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A standard definition of clinically significant MBL deficiency is not presently available but a diagnostic approach that incorporates both serum concentrations and genotyping seems sensible. Some patients with genotypes that are not associated with deficiency can still have very low MBL serum concentrations and, alternatively, serum concentrations can increase with the acute-phase response. One pragmatic approach analogous to that recommended by the American Thoracic Society and European Respiratory Society for α1-antitrypsin deficiency might be for clinicians to initially measure the serum concentration of MBL in patients with bronchiectasis. If the serum level is low, genotyping could then be undertaken. A cutoff of 200 ng/mL, as used in the study by Chalmers and colleagues, classified 19% of patients with bronchiectasis as MBL deficient. Better access to testing facilities and further studies are required to confirm the findings of the present study5 before testing for MBL deficiency becomes routine practice in non-cystic fibrosis bronchiectasis. The present findings also raise some interesting questions for future research. MBL deficiency is relatively common in the general population and does not seem to predispose to an increased risk of infection in the absence of other predisposing factors. How do other predisposing factors interact with MBL deficiency to increase the risk of infection and cause severe disease or poor longitudinal outcomes in bronchiectasis? Could serial MBL concentrations in serum and sputum be used as markers for early detection of exacerbations or determination of the duration of antibiotic treatment? Does azithromycin interact with MBL to improve phagocytic activity in macrophages? Although some evidence suggests that azithromycin increases mannose receptor (a pattern-recognition receptor in the same family as MBL) expression and phagocytic activity in

alveolar macrophages, the effect of azithromycin on MBL expression is unclear.10 Chalmers and colleagues should be commended for undertaking such a large study in this population of patients. Their study builds on a large body of evidence suggesting that MBL deficiency has an important impact on innate immunity and increases susceptibility to bacterial, viral, and fungal infections in various organ systems. *Conroy Wong, Lata Jayaram, Leon Chang Counties Manukau District Health Board, Department of Respiratory Medicine, Middlemore Hospital, Otahuhu, Auckland 2025, New Zealand (CW, LC) and Western Health, Department of Respiratory and Sleep Medicine, Footscray, Melbourne, Australia (LJ) [email protected] We declare that we have no conflicts of interest. 1 2

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Netea MG, van der Meer JW. Immunodeficiency and genetic defects of pattern-recognition receptors. N Engl J Med 2011; 364: 60–70. Rohmann K, Tschernig T, Pabst R, Goldmann T, Dromann D. Innate immunity in the human lung: pathogen recognition and lung disease. Cell Tissue Res 2011; 343: 167–74. Eisen DP. Mannose-binding lectin deficiency and respiratory tract infection. J Innate Immun 2010; 2: 114–22. Jack DL, Turner MW. Anti-microbial activities of mannose-binding lectin. Biochem Soc Trans 2003; 31: 753–57. Chalmers JD, McHugh BJ, Doherty C, et al. Mannose-binding lectin deficiency and disease severity in non-cystic fibrosis bronchiectasis: a prospective study. Lancet Respir Med 2013; published online Jan 28. http://dx.doi.org/10.1016/S2213-2600(13)70001-8. Chalmers JD, Fleming GB, Hill AT, Kilpatrick DC. Impact of mannosebinding lectin insufficiency on the course of cystic fibrosis: a review and meta-analysis. Glycobiology 2011; 21: 271–82. Macfarlane JG, Jary H, Hester KL, et al. Low serum mannose-binding lectin level is not associated with disease severity in non-cystic fibrosis bronchiectasis. Innate Immun 2012; 18: 787–92. Albert RK, Connett J, Curtis JL, et al. Mannose-binding lectin deficiency and acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2012; 7: 767–77. Petersen KA, Matthiesen F, Agger T, et al. Phase I safety, tolerability, and pharmacokinetic study of recombinant human mannan-binding lectin. J Clin Immunol 2006; 26: 465–75. Hodge S, Hodge G, Jersmann H, et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 178: 139–48.

