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

Abstract

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.

Figure 1

Considering the benefit-risk balance and its individual determinants when personalizing COPD treatment choices. When deciding which pharmacological treatment option the clinician will prescribe to a given patient, he/she has to consider (i) expected benefits (left), which are determined by individual presentation and underlying mechanisms and (ii) possible risks (right), which depend on individual risk factors and comorbidities.

Figure 2

Diagram depicting the inter-relationships (small arrows) between the ‘exposome’ (a term that describes the “totality of human environmental exposures, from conception onwards” (102)), the genetic background of the individual (Genome), the Endotype (biological networks that enable and restrict reactions) and the final clinical expression of the disease (Clinical Phenotype). Large arrows indicate different therapeutic strategies. For further explanation, see text.

Figure 3

Our current understanding of potential endotypes of COPD. Depicted are the relationships between inflammation, cellular changes, structural changes and physiological dysfunction in COPD, and the role that chronic infection can play in perpetuating inflammation. Superimposed are potential endotypes of COPD (in red text) that relate to subtypes of inflammation, the presence of colonization with pathogenic bacteria and the absence of a mechanism protective against extracellular matrix destruction (alpha-1 antitrypsin deficiency).