Loss of Control of Asthma Following Inhaled

Corticosteroid Withdrawal Is Associated

With Increased Sputum Interleukin-8 and
Neutrophils *
Kittipong Maneechotesuwan, Sarah Essilfie-Quaye, Sergei A.
Kharitonov, Ian M. Adcock and Peter J. Barnes
Chest 2007;132;98-105; Prepublished online June 5, 2007;
DOI 10.1378/chest.06-2982
The online version of this article, along with updated information and
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Chest is the official journal of the American College of Chest

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Copyright2007by the American College of Chest Physicians, 3300
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2007 American College of Chest Physicians

Original Research
ASTHMA

Loss of Control of Asthma Following

Inhaled Corticosteroid Withdrawal Is
Associated With Increased Sputum
Interleukin-8 and Neutrophils*
Kittipong Maneechotesuwan, MD, PhD; Sarah Essilfie-Quaye, BSc;
Sergei A. Kharitonov, MD, PhD; Ian M. Adcock, PhD; and
Peter J. Barnes, DM, DSc, FCCP

Background: The role of neutrophils in exacerbations of asthma is poorly understood. We

examined the effect of withdrawal of inhaled corticosteroids on sputum inflammatory indexes in
a double-blind study in patients with moderate, stable asthma.
Methods: Following a 2-week run in period, 24 subjects were randomized to receive either
budesonide (400 g bid) or placebo, and the study was continued for another 10 weeks.
Results: Loss of asthma control developed in 8 of 12 patients over the 10-week period of steroid
withdrawal, whereas only 1 of 10 patients with budesonide treatment had exacerbations. Those
with an exacerbation had increased sputum interleukin (IL)-8 (p < 0.0001) and increased sputum
neutrophil numbers (p < 0.0001) compared to those without an exacerbation. The significant
elevation in sputum IL-8 and neutrophil counts initially occurred 2 weeks prior to an exacerbation. Sputum neutrophilia correlated positively with changes in IL-8 levels (r2 0.76, p 0.01).
Conclusions: Rapid withdrawal of inhaled corticosteroids results in an exacerbation of asthma
that is preceded by an increase in sputum neutrophils and IL-8 concentrations, in contrast to an
increase in eosinophils reported in previous studies in which inhaled steroids are slowly tapered.
(CHEST 2007; 132:98 105)
Key words: asthma; exacerbation; interleukin-8; neutrophil
Abbreviations: IL interleukin; PC20 provocative concentration of methacholine causing a 20% fall in FEV1

eosinophilic airway inflammation is recA lthough

ognized as an important feature of some patients

with chronic, stable asthma,1,2 evidence supports an

important role of neutrophils in acute exacerbations.35 In stable asthma, there is typically an infiltrate of eosinophils, which occurs in response to
cytokines such as interleukin (IL)-5, secreted by
*From Airways Disease Section, National Heart and Lung Institute, Imperial College, London, UK.
Currently at the Division of Respiratory Disease and Tuberculosis, Department of Internal Medicine, Siriraj Hospital, Mahidol
University, Thailand.
Funding for research was provided by the Royal Government of
Thailand for sponsoring Dr. Maneechotesuwan, and AstraZeneca
(Lund, Sweden).
Drs. Barnes, Kharitonov, and Adcock obtained research funding
from several pharmaceutical companies interested in the treatment of asthma, including AstraZeneca, GlaxoSmithKline, and
Novartis.

T-helper type 2 lymphocytes.6 In contrast, during

acute exacerbations of asthma, the airway inflammatory response is both more intense and heterogeneous.35,7 The increased intensity of airway inflammation is reflected by an elevated total cell count in
sputum.35,8 The heterogeneity of the inflammatory
response is reflected by an increase in neutrophils as
well as eosinophils, and there are reports of exacerbations without sputum eosinophilia.35 There is also
Manuscript received December 12, 2006; revision accepted
March 23, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Peter J. Barnes, DM, DSc, FCCP, Airways
Disease Section, Dovehouse St, London, SW3 6LY, UK; e-mail:
p.j.barnes@imperial.ac.uk
DOI: 10.1378/chest.06-2982

