Ngaire A. Coombs

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

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. Blood eosinophil levels in COPD predict the nature of inflammation at future exacerbations and may guide therapy http://ow.ly/W10o30dNQiq

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

BackgroundEmphysema 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. MethodsTwenty-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.ResultsThe 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.ConclusionMultiple 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 registrationTrial 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.

S37 The persistence of eosinophilic inflammation in copd over time – aeris cohort

Introduction The importance of eosinophilic inflammation in COPD is in its ability to predict an enhanced response to treatment, such as corticosteroids. However, little is know about the persistence of higher eosinophils, or its associations with infectious aetiology during clinical stability and exacerbation. We investigated the natural history of eosinophilic inflammation over time and studied eosinophil-associated acute exacerbations of COPD and the impact of seasonality in a cohort of COPD patients. Methods 127 subjects with moderate to very severe COPD were enrolled into the AERIS cohort (NCT01360398) and were reviewed monthly for scheduled visits and during exacerbations. Blood sampling was performed quarterly and at exacerbations. Higher blood eosinophils (BE) were defined as ≥2%. Based on frequency of higher BE over the study, subjects were divided into predominantly (PE), intermittent (IE) and rarely eosinophilic (RE) groups. Results Blood eosinophil levels ≥2% were prevalent at baseline (68.3%) and at exacerbations (51.1%). Over the study 57.6% of subjects had predominantly, 16.16% intermittently and 26.26% rarely ≥2% blood eosinophils. Higher BE at enrolment was strongly associated with a predominantly high BE profile for the year (AUC 0.841 p < 0.001) and with greater odds of ≥2% eosinophils at exacerbation (OR 9.60 p < 0.001). The odds of ≥2% BE at exacerbation were higher in the PE group compared to the rarely group (OR 12.00, p < 0.001). A larger proportion of exacerbations were eosinophilic in the Summer than Winter (OR 2.57, p = 0.001). The odds of bacterial presence at exacerbation was higher in Winter than Summer among those in the PE group (OR 4.74, CI: 1.43; 15.71, p = 0.011), but not among those in the RE group (OR 1.15, CI: 0.29; 4.56, p = 0.838). Conclusion Our data suggests that it is possible to stratify COPD patients by stable state blood eosinophil levels. This measure is easily accessible and provides important insights into the longitudinal inflammatory phenotype of COPD. Persistent higher blood eosinophil levels were associated with risk of bacterial infection at exacerbation, and seasonality of exacerbation. Intervention studies are required to establish clear treatment algorithms utilising this measure to stratify therapy.

S67 Mortality in copd patients following community acquired pneumonia: a population database analysis of linked healthcare records

Introduction Community acquired pneumonia (CAP) is a common occurrence in patients with chronic obstructive pulmonary disease (COPD), yet controversy still remains about its affect on outcome. We therefore investigated the impact of CAP on mortality in a cohort of COPD patients identified from the Hampshire Health Record analytical database, a local NHS database containing linked, anonymised primary and secondary care records. Methods Patients were defined as having COPD if they had a diagnostic Read code in their primary care record at any time prior to the 1st January 2010 and were aged ≥40 years at the start of the study. CAP episodes occurring over a 5-year period from 1st January 2010 were identified using Read and ICD-10 codes. The outcome measure was all-cause mortality following a CAP diagnosis. Cox proportional hazard modelling was used to estimate hazard ratios (HR) and confidence intervals (CI), adjusting for age, sex, GOLD stage, smoking status and inhaled corticosteroid use (ICS)). Results The cohort comprised 14506 COPD patients. The mean age was 70.3 (±10.8) years and 53.6% were male. 1931 (13.3%) patients had at least one CAP and 2870 (19.8%) deaths occurred over the study period. 28.2% of patients diagnosed with CAP died compared to only 9.7% of those without a CAP diagnosis (p < 0.001). Logistic regression analysis, controlling for potential confounders identified CAP as an independent risk factor for future mortality (odds ratio 2.72; CI 2.37–3.12, p < 0.001). Compared to younger individuals (40–59 years) those aged 60–79 and >80 years had the highest mortality risk following CAP (HR 2.65; CI 1.61–4.34, HR 7.03; CI 4.27–11.57 respectively, both p < 0.001). Concurrent use of inhaled Fluticasone or Budesonide were associated with reduced mortality risk following CAP (HR 0.82; CI: 0.68–0.98 p = 0.029, HR 0.55; CI: 0.39–0.76 p < 0.001, respectively) (Figure 1). Conclusion CAP in COPD is associated with increased risk of mortality, especially in older individuals. Although known to increase CAP risk, ICS use appears to reduce risk of mortality following CAP. Further research to understand the mechanisms underlying CAP risk in COPD and modulating effects of ICS is key, to guide development of future, targeted preventative strategies. Abstract S67 Figure 1 Survival comparisons following CAP in COPD patients, stratified by Fluticasone (A) or Budesonide (B) use

