Chapter 15
Anti-inflammatory
therapies in
bronchiectasis
D.J. Smith*,#, A.B. Chang",+,1 and S.C. Bell*,#,+
Although the use of anti-inflammatory therapies in bronchiectasis remains an attractive proposition, there is currently
insufficient evidence to support the use of inhaled and oral
corticosteroids, non-steroidal anti-inflammatory drugs and
macrolides. Individual patient trials may be warranted for
inhaled corticosteroids and macrolides. It is hoped that recently
completed and ongoing randomised control trials of macrolides
will better define the use and safety in bronchiectasis. There
remains an urgent need to perform adequately powered
multicentre trials of other potentially useful therapies.
It is anticipated that specialised bronchiectasis clinics will
provide greater opportunities to study disease epidemiology
and pathogenesis and allow better definition of study population for inclusion within future trials. There is a need for a more
defined study population and a widely accepted definition of a
pulmonary exacerbation in bronchiectasis which may be
applied uniformly across studies to allow direct comparison of
study outcomes. Finally, care should be taken to ensure
adequate follow-up to detect potential adverse effects of new
therapies, particularly on microbial resistance patterns.
Keywords: Anti-inflammatory therapy, bronchiectasis,
inflammation, inhaled corticosteroids, macrolides
*Dept of Thoracic Medicine,
#
School of Medicine, University of
Queensland, The Prince Charles
Hospital, Chermside,
"
Queensland Children’s Respiratory
Centre,
+
Queensland Children’s Medical
Research Institute, Herston,
Queensland, and
1
Menzies School of Health Research,
Charles Darwin University, Darwin,
Northern Territory, Australia.
Correspondence: S.C. Bell, Dept of
Thoracic Medicine, The Prince
Charles Hospital, Rode Road,
Chermside, Brisbane, QLD, 4032,
Australia, Email
[email protected]
D.J. SMITH ET AL.
Summary
Eur Respir Mon 2011. 52, 223–238.
Printed in UK – all rights reserved.
Copyright ERS 2011.
European Respiratory Monograph;
ISSN: 1025-448x.
DOI: 10.1183/1025448x.100004510
B
223
ronchiectasis is an under-recognised condition characterised by pathological dilatation of
bronchi, persistent neutrophilic airway inflammation and, in many, chronic bacterial
infection. Bronchiectasis develops in the susceptible host through a vicious cycle of airway
infection and inflammation [1]. The causes of non-cystic fibrosis (CF) bronchiectasis are diverse,
the cohort populations are heterogeneous and the evidence to support therapies limited [2].
Factors which may have contributed to the limited evidence for treatment are likely to include
population and disease severity heterogeneity, limited funding sources for clinical trials and the
diverse manner that patients with bronchiectasis are managed. This appears to be changing with
the advent of specialised bronchiectasis clinics which are providing an opportunity to develop
focused research programmes. There are a limited number of high-quality randomised controlled
trials (RCT’s) cited in recently published management guidelines for bronchiectasis [3–5].
Airway biology in bronchiectasis
Cohort studies of patients with bronchiectasis reveal Haemophilus influenzae and Pseudomonas
aeruginosa to be the most frequently isolated organisms from airway secretions. Streptococcus
pneumoniae, Moraxella species and nontuberculous mycobacteria (NTM) are reported less
commonly [6–8]. Although infection triggers inflammation, ongoing neutrophilic infiltration of
the airways is apparent even in the absence of persistent infection, suggesting dysregulation of
immune responses [9]. Neutrophils are the predominant inflammatory cell found in sputum and
bronchoalveolar lavage fluid (BALF) in patients with bronchiectasis [9, 10]. It is hypothesised that
neutrophil apoptosis and clearance may be defective in bronchiectasis [11]. Non-apoptosed cells
die by necrosis leading to exudation of toxic products (e.g. exoenzymes, oxygen free radicals,
myeloperoxidase, etc.) which cause both localised tissue damage and provide an ongoing stimulus
for the inflammatory response. Macrophages, lymphocytes and eosinophils are similarly present in
increased number in the bronchiectatic airway, however, their role is poorly defined [12].
ANTI-INFLAMMATORY THERAPY
Acute respiratory exacerbations in patients with bronchiectasis are poorly understood but are
thought to be related, in part, to increased load of existing airway bacteria and/or infection with a
new bacterial pathogen. These changes provide rationale for the use of targeted antibiotics in
patients with bronchiectasis during respiratory exacerbations which are discussed in detail in the
chapter by FOWERAKER and WAT [13].
Targeting inflammation in bronchiectasis
An alternative approach to targeting infection with antimicrobial agents is to attempt to modify
the immune response to infection. In this chapter we focus on the use of anti-inflammatory agents
and examine the evidence for the use and potential pitfalls of these therapies. We also explore
future treatment options and studies that are in progress.
Anti-inflammatory therapies will be discussed in one of three broad categories: 1) general antiinflammatory therapies which have broad immunosuppressive effects on inflammatory pathways
(e.g. corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDS)); 2) novel antiinflammatory therapies which have immunomodulatory properties in addition to the cellular
effects for which they are conventionally utilised (e.g. macrolides and hydroxy-methyl-glutarylcoenzymeA (HMGCoA) reductase inhibitors); and 3) targeted anti-inflammatory therapies which
block a specific mediator of the immune response (e.g. anti-immunoglobulin E or anti-tumour
necrosis factor (TNF)-a).
