5, 6.5) [4] 2.0 (6.0, 3.0) [5] 15.0 (23.0, 5.0) [6] 2.5 (5.0, 3.0) [4]
RV (% predicted) 43.5 (50.0, 34.0) [8] 19.0 (21.0, 7.0) [4] 47.5 (64.5, 7.5) [4] 7.0 (13.0, 12.0) [5] 36.5 (51.0, 27.0) [6] 16.0 (3.5, 29.0) [4]
FEV
1
/FVC
0.006 (0.036, 0.035) [8] 0.015 (0.027, 0.063) [4] 0.044 (0.077, 0.025) [4] 0.045 (0.050, 0.018) [5] 0.021 (0.031, 0.031) [6] 0.004 (0.034, 0.032) [4]
Resting, room air
(mm Hg)
Pao
2
8.0 (1.0, 9.0) [7] 2.0 (1.5, 3.5) [4] 1.0 (2.0, 11.5) [4] 1.0 (1.0, 1.0) [5] 7.0 (7.0, 11.0) [5] 2.0 (3.5, 1.5) [4]
Paco
2
(mm Hg)
2.0 (5.0, 3.0) [7] 1.5 (3.5, 2.0) [4] 0.0 (3.5, 3.0) [4] 4.0 (4.0, 2.0) [5] 2.0 (3.0, 0.0) [5] 2.0 (3.5, 1.0) [5]
Quality of
Well-Being
scale
0.027 (0.101, 0.033) [8] 0.038 (0.016, 0.091) [5] 0.021 (0.175, 0.071) [4] 0.060 (0.000, 0.063) [5] 0.037 (0.011, 0.067) [6] 0.033 (0.003, 0.088) [5]
SGRQ 4.6 (11.9, 6.9) [8] 8.1 (1.6, 22.8) [5] 10.4 (3.7, 27.3) [4] 10.1 (4.6, 14.5) [5] 4.4 (7.3, 2.7) [6] 8.2 (5.8, 11.4) [5]
UCSD Shortness
of Breath score
1.5 (6.0, 22.0) [8] 4.0 (8.0, 16.0) [5] 12.0 (22.0, 21.0) [4] 4.0 (0.0, 11.0) [5] 15.5 (49.0, 6.0) [6] 2.0 (8.0, 1.0) [5]
a
Median values (25th, 75th).
FEV
1
forced expiratory volume in 1 second; FVC forced vital capacity; LVRS lung volume reduction surgery; RV residual volume; SGRQ St. George’s Respiratory
Questionnaire; TLC total lung capacity; UCSD University of California, San Diego.
The table presents the difference between the baseline value and the specified visit.
The number in square brackets indicates the number of subjects for whom the observation is available.
243Ann Thorac Surg STOLLER ET AL
2007;83:241–51 AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS
GENERAL THORACIC
Page 3
levels were in the severe deficiency range of 38 to 71 mg/dL.
One subject, with a serum level 38 mg/dL (phenotype
reported unknown), was randomized to medical treat-
ment and did not return for any clinic visits.
Comparison of the 16 eligible individuals with the 13
ineligible AAT-deficient individuals showed no signifi-
cant baseline differences. Table 1 presents the baseline
characteristics of the 16 AAT-deficient NETT subjects,
stratified by allocation to LVRS (n 10) or medical
treatment (n 6). The mean SD age was 64.5 7 years,
12.5% were women, and the baseline mean postbron-
chodilator FEV
1
was 28.2% 6.4% predicted. Ten of the
AAT-deficient subjects were randomized to LVRS, and
all underwent the procedure.
Two of the 16 subjects died within 24 months for an
overall 6-month survival rate of 87% (95% confidence
interval [CI], 69% to 100%). The survival rate at 12 and 24
months was 87% (95% CI, 69% to 100%); no deaths
occurred from 6 to 24 months. None of the 12 AAT-
deficient subjects assessed at 6 months showed increased
exercise capacity by more than 10 watts, though such
improvement was seen in 25% at 12 months and in 20%
at 24 months. Improvement in the St. George’s Respira-
tory Questionnaire (SGRQ) score by more than 8 (twice
the minimal clinically important difference) was ob-
served in 23% at 6 months, in 12.5% at 12 months, and in
10% at 24 months.
Although the small number of AAT-deficient sub-
jects precluded meaningful statistical comparison,
Table 2 describes outcomes of the 16 AAT-deficient
individuals by treatment group. Two subjects in the
LVRS group died within 6 months, for an overall LVRS
mortality rate of 20% (95% CI, 0.0% to 44.0%), and a
rate of 0.010 deaths per person-year compared with 0
deaths per person-year in medically treated subjects
and 0.004 deaths per person-year for the whole AAT-
deficient cohort. More subjects allocated to LVRS than
to medical therapy had increased exercise capacity by
more than 10 watts at 24 months (2/6, [33.3%] versus
0/4 [0%]). Also, at 24 months, LVRS recipients showed
a mean 4.4-unit fall (improvement) in the SGRQ score
versus a mean 8.2-unit rise in medically treated sub-
jects (Wilcoxon rank sum, p 0.11). Improvement in
the SGRQ (by 8 points) was observed more fre-
quently in LVRS-treated subjects at all time points.
To compare outcomes of LVRS between AAT-deficient
and AAT-replete subjects, the analysis was restricted to
the 1185 NETT subjects with available AAT levels. Ten
AAT-deficient and 578 AAT-replete subjects were ran-
domized to LVRS; 554 (95.8%) of the 578 replete subjects
and all 10 (100%) AAT-deficient subjects underwent the
procedure (Table 3).
