Eur Respir J 1997; 10: 994–999
Printed in UK - all rights reserved
Copyright ERS Journals Ltd 1997
European Respiratory Journal
ISSN 0903 - 1936
Effect of roxithromycin on airway responsiveness
in children with bronchiectasis:
a double-blind, placebo-controlled study
Y.Y. Koh, M.H. Lee, Y.H. Sun, K.W. Sung, J.H. Chae
Dept of Pediatrics, College of Medicine,
Seoul National University, Seoul, Korea.
Correspondence: Y.Y. Koh
Dept of Pediatrics
Seoul National University Hospital
28 Yongon Dong
Keywords: Airway responsiveness
Received: July 16 1996
Accepted after revision December 10 1996
This study was supported by grant No. 2-
94-112 from the Seoul National University
Hospital Research Fund.
Bronchiectasis is a chronic lung disease characterized
by permanent dilatation of the bronchi, loss of connec-
tive tissue and fibrosis . The key pathogenic factors
are postulated to be chronic bronchial sepsis and persis-
tent airway inflammation [2, 3]. Airway hyperrespon-
siveness (AHR), the hallmark of bronchial asthma, is
frequently associated with bronchiectasis [4–6]. Although
the mechanism underlying AHR in bronchiectasis is not
completely understood, AHR may play a part in the
pathogenesis of bronchiectasis by reducing the efficiency
of respiratory clearance mechanisms and thereby pro-
moting microbial colonization and inflammation .
The recent trend in the treatment of bronchiectasis is
long-term antibiotic therapy to decrease the inflamma-
tory load in the bronchial tree. This may interrupt the
"vicious" cycle of infection and inflammation . Stud-
ies with higher dose and longer term antibiotics have
shown better clinical response and reduction of lung
inflammation for longer periods after cessation of treat-
ment, in patients with chronic bronchial infection [8–10].
In the course of long-term antibiotic therapy, changes
in airway responsiveness (AR) have seldom been stud-
ied. KELLY et al.  have shown that a 3 week course
of amoxycillin reduced the degree of AR in patients with
bronchiectasis. Recently, some of the macrolide antibio-
tics, such as erythromycin and roxithromycin, have been
shown to be effective in reducing AHR in bronchial as-
thma [12, 13]. This prompted us to assess the effects of
these drugs on the increased AR in bronchiectasis. In
this study, roxithromycin was chosen rather than ery-
thromycin, because the former is more potent than the
latter in terms of anti-inflammatory action , which is
presumed to be one of the mechanisms in reducing AHR.
The purpose of this study was to determine whether roxi-
thromycin could reduce the degree of AR in bronchiec-
Effect of roxithromycin on airway responsiveness in children with bronchiectasis: a
double-blind, placebo-controlled study. Y.Y. Koh, M.H. Lee, Y.H. Sun, K.W. Sung, J.H.
Chae. ©ERS Journals Ltd 1997.
ABSTRACT: Increased airway responsiveness (AR) is frequently associated with
bronchiectasis. Roxithromycin is a new semisynthetic macrolide antibiotic that also
has anti-inflammatory activities. This study was designed to see whether roxithro-
mycin could favourably alter the degree of AR in patients with bronchiectasis and
Twenty five children with bronchiectasis, who had an increased AR (defined as
a provocative concentration of methacholine causing a 20% fall in forced expira-
tory volume in one second (FEV1) (PC20) <25 mg·mL-1evaluated by the dosime-
ter method), were randomized, double-blind into two parallel groups. Thirteen of
the children were treated with roxithromycin (4 mg·kg-1b.i.d.) for 12 weeks and
12 received placebo. FEV1, sputum purulence and leucocyte scores were assessed
every 3 weeks. To estimate AR, high-dose methacholine challenge tests were per-
formed before and after treatment. On the dose-response curve to methacholine,
PD20 and maximal response (two indices of AR) were measured.
Changes in FEV1 were not observed during the course of the study in both groups.
