Research

JAMA Internal Medicine | Original Investigation

Azithromycin for Acute Exacerbations of Asthma

The AZALEA Randomized Clinical Trial
Sebastian L. Johnston, MBBS, PhD; Matyas Szigeti, MSc; Mary Cross, BA (Hons);
Christopher Brightling, MBBS, PhD; Rekha Chaudhuri, MBBS, MD; Timothy Harrison, MBBS, PhD;
Adel Mansur, MBBS, PhD; Laura Robison, BSc; Zahid Sattar, BSc, PhD; David Jackson, MBBS, PhD;
Patrick Mallia, MBBS, PhD; Ernie Wong, MBBS, BSc; Christopher Corrigan, MA, PhD; Bernard Higgins, MBBS;
Philip Ind, MB, BChir, PhD; Dave Singh, MB, BChir, MD; Neil C. Thomson, MBChB, MD; Deborah Ashby, PhD, CStat;
Anoop Chauhan, MBBS, PhD; for the AZALEA Trial Team

Invited Commentary
IMPORTANCE Guidelines recommend against antibiotic use to treat asthma attacks. A study pages 1637 and 1649
with telithromycin reported benefit, but adverse reactions limit its use. Related article page 1639

Supplemental content
OBJECTIVE To determine whether azithromycin added to standard care for asthma attacks in
adults results in clinical benefit. CME Quiz at
jamanetworkcme.com and
CME Questions 1732
DESIGN, SETTING, AND PARTICIPANTS The Azithromycin Against Placebo in Exacerbations of
Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United
Kingdom–based multicenter study in adults requesting emergency care for acute asthma
exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for
more than 6 months were recruited within 48 hours of presentation to medical care with an
acute deterioration in asthma control requiring a course of oral and/or systemic
corticosteroids.

INTERVENTIONS Azithromycin 500 mg daily or matched placebo for 3 days.

MAIN OUTCOMES AND MEASURES The primary outcome was diary card symptom score 10
days after randomization, with a hypothesized treatment effect size of −0.3. Secondary
outcomes were diary card symptom score, quality-of-life questionnaires, and lung function
changes, all between exacerbation and day 10, and time to a 50% reduction in symptom
score.

RESULTS Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized
within 48 hours of presentation. The major reason for nonrecruitment was receipt of
antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug
administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics
were well balanced across treatment arms and centers. The primary outcome asthma
symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the
azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using
multilevel modeling, there was no significant difference in symptom scores between
azithromycin and placebo at day 10 (difference, −0.166; 95% CI, −0.670 to 0.337), nor on any
day between exacerbation and day 10. No significant between-group differences were
observed in quality-of-life questionnaires or lung function between exacerbation and day 10,
or in time to 50% reduction in symptom score.
Author Affiliations: Author
affiliations are listed at the end of this
CONCLUSIONS AND RELEVANCE In this randomized population, azithromycin treatment
article.
resulted in no statistically or clinically significant benefit. For each patient randomized, more
Group Information: The AZALEA
than 10 were excluded because they had already received antibiotics. Trial Team members are listed in
Supplement 1.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01444469 Corresponding Author: Sebastian L.
Johnston, MBBS, PhD, Airway
Disease Infection Section, National
Heart and Lung Institute, Imperial
College London, Norfolk Pl, London
JAMA Intern Med. 2016;176(11):1630-1637. doi:10.1001/jamainternmed.2016.5664 W2 1PG, England (s.johnston
Published online September 19, 2016. @imperial.ac.uk).

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 Azithromycin for Acute Exacerbations of Asthma Original Investigation Research

