Association of β-blocker use with survival and pulmonary function in patients with chronic obstructive pulmonary and cardiovascular disease: a systematic review and meta-analysis

No More Equivalence Trials for Antibiotics in Exacerbations of COPD, Please

Is It the Heart or the Lung? Sometimes It Is Both.

Management of chronic obstructive pulmonary disease: Moving beyond the asthma algorithm

A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD

Introduction

Antibiotics for treatment and prevention of exacerbations of chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) continue to have considerable impact on disease burden and mortality worldwide. Early diagnosis still remains a challenge, with low uptake of spirometry in many countries. Implementing best practice management for airways disease is a critical goal for health-care systems—the management now includes pharmacological and non-pharmacological approaches to the lung disease, as well as recognition and treatment of comorbidities. Finally, the pathogenesis of airways disease continues to be fertile field of investigation, in order to better prevent disease, slow progression and identify relevant biomarkers. A large number of studies published in Respirology in 2012 have addressed all of these important clinical and scientific issues, and made major contributions to advance this field and hopefully improve outcomes for patients with asthma and COPD. Despite years of research, the origins of asthma remain obscure. Although there is clearly a genetic disposition to developing asthma, gene-association studies have so far failed to reveal clear insights into the development of asthma (reviewed in Respirology in 20111), indicating that asthma is likely to result from a complex interaction between genes and environment. Moreover, marked changes in the prevalence of asthma in recent decades indicate that changing environmental exposures must be to blame. Air pollution is known to exacerbate asthma symptoms and has been one of the factors suspected of causing the disease in the first place. Gowers et al. reviewed the association between air pollution and asthma for the Department of Health in the United Kingdom.2 In fact, they found little evidence for an association between pollution and asthma prevalence. If anything, time trends indicated a negative rather than positive association, but there is some evidence for an increased incidence of asthma in people living very close to roads carrying heavy traffic. The overall impact of this traffic pollution on asthma incidence is not likely to be large. Air pollution of different kind was studied by Havstad et al. who studied the impact of early-life exposure to environmental tobacco smoke on the development of atopy by 2–3 years in a cohort of children.3 Using propensity score matching, they found that tobacco smoke exposure increased the risk of positive skin prick or specific immunoglobulin E (IgE) tests in children whose mothers were not atopic, but paradoxically decreased the risk in those with a positive history of maternal atopy. This interaction between maternal atopy and the effect of environmental tobacco smoke on children's risk for atopy may help to explain some of the conflicting data from previous studies. An accompanying editorial emphasizes that exposing children to tobacco smoke should of course be avoided because of the many other adverse effects,4 but the paper, like that of Gowers et al.,2 demonstrates the need to better understand how genes and environment interact to cause atopy. Other changes in lifestyle and exposures may also help to explain increases in asthma prevalence. The well-recognized association between asthma and obesity was reviewed in Respirology and the mechanism for the association continues to elude researchers.5 Changing dietary exposures could be part of the explanation. A novel association between soft drink consumption, tobacco smoking and airway disease was reported by Shi et al.6 In a large cross-sectional telephone survey of Australian adults, consumption of more than half a litre a day of soft drinks was associated with both asthma and COPD. The association was only apparent among smokers in whom soft drinks and smoking appeared to have additive effects. If these findings are confirmed in other studies, they suggest a lifestyle intervention to prevent airways disease. One of the problems in identifying the origins of asthma is that clinical asthma comprises a number of distinct phenotypes. It has recently been proposed that these phenotypes represent truly different diseases with different causes (also called ‘endotypes’) rather than simply being different and variable expressions of the same underlying pathology.7 Defining asthma phenotypes on the basis of the cellular profile of induced sputum has become increasingly important as studies indicate that eosinophilic airway inflammation responds better to corticosteroid treatment than neutrophilic inflammation.8 Phenotypes are increasingly used to target novel asthma treatments, such as the anti-interleukin (IL)-5 monoclonal antibody targeted to eosinophilic asthma.9 Specific treatments for non-eosinophilic asthma have not been established however. Choi et al. studied sputum inflammatory profiles in patients with refractory asthma requiring high-dose corticosteroid therapy selected from a large asthma cohort.10 Those with persistent airway obstruction had a longer duration of asthma and had predominantly neutrophilic inflammation, whereas refractory asthma without persistent airway obstruction was more likely to be eosinophilic. The authors suggest that this provides a rationale for developing new medications for individualized treatment in these patients. However, two studies in Respirology show that eosinophilic airway inflammation varies over time even in the absence of corticosteroid treatment. Hancox et al. found that the eosinophilic/non-eosinophilic classification was not stable over time in two clinical asthma treatment trails: even though the sputum phenotype was determined at a time when the patients were not taking