Contemporary Concise Review 2019: Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major health burden throughout the world.1 The burden is disproportionately higher in Asia (than elsewhere) where ~2 million individuals die each of year from this disease, representing two-thirds of all COPD deaths around the world.2 Owing largely to population growth and ageing, this number is expected to grow to 3 million deaths/year by the year 2040.2 Most of the morbidity and mortality among COPD patients occur during acute exacerbations, which are characterized by abrupt worsening of patient symptoms (most typically dyspnoea and cough) and reduction in lung function beyond the normal day-to-day variations in these parameters.1 Although most of these exacerbations are treated symptomatically in an outpatient setting with bronchodilators, oral corticosteroids and/or antibiotics, some patients require urgent attention in emergency departments.1 Despite their importance, COPD exacerbations, especially those requiring hospitalizations, have not been well characterized. Several published studies in 2019 have provided some important insights into COPD exacerbations. For instance, Sprooten et al., in a contemporary cohort of patients hospitalized with COPD, showed that despite the progress in the management of COPD exacerbations over the past 30 years, severe COPD exacerbations remain highly lethal with 1 in 10 patients dying in hospital from complications related to their exacerbation (and 16% dying within 90 days of hospitalization) and 1 in 3 patients requiring mechanical ventilation for hypercapnic respiratory failure.3 Importantly, the investigators found that these adverse events could be accurately predicted by measuring the patient's arterial carbon dioxide tension (PaCO2) at the time of hospital admission. Mortality (from ventilatory failure) could be avoided (with modern treatment) when patients' PaCO2 was less than 60 mm Hg, whereas mortality was extremely high when patients' PaCO2 was 70 mm Hg or greater. One under-appreciated clinical feature of COPD is reduced mobility. Cordova-Rivera et al. applied wearable accelerometer on 67 patients with moderate COPD (mean forced expiratory volume of 1 s (FEV1) of 56% and mean age of 70 years) and found that on average patients walked 2858 steps/day.4 In contrast, control subjects (i.e. those without COPD) walked 7640 steps/day. Interestingly, steps walked per day was significantly related to the subjects' 6-min walk distance, explaining 52% of its total variance (P < 0.001). Patients' mobility is further reduced during exacerbations. Orme et al. showed that patients, who were hospitalized for an acute COPD exacerbation, walked, on average, only ~600 steps/day,5 which did not improve over the course of their hospitalization despite improvements in their clinical condition. Together, these data highlight the pressing need to develop and implement interventions to encourage mobility and enhance physical activity of COPD patients especially during exacerbations. Another important complication of acute exacerbations are cardiovascular events, which are defined as acute myocardial infarction, stroke or cardiovascular deaths. Using the Danish nationwide health registries, Reilev et al. showed that during acute exacerbations, COPD patients have a fourfold increase in the risk of cardiovascular mortality, and a threefold increase in acute myocardial infarction and stroke.6 These cardiovascular risks increased to nearly sixfold during severe exacerbations requiring hospitalizations. Although the exact mechanisms linking cardiovascular events with acute COPD exacerbations remain elusive, animal and human experimental studies have implicated widespread neutrophilic inflammation related to viral or bacterial infections in the lungs as well as in coronaries and carotid arteries as a possible culprit.7, 8 Regardless of the pathways involved, careful cardiovascular assessment is required during acute COPD exacerbations to ensure that these cardiovascular complications are diagnosed promptly and treated with appropriate therapies. Given the high prevalence of cardiovascular complications during acute COPD exacerbations, cardiopulmonary imaging may be helpful in the assessment of COPD patients during major 'lung attacks'. To address this need, Leong et al. developed a novel computerized tomography (CT) protocol that enables visualization of lungs (for the analysis of significant pulmonary pathology including pneumonic infiltrates, emphysema and masses), coronary arteries (for the analysis of calcification and plaques), heart (for the estimation of cardiac function and detection of valvular diseases) and pulmonary arteries (for the detection of thromboembolism and measurement of pulmonary artery size) on the same scan.9 Once fully implemented, this protocol will allow an 'all-in-one' approach to cardiopulmonary imaging during acute exacerbations and enable identification of 'treatable' pulmonary and cardiovascular traits, which when modified will lead to improved health outcomes of COPD patients. It is well accepted from clinical and epidemiological studies that a majority of acute exacerbations are triggered by a viral respiratory tract infection. These 'macro' exacerbations generally last several weeks, leading to intensification of treatment and urgent visits to physicians and clinics. COPD