Little is known about the role of physical activity in the course of chronic obstructive pulmonary disease (COPD).To assess changes in physical activity in COPD in relation to severity stages and changes in other disease components, and to evaluate the longitudinal association between sustained physical inactivity and disease progression.In this prospective cohort study, we measured physical activity (multisensory armband), airflow obstruction (FEV1), health status (St. George's Respiratory Questionnaire), exercise capacity (6-min-walk distance [6MWD]), muscle mass (fat-free mass [FFM]), and systemic inflammation (fibrinogen and high-sensitivity C-reactive protein) over a 3-year period in 137 patients with COPD and 26 with chronic bronchitis (normal spirometry).Independent of baseline disease severity, steps per day, total daily energy expenditure, and (daily) physical activity level (PAL) decreased by 393, 76 kcal, and 0.04 per year, respectively. The decline in PAL was significantly associated with a decline in FEV1 and an increase in St. George's Respiratory Questionnaire total score. Changes in 6MWD, FFM, and inflammatory markers were not associated with changes in PAL. Independent of FEV1, sustained physical inactivity (i.e., PAL(T0andT1) < 1.40) was related to a greater decline in 6MWD and FFM compared with that in patients with some level of activity (i.e., PAL(T0and/orT1) ≥ 1.40; difference, 17 m/yr and 0.87 kg/yr, respectively).Over time, physical activity substantially decreases across all severity stages of COPD, and this decline is paralleled by a worsening of lung function and health status. Sustained physical inactivity is associated with a progression of exercise intolerance and muscle depletion.
Background: Chronic obstructive pulmonary disease (COPD) is commonly associated with ageing, with the prevalence and severity increasing by age. Smoking-induced premature ageing is thought to contribute to COPD, particularly lung emphysema. This study aimed to explore the relationship between lung function impairment and skin texture, as a marker of biological or premature ageing, in COPD patients. Methods: A subcohort from the COSYCONET COPD-study was analyzed, where skin-relief replicas of the eye’s outer corner and mid-lower inner arm were collected, along with semi-quantitative facial photographs. We examined the correlation between skin parameters and lung function, particularly the diffusing capacity (TLCO) as an indicator of emphysema. Results: Among 46 COPD patients (69 ± 8 years, 52% female), skin texture from the inner forearm, but not from the eye corner, was significantly associated with TLCO% predicted, with a higher skin roughness correlating with a lower TLCO (p = 0.015). This relationship persisted after adjusting for age, BMI, sex, pack years, and smoking status. No significant associations were found with facial photographs. Conclusions: These findings suggest that systemic ageing, reflected in inner arm skin texture, is linked to lung emphysema. Skin ageing markers may be valuable in future interventional studies involving anti-ageing treatments.
Abstract Background The evidence regarding effects of statins on exacerbation risk in COPD remains controversial. Previous studies often excluded patients with cardiovascular comorbidities despite their high prevalence in COPD and role for exacerbations. Based on the cardioprotective properties of statins, we hypothesised that statins may reduce the risk of exacerbations especially in patients with cardiovascular comorbidities. Methods One thousand eight hundred eighty seven patients of the German COPD cohort COSYCONET (COPD and Systemic Consequences Comorbidities Network) of GOLD grades 1–4 (37.8% female, mean age 64.78 ± 8.3) were examined at baseline and over a period of 4.5 years for the occurrence of at least one exacerbation or severe exacerbation per year in cross-sectional and longitudinal analyses adjusted for age, gender, BMI, GOLD grade and pack-years. Due to their collinearity, various cardiovascular diseases were tested in separate analyses, whereby the potential effect of statins in the presence of a specific comorbidity was tested as interaction between statins and comorbidity. We also identified patients who never took