P53 Predicting poor outcomes in COPD patients deemed ‘low risk’ by dose score

Introduction COPD continues to cause a substantial symptom, mortality and financial burden in the UK. Current treatment strategies are predominantly reactive as insufficient evidence exists to successfully target clinical resource into pre-emptive ‘early interventions’. The DOSE (dyspnoea, obstruction, smoking status and exacerbation) score has been validated as a risk predictor for mortality, hospitalisation and poorer health status. However, only a small proportion of COPD patients with poor outcomes have high DOSE scores. We sought to establish if clinical characteristics can be used to pre-emptively identify those COPD patients vulnerable to future poor health status by using an electronic database of anonymised patient records-the Hampshire Health Record Analytical Database (HHRA). Methods Within our HHRA database COPD cohort, we identified a cohort of 6890 patients who fell into the ‘low risk’ category by DOSE score (<4). Within this group, a subset met the criteria for poor COPD outcomes over the next four years, defined as; death (all cause), COPD related hospital admission, a DOSE score increase of ≥2 points or a subsequent DOSE score of ≥4 (high risk). We used logistic regression analysis to examine the association between demographic and clinical characteristics documented by Read code at baseline and those who subsequently fell into the poor outcomes subgroup. Results In our ‘low risk’ cohort of 6890 COPD patients, 5000 held sufficient data to be included in the analysis. After four years, 2211 (44.2%) of those 5000 patients fell into the poor outcomes subgroup. As shown in Table 1, poor future outcomes were significantly associated with age, high deprivation decile, low BMI, certain comorbidities, a raised eosinophil percentage (≥2%) and the prescription (in the preceding twelve months) of nebulised bronchodilators, inhaled bronchodilators and an ICS/LABA combination inhaler. A BMI of >25 and rhinosinusitis were associated with a lower risk of poor future outcomes. Conclusions Poor future clinical outcomes appear to be associated with certain clinical characteristics in a COPD database cohort deemed low risk by DOSE score. These findings warrant further validation in a clinical cohort and investigation into the effect of pre-emptive optimisation of these characteristics on health outcomes. Abstract P53 Table 1 Associations between clinical characteristics and odds of future poor clinical outcome *Variables excluded from model due to statistical insignificance: gender, IHD, hypertension, osteoporosis, GORD, diabetes, total number of comotbities. **Decile 10 represents least deprived.

S93 Pulmonary Matrix Metalloproteinases and Small Airways Disease in COPD – The Origins of Airflow Obstruction?