98

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2007 American College of Chest Physicians

evidence for increased expression of the potent

neutrophil chemoattractant IL-8,3 in addition to the
presence of IL-5. There is heterogeneity in the
concentrations of IL-8 in patients with moderate
asthma and the strong correlation between the concentration of IL-8 release by peripheral blood mononuclear cells9 and the frequency of asthma exacerbations.10
Leukocytes, particularly neutrophils and eosinophils, are the first cells recruited to the site of tissue
damage after an inflammatory insult.11 These cells
are then removed by apoptosis during the resolution
of the inflammatory response. Neutrophils are the
predominant inflammatory leukocyte characterizing
airway inflammation in acute severe asthma, and this
may influence the clinical presentation, predisposing
to a sudden severe attack.35 IL-8 is a key chemokine
involved in the recruitment of neutrophils to the area
of inflammation, but few studies have characterized
the kinetics of IL-8 production in sputum over a
period of time prior to the onset of a clinical asthma
exacerbation. Because it is not possible to obtain this
information prospectively with a naturally occurring
exacerbation, we induced loss of control of asthma by
withdrawing inhaled corticosteroids so that we were
able to make prospective measurements of inflammatory indexes in induced sputum. This was done in
a double-blind controlled manner so that steroid
withdrawal could be compared with continued therapy with inhaled corticosteroids.

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.

Materials and Methods

Subjects
Twenty-four nonsmoking patients (10 men) with moderate,
persistent asthma participated in the study. The inclusion criteria
were age 18 to 60 years of age and a history of stable asthma as
defined by the American Thoracic Society. Patient characteristics
are summarized in Table 1. All patients had a baseline FEV1
70% of predicted, FEV1 reversibility 15%, and required
regular treatment with moderate doses of inhaled corticosteroids
(beclomethasone dipropionate, 800 g/d or equivalent) for 3
months. All patients were hyperresponsive as measured by a
provocative concentration of methacholine causing a 20% fall in

Table 1Patient Characteristics*

Characteristics

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

*Data are presented as mean SEM unless otherwise indicated.

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FEV1 (PC20) 8 mg/mL. None of the patients had a history of

respiratory disease other than asthma, and none required oral
glucocorticoid treatment within 3 months before study entry and
used any other medication except study medication during the
trial. The patients were included during a clinically well-controlled period without symptoms of an upper respiratory tract
infection for 4 weeks prior to the study. The study was approved
by the Royal Brompton and Harefield NHS Hospital Trust Ethics
Committee, and informed consent was given by all patients.

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
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2007 American College of Chest Physicians

99

age of predicted. Baseline values were measured after 15 min of

rest and taken as the highest of three readings. Single readings
only were taken at other times. Airway hyperresponsiveness to
methacholine was assessed using the method of Sterk and
colleagues.13 Methacholine was inhaled by tidal breathing in
doubling concentrations (0.015 to 32 mg/mL) for 2 min at 5-min
intervals. Measurements of FEV1 were made at baseline and
after each dose. The challenge test was discontinued if FEV1
dropped 20% from baseline. PC20 was calculated by linear
interpolation of the log-dose response curves.13
Sputum Induction and Processing
Sputum was induced by inhalation for 15 min of 3.5% saline
solution via an ultrasonic nebulizer (model 2000; DeVilbis;
Heston, UK), as previously described.14 After each inhalation
period, patients were asked to rinse their mouth and were
encouraged to expectorate sputum. Briefly, the whole sputum
sample was processed with dithiothreitol (Sigma Chemicals;
Poole, UK). The homogenized sputum was centrifuged at 1,500g
for 10 min. The supernatant was separated and frozen at 70C
until further analysis. Total cell counts were made on a hemocytometer slide, using Kimura stain, and slides were prepared
(Cytospin; Shandon; Runcorn, UK) and stained with May-Grunwald-Giemsa stain. Differential cell counts were made by a
blinded observer. Three hundred nonsquamous cells were
counted on two slides for each sample in a blind way. Differential
cell counts are expressed as percentages of nonsquamous cells.
Two of the sputum samples from the same patient in budesonide
treatment group at different visits were withdrawn from analysis
because of containing 80% squamous cells (Table 2).
IL-8 Assay
The concentration of IL-8 in sputum supernatant was determined using commercially available enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN) according to the
manufacturer instructions.
Statistical Analysis
Results are reported as mean SEM. We compared patients
who lost control of asthma with those who did not after corticosteroid withdrawal. All statistical tests were two sided, and
significance was accepted at the level of 95% and p 0.05 using

statistical software (GraphPad Prism; GraphPad Software; San

Diego, CA). To determine whether changes in sputum neutrophil
counts and sputum IL-8 levels accompanied asthma exacerbation, the differences of the last-visit measurements from baseline
were used for analysis of correlation with Pearson productmoment technique. The data from subjects with and without
exacerbation at each time point were categorized as a group
before analysis. Sputum neutrophil counts, percentage of neutrophils, and IL-8 levels 2 weeks prior to an exacerbation were
compared to those of the week-8 inflammatory markers in
nonexacerbation group using the unpaired t test. The last-visit
measurements of the exacerbation and nonexacerbation groups
were also evaluated by the unpaired t test.

