Macrolide antibiotics and asthma treatment

Treatment for acute asthma exacerbations is a major need

not adequately met by current therapies. Although virus
infections are the major cause of acute exacerbations, other
factors can increase the risk/severity of exacerbations.
Increasing evidence suggests atypical bacterial infections
contribute to exacerbation severity, as well as stable asthma,
particularly severe asthma. Macrolide antibiotics and the new
ketolide antibiotic telithromycin are active against atypical
bacteria and also have anti-inflammatory activity. A recent
study has shown telithromycin to be effective in the treatment
of acute exacerbations of asthma, although the mechanism or
mechanisms of action were not determined. Controlled studies
report small improvements in lung function with macrolide
treatment of stable asthma. Further studies are urgently required
to assess the role of such therapies in acute exacerbations and in
severe stable asthma, in which the risk/benefit ratios are likely
to be most in favor of therapy demonstrated to be effective.
(J Allergy Clin Immunol 2006;117:1233-6.)
Key words: Asthma, asthma exacerbation, macrolide, atypical
bacterial infection, Chlamydophila pneumoniae, Mycoplasma
pneumoniae

Asthma is an inflammatory airway disease affecting up

to one third of children and 10% of adults in westernized
countries. Despite the rapidly increasing prevalence of the
disease, overall trends in asthma mortality in recent years
have not seen a parallel increase, and in many countries
mortality appears to be stable or even to be decreasing.
This dichotomy could be explained by a reduction in the
severity of asthma alongside the increase in prevalence;
however, this seems an unlikely explanation, and there
is no evidence to support it. Much more likely is the
hypothesis that asthma mortality has been to a large degree
effectively controlled by the use of prophylactic therapies.
There is clear evidence to support this hypothesis because
acute exacerbations of asthma are clearly reduced by the
use of prophylactic therapy.1,2
Despite this success, we have a long way to go because
asthma mortality remains unacceptably high and a great
deal of asthma morbidity continues to occur despite the
From the Department of Respiratory Medicine, National Heart and Lung
Institute, and the Wright Fleming Institute of Infection and Immunity,
Imperial College London.
Disclosure of potential conflict of interest: S. Johnston has consulting arrangements with Sanofi-Aventis, Pfizer, and GlaxoSmithKline.
Received for publication March 21, 2006; revised March 27, 2006; accepted
for publication March 30, 2006.
Available online May 10, 2006.
Reprint requests: Sebastian L. Johnston, MD, PhD, Department of Respiratory
Medicine, National Heart and Lung Institute, and the Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Place,
London, W2 1PG, United Kingdom. E-mail: s.johnston@imperial.ac.uk.
0091-6749/$32.00
2006 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2006.03.035

Abbreviation used
TELICAST: Telithromycin, Chlamydophila, and Asthma

availability of these effective therapies. Such continued

morbidity and mortality could relate to lack of use of
therapy by asthmatic patients, but it could also relate to
these therapies failing to address aspects of disease pathogenesis. It is generally recognized that inhaled corticosteroids are very effective at treating allergic asthma
predominantly driven by TH2 lymphocytes, mast cells,
and eosinophils. However, they are perceived to be much
less effective at treating TH1- and neutrophil-driven inflammation. Acute exacerbations of asthma and severe asthma
are phenotypes of asthma poorly treated with optimal currently available therapies, and they are also phenotypes of
asthma associated with neutrophilic inflammation.
These poorly responsive phenotypes of asthma might
be better treated by using novel approaches to asthma
therapy. Accumulating evidence suggests infections with
Chlamydophila pneumoniae, Mycoplasma pneumoniae,
or both might play a role in the pathogenesis of these
asthma phenotypes3 and that novel approaches to therapy
could be rewarding. The aim of this perspective is to review briefly the evidence supporting a role for these infections in the relevant asthma phenotypes and to discuss the
possible therapeutic benefit of treatment with macrolides
or related antibacterial therapies.

