Reviews and feature article
Therapeutic approaches to asthma–chronic obstructive pulmonary disease overlap syndromes

https://doi.org/10.1016/j.jaci.2015.05.052Get rights and content

The recognition that there are some patients with features of asthma and chronic obstructive pulmonary disease (COPD) has highlighted the need to develop more specific treatments for these clinical phenotypes. Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on TH2 cells antagonists. Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen-activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty. Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long-acting β2-agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness.

Section snippets

Treating eosinophilic COPD

The presence of increased eosinophil counts in sputum (>3%) or blood (>400/dL) might predict a clinical response to inhaled corticosteroids (ICSs), and these patients can have increased airway reversibility.4, 5, 6, 7 These patients can have both asthma and COPD (because these are both common diseases), or they might represent a variant of COPD. It is appropriate to treat these patients with bronchodilators and ICSs. However, even high doses of oral corticosteroids might not suppress

Targeting neutrophilic inflammation

Increased airway neutrophils counts are found in patients with COPD, some patients with severe asthma, and smoking asthmatic patients, but it is not clear to what extent this inflammation contributes to disease expression. Neutrophils release reactive oxygen species, proteases, and inflammatory mediators, which might exacerbate the disease and are poorly responsive to corticosteroids. This suggests that reducing neutrophilic inflammation might provide clinical benefit, but this must be balanced

Reversing corticosteroid resistance

Resistance to the anti-inflammatory effects of corticosteroids might be an important factor in determining asthma severity and is a major barrier to effective therapy in patients with severe asthma, smoking asthmatic patients, and patients with COPD. Several molecular mechanisms have now been described to account for corticosteroid resistance in asthmatic patients, including activation of p38 MAPK, JNK and ERK activity, increased expression of an alternatively spliced variant of glucocorticoid

Bronchodilatation

Long-acting inhaled bronchodilators, including long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists/anticholinergics (LAMAs), are the mainstay of treatment in patients with COPD and are equally effective because they reduce air trapping by relaxing airway smooth muscle as a result of reducing the effects of intrinsic cholinergic tone.154 Air trapping increases with exertion (dynamic hyperinflation), leading to exertional dyspnea, which is the major symptom of COPD.155 In

Future directions

The recognition that there are several phenotypes of asthma, COPD, and ACOS suggest that more specific treatments might be beneficial, particularly in patients whose symptoms are not controlled by maximal doses of currently recommended treatments, such as ICSs and bronchodilators. To select appropriate therapy will require biomarkers that are predictive of response to specific therapy. These include blood biomarkers, such as eosinophil counts and levels of plasma periostin and fraction of

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    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

    Supported by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, United Kingdom.

    Disclosure of potential conflict of interest: P. J. Barnes has received research support from GlaxoSmithKline, AstraZeneca, Pfizer, Chiesi, Takeda, Nycomed/Takeda, Novartis, and Aquinox; has received consulting fees or honoraria from AstraZeneca, Chiesi, Novartis, Zambon, and Boehringer Ingelheim; has received fees for participation in review activities from GlaxoSmithKline; is on Scientific Advisory Boards for Boehringer Ingelheim and Pfizer; has consultant arrangements with Glenmark and Sun Pharma; has provided expert testimony on behalf of Boehringer Ingelheim and Teva; and has received payment for lectures from AstraZeneca, Nycomed, Chiesi, Novartis, and Pfizer.

    Terms in boldface and italics are defined in the glossary on page 532.

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