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Thorax Online First, published on January 3, 2013 as 10.1136/thoraxjnl-2012-202698
Asthma

ORIGINAL ARTICLE

Azithromycin for prevention of exacerbations in

severe asthma (AZISAST): a multicentre randomised
double-blind placebo-controlled trial
Guy G Brusselle,1 Christine VanderStichele,1 Paul Jordens,2 Ren Deman,3
Hans Slabbynck,4 Veerle Ringoet,5 Geert Verleden,6 Ingel K Demedts,7
Katia Verhamme,8 Anja Delporte,1 Bndicte Demeyere,1 Geert Claeys,9
Jerina Boelens,9 Elizaveta Padalko,9 Johny Verschakelen,10 Georges Van Maele,11
Ellen Deschepper,11 Guy F P Joos1

Additional material is ABSTRACT

published online only. To view Background Patients with severe asthma are at Key messages
please visit the journal online
(http://dx.doi.org/10.1136/
increased risk of exacerbations and lower respiratory tract
thoraxjnl-2012-202698). infections (LRTI). Severe asthma is heterogeneous,
encompassing eosinophilic and non-eosinophilic (mainly What is the key question?
For numbered afliations see
end of article. neutrophilic) phenotypes. Patients with neutropilic airway Does maintenance treatment with low-dose
diseases may benet from macrolides. azithromycin decrease the rate of exacerbations
Correspondence to Methods We performed a randomised double-blind in adult patients with severe asthma and
Dr Guy G Brusselle, placebo-controlled trial in subjects with exacerbation-
Department of Respiratory
frequent exacerbations?
Medicine, Ghent University prone severe asthma. Subjects received low-dose
Hospital, De Pintelaan 185, azithromycin (n=55) or placebo (n=54) as add-on What is the bottom line?
Ghent B-9000, Belgium; treatment to combination therapy of inhaled Azithromycin is a new option for prevention of
[email protected] corticosteroids and long-acting 2 agonists for 6 months. exacerbations in patients with non-eosinophilic
The primary outcome was the rate of severe severe asthma.
Received 7 September 2012
Revised 13 November 2012 exacerbations and LRTI requiring treatment with Why read on?
Accepted 26 November 2012 antibiotics during the 26-week treatment phase. Severe asthma is a heterogeneous disease
Secondary efcacy outcomes included lung function and requiring different add-on treatments according
scores on the Asthma Control Questionnaire (ACQ) and to the underlying asthma phenotype
Asthma Quality of Life Questionnaire (AQLQ). (eosinophilic vs non-eosinophilic (eg,
Results The rate of primary endpoints (PEPs) during neutrophilic) airway inammation).
6 months was not signicantly different between the two
treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per
subject in the azithromycin group versus 0.81 PEPs (95% CI
0.61 to 1.09) in the placebo group (p=0.682). In a with patients with mild-to-moderate asthma, adult
predened subgroup analysis according to the inammatory patients with severe asthma have a higher need for
phenotype, azithromycin was associated with a signicantly medications, have more persistent symptoms and
lower PEP rate than placebo in subjects with non- impaired lung function. Importantly, subjects with
eosinophilic severe asthma (blood eosinophilia 200/ml): severe asthma have a greater frequency and severity
0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% of exacerbations of asthma, which puts them at risk
CI 0.72 to 1.48) (p=0.013). Azithromycin signicantly of emergency department visits and hospitalisa-
improved the AQLQ score but there were no signicant tions.3 Moreover, severe asthma has been shown to
between-group differences in the ACQ score or lung be a risk factor for lower respiratory tract infections
function. Azithromycin was well tolerated, but was (LRTI), including pneumonia.4
associated with increased oropharyngeal carriage of Asthma is characterised by clinical and biological
macrolide-resistant streptococci. heterogeneity.1 4 Besides the well-known allergic
Conclusions Azithromycin did not reduce the rate of eosinophilic asthma phenotype, half of patients
severe exacerbations and LRTI in patients with severe with mild-to-moderate asthma have persistently
asthma. However, the signicant reduction in the PEP rate non-eosinophilic disease.5 Interestingly, peripheral
in azithromycin-treated patients with non-eosinophilic blood eosinophil counts correlate well with sputum
severe asthma warrants further study. eosinophilia, and a threshold of 220 eosinophils/ml
ClinicalTrials.gov number NCT00760838. blood was the best biomarker of sputum eosino-
To cite: Brusselle GG, philia.5 Several phenotypes of severe asthma have
VanderStichele C, Jordens P, been discerned by the Severe Asthma Research
et al. Thorax Published
Online First: [ please include Program, demonstrating substantial differences in
Day Month Year] INTRODUCTION eosinophil and neutrophil counts in sputum.4 The
doi:10.1136/thoraxjnl-2012- Severe asthma is associated with substantial morbid- non-eosinophilic asthma phenotype responds
202698 ity, disability and healthcare costs.1 2 In comparison poorly to currently available anti-inammatory

