Elsevier

The Lancet

Volume 385, Issue 9979, 2–8 May 2015, Pages 1789-1798
The Lancet

Series
Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management

https://doi.org/10.1016/S0140-6736(15)60693-6Get rights and content

Summary

Chronic obstructive pulmonary disease (COPD) is a common, complex, and heterogeneous disorder that is responsible for substantial and growing morbidity, mortality, and health-care expense worldwide. Of imperative importance to decipher the complexity of COPD is to identify groups of patients with similar clinical characteristics, prognosis, or therapeutic needs, the so-called clinical phenotypes. This strategy is logical for research but might be of little clinical value because clinical phenotypes can overlap in the same patient and the same clinical phenotype could result from different biological mechanisms. With the goal to match assessment with treatment choices, the latest iteration of guidelines from the Global Initiative for Chronic Obstructive Lung Disease reorganised treatment objectives into two categories: to improve symptoms (ie, dyspnoea and health status) and to decrease future risk (as predicted by forced expiratory volume in 1 s level and exacerbations history). This change thus moves treatment closer to individualised medicine with available bronchodilators and anti-inflammatory drugs. Yet, future treatment options are likely to include targeting endotypes that represent subtypes of patients defined by a distinct pathophysiological mechanism. Specific biomarkers of these endotypes would be particularly useful in clinical practice, especially in patients in which clinical phenotype alone is insufficient to identify the underlying endotype. A few series of potential COPD endotypes and biomarkers have been suggested. Empirical knowledge will be gained from proof-of-concept trials in COPD with emerging drugs that target specific inflammatory pathways. In every instance, specific endotype and biomarker efforts will probably be needed for the success of these trials, because the pathways are likely to be operative in only a subset of patients. Network analysis of human diseases offers the possibility to improve understanding of disease pathobiological complexity and to help with the development of new treatment alternatives and, importantly, a reclassification of complex diseases. All these developments should pave the way towards personalised treatment of patients with COPD in the clinic.

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, complex, and heterogeneous condition that is responsible for substantial and growing morbidity, mortality, and health-care expenses worldwide.1 In this context, complexity relates to many different components with non-linear dynamic interactions, whereas heterogeneity implies that not all of these components are present in all patients at any given timepoint or in the same patient at different timepoints.2 To address this complexity and heterogeneity, identification of groups of patients with similar clinical characteristics, prognosis or treatment needs (so-called clinical phenotypes), is imperative.3 On one hand, this strategy is logical for research because it might create an increasingly homogeneous selection of patients in whom to decipher the complexity of COPD. On the other hand, this strategy might be of restricted clinical value because, first, clinical phenotypes can overlap in the same patient and, second, the same clinical phenotype could result from different biological mechanisms (ie, aetiological heterogeneity). Although the development of therapeutic approaches has increasingly attempted to address these complexities, so far most treatment options belong to a restricted number of pharmacological classes—ie, bronchodilators (eg, short-acting beta-2 agonists [SABA] and long-acting beta-2 agonists [LABA]), antimuscarinics (eg, short-acting antimuscarinic agent [SAMA] and long-acting antimuscarinic agent [LAMA]), and inhaled corticosteroids.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) was established in 1998 to improve the diagnosis, management, and prevention of COPD. A challenge for GOLD has since been to provide recommendations for the correct use of the available treatments and at the same time to flexibly position recommendations to allow the use of future innovative treatments that have the potential to target a personalised medicine approach. Another challenge faced by GOLD and other guideline or strategy documents is the paucity of evidence on how clinicians can identify patients who are most likely to benefit from available COPD treatments. This difficulty underlines the need for new treatment approaches in conjunction with refining of the way treatment indications are established. Finally, in most patients COPD is associated with other chronic diseases, a factor that should be addressed globally. This comorbidity might decrease the likelihood that treatments targeting only the COPD component will change the natural history of a patient's disease.

This Series paper addresses the strengths and limitations, including gaps in the evidence, of the approaches taken to move treatment of COPD towards personalised medicine, and also addresses potential future approaches to position emerging treatments that will probably target specific biological pathways. As such, we review the concept of an endotype, a subtype of a clinical disorder defined by a distinct pathophysiological mechanism,4 because it could be associated with future COPD treatments, and also review the role of biomarkers in marking endotypes and directing treatment.

Section snippets

GOLD revolution

The GOLD 20015 and 20066 reports used airflow limitation alone (as assessed by the forced expiratory volume in 1 s [FEV1] value) to assess disease severity. Bronchodilators were recommended as treatments to improve lung function and reduce symptoms in all patients, with inhaled corticosteroids reserved for patients with severe and very severe airflow limitation and repeated exacerbations. In 2011, the GOLD document acknowledged that use of FEV1 alone to assess disease severity was an overly

COPD endotypes

As previously discussed, an endotype4 is a subtype of a clinical disorder defined by a distinct pathophysiological mechanism, whereas a clinical phenotype3 is a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (ie, symptoms, exacerbations, response to treatment, rate of disease progression, or death; figure 2). In the past decade, studies aiming to identify and characterise subpopulations of

Conclusions and future directions

We will gain empiric knowledge from proof-of-concept trials in COPD with emerging drugs that target specific inflammatory pathways (eg, monoclonal antibodies against interleukins 4, 5, 6, 13, 17, and 1β).96 Yet, at least two reasons exist for caution as these clinical trials are approached. First, a given endotype might possibly be relevant for only a small subset of the population with this disease. If so, these trials will have to consider either enrolment of only people who are likely to

Search strategy and selection criteria

For this Series paper, we used several search approaches. We searched the Cochrane Library, Medline, and Embase using the search term “COPD” in combination with “clinical trial”, “effectiveness”, or “systematic review”, for 1 year between Jan 1, 2014 and Feb 28, 2015. For the years preceding this search we used the bibliography cited in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document (GOLD search strategy used COPD, filters “human”, “all adult”, or “items” with

References (107)

  • CE Brightling et al.

    Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study

    Lancet Respir Med

    (2014)
  • M Bafadhel et al.

    Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD

    Chest

    (2011)
  • FJ Martinez et al.

    Procalcitonin-guided antibiotic therapy in COPD exacerbations: closer but not quite there

    Chest

    (2007)
  • O Sibila et al.

    Identification of airway bacterial colonization by an electronic nose in chronic obstructive pulmonary disease

    Respir Med

    (2014)
  • AT Hill et al.

    Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis

    Am J Med

    (2000)
  • BL Barker et al.

    Association between pathogens detected using quantitative polymerase chain reaction with airway inflammation in COPD at stable state and exacerbations

    Chest

    (2015)
  • D Stolz et al.

    Copeptin, C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD

    Chest

    (2007)
  • J Vestbo et al.

    Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary

    Am J Respir Crit Care Med

    (2013)
  • A Agusti

    The path to personalised medicine in COPD

    Thorax

    (2014)
  • MK Han et al.

    Chronic obstructive pulmonary disease phenotypes: the future of COPD

    Am J Respir Crit Care Med

    (2010)
  • Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease NHLBI/WHO workshop

  • Global strategy for diagnosis, management, and prevention of chronic obstructive pulmonary disease

  • A Agusti et al.

    Characterisation of COPD heterogeneity in the ECLIPSE cohort

    Respir Res

    (2010)
  • M Miravitlles et al.

    A new approach to grading and treating COPD based on clinical phenotypes: summary of the Spanish COPD guidelines (GesEPOC)

    Prim Care Respir J

    (2013)
  • V Koblizek et al.

    Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care

    Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

    (2013)
  • DP Tashkin et al.

    Formoterol and tiotropium compared with tiotropium alone for treatment of COPD

    COPD

    (2009)
  • FJ Lin et al.

    Evaluation of changes in guidelines for medication management of stable chronic obstructive pulmonary disease

    J Eval Clin Pract

    (2013)
  • JE Frampton

    QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease

    Drugs

    (2014)
  • C Karner et al.

    Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease

    Cochrane Database Syst Rev

    (2011)
  • JR Hurst et al.

    Susceptibility to exacerbation in chronic obstructive pulmonary disease

    N Engl J Med

    (2010)
  • A Rossi et al.

    INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD

    Eur Respir J

    (2014)
  • IA Yang et al.

    Inhaled corticosteroids for stable chronic obstructive pulmonary disease

    Cochrane Database Syst Rev

    (2012)
  • PS Burge et al.

    Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

    BMJ

    (2000)
  • W Szafranski et al.

    Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease

    Eur Respir J

    (2003)
  • PM Calverley et al.

    Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease

    N Engl J Med

    (2007)
  • NJ Nadeem et al.

    Withdrawal of inhaled corticosteroids in individuals with COPD—a systematic review and comment on trial methodology

    Respir Res

    (2011)
  • H Magnussen et al.

    Withdrawal of inhaled glucocorticoids and exacerbations of COPD

    N Engl J Med

    (2014)
  • H Magnussen et al.

    Inhaled glucocorticoids and COPD exacerbations

    N Engl J Med

    (2015)
  • P van der Valk et al.

    Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study

    Am J Respir Crit Care Med

    (2002)
  • EF Wouters et al.

    Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial

    Thorax

    (2005)
  • EJ Welsh et al.

    Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease

    Cochrane Database Syst Rev

    (2013)
  • SD Aaron et al.

    Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial

    Ann Intern Med

    (2007)
  • JA Wedzicha et al.

    The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide

    Am J Respir Crit Care Med

    (2008)
  • LJ Nannini et al.

    Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease

    Cochrane Database Syst Rev

    (2012)
  • LJ Nannini et al.

    Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease

    Cochrane Database Syst Rev

    (2013)
  • KM Kew et al.

    Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis

    Cochrane Database Syst Rev

    (2014)
  • A Agustí et al.

    Personalized Respiratory Medicine: Exploring the Horizon, Addressing the Issues. Summary of a BRN-AJRCCM Workshop Held in Barcelona on June 12, 2014

    Am J Respir Crit Care Med

    (2015)
  • DP Tashkin et al.

    A 4-year trial of tiotropium in chronic obstructive pulmonary disease

    N Engl J Med

    (2008)
  • JE McDonough et al.

    Small-airway obstruction and emphysema in chronic obstructive pulmonary disease

    N Engl J Med

    (2011)
  • P Chanez et al.

    Corticosteroid reversibility in COPD is related to features of asthma

    Am J Respir Crit Care Med

    (1997)
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