any steroid treatment, nearly all patients with ‘non-eosinophilic asthma’ had raised sputum eosinophils at some point.11 Similarly, the study of Bacci et al. (discussed in the Airway Biology section) provided evidence that inflammatory phenotypes based on sputum cell analysis are not stable over time.12 Another report last year found that sputum phenotypes are not stable in children either.13 Hence, characterization of asthma and long-term treatment decisions should not be based on a single sputum specimen.14 Induced sputum analysis remains valuable for assessing patients with difficult asthma, but the resources required to obtain and analyse frequent sample will inhibit its widespread use. Although not yet established in the management of asthma, measuring of exhaled nitric oxide (eNO) offers a more practical way to monitor airway inflammation than monitoring of induced sputum.15 Affordable handheld electrochemical nitric oxide analysers are now available, making this a realistic possibility for many services. Kim et al. compared eNO measurements using the handheld Niox Mino (Aerocrine AB, Solna, Sweden) electrochemical analyser with a Sievers (GE Analytical Instruments, Boulder, CO, USA) chemiluminesence analyser.16 Correlation between the two machines was good (r = 0.88), but agreement in absolute values was only moderate: the Mino tended to give about 15% lower readings. The handheld machines are convenient but differences between machines need to be taken into account when interpreting eNO values. Although measuring airway inflammation is appealing, more simple clinical assessments remain the mainstay of asthma management. Ko et al. found that a single measurement of the Asthma Control Test—a score based on a simple 5-item questionnaire—correlated with asthma control assessments by physicians and predicted exacerbations and emergency health-care use over the following 6 months in a cohort of patients attending tertiary care in Hong Kong.17 The baseline Asthma Control Test score was better at predicting exacerbations than lung function, peak flow or eNO measurements. Simple management of asthma was also supported by a large randomized control trial comparing adjustment of inhaled steroid doses using eNO, clinical physician guidance and patient symptom-based adjustment using inhaled corticosteroids (ICS) each time they required β-agonist. No difference was found between the strategies, with the trends favouring patient symptom-led adjustment.9 Improvements in computed tomography (CT) scanning technology and lower radiation doses have enabled the use of high-resolution scans to study airway structure and differentiate between diseases, sites of inflammation and treatment response without the need for tissue biopsies.18 Kurashima et al. found that airway lumens were smaller in the 3rd- to 6th-generation bronchi in asthma but not COPD, whereas both diseases demonstrated airway wall thickening.19 These small airway diameters correlated with lung function in asthma not COPD. Hoshino and Ohtawa used high-resolution CT scans to assess changes in large airway remodelling before and after 24 weeks treatment with combination long-acting β-agonist (LABA) and ICS or ICS alone in a double-blind randomized controlled trial.20 Combination therapy reduced airway wall thickness and increased the airway luminal area to a greater extent than ICS alone. The improvements in airway wall thickness in the combination group correlated with reductions in sputum eosinophils and improvements in forced expiratory volume in 1 s (FEV1). The mechanisms for this positive interaction between ICS and LABA are not known, but the findings offer hope that airway remodelling can effectively treated and/or prevented by combination therapy. An accompanying editorial by King and Farah emphasizes the need for confirmatory and long-term studies as well as investigations of the effects on smaller airways that remain beyond the resolution of the scans.21 The findings of Hoshino and Ohtawa of a positive interaction between LABA and ICS on remodelling is relevant to the current concerns over the safety of LABA in asthma.20 Among the most controversial issues this year is the American Food and Drug Administration requirement that the manufacturers of LABA undertake large safety studies of the combination on LABA with ICS. It is accepted that using LABA without ICS is not acceptable in asthma, but it has been suggested that these large safety studies of combination therapy are futile because they will not be powered to address the question of whether they cause a small excess of asthma deaths.22 In the meantime, a recent meta-analysis demonstrates that withdrawing LABA once asthma control has been achieved, as currently recommended by the Food and Drug Administration, leads to a deterioration in control.23 Cough-variant asthma is another well-recognized but poorly understood phenotype. Ohkura et al. compared coughing during methacholine-induced bronchoconstriction in patients with cough-variant asthma (but normal cough sensitivity to capsaicin challenge) and normal controls.24 Patients with cough-variant asthma had increased cough during even mild methacholine-induced bronchoconstriction. After treatment with inhaled steroids, the number of coughs diminished to be similar to normal controls, indicating that increased cough sensitivity to bronchoconstriction is a feature of this disease variant, but that it responds to anti-inflammatory treatment. For non-asthmatic refractory chronic cough, an exciting discovery this year was that gabapentin is an effective treatment in a double-blind randomized controlled trial.25 Gabapentin is an anticonvulsant that is also used to treat neuropathic pain, suggesting that its effect on chronic cough may be due to suppression of central cough reflexes. The paradigm of Th1- versus Th2-mediated inflammation would suggest that asthma (predominantly a Th2 disease) would be less uncommon in sarcoidosis—regarded as a Th1 disorder. However, Wilsher et al. found that the prevalence of positive specific IgE tests for common aeroallergens (34%) and