General anti-inflammatory agents
Corticosteroids
224
Corticosteroids have broad anti-inflammatory effects through inhibition of inflammatory
mediator synthesis and release and impairment of inflammatory cell migration [14].
Corticosteroids stimulate eosinophil apoptosis but paradoxically inhibit neutrophil apoptosis
which, in part, possibly explains their variable anti-inflammatory effectiveness in different clinical
settings [15]. Inhaled corticosteroids improve asthma control [16, 17] and are associated with
reduction in exacerbation frequency in chronic obstructive pulmonary disease (COPD) [18], yet
their withdrawal in patients with CF has minimal impact on symptoms, lung function or
exacerbations [19]. Short courses of oral steroids have an established role in the treatment of
exacerbations of asthma and COPD [20, 21]; however, their role in CF is more controversial [22].
Inhaled corticosteroids
Recently, KAPUR et al. [23] identified six RCTs of inhaled steroids in non-CF bronchiectasis
(table 1). The meta-analysis of these studies failed to provide conclusive evidence that inhaled
corticosteroids result in a clinically significant improvement in lung function, affect exacerbation
rates or improve quality of life in patients with bronchiectasis (fig. 1).
Two larger and longer trials studying fluticasone diproprionate (500 mg b.i.d.) in adults with
bronchiectasis, demonstrated a reduction in sputum quantity [28, 29]. In a post hoc analysis TSANG
et al. [28] observed that this effect was most pronounced in those patients with chronic P. aeruginosa
infection. However, each of these studies had significant limitations including no placebo arm in the
former and variable baseline sputum production in the treatment arms in the latter, precluding their
data from being included in the assessment of this outcome measure in the Cochrane Review.
Although therapy was generally well tolerated for the duration of the trials, long-term safety is
uncertain in dosage regimens which would currently be considered to be high. In addition, one shortterm study [25], the data on density of total bacteria, commensal bacteria and P. aeruginosa in sputum
showed an increasing trend after 4 weeks of therapy with inhaled steroids.
Based on the available evidence from these published studies, KAPUR et al. [23] concluded that there is
currently insufficient evidence of both benefit and safety to recommend routine use of inhaled
corticosteroids in patients with bronchiectasis, however, it may be appropriate to consider a trial in
severely symptomatic patients on a case by case basis, with close monitoring for adverse effects.
D.J. SMITH ET AL.
The earliest study, published in 1992 by ELBORN et al. [24], enrolled 20 patients in a 12-week
crossover trial of high-dose beclomethasone diproprionate/placebo (6 weeks drug, 6 weeks
placebo). Despite five patients dropping out of the study, the authors reported an 18% reduction
in volume of sputum and reduced bronchoprovocation during histamine challenge testing. A
subsequent study demonstrated inhaled fluticasone diproprionate reduced sputum levels of proinflammatory mediators (interleukin (IL)-8, leukotriene B4 (LTB4) and IL-1b) and sputum
leukocyte density in bronchiectasis [25]. Combined with the consistent finding that inhaled steroids
have no effect on sputum bacterial load [25], this suggests that any beneficial effect they may exert is
most likely explained by anti-inflammatory as opposed to antimicrobial activity. Studies by TSANG
et al. [26] and JOSHI and SUNDARAM [27] reported no change in exhaled nitric oxide and no change in
lung function, respectively.
Oral corticosteroids
There is currently no evidence supporting the use of oral corticosteroids. A Cochrane Review by
LASSERSON et al. [30] failed to identify any RCTs in non-CF bronchiectasis either for short-term
(during an exacerbation) or long-term use. The only evidence of potential benefit is from the
paediatric CF literature in which prednisolone at a dose of 1 mg?kg-1 on alternate days was
associated with reduced rate of lung function decline [22]. The long-term adverse effects including
effects on growth and cataract resulted in the early termination of the trial.
NSAIDS
225
NSAIDS non-selectively block the activation of the cyclo-oxygenase pathway of pro-inflammatory
prostaglandins. A landmark placebo controlled RCT examined the effects of ibuprofen in people
with CF [31]. The study included 85 patients (age range 5–39 years) and demonstrated that those
treated with high-dose ibuprofen (dose range 16.2–31.6 mg?kg-1) experienced a slower rate of
decline in forced expiratory volume in 1 second (FEV1), as well as improved maintenance of
weight when compared with control subjects over the 4-year study period. Post hoc analysis
revealed these effects to be most pronounced in those participants ,13 years of age at study
commencement. Ibuprofen therapy was well tolerated with only one patient withdrawing due to
side-effects clearly attributable to ibuprofen (conjunctivitis and epistaxis).
226
RCT
(parallel)
China
(Hong
Kong)
India
China
(Hong
Kong)
T SANG
[26]
T SANG
[28]
Drug
Fluticasone
proprionate
(500 mg b.i.d. or
250 mg b.i.d.)