A significant improvement in sputum features was noted after 6 weeks of treat-
ment in the roxithromycin group. After 12 weeks of roxithromycin therapy, the
geometric mean (range of 1 SD) of provocative cumulative dose producing a 20%
fall in FEV1 (PD20) increased significantly (p<0.01) to 169.2 (83.2–344.2) breath units
(BU) (1 BU denotes one inhalation of 1 mg·mL-1methacholine) and the mean±SD
of maximal response decreased significantly (p<0.01) to 32.5±6.8%, as compared
with the initial values (PD20 87.1 (47.3–160.4) BU; maximal response 40.9±7.4%).
No significant changes in either parameter were observed in the placebo group.
Our results indicate that roxithromycin may decrease the degree of airway
responsiveness in patients with bronchiectasis and increased airway responsive-
ness. Further study is necessary to determine the mechanism by which roxithromycin
reduces airway responsiveness in bronchiectasis and its clinical impact.
Eur Respir J 1997; 10: 994–999.
EFFECT OF ROXITHROMYCIN ON AR IN BRONCHIECTASIS
placebo-controlled study of the effect of 12 weeks of
roxithromycin on the degree of AR in children with cli-
nically stable bronchiectasis and increased AR. In the
last decade, it has been recognized that AHR has two
distinct components: firstly, an increased sensitivity of
the airways as shown by a leftward shift of the dose-
response curve, e.g. decreased provocative concentra-
tion of agonist producing a 20% fall in forced expiratory
volume in one second (FEV1) (PC20) ; and, second-
ly, excessive airway narrowing as reflected by an ele-
vated or absent maximal response plateau . It can
be argued that the latter is clinically a more relevant
component of AHR than the former per se because it
reflects the potential severity of airways obstruction in
the individual patient . Therefore, we measured not
only bronchial sensitivity but also maximal response on
the dose-response curve to methacholine, before and
after roxithromycin treatment.
Materials and methods
Twenty five bronchiectatic children (14 boys and 11
girls, with a mean age of 13 yrs) with an increased AR
completed this study (table 1). The diagnosis of bronchi-
ectasis was based on clinical features and was confirmed
by computed tomography, with bronchography when
necessary. Among 63 children with bronchiectasis who
had been followed up at our clinic and were old enough
to have an increased AR, defined as a PC20 <25 mg·mL-1
evaluated by the dosimeter method , in the prelim-
inary methacholine challenge test. Two of the children
subsequently withdrew from the study because of non-
compliance. Of the 25 subjects who completed the study,
the presumed causes of bronchiectasis were: measles (1
case); tuberculosis (5); ciliary dyskinesis (6); and idio-
pathic (13). There were no patients with cystic fibrosis,
humoral immune deficiency or bronchopulmonary asp-
ergillosis. Nine subjects were atopic, as judged by at
least one wheal >3 mm on skin-prick test with common
airborne allergens. Seven patients had asthma, which was
defined by a history of episodes of dyspnoea, cough and
wheezing, and either a >15% increase in FEV1 after
inhaled bronchodilator during the acute episode/stable
state, or a spontaneous diurnal variation in peak expira-
tory flow rate >20%. These patients were being treated
with inhaled β2-agonist (terbutaline or salbutamol) on
an as-needed basis.
All the subjects were in a stable clinical state at the
time of study and continued their usual postural drainage
routine and other prescribed treatment (chest percussion
and vibration, and mucolytics, such as ambroxol or S-
carboxymethylcysteine) throughout the study. No other
drugs, such as cromolyn sodium or inhaled corticos-
teroids, had been used. None of the patients had received
antibiotics or corticosteroids within 1 month before enter-
ing the study. There was no history of upper respira-
tory tract infection for at least 4 weeks prior to the study.
The parents of the patients gave informed consent for
the study, and the protocol was approved by the Hospital
The study was conducted in a double-blind, random-
ized, placebo-controlled fashion after the preliminary
methacholine challenge test. A doctor (not responsible
for follow-up or data analysis) was assigned the task of
dividing the patients into two groups. After the division,
each subject performed the high-dose methacholine
inhalation test. Lung function was measured with a com-
puterized spirometer (Microspiro-HI 298, Chest, Japan),
and the largest value of the triplicate FEV1 at each time-
line FEV1 was more than 60% of predicted value .
