Lata Jayaram

Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial

BACKGROUND Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis. METHODS We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St Georges respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493. FINDINGS 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7·21 to 0·72; p=0·108). INTERPRETATION Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year. FUNDING Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.

Combined Therapy with Tiotropium and Formoterol in Chronic Obstructive Pulmonary Disease: Effect on the 6-Minute Walk Test

Abstract Combined therapy with tiotropium and long-acting beta 2 agonists confers additional improvement in symptoms, lung function and aspects of health-related quality of life (QOL) compared with each drug alone in patients with COPD. However, the efficacy of combined therapy on walking distance, a surrogate measure of daily functional activity and morbidity remains unclear. The aim was, therefore, to quantify the benefit of this therapy on the six minute walk test. Secondary outcomes included change in lung function, symptoms, the BODE index and QOL. In a double-blind, crossover study, 38 participants with moderate to severe COPD on tiotropium were randomised to receive either formoterol or placebo for 6 weeks. Following a 2-week washout period, participants crossed over to the alternate arm of therapy for a further 6 weeks. Thirty-six participants, with an average age of 64.3 years and FEV1 predicted of 53%, completed the study. Combined therapy improved walking distance by a mean of 36 metres [95% CI: 2.4, 70.1; p = 0.04] compared with tiotropium. FEV1 increased in both groups (160 mL combination therapy versus 30 mL tiotropium) with a mean difference of 110 mL (95% CI: −100, 320; p = 0.07) between groups, These findings further support the emerging advantages of combined therapy in COPD. Australian New Zealand Clinical Trials.

Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting β2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a β2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat® Soft Mist™ inhaler at doses of 2.5/5 μg and 5/5 μg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting β2-agonist with long-acting muscarinic antagonist combinations and delivery devices.

Bronchiectasis in the Last Five Years: New Developments

Bronchiectasis, a chronic lung disease characterised by cough and purulent sputum, recurrent infections, and airway damage, is associated with considerable morbidity and mortality. To date, treatment options have been limited to physiotherapy to clear sputum and antibiotics to treat acute infections. Over the last decade, there has been significant progress in understanding the epidemiology, pathophysiology, and microbiology of this disorder. Over the last five years, methods of assessing severity have been developed, the role of macrolide antibiotic therapy in reducing exacerbations cemented, and inhaled antibiotic therapies show promise in the treatment of chronic Pseudomonas aeruginosa infection. Novel therapies are currently undergoing Phase 1 and 2 trials. This review aims to address the major developments within the field of bronchiectasis over this time.

Relationship between Sleep Duration and Risk Factors for Stroke

Stroke is a leading cause of death and disability worldwide. While various risk factors have been identified, sleep has only been considered a risk factor more recently. Various epidemiologic studies have associated stroke with sleep such as sleep duration, and laboratory and clinical studies have proposed various underlying mechanisms. The pathophysiology is multifactorial, especially considering sleep affects many common risk factors for stroke. This review aims to provide an outline of the effect of sleep duration on common stroke risk factors. Appropriate sleep duration, especially in patients who have stroke risk factors, and increasing awareness and screening for sleep quality may contribute to primary prevention of stroke.

Pulmonary cavitary Mycobacterium kyorinense (M. kyorinense) infection in an Australian woman

We describe a patient with pulmonary cavitary pneumonia from whom we serially isolated Mycobacterium kyorinense, an organism not previously reported in Australia, or associated with cavitary disease. We discuss the clinical presentation, the isolation of the organism on several specimens and initial management. M. kyorinense is a recently characterized species, which has previously only been described in Japan and Brazil [1].

Azithromycin in non-cystic-fibrosis bronchiectasis – Authors' reply

www.thelancet.com Vol 381 January 5, 2013 27 2 Mosley H, Chen LC. Analytical framework for the study of child survival in developing countries. Popul Dev Rev 1984; 10 (suppl): 25–45. 3 Sanda S. Niger’s success in child survival. Lancet 2012; 380: 1127–28. 4 Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094. 5 Imdad A, Yakoob MY, Sudfeld C, Haider BA, Black RE, Bhutta ZA. Impact of vitamin A supplementation on infant and childhood mortality. BMC Public Health 2011; 11 (suppl 3): S20. infection with macrolide-resistant Mycobacterium avium complex. We wholeheartedly agree with the suggestion to screen candidates for NTM before starting azithromycin monotherapy, but we also recommend that physicians be vigilant in monitoring for symptoms and signs of NTM lung disease and for having a low threshold for repeating sputum microbiology tests for acid-fast bacilli. The risk of inducing macrolide resistance might vary geographically; research is needed to address this concern.