4 weeks
52 weeks
8 weeks
(4 weeks
each arm,
2 week
washout)
52 weeks
36 weeks
Yes
Yes
Yes
Yes
Yes
12 weeks
(6 weeks
each arm,
no washout)
Yes
93
86
20
60
24
20
Placebo Duration Subjects
n
Findings
No change in
lung function
No change in eNO
None
None reported
but trend
towards
increased
sputum
density
of commensal
flora and
P. aeruginosa
Not reported
Oral
candidiasis
(n51)
Adverse
events
Sputum volume
Reduced sputum
Sore throat
and purulence, volume, no change in
(n57)
exacerbation rates, exacerbation rates,
lung function
sputum purulence,
lung function
HRQoL
Improved dyspnoea, Dry mouth (n58),
reduced sputum
local irritation
volume, reduced
(n54), dysphonia
b-agonist use
(n54), oral
(high-dose group)
candidiasis
(n52), aphthous
ulcer (n51)
Lung function
eNO
Lung function,
Improved FEV1,
PD20 metacholine, improved morning
sputum producPEFR, improved
tion, pulmonary
cough, reduced
symptoms
sputum volume
24 h sputum
Reduced sputum
(volume/leukocyte
leukocyte density,
counts/microbial
reduced IL-1b,
concentrations/
IL-8 and LTB4,
IL-1/IL-8/TNF-a/ no change in sputum
volume, no change in
LTB4),
lung function
lung function
Outcome
measures
DBRCT: double-blind (DB) randomised controlled trial (RCT); b.i.d.: twice daily; FEV1: forced expiratory volume in 1 second; PD20: provocative dose causing a 20% fall in FEV1;
PEFR: peak expiratory flow rate; IL: interleukin; TNF-a: tumour necrosis factor-a; LTB4: leukotriene B4; P. aeruginosa: Pseudomonas aeruginosa; eNO: exhaled nitric oxide;
HRQoL: health-related quality of life. #: the only blinded component of this study was for the dose of inhaled corticosteroids.
Bronchiectasis
Adults
Bronchiectasis,
Fluticasone
(mean age
nonsmokers
proprionate
56 yrs)
(500 mg b.i.d.)
DBRCT
Adults/
Bronchiectasis, Beclomethasone
(crossover)
children 12% improvement diproprionate
(15–60 yrs)
post(400 mg b.i.d.)
bronchodilator
FEV1
DBRCT
Adults
Bronchiectasis, no Fluticasone
(parallel)
(mean age
oral/inhaled
proprionate
58 yrs)
corticosteroids
(500 mg b.i.d.)
Fluticasone
proprionate
(500 mg b.i.d.)
Bronchiectasis, Beclomethasone
no prior
diproprionate
oral/inhaled
(750 mg b.i.d.)
corticosteroids
Inclusion
criteria
Adults
Bronchiectasis
(mean age .10 mL sputum
55 yrs)
per 24 h
RCT-non
Adults
MARTINEZ- Spain
DB# (parallel) (mean age
GARCIA
[29]
69 yrs)
J OSHI
[27]
DBRCT
(parallel)
China
(Hong
Kong)
T SANG
[25]
Population
DBRCT Adults (30–
(crossover)
65 yrs)
UK
E LBORN
[24]
Design
Country
Study
Table 1. Randomised controlled trials of inhaled corticosteroids in bronchiectasis
ANTI-INFLAMMATORY THERAPY
ICS
Mean±SD
Total
Placebo Total Weight
%
Mean±SD
FEV1 L#
0.011±0.11
-0.045±0.14
JOSHI [27]
10
0.064±0.154
MARTINEZ [29]
29 0.038±0.107
0.2±0.87
0±0.739
TSANG [25]
12
Subtotal (95% Cl)
51
Heterogeneity: χ2 = 0.59, df = 2 (p = 0.74); I2 = 0%
Test for overall effect: Z = 3.04 (p = 0.002)
FVC L#
JOSHI [27]
10
0.038±0.16
-0.067±0.16
MARTINEZ [29]
29 -0.062±0.181
0.025±0.104
TSANG [25]
12
0.1±1
0±1
Subtotal (95% Cl)
51
Heterogeneity: χ2 = 0.05, df = 2 (p = 0.98); I2 = 0%
Test for overall effect: Z = 2.66 (p = 0.008)
Peak flow L.min-1#
JOSHI [27]
10
17±27.36
-7.8±47.82
12
TSANG [25]
35±111
-2±122.58
Subtotal (95% Cl)
22
Heterogeneity: χ2 = 0.06, df = 1 (p = 0.81); I2 = 0%
Test for overall effect: Z = 1.60 (p = 0.11)
Diffusion capacity % pred¶
84.2±10
29
86.9±10
MARTINEZ [29]
71.8±28.63
12
70±21.86
TSANG [25]
Subtotal (95% Cl)
41
Heterogeneity: χ2 = 0.01, df = 1 (p = 0.93); I2 = 0%
Test for overall effect: Z = 1.03 (p = 0.30)
RV % pred¶
108±10
29
106±29.2
MARTINEZ [29]
109±48.11
12 135.8±59.46
TSANG [25]
Subtotal (95% Cl)
41
Heterogeneity: χ2 = 1.44, df = 1 (p = 0.23); I2 = 31%
Test for overall effect: Z = 0.28 (p = 0.78)
TLC % pred¶
MARTINEZ [29]
89.6±10
86.4±10
29
TSANG [25]
83.8±19.32
87.5±20.83
12
Subtotal (95% Cl)
41
Heterogeneity: χ2 = 0.64, df = 1 (p = 0.42); I2 = 0%
Test for overall effect: Z = 1.01 (p = 0.31)
Mean difference
IV, fixed, 95% Cl
10 27.7
28 71.5
12 0.8
50 100
0.06 (-0.05_0.17)
0.10 (0.03_0.17)
0.20 (-0.45_0.85)
0.09 (0.03_0.15)
10 23.0
28 76.3
12 0.7
50 100
0.11 (-0.04_0.25)
0.09 (0.01_0.16)
0.10 (-0.70_0.90)
0.09 (0.02_0.16)
10 88.2 24.80 (-9.35_58.95)
12 11.8 37.00 (-56.56_130.56)
22 100 26.23 (-5.84_58.31)
28 93.9
12 6.1
40 100
2.70 (-2.49_7.89)
1.80 (-18.58_22.18)
2.65 (-2.39_7.68)
10 84.6 2.00 (-16.46_20.46)
12 15.4 -26.80 (-70.08_16.48)
22 100 -2.43 (-19.41_14.55)
28
12
40
3.20 (-1.99_8.39)
90.5
9.5 -3.70 (-19.77_12.37)
2.55 (-2.39_7.49)
100
Mean difference
IV, fixed, 95% Cl
◆
◆
D.J. SMITH ET AL.