Kaplan-Meier mortality estimates for AAT-deficient
and AAT-replete subjects undergoing LVRS were similar
(Fig 1; log-rank p 0.8), with respective mortality rates at
24 months of 20% (95% CI, 0%, 45%) and 18% (95% CI,
14%, 21%). No significant difference in the rate of achiev-
ing increased exercise capacity by more than 10 watts
was observed between AAT-deficient versus AAT-
replete subjects, although a trend at 6 months favoring
AAT-replete subjects was noted (p 0.055).
Table 4 presents the subset classification of study
Table 3. Baseline Features of AAT-Deficient and AAT-Replete Subjects Who Underwent Lung Volume Reduction Surgery
a
Feature AAT Deficient (n 10) AAT Replete As Treated (n 554)
AAT serum level (mg/dL) 58.5 (55.0, 71.0) 156.5 (137.0, 177.0)
Age (median, range), years 65.8 (55.4, 77.0) 67.8 (39.7, 84.8)
White, n (%) 10 (100) 531 (95.9)
Female, n (%) 2 (20) 228 (41.2)
FEV
1
% predicted (post-bronchodilator)
27.0 (26.0, 32.0) 26.0 (21.0, 32.0)
FEV
1
/FVC (post-bronchodilator)
0.281 (0.243, 0.319) 0.315 (0.270, 0.352)
Maximum exercise capacity (watts) 65.0 (46.0, 78.0) 35.0 (25.0, 50.0)
SGRQ overall score 42.5 (35.0, 54.0) 52.7 (44.3, 61.4)
6-minute walk distance (feet) 1489.5 (1398.0, 1637.0) 1207.0 (1007.0, 1437.0)
Upper lobe predominant emphysema, n (%) 7 (70) 358 (64.6)
Perfusion ratio 0.310 (0.190, 0.580) 0.230 (0.150, 0.390)
Post-bronchodilator mean (TLC % predicted) 129.5 (121.0, 135.0) 127.0 (116.0, 136.0)
Post-bronchodilator RV (% predicted) 216.0 (180.0, 229.0) 213.0 (188.0, 248.0)
Dlco (% predicted) 26.5 (22.0, 38.0) 28.0 (21.0, 35.0)
Room air resting
Pao
2
(mm Hg)
64.5 (58.0, 70.0) 64.0 (57.0, 71.0)
Paco
2
(mm Hg)
43.0 (42.0, 43.0) 43.0 (39.0, 47.0)
Quality of Well-Being Scale, 3-day mean score 0.614 (0.498, 0.654) 0.570 (0.503, 0.644)
UCSD Shortness of Breath score 52.0 (37.0, 71.0) 64.0 (49.0, 74.0)
a
Median and quartiles are shown unless otherwise stated.
AAT ⫽␣-1 antitrypsin; Dlco diffusing capacity of the lung for carbon dioxide; FEV
1
forced expiratory volume in 1 second; FVC forced
vital capacity; RV residual volume; SGRQ St. George’s Respiratory Questionnaire; TLC total lung capacity; UCSD University of
California, San Diego.
244 STOLLER ET AL Ann Thorac Surg
AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS 2007;83:241–51
GENERAL THORACIC
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subjects according to the primary NETT analysis [1].Of
the 10 AAT-deficient subjects undergoing LVRS, 7 were
in the upper-lobe-predominant emphysema, high-
exercise group. Both deaths within 24 months occurred in
members of this group.
Table 5 presents the outcomes among AAT-deficient
and AAT-replete subjects undergoing LVRS. After
correction for multiple comparisons, the only signifi-
cant difference was a better outcome in AAT-replete
subjects, shown by a greater increase in exercise ca-
Fig 1. Kaplan-Meier survival analysis of
-1 antitrypsin (AAT)-deficient versus AAT-replete individuals undergoing lung volume reduction
surgery (LVRS). Median follow-up time in the AAT-deficient subjects was 43.5 months versus 45.9 months for the AAT-replete subjects. Sur-
vival estimates were similar between the two groups (p 0.081, log-rank test).
Table 4. Classification of Subjects by Upper Versus Non-Upper Lobe Emphysema and High Versus Low Exercise Capacity
After Rehabilitation
AAT Deficient
LVRS Recipients
(n 10) (%)
Medical Treatment
(n 6) (%)
AAT Replete
Undergoing LVRS
(n 554) (%)
Upper lobe, low exercise 0 1 (16.7) 133 (24.0)
Non-upper lobe, low exercise 0 1 (16.7) 69 (12.5)
Upper lobe, high exercise 7 (70.0) 0 186 (33.6)
Non-upper lobe, high exercise 3 (30.0) 4 (66.7) 98 (17.7)
High risk
a
0 0 68 (12.3)
a
High-risk subjects had forced expiratory volume in 1 second (FEV
1
) 20% predicted and diffusing capacity of carbon dioxide of 20% predicted, or FEV
1
20% predicted and nonheterogenous emphysema on chest computed tomographic scan. None of the NETT subjects in the high-risk subset had severe
-1 antitrypsin deficiency.
AAT ⫽␣-1 antitrypsin; LVRS lung volume reduction surgery.