The subjects were studied between October 1995 and
February 1996. Inhaled β2-agonist was withheld for at
least 12 hours before each test. High-dose methacho-
line inhalation tests were carried out using a modifica-
tion of the method described by CHAI et al. . The
concentrations (0.075, 0.15, 0.3, 0.625, 1.25, 2.5, 5, 10,
25, 50, 100, 150, 200 mg·mL-1) of methacholine (Sigma
Chemical, MO, USA) were prepared with dilution in
buffered saline (pH 7.4). A Rosenthal-French dosimeter
(Laboratory for Applied Immunology, MD, USA), trig-
gered by a solenoid valve set to remain open for 0.6 s,
was used to generate the aerosol from a DeVilbiss 646
nebulizer (DeVilbiss, PA, USA), with pressurized air at
20 psi. Each subject inhaled five inspiratory capacity
breaths of buffered saline and increasing concentrations
of methacholine at 5 min intervals. This gave an output
of 0.009±0.0014 mL (mean±SD) per inhalation. FEV1 was
measured 60–90 s after each inhalation.
Table 1. – Baseline characteristics of study population
Cause of bronchi-
ectasis n (%)
prick test n (%)
Asthma n (%)
FEV1 % pred#
#: mean±SD. ‡: geometric mean, and range of 1 SD in paren-
thesis. M: male; F: female; PD20: provocative cumulative dose
producing a 20% fall in FEV1: BU: breath unit (1 BU denotes
one inhalation of 1 mg·mL-1methacholine); ∆FEV1,max: max-
imal response to methacholine expressed as the percentage fall
in FEV1; FEV1: forced expiratory volume in one second; %
pred: percentage of predicted value.
Y.Y. KOH ET AL.
The inhalation was continued until FEV1 fell by more
than 50% from the postsaline value; or the maximal
response plateau was reached; or the highest dose of
methacholine had been given. For safety reasons, sub-
jects were given the opportunity to stop the challenge
test if they felt too much discomfort. The response was
expressed as the percentage fall of FEV1 (∆FEV1) from
mean postsaline value, and was plotted against log cumu-
lative dose of inhaled methacholine expressed as breath
units (BU). One BU denotes one inhalation of 1 mg·mL-1
methacholine. The dose-response curves were charac-
terized by their position and maximal response. The posi-
tion was expressed as the provocative cumulative dose
of methacholine producing a 20% fall in FEV1 (PD20),
which was calculated by log-linear interpolation be-
tween two adjacent data points. The maximal response
was defined as the level of maximal response plateau,
by averaging the consecutive points on the plateau or
of the last data point of the dose-response curve if a
plateau could not be obtained. A maximal response
plateau occurred if three or more data points of highest
concentrations fell within a 5% response range .
After the initial methacholine test, 14 patients were
given 4 mg·kg-1of roxithromycin (Roussel Uclaf, Paris,
France) twice a day, and 13 were given placebo. This
dose has been shown to be effective in the treatment of
acute exacerbation of bronchiectasis in our clinic, and
is also commonly administered for the treatment of acute
respiratory infection in the paediatric population .
During the treatment period, the patients were assessed
by one of the research group every 3 weeks, and FEV1
was measured on each occasion. Sputum was collected
on waking each visit day, and was examined for its
colour and polymorphonuclear leucocyte (PMN) counts.
Sputum colour was noted by the same assessor and clas-
sified as follows: mucoid=1; mucopurulent=2; puru-
lent=3. Sputum smears were treated with Wright's stain.
An average number of PMNs in three fields at ×400
magnification (high power field (hpf)) was recorded and
scored as follows: <20 PMN·hpf-1=1; 20–50 PMN·hpf-1
=2; >50 PMN·hpf-1=3.