Study or subgroup
◆
◆
-50 -25
0
25 50
Favours placebo Favours ICS
Figure 1. Forest plot of lung function indices comparing adults with bronchiectasis (in stable state) on inhaled
corticosteroids (ICS) versus controls. FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; %
pred: % predicted; RV: residual volume; TLC: total lung capacity. #: end study minus baseline values; ": end of
study values. Reproduced from [23] with permission from the publisher.
227
A Cochrane Review by LANDS and STANOJEVIC [32] of NSAIDs in CF, including four RCTs,
concluded that high-dose ibuprofen is capable of slowing disease progression; whilst NSAIDs are
an attractive potential therapy in patients with bronchiectasis the benefits of treatment
demonstrated in patients with CF cannot necessarily be extrapolated. This has been demonstrated
with the use of human recombinant DNase, which when trialled in non-CF bronchiectasis resulted
in increased pulmonary exacerbations and greater decline in lung function [33].
Two recent Cochrane Reviews of oral and inhaled NSAID therapy in non-CF bronchiectasis were
able to identify only one study suitable for inclusion [34, 35]. In this study 25 adults with chronic
lung disease (eight bronchiectasis, 12 chronic bronchitis and five diffuse panbronchiolitis) received
inhaled indomethacin or placebo for 14 days. In the treatment group (inhaled indomethacin)
compared with placebo, there was a significant reduction in sputum production over 14 days
(difference -75 g?day-1; 95% CI -134.61– -15.39) and significant improvement in dyspnoea score
(difference -1.90; 95% CI -3.15– -0.65). There was no significant difference between groups in
lung function or blood indices [36].
Novel immunomodulatory agents
Macrolides
ANTI-INFLAMMATORY THERAPY
Macrolides have been in clinical use as antimicrobial agents for .50 years. There are three classes
of macrolides based on the central ring structure: 14-membered ring macrolides (e.g.
erythromycin, roxithromycin and clarithromycin); 15-membered ring macrolides (also known
as ‘‘azolides’’, e.g. azithromycin); and 16-membered ring macrolides (e.g. spiramycin and
josamycin) (fig. 2). The variation in structure of each class influence pharmacokinetic and
pharmacodynamic properties [38]. Importantly, compared with other classes, the 15-membered
ring structure azolides have less drug interaction, improved gastrointestinal tolerance and
enhanced ability to concentrate within the neutrophil [39].
Antimicrobial properties
Macrolides exert their antimicrobial action against Gram-positive, Gram-negative and intracellular
organisms by binding to ribosomal subunits required for protein replication. Of particular relevance
to their use in bronchiectasis is their antimicrobial activity against H. influenzae, Moraxella
catarrhalis and S. pneumoniae. Similarly their activity against ‘‘atypical’’ respiratory pathogens
(including Legionella pneumophila, Chlamydia spp. and Mycoplasma pneumoniae) has led to their
widespread usage in the treatment of community-acquired pneumonia [40, 41].
At least two compounds (clarithromycin and azithromycin) have demonstrated activity in NTM
infection and are important components of multi-drug regimes for treatment of Mycobacterium
avium complex [42]. If adherence to treatment regimens is poor or if macrolide monotherapy is
administered, NTM species may develop resistance. This may result in poorer clinical outcome [43].
This is a major concern when macrolides are prescribed in disease processes where mycobacterial
infections can co-exist. The recently published Australia and New Zealand bronchiectasis guidelines
recommend screening for NTM prior to initiation of macrolide therapy and regular sputum
surveillance during treatment [5].
Anti-pseudomonal properties
228
The reported prevalence of P. aeruginosa infection in bronchiectasis varies from 12% to 33% [8]
and is associated with radiological disease severity [44], increased lung function decline [45] and
mortality [46]. Mucoid transformation of P. aeruginosa allows alginate secretion and biofilm
production which provides a physical barrier from the immune system and contributes to
persistent airway infection and inflammation [47]. P. aeruginosa within biofilms can communicate
through quorum sensing systems (las and rhl) which are important in coordination of the
expression of virulence factors and biofilm maturation [48]. Azithromycin has been shown to
suppress both lasI and rhlI in vitro [49].