Resetting the hyperinflated emphysematous lung: coils inside or staples outside? Published Online April 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70051-1 See Articles page 233

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Emphysema is a serious chronic respiratory disease that affects tens of millions of people around the world who have increasing dyspnoea, restricted exercise tolerance, frequent infectious exacerbations, poor quality of life, and a risk for premature death.1 In addition to smoking cessation,

several medical treatment options are available— eg pharmacotherapy, supplementary oxygen, and pulmonary rehabilitation.2 However, when a substantial proportion of the lung is destroyed, such treatment is no longer effective. More invasive interventions such as lung transplantation or lung www.thelancet.com/respiratory Vol 1 May 2013

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www.thelancet.com/respiratory Vol 1 May 2013

patients with homogeneous emphysema, resulted in only a small and transient reduction of functional and radiological residual volume and improvement in vital capacity and airway obstruction.11 In the third strategy, biological and polymeric substances are injected in target zones sealing the emphysematous lung.6 A large trial is ongoing (NCT01449292), but no results have been published thus far. In the fourth technique, vapour is applied endobronchially in targeted areas, causing thermal damage and thereby collapsing the lung.12 No controlled studies have been done so far. Finally, the fifth strategy is to insert nitinol coils that recover to a non-straight, pre-determined shape on deployment.13 The intended physiological benefit of implanted coils is to bend the airways, restoring its tethering effect on the smaller airways (ie, pulling them open), and to compress diseased lung parenchyma, thereby reducing volume and restoring elastic recoil in a similar manner to LVRS. In this issue of The Lancet Respiratory Medicine, Pallav Shah and colleagues report findings from their randomised controlled study (RESET)14 in the UK, in which they compared volume reduction with endobronchial coils (LVRC; treatment group) versus standard medical care (usual care group). In the treatment group, patients were treated bilaterally with a 1 month interval between both bronchoscopic procedures. Individuals in the treatment group had a greater decrease in St George’s Respiratory Questionnaire (SGRQ) dyspnoea score at 90 days, the primary outcome, than did those in the usual care group (between-group difference in change from baseline –8·36 points [95% CI –16·24 to –0·47]; p=0·04). Those in the treatment group also had a favourable outcome in terms of three of the secondary outcomes: 6-min walk test (p7 days) in nearly 50% of the patients, which in turn extended their duration of chest tube drainage and hospital stay. Additionally, mortality risk was reduced in a subset of patients with a low exercise capacity at baseline. In the past decade, less invasive approaches have been developed.4 Five types of endobronchial interventions have been reported,5,6 but only three have been investigated in randomised clinical trials. In the first technique, one-way endobronchial valves are inserted into pulmonary segments, leading to hyperinflated areas that allow air to exit but not enter the lungs, thereby reducing air trapping. This bronchoscopic procedure comes with an increased risk of COPD exacerbation, haemoptysis, and pneumonia. The findings of a randomised trial (VENT; 220 patients) done in both the USA7 and in Europe8 that compared the endobronchial valve Zephyr (Pulmonx Inc; Redwood City, CA, USA) versus standard medical care were disappointing, with the intervention giving statistically significant but not clinically meaningful improvement in lung function, exercise tolerance, and symptoms. Similar conclusions can be drawn from another randomised, sham-controlled bronchoscopy trial in Europe that used a different endobronchial valve (IBV; Spiration Inc, Redmond, WA, USA).9 These studies identified the importance of emphysema phenotype with better results in patients seen with greater heterogeneity in emphysema distribution, intact fissures between lobes, and complete lobar occlusion. An endobronchial catheter system (Chartis; Pulmonx Inc, Redwood City, CA, USA) was developed to study presence of collateral ventilation so that response to treatment with endobronchial valves can be predicted in advance.10 In the second technique, a small extra-anatomical bypass is created and stented between a central airway and zones of hyperinflated parenchyma allowing trapped air to exit. A randomised, bronchoscopy sham-controlled trial (EASE) showed that this technique, intended for

