(Chest. 2000;117:1633-1637.)
© 2000
American College of Chest Physicians
Inhaled Corticosteroids in Stable COPD Patients*
Do They Have Effects on Cells and Molecular Mediators of Airway Inflammation?
Bruno Balbi, MD, PhD;
Maria Majori, MD;
Stefano Bertacco, MD;
Giuseppe Convertino, MD;
Angelo Cuomo, MD;
Claudio F. Donner, MD, FCCP and
Alberto Pesci, MD, FCCP
*
From the Salvatore Maugeri Foundation (Drs. Balbi, Convertino, and Donner), Scientific Institute for Care and Research, Rehabilitation Institute of Veruno, Section of Varallo Sesia, Italy; and the Department of Respiratory Diseases (Drs. Majori, Bertacco, Cuomo, and Pesci), University of Parma, Italy.
Correspondence to: Bruno Balbi, MD, PhD, Salvatore Maugeri Foundation, Rehabilitation Institute of Veruno, Section of Varallo Sesia, Via Gippa 3, 13019 Varallo Sesia (Vc), Italy;
 |
Abstract
|
|---|
Study objective: To investigate possible changes in
cells and molecular mediators of airway inflammation following inhaled
steroid treatment of stable COPD patients.
Design:
Six-week open preliminary prospective study.
Setting:
A university respiratory disease clinic.
Patients:
Stable COPD patients with mild disease.
Intervention:
Six-week treatment with inhaled beclomethasone (1.5 mg die).
Measurements: The levels of interleukin (IL)-8,
myeloperoxidase, eosinophilic cationic protein and tryptase, and cell
numbers in bronchial lavage specimens were determined,
and the symptom score, the endoscopic bronchitis index, and functional
parameters were recorded.
Results: After treatment
there were significant reductions in the lavage levels of IL-8 ([mean
± SEM] 1,603.4 ± 331.2 vs 1,119.2 ± 265.3 pg/mL,
respectively; p = 0.01) and myeloperoxidase (1,614.5 ± 682.3 vs
511.2 ± 144.2 µg/L, respectively; p = 0.05), in cell numbers
(250.6 ± 27.7 vs 186.3 ± 11.5 cells x 103/mL,
respectively; p = 0.04), neutrophil proportion (59.7 ± 14.3% vs
31.5 ± 10.1%; p = 0.01), symptom score (4.5 ± 0.6 vs
1.4 ± 0.5; p = 0.01), and bronchitis index (8.5 ± 0.8 vs
5.5 ± 0.7; p = 0.007).
Conclusions: In stable
patients with COPD, inhaled steroid treatment may induce changes on
some cellular and molecular parameters of airway
inflammation.
Key Words: airway inflammation • COPD • interleukin-8 • myeloperoxidase
|
Introduction
|
|---|
It
has been shown that airway inflammation plays an important role in the
pathogenesis of COPD.1
2
3
4
5
6
7
8
9
10
11
12
Thus, treatment with
anti-inflammatory medication has been advocated, and a number of both
short-term and long-term controlled trials using inhaled
corticosteroids and evaluating clinical and functional parameters have
been published.13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
However, the results of these
studies often are conflicting,28
and international
guidelines recommend that steroids should be used only in certain
subpopulations of patients, although these subpopulations are not
easily recognizable before a steroid trial.29
30
Surprisingly, only a few studies have investigated the biological
effects of inhaled steroids on airway inflammation. One study, to the
best of our knowledge, was performed by evaluating airway lavage
specimens,17
and three studies were performed by
evaluating sputum samples.31
32
33
The aim of this
preliminary study was to investigate the effects on airway inflammation
of short-term treatment with high-dose inhaled corticosteroids in
stable patients with mild COPD by comparing cells and soluble mediators
of inflammation in bronchial lavage specimens obtained before and after
treatment.
|
Materials and Methods
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|---|
To obtain preliminary data on the possible changes in cells and
mediators of airway inflammation in stable patients with COPD, we
designed a short-term open clinical study. We studied eight patients
(seven men and one woman; mean [± SEM] age, 61.1 ± 2.6
years) with chronic bronchitis and COPD. The inclusion criteria were
the following:
- FEV1 < 75% of predicted values
(actual observed values, 69.8 ± 2.1% of predicted) and no
improvement in FEV1 values of > 12% and
200 mL after inhalation of 200 mg salbutamol;
- FEV1/FVC ratios after bronchodilator use
that are < 88% of predicted in men and < 89% of predicted in
women (actual observed values, 63.7 ± 1.4% of predicted); and
- A history of cigarette smoking, with a minimum of 16.5
pack-years in patients who were current smokers at the time of
evaluation. The patients had failed a smoking cessation program.