EVIDENCE FOR INCREASED SUSCEPTIBILITY

TO INFECTIONS IN PATIENTS WITH ASTHMA
Asthmatic individuals have increased susceptibility to
rhinovirus infection in that they have more severe and
more prolonged lower respiratory tract symptoms and
greater reductions in lung function when infected than
do healthy subjects.4 The mechanisms of this increased susceptibility are poorly understood, but one mechanism likely
to play a significant role has been recently discovered.
Primary bronchial epithelial cells from asthmatic subjects
infected with rhinovirus in vitro were found to replicate
rhinovirus efficiently, whereas those from healthy subjects
were almost completely resistant to infection.5 The increased permissiveness to rhinovirus replication in the
asthmatic cells was found to be due to profoundly deficient
IFN-b production, and replacement of IFN-b rendered
asthmatic cells as resistant to infection as normal cells.
These data might at least in part explain the increased susceptibility to virus infection in patients with asthma and are
entirely consistent with the known important role of virus
infection in precipitating acute exacerbations of asthma.
1233

Asthma diagnosis and

treatment

Sebastian L. Johnston, MD, PhD London, United Kingdom

1234 Johnston

Asthma diagnosis and

treatment

It has recently been reported that asthma is a risk factor

for invasive pneumococcal disease,6 suggesting that asthmatic patients might also have increased susceptibility
to bacterial infections. The mechanisms of this possible
increased susceptibility are not known, but these data
make investigating the role of C pneumoniae and M pneumoniae in asthma all the more interesting because it is
possible that asthmatic patients are also more susceptible
to infection with these organisms.

ROLE OF C PNEUMONIAE AND

M PNEUMONIAE IN STABLE ASTHMA
We have recently demonstrated that atopic asthmatic
adults have increased frequencies of detection of C pneumoniae than do healthy subjects. In this study 74 spouse pairs
consisting of an atopic asthmatic volunteer and a nonatopic
healthy volunteer underwent regular nasal aspirate sampling, independent of symptoms, every 2 weeks during a
3-month period. The spouse pair design was undertaken
to match for exposure to infectious agents as closely as possible. In atopic asthmatic patients 23 (6.4%) of 362 samples
were positive for C pneumoniae compared with 8 (2.3%) of
347 from healthy volunteers (P 5 .007).7 In terms of numbers of patients with positive results for C pneumoniae at
some time during the study, 16 (22%) of 74 asthmatic patients were infected on one or more occasions compared
with 7 (9%) of 74 healthy subjects (P 5 .012).
Similar evidence of increased infection rates in asthma
have been reported for M pneumoniae, as well as for C
pneumoniae. In a study of 55 patients with chronic stable
asthma and 20 healthy control subjects, PCR for these
organisms was carried out on multiple upper and lower
airway samples. Overall, 56% of asthmatic subjects had a
positive PCR result for one or the other organism, the great
majority of which were detected in bronchial samples.
M pneumoniae was detected in 23 (42%) asthmatic subjects
compared with only 1 (5%) control subject (P 5 .007), and
C pneumoniae was detected in 7 (13%) asthmatic subjects
and no control subjects (P 5 .04).8
These studies confirm increased detection of both
organisms in patients with asthma, although their relative
importance clearly requires further study. They are also
supported by a large number of serologic studies (mostly
investigating C pneumoniae), the majority of which also
find increased positivity in subjects with asthma, with
some also reporting dose-response relationships between
serologic positivity and asthma severity. These studies
have been recently reviewed in detail elsewhere.3

ROLE OF C PNEUMONIAE AND

M PNEUMONIAE IN ASTHMA
EXACERBATIONS
Viral infections have been established by a number
of studies to be associated with 80% to 85% of asthma
exacerbations in children and around 70% to 75% of