a history of asthma (21.5%) were similar in patients with sarcoidosis to that reported in the general population.26 In another study from the same group, Young et al. found that 44% of patients with sarcoidosis had airway hyperresponsiveness to histamine (a direct airway challenge), whereas only 11% were hyperresponsive to an indirect challenge using hypertonic saline.27 Hyperresponsiveness to histamine was more common in those with lower baseline FEV1 values and those with fibrotic and reticular patterns on lung CT. The findings suggest that the high prevalence of histamine responsiveness in patients with sarcoidosis is likely to be distinct from asthma (because of the low prevalence of hypertonic saline responsiveness) and is more likely to be due to airway remodelling caused by granulomatous airway inflammation. The development of COPD is related to both genetic and environmental factors. For genetic factors, a recent study by Guan et al. from China found that D2S388-5 microsatellite polymorphism located upstream of the surface lung surfactant protein B gene on chromosome 2 may be associated with susceptibility to COPD in Xinjiang Kazakhs.28 Another genetic factor, nucleotide-binding and oligomerization domain (NOD) 2 genes polymorphism, has also been found to have some potential association with COPD in a study from Japan. The distribution of NOD2 rs1077861 genotypes differed between COPD patients and non-COPD smokers and was associated with a lower FEV1 % predicted value in the TT when compared with the TA/AA genotypes.29 For environmental factors, exposure to noxious particles or gases is associated with the development of COPD.30 A study from Johannessen et al. found that exposure to environmental tobacco smoking during childhood was associated with COPD and respiratory symptoms in adulthood mainly in women in a cross-sectional study in Norway. In men, the most important risk factor is still acting smoking.31 The relationship of air pollution and COPD is reviewed by Ko and Hui.32 Outdoor air pollution (such as ambient air pollution) and indoor pollution (such as second-hand smoking and biomass fuel combustion exposure) are associated with the development of COPD and outdoor air pollution is a significant environmental trigger for acute exacerbation of COPD. Zeng et al. reviewed the aetiology of COPD in non-smoking subjects and risk factors may include genetic factors, long-standing asthma, outdoor air pollution, environmental smoke exposure, biomass smoke, occupational exposure, diet, recurrent respiratory infection in early childhood and tuberculosis.33 Interestingly, statins34 and even soft drink consumption6 have been found to have association with COPD. A cross-sectional study from Japan found that the prevalence of airflow limitation among patients who used statins was approximately five times lower than that among patients who did not use statins. However, statin use was not significantly associated with a lower prevalence of airflow limitation in multivariate analysis.34 Statins thus cannot be advocated for prevention of airflow obstruction at this stage. A study from South Australia assessed the relationship between soft drink consumption and presence of asthma/COPD in over 16 000 subjects.6 and noted the odds ratio for having COPD was 1.79 (95% confidence interval: 1.32–2.43) in multivariate analysis by comparing those who consumed more than half a litre of soft drink per day with those who did not consume soft drinks. The reason behind these associations is unclear and a causative relationship cannot be drawn from these studies. Comorbidities are common in COPD patients and the latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline has also emphasized that comorbid illness in COPD patients should be managed appropriately.30 The link between COPD and coronary artery disease is strong and complex. Coronary artery disease has a strong effect on the severity and prognosis of COPD and vice versa, including acute exacerbations.35 Ito and colleagues found that depression and sleep disorders were both common in patients with COPD.36 McSharry et al. found that sleep quality is poor in severe COPD patients with reduced sleep efficiency and reduced percentage of rapid eye movement sleep. There was a significant association between daytime hypoxaemia and sleep efficiency.37 However, depression, but not sleep disorder, is an independent risk factor for exacerbations and hospitalizations among COPD patients.36 The economic burden of COPD is huge and a recent study from Singapore showed that in 2009, COPD admissions represented 3.4% of all hospital discharges. Hospitalization was found to be the major cost driver, accounting for 73% of the total COPD burden, Between 2005 and 2009, attendances at primary care clinics, emergency departments and specialist clinics accounted for 3%, 5% and 17% of overall COPD costs, respectively.38 There are some new developments in the assessment of COPD using tools like CT and exercise tests. Degree of hyperinflation39 and airway dimensions18, 19 in COPD patients can be measured using CT parameters. Tanabe and colleagues applied a novel CT index to assess lung volume. This DLV% index measures the ratio of lung volume region adjacent to the diaphragm dome (D) to total lung volume (LV). Using this index, it was found that a reduced lung volume around the diaphragm correlated with lung hyperinflation and health-related quality of life, independent of emphysema severity.39 A recent study by Galban et al. adapted the parametric response map, a voxel-wise image analysis technique, for assessing COPD phenotype. In their study, whole-lung CT scans acquired at inspiration and expiration of COPD patients were analysed. Parametric response map identified the extent of functional small airways disease and emphysema as well as provided CT-based evidence that supports the concept that functional small airways disease precedes emphysema with increasing COPD severity.40 Phenotyping COPD by image biomarkers is currently under investigation and offers potential development of personalized therapy for