Plasma Metabolomic Signatures of Chronic Obstructive Pulmonary Disease and the Impact of Genetic Variants on Phenotype-Driven Modules.

Introduction and objectivesIndividuals with Chronic Obstructive Pulmonary Disease (COPD) have increased risk of severe pneumonia and poor outcomes when they develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hoffmann 2020)....

Maintenance pharmacotherapy of mild and moderate COPD: What is the Evidence?

Year in review 2017: Chronic obstructive pulmonary disease and asthma.

Little information exists regarding the epidemiology of the chronic bronchitis phenotype in unselected chronic obstructive pulmonary disease (COPD) populations. We examined the prevalence of the chronic bronchitis phenotype in COPD and non-COPD subjects from the PLATINO study, and investigated how it is associated with important outcomes. Post-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.70 was used to define COPD. Chronic bronchitis was defined as phlegm on most days, at least 3 months per year for ≥ 2 yrs. We also analysed another definition: cough and phlegm on most days, at least 3 months per year for ≥ 2 yrs. Spirometry was performed in 5,314 subjects (759 with and 4,554 without COPD). The proportion of subjects with and without COPD with chronic bronchitis defined as phlegm on most days, at least 3 months per year for ≥ 2 yrs was 14.4 and 6.2%, respectively. Using the other definition the prevalence was lower: 7.4% with and 2.5% without COPD. Among subjects with COPD, those with chronic bronchitis had worse lung function and general health status, and had more respiratory symptoms, physical activity limitation and exacerbations. Our study helps to understand the prevalence of the chronic bronchitis phenotype in an unselected COPD population at a particular time-point and suggests that chronic bronchitis in COPD is possibly associated with worse outcomes.

Chronic obstructive pulmonary disease (COPD) case-finding aims to detect airflow obstruction in symptomatic smokers and ex-smokers. We used a clinical algorithm including smoking, symptoms, and spirometry to classify smokers into COPD risk phenotypes. In addition, we evaluated the acceptability and effectiveness of including smoking cessation advice in the case-finding intervention. Smoking, symptoms, and spirometry abnormalities (airflow obstruction: forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] <0.7 or preserved-ratio spirometry (FEV1<80% of predicted value and FEV1/FVC ratio ≥ 0.7)] were assessed in a group of 864 smokers aged ≥ 30 years. The combination of these parameters allowed the identification of 4 phenotypes: Phenotype A (no symptoms, normal spirometry; reference), Phenotype B (symptoms; normal spirometry; possible COPD), Phenotype C (no symptoms; abnormal spirometry; possible COPD), and Phenotype D (symptoms; abnormal spirometry; probable COPD). We assessed phenotype differences in clinical variables and modeled the trend from phenotype A to phenotype D. Smoking cessation advice based on spirometry was provided. Follow-up was done by telephone 3 months later. Using smokers without symptoms or abnormal spirometry (phenotype A; n=212 [24.5%]) as a reference, smokers were classified into possible COPD (phenotype B;n=332 [38.4%]; and C: n=81 [9.4%]) and probable COPD (phenotype D: n=239 [27.2%]). The trend from baseline phenotype A to probable COPD phenotype D was significant for the number of cigarettes/day and the number of years of smoking (p=0.0001). At follow-up, 58 (7.7%) of the respondents (n=749) reported that they had quit smoking. Our clinical algorithm allowed us to classify smokers into COPD phenotypes whose manifestations were associated with smoking intensity and to significantly increase the number of smokers screened for COPD. Smoking cessation advice was well accepted, resulting in a low but clinically significant quit rate.

Predictive validity of chronic obstructive pulmonary disease phenotypes in inpatient elective surgery: a population-based study.