Treatable traits can be identified in a severe asthma registry and predict future exacerbations: Treatable traits in severe asthma

A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk.

ELTGOL airway clearance in bronchiectasis: laying the bricks of evidence

The thought that flickers almost as a reflex when we think about airway clearance techniques in bronchiectasis is “where is the evidence?” A solid foundation for the efficacy of treatments should be based on randomised controlled trials. Currently, the evidence base is sparse but fortunately the field has not been abandoned. ELTGOL therapy is one of the best evidence-based airway clearance techniques for bronchiectasis http://ow.ly/vXmU30gZUSR

Mannose-binding lectin and innate immunity in bronchiectasis

www.thelancet.com/respiratory Vol 1 May 2013 179 Pathogenic microorganisms often thrive in the infl ammatory milieu of the bronchiectatic airway where innate and adaptive defence mechanisms can be impaired. Although genetic defects of the adaptive immune system causing immunodefi ciency syndromes are well characterised, genetic defects that impair the recognition of microbes by the innate immune system have only recently been identifi ed. For example, polymorphisms in the gene for mannosebinding lectin (MBL), a receptor of the innate immune system that recognises microbial carbohydrates, can lead to defi ciency of MBL and increased susceptibility to infection. When the lungs are exposed to a new pathogen, the fi rst line of defence is the innate immune system, which results in a swift and semi-specifi c response. Cells of the innate immune system, which include dendritic cells and macrophages, recognise highly conserved structures called pathogen-associated molecular patterns (PAMPs) that are shared by large groups of microorganisms. PAMPs are recognised by pattern-recognition receptors, which activate the cells of the innate immune system to rapidly attack and kill microbes. MBL is a soluble pattern-recognition receptor that is synthesised in the liver and is released into the systemic circulation as a component of the acutephase response. It is not produced locally in the lungs and is thought to leak into the airways and alveoli from the systemic circulation, particularly in the presence of infl ammation. MBL binds to various respiratory pathogens including Haemophilus infl uenzae and Pseudomonas aeruginosa, which are commonly identifi ed in the airways of patients with bronchiectasis, and enhances the killing of these organisms by activation of the lectin complement pathway and by facilitating phagocytosis by opsonisation. In The Lancet Respiratory Medicine, James Chalmers and colleagues report a large, prospective study assessing the relation between MBL defi ciency and clinical outcomes during a 4 year follow-up of patients with non-cystic fi brosis bronchiectasis. 55 (12%) of 470 patients with bronchiectasis had genotypes associated with MBL defi ciency. These patients had more frequent exacerbations and were more likely to be chronically colonised with bacteria, particularly by P aeruginosa, than were patients with genotypes not associated with MBL defi ciency. One strength of the study was the measurement of both MBL defi cient genotypes and serum concentrations, which were strongly correlated. Serum MBL defi ciency (<200 ng/ mL) was also associated with increased exacerbation frequency. The results of Chalmers and colleagues’ study are consistent with the fi ndings from studies of patients with cystic fi brosis in which MBL defi ciency has been associated with increased severity of disease. In patients with cystic fi brosis, MBL defi ciency results in earlier acquisition of P aeruginosa, reduced pulmonary function, and increased mortality. However, a retrospective study of patients with non-cystic fi brosis bronchiectasis reported no association between low MBL concentrations and exacerbation frequency. Several confl icting results have also been published from studies assessing the association between low levels of MBL and acute exacerbations of chronic obstructive pulmonary disease. What are the clinical implications of Chalmers and colleagues’ study? The study provides evidence that MBL defi ciency is a new risk factor for infection and acute exacerbations in patients with non-cystic fi brosis bronchiectasis. Identifi cation of patients at high risk of development of severe disease could direct clinicians to undertake more intensive management and follow-up of these patients with a view to reducing rates of hospital admission and mortality. Such stratifi cation is increasingly relevant because of the growing range of treatments that is emerging for bronchiectasis. These treatments include long-term azithromycin, nebulised gentamicin, inhaled mannitol, inhaled dry powder ciprofl oxacin, and nebulised liposomal ciprofl oxacin. Recombinant human MBL might also become a treatment option, after it was reported in a phase 1 study to be safe, well tolerated, and able to restore activity of the lectin pathway of complement. Mannose-binding lectin and innate immunity in bronchiectasis