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

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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

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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.

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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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