BackgroundThe Spanish chronic obstructive pulmonary disease (COPD) guideline phenotypes patients according to the exacerbation frequency and COPD subtypes. In this study, we compared the patients’ health-related quality of life (HRQoL) according to their COPD phenotypes.MethodsThis was a cross-sectional study of COPD patients who attended the outpatient clinic of the Serian Divisional Hospital and Bau District Hospital from 23th January 2018 to 22th January 2019. The HRQoL was assessed using modified Medical Research Council (mMRC), COPD Assessment Test (CAT), and St George’s Respiratory Questionnaire for COPD (SGRQ-c).ResultsOf 185 patients, 108 (58.4%) were non-exacerbators (NON-AE), 51 (27.6%) were frequent exacerbators (AE), and the remaining 26 (14.1%) had asthma-COPD overlap (ACO). Of AE patients, 42 (82.4%) had chronic bronchitis and only 9 (17.6%) had emphysema. Of the 185 COPD patients, 65.9% had exposure to biomass fuel and 69.1% were ex- or current smokers.The scores of mMRC, CAT, and SGRQ-c were significantly different between COPD phenotypes (p < 0.001). There were significantly more patients with mMRC 2–4 among AE (68.6%) (p < 0.001), compared to those with ACO (38.5%) and NON-AE (16.7%). AE patients had significantly higher total CAT (p = 0.003; p < 0.001) and SGRQ-c (both p < 0.001) scores than those with ACO and NON-AE. Patients with ACO had significantly higher total CAT and SGRQ-c (both p < 0.001) scores than those with NON-AE.AE patients had significantly higher score in each item of CAT and component of SGRQ-c compared to those with NON-AE (all p < 0.001), and ACO [(p = 0.003–0.016; p = < 0.001–0.005) except CAT 1, 2 and 7. ACO patients had significantly higher score in each item of CAT and component of SGRQ-c (p = < 0.001–0.040; p < 0.001) except CAT 2 and activity components of SGRQ-c.ConclusionsThe HRQoL of COPD patients was significantly different across different COPD phenotypes. HRQoL was worst in AE, followed by ACO and NON-AE. This study supports phenotyping COPD patients based on their exacerbation frequency and COPD subtypes. The treatment of COPD should be personalised according to these two factors.

COPD—more than just tobacco smoke

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

Bioactive lipids in emphysema. Decoding fat to reveal COPD phenotypes.