A
sthma morbidity, mortality, and major health care costs
result from acute attacks (exacerbations).1 The major- Key Points
ity of patients with asthma report an exacerbation in
Question Does addition of azithromycin to standard care improve
the past year, with more than one-third of children and more outcomes in adults requesting acute medical care for asthma
than one-fourth of adults requiring consequent urgent medi- attacks?
cal care.2
Findings This randomized clinical trial found no statistically or
Respiratory viral infections are a frequent cause of asthma
clinically significant benefit in symptoms, lung function, or speed
exacerbations in children3,4 and adults.5-7 Atypical bacterial of recovery. For every 1 patient randomized, more than 10 had to
(Mycoplasma pneumoniae and Chlamydophila pneumoniae) in- be excluded because they had already received antibiotics.
fection and/or reactivation is also associated, with serologic
Meaning Widespread use of antibiotics despite guideline
positivity rates of 40% to 60% in some studies,8-12 indicating
recommendations limited interpretation of the results of this study.
that viral and atypical bacterial infections may interact in in-
creasing asthma exacerbation risk.
People with asthma have increased susceptibility to strep- than 65 years with a less than 5 pack-year smoking history, with
tococcal infections,13-15 increased carriage of bacterial patho- a documented history of asthma for more than 6 months, and
gens identified by culture16 and molecular techniques,17 and recruitment within 48 hours of presentation to medical care
impaired interferon and type 1 T helper cell responses to bac- with an acute deterioration in asthma control (increased
terial polysaccharides.18,19 Viral infection impairs antibacte- wheeze, dyspnea, and/or cough) necessitating a course of oral
rial innate immune responses20 and increases bacterial ad- and/or systemic corticosteroids (based on clinical judgement
herence to bronchial epithelium.21 Thus, bacterial infections by attending physicians) and a peak expiratory flow (PEF) or
are more common and more severe in patients with asthma, forced expiratory volume in 1 second (FEV1) less than 80% pre-
viruses increase susceptibility to bacterial infection, and acute dicted or patient’s best at presentation, at recruitment, or in
wheezing episodes in children younger than 3 years were as- the time elapsed between presentation and recruitment.
sociated with both bacterial and viral infection.22 The main exclusion criteria were use of oral and/or sys-
Patients with asthma exacerbations treated with telithro- temic antibiotics within 28 days of enrollment, need for in-
mycin had greater reductions in asthma symptoms, improve- tensive care, substantial lung disease other than asthma, long-
ment in lung function, and faster recovery compared with term use of more than 20 mg oral corticosteroid daily, known
placebo.12 However, toxic effects to the liver limit telithromy- QT-interval prolongation, history of bradyarrhythmias and/or
cin treatment to life-threatening infections, and guidelines rec- tachyarrhythmias or uncompensated heart failure, and pa-
ommend that antibiotics should not be administered rou- tients taking drugs known to prolong the QT interval.
tinely in patients with asthma exacerbations.23,24 The primary outcome was diary card summary symptom
The Azithromycin Against Placebo in Exacerbations of score, with symptoms including wheezing, breathlessness, and
Asthma (AZALEA) study investigated the effectiveness of coughing assessed at 10 days after randomization (as in the
azithromycin treatment when added to standard care for adult telithromycin study).12 Secondary outcomes included the acute
patients with asthma exacerbations, closely following the Asthma Quality of Life Questionnaire (AQLQ), the mini AQLQ,
telithromycin study design, with the aim of providing confir- FEV1, forced vital capacity (FVC), FEV1/FVC, forced mid-
mation or otherwise of those results. expiratory flow (FEF25%-75%), forced expiratory flow at 50% ex-
Macrolide antibiotics might benefit asthma exacerbations piration (FEF50%), PEF, and time to 50% reduction in symp-
through antimicrobial activity and/or anti-inflammatory tom score. Primary and secondary outcomes were assessed
properties25; and azithromycin, but not telithromycin, has been over the time course of the exacerbation to 10 days, and sub-
shown to have antiviral properties,26 augmenting production group analyses were planned in relation to initial standard
of interferons that are deficient in patients with asthma.19,27 A and/or atypical bacteriologic and virologic status.
mechanistic and exploratory aim of AZALEA was to determine Spontaneous or induced sputum samples were obtained
whether treatment benefited patients with these infections. where possible at exacerbation and sent for quantitative bac-
teria culture. A nasal mucus sample and nasal and throat swab
samples were obtained where possible at exacerbation, and
these and spontaneous or induced sputum samples were ana-
Methods lyzed by means of viral and atypical bacterial polymerase chain
Study Design reactions (PCRs) and acute and convalescent serum samples
This United Kingdom–based multicenter, double-blind, pla- were sent for atypical bacterial serologic analysis.
cebo-controlled study randomized eligible patients to azithro- The trial received approval from the National Research Eth-
mycin 500 mg daily or placebo for 3 days on day 1 (visit 1), with ics Committee, Bloomsbury, London, England, and all pa-
posttherapy assessments at visits on days 5 (visit 2) and 10 (visit tients gave written informed consent. Additional methods are
3) and for serum sampling at 6 weeks (visit 4) (see trial proto- available in the eMethods in Supplement 1.
col in Supplement 2).
The main inclusion criteria were that participants be adults Statistical Analyses
aged 18 to 55 years with any smoking history, aged 56 to 65 The sample size calculations hypothesized a treatment mean
years with a less than 20 pack-year smoking history, or older (SD) effect size of −0.3 (0.783) based on the primary outcome

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 Research Original Investigation Azithromycin for Acute Exacerbations of Asthma

