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1.  Oxygen therapy in acute exacerbations of chronic obstructive pulmonary disease 
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the history of this debilitating lung condition. Associated health care utilization and morbidity are high, and many patients require supplemental oxygen or ventilatory support. The last 2 decades have seen a substantial increase in our understanding of the best way to manage the respiratory failure suffered by many patients during this high-risk period. This review article examines the evidence underlying supplemental oxygen therapy during exacerbations of COPD. We first discuss the epidemiology and pathophysiology of respiratory failure in COPD during exacerbations. The rationale and evidence underlying oxygen therapy, including the risks when administered inappropriately, are then discussed, along with further strategies for ventilatory support. We also review current recommendations for best practice, including methods for improving oxygen provision in the future.
PMCID: PMC4230177  PMID: 25404854
chronic obstructive pulmonary disease (COPD); exacerbation; oxygen therapy; respiratory failure; hypercapnia
2.  The causes and consequences of seasonal variation in COPD exacerbations 
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.
PMCID: PMC4199860  PMID: 25336941
exacerbations of COPD; seasonality; winter mortality; winter morbidity
3.  Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease 
Respiratory Research  2014;15(1):114.
There has been increasing interest in the use of newer, culture-independent techniques to study the airway microbiome of COPD patients. We investigated the relationships between the three common potentially pathogenic microorganisms (PPMs) Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, as detected by quantitative PCR (qPCR), and inflammation and health status in stable patients in the London COPD cohort.
We prospectively collected sputum, serum and plasma samples for analysis of airway bacterial presence and load, and airway and systemic inflammation from 99 stable COPD patients between January 2011 and October 2012. Health status was measured with St George’s Respiratory Questionnaire and COPD Assessment Test.
Airway inflammation and plasma fibrinogen, but not C-reactive protein, were greater in samples with PPM detection (p < 0.001, p = 0.049 and p = 0.261, respectively). Increasing total bacterial load was associated with increasing airway (p < 0.01) but not systemic inflammation (p > 0.05). Samples with high total bacterial loads had significantly higher airway inflammation than both samples without PPM detection and those with lower loads. Haemophilus influenzae presence was associated with significantly higher levels of airway but not systemic inflammation for all given pathogen loads (p < 0.05), and was significantly greater than with other PPMs. No association was observed between inflammation and health status (p > 0.05).
Airway and systemic inflammation, as measured by fibrinogen, is greater in stable COPD patients with PPMs detected using the culture-independent qPCR technique. The airway, but not systemic inflammatory response, appears to have a total pathogen-load threshold and appears attributable to Haemophilus influenzae. However, discordance between inflammation and health status was observed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0114-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4173051  PMID: 25218165
COPD; Inflammation; Bacteria; Colonisation
4.  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>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>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>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>A polymorphism was found to increase F2R expression by 2.6-fold (P < 0.001). The rs2227744G>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>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.
PMCID: PMC4137163  PMID: 24973402
PAR-1; F2R; SNP; COPD; COPD exacerbation
5.  Daily activity during stability and exacerbation of chronic obstructive pulmonary disease 
During most COPD exacerbations, patients continue to live in the community but there is little information on changes in activity during exacerbations due to the difficulties of obtaining recent, prospective baseline data.
Patients recorded on daily diary cards any worsening in respiratory symptoms, peak expiratory flow (PEF) and the number of steps taken per day measured with a Yamax Digi-walker pedometer. Exacerbations were defined by increased respiratory symptoms and the number of exacerbations experienced in the 12 months preceding the recording of daily step count used to divide patients into frequent (> = 2/year) or infrequent exacerbators.
The 73 COPD patients (88% male) had a mean (±SD) age 71(±8) years and FEV1 53(±16)% predicted. They recorded pedometer data on a median 198 days (IQR 134–353). At exacerbation onset, symptom count rose by 1.9(±1.3) and PEF fell by 7(±13) l/min. Mean daily step count fell from 4154(±2586) steps/day during a preceding baseline week to 3673(±2258) step/day during the initial 7 days of exacerbation (p = 0.045). Patients with larger falls in activity at exacerbation took longer to recover to stable level (rho = −0.56; p < 0.001). Recovery in daily step count was faster (median 3.5 days) than for exacerbation symptoms (median 11 days; p < 0.001). Recovery in step count was also faster in untreated compared to treated exacerbation (p = 0.030).
Daily step count fell faster over time in the 40 frequent exacerbators, by 708 steps/year, compared to 338 steps/year in 33 infrequent exacerbators (p = 0.002).
COPD exacerbations reduced physical activity and frequent exacerbations accelerate decline in activity over time.
PMCID: PMC4057595  PMID: 24885188
COPD; Exacerbation; Daily step-count; Physical activity; Daily monitoring
6.  Cardiovascular Risk, Myocardial Injury, and Exacerbations of Chronic Obstructive Pulmonary Disease 
Rationale: Patients with chronic obstructive pulmonary disease (COPD) have elevated cardiovascular risk, and myocardial injury is common during severe exacerbations. Little is known about the prevalence, magnitude, and underlying mechanisms of cardiovascular risk in community-treated exacerbations.