COPD patients. There are also different field and laboratory tests for measuring exercise capacity in COPD patients. Hill and colleagues compared the 6-min walk test, incremental shuttle walk test and endurance shuttle walk test with a ramp cycle ergometer test in a group of patients with moderate COPD and found that these tests all elicited a similar peak rate of oxygen uptake and heart rate response. This suggested that that both self- and externally paced field tests can progress to high intensities.41 Field tests can probably offer a reasonable alternative for the evaluation of patients with moderate COPD.42 The revised was published in were indicated as the or in the treatment of all of patients with COPD. A new of and long-acting have as the most effective for control in patients with COPD. et al. reported the of one such when compared with in patients from 6 for found that provided significant and improvements in and in COPD with that reported in other from clinical indicate that may prevent acute exacerbations of However, the underlying mechanism for this effect is et al. showed that treatment in patients with COPD the and of both and by and This a effect of the in by the of and by the airway The long-term safety of this and its in to other treatment need evaluation before it a acute exacerbation of it is difficult for physicians to differentiate COPD from heart common and comorbidities. and colleagues the of for the diagnosis of in patients with severe acute exacerbations of COPD and in 2 care found that the was more in patients with normal function sensitivity and than those in and required adjustment of the to a et al. in a trial of patients with acute COPD and from heart compared treatment with versus reported more rapid in with the combination treatment but difference in This is a to the and treatment of heart during apparent COPD and sleep disorders are common and important in severe Ito et al. in a study of COPD patients and normal that only depression but not sleep disorders is associated with the increased risk of exacerbations and The management of and depression was the of a by and colleagues in they treatment with the of clinical on this important of COPD with sputum to exacerbations and poor quality of in patients with COPD. In a et al. that inhaled treatment may improve the quality of in patients with by sputum studies are to the of this is an important goal in patients with COPD.30 It quality of and the of greater and pulmonary is an effective way to in COPD long-term monitoring and of at is to the of any exercise In this et al. found that a value was correlated with severe This may be a practical of patients can and to with are and is a intervention for patients with acute exacerbations of COPD who to to treatment. It may be as the current of care in this clinical Moreover, in patients with COPD on the of and mortality from to However, there is a need to improve the practical assessment of the response to in the acute In this et al. reviewed the of for the of during acute However, they were to positive from randomized The clinical may be that of may not be a of response to and should continue to on parameters. the disease the treatment of COPD become less effective and symptoms become more for such patients need to early to complex with about values and for care including of et in a of the the approaches to care at the of in patients with severe interaction susceptibility to airway diseases such as asthma and COPD. association studies have found associations of specific single with the development of asthma or COPD. in Respirology have also on genetic of airway A meta-analysis of studies of the polymorphism in found increased risk of asthma in or with A genetic association study of COPD patients and non-COPD in Japan single in the genes and recognition that The A of single polymorphism rs1077861 in NOD2 was associated with increased risk of COPD, and NOD2 gene in with studies such as these interaction in inflammation and in the development of airway smoking is the major cause of other causes include air pollution and occupational In the development of childhood asthma, an and respiratory are The link between respiratory and Th2 has been demonstrated in asthma in with respiratory in induced airway inflammation and by and reduced to infection may also to asthma pathogenesis and as by studies of airway in In a of asthma, the as an for to by has been as a risk factor for In the Respirology on obesity and respiratory Farah and potential mechanisms for the effects of obesity in including of from tissue and changes that lung have found increased of tissue in patients with The of asthma is by Th2 IgE and cell with of the airway In non-eosinophilic asthma in some patients. In a study of patients with non-eosinophilic asthma of patients also had sputum during over 6 This was more common when they were treated with the alone without inhaled compared with This in Respirology supports the of LABA for asthma and the potential of airway inflammatory phenotype. The airway inflammation of COPD is by and A number of studies in Respirology have on other of are a of that and function more like but also link to the of were lower in the of patients with stable COPD and decreased during acute is a recognition that A study of lung tissue showed that from COPD patients and smokers had increased protein of compared with smoke exposure in increased of and increased and exposure to the smoke could inflammatory to and other of recognition in the Other have also been in COPD. of was in small airway of COPD patients and compared with in with gene of and from that had high Hence, of in the airways could to susceptibility to in the of COPD patients and Airway remodelling is an important feature of chronic In a study in airway of was increased in patients with severe asthma, compared with mild asthma or and was induced following bronchoconstriction with or has been to be for and is a potential of airway remodelling in The pathogenesis of COPD is by a response to environmental to lung that for inflammation, These have been in a number