Impact of radiologically stratified exacerbations: insights into pneumonia aetiology in COPD.

BACKGROUND: COPD patients have increased risk of developing pneumonia, which is associated with poor outcomes. It can be symptomatically indistinguishable from exacerbations, making diagnosis challenging. Studies of pneumonia in COPD have focused on hospitalised patients and are not representative of the ambulant COPD population. Therefore, we sought to determine the incidence and aetiology of acute exacerbation events with evidence of pneumonic radiographic infiltrates in an outpatient COPD cohort. METHODS: One hundred twenty-seven patients with moderate to very severe COPD aged 42-85 years underwent blood and sputum sampling over one year, at monthly stable visits and within 72 h of exacerbation symptom onset. 343 exacerbations with chest radiographs were included. RESULTS: 20.1% of exacerbations had pneumonic infiltrates. Presence of infiltrate was highly seasonal (Winter vs summer OR 3.056, p = 0.027). In paired analyses these exacerbation events had greater increases in systemic inflammation. Bacterial detection rate was higher in the pneumonic group, with Haemophilus influenzae the most common bacteria in both radiological groups. Viral detection and sputum microbiota did not differ with chest radiograph appearance. CONCLUSIONS: In an outpatient COPD cohort, pneumonic infiltrates at exacerbation were common, and associated with more intense inflammation. Bacterial pathogen detection and lung microbiota were not distinct, suggesting that exacerbations and pneumonia in COPD share common infectious triggers and represent a continuum of severity rather than distinct aetiological events. TRIAL REGISTRATION: Trial registration Number: NCT01360398 .

Impact and associations of eosinophilic inflammation in COPD: analysis of the AERIS cohort.

Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) predicts response to treatment, especially corticosteroids. We studied the nature of eosinophilic inflammation in COPD prospectively to examine the stability of this phenotype and its dynamics across exacerbations, and its associations with clinical phenotype, exacerbations and infection.127 patients aged 40-85 years with moderate to very severe COPD underwent repeated blood and sputum sampling at stable visits and within 72 h of exacerbation for 1 year.Blood eosinophils ≥2% was prevalent at baseline, and predicted both predominantly raised stable-state eosinophils across the year (area under the curve 0.841, 95% CI 0.755-0.928) and increased risk of eosinophilic inflammation at exacerbation (OR 9.16; p<0.001). Eosinophils ≥2% at exacerbation and eosinophil predominance at stable visits were associated with a lower risk of bacterial presence at exacerbation (OR 0.49; p=0.049 and OR 0.25; p=0.065, respectively). Bacterial infection at exacerbation was highly seasonal (winter versus summer OR 4.74; p=0.011) in predominantly eosinophilic patients.Eosinophilic inflammation is a common and stable phenotype in COPD. Blood eosinophil counts in the stable state can predict the nature of inflammation at future exacerbations, which when combined with an understanding of seasonal variation provides the basis for the development of new treatment paradigms for this important condition.

Relationship between pulmonary matrix metalloproteinases and quantitative CT markers of small airways disease and emphysema in COPD.

BACKGROUND: Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and drive tissue remodelling, key processes in the pathogenesis of COPD. The development of small airway disease has been identified as a critical mechanism in the early development of airflow obstruction but the contribution of MMPs in human disease is poorly characterised. OBJECTIVES: We investigated the role of MMPs and inflammatory cytokines in the lung by quantifying levels and determining relationships with the key pathological components of COPD in patients and healthy controls. METHODS: We analysed levels of MMPs and inflammatory cytokines in bronchoalveolar lavage from 24 COPD and 8 control subjects. Each subject underwent spirometry and high-resolution CT. Image analysis quantitatively assessed emphysema, bronchial wall thickening and small airways disease. RESULTS: Multiple MMPs (MMP-1, -2, -3, -8, -9 and -10) and cytokines (interleukin (IL) 6 and IL-8) were elevated in lungs of subjects with COPD. MMP-3, -7, -8, -9, -10 and -12 concentrations closely associated with CT markers of small airways disease. Emphysema severity was also associated with MMP-3, -7 and -10. However, there were no strong relationships between MMPs and bronchial wall thickness of the larger airways. CONCLUSIONS: Pulmonary MMP concentrations are directly associated with the extent of gas trapping and small airways disease identified on CT scan. This study suggests that MMPs play a significant role in small airways remodelling, a key feature in the pathogenesis of COPD. TRIAL REGISTRATION NUMBER: NCT01701869.

Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases.

BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types. RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs. CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism. TRIAL REGISTRATION: Trial registration number NCT01701869 .

Seasonality, risk factors and burden of community-acquired pneumonia in COPD patients: a population database study using linked health care records.

