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2012 Research Highlights

Bronchiectasis: breaking the cycle of inflammation
and infection
Bronchiectasis was first described by Rene Laennec in 124 patients chronically infected with potentially Published Online
January 14, 2013
1819. It remains an orphan disease and the paucity pathogenic microorganisms, the infection was caused http://dx.doi.org/10.1016/
of randomised controlled trials draw attention to this by Pseudomonas aeruginosa. Ciprofloxacin dry powder S2213-2600(13)70005-5

disease. 133 trials were identified for bronchiectasis inhalation (DPI) 32·5 mg or placebo from a T-326
in a PubMed search on Dec 10, 2012, compared with inhaler was administered twice daily for 28 days. At the
3253 for chronic obstructive pulmonary disease, 5405 end of the treatment, patients given ciprofloxacin had
for lung cancer, and 8748 for asthma. In 2012, research a greater than three times reduction in log bacterial
into bronchiectasis moved forward substantially and we count—equivalent to greater than 99·9% reduction in
present the headlines from the British Thoracic Society bacterial load—than in patients given placebo. 35% of
(BTS) national audit and quality standards, and research the patients given ciprofloxacin DPI had eradication
into new treatments to break the cycle of bronchial of pathogen compared with 8% of those in the control
inflammation and infection in bronchiectasis. group. The inhaled ciprofloxacin was well tolerated and
The BTS national secondary-care audits drew there was no investigator-reported bronchospasm. This
attention to management being less than optimum and side-effect was common in previous studies of patients
not in accordance with the guidelines.1 To improve the treated with nebulised antibiotics and occurred in about
care of patients with bronchiectasis, the BTS published 20% of cases. Further studies are needed to assess the
11 quality statements relevant to both primary and long-term efficacy on key endpoints—eg, time to next
secondary care (panel).2 exacerbation and frequency of exacerbations.
In bronchiectasis, both infection and inflammation In one such long-term randomised controlled
of the airways are thought to be key in the ongoing study, Murray and colleagues4,6 investigated the anti-
“vicious cycle” described by Cole in 1984.3 We assessed inflammatory and clinical benefits of continuous
385 stable patients with bronchiectasis and noted
that bacterial load affected bronchial and systemic
inflammation.4 The inflammatory response in the Panel: Quality standards for clinically significant
bronchiectasis in adults
airways (sputum myeloperoxidase and free neutrophil
elastase activities, and interleukin-8, interleukin-1β, • Ensure diagnostic accuracy through confirmation of a
and tumour necrosis factor-α concentrations) starts clinical diagnosis of bronchiectasis with a CT of the chest
using 1 mm slices.
at 105 colony forming units (cfu) per mL and rises with
• Investigate specific treatable causes (allergic
increasing bacterial load. The systemic inflammatory bronchopulmonary aspergillosis, common variable
response (increase in concentrations of E selectin, immunodeficiency, and cystic fibrosis).
intercellular adhesion molecule-1, and vascular cell • Regular chest clearance techniques to be taught by a
adhesion molecule) did not occur until bacterial loads specialist respiratory physiotherapist.
• Pulmonary rehabilitation to be provided in patients with
were at least 107 cfu per mL. Clinically, patients with high significant breathlessness.
bacterial loads had worse health-related quality of life, • Monitor sputum bacteriology during stability.
and more outpatient exacerbations and unscheduled • Monitor sputum bacteriology at the start of an exacerbation
hospital admissions. The work by our group reinforces before the initiation of antibiotics.
• Assess patients before and after intravenous antibiotic.
the inflammation and infection cycle hypothesis. The
• Ensure that suitable patients have an available service for
aim of the ongoing research is to investigate whether provision of inhaled antibiotic.
anti-infective treatment can break this cycle by reducing • Make available domiciliary intravenous antibiotics for chest
or clearing the bacterial load. infections in patients requiring it.
Wilson and colleagues5 undertook a phase 2, • Prepare a written self-management plan for each individual.
• Provide secondary-care follow-up as per British Thoracic
double-blind, randomised controlled trial to assess
Society national guidelines.
short-term inhaled antibiotics.5 In just over half of