The exclusion criteria were the following:
- Occupational or other type of exposure to substances known
to cause lung disorders;
- A history of systemic or other pulmonary disease or of
congenital and/or acquired systemic immunodeficiency;
- Bronchitic exacerbation within the preceding month;
- Therapy with inhaled or systemic corticosteroids within 3
months before entry into the study; and
- Since it is known that among patients with COPD who respond to
steroids many may present with features of asthma,29
30
particular emphasis was put on excluding from the study subjects who
had atopy, or a personal or family history of allergic disease, or
seasonal or recurrent wheezing, childhood asthma, or respiratory
problems. In this context, all patients underwent skin tests for common
allergen extracts, and all of them had negative skin tests.
A symptom score, comprising scores for cough, sputum, and
dyspnea, was recorded for each patient, as previously
described.2
Peripheral blood was drawn from each subject,
and a CBC count, including a leukocyte differential count, and a
determination of the levels of total IgE (PRIST; Pharmacia; Uppsala,
Sweden) were performed. To investigate airway inflammation, fiberoptic
bronchoscopy (model 1T10 bronchoscope; Olympus; Tokyo, Japan)
with inspection of bronchial mucosa and of all segmental bronchi was
performed in all subjects. Bronchoscopies all were performed by the
same investigator (A.P.). During bronchoscopy, the bronchitis index,
comprising four scores for erythema, edema, fragility, and secretion,
as previously described,2
was recorded for each patient.
In addition, a bronchial lavage was performed by introducing 50 mL
prewarmed, sterile saline solution through the bronchoscope that was
wedged into a segmental bronchus, usually in the middle lobe or in the
lingula, and then aspirating the fluid almost
immediately.6
Bronchial lavage has been shown to be useful
for investigating the changes associated with airway
inflammation.2
5
6
17
The lavage fluid then was processed
to separate cells from supernatants. The total and differential cell
counts were performed, the latter by using the May-Grunwald-Giemsa and
toluidine blue methods (Sigma; St. Louis, MO).6
Supernatants from bronchial lavages were assayed for the levels of
interleukin (IL)-8 (enzyme-linked immunosorbent assay; Amersham
International; Buckinghamshire, UK) after concentration of the samples
using concentrators (Centriprep; Amicon; Beverly, MA), and for
the levels of myeloperoxidase, eosinophilic cationic protein, and
tryptase (Pharmacia).6
Thereafter, the treatment of patients with inhaled beclomethasone,
1,500 µg/d (500 µg tid with a metered-dose inhaler), was initiated.
Patients were asked to continue smoking the same number of cigarettes
per day as at the time of entry. The smoking patterns of the study
subjects were followed by self-reported questionnaires filled out at
the second visit after treatment had been stopped and also by follow-up
calls at the third week of treatment. During the study, no
patients needed a change in dosage of the inhaled ß-agonist,
anticholinergic, or theophylline. At six weeks of therapy,
patients were reevaluated with a physical examination and pulmonary
function tests, with the symptom score being recorded again, then a
second bronchoscopy was performed, with procedures and sampling
processes as discussed above. Lavages were performed in each subject in
the same segment both before and after treatment.
This study protocol was approved by the local ethics committee. Each
subject gave informed consent. Group data are expressed as mean
± SEM. Changes observed after treatment were tested for significance
using the Wilcoxon signed rank test for paired samples. A p value
< 0.05 was regarded as significant. Statistical analysis was
performed by using computer software (SPSS, version 4.0; SPSS; Chicago,
IL).
|
Results
|
|---|
The clinical and functional baseline characteristics of COPD
patients are shown in Table 1
. Generally, the 6-week course of treatment with inhaled beclomethasone
dipropionate was well-tolerated, and no significant side effects,
except for a casual report of hoarseness, were recorded. All patients
completed the study. All patients underwent bronchoscopic procedures
without any significant complication.