A close check was kept on the drug supplies of the
patient, and used packets or sachets were checked to
monitor compliance. After 12 weeks of treatment, the
high-dose methacholine inhalation tests were repeated,
and the same parameters were measured as in the initial
tests. Roxithromycin was stopped 24 h before these
methacholine inhalation tests.
Mean and standard deviation values were calculated
for the variables. All PD20 values were log-transformed
before analysis. Analysis of variance (ANOVA) was
used to analyse difference in the variables between the
two groups. Comparisons of FEV1 between pretreat-
ment and the following visits were analysed for each
group, using paired t-tests, while the comparisons of
noncontinuous variables (sputum purulence and leuco-
cyte scores) were analysed using Wilcoxon signed rank
test. The changes of PD20 or maximal response before
treatment compared to after treatment were assessed
with paired t-tests. All the analyses were made using
StatView II (Abacus Concept Inc., Berkeley, USA) on
a Macintosh computer (Apple Computer Inc., Cupertino,
USA). A p-value of less than 0.05 was considered sta-
The high-dose methacholine inhalation tests were well
tolerated. Two subjects (one in each group) were with-
drawn from the study because of noncompliance with
medication or regular check-up. There were no signifi-
cant differences between the roxithromycin group and
the placebo group with respect to age, height, weight,
causes of bronchiectasis, or atopy. Three asthmatic pati-
ents belonged to the roxithromycin group, and four asth-
matics to the placebo group. In the initial methacholine
challenge test, three of the roxithromycin group and two
of the placebo group did not attain a maximal response
plateau. There were no differences in baseline FEV1,
PD20 and maximal response to methacholine expressed
as the percentage fall in FEV1 (∆FEV1,max) between the
two groups (table 1).
Table 2 summarizes the changes of FEV1 (% predic-
ted), sputum purulence and leucocyte scores during the
study period, with reference to baseline values. There
was no significant change in FEV1 throughout the period
in either group. The patients in the roxithromycin group
showed a significant improvement in the sputum puru-
lence scores by the sixth week of treatment (p<0.05),
which was maintained for the rest of the study period.
Sputum leucocyte scores showed a similar trend, in which
significant improvements occurred by the sixth week of
treatment in the roxithromycin group. The placebo group
did not show significant alterations either in sputum
Table 2. – The values of FEV1 and sputum scores before and during treatment with roxithromycin or placebo
Weeks of treatment
FEV1 % pred
Sputum purulence score
Sputum leucocyte score
Values are presented as mean±SD. *: p<0.05; **: p<0.01, compared to the value before treatment. For definitions see legend to
EFFECT OF ROXITHROMYCIN ON AR IN BRONCHIECTASIS
purulence or leucocyte scores throughout the period. All
of the patients, with the exception of two in the placebo
group, remained clinically stable without any evidence
of infective exacerbations. These two patients experienc-
ed acute exacerbations, as evidenced by fever, increased
Pseudomonas aeruginosa in one case and Haemophilus
influenzae in the other. They were prescribed cephalosporin
or amoxycillin with clavulanic acid, based on sensitiv-
The changes in PD20 for the two groups are depicted
in figure 1. In the roxithromycin group, nine subjects
showed an increase in PD20 by more than a single twofold
dilution of methacholine. All three asthmatics came under
this category. In the placebo group, one subject exhib-
ited an increase and one subject a decrease in PD20 by
twofold magnitude. None of the four asthmatics showed
such a change. In the roxithromycin group, the geo-
metric mean value (range of 1 SD) of PD20 was signif-
icantly increased to 169.2 (83.2–344.2) BU, compared
with that before treatment, 87.1 (47.3–160.4) BU (p<
0.01) (fig. 1a). The change was not significant in the
placebo group, from 74.2 (36.6–150.4) to 82.7 (41.8–
163.7) BU (p>0.1) (fig. 1b).
The changes of ∆FEV1,max are presented in figure 2.