245Ann Thorac Surg STOLLER ET AL
2007;83:241–51 AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS
GENERAL THORACIC
Page 5
Table 5. Change in Outcomes at 6, 12 and 24 Months After Lung Volume Reduction Surgery in
-1 Antitrypsin Deficient Versus Replete Subjects
6 Months 12 Months 24 Months
AAT Deficient AAT Replete AAT Deficient AAT Replete AAT Deficient AAT Replete
Median [n] Median [n] Median [n] Median [n] Median [n] Median [n]
% with change in
exercise capacity
10 watts
0 (0.0%) [8] 164 (36.8%) [446] 1 (25.0%) [4] 127 (33.8%) [376] 2 (33.3%) [6] 87 (28.3%) [307]
% with decrease in
SGRQ 8 pts
3 (37.5%) [8] 279 (59.9%) [466] 1 (25.0%) [4] 241 (58.5%) [412] 1 (16.7%) [6] 183 (48.8%) [375]
Change in exercise
capacity
5.5 (22.5, 0.5) [8
ab
]
5.0 (1.0, 15.0) [446] 8.5 (20.5, 3.5) [4] 5.0 (3.5, 15.0) [376] 12.5 (14.0, 11.0) [6] 4.0 (8.0, 14.0) [307]
6-minute walk
distance (feet)
42.0 (86.0, 135.0) [7] 65.5 (69.0, 200.5) [448] 14.0 (358.0, 268.5) [4] 40.0 (120.0, 187.0) [371] 69.0 (292.0, 160.0) [6] 0.0 (199.0, 168.0) [315]
FEV
1
, post-
bronchodilator
(L)
0.080 (0.10, 0.30) [8] 0.190 (0.03, 0.35) [460] 0.045 (0.16, 0.18) [4] 0.120 (0.01, 0.29) [397] 0.020 (0.16, 0.12) [6] 0.090 (0.04, 0.23) [333]
FEV
1
(% predicted)
3.0 (3.0, 9.5) [8] 7.0 (1.0, 13.0) [460] 0.5 (3.5, 5.0) [4] 5.0 (0.0, 11.0) [397] 0.5 (6.0, 6.0) [6] 4.0 (1.0, 9.0) [333]
FEV
1
by 20%
baseline value
3 (37.5%) [8] 266 (57.8%) [460] 1 (25.0%) [4] 187 (47.1%) [397] 2 (33.3%) [6] 128 (38.4%) [333]
TLC (% predicted) 18.5 (23.0, 10.5) [8] 15.0 (23.0, 8.0) [459] 15.0 (21.5, 6.5) [4] 14.0 (22.0, 7.0) [396] 15.0 (23.0, 5.0) [6] 14.0 (22.0, 7.0) [331]
RV (% predicted) 43.5 (50.0, 34.0) [8] 53.0 (78.0, 30.0) [459] 47.5 (64.5, 7.5) [4] 51.0 (73.5, 26.0) [396] 36.5 (51.0, 27.0) [6] 50.0 (73.0, 25.0) [331]
FEV
1
/FVC (post-
bronchodilator)
0.006 (0.036, 0.035) [8] 0.027 (0.008, 0.068) [460] 0.044 (0.077, 0.025) [4
a
]
0.009 (0.024, 0.046) [397] 0.021 (0.031, 0.031) [6] 0.06 (0.031, 0.040) [333]
Resting, room air 8.0 (1.0, 9.0) [7] 5.0 (1.0, 11.0) [455] 1.0 (2.0, 11.5) [4] 3.0 (2.0, 11.0) [389] 7.0 (7.0, 11.0) [5] 4.0 (3.0, 9.0) [321]
Pao
2
(mm Hg)
8.0 (1.0, 9.0) [7] 5.0 (1.0, 11.0) [455] 1.0 (2.0, 11.5) [4] 3.0 (2.0, 11.0) [389] 7.0 (7.0, 11.0) [5] 4.0 (3.0, 9.0) [321]
Paco
2
(mm Hg)
2.0 (5.0, 3.0) [7] 2.0 (5.0, 1.0) [455] 0.0 (3.5, 3.0) [4] 1.0 (5.0, 1.0) [389] 2.0 (3.0, 0.0) [5] 1.0 (4.0, 2.0) [321]
Quality of
Well-Being scale
0.027 (0.101, 0.033) [8] 0.012 (0.057, 0.085) [468] 0.021 (0.175, 0.071) [4] 0.007 (0.063, 0.085) [413] 0.037 (0.011, 0.067) [6] 0.0 (0.108, 0.096) [377]
SGRQ 4.6 (11.9, 6.9) [8
a
]
11.2 (21.1, 2.5) [466] 10.4 (3.7, 27.3) [4
a
]
10.8 (21.3, 0.1) [412] 4.4 (7.3, 2.7) [6] 7.3 (18.1, 3.3) [375]
UCSD Shortness of
Breath score
1.5 (6.0, 22.0) [8
a
]
15.0 (29.0, 3.0) [468] 12.0 (22.0, 21.0) [4] 16.0 (32.0, 1.0) [414] 15.5 (49.0, 6.0) [6] 10.0 (28.0, 5.0) [377]
a
Wilcoxon rank sum test comparing the difference between AAT deficient versus replete subjects achieves significance (p 0.05).
b
Wilcoxon rank sum test comparing the difference between AAT
deficient versus replete subjects achieves significance after Bonferroni correction for 3 comparisons (p 0.016).
AAT ⫽␣-1 antitrypsin; FEV
1
forced expiratory volume in 1 second; FVC forced vital capacity; SGRQ St. George’s Respiratory Questionnaire; TLC total lung capacity; RV
residual volume; UCSD University of California, San Diego.
The table presents differences between the baseline value and that at the specified time point using either the median (25
th
,75
th
percentile) or the number (%).
The number in square brackets indicates the number of subjects for whom the observation is available.
246 STOLLER ET AL Ann Thorac Surg
AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS 2007;83:241–51
GENERAL THORACIC
Page 6
pacity at 6 months (Wilcoxon rank sum, p 0.006).
