2012 Research Highlights

Chronic obstructive pulmonary disease: important advances

www.thelancet.com/respiratory Vol 1 March 2013

classification will improve management and outcomes remains to be established in prospective studies, such as the study by Han and colleagues.3 The new GOLD strategy also emphasises the importance of assessment of comorbidities, since these have a major effect on outcome. The management of these comorbid diseases, an increasing number of which are non-pulmonary disorders, in patients with COPD is being debated. In a recent study, investigators recorded almost 80 comorbidities (the so-called comorbidome) in a large cohort of COPD patients; in a multivariate analysis, 12 of these comorbidities contributed independently to increased mortality.4 Surprisingly, anxiety was one the strongest predictors of mortality in this cohort, the reasons for which are unknown. All the patients in this cohort were smokers, so in the absence of an age-matched control group of smokers with normal lung function or a group of patients with non-smoking COPD (up to 30% of patients with COPD in recent surveys),5 it is difficult to separate the effects of COPD from those of smoking. Many comorbidities in patients with COPD have been linked to systemic inflammation, possibly as a consequence of overflow of peripheral lung inflammation into the systemic circulation. In a large cohort of patients with COPD, those with persistent systemic inflammation

Published Online January 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(12)70063-2

John Bavosi/Science Photo Library

Chronic obstructive pulmonary disease (COPD) is now generally recognised as one of the most important noncommunicable diseases in the world, and its prevalence is increasing as the global population ages. Although enormous progress has been made in our understanding of the underlying inflammatory mechanisms and clinical phenotypes, there is still a long way to go in the development of drugs that prevent progression of the disease, reduce its mortality and comorbidities, and effectively treat acute exacerbations. For these reasons, interest in COPD research has grown rapidly, as shown by an escalating number of publications, not only in specialist respiratory journals, but also in general medical journals. New journals specifically dedicated to COPD are also emerging. In 2012 alone, more than 3000 articles about the disease were published, which makes selection of the highlights difficult. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has had a huge effect on the diagnosis and management of COPD worldwide and has been used to inform local guidelines. In 2012, its strategy document was revised substantially.1 Previously, the focus had been on the importance of spirometry for the classification of disease severity and the need for treatment, but in the recent revision, a more global assessment of disease effect is recommended, with measurement of symptoms (by validated questionnaires), history of exacerbations, and the presence of comorbidities, in addition to spirometry, required to guide disease management. On the basis of forced expiratory volume in 1 s (FEV1, % predicted), symptom scores, and exacerbation history, patients can be classified into four categories: A, FEV1 greater than 50% predicted and few symptoms or exacerbations; B, similar disease severity with more symptoms; C, FEV1 less than 50% predicted and few symptoms or exacerbations; and D, FEV1 less than 50% predicted with more symptoms and exacerbations. Application of this categorisation to a large general population in Denmark enabled the risk of exacerbations and mortality to be predicted.2 Unexpectedly, patients in category B had a higher mortality rate than did those in category C, despite having a higher FEV1, and poor survival was associated with deaths from cardiovascular disease and lung cancer in particular. Whether this new

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2012 Research Highlights

(measured by six blood biomarkers during 3 years) have a substantially higher mortality rate and exacerbation frequency than patients without such inflammation.6 In the future, anti-inflammatory treatment might be developed to target this systemic inflammation to improve COPD and alleviate its comorbidities. Chronic colonisation of the lower airways with bacteria such as Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis is an important aspect of COPD because it is linked to acute exacerbations and increased disease progression. A recent report showed that multiplex quantitative PCR to amplify bacterial DNA was more sensitive than was routine culture, and that a higher bacterial load in the stable state was related to disease severity and predicted future exacerbations, which were associated with a notable increase in bacterial load.7 16S rRNA gene amplification can be used to detect many species of bacteria in the lower airways of healthy people, and in patients with COPD, which are not isolated by conventional bacterial culture methods. Quantitative PCR shows an increase in total bacterial load during exacerbations, in more severe disease, and in patients treated with inhaled corticosteroids compared with mild stable disease.8 The use of long-term antibiotics, such as macrolides, in management of stable disease is uncertain since, although these antibiotics might reduce bacterial load and exacerbations, they result in the long-term overgrowth of other pathogenic bacteria. Even the use of antibiotics in the management of acute exacerbations of COPD has been questioned because demonstration of clinical benefit has been difficult, perhaps because many exacerbations might be triggered by viral infections. In a placebo-controlled study of amoxicillin and clavulanate to treat acute exacerbations in more than 300 patients with mild-to-moderate COPD, investigators showed a clear benefit in terms of recovery from exacerbations, but importantly also in prolongation of time to the next exacerbation.9 High doses of inhaled corticosteroids are used in many patients with COPD (which contradicts

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the GOLD guidelines’ recommendation1) and this is associated with an increased incidence of pneumonia. A recent population-based study showed that patients with COPD who are treated with inhaled steroids have a roughly 16-fold increased risk of developing nontuberculous mycobacterial lung infections,10 which adds further support to the increasing concern about the use of high-dose inhaled steroids in patients with this disease. Peter J Barnes National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK [email protected] PJB has served on the scientific advisory boards of AstraZeneca, BoehringerIngelheim, Chiesi, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Nycomed/Takeda, Pfizer, Prosonix, Teva, and UCB. He has received research funding from Aquinox Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Chiesi, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Nycomed/Takeda, Pfizer, and Prosonix. He is also a cofounder of RespiVert (now part of Johnson & Johnson), which has discovered novel inhaled anti-inflammatory treatments for COPD. 1

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Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2012; published online Aug 9. DOI:10.1164/rccm.201204-0596PP. Lange P, Marott JL, Vestbo J, et al. Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med 2012; 186: 975–81. Han MK, Muellerova H, Curran-Everett D, et al. GOLD 2011 disease severity classification in COPDGene: a prospective cohort study. Lancet Respir Med 2012; published online Aug 18. http://dx.doi.org/10.1016/S22132600(12)70044-9. Divo M, Cote C, de Torres JP, et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 155–61. Hooper R, Burney P, Vollmer WM, et al. Risk factors for COPD spirometrically defined from the lower limit of normal in the BOLD project. Eur Respir J 2012; 39: 1343–53. Agusti A, Edwards LD, Rennard SI, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One 2012; 7: e37483. Garcha DS, Thurston SJ, Patel AR, et al. Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD. Thorax 2012; 67: 1075–80. Sze MA, Dimitriu PA, Hayashi S, et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1073–80. Llor C, Moragas A, Hernandez S, Bayona C, Miravitlles M. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 716–23. Andrejak C, Nielsen R, Thomsen VO, Duhaut P, Sorensen HT, Thomsen RW. Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax 2012; published online July 10. DOI:10.1136/thoraxjnl-2012-201772.

www.thelancet.com/respiratory Vol 1 March 2013

Chronic obstructive pulmonary disease: important advances.

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