Three subjects (one in the roxithromycin group and two
in the placebo group) who failed to attain the maximal
response plateau both before and after treatment, were
excluded from the analysis. In the roxithromycin group,
two subjects without the plateau before treatment show-
ed the plateau after treatment, and were included in the
analysis. Mean value (±SD) of ∆FEV1,max was decreased
significantly to 32.5 (±6.8)% 12 weeks after roxithromy-
cin treatment, compared to 40.9 (±7.4)% before treat-
ment (p<0.01) (fig. 2a). The change was not significant
in the placebo group, from 36.5 (±6.5) to 37.2 (±6.7)%
(p>0.1) (fig. 2b).
This study has shown that administration of roxithro-
mycin for 12 weeks reduced bronchial sensitivity and
maximal response on the dose-response curve to metha-
choline in children with bronchiectasis and increased AR.
The geometric mean of PD20 increased significantly after
the medication, and nine of the 13 patients showed an
increase in PD20 of more than a single two-fold dilution
of methacholine, a value that is considered to be signif-
icant . ∆FEV1,max, defined as the level of plateau
or maximal percentage fall in FEV1, decreased signifi-
cantly, despite possible underestimation of the differ-
ence. Neither PD20 nor ∆FEV1,max changed after placebo
treatment. The present results indicate that roxithromy-
cin may reduce AHR in patients with bronchiectasis.
Only subjects with increased AR were studied, because
our previous investigation had shown that AR was un-
changed by roxithromycin in subjects with normal AR
. The difference in effect between the subjects with
increased and normal AR could be related to the find-
ings that inhaled corticosteroids reduced the maximal
response plateau  and bronchial sensitivity  in
asthma, whereas they had no effect on either component
in normal subjects . Twelve weeks were chosen for
duration of treatment in the present study, because our
previous open study  indicated that the changes of
AR were quite modest after 8 weeks of administration.
AHR has been reported to occur in patients with
bronchiectasis [4–6], although the technique of mea-
surement and criteria for AHR has varied among stud-
ies. BAHOUS et al.  noted that 69% of 29 subjects with
bronchiectasis had AHR, and this was significantly re-
lated to clinical features of asthma. Others have report-
ed an increased prevalence of AHR to methacholine of
33 and 45% in adult bronchiectatic subjects [5, 6]. In
the present study, the frequency of increased AR (43%)
Fig. 2. – a) Individual ∆FEV1,max values before and 12 weeks after
roxithromycin treatment. b) Individual ∆FEV1,max values before and
12 weeks after placebo treatment. Means and 1 SD are indicated with
horizontal bars. *: subject without maximal response plateau before
treatment but with the plateau after treatment; ●: asthmatic subject;
: atopic nonasthmatic subject; : nonatopic nonasthmatic subject.
NS: nonsignificant; FEV1,max: maximal response to methacholine expr-
essed as the percentage fall in forced expiratory volume in one second.
Fig. 1. – a) Individual PD20 values before and 12 weeks after rox-
ithromycin treatment. b) Individual PD20 values before and 12 weeks
after placebo treatment. Means and 1 SD are indicated with horizon-
tal bars. ●: asthmatic subject; : atopic nonasthmatic subject;
atopic nonasthmatic subject. FEV1: forced expiratory volume in one
second; PD20: provocative cumulative dose producing a 20% fall in
FEV1; NS: nonsignificant; BU: breath unit (1 BU denotes one inhala-
tion of 1 mg·mL-1methacholine).
Y.Y. KOH ET AL.
appears to be comparable to the above results. How-
ever, taking account of the higher value of our criteria
for increased AR (PC20 <25 mg·mL-1 ) compared to
those of other studies (PC20 <5 mg·mL-1 , PC20 <8
mg·mL-1 ), the frequency of increased AR was lower
in our study. This may be due to the difference in age
of the study population or the technique of measure-
ment of AR (dosimeter method  in the present study
versus the tidal breathing method  in other studies
[5, 6]). Concomitant asthma cannot be the main cause
of increased AR in bronchiectatic subjects [4, 29], because
the majority of those who were hyperreactive did not
fulfil our criteria for asthma.