Comparison of the percentage increase from baseline
FEV
1
value over time (Fig 2)
showed no significant
differences at any time point, with a trend toward
greater percentage increases at 6 and 24 months in
AAT-replete LVRS recipients. Specifically, the median
increase in FEV
1
compared with baseline at 6 months
was 27% in AAT-replete individuals versus 8% in
AAT-deficient individuals, 16% and 4% at 12 months,
and 13% and 0.3% at 24 months, respectively.
Comment
The main findings in this study of outcomes of LVRS in
patients with severe deficiency of AAT are:
1. The prevalence of individuals with severe AAT
deficiency in NETT is low, such that AAT-deficient
subjects seem under-represented in NETT com-
pared with other groups of patients with COPD
[10–12].
2. In contrast to most groups of AAT-deficient individ-
uals with emphysema, AAT-deficient participants in
NETT were predominantly male (87.5%), and 50%
had upper-lobe-predominant emphysema.
3. A trend was observed toward higher mortality in
AAT-deficient individuals randomized to LVRS
versus those receiving medical treatment.
4. Other comparisons of outcomes among AAT-defi-
cient subjects undergoing LVRS versus medical
treatment showed mixed results; specifically, more
frequent improvement in SGRQ scores was ob-
served among medically treated subjects at all time
points, but a trend favoring LVRS was observed in
the rate of achieving enhanced exercise capacity by
more than 10 watts at 24 months.
5. A comparison of outcomes between AAT-deficient
and AAT-replete subjects undergoing LVRS sug-
gested better outcomes in AAT-replete individuals,
for example, a greater increase in exercise capacity
at 6 months and trends toward higher and more
prolonged FEV
1
improvement after surgery.
The findings of this analysis extend to 49 the number of
reported patients with severe AAT deficiency undergo-
ing LVRS [4–6]. To date, published experience with
LVRS in patients with AAT deficiency has, to our knowl-
edge, been limited to 39 patients in three series [4–6].A
comparison of these series shows differences in surgical
interventions and outcomes, as well as differences in the
characteristics of the patients studied. Cassina and col-
leagues [5], for example, evaluated 12 consecutive PI*ZZ
AAT-deficient patients undergoing LVRS [5] and ob-
served similar though shorter-lived improvement after
LVRS than that experienced by 18 AAT-replete individ-
uals undergoing standard upper lobe LVRS.
Gelb and colleagues [4] described no change in the
FEV
1
at 27 months in 6 PI*ZZ AAT-deficient individuals
who underwent targeted resection of the lower lobes
(including segmentectomy and lobectomy), but noted
small improvements in other pulmonary function mea-
sures such as total lung capacity, residual volume, diffus-
ing capacity of the lung for carbon dioxide, and static
lung recoil pressure.
Most recently, Tutic and colleagues [6] reported out-
comes in 21 patients with severe AAT deficiency (18
PI*ZZ, 2 PI*SZ, and 1 PI*Z Null), 10 of whom underwent
lower lobe resection, and the remainder, upper lobe
LVRS. As in the series by Cassina and colleagues [5],
significant improvements in lung function, exercise ca-
pacity, and dyspnea (ie, FEV
1
, lung volumes, arterial
blood gases, 6-minute walk distance, and Medical Re-
Fig 2. Percentage change in forced
expiratory volume in 1 second
(FEV
1
) in liters from baseline in
-1
antitrypsin (AAT)-deficient (grey)
versus AAT-replete subjects (black)
undergoing lung volume reduction
surgery. For each line, horizontal
line is median, control box is 25–
75% percentile and total line length
indicates 1.5 times the interquartile
range. (A1
-1.)
247Ann Thorac Surg STOLLER ET AL
2007;83:241–51 AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS
GENERAL THORACIC
Page 7
search Council dyspnea score) were evident but were of
shorter duration than in the AAT-replete patients with
whom their results were compared.
Comparison of results of LVRS among the three
available studies [4–6] with these results from NETT is
hampered by potentially important differences in the
characteristics of the patients and in the surgical tech-
niques used in the respective studies. For example, the
mean age of the 12 AAT-deficient subjects in the report
by Cassina and colleagues [5] was 49 10 years. These
individuals underwent bilateral muscle-sparing an-
teroaxillary thoracotomy to resect areas of the lung that
trapped air, “typically . . . of . . . basal distribution.” In
the series by Gelb and colleagues [4], the 6 patients
were older (mean age, 61 9 years) and underwent
bilateral lower lobe LVRS by a thoracoscopic approach.
The median age of patients in the series by Tutic and
colleagues [6] was 56 years (range, 38 to 74 years) and
a variety of surgical approaches were undertaken; for
example, 3 AAT-deficient patients underwent unilat-
eral LVRS alone and 2 patients with “complete lower
lobe destruction” underwent anatomic lobectomy. Of
the total 21 AAT-deficient patients undergoing LVRS,
10 underwent lower lobe resection, 4 had upper lobe
resection, and 7 had resection of portions of both the
upper and lower lobes. In the NETT study, AAT-
deficient subjects undergoing LVRS were older than
subjects in the preceding series (median age, 66 years).
As in the earlier reports, NETT LVRS recipients under-
went resection of the most diseased portions of the lung;
however, in contrast to the usual basilar distribution of
emphysema in individuals with severe AAT deficiency
[13], 70% of AAT-deficient LVRS recipients in NETT had
upper-lobe-predominant emphysema. This may reflect a
selection bias in NETT towards patients with predomi-
nantly upper lobe disease but highlights the point that
patients with AAT deficiency should be evaluated for
LVRS based on the same characteristics as other patients
and not excluded because of AAT deficiency alone.