The amounts of bronchial lavage fluid recovered during the bronchoscopy
procedures that were performed before and after treatment were similar
(before, 34 ± 4 mL; after, 32 ± 5 mL; p > 0.5). After
treatment, there was a reduction in the bronchial lavage levels of IL-8
(before, 1,603.4 ± 331.2 pg/mL; after, 1,119.2 ± 265.3 pg/mL;
p = 0.01) and myeloperoxidase (before, 1,614.5 ± 682.3 µg/L;
after, 511.2 ± 144.2 µg/L; p = 0.05) (Fig 1
). No significant changes were observed in the levels of eosinophilic
cationic protein and tryptase. The total number of bronchial lavage
cells declined significantly after treatment compared with baseline
values (250.6 ± 27.7 vs 186.3 ± 11.5 cells
x 103/mL; p = 0.04) (Fig 1)
. This reduction
was associated with important changes in the proportions of cells
present in the bronchial lavage specimens. The percentage of
neutrophils was significantly reduced in lavage specimens after
treatment (before, 59.7 ± 14.3%; after, 31.5 ± 10.1%;
p = 0.01) (Fig 1)
, while, conversely, there was an increase in the
percentage of macrophages (before, 38.1 ± 14.4%; after,
60.9 ± 9.6%; p = 0.03) and lymphocytes (before, 1.4 ± 0.5%;
after, 6.2 ± 1.6%; p = 0.008). No significant changes were
observed in the proportions of eosinophils or mast cells.
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Figure 1.. Inflammatory mediators and cells in bronchial
lavage fluid. Levels of IL-8 (upper left) and
myeloperoxidase (upper right), and the total numbers of
cells (lower left) and the percentage of neutrophils
(lower right) in bronchial lavage specimens from stable
patients with mild COPD before and after a 6-week treatment with
inhaled beclomethasone. Each symbol ( ) represents a patient before
and after treatment. Bars show the means.
|
|
After the 6-week course of inhaled beclomethasone, we observed a
significant change in the cough score (before, 1.5 ± 0.2; after,
0.8 ± 0.3; p = 0.01) and in the dyspnea score (before,
1.0 ± 0.2; after, 0.75 ± 0.3; p = 0.01). No differences were
seen for the sputum score. Accordingly, there was a significant
reduction in the total symptom score (before, 4.5 ± 0.6; after,
1.4 ± 0.5; p = 0.01). During bronchoscopy, we observed after
treatment a significant reduction in the erythema score (before,
2.0 ± 0.18; after, 1.5 ± 0; p = 0.01) and in the secretion
score (before, 2.0 ± 0.32; after, 1.0 ± 0.18; p = 0.03). No
significant differences were seen for the edema and fragility scores.
Accordingly, there was a significant reduction in the total bronchitis
index (before, 8.5 ± 0.8; after, 5.5 ± 0.7; p = 0.007).
A comparison of the functional data obtained before and after the
6-week treatment with inhaled beclomethasone showed no significant
differences for the values of FEV1 or of the
midexpiratory phase of forced expiratory flow (not shown).
|
Discussion
|
|---|
By comparing airway cell and soluble mediator data that were
obtained from stable patients with mild COPD who are current smokers
before and after short-term treatment with inhaled, high-dose
beclomethasone, the results of this study show that some parameters of
airway inflammation, namely, the number and proportions of inflammatory
cells and the levels of two important mediators of inflammatory
processes, together with some clinical and endoscopic data, may change
after this therapy, while no changes occurred in the results of lung
function tests.