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,

Table 2Total and Specific Sputum Cell Counts After Budesonide*

Weeks of Budesonide Treatment
Variables
Patients, No.
FEV1 , % predicted
Exacerbation, No.
Total cells, 106/mL
Neutrophils, %
Neutrophils, 106/mL
Eosinophils, %
Eosinophils, 106/mL
Macrophages, %
Macrophages, 106/mL
Lymphocytes, %
Lymphocytes, 106/mL

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.
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2007 American College of Chest Physicians

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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2007 American College of Chest Physicians

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.

2,690.5 154.7 ng/mL vs 1,420.7 149.2 ng/mL,

p 0.0001, respectively]. The increase in percentage of neutrophils was also observed at the same
period of time (Table 4) [mean, 42.0 3.3% vs
23.6 3.5%, p 0.02; and 51.1 1.9% vs
29.5 4.2%, p 0.0009, respectively]. Sputum
neutrophilia correlated positively with changes in
IL-8 levels (Fig 3) [r2 0.76, p 0.01].
No significant differences were observed in
baseline total sputum cell and differential cell
counts between the budesonide treatment group

and steroid withdrawal groups (Tables 2, 3). In

contrast, there were significant differences in sputum lymphocyte counts (p 0.01) and percentage
of macrophages (p 0.0001) at the onset of exacerbation (Table 4; Fig 2, center, right, D, and
bottom, left, E).
Sputum Eosinophils
No significant differences in the percentages of
eosinophils and absolute eosinophil number in spu-

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Table 4 Measurements of Sputum Indices of Exacerbation and Nonexacerbation Groups*

Variables
IL-8, ng/mL
2 wk before visit
Last visit
Total cell counts, 106
2 wk before visit
Last visit
Neutrophils, %
2 wk before visit
Last visit
Eosinophils, %
2 wk before visit
Last visit
Lymphocytes, %
2 wk before visit
Last visit
Macrophages, %
2 wk before visit
Last visit

Exacerbation
(n 9)

Nonexacerbation
(n 13)

p Value

95% Confidence Interval

of Difference

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

*Data are presented as mean SEM unless otherwise indicated.

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

Figure 3. Relationship between changes in IL-8 concentrations

and neutrophil numbers in sputum obtained from the asthmatic
patients with severe exacerbations. Symbols represent individual
asthmatic patients. IL-8 concentrations correlated positively and
significantly with sputum neutrophilia.
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exacerbations following steroid withdrawal. This may

result from the increase in sputum IL-8 observed
prior to the onset of an exacerbation. Taken together,
our findings demonstrated that sequential monitoring of sputum IL-8 and neutrophils might be useful
for predicting an episode of severe exacerbation in
moderate persistent asthma after corticosteroid
withdrawal. This study also confirms that the mechanisms underlying asthma exacerbation are highly
variable.2,12,1517
There is growing evidence that reducing asthma
exacerbations is achieved by targeting therapy to
eosinophilic inflammation. An eosinophilic exacerbation is triggered by allergen exposure. However,
several studies35,18 have demonstrated increased
neutrophil numbers in airway secretions and airway
tissue from patients with acute severe asthma. Sputum neutrophilia may be mediated by IL-8, a chemokine that selectively attracts neutrophils. IL-8 is
increased in sputum of asthmatic subjects during
exacerbations in association with sputum neutrophilia.3,15,16 However, there is no clear relationship
between the type of airway inflammation and asthmatic exacerbations,19 possibly due to differences in
the methodology, specifically the use of steroid
tapering.12 Furthermore, the pathophysiologic
mechanisms underlying asthma exacerbations following abrupt steroid withdrawal in moderate persistent asthmatics may be distinct from those seen
with gradual steroid tapering. The neutrophilic airway inflammation in the present study may reflect
the sudden withdrawal of inhaled corticosteroids and
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2007 American College of Chest Physicians