Overall, the results of the current study are mixed, with
some favoring medical therapy and others LVRS. In the
context that these mixed results do not permit a firm
conclusion about the efficacy of LVRS compared with
medical therapy, caution in recommending LVRS for
AAT-deficient individuals must be based on the higher
mortality trends observed. We also suggest caution in
applying these findings to the general population of
AAT-deficient patients because of the somewhat atypical
characteristics of AAT-deficient NETT participants re-
ceiving LVRS.
First, the prevalence of severe AAT deficiency among
COPD populations has been shown to be 1.9% to 2.8%
[10, 11], whereas only 1.3% of NETT participants (16/1218)
had severe AAT deficiency, suggesting that AAT-
deficient individuals are under-represented in the NETT
cohort. Furthermore, features of the AAT-deficient NETT
participants differ from those in other AAT-deficient
groups in potentially important ways. For example, in
contrast to the roughly even gender distribution of sub-
jects in the National Heart, Lung, and Blood Institute
AAT Registry [11], 80% of AAT-deficient NETT partici-
pants were male. Also, although the typical panlobular
emphysema of AAT deficiency more commonly involves
the lung bases [12–15] in NETT, 70% of AAT-deficient
subjects undergoing LVRS had upper-lobe-predominant
emphysema. A recent detailed CT analysis of PI*ZZ
subjects by Parr and colleagues [13], for example, indi-
cated that 64% demonstrated basal predominance of
emphysema and that only 36% had upper-lobe-
predominant emphysema.
Several important limitations of the current study
warrant mention. First, as in the three earlier reports
[4–6], the number of AAT-deficient subjects undergoing
LVRS was small. Second, AAT-deficient subjects under-
going LVRS in NETT more frequently resembled those
with “usual” AAT-replete emphysema in having pre-
dominantly upper lobe disease. Third, because none of
the 10 patients undergoing LVRS in this series fall into the
group with the most favorable response to LVRS in the
NETT trial (ie, upper-lobe-predominant disease with low
exercise capacity after rehabilitation [1]), we cannot dis-
count the possibility that the less favorable outcomes
relate to these baseline prognostic features rather than to
their having AAT deficiency. Finally, because the AAT-
deficient subjects in the NETT trial were generally older
than AATD subjects undergoing LVRS in other series
[4–6] and other AAT-deficient individuals for whom
LVRS is considered in clinical practice, caution is needed
in applying our results to other settings.
In conclusion, comparison of LVRS versus medical
treatment in AAT-deficient subjects in NETT suggested a
trend toward higher mortality in LVRS recipients. Also,
our findings suggest that overall, the benefits of LVRS are
more modest in AAT-deficient subjects than in AAT-
replete individuals and are in accord with some others in
recommending caution about LVRS for individuals with
severe deficiency of AAT.
The National Emphysema Treatment Trial (NETT) is supported
by contracts with the National Heart, Lung, and Blood Institute
(N01HR76101, N01HR76102, N01HR76103, N01HR76104,
N01HR76105, N01HR76106, N01HR76107, N01HR76108,
N01HR76109, N01HR76110, N01HR76111, N01HR76112,
N01HR76113, N01HR76114, N01HR76115, N01HR76116,
N01HR76118, and N01HR76119), the Centers for Medicare and
Medicaid Services (CMS; formerly the Health Care Financing
Administration); and the Agency for Healthcare Research and
Quality (AHRQ).
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3. Miller JD, Berger RL, Malthaner RA, et al. Lung volume
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with advanced emphysema. Chest 2005;127:1166–77.
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Appendix
National Emphysema Treatment Trial Research Group
(NETT) Credit Roster
Members of the NETT Research Group
Office of the Chair of the Steering Committee, University of
Pennsylvania, Philadelphia, PA: Alfred P. Fishman, MD (Chair);
Betsy Ann Bozzarello, Ameena Al-Amin.
Clinical Centers
Baylor College of Medicine, Houston, Texas: Marcia Katz, MD
(Principal Investigator); Carolyn Wheeler, RN, BSN (Principal
Clinic Coordinator); Elaine Baker, RRT, RPFT; Peter Barnard,
PhD, RPFT; Phil Cagle, MD; James Carter, MD; Sophia Chatzi-
ioannou, MD; Karla Conejo-Gonzales; Kimberly Dubose, RRT;
John Haddad, MD; David Hicks, RRT, RPFT; Neal Kleiman, MD;
Mary Milburn-Barnes, CRTT; Chinh Nguyen, RPFT; Michael
Reardon, MD; Joseph Reeves-Viets, MD; Steven Sax, MD; Amir
Sharafkhaneh, MD; Owen Wilson, PhD; Christine Young PT;
Rafael Espada, MD (Principal Investigator 1996 –2002); Rose
Butanda (1999–2001); Minnie Ellisor (2002); Pamela Fox, MD
(1999–2001); Katherine Hale, MD (1998–2000); Everett Hood,
RPFT (1998–2000); Amy Jahn (1998–2000); Satish Jhingran, MD
(1998–2001); Karen King, RPFT (1998 –1999); Charles Miller III,
PhD (1996 –1999); Imran Nizami, MD (Co-principal Investigator,
2000–2001); Todd Officer (1998–2000); Jeannie Ricketts (1998
2000); Joe Rodarte, MD (Co-principal Investigator 1996–2000);
Robert Teague, MD (Co-principal Investigator 1999 –2000);
Kedren Williams (1998–1999).