Copyright
Brusselle GG,Article author
et al. Thorax (ordoi:10.1136/thoraxjnl-2012-202698
2013;0:18. their employer) 2013. Produced by BMJ Publishing Group Ltd (& BTS) under licence.
1
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Asthma

therapy.5 6 Subjects with severe asthma are older with longer Assessments
disease duration, have less atopy by skin tests and frequently Assessments included asthma and medical history, vital signs,
need oral corticosteroid courses despite multiple controller physical examination, electrocardiography, imaging, pulmonary
medications including high doses of inhaled corticosteroids.4 function tests, FeNO measurements, blood testing and question-
Relative corticosteroid insensitivity has indeed been implicated naires (including the Asthma Control Questionnaire (ACQ)
in patients with severe asthma and in smokers with asthma.7 and the Asthma Quality of Life Questionnaire (AQLQ)). A full
Macrolides have immunomodulatory and anti-inammatory description of the assessments is given in the online supplemen-
effects in addition to their antibacterial effects.8 Maintenance tary appendix.
treatment with macrolides such as azithromycin has been proved
to be effective in chronic neutrophilic airway diseases including
cystic brosis, bronchiectasis and diffuse panbronchiolitis.912 Outcomes
In an observational study, we have demonstrated the benets The primary efcacy outcome was the rate of primary endpoints
of short-term macrolide treatment in patients with severe (severe asthma exacerbations and/or LRTI requiring antibiotics)
asthma.13 Recently, erythromycin and azithromycinadded to during the 26-week treatment phase. Severe asthma exacerba-
usual therapyhave been shown to prevent exacerbations in tions were dened as deterioration in asthma leading to at least
patients with chronic obstructive pulmonary disease (COPD), a one of the following: (1) hospitalisation; (2) emergency room
predominantly neutrophilic airway disease.1416 visit; and/or (3) need for systemic corticosteroids for at least
We conducted a randomised double-blind placebo-controlled 3 days.17
trial to test the hypothesis that long-term add-on treatment with Secondary efcacy outcomes included lung function (forced
azithromycin decreases the frequency of acute exacerbations and expiratory volume in 1 s (FEV1) pre- and post-bronchodilation),
LRTI in patients with exacerbation-prone severe asthma. Since morning and evening peak expiratory ow (PEF), quality of life
severe asthma is a heterogeneous syndrome, we predened to (AQLQ score) and asthma control (ACQ score). All secondary
analyse the efcacy of azithromycin according to the type of outcomes were ascertained at visits 2, 3, 4, 5 and 6 (at random-
underlying inammation (non-eosinophilic (mainly neutrophilic) isation and weeks 4, 10, 18 and 26 of the treatment period),
or eosinophilic asthma). except for the questionnaires which were completed by the
patient at visits 2, 4 and 6 only. Safety endpoints encompassed
METHODS adverse events, serious adverse events and adverse events
Study patients leading to discontinuation.
Patients were considered eligible if they were 1875 years of
age, had a diagnosis of persistent asthma, a history consistent Statistical analysis
with Global Initiative for Asthma step 4 or 5 clinical features, The primary outcome analysis was conducted within the
