Jennifer Quint

Defective macrophage phagocytosis of bacteria in COPD

Exacerbations of chronic obstructive pulmonary disease (COPD) are an increasing cause of hospitalisations and are associated with accelerated progression of airflow obstruction. Approximately half of COPD exacerbations are associated with bacteria and many patients have lower airways colonisation. This suggests that bacterial infection in COPD could be due to reduced pathogen removal. This study investigated whether bacterial clearance by macrophages is defective in COPD. Phagocytosis of fluorescently labelled polystyrene beads and Haemophillus influenzae and Streptococcus pneumoniae by alveolar macrophages and monocyte-derived macrophages (MDM) was assessed by fluorimetry and flow cytometry. Receptor expression was measured by flow cytometry. Alveolar macrophages and MDM phagocytosed polystyrene beads similarly. There was no difference in phagocytosis of beads by MDM from COPD patients compared with cells from smokers and nonsmokers. MDM from COPD patients showed reduced phagocytic responses to S. pneumoniae and H. influenzae compared with nonsmokers and smokers. This was not associated with alterations in cell surface receptor expression of toll-like receptor (TLR)2, TLR4, macrophage receptor with collagenous structure, cluster of differentiation (CD)163, CD36 or mannose receptor. Budesonide, formoterol or azithromycin did not suppress phagocytosis suggesting that reduced responses in COPD MDM were not due to medications. COPD macrophage innate responses are suppressed and may lead to bacterial colonisation and increased exacerbation frequency.

Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease

RATIONALE Exacerbations are important events in chronic obstructive pulmonary disease. Preventing exacerbations is a key treatment goal. Observational data suggest that after a first exacerbation, patients may be at increased risk of a second exacerbation, but this has not been specifically studied. We hypothesized that exacerbations may cluster together in time, a finding that would have important implications for targeting preventative interventions and the analysis of clinical trial data. OBJECTIVES To assess whether exacerbations are random events, or cluster in time. METHODS A total of 297 patients in the London chronic obstructive pulmonary disease cohort recorded daily symptoms and were assessed for a total of 904 patient-years. The observed timing of second exacerbations after an initial exacerbation was compared with that expected should exacerbations occur randomly. MEASUREMENTS AND MAIN RESULTS The observed timing distribution of second exacerbations differed significantly (P < 0.001) from the expected exponential function (shape parameter of the fitted Weibull function, 0.966 [95% confidence interval, 0.948-0.985]), suggesting that more second exacerbations occurred sooner than later and that exacerbations cluster together in time. Twenty-seven percent of first exacerbations were followed by a second recurrent event within 8 weeks. Approximately one third of exacerbations were recurrent exacerbations. Although initial exacerbations were milder than isolated events, they were not less likely to receive treatment, and under-treatment of initial events is not a plausible explanation for exacerbation recurrence. Recurrent exacerbations contribute significantly to overall exacerbation frequency (rho = 0.81; P < 0.0001). CONCLUSIONS Exacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial excerbation.

Relationship between depression and exacerbations in COPD

Chronic obstructive pulmonary disease is associated with exacerbations. Some patients are prone to frequent exacerbations and these individuals have a worse quality of life, greater limitation of their daily activity and faster disease progression than patients with less frequent exacerbations. A prospective study in a well-characterised cohort was performed and it was assessed whether depression, as determined by the Centre for Epidemiologic Studies Depression Scale, was related to exacerbation frequency, systemic inflammation and various social factors. The associations of any increase in depressive symptoms at exacerbation were also investigated. Frequent exacerbators had a significantly higher median (interquartile range) baseline depression score than infrequent exacerbators (17.0 (7.0–25.0) and 12.0 (6.0–18.0), respectively). Depressed patients spend significantly less time outdoors and had significantly worse quality of life as measured by the St Georges Respiratory Questionnaire. Depression increased significantly in patients from baseline to exacerbation (12.5 (5.0–19.0) and 19.5 (12.0–28.0) respectively). The present study is the first to show a relationship between depression and exacerbation frequency in patients with chronic obstructive pulmonary disease. The finding that frequent exacerbators are more depressed than infrequent exacerbators is relevant, as exacerbation frequency is an important outcome measure in chronic obstructive pulmonary disease.

Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population based cohort study

There is a paucity of data on incidence, prevalence and mortality associated with non-cystic fibrosis bronchiectasis. Using the Clinical Practice Research Datalink for participants registered between January 1, 2004 and December 31, 2013, we determined incidence, prevalence and mortality associated with bronchiectasis in the UK and investigated changes over time. The incidence and point prevalence of bronchiectasis increased yearly during the study period. Across all age groups, the incidence in women increased from 21.2 per 100 000 person-years in 2004 to 35.2 per 100 000 person-years in 2013 and in men from 18.2 per 100 000 person-years in 2004 to 26.9 per 100 000 person-years in 2013. The point prevalence in women increased from 350.5 per 100 000 in 2004 to 566.1 per 100 000 in 2013 and in men from 301.2 per 100 000 in 2004 to 485.5 per 100 000 in 2013. Comparing morality rates in women and men with bronchiectasis in England and Wales (n=11 862) with mortality rates in the general population from Office of National Statistics data showed that in women the age-adjusted mortality rate for the bronchiectasis population was 1437.7 per 100 000 and for the general population 635.9 per 100 000 (comparative mortality figure of 2.26). In men, the age-adjusted mortality rate for the bronchiectasis population was 1914.6 per 100 000 and for the general population 895.2 per 100 000 (comparative mortality figure of 2.14). Bronchiectasis is surprisingly common and is increasing in incidence and prevalence in the UK, particularly in older age groups. Bronchiectasis is associated with a markedly increased mortality. Bronchiectasis is increasing in incidence and prevalence in the UK, and is associated with an increased mortality http://ow.ly/Sh3Y9

Serum IP-10 as a Biomarker of Human Rhinovirus Infection at Exacerbation of COPD

BACKGROUND Human rhinovirus (HRV) is the most frequent virus associated with COPD exacerbations. Viral infections increase exacerbation severity and likelihood of hospitalization. As ease of sampling blood makes serum a more practical marker than sputum, we investigated whether changes in serum interferon-gamma-inducible protein 10 (IP-10) from baseline to exacerbation were higher in airway HRV-positive exacerbations and whether IP-10 levels related to HRV load. METHODS One hundred thirty-six patients with COPD and 70 controls were included over 2 years and 72 exacerbations sampled. HRV positivity and load were determined by reverse transcriptase-polymerase chain reaction in nasopharyngeal swabs and/or sputum at baseline and exacerbation. IP-10 was measured by enzyme-linked immunosorbent assay in serum and compared with HRV load. RESULTS At baseline, serum IP-10 was higher in patients with COPD than controls; medians were 149.4 pg/mL (103-215) and 111.7 pg/mL (82-178), P = .02. The presence of HRV at baseline did not increase IP-10: patients with COPD, 166.9 pg/mL (110-240) and 149.4 pg/mL (103-215), P = .30; controls, 136.4 pg/mL (77-204) and 111.7 pg/mL (82-178), P = .53. IP-10 increased significantly from baseline to exacerbation in HRV-positive exacerbations: 154.9 pg/mL (114.0-195.1) to 207.5 pg/mL (142.1-333.5), P = .009. There was no change in IP-10 between baseline and exacerbation in HRV-negative exacerbations: 168.3 pg/mL (94.3-249.8) and 175.6 pg/mL (107.2-290.4), P = .49. At exacerbation, IP-10 correlated with sputum viral load: rho = 0.48; P = .02. In receiver operating characteristics analysis, the combination of IP-10 and coryzal symptoms gave an area under the curve of 0.82 (95% CI, 0.74-0.90). CONCLUSIONS IP-10 increases from baseline to exacerbation in HRV-positive exacerbations and correlates with sputum HRV load. Serum IP-10 may be useful as a novel marker for these events.

Determinants and impact of fatigue in patients with chronic obstructive pulmonary disease.

RATIONALE The perception of fatigue in COPD has been associated with reduced health status. We have shown that exacerbations are associated with reduced activity and health status. However, the relationship between fatigue and exacerbation is unknown. OBJECTIVES To investigate the hypothesis that increased fatigue is related to physical inactivity and COPD exacerbations. METHODS Fatigue was studied in COPD and age-matched control subjects. The relationship between fatigue and stable patient characteristics in COPD, and the effect of exacerbation on fatigue were evaluated. MEASUREMENTS 107 COPD patients mean age 69 years (range 43-86), FEV(1) 53% (SD 21), and 30 aged-matched control subjects; Functional Assessment of Chronic Illness Therapy-Fatigue Scale, Centre for Epidemiological Studies Depression Scale. MAIN RESULTS Fatigue in COPD patients was significantly increased compared to control subjects (mean 35.3 units (SD 11.0) versus 43.2 (10.5), p=0.001). Increase in fatigue in COPD was related to reduced time spent outdoors (r=-0.43, p<0.001), increase in depression (r=-0.59, p<0.001) and annual exacerbation frequency (r=-0.27, p=0.005). Fatigue increased at exacerbation in 31/32 patients. Overall, fatigue increased by 8.3 units (5.9), p<0.001. Change in fatigue at exacerbation was related to increase in depression (r=-0.46, p=0.008). Fatigue recovered at 6 weeks following exacerbation. CONCLUSIONS The perception of fatigue increased in patients with COPD compared to age-matched control subjects, and associated with morbidity when patients were stable and at exacerbation.

Respiratory syncytial virus persistence in chronic obstructive pulmonary disease.