Macrolides have also been shown to suppress
various P. aeruginosa virulence factors including
protease, elastase, leucocidin, pyocyanin, phospholipase C and exotoxin A [51–53]. Suppression
of P. aeruginosa virulence varied depending on P.
aeruginosa strains studied and the specific macrolide used. In general, azithromycin has been
shown to be more effective than other macrolides
[51, 52]. Azithromycin has also been shown to
inhibit P. aeruginosa antibiotic efflux pumps
thereby potentially contributing to synergy and
increasing the efficacy of other classes of antimicrobials [54]. Although these studies suggest
macrolides are capable of impairing P. aeruginosa
virulence, it is important to highlight that most of
these studies were performed with laboratory
strains of P. aeruginosa using in vitro systems.
a)
O
CH3 HO
H3C
OH
CH3
O
HO
N
O
CH3
HO
H3C
O
CH3
CH3
O CH3
O
CH3
OH
O
CH3 O
CH3
H3C
b)
CH3
H3C
OH
CH3
O
HO
CH3
N
HO
N
H3C
O
CH3
HO
H3C
CH3
O
CH3
O
CH3
O
CH3
CH3
O
OH
O
CH3
CH3
c)
N
O
Anti-inflammatory properties
Anti-inflammatory properties of macrolides were
first considered in the 1970s when observational
studies noted that steroid-dependent asthmatics
were able to reduce their dose of oral corticosteroid dose while prescribed erythromycin and
triacetyloleandomycin [55]. The steroid sparing
effect was later confirmed in prospective studies in
patients with severe corticosteroid dependent
asthma [56]. Furthermore, a reduction in bronchial hyperreactivity in asthmatic subjects was
seen in patients receiving erythromycin, clarithromycin or roxithromycin [57–59].
CH3
H3C
CH3
D.J. SMITH ET AL.
P. aeruginosa is considered to be inherently
resistant to macrolides as the in vitro minimal
inhibitory concentration (MIC) is significantly
higher than the concentration achievable in vivo
[50]. However sub-MIC concentrations of macrolides may inhibit P. aeruginosa virulence. Type IV
pili on the surface membrane of P. aeruginosa
increase the organism’s motility and are believed
to be critical in adhesion of P. aeruginosa to
epithelial cells and colony expansion, and in
facilitating biofilm formation. Sub-MIC concentrations of clarithromycin inhibit adherence of P.
aeruginosa to cell surface pili and retard biofilm
maturation in vitro [50].
CH3
O
CH3
CH3
OH
CH3
CH3 CH3
OH
N
O
H3C
O
O
O
OH
O
OH CH3
OH
O
O
CH3
CH3
Figure 2. Structure of macrolides (representative
examples). a) 14-membered ring (erythromycin);
b) 15-membered ring (azithromycin); and c) 16membered ring (spiramycin I). Reproduced from
[37] with permission from the publisher.
229
However, it was in the 1980s when use of
macrolides revolutionised the treatment of diffuse
panbronchiolitis (DPB) that their immunomodulatory properties came under closer scrutiny.
DPB is an idiopathic inflammatory airway condition found almost exclusively within the South
East Asian populations (especially in Japan), which histologically is characterised by intense
neutrophilic inflammation of the bronchioles [60]. Its typical onset is in the second to fifth decade
of life which, when untreated, progresses to severe bronchiectasis, chronic airway infection and
ultimately respiratory failure. Prior to the introduction of macrolides in the mid 1980s, 10-year
survival rates were low (,33%) [61], and even lower in those patients with chronic P. aeruginosa
infection [62]. Since the introduction of erythromycin and subsequently other macrolides, survival
has improved dramatically achieving 10-year survival rates .90% [61].
Immunomodulatory properties
Herin we briefly review the supportive evidence with more comprehensive reviews in the literature
[63, 64]. While anti-inflammatory actions of macrolides are well established, the differences seen
in some studies are probably attributable to variance in methodology, model system used and the
macrolide agent studied.
ANTI-INFLAMMATORY THERAPY
Endotoxins produced by invading bacteria stimulate human epithelial cells both directly and
through toll-like receptors, triggering an inflammatory cascade leading to the activation of nuclear
factor (NF)-kb [65]. NF-kb is central in regulating transcription of genes which encode proinflammatory mediators, including IL-6, IL-8, TNF-a (cytokines) and the intercellular adhesion
molecule-1 (ICAM-1). In vitro studies have demonstrated both erythromycin and clarithromycin
to be capable of inhibiting NF-kb activation [66, 67] and complimentary studies have
independently demonstrated release of lower levels of IL-1, IL-6, IL-8 and ICAM-1 from
activated bronchial epithelial cells when exposed to macrolides [68–70].
Neutrophils recruited to the site of inflammation become activated allowing phagocytosis
of microorganisms and production of proteases (including neutrophil elastase and matrixmetalloproteinases (MMP)-9), and reactive oxygen species (ROS) responsible for the ‘‘oxidative
burst’’ believed to be fundamental to killing the phagacytosed microorganism [71, 72]. In the
setting of infection, spillage of these proteases and ROS from necrotic neutrophils contributes
towards localised tissue damage and provides ongoing stimulus to the inflammatory process.
Macrolides are able to modulate neutrophil function by several mechanisms. In an animal model
of bronchiectasis, macrolides inhibit ICAM-1 expression which may reduce neutrophil migration
to the site of inflammation [64]. Various 14-membered macrolides have been shown to inhibit the
oxidative burst [72] and similarly erythromycin and flurythromycin inhibit the release of
neutrophil elastase [73].
Interestingly, macrolides are associated with increased neutrophil degranulation [63]. A shortterm study of the effect of azithromycin (3 days) in healthy volunteers demonstrated an
immediate increase in neutrophil degranulation and circulating ROS, but decreased IL-8. This was
followed by a delayed inhibitory effect on oxidative burst, myeloperoxidase, IL-6 and increased
neutrophil apoptosis [74]. These in vitro studies provide impetus for studying the potential impact
of macrolides on neutrophil dominated airway diseases such as bronchiectasis.
