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Original Research
ASTHMA
98
Original Research
Design
In order to determine the onset of asthma exacerbation after
corticosteroid withdrawal, the study was conducted in a randomized, double-blind, placebo-controlled manner by comparing the
effects of 10 weeks of treatment with budesonide (400 g bid or
placebo via Turbuhaler; AstraZeneca; Lund, Sweden). The study
periods consisted of a 2-week run in phase and a 10-week
exacerbation-induction phase. Before the start of the study,
patients were screened on 2 separate days. Long-acting 2agonists and theophylline preparations were discontinued at least
72 h before the first screening visit. On the first day, FEV1 was
measured before and after inhalation of 400 g of albuterol by
metered-dose inhaler with a large-volume spacer device, and on
the second visit a methacholine challenge test was performed.
The patients stopped regular asthma medication for 2 weeks.
Thereafter, patients were randomized to receive either matched
placebo or budesonide, 400 g bid, via Turbuhaler. Patients who
had exacerbations during the run-in period were excluded from
the study. Patients visited the hospital at the end of the run-in
period, at 2-week intervals during the exacerbation-induction
period, and at the time of an exacerbation to undertake lung
function testing and sputum induction. During the study, the
patients kept a diary to record morning and evening peak
expiratory flow measurements.
Run-in Phase
During the 2-week run-in phase, all patients had to have stable
disease without lower respiratory tract infection. Throughout the
study, only terbutaline via Turbuhaler was permitted on an
on-demand basis as a rescue inhaler. A study physician was
accessible by telephone 24 h/d.
Steroid Withdrawal
Budesonide
Age, yr
Male/female gender, No.
Atopy, No.
Postbronchodilator FEV1, L
Reversibilty, %
PC20, mg/mL
36.9 2.5
4/8
10
3.87 0.17
20.4 1.0
0.98 0.26
38.3 3.1
5/7
9
3.75 0.1
20.7 1.2
0.99 0.27
Induction of Exacerbation
Steroid withdrawal was performed by inhalation of placebo,
and the study was discontinued when an exacerbation developed
or when no exacerbation of asthma occurred within the 10-week
study period. Patients undergoing exacerbation during treatment
period were withdrawn from the study. Thereafter, inhaled
budesonide was increased to 800 g bid, and systemic corticosteroids (prednisolone 30 mg/d) were administered.
An exacerbation was defined as at least one of three criteria12,13: (1) a drop in morning peak flow 20% below baseline
(mean of the last 7 days run-in period) on 2 consecutive days; (2)
wakening due to asthma on 2 consecutive nights, and requiring
rescue medication; (3) 50% increase in 24-h rescue medication
use on at least 2 consecutive days compared to mean use during
the last 7 days of the run-in period, which also exceeded the
equivalent of four puffs of terbutaline. FEV1 was then measured
within 24 h of the exacerbation.
Lung Function Measurements and Methacholine
Challenge Tests
FEV1 and FVC were measured using a dry wedge spirometer
(Vitalograph; Buckingham, UK). Values are expressed as percentCHEST / 132 / 1 / JULY, 2007
99
Results
Patient Characteristics
Patient characteristics are shown in Table 1. Two
patients in the budesonide treatment group were
excluded from the analysis: one was unable to attend
for all of the study visits, and the other provided
induced-sputum specimens containing squamous
cell counts 80%.
Exacerbations
Eight of 12 patients had an exacerbation over the
10-week period of steroid withdrawal (Table 3). The
remaining four subjects did not have an exacerbation
during the 10 weeks of follow-up. Only 1 of 10
patients in the budesonide treatment group had an
asthma exacerbation at week 2 (Table 2).
Sputum IL-8 and Neutrophils
Overall, the patients with an exacerbation after
steroid cessation had significantly increasing levels of
sputum IL-8, percentage of neutrophils, and sputum
neutrophils 2 weeks prior to an exacerbation and at
the onset of exacerbation (Fig 1, top left, A, top right,
10
72.3 1.5
10
73.4 2.1
1
3.2 0.3
41.3 4.1
1.3 0.5
2.6 0.8
0.09 0.02
53.3 3.9
1.7 0.2
2.8 0.7
0.1 0.01
10
71.8 0.9
10
73.7 0.6
10
73.2 1.1
10
72.8 1.7
3.6 0.2
38.2 2.1
1.4 0.4
1.8 0.6
0.06 0.03
57.6 2.7
2.1 0.2
2.5 0.7
0.1 0.02
3.2 0.2
36.4 5.2
1.2 0.5
1.2 0.5
0.04 0.01
60 5.5
2.0 0.2
2.4 0.6
0.07 0.02
3.5 0.4
37.7 3.8
1.3 0.6
0.45 0.2
0.01 0.004
59.7 4.8
2.1 0.9
2.1 1
0.08 0.03
3.6 0.6
38.4 4.5
1.3 0.7
0.3 0.1
0.02 0.01
59.5 4.9
2.2 0.4
2.0 0.7
0.1 0.03
3.4 0.3
33.9 3.7
1.2 0.6
4.8 1.0
0.2 0.03
57.9 3.4
1.9 0.2
3.3 0.9
0.1 0.01
10
*Data are presented as mean SEM for the patients indicated, unless otherwise indicated.
