The causes and consequences of seasonal variation in COPD exacerbations

Gavin C Donaldson, Jadwiga A Wedzicha Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Abstract: The time of year when patients experience exacerbations of chronic obstructive pulmonary disease is a much-overlooked feature of the disease. The higher incidence of exacerbations in winter has important consequences for patients in terms of increased morbidity and mortality. The seasonality also imposes a considerable burden on already-overloaded health care services, with both primary care consultations and hospital admissions increasing in number. The seasonality of exacerbations varies with latitude, and is greater in more temperate climates, where there may be less protection from outdoor and indoor cold exposure. The precise causes of the seasonality are unknown, but thought to be partly due to the increased prevalence of respiratory viral infections circulating in cold, damp conditions. Increased susceptibility to viral infection may also be a mechanism mediated through increased airway inflammation or possibly reduced vitamin D levels. The seasonality of exacerbations informs us about the triggers of exacerbations and suggests possible strategies to reduce their number. Keywords: exacerbations of COPD, seasonality, winter mortality, winter morbidit

Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations

The FORWARD study is a randomised, double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate (BDP/FOR), 100/6 μg pMDI, 2 inhalations BID, vs. FOR 12 μg pMDI, 1 inhalation BID, in severe COPD patients with a history of exacerbations. Co-primary endpoints were exacerbation rate over 48 weeks and pre-dose morning FEV1 at 12 weeks. The ITT population included 1186 patients (69% males, mean age 64 years) with severe airflow limitation (mean post-bronchodilator FEV1 42% predicted). Salbutamol as rescue therapy, theophylline and tiotropium (if stable regimen prior to screening) were allowed. Compared to FOR, BDP/FOR: (1) reduced the exacerbation rate (rate ratio: 0.72 [95% confidence interval 0.62–0.84], p < 0.001); (2) improved pre-dose morning FEV1 (mean difference: 0.069 L [0.043–0.095] p < 0.001); (3) prolonged the time to first exacerbation; (4) improved the SGRQ total score. The percentage of patients with adverse events was similar (52.1% with BDP/FOR and 49.2% with FOR). Pneumonia incidence was low, slightly higher with BDP/FOR (3.8%) than with FOR (1.8%). No difference for laboratory values, ECG or vital signs. Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of patients with severe COPD and history of exacerbations as compared to FOR alone

Associations between gastro-oesophageal reflux, its management and exacerbations of chronic obstructive pulmonary disease

To determine factors, overall and by sex, associated with self-reported gastro-oesophageal reflux disease (GORD) in chronic obstructive pulmonary disease (COPD) patients, and to evaluate relationships between GORD, its modification by acid suppression medications (Proton Pump Inhibitors [PPI]/histamine-2 receptor antagonists [H2RA]) and exacerbations of COPD and mortality

Predicting mortality after acute coronary syndromes in people with chronic obstructive pulmonary disease

Objective To assess the accuracy of Global Registry of Acute Coronary Events (GRACE) scores in predicting mortality at 6 months for people with chronic obstructive pulmonary disease (COPD) and to investigate how it might be improved. Methods Data were obtained on 481 849 patients with acute coronary syndrome admitted to UK hospitals between January 2003 and June 2013 from the Myocardial Ischaemia National Audit Project (MINAP) database. We compared risk of death between patients with COPD and those without COPD at 6 months, adjusting for predicted risk of death. We then assessed whether several modifications improved the accuracy of the GRACE score for people with COPD. Results The risk of death after adjusting for GRACE score predicted that risk of death was higher for patients with COPD than that for other patients (RR 1.29, 95% CI 1.28 to 1.33). Adding smoking into the GRACE score model did not improve accuracy for patients with COPD. Either adding COPD into the model (relative risk (RR) 1.00, 0.94 to 1.02) or multiplying the GRACE score by 1.3 resulted in better performance (RR 0.99, 0.96 to 1.01). Conclusions GRACE scores underestimate risk of death for people with COPD. A more accurate prediction of risk of death can be obtained by adding COPD into the GRACE score equation, or by multiplying the GRACE score predicted risk of death by 1.3 for people with COPD. This means that one third of patients with COPD currently classified as low risk should be classified as moderate risk, and could be considered for more aggressive early treatment after non-ST-segment elevation myocardial infarction or unstable angina

Defective monocyte-derived macrophage phagocytosis is associated with exacerbation frequency in COPD

Background Lower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters. Methods Monocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR. Results Phagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs. 2.5 × 103 RFU, p < 0.01). There was no correlation for S. pneumoniae. There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators. Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation. In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state. Conclusion Impaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial

Upper respiratory symptoms worsen over time and relate to clinical phenotype in COPD.