Macrolides and mucus hypersecretion
Mucus hypersecretion is a hallmark of bronchiectasis, which in combination with impaired
mucociliary clearance produces a local environment conducive to chronic infection. Mucins
(macromolecular glycoproteins) are major constituents of mucus and are encoded by a number of
genes. One such gene, MUC5AC is specifically expressed by bronchial epithelial goblet cells [75] and
in vitro studies demonstrate erythromycin and clarithromycin attenuate lipopolysaccharide-induced
increased MUC5AC gene expression [64]. Azithromycin demonstrates similar effects on the
MUC5AC gene in P. aeruginosa quorum sensing mediator stimulated human epithelial cells [76].
These effects are supported by in vivo responses to macrolides in varied animal models [77, 78].
230
In summary, the potential benefits of macrolide therapy in patients with bronchiectasis may result
from antimicrobial properties and effects on biofilm development in patients with P. aeruginosa
infection, by down-regulating acute and chronic inflammatory responses and limiting mucus
hypersecretion.
Clinical trials of macrolides
To date there have been limited studies examining the effectiveness of macrolides for treatment of
non-CF bronchiectasis. Those published studies have been performed in small patient populations
and have varied considerably in study design including duration, dose and specific macrolide,
outcome measures and whether a control group was used as a comparator (table 2).
The first double-blind, placebo-controlled RCT of macrolides in non-CF bronchiectasis compared
the effect of roxithromycin (4 mg?kg-1 b.i.d.)/placebo for 12 weeks in children with a clinical
diagnosis of bronchiectasis and evidence of airway hyperreactivity [79]. There was a significant
reduction in sputum purulence, leukocyte concentration and a reduction in airway reactivity
(provocative dose causing a 20% fall in FEV1 to metacholine). However, there was no change in
lung function when compared with placebo.
A double-blind RCT of erythromycin in adults with non-CF bronchiectasis compared 8 weeks
of erythromycin (500 mg b.i.d., n514) with placebo (10 patients) during a period of clinical
stability [81]. Three patients, each receiving erythromycin withdrew (adverse effect n51, poor
adherence n52). A ‘‘per protocol’’ analysis based on those who completed the trial demonstrated an improvement in lung function (mean increase in FEV1 and forced vital capacity of
140 mL and 120 mL, respectively) and decreased sputum production in those receiving
erythromycin. There were no differences in levels of inflammatory cytokines (IL-8, TNF-a or
LTB4) in sputum.
Several uncontrolled studies have also been reported. An open label, randomised, crossover study
of 6 months of azithromycin 500 mg twice weekly and standard treatment in 12 patients (11
included in analysis) demonstrated a reduction in the number of exacerbations requiring
antibiotics (five versus 16, p,0.019) and sputum volume during azithromycin therapy and no
change in lung function [82]. Notably, the investigators aimed to recruit 30 subjects for the study
based on pre-study power estimates.
D.J. SMITH ET AL.
In a second macrolide trial also in children with stable non-CF bronchiectasis, YALCIN et al. [80]
compared the impact of clarithromycin with conventional treatment administered for 3 months
on immune mediators within BALF. The study demonstrated greater reduction in sputum volume
and BALF total cell counts, neutrophil ratios and IL-8 levels in the clarithromycin group.
Interestingly, there was no significant change in sputum microbiology. This study had the major
limitation of the lack of a placebo.
A prospective cohort study of azithromycin in adult patients with frequent pulmonary
exacerbations (.4 in the year prior to enrolment), employed a treatment protocol of azithromycin
500 mg?day-1 for 6 days, then 250 mg?day-1 for 6 days, followed by maintenance treatment of
250 mg three times per week [83]. Six (15%) of the 39 patients recruited withdrew due to adverse
effects. Analysis based on those who tolerated therapy demonstrated a reduction in exacerbation
rate (from 0.71 to 0.13 per month, p,0.001), reduction in number of courses of antibiotics (0.08
to 0.003 per month, p,0.001) and a trend to improvement in lung function parameters.
Respiratory symptoms improved in those treated with azithromycin over a mean follow-up period
of 20 months (in-house symptom questionnaire).
Finally a cohort study of 56 adult patients treated with azithromycin 250 mg three times per week,
of which 50 patients completed a minimum of 3 months (mean duration 9.1 months),
demonstrated a reduction in exacerbation rate and sputum production (compared with the
6 months prior to treatment) and an improvement in FEV1 (only 29 patients assessable) [84].
231
In summary, these small studies have demonstrated that macrolide therapy is generally well
tolerated and reduces sputum volume, however, effect on pulmonary function is unclear. Several
studies have reported significant participant dropout due to gastrointestinal adverse events.
Routine use of macrolides cannot be supported based on current evidence and there is an urgent
need for large randomised placebo controlled trials to assess tolerability, clinical impact, which
232
DBRCT Adult (mean Bronchiectasis Erythromycin
(parallel) age 55 yrs)
.10 mL
(500 mg b.i.d.)
sputum per
24 h
Open label
Adult
Bronchiectasis Azithromycin
(crossover) (mean age
(500 mg b.i.d.)