cebo (Figure 1). The major reason for nonrecruitment was al-
Figure 1. Consolidated Standards of Reporting Trials Diagram of the
Azithromycin for Acute Exacerbations of Asthma (AZALEA) Trial
ready receiving antibiotics (2044 [44.6%] screened patients).
Clinical characteristics of randomized patients are sum-
4582 Patients assessed for eligibility marized in Table 1. Study participants’ mean (SD) age was 39.9
(14.82) years (median [interquartile range] age, 38.4 [26.7-
49.5] years), with 69.8% female. Underlying asthma severity,
4383 Excluded
2044 Antibiotic treatment smoking status, exacerbation severity, and median time from
660 Other presentation to trial drug administration are presented in
417 Underlying health condition
315 Discharged Table 1. Pulmonary function at baseline (exacerbation, visit 1)
259 Age is presented in Table 2 and includes mean (SD) PEF, 69.4%
220 >48 Hours after presentation
191 Declined to participate
(22.7%) of predicted; FEV1, 64.8% (21.4%) of predicted; and
130 Unknown reason FEV1/FVC, 69.2% (13.5%). Baseline characteristics were well
110 No requirement for steroid
treatment
balanced across treatment arms and centers.
30 Not English speaking Of the 199 patients randomized, all attended visit 1 (ran-
7 No asthma exacerbation
domization), 21 (10.6%) missed visit 2, 28 (14.1%) missed visit
3, and 39 (19.6%) missed visit 4; 159 (80%) patients attended
199 Randomized all follow-up visits. Missing visits and/or data were balanced
between the treatment arms. Day 1 was defined as the day of
administration of study drug.
97 Randomized to receive 102 Randomized to receive placebo
azithromycin 102 Received placebo as
97 Received azithromycin as randomized
randomized
Primary Outcome Analysis
Mean (SD) asthma symptom scores (from 0 = no symptoms to
6 = severe symptoms) were 4.14 (1.38) at baseline (exacerba-
87 Symptom diary scores analyzed 89 Symptom diary scores analyzed
96 Acute and Mini AQLQ scores 100 Acute and Mini AQLQ scores
tion) and 2.09 (1.71) at day 10 for the azithromycin group and
analyzed analyzed 4.18 (1.48) and 2.20 (1.51), respectively, for placebo. Using mul-
97 Pulmonary functions analyzed 101 Pulmonary functions analyzed
tilevel modeling, there was no statistically significant differ-
ence in symptom scores between groups at day 10 (differ-
AQLQ indicates Asthma Quality of Life Questionnaire.
ence, −0.166; 95% CI, −0.670 to 0.337) (Figure 2 and eTable 3
in Supplement 1).
of the telithromycin study12 and used a significance level of
1% with 80% power, assuming a dropout rate of 15%.12 We pro- Secondary Outcome Analyses
posed to recruit 190 patients to each arm. To run the trial within Multilevel modeling revealed no significant between-group dif-
the project funding 1-year timeline, we planned 10 centers, each ferences in symptom scores on any day between baseline and
recruiting roughly 38 patients. day 10 (Figure 2 and eTable 3 in Supplement 1). Significant be-
All patients who returned at least 1 diary card and re- tween-group differences were seen in neither the acute AQLQ,
ceived study drug were included in the intention-to-treat analy- the mini AQLQ (Figure 3A and B and eTables 7-10 in
ses. Because the timing of greatest magnitude of any treat- Supplement 1), nor in any measure of lung function (eTables
ment effect was not known, multilevel modeling was used to 11 and 12 in Supplement 1) on any day from baseline to day 10,
calculate the estimated differences in primary and secondary and there was no difference in time to 50% reduction in symp-
outcomes between treatment groups for each day from ran- tom score (hazard ratio, 1.03; 95% CI, 0.71-1.49) (Figure 3C).
domization to day 10. A Cox model was used to calculate the
hazard ratio for time to 50% reduction in symptom score. De- Pathogen Detection Results
tails of the statistical model, model selection process, and treat- One hundred five (52.8%) patients provided sputum samples
ment of missing data are in the eMethods in Supplement 1. All for bacterial culture, 191 (96.0%) nasal and throat swabs and/or
analyses were performed using Stata 13. A statistical analysis nasal mucus samples for virus and atypical bacterial PCR, and
plan was prepared by the trial statistician prior to unblinding. 158 (79.4%) acute (IgM) and acute and convalescent (IgG, IgA)
serum samples for atypical bacterial serologic analysis. A bac-
terial and/or atypical bacterial test positive result occurred in
21 (10.6%) patients (9 [9.3%] active, 12 [11.8%] placebo). Nasal
Results and/or throat swab and/or mucus and/or sputum virus PCRs
Recruitment Details and Clinical Characteristics had positive results in 36 (18.1%) patients (16 [16.5%] active,
Recruitment from 31 sites (30 secondary care hospitals, 1 pri- 20 [19.6%] placebo).
mary care center) lasted 2.5 years, from October 12, 2011, to
April 30, 2014. The recruitment period was longer than planned Subgroup Analyses
because of recruitment difficulties arising from the large num- There were no differences in the primary outcome asthma
bers of patients excluded. A total of 4582 patients were symptom score between treatment groups in patients with
screened, of whom 390 patients met eligibility criteria. A total positive sputum bacterial culture results, atypical bacterial
of 199 were randomized, 97 to active treatment and 102 to pla- PCR and/or serologic analysis results, or virus PCR test