J ALLERGY CLIN IMMUNOL

JUNE 2006

asthma exacerbations in adults. Virus infections have also

been shown to interact with both allergen exposure9 and air
pollution10 in increasing the risk of exacerbation and the
severity of lower respiratory tract symptoms, respectively,
indicating that viruses frequently interact with other cofactors in increasing the risk/severity of asthma exacerbations.
We have reported similar possible interactions for
C pneumoniae in both children and adults. In schoolage children around 30% had detectable C pneumoniae
specific secretory IgA levels in their nasal aspirates while
their symptoms were stable, and a significant relationship
was found between C pneumoniaespecific secretory IgA
levels and the frequency of exacerbations reported during
the year of the study (P < .01).11 These data suggest a
relationship between C pneumoniae infection and the
risk of asthma exacerbation.
A similar relationship was seen in 54 adults investigated
on presentation to the emergency department with acute
asthma exacerbations. All subjects underwent sputum
induction and spirometry within 4 hours of presentation
and had acute and convalescent serology for C pneumoniaespecific IgA and IgG. Twenty (38%) subjects had evidence of an increase in C pneumoniae antibody levels, 15
of which had an increase in IgA levels, suggesting reactivation of chronic infection.12 Patients with C pneumoniae
serologic responses also had higher sputum neutrophil
counts (4.6 vs 1.2 3 106 cells/mL, P 5 .02), as well as
higher sputum eosinophilic cationic protein levels (3981
vs 1122 ng/mL, P 5 .02), than those who symptoms
also exacerbated but without evidence of serologic responses, suggesting that C pneumoniae reactivation might
be associated with increased airway inflammation.
Notably, 76% of these subjects also had evidence of virus
infection,13 suggesting that C pneumoniae reactivation
plays an important role in the pathogenesis of virusinduced acute asthma exacerbations.
There are few data available on the role of M pneumoniae
in acute exacerbations of asthma, but one study did detect
this organism in 18% of acute exacerbations in children.10

MACROLIDE AND KETOLIDE ANTIBACTERIAL

AGENTS
A number of different antibacterial agents have activity
against C pneumoniae and M pneumoniae, including tetracyclines, macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin), and the ketolide telithromycin.
Newer macrolides accumulate intracellularly and have
good activity against atypical organisms.
The ketolides are a new class of antibacterial agents
related to macrolides but that have structural modifications
that confer a broader range of antibacterial activity.
Telithromycin is the first ketolide to be approved for
clinical use and is also known to accumulate in epithelial
cells, making it well suited for the treatment of infections
caused by intracellular organisms.
Macrolides and ketolides also have proved anti-inflammatory activity, including suppression of neutrophilic

Johnston 1235

Asthma diagnosis and

treatment

J ALLERGY CLIN IMMUNOL

VOLUME 117, NUMBER 6

FIG 1. Telithromycin treatment increases the magnitude of improvements in symptoms (A) and lung function
(B), as well as hastening recovery from acute exacerbations of asthma in adult asthmatic subjects (C).17

inflammation, making them interesting in the context of

asthma phenotypes involving such inflammation, as well
as those in which the pathogenesis might be influenced by
atypical bacterial infections.

ROLE OF MACROLIDES IN PATIENTS WITH

STABLE ASTHMA
A Cochrane review of macrolide treatment studies in
patients with chronic stable asthma identified only 5 studies (including 357 patients) that met the required criteria (randomized placebo-controlled study of macrolide
therapy of >4 weeks duration).14 There was an overall
positive effect on symptoms with macrolide therapy.
However, these were not sufficiently consistent to permit
recommendations regarding clinical care.
Furthermore, only one study investigated atypical bacterial infection, although this was the largest study,
contributing 232 of the 357 subjects. The Chlamydophila
pneumoniae, Asthma, Roxithromycin, Multinational
study of adult patients with serologic evidence of C pneumoniae infection (IgG antibodies to C pneumoniae 1:64,
IgA antibodies 1:16, or both) observed 6 weeks of treatment with roxithromycin to be associated with a significant
improvement in lung function, although not in asthma
symptoms.15
A significantly greater increase in peak expiratory flow
from baseline was seen in roxithromycin-treated patients
at 6 weeks (difference between groups, 12 L/min; P 5
.02), although this benefit was not sustained at follow-up
visits. These data suggest some temporary clinical benefit
might be gained with macrolide therapy, although many
questions were left unanswered because the presence of
C pneumoniae infection in the airways and possible antiinflammatory mechanisms of action were not investigated,
and M pneumoniae was not investigated at all.
A more recent randomized double-blind study evaluated the effect of treatment with clarithromycin or placebo