Systemic Steroid Exposure is Associated with Differential Methylation in Chronic Obstructive Pulmonary Disease. E.S. Wan, W. Qiu, A. Baccarelli, V.J. Carey, H. Bacherman, S.I. Rennard, A. Agusti, W.H. Anderson, D.A. Lomas, D.L. Demeo. Am J Respir Crit Care Med. 2012 Oct 11. [Epub ahead of print].RATIONALE: Systemic glucocorticoids are used therapeutically to treat a variety of medical conditions. Epigenetic processes such as DNA methylation may reflect exposure to and may be involved in mediating the responses and side effects associated with these medications.OBJECTIVE: To test the hypothesis that differences in DNA methylation are associated with current systemic steroid use.METHODS: We obtained DNA methylation data at 27,578 CpG sites in 14,475 genes throughout the genome in two large, independent cohorts: the International COPD Genetics Network (ndiscovery = 1085) and the Boston Early Onset COPD study (nreplication = 369). Sites were tested for association with current systemic steroid use using generalized linear mixed models.MAIN RESULTS: 511 sites demonstrated significant differential methylation by systemic corticosteroid use in all 3 of our primary models. Pyrosequencing validation confirmed robust differential methylation at CpG sites annotated to genes such as SLC22A18, LRP3, HIPK3, SCNN1A, FXYD1, IRF7, AZU1, SIT1, GPR97, ABHD16B, and RABGEF1. Functional annotation clustering demonstrated significant enrichment in intrinsic membrane components, hemostasis and coagulation, cellular ion homeostasis, leukocyte and lymphocyte activation and chemotaxis, protein transport, and responses to nutrients.CONCLUSIONS: Our analyses suggest systemic steroid use is associated with site-specific differential methylation throughout the genome. Differentially methylated CpG sites were found in both biologically plausible and previously unsuspected pathways; these genes and pathways may be relevant in the development of novel targeted therapies.Comments: For many COPD patients oral steroids seem to be more effective than inhaled steroids even at very low doses. The reasons for this are likely multifactorial but may include systemic steroids having effects on certain extrapulmonary manifestations of COPD that nonetheless effect their symptoms and propensity for exacerbations. The ability of this research to identify potential systemic therapeutic targets that may provide benefits without the adverse consequences of long term systemic steroids would be a significant advance.The Effect of Emphysema on Computed Tomographic Measures of Airway Dimensions in Smokers. A.A. Diaz, M.K. Han, C.E. Come, R.S. Estepar, J.C. Ross, V. Kim, M.T. Dransfield, D. Curran-Everett, J.D. Schroeder, D.A. Lynch, J. Tschirren, E.K. Silverman, G.R. Washko. Chest. 2012 Oct 8. [Epub ahead of print]BACKGROUND: In CT scans of smokers with COPD, the subsegmental airway wall area percent (WA%) is greater and more strongly correlated with FEV1% predicted than WA% obtained in the segmental airways. Since emphysema is linked to loss of airway tethering and may limit airway expansion, increases in WA% may be related to emphysema and not solely due to remodeling. We aimed to first determine if the stronger association of subsegmental vs. segmental WA% with FEV1% predicted is mitigated by emphysema; and second, to assess the relationships between emphysema, WA%, and total bronchial area (TBA).METHODS: We analyzed CT segmental and subsegmental WA% (WA% = 100*wall area/TBA) of six bronchial paths and corresponding lobar emphysema, lung function, and clinical data in 983 smokers with COPD.RESULTS: Compared to segmental, the subsegmental WA% had a greater effect on FEV1% predicted (–0.8 to –1.7% vs. –1.9 to –2.6% per 1-unit increase in WA%, respectively; P<0.05 for most bronchial paths). After adjusting for emphysema, the association between subsegmental WA% and FEV1% predicted was weakened in two bronchial paths. Increases in WA% between bronchial segments correlated directly with emphysema in all bronchial paths (P<0.05). In multivariate regression models, emphysema was directly related to subsegmental WA% in most bronchial paths and inversely related to subsegmental TBA in all bronchial paths.CONCLUSION: The greater effect of subsegmental WA% on airflow obstruction is mitigated by emphysema. Part of the emphysema effect might be due to loss of airway tethering leading to reduction in TBA and increase in WA%.Comments: Several studies have identified the central role of small airway damage in the pathophysiology of COPD. The role of alveolar destruction from emphysema and loss of smaller airway tethering has been proposed in past and is supported by this study. While it is typically proposed that only 20–30% of COPD patients have significant emphysema it is possible that we underestimate the presence of emphysema in patients typically considered to be purely chronic bronchitis that do not have CT performed. It is possible also that CT scan may underestimate emphysematous changes that may be only appreciated on direct tissue examination. Further studies are needed to elucidate the importance of these findings.Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case-control study (CONSISTE study). P. de Lucas-Ramos, J.L. Izquierdo-Alonso, J.M. Moro, J.F. Frances, P.V. Lozano, J.M. Bellon-Cano; CONSISTE study group. Int J Chron Obstruct Pulmon Dis. 2012;7:679-86. Epub 2012 Oct 1.INTRODUCTION: Chronic obstructive pulmonary disease (COPD) patients present a high prevalence of cardiovascular disease. This excess of comorbidity could be related to a common pathogenic mechanism, but it could also be explained by the existence of common risk factors. The objective of this study was to determine whether COPD patients present greater cardiovascular comorbidity than control subjects and whether COPD can be considered a risk factor per se.METHODS: 1200 COPD patients and 300 control subjects were recruited for this multicenter, cross-sectional, case-control study.RESULTS: Compared with the control group, the COPD group showed a significantly higher prevalence of ischemic heart disease (12.5% versus 4.7%; P < 0.0001), cerebrovascular disease (10% versus 2%; P < 0.0001), and peripheral vascular disease (16.4% versus 4.1%; P < 0.001). In the univariate risk analysis, COPD, hypertension, diabetes, obesity, and dyslipidemia were risk factors for ischemic heart disease. In the multivariate analysis adjusted for the remaining factors, COPD was still an independent risk factor (odds ratio: 2.23; 95% confidence interval: 1.18–4.24; P = 0.014).CONCLUSION: COPD patients show a high prevalence of cardiovascular disease, higher than expected given their age and the coexistence of classic cardiovascular risk factorsComments: In this study both cases and controls had to be over 40, minimum 10 pack year history and no other respiratory diagnoses. Controls were recruited largely from a group referred for tobacco consults and did not have pulmonary symptoms. This study showed that compared to smokers, smokers with COPD were significantly more likely to have comorbidities except for lung cancer. The rates of lung cancer were very low and the study was powered based on risk of ischemic heart disease. Ischemic heart disease was much higher in those with stage IV versus stage III but not with other groups. In multivariate analysis adjusted for smoking, age, dyslipidemia, hypertension COPD was still a risk factor for ischemic heart disease and for peripheral vascular disease and cerebral vascular disease. The relationship between atherosclerosis and COPD in smokers is compelling and may ultimately be incorporated in management guidelines with regard to screening and treatment paradigms for COPD.Treatment of COPD by clinical phenotypes. Putting old evidence into clinical practice. M. Miravitlles, J. Jose Soler-Cataluna, M. Calle, J.B. Soriano. Eur Respir J. 2012 Oct 11. [Epub ahead of print]Abstract: The new GOLD update has moved forward the principles of treatment of stable COPD by including the concepts of symptoms and risks into the decision of therapy; however, no mention of the concept of clinical phenotypes was included. It is recognized that COPD is a very heterogeneous disease and not all patients respond to all the drugs available for treatment. The identification of responders to therapies is crucial in chronic diseases to provide the most appropriate treatment and avoid unnecessary medications. The classically defined phenotypes of chronic bronchitis and emphysema, together with the newly described phenotypes of overlap COPD-asthma and frequent exacerbator allow a simple classification of patients that share clinical characteristics and outcomes and, more importantly, similar responses to existing treatments.These clinical phenotypes can help clinicians identify patients that respond to specific pharmacologic interventions. As an example, frequent exacerbators are the only subjects with an indication for anti-inflammatory treatment in COPD. Among them, those with chronic bronchitis are the only candidates to receive PDE4 inhibitors. Patients with overlap COPD-asthma phenotype show an enhanced response to inhaled corticosteroids and infrequent exacerbators should only receive bronchodilators. These well defined clinical phenotypes could potentially be incorporated into treatment guidelines.Comment: This article is a very nice review of the utility of current clinical phenotypes that can be used to guide initial therapeutic strategies. While the Gold guidelines current iteration has included risks and symptoms to the treatment guideline paradigm the proposed treatment by clinical phenotypes as outlined in this article is perhaps more user friendly for the practicing clinician. Indeed many clinicians can readily assess and identify clinical phenotypes in their patient population rather than remember the criteria for each quadrant of the current Gold Guideline paradigm. Ultimately however each patient is and individual and therapy should take many factors into consideration.