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 Azithromycin for Acute Exacerbations of Asthma Original Investigation Research

results (including any bacteria and/or virus positive test Safety

result) (eTables 13-15 and eFigures 6-8 in Supplement 1), Adverse events were infrequent (eTables 16-22 in Supplement
although patient numbers for these analyses were low. 1), with more gastrointestinal adverse events in the azithro-
mycin group compared with placebo (35 vs 24 events, respec-
Table 1. Baseline Characteristics of Patients by Treatment Group tively) (eTable 16 in Supplement 1). There was an increased fre-
Azithromycin Placebo quency of cardiac adverse events (4 vs 2, respectively) in the
Characteristic (n = 97) (n = 102) azithromycin group compared with placebo and a reduced fre-
Age, median (IQR), y 39.1 (28.9-49.5) 36.2 (25.4-49.3) quency of respiratory, thoracic, and mediastinal (63 of 64 re-
Sex, No. (%) spiratory) adverse events (27 vs 37, respectively) (eTables 16
Male 33 (34) 27 (26) and 20 in Supplement 1), suggesting that antibiotic therapy pos-
Female 64 (66) 75 (74) sibly reduced respiratory adverse events in this population.
Asthma severity (n = 198), No. (%)28
Step 1: mild intermittent asthma 7 (7) 13 (13)
Step 2: regular preventer therapy 30 (31) 26 (26)
Discussion
Step 3: initial add-on therapy 31 (32) 27 (27)
Step 4: persistent poor control 22 (23) 22 (22) In the patients with asthma exacerbations randomized to treat-
Step 5: continuous/frequent oral 7 (7) 13 (13) ment or placebo in this study, the addition of azithromycin to
steroids
Smoking status, No. (%)
Never 60 (62) 61 (60) Figure 2. Primary Outcome Symptom Diary Scores From Randomization
to Day 10
Former 26 (27) 19 (19)
Current 11 (11) 21 (21) 6
Smoking pack-years for current 5 (1-12) [0-20] 5 (2-12) [0-22]
or former smokers (n = 75), 5 Active
median (IQR) [range] Placebo
Mean Diary Score

Asthma exacerbation (n = 198), 4

No. (%)
3
Mild exacerbation 5 (5) 3 (3)
Moderate exacerbation 26 (27) 35 (35) 2
Acute severe asthma 61 (63) 56 (55)
1
Life-threatening asthma 4 (4) 7 (7)
Near-fatal asthma 1 (1) 0 0
0 1 2 3 4 5 6 7 8 9 10
Time from presentation to receipt of 21 (12-29) 22 (14-28) Day
study drug (n = 192), median (IQR), h
Abbreviation: IQR, interquartile range. Error bars indicate standard error.

Table 2. Baseline (Exacerbation) Pulmonary Function by Treatment Arm

Percentile
Patients,
Pulmonary Function No. Mean (SD) 25th 50th 75th
Azithromycin
FEV1, L 95 1.9 (0.7) 1.4 1.8 2.5
FEV1% predicted, % 93 63.2 (21.8) 48 63 79
FVC, L 96 2.8 (1.0) 2.0 2.7 3.5
FEV1/FVC ratio 94 69.7 (13.3) 62.0 70.0 79.0
FEF25%-75%, L/s 80 1.6 (0.9) 0.9 1.4 2.1
FEF50%, L/s 76 1.9 (1.1) 1.1 1.7 2.6
PEF, L/min 93 290 (104) 215 283 348
PEF % predicted, % 92 65.7 (23.4) 47.0 67.0 79.0
Placebo
FEV1, L 96 2.1 (0.8) 1.5 2.0 2.6
FEV1% predicted, % 96 66.3 (21.0) 52.5 64.0 84.0
FVC, L 96 3.1 (1.0) 2.4 3.0 3.6 Abbreviations: FEF25%-75%, forced
FEV1/FVC ratio 96 68.8 (13.7) 58.0 69.0 79.5 mid-expiratory flow; FEF50%, forced
expiratory flow at 50% expiration;
FEF25%-75%, L/s 87 1.7 (1.1) 0.9 1.4 2.4
FEV1, forced expiratory volume in 1
FEF50%, L/s 84 2.0 (1.3) 1.1 1.7 2.8 second; FEV1/FVC, ratio of forced
PEF, L/min 96 323 (98) 248 341 390 expiratory volume in 1 second to
forced vital capacity; FVC, forced vital
PEF % predicted, % 95 73.0 (21.5) 56.0 75.0 90.0
capacity; PEF, peak expiratory flow.

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 Research Original Investigation Azithromycin for Acute Exacerbations of Asthma

son, to recruit the planned 380 patients. Our power calcula-

Figure 3. Secondary Outcome Acute and Mini Asthma Quality of Life
Questionnaire (AQLQ) Scores From Randomization to Day 10 and Time
tion deliberately mandated large patient numbers to provide
to 50% Reduction in Symptom Diary Score statistically robust data to settle the important clinical ques-
tion regarding antibiotic efficacy in this setting (for compari-
A Acute AQLQ score Active son, the telithromycin study randomized 270 patients).12 We
Placebo
7 also desired larger patient numbers to enhance subgroup analy-
ses aimed at potentially important mechanistic questions. Once
Mean Acute AQLQ Overall Score