71 yrs)
Cohort
Cohort
China
(Hong
Kong)
USA
UK
UK
T SANG
[81]
C YMBALA
[82]
D AVIES
[83]
A NWAR
[84]
No
No
No
Yes
No
Yes
204 weeks
52 weeks
(26 weeks
each arm,
4 weeks
washout)
Mean
80 weeks
8 weeks
12 weeks
12 weeks
56
39
12
24
34
25
Placebo Duration Subjects
n
Findings
Diarrhoea (n53)
Withdrew due to
rash (n51)
None
None
Adverse
events
Withdrew (n56);
abnormal liver
function (n52),
diarrhoea (n52),
rash (n51),
tinnitus (n51)
Exacerbation rates,
Reduced sputum
Withdrew
lung function,
volume, reduced
(n56)"; diarrhoea
(n53), abdominal
sputum volume/
exacerbation rates,
microbiology
reduced positive sputum cramps (n52),
skin rash (n52)
microbial cultures
Exacerbation
Reduced exacerbation
rates, antibiotic
rate, reduced antibiotic
usage, lung function
usage, improved
DL,CO, no change
in FEV1, FVC
Reduced sputum
Sputum
purulence/leukocyte
purulence/WCC,
counts, reduced airway
FEV1, PD20
metacholine
reactivity, fall in FEV1
Sputum volume,
Reduced sputum
lung function,
volume, reduced BALF
BALF (leukocyte
neutrophil ratio, IL-8,
counts, microbial increased FEF25–75, No
change in FEV1
cultures, IL-8,
IL-10, TNF-a)
24 h sputum
Reduced sputum
(volume/WCC/
volume, improved FEV1
and FVC, no change in
microbial
concentrations/ microbial concentration,
immune mediators#), no change in immune
lung function
mediators
Sputum volume,
Reduced sputum
exacerbation
volume, reduced
rates, lung function
exacerbations, no
change in lung function
Outcome
measures
DBRCT: double-blind randomised controlled trial (RCT); b.i.d.: twice daily; WCC: white cell count; FEV1: forced expiratory volume in 1 second; PD20: provocative dose causing a 20% fall in
FEV1; BALF: bronchoalveolar lavage fluid; IL: interleukin; TNF: tumour necrosis factor; FVC: forced vital capacity; FEF25–75%: forced expiratory flow at 25–75% FVC; q.d.: once daily; DL,CO:
diffusing capacity of the lung for carbon monoxide; MWF: Monday, Wednesday, Friday. #: immune mediators: IL-1a, TNF-a and leukotriene B4; ": seven adverse events in six patients.
Adult
Bronchiectasis, Azithromycin
(18–77 yrs)
.4
(500 mg q.d.
6 days,
exacerbations
prior 52 weeks 250 mg q.d.
6 days,
250 mg MWF)
Adult
Bronchiectasis, Azithromycin
(mean age
o3
(250 mg MWF)
63 yrs)
exacerbations
prior 26 weeks
Children Bronchiectasis, Clarithromycin
(7–18 yrs) no antibiotics in (15 mg?kg-1
b.i.d.)
prior 16 weeks
RCT
(parallel)
Turkey
Drug
Children Bronchiectasis, Roxithromycin
(mean age
airway
(4 mg?kg-1 b.i.d.)
13 yrs)
hyperreactivity
Inclusion
criteria
Y ALCIN
[80]
DBRCT
(parallel)
Population
South
Korea
Country Design
K OH
[79]
Study
Table 2. Clinical trials of macrolide therapy in bronchiectasis
ANTI-INFLAMMATORY THERAPY
macrolide is most beneficial and to assess the risk of macrolide resistant infections. This latter
point is important given the emerging evidence of macrolide resistance in Europe [85–87] and in the
CF population [88–90]. Several studies have either recently been completed, are actively recruiting or
about to commence, which will hopefully address some of these important issues (table 3).
HMGcoA reductase inhibitors
HMGcoA reductase inhibitors (‘‘statins’’) have established clinical utility as lipid lowering agents
in patients with hyperlipidaemia. They also have widely recognised anti-inflammatory and
immunomodulatory properties. In vitro studies of HMGCoA reductase inhibitors have
demonstrated inhibition of neutrophil migration and epithelial cell production of chemoattractants and proteases and potentiation of macrophage efferocytosis [72].
There are currently no studies of the use of HMGCoA reductase inhibitors for bronchiectasis, however,
the findings of the studies in other airway diseases suggest that future studies are worthwhile.
Targeted agents
There are currently no phase III trials of targeted therapies in inflammatory airway diseases, however, a
number of potential candidate agents specifically targeting neutrophilic inflammation are under
investigation.
D.J. SMITH ET AL.
In animal models of COPD, simvastatin has been shown to inhibit airway remodelling, lower
TNF-a and MMP-9 levels and reduce peribronchial and perivascular inflammation [91, 92]. A
recent systematic review identified nine studies using HMGCoA reductase inhibitors in patients
with COPD [93], however, only one of these was a prospective RCT. Collectively, these studies
demonstrated beneficial effects on pulmonary function, exacerbation rates and mortality and
provide the foundation for further study. Large, prospective RCTs are currently underway. Studies
in asthmatic subjects have yielded more variable results. Reduction in airway hyperreactivity has
been seen in one study [94], no benefit in another [95] and one retrospective review even
suggested HMGCoA reductase inhibitor use was associated with poorer clinical outcomes [96]. A
recent placebo-controlled, double-blind RCT of simvastatin 40 mg?day-1 in patients with steroid
responsive (eosinophilic) asthma failed to demonstrate any clinically significant steroid sparing
effect from the addition of simvastatin [97].