for 6 weeks in 55 patients with chronic stable asthma, 56%

of whom had M pneumoniae or C pneumoniae infection
detected by means of PCR.16 Treatment with clarithromycin was associated with a small improvement in lung function (FEV1) in patients with evidence of atypical infection
(P 5 .05), but no significant effect was seen in patients
who had negative PCR results or in placebo-treated
patients. This study suggests possible beneficial effects
of clarithromycin that might at least in part result from
antimicrobial activity.
These 2 studies suggest that atypical bacterial infection
might contribute to the pathogenesis of stable asthma, but
further studies will be required to confirm this. Such studies
should be placebo controlled and include assessment of
atypical bacterial infection, preferably with inclusion of
both infection-positive and infection-negative populations,
as well as assessing the possible anti-inflammatory mechanisms of action. Studies in more severe asthma would also
be welcomed because the possible benefits of treatment
might be greater in this population, whose needs are not
adequately met by currently available therapies.

ROLE OF MACROLIDES IN ASTHMA

EXACERBATIONS
Current treatment guidelines indicate that antibiotics
should not be given routinely in the treatment of acute
exacerbations of asthma because evidence indicates viral
infections to be the major cause. However, the evidence
discussed above for a possible contributing role for atypical bacterial infection in acute exacerbations has prompted
a recent study investigating the role of an antibiotic active
against these infections.
The Telithromycin, Chlamydophila, and Asthma
(TELICAST) study is a multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy
of oral telithromycin, 800 mg once daily, for 10 days
as a supplement to standard treatment for acute

1236 Johnston

Asthma diagnosis and

treatment

exacerbations of asthma in adults.17 This study of 278 patients with moderate-to-severe asthma exacerbations reported
significantly greater improvements in both symptoms and
lung function in patients receiving active treatment compared with those receiving placebo. Improvement in
asthma symptoms from exacerbation to the end of treatment in the telithromycin-treated patients was 51% versus
29% in placebo-treated patients (Fig 1, A; mean difference, 22% (95% CI, 36.6% to 7.9%]; P 5 .003). Several
markers of lung function also showed significantly greater
improvement, with FEV1 improving by 0.63 L in telithromycin-treated patients versus 0.34 L in placebo-treated
patients (Fig 1, B; mean difference between treatments,
0.29 L (95% CI, 0.12-0.46 L]; P 5 .001). Time to 50%
improvement in symptoms was 8 days in placebo-treated
patients compared with only 5 days in telithromycin-treated
patients (Fig 1, C; P 5 .03).
The observed treatment effects appear to be of clinical
importance and were achieved on top of the usual care
given for asthma exacerbations (including a standardized
regimen of oral prednisone if considered necessary). These
findings need confirmation with further studies but, if
confirmed, suggest that rewriting of treatment guidelines might be necessary.
A further aim of the TELICAST study was to shed light
on possible mechanisms of action of any observed treatment effect. To this end, intensive diagnostic testing was
carried out, including culture and several different PCR
assays for C pneumoniae and M pneumoniae in sputum
samples, as well as intensive serology for both organisms.
Sixty-one percent of patients met at least one criterion
for C pneumoniae positivity, M pneumoniae positivity
(mostly C pneumoniae), or both, although almost all positive criteria were serologic. However, there was no clear
indication of greater treatment effect in those with evidence of infection compared with that seen in those without. Diagnostic testing for these organisms is still clearly
not optimal and differs from one laboratory to another.
Further work improving diagnostic methodologies and
identifying patient groups most likely to benefit from these
new approaches to treatment is clearly needed.