6
recruitment obstacles became clear with such widespread an-
5 tibiotic use, a total of 31 centers were enrolled, inclusion crite-
4
ria were relaxed to change eligibility criteria from less than 24
to less than 48 hours from time of presentation, to include older
3 participants with low smoking histories, and recruitment was
2 extended to 2 years and 7 months. However, despite all these
efforts, only 199 participants were recruited by medication ex-
1
1 2 3 piry and funding end dates and the study was terminated de-
Visit spite not reaching its recruitment target. The study was there-
fore underpowered and a difference of 0.3 in mean symptom
B Mini AQLQ score score between treatment arms at 10 days cannot be excluded.
7 The different outcomes of the present and previous
studies,12 which used closely related therapies in similar study
Mean Mini AQLQ Overall Score

6
designs, require interpretation and/or explanation. The anti-
5 biotics studied are different, albeit related. Both drugs were used
4
at their standard recommended doses and durations of therapy.
The shorter duration of treatment with azithromycin (3 days
3 vs 10 days with telithromycin) is unlikely to explain the differ-
2 ence in outcome because azithromycin has a long tissue half-
life and is likely to have remained at therapeutic doses in the
1
1 2 3 lung for approximately 10 days.29 Azithromycin but not telithro-
Visit mycin has antiviral activity,26 so this is an unlikely explana-
tion. In terms of antibacterial activity against relevant respi-
C Time to 50% reduction in symptom scores ratory bacteria, telithromycin is reportedly more active than
1.00 azithromycin against Streptococcus pneumoniae but has simi-
Proportion Yet to Reach 50% Reduction

lar activity against both Moraxella catarrhalis and Haemophi-

0.75 lus influenzae.30-32 Because the present study only detected 3
S pneumoniae, 1 M catarrhalis, and no H influenzae infections
0.50
in the active treatment arm, differences in activity against these
organisms seem unlikely to explain the differing outcomes. In
terms of anti-inflammatory activities, both drugs reportedly
0.25
have similar activities when compared.25
A remarkable finding of this study was the number of pa-
0
0 1 2 3 4 5 6 7 8 9 10 tients (2044) excluded because they were already receiving an-
Visit tibiotic therapy for their asthma exacerbation despite treat-
ment guidelines recommending that such therapy not be
A and B, Acute and Mini AQLQ mean scores by visits for each treatment arm.
routinely given.23,24 For each patient randomized, more than
Error bars indicate standard error. C, Kaplan-Meier curves of time to a 50%
reduction in symptom diary score for each treatment arm (truncated at 10 days). 10 were excluded for this reason. This important finding has
obvious and worrying implications regarding antibiotic
stewardship33; in addition, such high antibiotic use rates may
standard medical care resulted in no statistically or clinically also have directly influenced the study outcome because it is
significant therapeutic benefit. The findings were consis- possible that patients who might potentially have benefitted
tently negative across 3 different symptom and quality-of-life from antibiotic therapy for their asthma exacerbation (through
scores, including 1 previously reporting statistically and clini- having sputum production, sputum purulence, fever) were ex-
cally significant benefit with telithromycin treatment.12 The cluded from the study through already having received them.
findings were also negative for all measures of lung function, The population remaining to be randomized could theoreti-
including FEV1, which was significantly improved in the pre- cally have been selected against for antibiotic responsive-
vious study,12 and for time to a 50% reduction in asthma symp- ness, through having no clinical indication that antibiotic
toms, which was significantly improved in the previous study.12 therapy might be of benefit. This is possible because patients
Recruitment proved challenging; initially there were 10 cen- being screened had often been seen by their primary care prac-
ters, each aiming to recruit 38 participants over 1 winter sea- titioner, by emergency department medical staff, and by a

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 Azithromycin for Acute Exacerbations of Asthma Original Investigation Research