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. 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BackgroundBlood biomarkers are increasingly used to stratify high risk chronic obstructive pulmonary disease (COPD) patients; however, there are fewer studies that have investigated multiple biomarkers and replicated in multiple large well-characterized cohorts of susceptible current and former smokers.MethodsWe used two MSD multiplex panels to measure 9 cytokines and chemokines in 2123 subjects from COPDGene and 1117 subjects from SPIROMICS. These biomarkers included: interleukin (IL)-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, eotaxin/CCL-11, eotaxin-3/CCL-26, and thymus and activation-regulated chemokine (TARC)/CCL-17. Regression models adjusted for clinical covariates were used to determine which biomarkers were associated with the following COPD phenotypes: airflow obstruction (forced expiratory flow at 1 s (FEV1%) and FEV1/forced vital capacity (FEV1/FVC), chronic bronchitis, COPD exacerbations, and emphysema. Biomarker-genotype associations were assessed by genome-wide association of single nucleotide polymorphisms (SNPs).ResultsEotaxin and IL-6 were strongly associated with airflow obstruction and accounted for 3–5% of the measurement variance on top of clinical variables. IL-6 was associated with progressive airflow obstruction over 5 years and both IL-6 and IL-8 were associated with progressive emphysema over 5 years. None of the biomarkers were consistently associated with chronic bronchitis or COPD exacerbations. We identified one novel SNP (rs9302690 SNP) that was associated with CCL17 plasma measurements.ConclusionWhen assessing smoking related pulmonary disease, biomarkers of inflammation such as IL-2, IL-6, IL-8, and eotaxin may add additional modest predictive value on top of clinical variables alone.Trial registrationCOPDGene (ClinicalTrials.gov Identifier: NCT02445183).Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) (ClinicalTrials.gov Identifier: NCT 01969344).