Respiratory syncytial virus (RSV) is predominantly recognized as a pediatric pathogen although sensitive molecular diagnostic techniques have led to its more frequent detection in some adult settings. In some studies RSV has been detected just as frequently in stable chronic obstructive pulmonary disease (COPD) patients as in those suffering disease exacerbations, leading to the suggestion that RSV may persist in COPD. Although some studies have found negligible RSV in stable COPD, others have detected RSV in one-quarter to one-third of stable COPD samples. Possible reasons for this discrepancy are explored within the article. A relationship between RSV detection and increased disease severity, including rate of decline in lung function and systemic/airway inflammation, has been found on both occasions it has been sought. Susceptibility to persistent RSV infection could involve both host and viral factors. Cigarette smoking and COPD are likely to result in impaired antiviral immunity, and RSV is capable of evading immune responses by inducing skewed type 2 T-helper cell responses, antagonizing antiviral cytokines, mimicking chemokines, inhibiting apoptosis, and entering immune-privileged cells such as pulmonary neurons. It can also escape an established immune response through antigenic drift. This article examines current evidence regarding persistence of RSV in COPD and its possible mechanisms. We also discuss various roles for RSV persistence in COPD pathogenesis. Further elucidation of the contribution of persistent RSV to the pathogenesis of COPD requires interventional studies. Persistence of RSV in COPD may have direct relevance to the pathogenesis of childhood diseases such as postbronchiolitic wheeze and asthma.

Effect of β blockers on mortality after myocardial infarction in adults with COPD: population based cohort study of UK electronic healthcare records

Objectives To investigate whether the use and timing of prescription of β blockers in patients with chronic obstructive pulmonary disease (COPD) having a first myocardial infarction was associated with survival and to identify factors related to their use. Design Population based cohort study in England. Setting UK national registry of myocardial infarction (Myocardial Ischaemia National Audit Project (MINAP)) linked to the General Practice Research Database (GPRD), 2003-11. Participants Patients with COPD with a first myocardial infarction in 1 January 2003 to 31 December 2008 as recorded in MINAP, who had no previous evidence of myocardial infarction in their GPRD or MINAP record. Data were provided by the Cardiovascular Disease Research using Linked Bespoke studies and Electronic Health Records (CALIBER) group at University College London. Main outcome measure Cox proportional hazards ratio for mortality after myocardial infarction in patients with COPD in those prescribed β blockers or not, corrected for covariates including age, sex, smoking status, drugs, comorbidities, type of myocardial infarction, and severity of infarct. Results Among 1063 patients with COPD, treatment with β blockers started during the hospital admission for myocardial infarction was associated with substantial survival benefits (fully adjusted hazard ratio 0.50, 95% confidence interval 0.36 to 0.69; P<0.001; median follow-up time 2.9 years). Patients already taking a β blocker before their myocardial infarction also had a survival benefit (0.59, 0.44 to 0.79; P<0.001). Similar results were obtained with propensity scores as an alternative method to adjust for differences between those prescribed and not prescribed β blockers. With follow-up started from date of discharge from hospital, the effect size was slightly attenuated but there was a similar protective effect of treatment with β blockers started during hospital admission for myocardial infarction (0.64, 0.44 to 0.94; P=0.02). Conclusions The use of β blockers started either at the time of hospital admission for myocardial infarction or before a myocardial infarction is associated with improved survival after myocardial infarction in patients with COPD. Registration NCT01335672.

Incidence of community-acquired lower respiratory tract infections and pneumonia among older adults in the United Kingdom: a population-based study

Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations.

Predictive accuracy of patient-reported exacerbation frequency in COPD

Chronic obstructive pulmonary disease (COPD) exacerbation frequency is important for clinical risk assessment and trial recruitment. In order to accurately establish exacerbation frequency, patients need to be followed for 1 yr, although this is not always practical. 1) Patient recall of exacerbation number during the year prior to recruitment to the London COPD cohort was compared with the number of exacerbations recorded on diary cards during the subsequent year; and 2) patient recall of their exacerbation number after 1 yr of follow-up was compared with documented exacerbations over the same year. A total of 267 patients (forced expiratory volume in 1 s 1.14 L) recorded worsening of respiratory symptoms on daily diary cards for 1 yr. Exacerbations were defined according to previously validated criteria. There was no difference between the exacerbation number recalled by patients prior to recruitment and the number detected during the first year (median 2.0 (interquartile range 1.0–4.0) and 2.0 (1.0–4.0); expected agreement 76.4%; agreement 84.6%; &kgr; = 0.3469). There was no difference between the number of exacerbations remembered by patients and the number recorded on diary cards over the same 1-yr period (2.0 (1.0–4.0) for both groups; expected agreement 74.9%; actual agreement 93.3%; &kgr; = 0.6146). Patients remember the number of exacerbations they have in a year. Accuracy is increased when comparing the same 1-yr period. Patient recall is sufficiently robust for stratification into frequent and infrequent exacerbator groups for subsequent years.