statins, always took statins, or initiated statin intake during the follow-up. Results One thousand three hundred six patients never took statins, 31.6% were statin user, and 12.9% initiated statins during the follow-up. Most cardiovascular diseases were significantly ( p < 0.05)may associated with an increased risk of COPD exacerbations, but in none of them the intake of statins was a significant attenuating factor, neither overall nor in modulating the increased risk linked to the specific comorbidities. The results of the cross-sectional and longitudinal analyses were consistent with each other, also those regarding at least 1 exacerbation or at least 1 severe exacerbation per year. Conclusion These findings complement the existing literature and may suggest that even in patients with COPD, cardiovascular comorbidities and a statin therapy that targets these comorbidities, the effects of statins on exacerbation risk are either negligible or more subtle than a reduction in exacerbation frequency. Trial registration Trial registration ClinicalTrials.gov, Identifier: NCT01245933. Other Study ID (BMBF grant): 01GI0881, registered 18 November 2010, study start 2010–11, primary completion 2013–12, study completion 2023–09. https://clinicaltrials.gov/study/NCT01245933?cond=COPD&term=COSYCONET&rank=3
The combination of chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) is associated with a higher prevalence of comorbidities and increased mortality. The impact of kidney function on patient-centered outcomes in COPD has not been evaluated.Patients from the German COPD and Systemic Consequences - Comorbidities Network (COSYCONET) cohort COPD were analysed. CKD was diagnosed if the estimated glomerular filtration rate (eGFR) measurements were < 60 mL/min/1.73m2 at study inclusion and six month later. The effect of CKD, on comorbidities, symptoms [modified British Medical Research Council dyspnoea scale], physical capacity [six-minute walk test, and timed up and go] and St George's Respiratory Questionnaire were analysed. Restricted cubic spline models were used to evaluate a nonlinear relationship between eGFR with patient-centered outcomes, cox survival analysis was applied to evaluate mortality.2274 patients were analysed, with CKD diagnosed in 161 (7.1%). Spline models adjusted for age, gender, BMI, FEV1 and cardiovascular comorbidities revealed independent associations between eGFR with modified British Medical Research Council dyspnoea scale, St George's Respiratory Questionnaire, (p < 0.001 and p = 0.011), six-minute walk test (p = 0.015) and timed up and go (p < 0.001). CKD was associated with increased mortality, independently from for other cardiovascular comorbidities (hazard ratio 2.3; p < 0.001).These data show that CKD is a relevant comorbidity in COPD patients which impacts on patient-centered outcomes and mortality.NCT01245933.
Rationale: Physical activity (PA) has been associated with mortality in patients with COPD. We aimed to investigate 1) this association across the disease severity and 2) whether the previously reported protective effect of PA is due to its quantity and/or intensity. Methods: We pooled data about PA (Sensewear armband), clincial characteristics and mortality from patients with COPD tested in Belgium (n=179), Spain (n= 173), Germany (n=168), United Kingdom (n=101) and Brazil (n=137) for these analyses. The quantity (daily step count) and intensity (mean METs during periods of at least 1.5 METs) of PA were included as exposures. Analyses (Cox proportional hazard regression) were adjusted for age, gender, severity of airflow limitation and BMI. Results: 758 patients (74% male, 67±8 years, FEV1 56±22 %pred, BMI 27±5 kg.m−2, 5881±4007 steps/day, mean PA intensity 3.18±0.52 METs) were included and 149 (20%) died during the 4-year follow up. Being more active was related to lower mortality risk (Hazard ratio, 95%CI 0.85 [0.79 to 0.91] per 1000 steps more, p<0.001). The association between PA quantity and mortality was similar across GOLD stages (interaction effect p=0.39, Figure 1A) and across intensity levels (interaction effect p=0.67, Figure 1B). Conclusion: The strength of the association between PA quantity and mortality is comparable across GOLD stages and across intensity levels.