CONCLUSIONS AND FUTURE STUDIES

REQUIRED
There is increasing evidence that infection with atypical
bacteria plays a role in the pathogenesis of stable asthma,
as well as in asthma exacerbations. The TELICAST study
provides evidence of a therapeutic benefit with treatment
with a ketolide antibiotic in asthma exacerbations. These
finding are provocative and require confirmation but, if
confirmed, could open new avenues for the treatment of
asthma phenotypes not adequately served by currently
available therapies. It will also be important to test whether
similar treatment benefits are observed with similar related
antibacterial agents, such as the macrolides.
The use of antibacterial agents carries with it risks,
such as adverse drug reactions and the promotion of the

J ALLERGY CLIN IMMUNOL

JUNE 2006

development of antibiotic resistance, and thus treatment

benefits must always be weighed against risks. The risk/
benefit ratio is likely to be greatest in the most severe
illnesses and with shorter duration of treatment: asthma
exacerbations fit this description very well. Whether
longer-term treatment is justified in patients with stable
asthma also requires further study. The risk/benefit ratio is
likely to be most favorable in patients with severe asthma,
and this author believes such studies should first be carried
out in this population.
REFERENCES
1. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med
2000;343:332-6.
2. Johnston NW, Johnston SL, Norman GR, Dai J, Sears MR. The September epidemic of asthma hospitalization: school children as disease vectors. J Allergy Clin Immunol 2006;117:557-62.
3. Johnston SL, Martin RJ. Chlamydophila pneumoniae and Mycoplasma
pneumoniae: a role in asthma pathogenesis? Am J Respir Crit Care
Med 2005;172:1078-89.
4. Corne JM, Marshall C, Smith S, Schreiber J, Sanderson G, Holgate ST,
et al. Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study. Lancet
2002;359:831-4.
5. Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, LazaStanca V, et al. Asthmatic bronchial epithelial cells have a deficient
innate immune response to infection with rhinovirus. J Exp Med 2005;
201:937-47.
6. Talbot TR, Hartert TV, Mitchel E, Halasa NB, Arbogast PG, Poehling
KA, et al. Asthma as a risk factor for invasive pneumococcal disease.
N Engl J Med 2005;352:2082-90.
7. Biscione GL, Corne J, Chauhan AJ, Johnston SL. Increased frequency of
detection of Chlamydophila pneumoniae in asthma. Eur Respir J 2004;
24:745-9.
8. Martin RJ, Kraft M, Chu HW, Berns EA, Cassell GH. A link between
chronic asthma and chronic infection. J Allergy Clin Immunol 2001;
107:595-601.
9. Murray CS, Poletti G, Kebadze T, Morris J, Woodcock A, Johnston S,
et al. A study of modifiable risk factors for asthma exacerbations: virus
infection and allergen exposure increase the risk of asthma hospitalization in children. Thorax 2005 Dec 29; (Epub ahead of print).
10. Chauhan AJ, Inskip HM, Linaker CH, Smith S, Schreiber J, Johnston SL, et al. Personal exposure to nitrogen dioxide (NO2) and
the severity of virus-induced asthma in children. Lancet 2003;361:
1939-44.
11. Cunningham AF, Johnston SL, Julious SA, Lampe FC, Ward ME.
Chronic Chlamydia pneumoniae infection and asthma exacerbations in
children. Eur Respir J 1998;11:345-9.
12. Wark PA, Johnston SL, Simpson JL, Hensley MJ, Gibson PG. Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in acute asthma. Eur Respir J 2002;20:834-40.
13. Wark PA, Johnston SL, Moric I, Simpson JL, Hensley MJ, Gibson PG.
Neutrophil degranulation and cell lysis is associated with clinical severity
in virus-induced asthma. Eur Respir J 2002;19:68-75.
14. Richeldi L, Ferrara G, Fabbri LM, Gibson PG. Macrolides for chronic
asthma (Cochrane Review). The Cochrane Library, Issue 1. Oxford:
Update Software; 2003.
15. Black PN, Blasi F, Jenkins CR, Scicchitano R, Mills GD, Rubinfeld AR,
et al. Trial of roxithromycin in subjects with asthma and serological
evidence of infection with Chlamydia pneumoniae. Am J Respir Crit
Care Med 2001;164:536-41.
16. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and
Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest
2002;121:1782-8.
17. Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB. The
effect of telithromycin in acute exacerbations of asthma. N Engl J Med
2006;354:1589-600.