COPD comprises various diseases in which not only the pathologic,
clinical, and functional features,12
29
30
but also the
biological phenomena that cause and maintain airway inflammation, may
differ between baseline (ie, nonexacerbated) and acute
exacerbations34
35
or according to the degree of airway
obstruction36
or history of cigarette
smoking.37
In this context, our previous characterization of airway inflammation
in patients who are current smokers with mild airflow
obstruction6
prompted us to test the hypothesis that in
this subpopulation of patients airway inflammation might be sensitive
to inhaled steroids. Although smoking cessation is the only proven
successful therapeutic intervention that is able to reduce the decline
of lung function, even the best cessation program have high failure
rates, and smoking cessation by itself may not be able to suppress
airway inflammation.12
29
30
38
In these patients, IL-8 is
one of the chemotactic factors that is produced in the airways in
response to the stimulus of cigarette smoke. This chemokine is able to
recruit inflammatory cells, mainly granulocytes, into the airways and
to activate them to release inflammatory mediators, such as
myeloperoxidase and eosinophilic cationic protein.2
5
6
This picture of an active inflammatory process that is ongoing in the
airways is one reason to study the biological response to inhaled
steroids in these COPD patients. COPD usually is characterized by a
slowly progressive and largely irreversible airflow limitation over
decades. In this scenario, it is conceivable that if steroids work in
patients with COPD, their anti-inflammatory activity would be required
in patients with a relatively "young" airway inflammation who have
already developed significant, but still mild/moderate, airflow
limitation together with clinical symptoms of disease. In
contrast, patients with more advanced disease and severe airflow
limitation may have features of airway inflammation (such as the type
and number of inflammatory cells in bronchial mucosa and more
pronounced remodeling in airway walls)29
30
36
that could
be less prone to respond to treatment with anti-inflammatory
medication.
The results obtained in this study after steroid treatment are
consistent with the known anti-inflammatory effects of steroids,
namely, that steroids are able to modulate the expression of many
cytokine genes, including IL-8, and to inhibit granulocyte chemotaxis
and degranulation,39
40
41
and are in agreement with the
only (to the best of our knowledge) similar study previously
conducted.17
After short-term therapy with an inhaled
steroid, Thompson et al17
observed a reduction in the
number of cells and in the levels of albumin, lactoferrin, and lysozyme
in lavage specimens. Other investigators evaluating patients’ sputum
after steroid treatment found a reduction in the chemotactic
activity31
and no changes in the amounts of
myeloperoxidase and eosinophilic cationic protein,31
32
while others observed lower numbers of neutrophils.33
Thus, the results of our study and of previous studies suggest that the
treatment of stable patients with COPD with inhaled steroids may induce
a biological response, which may be associated with changes in some
clinical and endoscopic data. However, steroid treatment did not change
the result of any lung function test in our patients, as was the case
in other short-term trials using inhaled steroids, particularly in
those including subjects who were smokers.14
16
18
Since this was an open pilot study including a small number of subjects
and not using a placebo control group, caution is needed in
interpreting the results, as it is difficult to draw conclusions on the
significance of the changes observed. In this context, although it is
unlikely, it is possible that some of the subjective symptomatic
improvements and improvements in endoscopic scores also may have been
observed with a placebo intervention.
Our study was not meant to be a controlled clinical trial. In this
context, the scarcity of published data demonstrating the effects of
steroids on airway inflammation in patients with COPD (the only article
with lavage data17
was published in 1992) is in contrast
with the widely diffused treatment of COPD patients with steroids. On
the other hand, this lack of sufficient background data is a major
drawback in designing a controlled clinical trial. Thus, our work was
designed to provide preliminary data on possible changes that inhaled
steroid treatment may induce on some parameters of airway inflammation
in patients with COPD.
In conclusion, the results of this study and the discrepancy between
the biological and functional response to steroids would perhaps
suggest the need for further, larger, and controlled studies that are
designed to evaluate whether subgroups of patients can be identified in
whom inhaled steroids may induce changes in airway inflammation as well
as in some clinical and/or functional outcome parameters.
|
Acknowledgements
|
|---|
We thank Drs. Antonino Di Stefano, Armando
Capelli, and Mirco Lusuardi, and Mrs. Rosemary Allpress for revising
the manuscript.
|
Footnotes
|
|---|
Abbreviation:
IL = interleukin
Supported in part by grants from the Salvatore Maugeri Foundation,
IRCCS "Ricerca Corrente," the Ministero dell’Università e
della Ricerca Scientifica e Tecnologica (Rome, Italy), and Chiesi SpA
(Parma, Italy).
Received for publication May 24, 1999.
Accepted for publication January 27, 2000.
|
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Abstract
Introduction