of studies in Respirology in the of may have effects in specific protein of was measured in the lung tissue of COPD with mainly in and was increased in sputum of COPD correlated with of lung function, and correlated with sputum and In another study, and tissue of were measured in from COPD patients and non-COPD of and as well as tissue of 1 and were increased in COPD, the of COPD is by acute as disease A study of patients with an exacerbation of COPD measured inflammatory biomarkers at and before of and were at the of the correlated with exacerbation severity and were reduced by the time of but not to normal of biomarkers behind clinical and could be in monitoring COPD studies into treatment in airways disease. In an asthma study, single in the region of the gene were associated with in a association study of subjects from clinical Although the function of is as yet in of by in airway increased protein of the suggesting a for in In the Respirology on into recent developments in tissue in to the The large airways have been for tissue with and or or In development of for the small airways has been more because of the and number of of the of lung will help to advance this the hope of for lung

COPD—more than just tobacco smoke

Cardiovascular disease, the ‘silent killer’ in chronic obstructive pulmonary disease (COPD),1 seldom presents a more vexed clinical challenge than during acute exacerbation of COPD (AECOPD). In this demanding situation, treatments have changed little in decades and new approaches are needed to improve outcomes.2 The conundrum is to achieve diagnostic certainty and assure therapeutic benefit in this extraordinarily complex situation. Both COPD and cardiovascular disease are characterized by exceptional heterogeneity, displaying myriad diverse pathologies and clinical manifestations. Pathology in both disease categories can range in severity from subclinical to severe and can be modified by wide-ranging medical comorbidities as well as social factors.3 Furthermore, during AECOPD, a slew of intercurrent, superimposed factors may influence COPD and cardiovascular disease—these include viral and bacterial infections, inflammation, hyperinflation and pharmaco-therapeutic effects.4 Consequently, cardiovascular disease and COPD may be present independently, coexist or masquerade as the other during AECOPD.5 Deciphering this complicated disease network6, 7 during a time of acute illness can be difficult. Clinicians are usually adept at recognizing severe but previously undiagnosed lung or cardiac pathology8; however, this phenomenon only represents the tip of the ‘diagnostic iceberg’. Populations with COPD are known to be enriched in cardiovascular risk factors such as smoking, age, physical inactivity and airflow limitation,1, 9 and during AECOPD, signs of cardiovascular dysfunction including cardiac biomarker elevation are common and of prognostic importance.4, 10 Thus, the challenge is to identify which cardiovascular pathology (or pathologies) are present in each individual. Until recently, this has been difficult to achieve. For example, apparently, fundamental data on the prevalence of heart failure and coronary atherosclerosis in individuals presenting to hospital with AECOPD had not been reported. To examine this question, we recently employed a novel dynamic (i.e. video) cardiac computed tomography (CT) protocol, examining the prevalence of severe heart failure with reduced ejection fraction and severe calcific coronary atherosclerosis in hospitalized AECOPD.11 Briefly, dynamic CT can assess multiple important parameters which were previously difficult to assess including coronary atherosclerosis, atrial, ventricular, pulmonary and systemic vascular function in addition to pulmonary pathologies.8 In this population with severe airflow limitation, during acute hospitalized COPD exacerbation, severe coronary disease was present in approximately one-third of patients, and heart failure with reduced ejection fraction was present in about 10% of patients. Both were clinically covert in up to two-thirds of these patients, that is, standard tools (clinical examination, cardiac enzymes, chest X-ray and electrocardiogram) did not detect these pathologies. Put another way, the diagnosis of key treatable traits12 during these acute COPD hospitalizations could only be achieved through advanced imaging technology—with noteworthy implications. First, the impact of cardiovascular disease is likely to have been underestimated in studies that did not directly assess cardiovascular-related mortality. For example, the UPLIFT study is frequently cited in support of the contention that in mild and moderate COPD cardiovascular deaths predominate and that in severe COPD respiratory deaths predominate.13, 14 This study used central mortality adjudication to determine causality and there was disagreement between site investigators and the adjudication committee in cardiovascular death attribution. Moreover, of deaths attributed by the adjudication committee to COPD exacerbation, data were incomplete in a majority.14 Taken together, these findings imply that cardiovascular deaths could have been unrecognized and may have been causal or at least a contributor to patient mortality. Second, the viewpoint of cardiovascular disease during AECOPD as an ‘alternate’ or ‘differential diagnosis’ may need to be reconsidered as this is likely to lead to underdiagnosis. The Global Initiative for Chronic Obstructive Lung Disease (GOLD)15 and COPD-X16 suggest a clinically directed approach to detection of cardiovascular disease during AECOPD, using descriptors such as ‘alternative’,16 ‘complications’16 (COPD-X) and ‘differential’15 (GOLD) to frame cardiovascular disease. Such terminology would imply that AECOPD and cardiovascular disease are mutually exclusive; however, it is clear that both diseases can be simultaneously present.10, 11 An additional conundrum for the clinician is that these influential documents acknowledge that the conventional clinical cardiovascular diagnostic armamentarium is blunted in COPD, but still suggest a clinically