Introduction and objectives Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extra-cellular matrix (ECM) and drive tissue remodelling, key processes in the pathogenesis of COPD. The development of small airway disease and emphysema have been identified as critical mechanisms in the development of airflow obstruction but the contribution of MMPs in human disease is poorly characterised. We investigated the role of MMPs in the lung by quantifying levels and determining relationships with the key pathological components of COPD, measured by CT, in patients and healthy controls. Methods 24 mild and moderate COPD and 8 control subjects were enrolled onto the study and underwent bronchoalveolar lavage (BAL) and high resolution CT. We analysed levels of MMPs in BAL using a Luminex immunoassay. Image analysis, performed using VIDA Apollo software, quantitatively assessed emphysema, bronchial wall thickening and small airways disease. Results Multiple MMPs (MMP-1, -2, -3, -8, -9 and -10) were significantly elevated in the lungs of COPD subjects. MMP -3, -7, -8, -9, -10, and -12 concentrations were closely associated with CT markers of small airways disease (Table 1). Emphysema severity was also associated with MMP-3, -7, -8 and -10. However there were no strong relationships between MMPs and bronchial wall thickness of the larger airways.Abstract S93 Table 1 Linear regression analysis between MMPs and CT measures of disease MMP-1# MMP-2# MMP-3# MMP-7# MMP-8# MMP-9# MMP-10# MMP-12# MMP-13# Emphysema% (LAA%) 0.01 0.02 0.25** 0.23** 0.15* 0.11 0.34** 0.01 0.01 Small airways Disease (E/I MLD) 0.14 0.14 0.53*** 0.29* 0.56*** 0.36** 0.50*** 0.24* 0.00 Bronchial wall area (Pi10) 0.03 0.00 0.00 0.01 0.04 0.01 0.00 0.17* 0.00 R2 values given. #These values were logged to improve normality of residuals. LAA% (n = 31), Pi10 (n = 31) and E/I MLD (n = 22). *p < 0.05 **p < 0.01 ***p < 0.001. Stepwise linear regression analysis identified MMP-10 to be the only significant predictor of emphysema (R2 0.34, p 0.001) that was independent of each of the other MMPs while MMP-8 was the only significant predictor of small airways disease (R2 0.56, p < 0.001) independent of each of the other MMPs. Conclusion Pulmonary MMP concentrations are directly associated with the extent of gas trapping and small airways disease identified on CT scan. This suggests that MMPs may play a significant role in the pathogenesis of COPD by causing breakdown of the pulmonary ECM leading to abnormal remodelling in both the small airways and lung parenchyma. Whilst most previous work has focused on MMPs and emphysema, this study shows the strongest associations were with small airways disease.

S121 Co-morbidity and Pneumonia Risk in COPD Patients: A Population Database Analysis of Primary Care Patients

Background Co-morbidities are common in COPD and have been associated with poorer clinical outcomes. Furthermore, patients with COPD are at an increased risk of developing Community acquired pneumonia (CAP). We investigated the impact of concurrent co-morbidity on the risk of developing CAP, in a cohort of COPD patients identified from the Hampshire Health Record analytical database, a local NHS database containing anonymised primary and secondary care records. Methods Patients defined as having COPD, had a diagnostic Read code (classification of clinical terms for electronic information coding) in their primary care record at any time prior to 1st January 2010 and were aged ≥40 years at the start of the study period. Using clinician-coded diagnoses, CAP episodes which occurred over a 1-year period from the 1st January 2010 were identified using Read and ICD-10 code lists and were defined as taking up to 70 days to resolve. Listed co-morbidities were based on coded entries at any time prior to 1st January 2010. Results Included were 6707 patients with a complete history in 2010 and valid data for all variables considered in the analysis. 55% of patients were men and 36% were current smokers, the mean age was 70 years. 189 patients (2.8%) had at least one CAP episode during 2010. Compared to patients without CAP, patients with CAP were more likely to have ischaemic heart disease (IHD p = 0.005), congestive heart failure (CHF p = 0.021), hypertension (p = 0.017), cerebrovascular disease (CVD p < 0.001), dementia (p < 0.001), and bronchiectasis (p = 0.001). Using logistic regression and controlling for potential confounders, CVD and dementia were independent risk factors for CAP (p = 0.009 and 0.007, respectively), while bronchiectasis trended towards significance (p = 0.073) (Table 1).Abstract S121 Table 1 Co-morbidities associated with CAP occurrence in COPD Conclusion In this large population database analysis, CVD and dementia were identified as being independently associated with an increased risk of CAP. Oro-pharyngeal dysfunction in CVD and use of sedative medications in dementia, may contribute to these findings. Further analysis of the complete cohort, over the full 5-year observation period will allow the formulation of robust conclusions about the important factors of CAP risk in COPD, including the impact of pharmacotherapy, blood markers and functional parameters.