Objectives: To investigate how COPD exacerbations and exacerbation frequency impact cardiovascular risk and myocardial injury, and whether this is related to airway infection and inflammation.
Methods: We prospectively measured arterial stiffness (aortic pulse wave velocity [aPWV]) and cardiac biomarkers in 98 patients with stable COPD. Fifty-five patients had paired stable and exacerbation assessments, repeated at Days 3, 7, 14, and 35 during recovery. Airway infection was identified using polymerase chain reaction.
Measurements and Main Results: COPD exacerbation frequency was related to stable-state arterial stiffness (rho = 0.209; P = 0.040). Frequent exacerbators had greater aPWV than infrequent exacerbators (mean ± SD aPWV, 11.4 ± 2.1 vs. 10.3 ± 2.0 ms−1; P = 0.025). Arterial stiffness rose by an average of 1.2 ms−1 (11.1%) from stable state to exacerbation (n = 55) and fell slowly during recovery. In those with airway infection at exacerbation (n = 24) this rise was greater (1.4 ± 1.6 vs. 0.7 ± 1.3 ms−1; P = 0.048); prolonged; and related to sputum IL-6 (rho = 0.753; P < 0.001). Increases in cardiac biomarkers at exacerbation were higher in those with ischemic heart disease (n = 12) than those without (n = 43) (mean ± SD increase in troponin T, 0.011 ± 0.009 vs. 0.003 ± 0.006 μg/L, P = 0.003; N-terminal pro–brain natriuretic peptide, 38.1 ± 37.7 vs. 5.9 ± 12.3 pg/ml, P < 0.001).
Conclusions: Frequent COPD exacerbators have greater arterial stiffness than infrequent exacerbators. Arterial stiffness rises acutely during COPD exacerbations, particularly with airway infection. Increases in arterial stiffness are related to inflammation, and are slow to recover. Myocardial injury is common and clinically significant during COPD exacerbations, particularly in those with underlying ischemic heart disease.
PMCID: PMC3863745  PMID: 24033321
chronic obstructive pulmonary disease; exacerbation; arterial stiffness; troponin; brain natriuretic peptide
7.  Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease 
BMC Medicine  2013;11:181.
Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.
PMCID: PMC3750926  PMID: 23945277
Chronic obstructive pulmonary disease (COPD); Exacerbations; Frequent exacerbator phenotype; Comorbidities
8.  Factors associated with change in exacerbation frequency in COPD 
Respiratory Research  2013;14(1):79.
Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to year, some will, and the factors associated with this behaviour have not been examined.
1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were defined by health care utilisation. Patient characteristics compared between those patients who did or did not change exacerbation category from year 1 to year 2.
Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE. More severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the preceding year, small falls in FEV1 and 6-minute walking distance were associated with changing from IE to FE, and small falls in platelet count associated with changing from FE to IE.
No parameter clearly predicts an imminent change in exacerbation frequency category.
Trial registration
SCO104960, identifier NCT00292552
PMCID: PMC3733814  PMID: 23899210
COPD; Exacerbations; Exacerbation frequency; Exacerbation phenotype
10.  Intersession Repeatability of Acoustic Rhinometry Measurements in Healthy Volunteers 
Acoustic rhinometry is a rapid, reliable and non-invasive technique for the evaluation of conditions associated with impaired nasal patency. This study aimed to examine the intersession repeatability of acoustic rhinometry measurements of unilateral and combined nasal parameters in a group of healthy volunteers.
Twenty healthy volunteers were studied. In each subject, acoustic rhinometry measurements were performed on five consecutive days, with multiple recordings. Five clinically relevant parameters were measured in each session and the intersession repeatability of these measurements was expressed in terms of mean coefficient of variation, intraclass correlation coefficient and inter-item correlations.
Intraclass correlation coefficients showed a high, and greater repeatability over time for all the combined (mean) values compared to the unilateral values. All intraclass correlations for combined values were ≥0.80 confirming almost perfect agreement. All intraclass correlations and inter-item correlations were associated with P<0.001. The mean coefficient of variation was low (<10%) for all but the proximal minimum cross sectional area (MCA1) measurements.
Acoustic rhinometry provides highly repeatable measurements of nasal patency, which is best for combined (mean) nasal parameters. This property makes it suitable for use in the diagnosis and follow-up of conditions associated with nasal obstruction, either structural or functional.
PMCID: PMC3437417  PMID: 22977713
Acoustic rhinometry; Reproducibility of results; Nasal obstruction
11.  25-hydroxyvitamin D deficiency, exacerbation frequency and human rhinovirus exacerbations in chronic obstructive pulmonary disease 
25-hydroxyvitamin D deficiency is associated with COPD and increased susceptibility to infection in the general population.
We investigated whether COPD patients deficient in 25-hydroxyvitamin D were more likely to be frequent exacerbators, had reduced outdoor activity and were more susceptible to human rhinovirus (HRV) exacerbations than those with insufficient and normal levels. We also investigated whether the frequency of FokI, BsmI and TaqIα 25-hydroxyvitamin D receptor (VDR) polymorphisms differed between frequent and infrequent exacerbators.