Copyright © 2015 by the American Thoracic Society.Rationale: How nasal symptoms in patients with chronic obstructive pulmonary disease (COPD) change over time and resolve during naturally occurring exacerbations has not been described previously. Objectives: To evaluate the evolution and impact of upper airway symptoms in a well-defined COPD cohort when stable and at exacerbation. Methods: Patients in the LondonCOPDcohortwere asked about the presence of nasal symptoms (nasal discharge, sneezing, postnasal drip, blocked nose, and anosmia) over an 8-year period (2005-2013) every 3 months at routine clinic visits while in a stable state and daily during exacerbations with the use of diary cards. Data were prospectively collected, and, in a subgroup of patients,COPDAssessment Test scores and human rhinovirus identification by polymerase chain reaction were available. Patients were also defined as having infrequent or frequent exacerbations (<2 or ≥2 exacerbations/yr, respectively). Measurements and Main Results: At an aggregate of 4,368 visits, 209 patients with COPD were asked about their nasal symptoms. At 2,033 visits when the patients were stable, the odds ratio (OR) for nasal discharge increased by 1.32% per year (95% confidence interval [CI], 1.19-1.45; P<0.001); the OR for sneezing increased by 1.16%(95%CI, 1.05-1.29;P = 0.005); theORfor postnasal drip increased by 1.18% (95% CI, 1.03-1.36; P=0.016); and theOR for anosmia increased by 1.19% (95% CI, 1.03-1.37; P = 0.015). At visits when the patients were having exacerbations, nasal discharge was present for 7 days and blocked nose, sneezing, and postnasal drip increased for just 3 days. Anosmia did not change. Nasal dischargewasmore likely inpatientswith frequent exacerbations (OR, 1.96; 95% CI, 1.17-3.28; P= 0.011), and COPD Assessment Test scores were higher by 1.06 units (95% CI, 0.32-1.80; P=0.005) when patients were stable and higher by 1.30 units (95% CI, 0.05-2.57; P= 0.042) during exacerbations. Conclusions: Upper airway symptoms increase over time in patients with COPD and are related to the frequent exacerbation phenotype. These longitudinal changes may be due to increasing airway inflammation or to progression of COPD

Inhaled corticosteroids reduce senescence in endothelial progenitor cells from COPD patients

Cellular senescence contributes to the pathophysiology of chronic obstructive pulmonary disease (COPD) and cardiovascular disease. Using endothelial-colony-forming-cells (ECFC), we have demonstrated accelerated senescence in smokers and COPD patients compared to non-smokers. Subgroup analysis suggests that ECFC from COPD patients on inhaledcorticosteroids (ICS) (n=14; 8 on ICS) exhibited significantly reduced senescence (Senescence-associated-beta galactosidase activity, p21CIP1), markers of DNA damage response (DDR) and IFN-γ-inducible-protein-10 compared to COPD patients not on ICS. In vitro studies using human-umbilical-vein-endothelial-cells showed a protective effect of ICS on the DDR, senescence and apoptosis caused by oxidative-stress, suggesting a protective molecular mechanism of action of corticosteroids on endothelium

Impact of a functional polymorphism in the PAR-1 gene promoter in COPD and COPD exacerbations

Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G&gt;A in modulating PAR-1/ F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G&gt;A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G&gt;A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G&gt;A polymorphism was found to increase F2R expression by 2.6-fold ( P &lt; 0.001). The rs2227744G&gt;A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations ( P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G&gt;A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted. </jats:p