member of the on-call respiratory and/or medical team, so in (Medac C pneumoniae IgM sandwich enzyme-linked immuno-
many instances 3 independent physicians and/or teams had sorbent assay, Medac) so the discrepancy between the results
assessed them, including their suitability for antibiotic therapy. of this assay is difficult to explain. This major difference in fre-
It is likely therefore that those not prescribed antibiotics were quency of C pneumoniae IgM positivity may have contributed
negatively selected against, for suitability for antibiotics. This to the difference in clinical outcomes between the 2 studies.
interpretation is supported by the low bacterial and/or atypi- Sputum culture for standard bacteria was not performed in
cal bacterial positivity rate found in this study: only 9.3% of the telithromycin study.12 In the present study, 105 (52.8%) par-
azithromycin-treated participants. ticipants provided sputum samples for bacterial culture and
It is also possible that the population randomized were in positivity was observed in 6.0% (4.1% active, 7.8% placebo).
other ways not representative of the larger population screened These results, together with the negative outcomes in relation
because more than 2000 other patients were excluded from to therapy, suggest that the role of standard bacterial infection
the study for other reasons (Figure 1). The telithromycin study in the population studied was unlikely to be important.
did not report numbers of patients screened,12 so it is not pos- Interpretation of the outcome of this study must be con-
sible to determine to what extent these caveats may also have sidered in the light of prior knowledge that noninfectious
applied to that study. agents can also trigger exacerbations, and of other random-
A further difference is that all patients randomized to this ized placebo-controlled studies investigating the effects of simi-
study were required to be prescribed oral and/or systemic cor- lar therapies in acute wheezing episodes. In addition to the
ticosteroid treatment, whereas in the telithromycin study only telithromycin study reporting positive outcomes in asthma ex-
34.1% of patients randomized to active treatment required cor- acerbations in adults,12 azithromycin treatment during bron-
ticosteroid therapy.12 Requirement for corticosteroid treat- chiolitis in infancy was reported to reduce nasal lavage inter-
ment in this study was designed to reduce the number of milder leukin 8 levels, the occurrence of postbronchiolitic wheezing,34
exacerbations studied. However, if our study included largely and the duration of acute episodes of asthma-like symptoms
non–bacterially infected participants, this could have re- in 1- to 3-year-old children.35 Furthermore, in 1- to 6-year-old
sulted in us studying possible anti-inflammatory effects of children with histories of recurrent severe lower respiratory
azithromycin, in the face of the powerful anti-inflammatory tract infections (LRTIs), azithromycin treatment early during
effects of corticosteroids, with predictably negative results. an apparent respiratory tract infection reduced the likeli-
The clinical characteristics of the patients in our study com- hood of severe LRTI.36 Finally, low-dose azithromycin pro-
pared with those in the telithromycin study were similar in phylaxis for 6 months in participants with exacerbation-
terms of mean age (39.9 years in our study vs 39.5 in the prone severe asthma did not reduce the primary outcome (rate
telithromycin study), sex (30.2% male vs 32%), smoking sta- of severe exacerbations and LRTIs necessitating treatment with
tus (mean of 3.44 vs 2.15 pack-years), exacerbation symptom antibiotics); however, in a predefined subgroup analysis ac-
score severity (4.16 vs 2.9), and lung function at exacerbation cording to inflammatory phenotype, azithromycin treatment
(PEF, 69.4% vs 55.2% of predicted; FEV1, 64.8% vs 67.2% of benefitted participants with noneosinophilic severe asthma.37
predicted; FEV1/FVC, 69.2% vs 72%).12 Differences in clinical We therefore carried out a similar post hoc analysis but found
characteristics do not seem a likely explanation for the differ- no evidence of benefit in this subgroup (eResults in Supplement
ence in outcome of the 2 studies. 1). Thus, further study of azithromycin treatment in acute ex-
The studies differed strikingly in one regard: 61% of telithro- acerbations of asthma in adults and children in settings of low
mycin-treated but only 5.2% of azithromycin-treated patients rates of antibiotic use and stratifying on blood and/or sputum
had a positive test result for current atypical bacterial infection.12 cell counts seems justified.
Both studies used similar sampling and detection methods, al-
though the laboratories performing the analyses differed (GR
Micro London, England, for telithromycin; S.L.J.’s laboratory for
this study). Detection rates by PCR were low in both studies (3
Conclusions
positive in the telithromycin study and 0 positive in this study). In the patients randomized to treatment or placebo in this
In contrast, serological positive results differed markedly: the study, addition of azithromycin to standard medical care re-
telithromycin study positive results were almost all C pneumo- sulted in no statistically significant or clinically important ben-
niae IgM positives, while in our study only 1 sample was IgM efit. However, for each patient randomized, more than 10 were
positive for this organism. Both studies used the same assay excluded because they had already received antibiotics.

ARTICLE INFORMATION Cross, Robison, Sattar, Ashby); Institute for Lung Trust, Birmingham, England (Mansur); Severe and
Accepted for Publication: July 15, 2016. Health, University of Leicester, Leicester, England Brittle Asthma Unit, University of Birmingham,
(Brightling); Institute of Infection Immunity and Birmingham, England (Mansur); Respiratory
Published Online: September 19, 2016. Inflammation, University of Glasgow, Glasgow, Medicine and Allergy, King’s College London School
doi:10.1001/jamainternmed.2016.5664 Scotland (Chaudhuri, Thomson); Respiratory of Medicine, London, England (Corrigan);
Author Affiliations: National Heart and Lung Medicine, NHS Greater Glasgow and Clyde, Department of Asthma, Allergy and Respiratory
Institute, Imperial College London, London, Glasgow, Scotland (Chaudhuri); Nottingham Science, Guy’s and St. Thomas’ NHS Foundation
England (Johnston, Jackson, Mallia, Wong, Ind); Respiratory Research Unit, University of Trust, London, England (Corrigan); Respiratory
Imperial Clinical Trials Unit, School of Public Health, Nottingham, Nottingham, England (Harrison); Medicine, Newcastle University, Newcastle,
Imperial College London, London, England (Szigeti, Respiratory Medicine, Heart of England Foundation England (Higgins); Respiratory Medicine, Imperial