103

reflect the kinetics of inflammatory cells in an acute

exacerbation when neutrophils are the first cells to
infiltrate the airways.
There are several studies12,17,19,20 suggesting that
eosinophilic inflammation is associated with sputum
asthma exacerbations in response to controlled withdrawal of steroids. In addition, targeting management based on normalizing sputum eosinophils is
able to reduce asthma exacerbations.2123 Unexpectedly, the present study showed that a small number
of patients with steroid withdrawal did not have
asthma exacerbations, although they had eosinophilic
inflammation. The patients in whom the dose of
inhaled budesonide was maintained showed a reduction in sputum eosinophils, which may indicate
greater compliance with inhaled corticosteroids during the trial period. The difference in the relationship between sputum eosinophils and asthma exacerbation with the majority of current evidence is not
easily understood. We suggest that this may be due
to the fact that a 10-week period in our study is
inadequate to monitor the development of eosinophilic exacerbation. This is supported by the study of
Pizzichini and colleagues,24 who showed that breakthrough eosinophilic inflammation occurred at 4
weeks following steroid reduction and subsequent
asthma exacerbations developed within 12 weeks
thereafter. Clinical exacerbation depends on the
perception of breathlessness that is impaired by
eosinophilic inflammation.25 Patients with eosinophilic inflammation who had no clinical worsening
were moderately severe in terms of FEV1 and might
have impaired perception of dyspnea and therefore
were not aware of worsening asthma. Although the
strategy of titrating the inhaled corticosteroid dose
against sputum eosinophil counts reduced exacerbations, it by no means eliminated them. It is possible
that the residual exacerbations were neutrophilic in
nature.
Our results differ from those of Jatakanon et al20
and int Veen and colleagues,12 who induced loss of
control in asthma by gradual tapering of the steroid
dose, and both studies showed eosinophil predominance during exacerbations. As suggested above,
these results suggest that the pathophysiologic mechanism(s) of asthma exacerbation induced by complete withdrawal may be different from that induced
by steroid tapering. This may have important clinical
consequences in that patients with a loss of asthma
control as a result of stepping down inhaled corticosteroid dosage should be able to attenuate eosinophil
actions by increasing the inhaled steroid dose.23,26 In
contrast, exacerbations induced after abrupt steroid
cessation may need antineutrophilic agents such as
long-acting 2-agonists to attenuate the neutrophilic
inflammation.27

Increases in sputum IL-8 concentrations have

been reported to precede an acute asthma attack,28
but the time course of this increase is unknown. In
another study15 there was a significant elevation of
IL-8 levels in sputum samples from asthmatics who
had exacerbated compared to IL-8 concentrations
after the resolution of the exacerbation. However,
the onset of the elevation of IL-8 levels prior to the
development of asthma exacerbation has not been
previously investigated. The present study demonstrates that a marked increase in IL-8 level occurred
2 weeks before the symptomatic exacerbation (Fig 1,
top left, A). Clinically, this may have important
implications because there appears to be a window
during which it may be possible to adjust asthma
treatment, such as the addition of long-acting 2agonist, in an attempt to suppress IL-8 production
and subsequent neutrophilia leading to exacerbation.
Although corticosteroids promote neutrophil survival
as a result of delay in neutrophil apoptosis in vitro,29
we did not detect sputum neutrophilia in patients
with budesonide treatment despite a failure to suppress sputum IL-8 levels below that seen in the
run-in period.
In summary, the findings in this study in contrast
to earlier reports suggest that asthma exacerbations
following inhaled corticosteroid withdrawal are associated with increased sputum IL-8 and neutrophils.
Significant increase in sputum IL-8 and neutrophil
influx occurs 2 week prior to an exacerbation. Our
results may be used to encourage asthmatic patients
who have poor compliance with inhaled corticosteroid therapy are at risk for neutrophilic exacerbation
if they abruptly stop their corticosteroid therapy.

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CHEST / 132 / 1 / JULY, 2007

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105

Loss of Control of Asthma Following Inhaled Corticosteroid

Withdrawal Is Associated With Increased Sputum Interleukin-8 and
Neutrophils*
Kittipong Maneechotesuwan, Sarah Essilfie-Quaye, Sergei A. Kharitonov,
Ian M. Adcock and Peter J. Barnes
Chest 2007;132; 98-105; Prepublished online June 5, 2007;
DOI 10.1378/chest.06-2982
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