patients may also experience 'micro' exacerbations, which may last for a few hours or days. Although these events tend to be less severe in intensity than the macro-events, they nonetheless may lead to significant impairments in physical activity and exercise tolerance and reductions in patients' quality of life. Because patients do not regularly seek medical care during these micro-attacks, little is known about these events. To address this important gap in knowledge, Werchan et al. developed and validated a short questionnaire, which captures the triggers of both micro- and macro-events.10 The results of their study were interesting. Although, as expected, respiratory tract infections were the most important triggers for emergency admissions and urgent clinic visits (i.e. macro-events), patients endorsed changes in weather/climate as more important (and more frequent) determinants of 'micro-events' (leading to reduced health status). They also cited psychological factors such as depression and anxiety as very important triggers of both micro- and macro-exacerbation events. Further research will be needed to determine how these non-infectious factors contribute to exacerbations and whether they are 'treatable traits' (more on this later). One of the most important therapeutic developments in the treatment of acute COPD exacerbation has been the advent of non-invasive mechanical ventilation (NIMV). In those with hypercapnic respiratory failure, the use of NIMV during acute exacerbations reduces the risk of endotracheal intubation and mortality by 40–60%.11 However, as noted by van der Leest et al., its overall impact is reduced because many patients cannot tolerate the device during acute exacerbations.12 To increase tolerance, the expiratory positive airway pressure (EPAP) component of NIMV should be initially set to a relatively low pressure (3–6 cm H2O), ensuring that it is higher than the patients' intrinsic end-expiratory pressure (i.e. auto-positive end-expiratory pressure). This should be accompanied by a modestly high inspiratory positive airway pressure (IPAP) of 12–18 cm H2O to promote ventilation. Once patients acclimate, the IPAP can be gradually increased (in 2 cm H2O pressure increments) until the patient becomes eucapnic or reaches the maximal pressure tolerated, whichever comes first. A more novel approach may be using nasal high-flow therapy, which delivers humidified air (with or without supplemental oxygen) and is much better tolerated compared with NIMV.13 McKinstry et al. performed a randomized cross-over trial to compare the efficacy of nasal high-flow therapy against NIMV in stable hypercapnic COPD patients and showed that nasal high-flow therapy was able to reduce patients' PaCO2; however, overall, it was less effective than NIMV in reducing PCO2 (by ~3 mm Hg).13 As expected, nasal high-flow therapy was much better tolerated than NIMV. Although this study was not powered on clinical endpoints and did not evaluate patients who were acutely exacerbating, these data nonetheless provide optimism that high-flow therapy may be useful in some patients with hypercapnic respiratory failure, who are unable to tolerate NIMV. In addition to acute exacerbations, NIMV can be used in stable patients with chronic respiratory failure. Unlike a 'pill', NIMV protocols require individualization, typically in a laboratory for several nights under observation using polysomnography. Titration of NIMV pressures is by 'trial-and-error' and thus it is time-consuming and resource-intensive. Orr et al. evaluated the use of automated EPAP (auto-EPAP) and found that the two methods (auto-EPAP vs manual EPAP) were largely equivalent (or non-inferior to each other).14 With these 'smart' NIMV, the need for in-hospital NIMV titration may be significantly reduced. NIMV is highly effective in reducing rehospitalization rates in patients with severe COPD and persistent hypercapnia (PaCO2 >45 mm Hg). As highlighted by Suh et al., the use of high-intensity NIMV during the first 30 days post-hospital discharge reduces the risk of readmission by over 70%.15 However, it should be noted that the target IPAP is ~24 cm H2O and EPAP is ~4 cm H2O for these patients and with the explicit goal of reducing daytime PaCO2 by on average 20%. Low-dose NIMV is generally not effective in reducing adverse outcomes. Although NIMV is traditionally used to treat hypercapnic respiratory failure, a study by Gloeckl et al. suggests that it may have a useful indication during pulmonary rehabilitation. There is widespread consensus that pulmonary rehabilitation imparts clinical benefits for COPD patients; however, as noted by Holland, only ~1% of eligible COPD patients participate.16 Patients with severe COPD with elevated PaCO2 are generally excluded from participation in pulmonary rehabilitation owing to severe breathlessness and concerns about worsening hypercapnic respiratory failure during exercise. The study by Gloeckl et al. provides new hope for these patients.17 Using a randomized cross-over trial design, these investigators found that the use of NIMV in these COPD patients with stable hypercapnic respiratory failure led to a 39% increase in endurance time on a cycle ergometer than oxygen therapy alone with lower arterial PaCO2 and better oxygenation. On the other hand, as noted by Prieur et al., nasal high-flow therapy (at 60 