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 Research Original Investigation Azithromycin for Acute Exacerbations of Asthma

College Healthcare NHS Trust, London, England with the National Institute for Health Research 10. Cunningham AF, Johnston SL, Julious SA,
(Ind); Centre for Respiratory Medicine and Allergy, (NIHR) (Funders Reference No. 10/60/27). The trial Lampe FC, Ward ME. Chronic Chlamydia
Medicines Evaluation Unit, University of was supported by the NIHR Comprehensive pneumoniae infection and asthma exacerbations in
Manchester and University Hospital of South Biomedical Research Centre based at Imperial children. Eur Respir J. 1998;11(2):345-349.
Manchester NHS Foundation Trust, Manchester, College Healthcare NHS Trust and Imperial College 11. Johnston SL, Martin RJ. Chlamydophila
England (Singh); Respiratory Medicine, Portsmouth London. Dr Johnston is an NIHR senior investigator pneumoniae and Mycoplasma pneumoniae: a role in
Hospitals NHS Trust, Portsmouth, England and was supported by European Research Council asthma pathogenesis? Am J Respir Crit Care Med.
(Chauhan). FP7 Advanced Grant 233015, a Chair from Asthma 2005;172(9):1078-1089.
Author Contributions: Drs Johnston and Ashby UK (CH11SJ), and MRC Centre grant G1000758.
12. Johnston SL, Blasi F, Black PN, Martin RJ, Farrell
had full access to all of the data in the study and Role of the Funder/Sponsor: The funders had no DJ, Nieman RB; TELICAST Investigators. The effect
take responsibility for the integrity of the data and role in the design and conduct of the study; of telithromycin in acute exacerbations of asthma.
the accuracy of the data analysis. collection, management, analysis, and N Engl J Med. 2006;354(15):1589-1600.
Study concept and design: Johnston, Cross, interpretation of the data; preparation, review, or
Brightling, Chaudhuri, Harrison, Mansur, Robison, approval of the manuscript; and decision to submit 13. Talbot TR, Hartert TV, Mitchel E, et al. Asthma
Higgins, Ind, Singh, Thomson, Ashby, Chauhan. the manuscript for publication. as a risk factor for invasive pneumococcal disease.
Acquisition, analysis, or interpretation of data: N Engl J Med. 2005;352(20):2082-2090.
Disclaimer: The views expressed in this article are
Johnston, Szigeti, Cross, Brightling, Chaudhuri, those of the authors and not necessarily those of 14. Klemets P, Lyytikäinen O, Ruutu P, et al. Risk of
Harrison, Mansur, Robison, Sattar, Jackson, Mallia, the National Health Service, the NIHR, or the invasive pneumococcal infections among working
Wong, Corrigan, Higgins, Singh, Thomson, Ashby, Department of Health. age adults with asthma. Thorax. 2010;65(8):698-702.
Chauhan. 15. Pilishvili T, Zell ER, Farley MM, et al. Risk factors
Drafting of the manuscript: Johnston, Szigeti, Cross, Additional Contributions: We would like to thank
the patients who took part in the trial; Josephine for invasive pneumococcal disease in children in the
Mansur, Robison, Jackson, Wong, Corrigan. era of conjugate vaccine use. Pediatrics. 2010;126
Critical revision of the manuscript for important Marange, Research Nurse, Birmingham Heartlands
Hospital, UK, for assistance with patient (1):e9-e17.
intellectual content: Johnston, Szigeti, Brightling,
Chaudhuri, Harrison, Mansur, Robison, Sattar, recruitment; Elena Kulinskaya, PhD, Senior 16. Jounio U, Juvonen R, Bloigu A, et al.
Mallia, Wong, Corrigan, Higgins, Ind, Singh, Statistician, Imperial College, London, for help with Pneumococcal carriage is more common in
Thomson, Ashby, Chauhan. the power calculations; and the independent asthmatic than in non-asthmatic young men. Clin
Statistical analysis: Johnston, Szigeti, Sattar, Ashby. members of the Trial Steering Committee and Data Respir J. 2010;4(4):222-229.
Obtained funding: Johnston, Cross, Brightling, Monitoring and Ethics Committee (membership 17. Hilty M, Burke C, Pedro H, et al. Disordered
Mansur, Robison, Sattar, Thomson, Ashby. listed in Supplement 1). No compensation was microbial communities in asthmatic airways. PLoS
Administrative, technical, or material support: received beyond their salary for their contribution. One. 2010;5(1):e8578.
Johnston, Cross, Brightling, Robison, Sattar, 18. Message SD, Laza-Stanca V, Mallia P, et al.
Jackson, Mallia, Corrigan, Ind. REFERENCES
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Conflict of Interest Disclosures: Dr Johnston 2. Rabe KF, Vermeire PA, Soriano JB, Maier WC. 19. Contoli M, Message SD, Laza-Stanca V, et al. Role
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consultancy paid to institution from 21. Avadhanula V, Rodriguez CA, Devincenzo JP,
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board meetings from Novartis Pharmaceuticals, 5. Johnston SL, Pattemore PK, Sanderson G, et al. 22. Bisgaard H, Hermansen MN, Bønnelykke K,
AstraZeneca, Teva, and GlaxoSmithKline. The relationship between upper respiratory et al. Association of bacteria and viruses with
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attendance at scientific conferences and payments a time-trend analysis. Am J Respir Crit Care Med. birth cohort study. BMJ. 2010;341:c4978.
for lectures from Allergy Therapeutics; grants and 1996;154(3, pt 1):654-660.
personal fees for research collaborations and 23. British Thoracic Society; Scottish Intercollegiate
6. Wark PA, Johnston SL, Moric I, Simpson JL, Guidelines Network. British guideline on the
consultancy not connected with the present Hensley MJ, Gibson PG. Neutrophil degranulation
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and cell lysis is associated with clinical severity in iv1-iv121.
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Boehringer Ingelheim, and Diagenics; and personal 24. Global Initiative for Asthma. Global Strategy for
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Dr Higgins reports being a multicenter study, local Interleukin-10 gene expression in acute Update). http://ginasthma.org/wp-content/uploads
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Ingleheim, Chiesi, GlaxoSmithKline, Glenmark, Gibson PG. Chlamydia pneumoniae immunoglobulin macrolide solithromycin exerts superior
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the Medical Research Council (MRC), in partnership