received high doses of inhaled corticosteroids (1000 mg utica- intention-to-treat population. Unpaired and paired t tests were
sone or equivalent) plus inhaled long-acting 2 agonists for at used to assess between- and within-study group differences in
least 6 months prior to screening and had had at least two inde- symmetrically distributed continuous baseline characteristics and
pendent severe asthma exacerbations requiring systemic corti- post-treatment outcome measures, respectively. Exact Wilcoxon
costeroids and/or LRTI requiring antibiotics within the previous rank-sum and signed rank tests were used for skewed distributed
12 months. Subjects were never-smokers or ex-smokers with a variables. Proportions were compared between both treatment
smoking history of 10 pack-years. Their fractional excretion of groups using Fisher exact tests.
exhaled nitric oxide (FeNO) level was below the upper limit of Mean primary endpoint rates and mean exacerbation rates
normal. Exclusion criteria are specied in the online supplemen- per treatment group were investigated using Poisson or negative
tary appendix. Patients continued their maintenance treatment binomial regression as appropriate.18 For the rst primary end-
with high doses of inhaled corticosteroids and long-acting 2 point, log rank tests were performed and KaplanMeier curves
agonists during the trial. are shown to present the cumulative survival in the placebo and
azithromycin arms.
Study design and oversight Receiver operating characteristic curve analysis was performed
The AZIthromycin in Severe ASThma (AZISAST) study was a to assess the predictive power of the covariates. Statistical
randomised double-blind placebo-controlled parallel-group mul- analyses were performed using IBM SPSS statistics V.19 (SPSS
ticentre study (see online supplementary appendix gure S1). Inc, Chicago, Illinois, USA) and R V.2.14.1 (R Foundation for
The study protocol was approved by the central ethics commit- Statistical Computing, Vienna, Austria).
tee of Ghent University Hospital, and was reviewed by the local
ethics committees at each participating site. All patients pro-
vided written informed consent. RESULTS
Enrolment and baseline characteristics
Randomisation and masking The owchart of the AZISAST study is shown in gure 1.
After a 2-week run-in period, patients were randomly assigned A total of 109 of the 120 subjects screened were randomised
in a 1 : 1 ratio to receive add-on treatment with azithromycin or and constituted the intention-to-treat population. Fifty-ve sub-
placebo using a central web-based randomisation tool. The hos- jects were randomly assigned to receive azithromycin and 54
pital pharmacist (Ghent University Hospital) formulated the subjects to receive placebo. Overall, 97% of treatment visits
study drugs: capsules with 250 mg azithromycin ( prepared from were completed. Seven subjects who withdrew (two in the azi-
capsules of Zitromax) or placebo. After randomisation, the thromycin group and ve in the placebo group) completed a
patients took one capsule per day for 5 days and then one mean of four visits. Subjects in the two treatment arms were
capsule three times a week. The total treatment period was well matched with respect to baseline characteristics (table 1).
26 weeks (until visit 6), with a study drug-free follow-up period All patients received high-dose combination therapy of inhaled
of 4 weeks (washout period). corticosteroids and long-acting 2 agonists for at least 6 months