RATIONALE: Although approximately half of individuals receiving lung cancer screening (LCS) may have chronic obstructive pulmonary disease (COPD), up to 67% of patients with airflow obstruction or low-dose CT (LDCT)-detected emphysema have not received this diagnosis prior to LCS. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) now recommends targeted spirometry during LCS for people at high risk for COPD or when COPD-related LDCT findings are detected. However, screen-eligible individuals with GOLD 3-4 COPD may experience a suboptimal balance of LCS benefits and harms. Therefore many knowledge gaps remain regarding the optimal methods for leveraging LCS eligibility and COPD detection. The objective of this retrospective cohort study was to examine COPD prevalence among screen-eligible individuals receiving LCS. METHODS: Baseline characteristics for individuals screened through a centralized LCS Program between January 2018- August 2024 were extracted from a prospectively maintained LCS Registry, stratified by self-report of COPD, chronic bronchitis, or emphysema diagnosis at the time of entry into the LCS Program. Additional data were extracted from the electronic health record (EHR), including ICD-10 diagnoses of Emphysema (J43[asterisk]) and COPD exacerbation (J44[asterisk]), pulmonary function testing (PFT) order and completion status, medications, and hospitalization for a primary respiratory diagnosis. RESULTS: Among the study cohort of 3,711 USPSTF-eligible individuals completing LCS, 1,158 individuals (31.2%) self-reported a pre-LCS diagnosis of COPD, chronic bronchitis, or emphysema on their baseline intake form. This subgroup was more often female, had former smoking status, and greater smoking intensity compared with LCS participants who did not self-report a COPD diagnosis. (Table 1) More than half of LCS participants overall (2,068, or 55.7%) had emphysema described on their LDCT report. In contrast, just 1,572 individuals (42.4%) had an EHR diagnosis of emphysema, although the timeframe of diagnosis relative to LCS could not be determined. Only 29.3% of LCS participants (and 49.9% of those with self-reported COPD) had a PFT order, and just 19% and 32.7% completed PFTs, respectively. Among the entire cohort 17.3% had a COPD exacerbation, 15.0% had a prescription for prednisone or methylprednisolone, and 6.7% were hospitalized for a respiratory diagnosis. CONCLUSIONS: In a cohort of LCS participants, COPD diagnosis ascertained from the EHR was discordant with COPD prevalence based on self-report. Moreover, PFT may be underutilized among individuals with self-reported COPD or LDCT-detected emphysema. A prospective clinical trial is planned to characterize lung cancer risk, COPD phenotypes, and LCS and COPD outcomes among USPSTF-eligible individuals receiving screening.

Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in patients with heart failure (HF). The primary aims were to determine the prevalence of COPD and to test the accuracy of self-reported COPD in patients admitted with HF. Secondary aims were to study a possible relationship between right and left ventricular function and pulmonary function. Prospective substudy. Systematic screening at 11 centres. Consecutive patients (n = 532) admitted with HF requiring medical treatment with diuretics and an episode with symptoms corresponding to New York Heart Association class III-IV within a month prior to admission. Forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were measured by spirometry and ventricular function by echocardiography. The diagnosis of COPD and HF were made according to established criteria. The prevalence of COPD was 35%. Only 43% of the patients with COPD had self-reported COPD and one-third of patients with self-reported COPD did not have COPD based on spirometry. The prevalence of COPD in patients with preserved left ventricular ejection fraction (i.e. LVEF >or=45%) was significantly higher than in patients with impaired LVEF (41% vs. 31%, P = 0.03). FEV(1) and FVC were negatively correlated with right ventricular end-diastolic diameter and tricuspid annular plane systolic excursion and FVC positively correlated with systolic gradient across the tricuspid valve. Chronic obstructive pulmonary disease is frequent in patients admitted with HF and self-reported COPD only identifies a minority. The prevalence of COPD was high in both patients with systolic and nonsystolic HF.