Brigham and Women’s Hospital, Boston, Massachusetts: John
Reilly, MD (Principal Investigator); David Sugarbaker, MD (Co-
principal Investigator); Carol Fanning, RRT (Principal Clinic
Coordinator); Simon Body, MD; Sabine Duffy, MD; Vladmir
Formanek, MD; Anne Fuhlbrigge, MD; Philip Hartigan, MD;
Sarah Hooper, EP; Andetta Hunsaker, MD; Francine Jacobson,
MD; Marilyn Moy, MD; Susan Peterson, RRT; Roger Russell,
MD; Diane Saunders; Scott Swanson, MD (Co-principal Inves-
tigator, 1996–2001).
Cedars-Sinai Medical Center, Los Angeles, California: Rob
McKenna, MD (Principal Investigator); Zab Mohsenifar, MD
(Co-principal Investigator); Carol Geaga, RN (Principal Clinic
Coordinator); Manmohan Biring, MD; Susan Clark, RN, MN;
Jennifer Cutler, MD; Robert Frantz, MD; Peter Julien, MD;
Michael Lewis, MD; Jennifer Minkoff-Rau, MSW; Valentina
Yegyan, BS, CPFT; Milton Joyner, BA (1996–2002).
Cleveland Clinic Foundation, Cleveland, Ohio: Malcolm
DeCamp, MD (Principal Investigator); James Stoller, MD (Co-
principal Investigator); Yvonne Meli, RN,C (Principal Clinic
Coordinator); John Apostolakis, MD; Darryl Atwell, MD; Jeffrey
Chapman, MD; Pierre DeVilliers, MD; Raed Dweik, MD; Erik
Kraenzler, MD; Rosemary Lann, LISW; Nancy Kurokawa, RRT,
CPFT; Scott Marlow, RRT; Kevin McCarthy, RCPT; Pricilla
McCreight, RRT, CPFT; Atul Mehta, MD; Moulay Meziane, MD;
Omar Minai, MD; Mindi Steiger, RRT; Kenneth White, RPFT;
Janet Maurer, MD (Principal Investigator, 1996–2001); Terri
Durr, RN (2000–2001); Charles Hearn, DO (1998 –2001); Susan
Lubell, PA-C (1999–2000); Peter O’Donovan, MD (1998 –2003);
Robert Schilz, DO (1998–2002).
Columbia University, New York, in consortium with Long
Island Jewish Medical Center, New Hyde Park, New York: Mark
Ginsburg, MD (Principal Investigator); Byron Thomashow, MD
(Co-principal Investigator); Patricia Jellen, MSN, RN (Principal
Clinic Coordinator); John Austin, MD; Matthew Bartels, MD;
Yahya Berkmen, MD; Patricia Berkoski, MS, RRT (Site coordi-
nator, LIJ); Frances Brogan, MSN, RN; Amy Chong, BS, CRT;
Glenda DeMercado, BSN; Angela DiMango, MD; Sandy Do, MS,
PT; Bessie Kachulis, MD; Arfa Khan, MD; Berend Mets, MD;
Mitchell O’Shea, BS, RT, CPFT; Gregory Pearson, MD; Leonard
Rossoff, MD; Steven Scharf, MD, PhD (Co-principal Investigator,
1998–2002); Maria Shiau, MD; Paul Simonelli, MD; Kim Stavro-
lakes, MS, PT; Donna Tsang, BS; Denise Vilotijevic, MS, PT;
Chun Yip, MD; Mike Mantinaos, MD (1998–2001); Kerri
McKeon, BS, RRT, RN (1998 –1999); Jacqueline Pfeffer, MPH, PT
(1997–2002).
Duke University Medical Center, Durham, North Carolina:
Neil MacIntyre, MD (Principal Investigator); R. Duane Davis,
MD (Co-principal Investigator); John Howe, RN (Principal Clinic
Coordinator); R. Edward Coleman, MD; Rebecca Crouch, RPT;
Dora Greene; Katherine Grichnik, MD; David Harpole, Jr., MD;
Abby Krichman, RRT; Brian Lawlor, RRT; Holman McAdams,
MD; John Plankeel, MD; Susan Rinaldo-Gallo, MED; Sheila
Shearer, RRT; Jeanne Smith, ACSW; Mark Stafford-Smith, MD;
Victor Tapson, MD; Mark Steele, MD (1998–1999); Jennifer
Norten, MD (1998–1999).
Mayo Foundation, Rochester, Minnesota: James Utz, MD
249Ann Thorac Surg STOLLER ET AL
2007;83:241–51 AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS
GENERAL THORACIC
Page 9
(Principal Investigator); Claude Deschamps, MD (Co-principal
Investigator); Kathy Mieras, CCRP (Principal Clinic Coordina-
tor); Martin Abel, MD; Mark Allen, MD; Deb Andrist, RN;
Gregory Aughenbaugh, MD; Sharon Bendel, RN; Eric Edell,
MD; Marlene Edgar; Bonnie Edwards; Beth Elliot, MD; James
Garrett, RRT; Delmar Gillespie, MD; Judd Gurney, MD; Boleyn
Hammel; Karen Hanson, RRT; Lori Hanson, RRT; Gordon
Harms, MD; June Hart; Thomas Hartman, MD; Robert Hyatt,
MD; Eric Jensen, MD; Nicole Jenson, RRT; Sanjay Kalra, MD;
Philip Karsell, MD; Jennifer Lamb; David Midthun, MD; Carl
Mottram, RRT; Stephen Swensen, MD; Anne-Marie Sykes, MD;
Karen Taylor; Norman Torres, MD; Rolf Hubmayr, MD (1998
2000); Daniel Miller, MD (1999–2002); Sara Bartling, RN (1998
2000); Kris Bradt (1998–2002).