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Asthma

Figure 1 Numbers of patients who were enrolled, assigned to a study group and completed the study. Subjects were recruited by respiratory
physicians at the seven participating clinical centres. Patients who completed the 26-week course of the study drug were asked to return 4 weeks
later for a washout visit. ULN, upper limit of normal; ITT, intention-to-treat.

prior to study entry and continued this treatment throughout 1.07) in the placebo group (estimated primary endpoint rate
the entire study. ratio for azithromycin vs placebo 0.89, 95% CI 0.58 to 1.37,
p=0.600). After imputation, the estimated adjusted primary
Efcacy endpoint rate during 6 months was 0.75 (95% CI 0.55 to 1.01)
Primary outcome in the azithromycin group and 0.81 (95% CI 0.61 to 1.09) in
The median treatment period was 183 days in both the azithro- the placebo group (estimated rate ratio 0.92, 95% CI 0.60 to
mycin group and the placebo group ( p=0.269). During this 1.40, p=0.682). A negative binomial regression model did not
period a total of 39 primary endpoints (mean rate 0.72 per alter the results.18 When sensitivity analyses restricting the
26 weeks) occurred in the azithromycin group and 43 primary primary endpoint to severe exacerbations of asthma were per-
endpoints (mean rate 0.81 per 26 weeks) in the placebo group formed, the estimated severe exacerbation rate based on a
( p=0.698). In the azithromycin group, 26 (47%) subjects had at Poisson regression model was 0.55 (95% CI 0.38 to 0.78) in the
least one primary endpoint compared with 26 (48%) in the azithromycin group and 0.52 (95% CI 0.36 to 0.75) in the
placebo group (relative risk 0.98, 95% CI 0.68 to 1.43, placebo group (estimated primary endpoint rate ratio for azi-
p=1.000). The cumulative survival times based on the rst thromycin vs placebo 1.05, 95% CI 0.63 to 1.76, p=0.847).
primary endpoint per patient are shown as KaplanMeier sur-
vival curves for both treatment arms in gure 2A ( p=0.801). Predened subgroup analyses
The number of primary endpoints per patient is shown in gure Since severe asthma is biologically heterogeneous, we performed
2B ( p=0.698). a predened subgroup analysis comparing the efcacy of azi-
Thirty severe exacerbations of asthma occurred in the azithro- thromycin depending on blood eosinophilia at baseline. In sub-
mycin group compared with 27 in the placebo group jects with severe asthma and blood eosinophilia 200/ml
( p=1.000). Twenty patients in the azithromycin group and 29 (non-eosinophilic severe asthma), azithromycin signicantly
patients in the placebo group experienced a LRTI requiring anti- reduced the rate of primary endpoints and of severe exacerba-
biotics ( p=0.826). There were two hospital admissions for tions compared with placebo (gure 2C). The estimated
exacerbations of asthma in the azithromycin group and two in primary endpoint rate for non-eosinophilic severe asthma was
the placebo group ( p=1.000). 0.44 (95% CI 0.25 to 0.78) in the azithromycin group and 1.03
The estimated primary endpoint rate based on a Poisson (95% CI 0.72 to 1.48) in the placebo group (estimated primary
regression model without adjustment was 0.71 (95% CI 0.52 to endpoint rate ratio for azithromycin vs placebo 0.43, 95% CI
0.97) in the azithromycin group and 0.80 (95% CI 0.59 to 0.22 to 0.84, p=0.013). The estimated severe exacerbation rate

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Asthma

Table 1 Baseline characteristics of subjects in the intention-to-treat population