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usual care group) were small and study followup (90 days) was short by comparison with the NETT trial (24 months’ follow-up). Despite proven safety in feasibility studies,13 longer follow up is needed to investigate what will happen when coils start migrating outside the airway. Migration of endobronchial or endovascular metal stents into the lung, which causes life-threatening problems, is a complication well known to thoracic surgeons. Patients with different affected lobes and different morphological subtypes were included in RESET, but no percentages of each subtype were reported. Too few patients were included to allow subgroup analyses to identify the most responsive group of patients, or whether LVRC can be an alternative for patients not suited for LVRS or endobronchial valves. Moreover, the effect of a pulmonary rehabilitation programme provides results similar to those seen by Shah and colleagues, with a mean decrease in SGRQ of 8·3 and an increase in 6-minute walk distance of 48·2 m.15 Therefore, we would advise patients with emphysema to enter a rehabilitation programme before undergoing new interventional therapeutic options. LVRC looks a promising technique that can achieve meaningful clinical improvement compared with endobronchial valves and airway bypass. It applies a concept similar to LVRS that is effective independent of collateral ventilation. The results reported in this small study should be substantiated in ongoing trials, including more patients and longer follow-up. Until then, bronchoscopic lung volume reduction with coils should not be considered as an effective, durable, and less invasive alternative compared with the current standard surgical method with staples to reset the hyperinflated lungs in patients with severe emphysema.

*Dirk Van Raemdonck, Geert M Verleden University Hospitals Leuven and KU Leuven, Leuven, Belgium (DVR, GMV) [email protected] We declare that we have no conflicts of interest. DVR is a senior clinical investigator supported by grant G.3C04.99 from Fund for Scientific ResearchFlanders. 1 2 3

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Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007; 370: 765–73. Wouters EFM. Management of severe COPD. Lancet 2004; 364: 883–95. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Eng J Med 2003; 348: 2059–73. Van Raemdonck D, Ninane V. Lung volume reduction for severe emphysema: do we need a scalpel or a scope? Eur Respir Rev 2012; 19: 242–47. Herth FJ, Gompelmann D, Ernst A, Eberhardt R. Endoscopic lung volume reduction. Respiration 2010; 79: 5–13. Taneja A. Bronchoscopic interventions in the management of chronic obstructive pulmonary disease. Curr Opin Pulm Med 2013; 19: 145–51. Sciurba FC, Ernst A, Herth FJ, et al. A randomized study of endobronchial valves for advanced emphysema. N Eng J Med 2010; 363: 1233–44. Herth FJ, Noppen M, Valipour A, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J 2012; 39: 1334–42. Ninane V, Geltner C, Bezzi M, et al. Multicentre European study for the treatment of advanced emphysema with bronchial valves. Eur Respir J 2012; 39: 1319–25. Herth FJ, Eberhardt R, Gompelmann D, et al. Radiological and clinical outcomes of using Chartis™ to plan endobronchial valve treatment. Eur Respir J 2013; 41: 302–08. Shah PL, Slebos DJ, Cardoso PF, et al. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicenter trial. Lancet 2011; 378: 997–1005. Snell G, Herth FJ, Hopkins P, et al. Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema. Eur Respir J 2012; 39: 1326–33. Slebos DJ, Klooster K, Ernst A, et al. Bronchoscopic lung volume reduction coil treatment of patients with severe heterogeneous emphysema. Chest 2012; 142: 574–82. Shah PL, Zoumot Z, Singh S, et al. Endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): a randomised controlled trial. Lancet Respir Med 2013; published online April 23. http:// dx.doi.org/10.1016/S2213-2600(13)70047-X Carone M, Patessio A, Ambrosino N, et al. Efficacy of pulmonary rehabilitation in chronic respiratory failure (CRF) due to chronic obstructive pulmonary disease (COPD): the Maugeri study. Respir Med 2007; 101: 2447–53.

The WHO FCTC: the challenge of implementation Published Online May 3, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70048-1 See Editorial page 175 See Review page 241 See Series Lancet 2013; 381: 1570, 1581, and 1588

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According to WHO, tobacco use killed 100 million people in the 20th century and, if trends continue, it will kill 1 billion people in the 21st century.1 Furthermore, by the year 2030, 80% of these deaths will be in lowincome and middle-income countries. The WHO Framework Convention on Tobacco Control (FCTC) was developed in response to the globalisation of the tobacco epidemic. Its objective was “to protect present

and future generations from the devastating health, social, environmental and economic consequences of tobacco consumption and exposure to tobacco smoke.”2 The convention has been widely embraced by the world community, and now includes 176 parties, representing 88·6% of the world’s population. However, despite much early enthusiasm, the success of the convention is threatened by a failure to engage www.thelancet.com/respiratory Vol 1 May 2013

Resetting the hyperinflated emphysematous lung: coils inside or staples outside?

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