2012 Research Highlights

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Bronchiectasis: breaking the cycle of infl ammation and infection

Bronchiectasis was fi rst described by Rene Laennec in 1819. It remains an orphan disease and the paucity of randomised controlled trials draw attention to this disease. 133 trials were identifi ed for bronchiectasis in a PubMed search on Dec 10, 2012, compared with 3253 for chronic obstructive pulmonary disease, 5405 for lung cancer, and 8748 for asthma. In 2012, research into bronchiectasis moved forward substantially and we present the headlines from the British Thoracic Society (BTS) national audit and quality standards, and research into new treatments to break the cycle of bronchial infl ammation and infection in bronchiectasis.

The BTS national secondary-care audits drew attention to management being less than optimum and not in accordance with the guidelines.1 To improve the care of patients with bronchiectasis, the BTS published 11 quality statements relevant to both primary and secondary care (panel).2

In bronchiectasis, both infection and infl ammation of the airways are thought to be key in the ongoing “vicious cycle” described by Cole in 1984.3 We assessed 385 stable patients with bronchiectasis and noted that bacterial load aff ected bronchial and systemic infl ammation.4 The infl ammatory response in the airways (sputum myeloperoxidase and free neutrophil elastase activities, and interleukin-8, interleukin-1β, and tumour necrosis factor-α concentrations) starts at 105 colony forming units (cfu) per mL and rises with increasing bacterial load. The systemic infl ammatory response (increase in concentrations of E selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule) did not occur until bacterial loads were at least 107 cfu per mL. Clinically, patients with high bacterial loads had worse health-related quality of life, and more outpatient exacerbations and unscheduled hospital admissions. The work by our group reinforces the infl ammation and infection cycle hypothesis. The aim of the ongoing research is to investigate whether anti-infective treatment can break this cycle by reducing or clearing the bacterial load.

Wilson and colleagues5 undertook a phase 2, double-blind, randomised controlled trial to assess short-term inhaled antibiotics.5 In just over half of

124 patients chronically infected with potentially pathogenic microorganisms, the infection was caused by Pseudomonas aeruginosa. Ciprofl oxacin dry powder inhalation (DPI) 32·5 mg or placebo from a T-326 inhaler was administered twice daily for 28 days. At the end of the treatment, patients given ciprofl oxacin had a greater than three times reduction in log bacterial count—equivalent to greater than 99·9% reduction in bacterial load—than in patients given placebo. 35% of the patients given ciprofl oxacin DPI had eradication of pathogen compared with 8% of those in the control group. The inhaled ciprofl oxacin was well tolerated and there was no investigator-reported bronchospasm. This side-eff ect was common in previous studies of patients treated with nebulised antibiotics and occurred in about 20% of cases. Further studies are needed to assess the long-term effi cacy on key endpoints—eg, time to next exacerbation and frequency of exacerbations.

In one such long-term randomised controlled study, Murray and colleagues4,6 investigated the anti-infl am matory and clinical benefi ts of continuous

Panel: Quality standards for clinically signifi cant bronchiectasis in adults

• Ensure diagnostic accuracy through confi rmation of a clinical diagnosis of bronchiectasis with a CT of the chest using 1 mm slices.

• Investigate specifi c treatable causes (allergic bronchopulmonary aspergillosis, common variable immunodefi ciency, and cystic fi brosis).

• Regular chest clearance techniques to be taught by a specialist respiratory physiotherapist.

• Pulmonary rehabilitation to be provided in patients with signifi cant breathlessness.

• Monitor sputum bacteriology during stability.• Monitor sputum bacteriology at the start of an exacerbation

before the initiation of antibiotics.• Assess patients before and after intravenous antibiotic. • Ensure that suitable patients have an available service for

provision of inhaled antibiotic. • Make available domiciliary intravenous antibiotics for chest

infections in patients requiring it. • Prepare a written self-management plan for each individual.• Provide secondary-care follow-up as per British Thoracic

Society national guidelines.