The CXC chemokines and their associated receptors (CXCR1/CXCR2) are believed to have a key
role in neutrophilic inflammation in pulmonary disease and recently a number of agents which
inhibit this pathway have been developed [98]. A phase II study of an anti-CXCL8 monoclonal
antibody in COPD has demonstrated safety and improvement in dyspnoea scores over 3 months
[99]. In a complimentary in vitro study ELR-CXC antagonists inhibited neutrophil chemotactic
factors in the sputum of bronchiectatic patients [100]. These studies suggest that further
investigation of these agents may be valuable.
Anti-TNF-a agents have an established role in treatment of systemic inflammatory diseases,
including rheumatoid arthritis [101] and Crohns disease [102]. In short-term trials of anti-TNF-a
agents in inflammatory lung diseases variable efficacy has been reported. While improvement in
exacerbation rates in asthma have been demonstrated [103], no effect was seen in patients with
COPD [104]. The major concerns associated with the use of these agents in patients with
pulmonary disease are the potential for the emergence of opportunistic infections, in particular the
re-activation of mycobacterial disease [105] and their possible association with acute deterioration
of fibrotic lung disease [106].
233
With the emerging array of anti-inflammatory monoclonal antibodies and targeted receptor
blocker drugs, new therapeutic options will potentially become available. Carefully conducted
trials will be required to support the use and examine adverse consequences. Although
manipulation of the immune response is an attractive prospect for treatment of a range of
234
DBRCT
(parallel)
DBRCT
(factorial
design),
stratified
by P.
aeruginosa
status
Australia
DBRCT
(parallel),
stratified by
P. aeruginosa
status
DBRCT
(parallel)
DBRCT
(parallel)
Design
New
Zealand
The
Netherlands
Australia
International
multicentre
study
(Australia,
New Zealand)
Country
Confirmed
bronchiectasis (HRCT)
Confirmed
bronchiectasis (HRCT),
o2 exacerbations in
prior 52 weeks, daily
productive cough,
clinically stable (4 weeks)
o1 pulmonary
exacerbation prior
52 weeks, confirmed
bronchiectasis or
chronic SLD
Inclusion criteria
Azithromycin
(250 mg q.d.)
140
130
26 weeks
72
26 weeks
52 weeks
118
Erthromycin
(400 mg b.i.d.)
48 weeks
Subjects
n
88
Duration
104 weeks
Azithromycin
(30 mg?kg-1?week-1)
Drug
Confirmed
Azithromycin
bronchiectasis (HRCT),
(500 mg MWF)
clinically stable, o1
exacerbations in prior
52 weeks
Adults (18– Bronchiectasis (HRCT +
Azithromycin
80 yrs
clinical), clinically
(250 mg q.d.) or
including
stable, o2 weeks hypertonic saline 7%
or both
indigenous
since antibiotics for
adults)
exacerbation
Adults (18–
80 yrs)
Adults
(.18 yrs)
Adults
(18–80
yrs)
Indigenous
children
(1–8 yrs)
Population
Completed
Study
completed,
yet to report
Ongoing
Exacerbations
Study completed,
(time to first/rate/severity),
yet to report
change in lung function,
HRQoL, change
in sputum cell count
HRQoL, exacerbation rate,
Recruitment to
change in lung function,
commence
change in symptoms score,
early 2011
change in airway
microbiology, sputum
inflammatory markers,
adverse events
Exacerbation rate, change in
lung function, change in
symptom scores, change in
airway microbiology, sputum
inflammatory markers,
HRQoL, adverse events
Exacerbation rate, antibiotic
usage, HRQoL, sputum
volume/inflammatory markers
Exacerbations (time to first/ Recruitment until
rate/severity), safety/adverse
Dec 2010
events, antimicrobial
resistance
Outcome
measures
BIS: bronchiectasis intervention study; BLESS: bronchiectasis and low-dose erythromycin study; BAT: bronchiectasis and long-term azithromycin treatment; EMBRACE:
effectiveness of macrolides in patients with bronchiectasis using azithromycin to control exacerbations; DBRCT: double-blind randomised controlled trial; SLD: suppurative lung
disease; HRCT: high-resolution computed tomography; b.i.d.: twice daily; HRQoL: health-related quality of life; q.d.: once daily; P. aeruginosa: Pseudomonas aeruginosa; MWF:
Monday, Wednesday, Friday.
EMBRACE
BAT
BLESS
BIS
Study
acronym
Table 3. Registered trials of macrolide therapy in bronchiectasis
ANTI-INFLAMMATORY THERAPY
inflammatory medical conditions, history advocates caution. In March 2006, six healthy
volunteers enrolled in a phase I trial were administered a first-in-man anti-CD28 humanised
monoclonal antibody (TG1412) designed to modulate regulatory T-cells. Within hours of
administration each volunteer experienced a severe cytokine storm resulting in multi-organ failure
[107]. Although all six survived, the most severely affected subject required intensive care support
for 3 weeks. Similarly, in a recent study in children and adults with CF the use of an LTB4
antagonist (BIIL284) resulted in increased respiratory exacerbations resulting in the study being
prematurely terminated after interim data analysis [108].
These studies highlight that in conditions characterised by infection associated with inflammation,
anti-inflammatory therapies may be associated with adverse consequences and require very careful
and detailed analysis.
Conclusion
Evidence for the use of anti-inflammatory therapies in bronchiectasis is limited and more
adequately powered studies are required [109, 110]. There is currently insufficient evidence to
support the use of inhaled and oral corticosteroids, NSAIDs and macrolides. Individual patient
trials may be warranted for inhaled corticosteroids and macrolides and other therapies remain
unproven with no evidence to support use as anti-inflammatory therapy in bronchiectasis.
Statement of interest
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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