The present study is the first double-blind, placebo-
controlled study of the effects of roxithromycin on AR
in patients with bronchiectasis. The effect of roxithromy-
cin is unlikely to result from changes of airway calibre,
as no changes in FEV1 were observed during the course
of treatment. We do not think that improvement in AR
is related to seasonal variation due to allergen avoid-
ance, because the placebo treatment was performed in
parallel with the roxithromycin treatment and had no
effect on AR. Nonetheless, we cannot rule out the possi-
bility that AR varies over time in patients with bronchiec-
tasis. In fact, two subjects in the placebo group exhibited
a significant change in PD20. A time span of 12 weeks
without interval challenge results appears long, and int-
erval data on AR would be particularly relevant in view
of the fact that FEV1 changes over time were not noted
in both groups. Further long-term study on the tempo-
ral variation of AR in bronchiectasis is necessary to clar-
ify this point.
The mechanism of action of roxithromycin in reduc-
mented maximal response are determined by, at least
partially, different mechanisms , the two phenom-
ena are both associated with airway inflammation .
Therefore, the diminution of bronchial sensitivity and
maximal response in this study could be interpreted as
a reduction of airway inflammation. It is not possible
from this study to establish whether the improvement
in AR is due to an antimicrobial or anti-inflammatory
action of roxithromycin. Since persistent airway inflam-
mation in bronchiectasis, which may contribute to AHR
, results from chronic bacterial sepsis [2, 3], it can
be assumed that decreasing the inflammatory load may
lead to improvement of AR. A preliminary study by
KELLY et al.  showed that intensive antibiotic ther-
apy with amoxycillin decreased PC20 to methacholine
in patients with bronchiectasis. Thus, the decrease in
AR with roxithromycin could have been simply due to
treating infection. Apart from its antimicrobial property,
roxithromycin has been reported to have anti-inflam-
matory actions, such as inhibition of neutrophil chemo-
taxis , or generation of reactive oxygen species by
polymorphonuclear leucocytes . It may also have
some inhibitory effects on cytokine secretion from leuco-
cytes . Recent studies [13, 34] have reported that roxi-
thromycin could reduce AHR in asthmatic children via
its anti-inflammatory action. This may well be the mecha-
nism underlying the beneficial effect of roxithromycin on
AR in the present study. Thus, the mechanism of action
of roxithromycin may be twofold, i.e. antimicrobial and
It has been suggested that AHR plays a part in the
pathogenesis of bronchiectasis by reducing the efficiency
of respiratory clearance mechanisms, thereby promot-
ing microbial colonization and inflammation . ELBORN
et al.  reported that inhaled corticosteroids were of
symptomatic benefit in bronchiectasis. They also noted
an increase in PC20 histamine by at least one doubling
dose in subjects with AHR. However, IP et al.  sug-
gested that, in patients with bronchiectasis, AHR was
not related to the severity of bronchial sepsis. In the
current study, although the decrease in AR in the rox-
ithromycin group paralleled an improvement in sputum
features as a whole, it should be noted that some patients
had no change in sputum features despite a decrease in
AR and vice versa. Because of the small number of
patients studied, the variable baseline conditions of AR
and sputum features, and the narrow range of their chan-
ges, we did not examine the association between the
changes of these parameters. Moreover, it is difficult to
estimate the clinical significance of the reduction of AR
in bronchiectasis related to antibiotics. Further studies
with other medications are needed to clarify these points.
In conclusion, this study has shown that roxithromycin
treatment for 12 weeks may decrease the degree of air-
way responsiveness in children with bronchiectasis who
have an increased airway responsiveness. It is not clear
whether the decreased airway responsiveness paralleled
clinical improvement. Further studies are necessary to de-
termine the mechanisms by which roxithromycin reduces
airway responsiveness in bronchiectasis and its clinical
impact and on differences in continuous versus inter-
mittent treatment with antibiotics.
Acknowledgement: The authors wish to thank
Hoechst-Marion-Roussel Korea Ltd, Seoul, Korea
for providing the placebo preparations.
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EFFECT OF ROXITHROMYCIN ON AR IN BRONCHIECTASIS