directed approach. Overall, current clinical approaches and cognitive frameworks to detecting cardiovascular disease during AECOPD are likely to result in underdiagnosis. Third, treatment opportunities are likely to be greater than previously anticipated. For coronary atherosclerosis, recent Dutch data systematically examining patients with COPD in community care indicate that over 90% of patients can be categorized as high or very high coronary risk.17 Our data complement this notion: 55% of individuals with hospitalized AECOPD had sufficiently severe coronary atherosclerosis to warrant aspirin and lipid-lowering therapy but most were not treated.18 Thus, it would be common for patients with AECOPD to have some degree of coronary atherosclerosis that is undertreated.11 In addition, emerging data suggest that therapeutic responses may vary according to cardiac imaging phenotype.19 Overall, as underdetection of impactful ‘traits’ such as severe coronary atherosclerosis is common, it would be reasonable to expect that addressing diagnosis and treatment during AECOPD would improve outcomes. Further work is required to ascertain whether imaging assessment, followed by cardiovascular phenotype-directed intervention, could improve outcomes in AECOPD and beyond. The role of advanced CT imaging in advancing approaches to cardiovascular disease in COPD is promising but nascent. Cardiac CT can help disentangle the protean (and frequently subclinical) manifestations of cardiovascular disease. Cardiovascular traits may have differential impacts on outcomes. Our data show that aortic stiffness has an important effect during AECOPD,20 and unpublished data indicate that ventricular parameters powerfully influence outcomes including mortality (Fig. 1). In conclusion, there is compelling evidence that a key treatable trait, cardiovascular disease in COPD, is underdiagnosed and undertreated. AECOPD are an opportune time to assess this pathology using innovations in cardiac imaging that overcome limitations of conventional diagnostic modalities. As clinicians grapple with the challenge of implementing precision medicine in AECOPD to improve outcomes, recognition and treatment of specific and impactful cardiovascular disease traits is an attractive target. P.L. is supported by the Australian National Health and Medical Research Council and the Royal Australasian College of Physicians. Views expressed are those of the authors and may not represent those of the funding bodies. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Nearly 16 million Americans, and more than 250 million people around the world, live with chronic obstructive pulmonary disease (COPD) and millions more remain undiagnosed. The COPD Foundation has been monitoring the global pandemic of a disease caused by the recently identified coronavirus family member SARS-CoV-2 named coronavirus disease 2019 (COVID-19). On April 17th, 2020 the World Health Organization (WHO) reported 2,078,605 confirmed cases and 139,515 deaths globally. 1 The COVID-19 pandemic has put patients with COPD and other comorbidities at a high risk for poor outcomes as noted by the U.S. Centers for Disease Control and Prevention (CDC). 2 Although there is limited published data on COVID-19 in COPD individuals (only 15 out of > 4815 PubMed references on April 17th), a recent article in the European Respiratory Journal evaluated 1590 laboratory-confirmed hospitalized cases in China

Simple SummaryThis is the first study to reveal that hospitalization frequency for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) before colon adenocarcinoma treatment is a severity-dependent and independent prognostic factor for overall survival in patients with stage I–III colon cancer receiving surgical resection and standard treatments. In patients with colon adenocarcinoma undergoing curative resection, those with chronic obstructive pulmonary disease (COPD) had poorer survival outcomes than had those without COPD. Hospitalization for AECOPD at least once within 1 year before colon adenocarcinoma diagnosis is an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for AECOPD within 1 year before diagnosis was associated with poorer survival. Our study may be applied to accentuate the importance of COPD management, particularly the identification of frequent exacerbators and the prevention of AECOPD, before standard colon adenocarcinoma treatments are initiated.Purpose: To investigate whether chronic obstructive pulmonary disease (COPD) and COPD severity (acute exacerbation of COPD (AECOPD)) affect the survival outcomes of patients with colon adenocarcinoma receiving standard treatments. Methods: From the Taiwan Cancer Registry Database, we recruited patients with clinical stage I–III colon adenocarcinoma who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into COPD and non-COPD (Group 1 and 2) groups through propensity score matching. Results: In total, 1512 patients were eligible for further comparative analysis between non-COPD (1008 patients) and COPD (504 patients) cohorts. In the multivariate Cox regression analysis, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality for Group 1 compared with Group 2 was 1.17 (1.03, 1.29). In patients with colon adenocarcinoma undergoing curative resection, the aHRs (95% CIs) for all-cause mortality in patients with hospitalization frequencies of ≥1 and ≥2 times for AECOPD within 1 year before adenocarcinoma diagnosis were 1.08 (1.03, 1.51) and 1.55 (1.15, 2.09), respectively, compared with those without AECOPD. Conclusion: In patients with colon adenocarcinoma undergoing curative resection, COPD was associated with worse survival outcomes. Being hospitalized at least once for AECOPD within 1 year before colon adenocarcinoma diagnosis was an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for AECOPD within 1 year before diagnosis was associated with poorer survival. Our study highlights the importance of COPD management, particularly the identification of frequent exacerbators and the prevention of AECOPD before standard colon adenocarcinoma treatments are applied.