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 Azithromycin for Acute Exacerbations of Asthma Original Investigation Research

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Invited Commentary

AZALEA Trial Highlights Antibiotic Overuse

in Acute Asthma Attacks
Guy G. Brusselle, MD, PhD; Eva Van Braeckel, MD, PhD

Asthma affects more than 300 million people worldwide, there were no significant between-group differences in sec-
causing variable symptoms of cough, chest tightness, and ex- ondary outcomes such as quality-of-life questionnaires, lung
ertional or nocturnal dyspnea due to chronic inflammation of function measurements during the exacerbation, or time to a
the lower airways and bronchial hyperresponsiveness. Acute 50% reduction in asthma symptoms. Therefore, addition of
episodes of worsening respiratory symptoms, called acute ex- azithromycin to standard medical care for acute asthma ex-
acerbations or asthma attacks, can be life-threatening, and in- acerbations did not result in a statistically or clinically signifi-
duce important costs, encom- cant benefit. Adverse events were infrequent in both treat-
passing both direct health ment groups, with more gastrointestinal adverse events in the
Related article page 1630 care expenses and indirect azithromycin group compared with placebo. No data are pro-
costs due to absence from vided on secondary ED visits or hospital (re-)admissions.
work or school. For many decades, asthma attacks have been In contrast, the Telithromycin, Chlamydophila, and Asthma
treated with inhaled short-acting bronchodilators and sys- (TELICAST) study has demonstrated clinical benefit of treat-
temic corticosteroids. There is thus a need for novel thera- ment with telithromycin (800 mg daily for 10 days) vs pla-
pies which—as add-on treatment to systemic corticosteroids— cebo in acute asthma exacerbations.2 However, severe ad-
could hasten clinical and functional recovery in patients verse reactions including liver toxicity limit the use of
experiencing an asthma attack and prevent complications. telithromycin in clinical practice. Why did the AZALEA trial
In this issue of JAMA Internal Medicine, Johnston et al1 re- have negative results, whereas the TELICAST study seemed
port the results of the Azithromycin Against Placebo for Acute to have positive results? First, there is a crucial difference in
Exacerbations of Asthma (AZALEA) trial. In this multicenter, trial design: all patients randomized in the AZALEA trial were
randomized, double-blind, placebo-controlled study in the required to receive systemic corticosteroid treatment, whereas
United Kingdom, they investigated the macrolide azithromy- only 34% of randomized patients received corticosteroids in
cin as a supplement to standard treatment in adult patients pre- the TELICAST study. Because the beneficial effects of macro-
senting to emergency departments (EDs) with an acute asthma lides might be partially attributed to their anti-inflammatory
exacerbation. Patients were mainly recruited from secondary properties, it is difficult to demonstrate benefit on top of the
care hospitals and needed to be enrolled within 48 hours of powerful anti-inflammatory effects of systemic corticoste-
initial presentation to medical care. Importantly, all patients roids, leading to predictably negative results in the AZALEA
received a course of oral or systemic corticosteroids. A total study as opposed to the TELICAST study. Second, in the
of 199 asthma patients (mean age, 40 years; 70% female) were AZALEA study only 5% of the azithromycin-treated patients
randomized to azithromycin 500 mg daily for 3 days or match- tested positive for current infection with Chlamydophila pneu-
ing placebo. The primary outcome, that is, diary card asthma moniae or Mycoplasma pneumoniae, whereas in the TELICAST
symptom score 10 days after randomization, was not differ- study 60% of telithromycin-treated patients had a positive IgM
ent between the azithromycin and placebo groups. Likewise, test result for one of these atypical organisms. Because both

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