National Jewish Medical and Research Center, Denver, Col-
orado: Barry Make, MD (Principal Investigator); Marvin Pomer-
antz, MD (Co-principal Investigator); Mary Gilmartin, RN, RRT
(Principal Clinic Coordinator); Joyce Canterbury; Martin Carlos;
Phyllis Dibbern, PT; Enrique Fernandez, MD; Lisa Geyman,
MSPT; Connie Hudson; David Lynch, MD; John Newell, MD;
Robert Quaife, MD; Jennifer Propst, RN; Cynthia Raymond, MS;
Jane Whalen-Price, PT; Kathy Winner, OTR; Martin Zamora,
MD; Reuben Cherniack, MD (Principal Investigator, 1997–2000).
Ohio State University, Columbus, Ohio: Philip Diaz, MD
(Principal Investigator); Patrick Ross, MD (Co-principal Investi-
gator); Tina Bees (Principal Clinic Coordinator); Jan Drake;
Charles Emery, PhD; Mark Gerhardt, MD, PhD; Mark King, MD;
David Rittinger; Mahasti Rittinger.
Saint Louis University, Saint Louis, Missouri: Keith Naun-
heim, MD (Principal Investigator); Robert Gerber, MD (Co-
principal Investigator); Joan Osterloh, RN, MSN (Principal
Clinic Coordinator); Susan Borosh; Willard Chamberlain, DO;
Sally Frese; Alan Hibbit; Mary Ellen Kleinhenz, MD; Gregg
Ruppel; Cary Stolar, MD; Janice Willey; Francisco Alvarez, MD
(Co-principal Investigator, 1999–2002); Cesar Keller, MD (Co-
principal Investigator, 1996–2000).
Temple University, Philadelphia, Pennsylvania: Gerard Criner,
MD (Principal Investigator); Satoshi Furukawa, MD (Co-
principal Investigator); Anne Marie Kuzma, RN, MSN (Principal
Clinic Coordinator); Roger Barnette, MD; Neil Brister, MD;
Kevin Carney, RN, CCTC; Wissam Chatila, MD; Francis Cor-
dova, MD; Gilbert D’Alonzo, DO; Michael Keresztury, MD;
Karen Kirsch; Chul Kwak, MD; Kathy Lautensack, RN, BSN;
Madelina Lorenzon, CPFT; Ubaldo Martin, MD; Peter Rising,
MS; Scott Schartel, MD; John Travaline, MD; Gwendolyn Vance,
RN, CCTC; Phillip Boiselle, MD (1997–2000); Gerald O’Brien,
MD (1997–2000).
University of California, San Diego, San Diego, California:
Andrew Ries, MD, MPH (Principal Investigator); Robert Kaplan,
PhD (Co-principal Investigator); Catherine Ramirez, BS, RCP
(Principal Clinic Coordinator); David Frankville, MD; Paul
Friedman, MD; James Harrell, MD; Jeffery Johnson; David
Kapelanski, MD; David Kupferberg, MD, MPH; Catherine
Larsen, MPH; Trina Limberg, RRT; Michael Magliocca, RN,
CNP; Frank J. Papatheofanis, MD, PhD; Dawn Sassi-Dambron,
RN; Melissa Weeks.
University of Maryland at Baltimore, Baltimore, in consor-
tium with Johns Hopkins Hospital, Baltimore, Maryland: Mark
Krasna, MD (Principal Investigator); Henry Fessler, MD (Co-
principal Investigator); Iris Moskowitz (Principal Clinic Coordi-
nator); Timothy Gilbert, MD; Jonathan Orens, MD; Steven
Scharf, MD, PhD; David Shade; Stanley Siegelman, MD;
Kenneth Silver, MD; Clarence Weir; Charles White, MD.
University of Michigan, Ann Arbor, Michigan: Fernando
Martinez, MD (Principal Investigator); Mark Iannettoni, MD
(Co-principal Investigator); Catherine Meldrum, BSN, RN,
CCRN (Principal Clinic Coordinator); William Bria, MD; Kelly
Campbell; Paul Christensen, MD; Kevin Flaherty, MD; Steven
Gay, MD; Paramjit Gill, RN; Paul Kazanjian, MD; Ella Kazerooni,
MD; Vivian Knieper; Tammy Ojo, MD; Lewis Poole; Leslie
Quint, MD; Paul Rysso; Thomas Sisson, MD; Mercedes True;
Brian Woodcock, MD; Lori Zaremba, RN.
University of Pennsylvania, Philadelphia, Pennsylvania:
Larry Kaiser, MD (Principal Investigator); John Hansen-
Flaschen, MD (Co-principal Investigator); Mary Louise Demp-
sey, BSN, RN (Principal Clinic Coordinator); Abass Alavi, MD;
Theresa Alcorn, Selim Arcasoy, MD; Judith Aronchick, MD;
Stanley Aukberg, MD; Bryan Benedict, RRT; Susan Craemer, BS,
RRT, CPFT; Ron Daniele, MD; Jeffrey Edelman, MD; Warren
Gefter, MD; Laura Kotler-Klein, MSS; Robert Kotloff, MD; David
Lipson, MD; Wallace Miller, Jr., MD; Richard O’Connell, RPFT;
Staci Opelman, MSW; Harold Palevsky, MD; William Russell,
RPFT; Heather Sheaffer, MSW; Rodney Simcox, BSRT, RRT;
Susanne Snedeker, RRT, CPFT; Jennifer Stone-Wynne, MSW;
Gregory Tino, MD; Peter Wahl; James Walter, RPFT; Patricia
Ward; David Zisman, MD; James Mendez, MSN, CRNP (1997–
2001); Angela Wurster, MSN, CRNP (1997–1999).