Published OnlineJanuary 14, 2013http://dx.doi.org/10.1016/S2213-2600(13)70005-5

2012 Research Highlights

e6 www.thelancet.com/respiratory Vol 1 March 2013

inhaled antibiotics over 1 year. 65 patients chronically infected with potentially pathogenic microorganisms (P aeruginosa in 37–48%) were given nebulised gentamicin 80 mg twice daily versus 0·9% saline for 12 months. Gentamicin temporarily cleared P aeruginosa in 31% of patients infected with this microorganism and in 93% of those infected with other potentially pathogenic microorganisms. In the absence of clearance, there was a signifi cant reduction in bacterial load. Clearance or a reduction in bacterial load resulted in a reduction in infl ammation of the airways and concentration of intercellular adhesion molecule-1, which in turn reduced exacerbation frequency and improved health-related quality of life. Although no serious adverse events, including microbial resistance, were reported, 6% of patients could not tolerate the nebulised antibiotic despite adjunctive bronchodilator therapy. However, at 3-month follow-up, after completion of treatment, patients relapsed, indicating that treatment has to be continuous or patients should have off -drug intervals of less than 3 months.

In view of the potential side-eff ects of anti-infective therapy, researchers have investigated anti-infl ammatory treatment as an alternative to target the cycle of infl ammation and infection. In the double-blind, randomised controlled EMBRACE study, Wong and colleagues7 investigated the long-term effi cacy of azithromycin as an anti-infl ammatory in patients with at least one exacerbation in the preceding year. 141 patients were administered azithromycin 500 mg three times a week or placebo for 6 months. In the azithromycin group, 48% of 71 patients were chronically infected with a potential pathogenic microorganism. Although no serious adverse events were reported, including microbial resistance, 27% of patients in the azithromycin group had gastrointestinal events (consequently 3% stopped treatment). The time until at least 25% of the patients had an exacerbation was much higher in the azithromycin group than in the placebo group (104 days [95% CI 48–186] vs 21 days [11–48]; hazard ratio 0·34 [0·20–0·56]; p<0·0001), and this eff ect persisted for 6 months after the end of treatment.

Further studies are needed to assess the long-term safety of both anti-infective and anti-infl ammatory

treatments, and to investigate local and systemic eff ects, bacterial resistance patterns, and eff ect on non-tuberculous mycobacteria. These mycobacteria are found in some patients and macrolides are an important part of the treatment. Internationally, there are concerns that long-term macrolides might lead to resistance in mycobacteria.

The results of these excellent proof-of-concept studies show that it is possible to break the cycle of infl ammation and infection with anti-infective and anti-infl ammatory agents, but the long-term safety of these treatments is not known. We need further studies to defi ne the optimum period of treatment, ascertain which agents are the best, assess whether dual treatment with anti-infl ammatory and anti-infective agents is more eff ective than is monotherapy, and defi ne the mode and frequency of treatment delivery. Should treatment be on–off every 28 days or continuous with or without a drug-free period? We look forward to further studies to take the research forward.

*Pallavi Mandal, Adam T HillMedical Research Council Centre for Infl ammation Research, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK (PM, ATH); and Department of Respiratory Medicine, Royal Infi rmary of Edinburgh, Edinburgh, UK (ATH)pallavimandal@gmail.com

We declare that we have no confl icts of interest.

1 Hill AT, Welham S, Reid K, Bucknall CE. British Thoracic Society. British Thoracic Society national bronchiectasis audit 2010 and 2011. Thorax 2012; 67: 928–30.

2 British Thoracic Society. Quality standards for clinically signifi cant bronchiectasis in adults. July, 2012. http://www.brit-thoracic.org.uk/Portals/0/Guidelines/Bronchiectasis/244457_BTS_Quality_Standards_Bronchiectasis.pdf (accessed Dec 10, 2012).

3 Davies RJ, Cole PJ. A new look at the pathogenesis and management of persistent bronchial sepsis: a “vicious circle” hypothesis and its logical therapeutic connotations. In: Davies RJ, ed. Strategies for the management of bronchial sepsis. Oxford: Medicine Publishing Foundation, 1984.

4 Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Short- and long-term antibiotic treatment reduces airway and systemic infl ammation in non-cystic fi brosis bronchiectasis. Am J Respir Crit Care Med 2012; 186: 657–65.

5 Wilson R, Welte T, Polverino E, et al. Ciprofl oxacin DPI in non-cystic fi brosis bronchiectasis: a phase II randomised study. Eur Respir J 2012; published online Sept 27. DOI:10.1183/09031936.00071312.

6 Murray MP, Govan JR, Doherty CJ, et al. A randomized controlled trial of nebulized gentamicin in non-cystic fi brosis bronchiectasis. Am J Respir Crit Care Med 2010; 183: 491–49.

7 Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fi brosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380: 660–67.