β-Adrenergic antagonist (β-blocker) use in patients with chronic obstructive pulmonary disease (COPD) has been avoided as a result of potential risk of pulmonary adverse effects. However, recent studies indicate that β-blocker use in patients with COPD can decrease outpatient visits and either decrease or have no effect on the number of hospitalizations. Long-term treatment with β-blockers has been shown to increase survival and decrease exacerbations in patients with COPD. To assess the impact of β-blocker use on the incidence of exacerbations in patients with COPD. In a retrospective cohort study of patients with COPD from 2 academic primary care practice sites who were seen in 2010, patients were identified using International Classification of Diseases, 9th revision, Clinical Modification codes for COPD and reviewing active medication lists for COPD-specific medications (tiotropium). Patients were classified as either a β-blocker user or a nonuser. Primary outcomes were incidence and severity of COPD exacerbations. Secondary outcomes included COPD exacerbations distinguished by β-blocker cardioselectivity and all-cause hospitalizations. The study enrolled 412 patients. Of those, 166 patients were β-blocker users and 246 were β-blocker nonusers. β-Blocker users were less likely to have a COPD exacerbation (OR 0.61, 95% CI 0.40-0.93) and had fewer mild exacerbations (OR 0.56; 95% CI 0.34-0.89). There was no significant difference in COPD exacerbations based on β-blocker cardioselectivity (OR 0.84, 95% CI 0.38-1.83). When controlled for, using a backwards stepwise logistic regression, β-blocker use was a variable in the model that predicted exacerbations but alone was not statistically significant (adjusted OR 0.62, 95% CI 0.39-1.01). Patients with COPD prescribed a β-blocker were significantly less likely to have a COPD exacerbation and had fewer mild COPD exacerbations.

Triple therapy with inhaled corticosteroid (ISC) / long-acting β2 agonist (LABA) / long-acting muscarinic antagonist (LAMA) in single inhaler expanded the possibilities for prevention of chronic obstructive pulmonary disease (COPD) exacerbations. Heterogeneity of COPD determines the needs in search of target population and efficacy markers for each existing therapy. Disease phenotype depends on a complex of factors, with respiratory viral infection among the most significant. Aim of the study was to assess the efficacy of triple therapy with ICS/LABA/LAMA in single inhaler for subsequent COPD exacerbations prevention and to search molecular markers of the efficacy depending the etiology of index exacerbation. Material and methods. It was a prospective observational study of three COPD patients’ strata: after COPD exacerbation required hospitalization with viral (n = 60), bacterial (n = 60) and viral-bacterial (n = 60) infection. Triple therapy in single inhaler (n = 104) or in free combinations (n = 76) were prescribed in real clinical practice. COPD was diagnosed according to spirography criteria. To establish the COPD exacerbation etiology the real time PCR of sputum or bronchoalveolar lavage fluid, standard cultural method, blood procalcitonin, as well as marker blood proteins, hyaluronic acid by ELISA measurement were done. Associations were revealed using Cox regression. Results. Triple therapy in single inhaler in comparison with free combinations decreased time to first re-exacerbation, hazard ratio (HR) in viral-associated index exacerbation strata was 0.38 (95% confidence interval (95% CI) 1.15–0.40), in bacterial – 0.47 (0.39–0.72), in viral-bacterial – 0.39 (0.14–0.39). In strata of COPD patients after viral and viral-bacterial exacerbations, in subgroups treated with triple therapy in single inhaler blood procollagen III N-terminal propeptide (PIIINP) (HR for group after viral index exacerbations was 1.03, 95 % CI 1.02–1.28, HR for group after viral-bacterial exacerbations was 1.04, 95 % CI 1.02–1.28), granulocyte-macrophage colony-stimulating factor (GM-CSF) (HR 1.03, 95 % CI 1.02–1.32, 1.01, 95 % CI 1.00–1.35, respectively) content was associated with time of re-exacerbations. Conclusions. Blood PIIINP and GM-CSF during COPD exacerbation are perspective markers of subsequent exacerbations within 1 year in patients after virus-associated or viral-bacterial index exacerbation. In these groups of patients triple therapy in single inhaler is more effective than free combination for subsequent exacerbations prevention.