University of Pittsburgh, Pittsburgh, Pennsylvania: Frank
Sciurba, MD (Principal Investigator); James Luketich, MD (Co-
principal Investigator); Colleen Witt, MS (Principal Clinic Coor-
dinator); Gerald Ayres; Michael Donahoe, MD; Carl Fuhrman,
MD; Robert Hoffman, MD; Joan Lacomis, MD; Joan Sexton;
William Slivka; Diane Strollo, MD; Erin Sullivan, MD; Tomeka
Simon; Catherine Wrona, RN, BSN; Gerene Bauldoff, RN, MSN
(1997–2000); Manuel Brown, MD (1997–2002); Elisabeth George,
RN, MSN (Principal Clinic Coordinator 1997–2001); Robert
Keenan, MD (Co-principal Investigator 1997–2000); Theodore
Kopp, MS (1997–1999); Laurie Silfies (1997–2001).
University of Washington, Seattle, Washingtgon: Joshua Ben-
ditt, MD (Principal Investigator), Douglas Wood, MD (Co-
principal Investigator); Margaret Snyder, MN (Principal Clinic
Coordinator); Kymberley Anable; Nancy Battaglia; Louie
Boitano; Andrew Bowdle, MD; Leighton Chan, MD; Cindy
Chwalik; Bruce Culver, MD; Thurman Gillespy, MD; David
Godwin, MD; Jeanne Hoffman; Andra Ibrahim, MD; Diane
Lockhart; Stephen Marglin, MD; Kenneth Martay, MD; Patricia
McDowell; Donald Oxorn, MD; Liz Roessler; Michelle Toshima;
Susan Golden (1998–2000).
Other Participants
Agency for Healthcare Research and Quality, Rockville, Mary-
land: Lynn Bosco, MD, MPH; Yen-Pin Chiang, PhD; Carolyn
Clancy, MD; Harry Handelsman, DO.
Centers for Medicare and Medicaid Services, Baltimore,
Maryland: Steven M Berkowitz, PhD; Tanisha Carino, PhD; Joe
Chin, MD; JoAnna Baldwin; Karen McVearry; Anthony Norris;
Sarah Shirey; Claudette Sikora Steven Sheingold, PhD
(1997–2004).
Coordinating Center, The Johns Hopkins University, Balti-
more, Maryland: Steven Piantadosi, MD, PhD (Principal Inves-
tigator); James Tonascia, PhD (Co-principal Investigator); Patri-
cia Belt; Amanda Blackford, ScM; Karen Collins; Betty Collison;
Ryan Colvin, MPH; John Dodge; Michele Donithan, MHS; Vera
Edmonds; Gregory L. Foster, MA; Julie Fuller; Judith Harle;
Rosetta Jackson; Shing Lee, ScM; Charlene Levine; Hope Liv-
ingston; Jill Meinert; Jennifer Meyers; Deborah Nowakowski;
Kapreena Owens; Shangqian Qi, MD; Michael Smith; Brett
Simon, MD; Paul Smith; Alice Sternberg, ScM; Mark Van Natta,
MHS; Laura Wilson, ScM; Robert Wise, MD.
250 STOLLER ET AL Ann Thorac Surg
AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS 2007;83:241–51
GENERAL THORACIC
Page 10
Cost Effectiveness Subcommittee: Robert M. Kaplan, PhD
(Chair); J. Sanford Schwartz, MD (Co-chair); Yen-Pin Chiang,
PhD; Marianne C. Fahs, PhD; A. Mark Fendrick, MD; Alan J.
Moskowitz, MD; Dev Pathak, PhD; Scott Ramsey, MD, PhD;
Steven Sheingold, PhD; A. Laurie Shroyer, PhD; Judith Wagner,
PhD; Roger Yusen, MD.
Cost Effectiveness Data Center, Fred Hutchinson Cancer
Research Center, Seattle, Washington: Scott Ramsey, MD, PhD
(Principal Investigator); Ruth Etzioni, PhD; Sean Sullivan, PhD;
Douglas Wood, MD; Thomas Schroeder, MA; Karma Kreizen-
beck; Kristin Berry, MS; Nadia Howlader, MS.
CT Scan Image Storage and Analysis Center, University of
Iowa, Iowa City, Iowa: Eric Hoffman, PhD (Principal Investiga-
tor); Janice Cook-Granroth, BS; Angela Delsing, RT; Junfeng
Guo, PhD; Geoffrey McLennan, MD; Brian Mullan, MD; Chris
Piker, BS; Joseph Reinhardt, PhD; Blake Robinswood; Jered
Sieren, RTR; William Stanford, MD.
Data and Safety Monitoring Board: John A. Waldhausen, MD
(Chair); Gordon Bernard, MD; David DeMets, PhD; Mark Fer-
guson, MD; Eddie Hoover, MD; Robert Levine, MD; Donald
Mahler, MD; A. John McSweeny, PhD; Jeanine Wiener-Kronish,
MD; O. Dale Williams, PhD; Magdy Younes, MD.
Marketing Center, Temple University, Philadelphia, Pennsyl-
vania: Gerard Criner, MD (Principal Investigator); Charles Solt-
off, MBA.
Project Office, National Heart, Lung, and Blood Institute,
Bethesda, Maryland: Gail Weinmann, MD (Project Officer);
Joanne Deshler (Contracting Officer); Dean Follmann, PhD;
James Kiley, PhD; Margaret Wu, PhD (1996–2001).
Other Acknowledgments
Arthur Gelb, MD, Lakewood Regional Medical Center, Lake-
wood, California.
251Ann Thorac Surg STOLLER ET AL
2007;83:241–51 AAT DEFICIENCY, LVRS IN EMPHYSEMA PATIENTS
GENERAL THORACIC
Page 11
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