BACKGROUND: Community-acquired pneumonia (CAP) is more common in patients with COPD than in the adult general population, with studies of hospitalized CAP patients consistently reporting COPD as a frequent comorbidity. However, despite an increasing recognition of its importance, large studies evaluating the incidence patterns over time, risk factors and burden of CAP in COPD are currently lacking. METHODS: A retrospective observational study using a large UK-based database of linked primary and secondary care records was conducted. Patients with a diagnosis of COPD aged ≥40 years were followed up for 5 years from January 1, 2010. CAP and exacerbation episodes were identified from hospital discharge data and primary care coding records, and rates were calculated per month, adjusting for mortality, and displayed over time. In addition, baseline factors predicting future risk of CAP and hospital admission with CAP were identified. RESULTS: A total of 14,513 COPD patients were identified: 13.4% (n=1,938) had ≥1 CAP episode, of whom 18.8% suffered from recurrent (≥2) CAP. Highest rates of both CAP and exacerbations were seen in winter. A greater proportion of frequent, compared to infrequent, exacerbators experienced recurrent CAP (5.1% versus 2.0%, respectively, P<0.001); 75.6% of CAP episodes were associated with hospital admission compared to 22.1% of exacerbations. Older age and increasing grade of airflow limitation were independently associated with increased odds of CAP and hospital admission with CAP. Other independent predictors of future CAP included lower body mass index, inhaled corticosteroid use, prior frequent exacerbations and comorbidities, including ischemic heart disease and diabetes. CONCLUSION: CAP in COPD demonstrates clear seasonal patterns, with patient characteristics predictive of the odds of future CAP and hospital admission with CAP. Highlighting this burden of COPD-associated CAP during the winter period informs us of the likely triggers and the need for more effective preventive strategies.

Associations between objectively assessed and questionnaire-based sedentary behaviour with BMI-defined obesity among general population children and adolescents living in England.

OBJECTIVES: Sedentary behaviour (SB) is an emerging candidate risk factor for obesity in young people. Evidence to date is conflicting and it is unclear how different SB types are associated with obesity independently of physical activity. The objective of this study was to examine associations between a range of objectively measured and questionnaire-based SB indicators with obesity and body mass index (BMI) to assess whether these associations were independent of physical activity. PARTICIPANTS: 4469 (705 with accelerometer data) children aged 5-15 years from the 2008 Health Survey for England. OUTCOMES: The outcome was adiposity, classified using age-specific and sex-specific BMI SD scores (continuous) and obesity cut-offs (binary). Questionnaire-based measures comprised TV time, non-TV sitting time (such as homework, drawing, time at a computer or playing video games), total sitting time (TV time+non-TV sitting time) and average daily MVPA time. Objective SB and moderate to vigorous physical activity (MVPA) time were measured using an Actigraph GT1M accelerometer, with cut-offs of 100 and 200 counts per minute for SB, and 2802 counts per minute for MVPA. Multiple logistic and multiple linear regression models examined associations between each indicator of sedentary time with obesity and BMI SD scores. RESULTS: TV time (but not non-TV sitting or objectively-measured SB) was consistently associated with higher levels of obesity and BMI SD score, even after adjusting for MVPA and other potential confounders. Weaker associations were observed for total sitting time. CONCLUSIONS: TV viewing (but not other forms of objectively-measured or questionnaire-based sedentary time) was associated with obesity in children and adolescents. Although a causal relationship cannot be established, TV time may be a reasonable target for obesity prevention in young populations.

Physical activity and risk of all-cause and cardiovascular disease mortality in diabetic adults from Great Britain: pooled analysis of 10 population-based cohorts.

OBJECTIVE To examine associations between specific types of physical activity and all-cause and cardiovascular disease (CVD) mortality in a large nationally representative sample of adults with diabetes from Great Britain. RESEARCH DESIGN AND METHODS There were a total of 3,038 participants (675 deaths) with diabetes in the Health Survey for England and the Scottish Health Surveys conducted between 1997 and 2008. Participants aged ≥50 years at baseline were followed up for an average of 75.2 months for all-cause and CVD mortality. Data were collected on self-reported frequency, duration, and intensity of participation in sports and exercise, walking, and domestic physical activity, from which the number of MET-hours/week were derived. Sex-specific medians of time spent in each type of physical activity (for those physically active) were calculated, and Cox proportional hazards regression conducted to examine type-specific associations between the level of physical activity and all-cause and CVD mortality risk. RESULTS Inverse associations with all-cause and CVD mortality were observed for overall physical activity in a dose-response manner after adjusting for covariates. Compared with those who individuals were inactive, participants who reported some activity, but below the recommended amount, or who met the physical activity recommendations had a 26% (95% CI 39-11) and 35% (95% CI 47-21) lower all-cause mortality, respectively. Similar results were found for below/above median physical activity levels. Sports and exercise participation was inversely associated with all-cause (but not CVD) mortality, as were above average levels of walking. Domestic physical activity was not associated with mortality. CONCLUSIONS Moderate physical activity levels were associated with better prognosis in diabetic adults.