Characteristic Placebo (N=54) Azithromycin (N=55) p Value

Sex, n
Male 16 (30%) 26 (47%) 0.077
Female 38 (70%) 29 (53%)
Age, years
Median (range), IQR 53 (2074), (3660) 53 (1976), (4664) 0.097
Age at onset of symptoms, years
Median (range), IQR 17 (172), (638) 20 (071), (340) 0.828
Asthma duration, years
Median (range) IQR 23 (163), (12.841.3) 27 (270), (1145) 0.263
Race, n (%) of subjects
Caucasian 54 (100%) 55 (100%)
Body mass index*
Mean (SD) 26.4 (5.4) 26.5 (4.9) 0.926
Positive atopic status, n (%) of subjects 38 (70%) 35 (64%) 0.542
Total IgE (IU/ml)
Median (range), IQR 87.3 (24500), (25.2702.7) 111.3 (15000), (30.4266.0) 0.685
History of nasal polyps, n (%) of subjects 6 (11%) 11 (20%) 0.291
Hospitalisations due to asthma in previous year, n (%) of subjects 13 (24%) 13 (24%) 1.000
Emergency room visits due to asthma in previous year, n (%) of subjects 8 (15%) 4 (7%) 0.237
Severe asthma exacerbations requiring OCS in previous year, n (%) of subjects 47 (87%) 49 (89%) 0.776
LRTI requiring antibiotics in previous year, n (%) of subjects 44 (82%) 46 (84%) 0.805
Severe asthma exacerbations and/or LRTI requiring antibiotics in previous year
N (mean) 3.0 (1.28) 3.4 (2.08) 0.536
FEV1 prebronchodilator (% of predicted)
Mean (SD) 84.8 (20.7) 80.1 (21.9) 0.287
FEV1/FVC ratio prebronchodilator
Mean (SD) 67.8 (12.1) 66.8 (12.3) 0.556
FEV1 postbronchodilator (% of predicted)
Mean (SD) 89.3 (19.2) 83.9 (21.7) 0.184
Improvement in FEV1 after BD use (%)
Mean (SD) 6.5 (9.0) 5.5 (7.6) 0.959
FeNO (ppb)
Median (range), IQR 17.5 (663), (1227.5) 18.0 (454), (1429) 0.519
Eosinophil count in blood (109/l)
Median (range), IQR 186 (401200), (109354) 208 (01240), (100370) 0.901
Score on ACQ-7
Mean (SD) 1.7 (1.0) 1.4 (0.9) 0.400
Score on AQLQ
Mean (SD) 5.2 (1.1) 5.5 (0.9) 0.287
Daily dose of inhaled corticosteroid (mg)
Median (range) 2000 (10004000) 2000 (10004000) 0.805
Regular use of oral prednisolone
N (%) of subjects 3 (6%) 9 (16%) 0.124
Daily maintenance dose (mg)
Median (range) 10 (2.517.5) 10 (2.510) 0.359
Use of montelukast (LTRA)
N (%) of subjects 26 (48%) 29 (53%) 0.703
*Body mass index is the weight in kilograms divided by the square of the height in metres.
Atopic status based on skin prick tests; if skin prick test was not interpretable or not available, the atopic status is based on serum RAST for standard aeroallergens (house dust mite,
animal dander (cat, dog), pollen (grass, tree) and Aspergillus fumigatus).
FeNO was measured at a flow rate of 50 ml/s and expressed as parts per billion (ppb).
The doses of inhaled corticosteroids were converted to the equivalent dose of beclomethasone dipropionate and expressed as beclomethasone dipropionate equivalent.
ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; LRTI, lower respiratory
tract infection; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroids.

for non-eosinophilic severe asthma was 0.26 (95% CI 0.12 to eosinophilic severe asthma was 0.96 (95% CI 0.66 to 1.41) in
0.54) in the azithromycin group and 0.62 (95% CI 0.39 to the azithromycin group compared with 0.50 (95% CI 0.28 to
0.99) in the placebo group (estimated severe exacerbation rate 0.88) in the placebo group (estimated rate ratio 1.93, 95% CI
ratio for azithromycin vs placebo 0.42, 95% CI 0.17 to 1.00, 0.98 to 3.81, p=0.058). In patients with eosinophilic severe
p=0.050). In contrast, the primary endpoint rate for asthma, the severe exacerbation rate was higher in the

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Figure 2 Primary endpoints during the course of the study. (A) Proportion of participants free from primary endpoints for 26 weeks according to
study group. The intention-to-treat analyses were based on the participants who were randomly assigned to azithromycin (N=55) or placebo (N=54).
A primary endpoint was dened as a severe asthma exacerbation requiring treatment with systemic corticosteroids, emergency room visit or
hospitalisation17 and/or an acute lower respiratory tract infection requiring treatment with antibiotics. (B) Distribution of the number of primary
endpoints among subjects in each study group during the treatment period of the study. (C) Proportion of subjects with non-eosinophilic severe
asthma (dened by a fraction of exhaled nitric oxide lower than the upper limit of normal and a blood eosinophilia 200/ml) free from primary
endpoints for 26 weeks, according to study group (azithromycin or placebo). In subjects with non-eosinophilic asthma, azithromycin signicantly
decreased the number of patients with at least one primary endpoint (9 of 27 (33%) azithromycin-treated subjects vs 18 of 29 (62%)
placebo-treated subjects; relative risk 0.54, 95% CI 0.29 to 0.98, p=0.037).