100
Original Research
Table 3Changes in Clinical Parameters and Sputum Neutrophils in Asthmatic Subjects Following Inhaled
Corticosteroid Withdrawal*
Weeks
Variables
Patients, No.
FEV1, % predicted
Exacerbations, No.
Total cells, 106/mL
Neutrophils, %
Neutrophils, 106/mL
Eosinophils, %
Eosinophils, 106/mL
Macrophages, %
Macrophages, 106/mL
Lymphocytes, %
Lymphocytes, 106/mL
10
12
73.5 0.9
0
3.7 0.3
31.0 2.6
1.1 0.1
3.8 0.5
0.1 0.02
60.6 2.7
2.3 0.3
4.2 0.7
0.1 0.02
12
66.9 1.1
4
6.0 0.8
39.7 2.3
2.5 0.4
4.2 0.7
0.2 0.04
50.9 2.6
2.9 0.4
4.5 0.7
0.2 0.04
8
67.5 1.6
1
5.7 0.8
40.8 3.6
2.5 0.5
5.3 0.9
0.3 0.04
50.2 2.9
2.7 0.3
3.8 0.9
0.2 0.05
7
67.7 1.7
1
6.9 0.9
35.6 5.9
2.7 0.7
6.4 1.3
0.4 0.06
51.8 5.7
3.3 0.3
4.9 0.8
0.3 0.05
6
67.9 1.7
2
7.7 0.7
28.2 8.4
2.4 0.8
6.4 1.3
0.4 0.07
60.9 7.1
4.5 0.6
4.7 0.5
0.4 0.05
4
71.1 0.4
0
6.4 0.4
14.3 1.3
0.9 0.1
8.1 1.1
0.5 0.06
73.6 3.0
4.7 0.5
4.5 1.7
0.3 0.1
*Data are presented as mean SEM for the patients indicated, unless otherwise indicated.
B, and bottom, C, respectively; Fig 2). The significant increase in IL-8 levels in induced sputum
occurred at 2-week prior to an exacerbation and at
the onset of exacerbation when compared with nonexacerbation (Table 4) [mean, 1,832.1 151 ng/mL
vs 1074.3 111.0 ng/mL, p 0.001; and
Figure 1. Changes in sputum IL-8 (top left, A), percentage of neutrophils (top right, B), and number of
neutrophils (bottom, C) in patients with or without an exacerbation (exac). Exacerbation data were derived from
those who were treated with placebo (eight cases) and with budesonide (one case), and the nonexacerbation
data included asthmatic subjects who were treated with budesonide (nine cases) and with placebo (four
cases). Data are shown as mean SEM. Comparisons of concentrations of IL-8 and neutrophil numbers in
sputum were made between the results 2 weeks prior to an exacerbation and those of nonexacerbation at
week 8 and between data at the exacerbation visit and those of the week-10 nonexacerbation.
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101
Figure 2. Changes in percentage of eosinophils (top, left, A) and number of eosinophils (top, right,
B), percentage of lymphocytes (center, left, C), number of lymphocytes (center, right, D),
percentage of macrophages (bottom, left, E), and number of macrophages (bottom, right, F) in
sputum collected from asthmatic subjects with and without an exacerbation. The exacerbation data
were derived from those who were treated with placebo (eight cases) and with budesonide (one
case), and the nonexacerbation data included asthmatic subjects who were treated with budesonide
(nine cases) and with placebo (four cases). All data are shown as mean SEM. Comparisons of
eosinophil numbers lymphocyte numbers and macrophage numbers in sputum were made between
the results 2 weeks prior to an exacerbation and those of nonexacerbation at week 8 and between
data on the exacerbation visit and those of the week-10 nonexacerbation. See Figure 1 legend for
expansion of abbreviation not used in text.
102
Original Research
Exacerbation
(n 9)
Nonexacerbation
(n 13)
p Value
1,832.1 151
2,690.5 154.7
1,074.3 111.0
1,420.7 149.2
0.001
0.0001
1,159.4 to 356.3
1,753 to 786.8
5.1 0.9
8.5 0.8
4.65 0.5
4.63 0.5
0.69
0.0007
1.77 to 2.61
1.84 to 5.89
42.0 3.3
51.1 1.9
23.6 3.5
29.5 4.2
0.02
0.0009
29.2 to 7.4
33.2 to 9.99
4.3 0.4
2.7 0.6
2.8 1.1
2.7 1.0
0.24
0.99
4.1 to 1.1
2.96 to 2.99
5.1 0.7
3.6 0.7
3.1 0.8
1.5 0.8
0.09
0.08
4.5 to 0.36
4.48 to 0.29
50.3 3.8
41.6 2.2
70.1 3.5
68.2 3.2
0.0003
0.0001
11.2 to 32.0
17.6 to 35.7
tum were observed either at the onset of exacerbation or 2 weeks before an exacerbation, compared
with nonexacerbation data (Table 4, Fig 2, top, left,
A, and top, right, B).
Discussion
We evaluated the use of sputum neutrophils and
IL-8 as predictors for the development of asthma
exacerbations. Our study indicates that neutrophils,
rather than eosinophils, are associated with asthma
103
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Original Research
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