To the Editor, Asthma is a heterogeneous disease encompassing several distinct sub-phenotypes with different etiologies and treatment responses,1 but we are lacking markers to differentiate patient subgroups. MicroRNAs (miRNAs) can regulate gene expression post-transcriptionally. Due to their high stability in body fluids, their easy detection, and their functional relevance in asthma, we and others have proposed extracellular miRNAs in noninvasive clinical samples as biomarkers for asthma.2, 3 Yet, extracellular miRNA profiles can be confounded by unspecific release of miRNAs from dying cells. Transfer of miRNAs by extracellular vesicles (EVs) is, however, supposedly a selective communication mechanism,4 and EV-miRNA levels have been shown to be altered in bronchoalveolar lavage (BAL) fluid of patients with asthma.5 In this pilot study, we profiled the EV-miRNA signature in plasma of patients with mild-to-moderate (AM) or severe eosinophilic asthma (AS) (as defined by ERS/ATS guidelines6) and healthy control (HC) subjects (Tables S1 and S2). Therefore, we isolated small EVs (EVs) (<200 nm) by size exclusion chromatography (SEC) (qEV, Izon Bioscience) from 1 mL plasma of 45 adult subjects with AM (n = 15) or AS (n = 14), and HC (n = 16) (Table S1). All study participants were enrolled in the all age asthma (ALLIANCE) cohort, a multi-center longitudinal asthma patient cohort of the German Center for Lung Research (DZL).7 SEC-isolated particles were confirmed to be <200 nm by nanoparticle tracking analysis (NTA) (ZetaView PMX 110, Particle Metrix) and were equal in concentration and size distribution across groups (Figure 1A). The median particle concentration isolated from 1 mL of plasma was 8.6 × 109 particles/mL (interquartile range [IQR]: 4.5 × 109-1.4 × 1010) for HC, 1.2 × 1010 particles/mL (IQR: 6.6 × 109-2.8 × 1010) for AM, and 1.0 × 1010 particles/mL (IQR: 3.9 × 109-3.6 × 1010) for AS. Furthermore, SEC fractions 7-9 used for sequencing were without protein contamination (Figure 1B) and expressed different amounts of typical small EV markers CD63, CD81, and/or CD9 (Figure S1). EV-RNA was isolated (miRNeasy Micro Kit; Qiagen) and subjected to RNA sequencing (RNA-seq) (HiSeq 2500, Illumina) of small RNAs (below 35 nt) according to Ref.8 While all samples achieved high Phred scores (>30) indicating excellent sequencing quality (Figure S2A), 46.42% of reads were short or unmapped (39.11%) (Figure 1C). From all mapped reads, 17.15% were classified as miRNAs, while 81.08% were ribosomal RNAs. In total, we detected 139 distinct EV miRNAs with ≥10 reads (AM: 115; AS: 114; HC: 128) (Figure S2B, Tables S3-S5), and 35 of which had read counts ≥ 50. Unsupervised clustering and principal component analysis did not separate the different groups (Figure S2C, D), indicating that there is no difference between asthma patients and healthy controls based on total EV-miRNA expression. However, miR-122-5p was significantly increased in all patients with asthma (log2 fold change (log2FC) = 1.74, false discovery rate (FDR) = 0.03) and in AS (log2FC = 1.77, FDR = 0.02) compared with healthy controls, while miR-3168 was decreased (log2FC = −1.28; FDR = 0.05) (Figure 1D). In AS, we found similar trend for miR-191-5p (log2FC = 0.39, FDR = 0.12) (Figure 1E). In a bivariate analysis, miR-191-5p normalized read counts correlated negatively with FEV1%pred (Spearman's R = −.38; P = .013) and lymphocyte percentage in blood (R = −.5; P = .0006) (Figure 1F). We found a positive correlation with blood neutrophil (R = .48; P = .0012) counts and a similar trend for blood eosinophil counts (R = .29; P = .058). miR-3168 read counts correlated significantly with blood eosinophils (R = −.28, P = .012), neutrophils (R = −.3, P = .05), and lymphocytes (R = .38, P = .012). Read counts of miR-122-5p positively correlated with both eosinophil (R = .32; P = .034) and neutrophil (R = .39; P = .0094) counts in blood, and trendwise with blood lymphocytes (R = −.28; P = .065) (Figure 1F). We do acknowledge that some correlation coefficients are quite low (R < .3) which could be due to the small sample size and needs to be confirmed in larger future studies. Next, we isolated EVs from additional plasma samples of the same subjects and 10 new subjects per group (Figure 2A), and found a strong trend for an increase of miR-122-5p (FC = 1.84; P = .07) in severe asthma, and in all asthma subjects (FC = 1.96; P = .09) (Figure 2A) by RT-qPCR, confirming the sequencing results. miR-191-5p did not differ significantly among the groups, and miR-3168 was not detectable by RT-qPCR. Of note, in a pilot approach both miRNAs could also be detected in EVs isolated from sputum supernatant samples of four healthy control and ten asthma subjects, and we have a first hint that they are increased in asthma compared with healthy controls (miR-122-5p: FC = 2.90; P = .014; miR-191-5p: FC = 2.69, P = .014) (Figure 2B). Ingenuity Pathway Analysis (IPA) of predicted targets of miR-122-5p and miR-191-5p revealed a concise network, containing the biological functions quantity of leukocytes, function of antigen-presenting cells, activation of antigen-presenting cells, function of Th2 cells, quantity of regulatory T lymphocytes, and differentiation of Th2 cells (Figure 2C). This is a first hint that miR-122-5p (and potentially miR-191-5p) could influence immune cell function upon uptake. This could systemically perpetuate the asthmatic phenotype and should be confirmed in larger studies, where also the specificity for asthma vs a general immune reaction should be assessed. The relatively low number of significantly altered miRNAs here might be due to the isolation of highly pure EVs by SEC. This is in line with previous reports,8 but SEC isolation is superior to other methods in separating EVs from contaminating proteins.9 Further, we have here focused on eosinophilic asthma of different severities, hampering comparisons of different asthma sub-phenotypes. This will require considerably larger patient numbers and was thus beyond the scope of this study. In summary, in relatively well-controlled asthma the total miRNA expression in plasma EVs is not different to controls. miR-122-5p is increased in plasma and sputum supernatant EVs derived from patients with (severe) asthma, and this miRNA correlated with immune cell types in the blood. Combined with the IPA-predicted role in lymphocyte differentiation and function, it is intriguing to speculate that this miRNA can sub-differentiate different forms of asthma, such as neutrophilic from eosinophilic asthma. This should be investigated in larger asthma cohort studies with a broad spectrum of clinically well-defined phenotypes and different treatment regimen also including steroid-naïve patients. The authors thank all included patients for their contribution. Furthermore, we thank Regine Wieland, Petra Hundack-Winter, Susann Prange, Vera Veith, and Lukas Hundack for their excellent support in patient recruitment and study logistics. This study was supported by an unrestricted grant (Next Generation Award) from Bencard Allergie GmbH to SB, which did not influence the content of the manuscript or the conclusions drawn. The authors declare no further conflict of interest relating to this manuscript. TB, HW, A-MK, FP, BW, OF E.vM., KFR, GH, and MVK designed and conducted the clinical study including patient recruitment and processing of plasma samples. DB, MWP, J.B, S.K-E., and SB performed experiments and critically analyzed the data. IRK performed the bivariate analysis with clinical data. SB had primary responsibility for the experimental study design and writing of the manuscript. All authors have contributed to discussion of the data and writing of the manuscript, and approved the final version. This study was supported by an unrestricted grant (Next Generation Award; Bencard Allergie GmbH) to SB The general costs of patient recruitment and study procedures are covered by unrestricted grants of the German Federal Ministry of Education and Research (BMBF) as part of the funding of the German Center for Lung Research (DZL) (for further details please see Ref. 7). The study was approved by the local ethics committee of the Medical School Luebeck, Schleswig-Holstein (Germany, Az. 12-215), and is registered at clinicaltrials.gov (Identifier: NCT02419274). All participants gave their written informed consent. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Rationale In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children. Objectives To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages. Methods In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28. Measurements and main results Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood. Conclusions Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.
