Twenty‐five years of <i>Respirology</i>: Advances in COPD

Over the past 25 years, there has been a tremendous improvement in our understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD) and its prevention, diagnosis and treatment; however, the global burden of COPD remains largely undefeated. One important advancement has been the definition of COPD, which once was defined as an inexorably ‘progressive’ disease, is now considered to be ‘preventable and treatable’,1 reflecting the marked improvements in therapies. Another important advancement has been in disease pathogenesis. On the basis of the classic ‘Fletcher–Peto’ curve, it was widely accepted that individuals developed COPD because of rapid decline in lung function over many years. However, it is now known that lung development plays an equally important role in disease pathogenesis and progression. For most, peak lung function is achieved in early adulthood, after which lung function gradually declines with ageing.2 There is compelling evidence that individuals born preterm or with a very low birthweight, or who experience recurrent or severe lung infection during childhood, never reach their full airway growth potential in adolescence and early adulthood, which significantly increases their risk of COPD in adult life.3 Such individuals will develop COPD later on in life, even though their rate of lung function loss is the same as that of the average person in the community. An important byproduct of this observation is the concept of ‘early COPD’, which refers to the genesis of COPD among individuals younger than 50 years of age who have ≥10 pack-years of smoking history and any of the following abnormalities: (i) early airflow limitation (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <lower limit of normal), (ii) compatible computed tomography (CT) abnormalities and (iii) rapid decline in FEV1 (>60 mL/year). Understanding the molecular drivers of early COPD and identifying these individuals in the community may be important as they may experience ‘exacerbation-like’ events (which may be overlooked or misdiagnosed by clinicians) and harbour modifiable inflammatory responses, which if treated, may prevent irreversible changes in the lung including emphysema, airway attrition, remodelling and fibrosis later on in the disease course. Treatment of early COPD may also prevent morbidity and mortality of COPD including exacerbations, hospitalizations and comorbidities such as lung cancer and cardiovascular diseases. Some areas of active investigation in early COPD include airway inflammation (innate and adaptive immunity), lung dysbiosis, mucous plugging, autoimmunity and respiratory infections. There are also active efforts to develop novel imaging and physiological technologies to accurately diagnose airway disease in susceptible individuals before these are detectable using standard spirometry.2 There has also been significant advancements in the genetics of COPD beyond alpha-1-antitrypsin deficiency. It is now known that approximately one-third of the risk in COPD can be attributed to genetics.4 Large-scale studies such as the Genetic Epidemiology of COPD,4 which is an ongoing cohort of >10 000 subjects, including smokers with a ≥10 pack-year history with and without COPD and healthy never smokers, have revealed over 100 novel loci in the genome that have been linked to COPD and its related phenotypes. Notable ‘hits’ include CHRNA3 (cholinergic receptor nicotinic a3 subunit), HHIP (hedgehog interacting protein) and SFPTD (surfactant protein D). Research is currently underway to determine which of these loci are causal risk factors and elucidate their biological function in the pathogenesis of COPD. Large cohort studies of COPD patients have also revealed important (and novel) phenotypes of COPD. For instance, we now know that women are at a higher risk of COPD and have greater severity of disease including more symptoms and increased rate of exacerbations for the same smoking history as male smokers. On the basis of the quantitative CT parameters, it has been shown that non-Hispanic African-Americans have less emphysema than non-Hispanic whites for the same degree of airway disease. Older COPD patients, those aged >65 years, have worse lung function and lower exercise tolerance and increased likelihood of having comorbidities compared to younger patients. Paradoxically, older age is associated with lower exacerbation rates and better quality of life. Severe COPD exacerbations are associated with accelerated decline in lung function especially among those with less severe airflow obstruction.5 There is increasing interest in using clinical traits, phenotypic information and genetics to identify COPD patients and most importantly predict their outcomes.6 There has also been rapid advancement in thoracic imaging especially in the use of chest CT to phenotype COPD patients. CT are now routinely used to quantify the burden of emphysema (using both lung densitometry for quantitative analysis and qualitative reading by trained radiologists) and small airway disease (by counting airways and functional small airway imaging) in COPD patients. While lungs are poorly visualized by traditional magnetic resonance imaging (MRI) techniques, the advent of hyperpolarized gases including helium or xenon coupled with novel image processing algorithms is now enabling accurate assessment in regional burden of emphysema and small airway disease and vascular remodelling.7 Micro-CT scan, which has resolution as fine as 16 μm (vs 0.6–1 mm for conventional CT images), allows the ex vivo study of the microarchitecture of the small airway and optical coherence tomography, an imaging technique that can generate three-dimensional images with micrometre resolution (two to three orders of magnitude finer than clinical CT and MRI) without ionizing radiation, can potentially evaluate the microstructures of the airway walls in vivo.8 Pharmacological therapies have also rapidly evolved over the past two decades. Whereas in the 1990s, the standard of care was the use of short-acting bronchodilators, clinicians now have a large repertoire of therapeutics to choose from including long-acting bronchodilators alone