e20032 Background: Chronic Obstructive Pulmonary Disease (COPD) is a prevalent condition among smokers, often leading to substantial morbidity. Lung cancer patients, many of whom have a history of smoking, frequently experience concurrent COPD and are at an increased risk of COPD exacerbations. However, the impact of COPDE on clinical outcomes in patients with lung cancer remains insufficiently studied. This study aims to explore the effects of COPDE on inpatient outcomes in this population, addressing an important gap in the current body of knowledge. Methods: Data from the 2019 National Inpatient Sample were analyzed to identify patients with a diagnosis of lung cancer using International Classification of Diseases, 10th Revision (ICD-10) codes. The study population was divided into two groups: those with COPD exacerbation (COPDE) and those without. Sociodemographic variables and comorbidities were compared between the groups. The primary outcome was all-cause in-hospital mortality, with several secondary outcomes also assessed. Multivariate regression models were utilized to evaluate differences in outcomes between the groups, with statistical significance set at p < 0.05. Results: Among 317,180 adult patients hospitalized with lung cancer, 10,155 (3.2%) were admitted with a diagnosis of chronic obstructive pulmonary disease exacerbation (COPDE). These patients were older on average (mean age: 70.1 years vs. 69.5 years) and included a higher proportion of females (54.6%) compared to males (45.4%). Patients with lung cancer and COPDE demonstrated significantly reduced odds of all-cause mortality (adjusted odds ratio [aOR]: 0.28; 95% confidence interval [CI]: 0.21–0.38; p < 0.001), concurrent pulmonary embolism (aOR: 0.39; 95% CI: 0.26–0.59; p > 0.001), acute kidney injury (aOR: 0.59; 95% CI: 0.51–0.69; p < 0.001), and sudden cardiac death (aOR: 0.31; 95% CI: 0.14–0.66; p = 0.002). Additionally, patients with COPDE had shorter hospital stays (mean length of stay: 4.4 days vs. 6.1 days; p < 0.001) and incurred lower hospitalization costs ($44,103 vs. $70,100; p < 0.001). Conclusions: Lung cancer patients with concurrent COPDE demonstrated significantly lower odds of mortality, acute kidney injury, pulmonary embolism, and sudden cardiac death. They also experienced shorter hospital stays and reduced hospitalization costs compared to those without COPDE. These findings provide important insights into the prognosis of lung cancer patients with COPDE, highlighting potential differences in outcomes that may guide clinical management strategies.

Objective Respiratory disease contributes to the excess mortality seen in rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD) is frequently encountered. The aim of this study was to investigate the risk of severe acute exacerbation, pneumonia, and death among patients with RA and COPD compared with patients with COPD alone. Method The study population was patients with hospital-based, outpatient follow-up for COPD identified from the Danish COPD registry. Diagnoses of RA, information about hospitalizations for acute exacerbations of COPD (AECOPD), pneumonia, and vital status were obtained from National Health Registries. Follow-up was 12 months after first outpatient contact for COPD. Hospitalizations for AECOPD and pneumonia, and risk of death in COPD with or without RA, were compared using Cox proportional hazards regression analysis. Covariates were balanced using inverse probability of treatment (IPT) weighting. Results The study included 58 655 patients with hospital-based follow-up for COPD, 2033 (3.5%) of whom had RA. More than 25% of the cohort experienced hospitalization with AECOPD and/or pneumonia in the first year after first outpatient COPD hospital contact. IPT-weighted unadjusted Cox regression analysis showed similar risk of hospitalization with AECOPD among patients with RA and COPD [hazard ratio (HR) 1.004, 95% confidence interval (CI) 0.89–1.13] and death (HR 1.13, 95% CI 0.98–1.30), but increased risk of hospitalization for pneumonia (HR 1.26, 95% CI 1.11–1.42). Conclusion The increased risk of pneumonia associated with RA may be attributed to immunosuppression. The findings should lead to increased focus on optimizing COPD therapies and preventive measures.