azithromycin group than in the placebo group: 0.82 (95% CI ACQ score (mean difference 0.12; 95% CI 0.44 to 0.21;
0.55 to 1.24) versus 0.38 (95% CI 0.20 to 0.72) estimated rate p=0.485). There were no signicant between-group differences
ratio 2.19, 95% CI 1.01 to 4.73, p=0.046). In the Poisson in the changes in FEV1 ( pre- and post-bronchodilator), morning
regression model there is a signicant interaction between the PEF, evening PEF, use of rescue medication and FeNO (table 2).
phenotype of severe asthma and treatment arm ( p=0.002).
Safety
Other efcacy outcomes No signicant differences were observed in the frequency of
At 26 weeks there was a signicant improvement in the AQLQ adverse events, serious adverse events or adverse events leading
score in the azithromycin group (0.32, 95% CI 0.08 to 0.57, to discontinuation of the study drug (see online supplementary
p=0.011) compared with a non-signicant trend in the placebo table S1). Importantly, no subject in the azithromycin group
group (0.20, 95% CI 0.01 to 0.41, p=0.057; table 2). There reported hearing loss.
were no signicant differences between the groups in the
change from baseline in AQLQ score (mean difference 0.12; Oropharyngeal colonisation and resistance to macrolides
95% CI 0.20 to 0.44; p=0.467). Two clinical centres studied resistance to macrolide antibiotics,
At 26 weeks, the mean improvement in the ACQ score was obtaining oropharyngeal swabs in 46 participants (23 in each
0.24 (95% CI 0.50 to 0.02, p=0.068) in the azithromycin treatment arm) at four visits (see online supplemental gure S1).
group compared with 0.12 (95% CI 0.33 to 0.08, p=0.222) Eleven subjects (47.8%) in the azithromycin group and nine
in the placebo group (table 2). There were no signicant subjects (39.1%) in the placebo group were colonised with
between-group differences in the change from baseline in the erythromycin-resistant streptococci in the oropharynx at

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Asthma

randomisation. At the end of the 26-week treatment period,

87% of the subjects in the azithromycin group and 35% of the

p Value

0.485
0.467
0.686
0.778
0.688
0.378
0.655
0.666
subjects in the placebo group were colonised with erythromycin-
resistant oropharyngeal streptococci ( p<0.001). During the

3.96 (15.40 to 23.32)

3.84 (23.10 to 30.78)
treatment period the proportion of streptococci resistant to

0.12 (0.44 to 0.21)

0.12 (0.20 to 0.44)

0.88 (3.44 to 5.19)

1.95 (2.42 to 6.33)
0.16 (0.88 to 0.55)
erythromycin increased from 17.2% to 73.8% in the azithromy-
DifferenceMean cin group and from 7.9% to 17.3% in the placebo group
(95% CI) (p<0.001; see online supplemental gure S3). The percentage
of macrolide-resistant streptococci numerically decreased from

1.6
73.8% to 45.9% in the azithromycin group during the 4-week
washout period ( p=0.104).

0.5 (6.7; 6.7)

ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; BD, bronchodilator; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow.
(N=4753)Mean
At 26 weeks after randomisation

DISCUSSION
Azithromycin

1.81 (45.27)
0.81 (48.47)
0.02 (10.06)
1.29 (12.50)
0.24 (0.93)
0.32 (0.89)

0.08 (1.14)
In this randomised double-blind placebo-controlled trial in
patients with severe asthma, add-on treatment with low-dose
(SD)

azithromycin for 6 months did not decrease the frequency of

the primary endpoint (severe exacerbations of asthma and LRTI
2.1 (4.2; 6.0)
(N=4550)Mean

requiring antibiotics). However, in a predened subgroup ana-

5.77 (48.20)
4.65 (78.68)
0.90 (11.79)
0.12 (0.70)
0.20 (0.73)

0.66 (8.84)
0.24 (2.11)

lysisnamely, in subjects with severe non-eosinophilic asthma

Placebo

(as dened by a FeNO lower than the upper limit of normal

and a blood eosinophilia 200/ml (the median value of blood
(SD)

eosinophilia in our ITT population))add-on treatment with

azithromycin was associated with a signicant reduction in
p Value

0.940
0.509
0.866
0.637
0.884
0.870
0.706
0.676

primary endpoints and in the rate of severe exacerbations.