L/min) did not improve exercise endurance during a high-intensity exercise test, although it had a slight salutary effect on arterial PCO2.18 Thus, NIMV but not nasal high-flow therapy can be recommended for patients with persistent hypercapnia during pulmonary rehabilitation. Over the past 20 years, there has been a tremendous progress in COPD management. However, as pointed out by Rhee et al., most of these recommendations have been generated from data arising from North America and Western Europe; thus, these data may not be fully applicable to the Asian populations.19 For instance, bronchiectasis and post-tuberculous lung diseases are common in Asia (especially southeast Asia) and thus many Asian COPD patients may also have these conditions. The presence of these pulmonary comorbidities may impact therapeutic choices as inhaled corticosteroids may increase the risk of pneumonia and reactivation of tuberculosis. Another notable feature of COPD patients in Asia is that low body mass index (BMI) is highly prevalent. Reduced BMI is a risk factor for poor outcomes in COPD including rapid lung function decline and increased risk of mortality.20 There is a pressing need to better understand COPD phenotypes in Asia and identify therapeutics that fully align with these phenotypes. In 2019, Mendy et al. reported an intriguing observation regarding the potential benefits of metformin in the treatment of diabetics with COPD.21 Metformin lowers blood glucose by increasing insulin sensitivity and inhibiting gluconeogenesis in the liver.22 Although the primary cellular target of metformin is complex I of mitochondria, which ultimately leads to the activation of AMP kinase, its molecular actions are pleiotropic including inhibition of inflammation (by suppressing monocyte differentiation into macrophages and decreasing circulating levels of pro-inflammatory cytokines), reduction of lipogenesis and alterations in the gut microbiome.22 Using data from the United States National Health and Nutrition Examination Survey (NHANES), Mendy et al. showed that the self-reported use of metformin was associated with a 70% reduction in the risk of respiratory mortality among those who also had chronic respiratory lung disease at the start of the survey. If these data can be recapitulated in high-quality randomized controlled trials, metformin may represent a novel therapeutic class of drugs to reduce morbidity and mortality of COPD patients. In the meantime, patients with COPD should be treated with bronchodilators and possibly inhaled corticosteroids, for those who are frequent exacerbators and have an elevated blood eosinophil count, defined as >300 cells/μL or have concomitant asthma.23 For those with resting hypoxaemia, supplemental (domiciliary) oxygen should be provided. However, this therapy is expensive. To reduce costs and make the therapy more efficient, some have advocated for oxygen to be delivered using a demand-activated device, which releases oxygen to patients during the inspiratory but not the expiratory breath cycle. Gloeckl et al. performed a systematic review and meta-analysis and found that demand-activated systems were non-inferior to continuous oxygen therapy in terms of their effects on patient's oxyhaemoglobin saturation or exercise performance.24 It should be noted that the overall quality of the clinical trials was low to intermediate grades. Nevertheless, the totality of evidence suggests that in most cases these devices can be used in lieu of conventional continuous oxygen delivery. It should be noted that supplemental domiciliary oxygen therapy is generally not indicated in patients with mild or borderline hypoxaemia (peripheral capillary oxygen saturation: 89–93% on room air at rest). However, data by Uemasu et al. indicate that these patients have about a 10% risk of developing hypoxaemic respiratory failure over ~5–6 years.25 The most powerful predictor of this event is a drop in PaO2 of 3 mm Hg or greater/year, which increases the risk by over 12-fold. Thus, although most patients with mild hypoxaemia do not require supplemental oxygenation, they should be followed up yearly with repeat testing for those whose PaO2 declines by 3 mm Hg or greater/year. Although patients commonly complain of chronic unproductive (dry) cough, it is rarely measured in clinical practice owing to a paucity of easily implementable questionnaires at the bedside that can accurately capture this symptom and because there is a lack of effective therapies for this trait. To address this gap in care, Koo et al. developed and validated a short survey (containing only five questions) to measure the frequency and the impact of cough in patients' daily life using a 5-point Likert scale.26 This instrument, once clinically validated (including determination of a minimal clinically important difference in score), will have utility in a wide range of settings including at the bedside, in therapeutic trials as well as epidemiological and clinical studies of COPD patients. Although medical schools have traditionally taught students that the airways below the vocal cords were sterile, with the advent of modern molecular techniques, it is now well established that human lungs have a rich microbiome, which becomes perturbed with smoking and in diseases such as COPD.27 In 2019, Taylor et al. provided a state-of-the-art review, describing the