www.thelancet.com/respiratory Vol 1 March 2013 e5

Azithromycin for prevention of Further studies are needed to assess the long-term exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised. there was a significant reduction in studies show that it is possible to break the cycle of bacterial load. We need further which in turn reduced exacerbation frequency and studies to define the optimum period of treatment. A randomized controlled trial of [0·20–0·56]. Edinburgh. Short. Strategies for the management microbial resistance. In the azithromycin 2 British Thoracic Society. Karalus N. ed. In view of the potential side-effects of anti. Cole PJ. 7 Wong C. July. 65 patients chronically treatments. have off-drug intervals of less than 3 months. placebo-controlled trial. 48% of 71 patients were chronically infected Portals/0/Guidelines/Bronchiectasis/244457_BTS_Quality_Standards_ Bronchiectasis. safety of both anti-infective and anti-inflammatory e6 www. 1984. The time until at least 25% of the in non-cystic fibrosis bronchiectasis. In: Davies RJ. Welte T. double-blind. with a potential pathogenic microorganism. and to investigate local and systemic infected with potentially pathogenic microorganisms effects. Respiratory Medicine.00071312. published online Sept 27. patients had an exacerbation was much higher in the 5 Wilson R. Bucknall CE. However. Adam T Hill infective therapy. 2012 Research Highlights inhaled antibiotics over 1 year. 2012. group had gastrointestinal events (consequently 3% 4 Chalmers JD. after Should treatment be on–off every 28 days or continuous completion of treatment.org. p<0·0001).pdf (accessed Dec 10. Polverino E. researchers have investigated anti. Smith MP. randomised controlled EMBRACE study. Govan JR. of these treatments is not known. British Thoracic Society national bronchiectasis audit 2010 and 2011. *Pallavi Mandal. Welham S. Queen’s Medical Research Institute. Eur Respir J 2012. Gentamicin temporarily cleared important part of the treatment. In the absence The results of these excellent proof-of-concept of clearance. British Thoracic Society.com/respiratory Vol 1 March 2013 . McHugh BJ. et al.thelancet. et al. ATH). Quality standards for clinically significant bronchiectasis in adults. These mycobacteria gentamicin 80 mg twice daily versus 0·9% saline are found in some patients and macrolides are an for 12 months. Clearance or a reduction in bacterial load inflammation and infection with anti-infective and resulted in a reduction in inflammation of the airways anti-inflammatory agents. http://www. inflammatory treatment as an alternative to target Edinburgh EH16 4TJ.1183/09031936. A new look at the pathogenesis and management of no serious adverse events were reported. including microbial resistance.and long-term antibiotic treatment reduces airway and systemic inflammation stopped treatment). Wong UK (ATH) and colleagues7 investigated the long-term efficacy of pallavimandal@gmail. 2012). Internationally. including persistent bronchial sepsis: a “vicious circle” hypothesis and its logical therapeutic connotations. at 3-month follow-up. Although 3 Davies RJ. 67: 928–30. indicating with or without a drug-free period? We look forward to that treatment has to be continuous or patients should further studies to take the research forward. there P aeruginosa in 31% of patients infected with this are concerns that long-term macrolides might lead to microorganism and in 93% of those infected with other resistance in mycobacteria. Oxford: Medicine Publishing Foundation. and nebulised antibiotic despite adjunctive bronchodilator define the mode and frequency of treatment delivery. Govan JR. bacterial resistance patterns. 47 Little France Crescent. 380: 660–67. patients relapsed. DOI:10. Royal Infirmary of Edinburgh. UK (PM. [95% CI 48–186] vs 21 days [11–48]. In the double. 186: 657–65. Doherty CJ. 141 patients 1 Hill AT. improved health-related quality of life. were administered azithromycin 500 mg three times Thorax 2012. treatment with anti-inflammatory and anti-infective were reported. blind. assess whether dual serious adverse events. but the long-term safety and concentration of intercellular adhesion molecule-1. least one exacerbation in the preceding year. hazard ratio 0·34 6 Murray MP. Medical Research Council Centre for Inflammation Research. and this effect persisted for nebulized gentamicin in non-cystic fibrosis bronchiectasis. Hill AT. 6 months after the end of treatment. a week or placebo for 6 months.brit-thoracic. Am J Respir Crit Care Med 2012. Reid K. 27% of patients in the azithromycin of bronchial sepsis. et al. therapy. Jayaram L. 6% of patients could not tolerate the agents is more effective than is monotherapy. Lancet 2012. Ciprofloxacin DPI in non-cystic fibrosis azithromycin group than in the placebo group (104 days bronchiectasis: a phase II randomised study. Am J Respir Crit Care Med 2010. Although no ascertain which agents are the best. and effect on (P aeruginosa in 37–48%) were given nebulised non-tuberculous mycobacteria.com azithromycin as an anti-inflammatory in patients with at We declare that we have no conflicts of interest. and Department of the cycle of inflammation and infection.uk/ group. Doherty C. potentially pathogenic microorganisms. 183: 491–49.