Azithromycin improved quality of life and was well tolerated.
1.58 (20.08 to 16.92)
3.88 (12.38 to 20.13)

Several studies have examined whether macrolides are bene-

0.01 (0.35 to 0.33)
0.09 (0.19 to 0.38)

0.28 (4.11 to 3.54)

0.26 (3.45 to 2.92)
0.13 (0.83 to 0.56)

cial in adult patients with asthma.1923 However, interpretation

DifferenceMean

of the studies is difcult because of the heterogeneous study

populations, the small number of patients studied and the short
study durations (less than 12 weeks).8 24 Most studies have been
(95% CI)

performed in patients with mild-to-moderate asthma.1921 23 25

In a proof-of-concept study, Simpson and colleagues demon-
strated that clarithromycinas add-on treatment to inhaled cor-
0 (4.5; 7.1)
(N=5053)Mean
At 10 weeks after randomisation

ticosteroids for 8 weeks in patients with severe asthma

Azithromycin

3.30 (42.10)
4.11 (36.10)
0.05 (0.98)
0.24 (0.84)

0.64 (9.99)
0.91 (7.61)
0.13 (1.18)

signicantly reduced airway concentrations of interleukin-8 and

neutrophil numbers and improved quality of life, especially in
(SD)

patients with refractory non-eosinophilic asthma.26 However,

the duration of this single-centre study was too short and the
2 (4.5; 5.0)
(N=4550)Mean

number of patients too small to examine the effect of macro-

1.72 (49.97)
7.98 (44.66)
0.04 (0.76)
0.15 (0.63)

0.92 (9.88)
1.17 (8.88)
0.26 (2.19)

lides on exacerbations. Also, in our multicentre study, treatment

with azithromycin signicantly improved quality of life at
Placebo

26 weeks compared with baseline. In both studies there were no

(SD)

changes in symptom scores, lung function or FeNO levels with

macrolide treatment.26
Absolute change in morning PEF, baseline to week 10 or 26 (l/min)

Since severe asthma is a heterogeneous syndrome, we prede-

Absolute change in evening PEF, baseline to week 10 or 26 (l/min)

ned to analyse the efcacy of azithromycin according to the

Change in use of rescue medication (number of puffs per day)

asthma phenotype (non-eosinophilic (mainly neutrophilic) or

Change in post-BD FEV1, baseline to week 10 or 26 (%)

eosinophilic asthma).1 2 Add-on treatment with azithromycin

Change in AQLQ total score, baseline to week 10 or 26

Change in pre-BD FEV1, baseline to week 10 or 26 (%)

signicantly decreased the rate of primary endpoints and of

Change in ACQ score, baseline to week 10 or 26

severe exacerbations in the subgroup of patients with

Secondary efficacy outcomes

non-eosinophilic severe asthma. In contrast, in subjects with

Change in FeNO (ppb), median (Q1; Q3)

eosinophilic severe asthma, there was a trend towards an

increased rate of primary endpoints in the azithromycin group,
in line with case reports describing the induction of Churg
Strauss syndrome in patients with eosinophilic asthma receiving
add-on treatment with azithromycin.27
The benecial effects of azithromycin in non-eosinophilic
severe asthma might be due to antibiotic properties or anti-
inammatory and immunomodulatory effects. Chronic respira-
Outcome
Table 2

tory infection with atypical bacteria such as Mycoplasma pneu-

moniae or Chlamydophila pneumoniae might play a role in the
pathogenesis of severe asthma.28 However, a trial of roxithro-
mycin in subjects with asthma and serological evidence of infec-
tion with C pneumoniae did not improve asthma control,20