methods, the potential application and limitations of current molecular techniques to interrogate the lower airway microbiome in COPD.28 Although the airway microbiome may have a broad-ranging impact in COPD patients, clinical translation of these techniques is closest in the setting of acute exacerbations where airway microbiome research has unveiled sputum microbial markers of mortality following hospitalizations.29 In one study, the presence of Staphylococcus species (which are pathogens in airways) and the absence of Veillonella species, which are normal commensals in the airways, were associated with a >10-fold increase in the risk of 1-year mortality.29 In the near future, the airway microbiome may become a treatable trait in COPD. Another important pathogen in the airways is Pseudomonas aeruginosa, whose presence in patients' sputum has been associated with poor health outcomes including increased risk of hospitalization among COPD patients.30 Crowded hospitals often co-localize patients with Pseudomonas colonization/infection with non-infected patients. This may increase the risk of nosocomial transmission of this bacteria to susceptible COPD patients. Stockwell et al. addressed this concern by evaluating sputum and cough aerosols generated by patients with a history of pseudomonal lung infection and determined the frequency of Pseudomonas in these media. They found that only one in three patients released Pseudomonas in cough aerosols (and in small quantities) and these organisms were viable for less than 15 min and propagated to a distance of 0–4 m from the source patient.31 These data provide some assurance that patient-to-patient transmission of Pseudomonas is unlikely in hospitals, except in rare cases where patients may be in very close proximity to infected patients, who are actively coughing. Although the traditional method of modulating the microbiome is by using antibiotics. In the future, it may be possible to coax phagocytes (e.g. macrophages) to attack the 'bad' microbes, while promoting the growth of 'good' bacteria. Another method may involve modulation of production of reactive oxygen species in phagasomes. Efforts are underway to limit tissue damage from reactive oxygen species, while maintaining host's ability to fight off microbial infection. This will likely require development of highly specific compounds that target mediators involved in this process.32 Another emerging area of COPD research is genetics. Hall et al. provided a comprehensive overview of the most salient findings from large-scale genome-wide association (GWA) studies in COPD over the past decade.33 These GWA studies have been largely powered on two phenotypes: (i) lung function parameters (and most notably FEV1 or FEV1/forced vital capacity (FVC) ratio) and (ii) a clinical diagnosis of COPD. Although there is significant overlap of genome-wide 'hits' between these two phenotypes, there are genetic loci that are distinct for each. For instance, polymorphisms in the nicotinic receptor (which may be responsible for nicotine addiction) have been implicated in the 'COPD' phenotype but not with the lung function parameters. These data are consistent with the emerging concept of 'multiple pathways' to COPD pathogenesis, which includes poor lung development (which may preferentially impact lung function measures) and rapid decline in lung function related to smoking (which may preferentially impact the risk of COPD).34 With novel molecular techniques, the biology of these implicated genes will be elucidated in the near future, which will lead to new therapeutic approaches for patients with COPD. Until then, McDonald and Gibson have advocated a treatable traits approach for the therapeutic management of COPD patients.35 This approach marries clinical traits (e.g. airflow limitation) with treatments that target these traits (e.g. bronchodilators to treat airflow limitation). Some of the treatable traits in COPD include airflow limitation, eosinophilic airway inflammation, cachexia, reduced mobility and smoking. Although this theory is intuitively appealing, future studies are needed to validate whether this diagnostic 'label-free' approach improves health outcomes of patients with COPD. Recent 'negative' clinical trials of biologics that inhibit the interleukin-5 pathway (and thus block airway eosinophilia in COPD) suggest that this approach is likely overly simplistic (in its current form) and will most likely require some refinement before it can be adopted into clinical practice.36, 37 In 2019, we have gained tremendous new insights on the pathophysiology of COPD, its treatments and phenotypes. Nevertheless, the overall burden of COPD is on the rise in Asia and many other parts of the world. Although COPD therapeutics have improved markedly over the past three decades, there is an urgent need to develop more effective therapies to prevent exacerbations and treat them when patients 'breakthrough'. Also, as highlighted by several papers in 2019, there is also a pressing need to enhance mobility and prevent cachexia and frailty of COPD, which is a source of morbidity and mortality in COPD. D.D.S. has received honoraria for speaking engagements from AstraZeneca and Boehringer Ingelheim, and funding for research projects from AstraZeneca, Boehringer Ingelheim and Merck.

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