or in combination, inhaled corticosteroids (ICS) and oral medications. Global Initiative for Chronic Obstructive Lung Disease (GOLD)1 recommends the use of long-acting bronchodilators (long-acting muscarinic antagonists (LAMA) and/or long-acting beta-agonist (LABA)) for most symptomatic patients as the first-line therapy and then to add ICS based on a history of exacerbations (e.g. ≥2/year) or blood eosinophil count (e.g. ≥300 cells/μL). There is general consensus that ICS monotherapy should be avoided in COPD patients. ICS should be used only in combination with a long-acting bronchodilator and even then extremely cautiously as ICS has been associated with significant adverse effects including pneumonia. Research over the past two decades has also shown that ICS can be discontinued safely in patients who are experiencing recurrent pneumonia or not experiencing clear benefits of the anti-inflammatory therapy. However, abrupt discontinuation is discouraged; a gradual de-escalation approach should be used for the withdrawal process. A landmark study has shown that daily low-dose azithromycin reduces the risk of exacerbation by ~25% above and beyond that achieved by inhaler therapies.9 However, the same study also showed that azithromycin therapy was associated with reduced hearing acuity and increased rates of antimicrobial resistance. Roflumilast, an oral phosphodiesterase-4 (PDE-4) inhibitor, reduces rates of exacerbation by ~25% in patients with chronic bronchitic symptoms; however, its use is limited owing to adverse effects including diarrhoea, weight loss and nausea. Proper inhaler technique is essential in optimizing patient outcomes and reducing side effects. However, in real life, most patients struggle with inhalers and commit serious errors. This is especially problematic when patients are asked to use several different inhalers. The availability of dual long-acting bronchodilators (LABA and LAMA) and ICS in one single device has in part addressed this issue. Development of new devices for drug deliveries, such as soft mist inhalers in addition to the conventional pressurized metered dose inhalers and dry powder inhalers, has also allowed more choices for clinicians and patients. Some devices require more dexterity to assemble and some require less inspiratory flow for drug inhalation. There is a growing interest in using biologics that target specific pathways in COPD pathogenesis for exacerbation prevention. For example, mepolizumab and benralizumb, which are monoclonal antibodies that modulate the interleukin-5 pathway and prevent mobilization of eosinophils from blood into tissues, have been evaluated in patients with increased blood eosinophil count. Although the rates of moderate and severe exacerbations were slightly reduced by these biologics, they have yet to receive regulatory approval for their use in ‘eosinophilic’ COPD because of a relatively poor efficacy signal.10 Biologics targeting other pathways are currently in Phase II or III trials. There is strong evidence to support the use of pulmonary rehabilitation as a treatment for both stable COPD patients and patients with recent COPD exacerbations. Pulmonary rehabilitation can improve exercise tolerance, symptoms and health-related quality of life of COPD patients. Supplemental oxygen can help COPD patient during acute exacerbation for treatment of hypoxia. In patients with chronic hypoxia, supplemental oxygen can reduce mortality. It is now known that long-term oxygen therapy is not beneficial for patients with stable COPD with resting or exercise-induced moderate desaturation.11 In patients with acute exacerbation of COPD with hypercapnic acidosis, non-invasive ventilation (NIV) decreases mortality, intubation rate, treatment failure, hospital length of stay and complications related to treatment. Nocturnal NIV may have beneficial effects on long-term clinical outcomes in some patients with COPD. The potential use of high-flow nasal cannulae needs further studies. Interventional therapy for COPD including lung volume reduction by endobronchial valve and lung transplantation may help the more severe patients. Endobronchial valve treatment is best considered for patients with severe emphysema who do not have interlobar collateral ventilation.12 In summary, the past 25 years have taught us that COPD is a heterogeneous condition with multiple phenotypes (which can be evaluated using clinical history, medical imaging and physiological testing), and genetic and molecular drivers (e.g. type 2 ‘eosinophilic’ vs type 1/17 ‘neutrophilic’ endo-phenotypes). While COPD can be a progressive disease, the disease in many patients can be controlled (or at least ameliorated) with treatment which includes long-acting bronchodilators (with or without ICS), smoking cessation, vaccination and pulmonary rehabilitation. Endoscopic and surgical interventions may be beneficial for a small subset of patients, who remain debilitated despite maximal medical therapy and do not have medical or social contraindications for these procedures. The future of COPD is bright. With ongoing advances in the epidemiology and genetics of COPD, novel therapeutic targets for disease modification and exacerbation prevention are in sight. Careful phenotyping of patients with the use of biomarkers will enable precision therapy and will open up a new era for individualized management of COPD, taking us from the current one-size-fits-all approach to management of treatable traits and personalized therapy. Ultimately, the community should strive to eradicate COPD by ‘curing’ it and ‘preventing’ it. The best target for this ambitious vision is to identify those with ‘early’ COPD and intervene with highly effective therapies. With current efforts underway in biomarker development and highly sensitive and safe in vivo imaging techniques, COPD may in the near future be ‘preventable, treatable and curable’. F.W.S.K. has no conflict of interest for disclosure in relation to this manuscript. D.D.S. has received honoraria for speaking engagements from AstraZeneca (AZ) and Boehringer Ingelheim (BI), and received research funding from AZ, BI and Merck for COPD-related projects.

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