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Asthma

which is in line with our observations that positive IgG anti- nasopharyngeal and oropharyngeal ora in azithromycin-treated
bodies to C pneumoniae did not predict therapeutic efcacy of subjects is of concern. In addition, the long-term effects of
azithromycin in severe asthma. macrolide treatment on microbial resistance in the community
Long-term treatment with azithromycin in our study appeared are not known.
to be safe, since the frequency and severity of adverse events
was not different from placebo. In particular, no subjects in the Author afliations
1
azithromycin-treated group mentioned hearing loss, which con- Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
2
Department of Respiratory Medicine, OLV Ziekenhuis, Aalst, Belgium
trasts with the hearing decrements reported by Albert et al in 3
Department of Respiratory Medicine, AZ Groeninge, Kortrijk, Belgium
patients with chronic obstructive pulmonary disease (COPD).15 4
Department of Respiratory Medicine, ZNA Middelheim, Antwerpen, Belgium
5
The older age of the subjects with COPD, more frequent Department of Respiratory Medicine, AZ Sint-Jan, Brugge, Belgium
6
comorbidities, the higher dose of azithromycin used and the Department of Respiratory Medicine, University Hospital Gasthuisberg, Leuven,
Belgium
intensive monitoring by means of audiometry in the COPD 7
Department of Respiratory Medicine, Heilig Hart Ziekenhuis, Roeselare, Belgium
study might explain this difference. Recently, a retrospective 8
Department of Epidemiology, Erasmus MC Rotterdam, Rotterdam, The Netherlands
observational database study has suggested a small increased risk 9
Department of Microbiology, Clinical Chemistry and Immunology, Ghent University
of cardiovascular death among patients with a high baseline risk Hospital, Ghent, Belgium
10
of cardiovascular disease taking azithromycin during 5 days for Department of Radiology, University Hospital Gasthuisberg, Leuven, Belgium
11
Biostatistics Unit, Department of Public Health, Ghent University Hospital, Ghent,
acute infections.29 Since we excluded patients with signicant Belgium
cardiovascular disease, a prolonged corrected QT interval or use
of drugs known to cause QT prolongation, there were no Acknowledgements We acknowledge all patients, physicians, clinical trial nurses,
serious cardiac adverse drug reactions in our study. data managers and other collaborators who contributed to the AZISAST study.
A concern of chronic treatment with azithromycin is the Contributors GGB: study design. GGB, CVS, PJ, RD, HS, VR, GVM, IKD, GFPJ:
induction of resistance to macrolides. Short-term treatment with patient recruitment, enrolment, randomisation and follow-up. AD, BD, JV: collection
of the data. GC, JB and EP: bacteriological and serological analyses. GGB, CVS, KV,
macrolides induced a signicant increase in macrolide-resistant
GVM, ED, GFPJ: analysis and interpretation of the data. GGB, GVM, KV, JB, EP, ED,
pharyngeal streptococci in healthy volunteers.30 In our study, GFPJ: writing of the report.
long-term treatment with azithromycin was associated with an
Competing interests None.
increased proportion of macrolide-resistant oropharyngeal
streptococci, conrming the increased incidence of macrolide Patient consent All patients provided written informed consent, as required by
Belgian Law and the Ethical Committees involved.
resistance in the nasopharyngeal ora in the COPD Clinical
Research Network study.15 However, in both studies, there is no Ethics approval The study protocol was approved by the central ethics committee
of Ghent University Hospital, and was reviewed by the local ethics committees at
evidence suggesting that colonisation with macrolide-resistant each participating site.
organisms increased the risk of LRTI or pneumonia.
Funding The AZIthromycin in Severe ASThma (AZISAST) study was an academic
Our study has several strengths, including the double-blind clinical trial, without sponsorship from the pharmaceutical industry. The study was
design, web-based randomisation and the concealment of alloca- funded by the Agency for Innovation by Science and Technology (IWT 70709),
tion. The AZISAST study also has limitations, including the Flanders, Belgium. The study sponsor (IWT) had no role in the study design; in the
absence of induced sputum or bronchoscopy to delineate the collection, analysis, and interpretation of data; in the writing of the report; and in
the decision to submit the paper for publication.
underlying airway inammation. However, to maximise the exter-
nal validity of our study, we did not perform induced sputum Provenance and peer review Not commissioned; internally peer reviewed.
examinations since this labour-intensive procedure is mainly per-
formed in specialised tertiary referral centres. Moreover, peripheral
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8 Brusselle GG, et al. Thorax 2013;0:18. doi:10.1136/thoraxjnl-2012-202698

 Downloaded from thorax.bmj.com on July 10, 2014 - Published by group.bmj.com

Azithromycin for prevention of

exacerbations in severe asthma (AZISAST):
a multicentre randomised double-blind
placebo-controlled trial
Guy G Brusselle, Christine VanderStichele, Paul Jordens, et al.

Thorax published online January 3, 2013

doi: 10.1136/thoraxjnl-2012-202698

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