There was no difference in 25-hydroxyvitamin D levels between frequent and infrequent exacerbators in the summer; medians 44.1nmol/L (29.1 – 68.0) and 39.4nmol/L (22.3 – 59.2) or winter; medians 24.9nmol/L (14.3 – 43.1) and 27.1nmol/L (19.9 – 37.6). Patients who spent less time outdoors in the 14 days prior to sampling had lower 25-hydroxyvitamin D levels (p = 0.02). Day length was independently associated with 25-hydroxyvitamin D levels (p = 0.02). There was no difference in 25-hydroxyvitamin D levels between baseline and exacerbation; medians 36.2nmol/L (IQR 22.4-59.4) and 33.3nmol/L (23.0-49.7); p = 0.43. HRV positive exacerbations were not associated with lower 25-hydroxyvitamin D levels at exacerbation than exacerbations that did not test positive for HRV; medians 30.0nmol/L (20.4 – 57.8) and 30.6nmol/L (19.4 – 48.7). There was no relationship between exacerbation frequency and any VDR polymorphisms (all p > 0.05).
Low 25-hydroxyvitamin D levels in COPD are not associated with frequent exacerbations and do not increase susceptibility to HRV exacerbations. Independent of day length, patients who spend less time outdoors have lower 25-hydroxyvitamin D concentration.
PMCID: PMC3403978  PMID: 22726649
12.  IL-1α/IL-1R1 Expression in Chronic Obstructive Pulmonary Disease and Mechanistic Relevance to Smoke-Induced Neutrophilia in Mice 
PLoS ONE  2011;6(12):e28457.
Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood.
Methodology and Principal Findings
The objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation.
Conclusions and Significance
This study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.
PMCID: PMC3232226  PMID: 22163019
13.  Domiciliary pulse-oximetry at exacerbation of chronic obstructive pulmonary disease: prospective pilot study 
The ability to objectively differentiate exacerbations of chronic obstructive pulmonary disease (COPD) from day-to-day symptom variations would be an important development in clinical practice and research. We assessed the ability of domiciliary pulse oximetry to achieve this.
40 patients with moderate-severe COPD collected daily data on changes in symptoms, heart-rate (HR), oxygen saturation (SpO2) and peak-expiratory flow (PEF) over a total of 2705 days. 31 patients had data suitable for baseline analysis, and 13 patients experienced an exacerbation. Data were expressed as multiples of the standard deviation (SD) observed from each patient when stable.
In stable COPD, the SD for HR, SpO2 and PEF were approximately 5 min-1, 1% and 10l min-1. There were detectable changes in all three variables just prior to exacerbation onset, greatest 2-3 days following symptom onset. A composite Oximetry Score (mean magnitude of SpO2 fall and HR rise) distinguished exacerbation onset from symptom variation (area under receiver-operating characteristic curve, AUC = 0.832, 95%CI 0.735-0.929, p = 0.003). In the presence of symptoms, a change in Score of ≥1 (average of ≥1SD change in both HR and SpO2) was 71% sensitive and 74% specific for exacerbation onset.
We have defined normal variation of pulse oximetry variables in a small sample of patients with COPD. A composite HR and SpO2 score distinguished exacerbation onset from symptom variation, potentially facilitating prompt therapy and providing validation of such events in clinical trials.
PMCID: PMC2978135  PMID: 20961450
15.  Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial 
Respiratory Research  2010;11(1):10.
Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations.
Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks' follow-up.
At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006).
There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George's Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%).
Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development.
Trial registration number, NCT00473460 (
PMCID: PMC2834642  PMID: 20109213
16.  Management and prevention of chronic obstructive pulmonary disease exacerbations: a state of the art review 
BMC Medicine  2009;7:40.
Exacerbations of chronic obstructive pulmonary disease (COPD) are important events in the natural history of this prevalent and devastating condition. This review provides a concise, state of the art summary on prevention and management of exacerbations. Considerable new data underpins evidence in support of many preventative interventions, pharmacological and non-pharmacological, that are now available. Challenges remain in developing new approaches, and delivering those that already exist to the right patient at the right time. Management of an exacerbation remains stepwise according to clinical severity, but there is now additional focus on addressing comorbidities and taking the opportunity at acute events to optimise preventative strategies for the future. Ultimately, exacerbations are heterogeneous events in a heterogeneous disease, and an individualised approach is paramount.
PMCID: PMC2734841  PMID: 19664218
17.  Exacerbation rate, health status and mortality in COPD – a review of potential interventions 
COPD is prevalent in Western society and its incidence is rising in the developing world. Acute exacerbations of COPD, about 50% of which are unreported, lead to deterioration in quality of life and contribute significantly to disease burden. Quality of life deteriorates with time; thus, most of the health burden occurs in more severe disease. COPD severity and frequent and more severe exacerbations are all related to an increased risk of mortality. Inhaled corticosteroids (ICS) have similar effects on quality of life but ICS/long-acting bronchodilator combinations and the long-acting antimuscarinic tiotropium all improve health status and exacerbation rates and are likely to have an effect on mortality but perhaps only with prolonged use. Erythromycin has been shown to decrease the rate of COPD exacerbations. Pulmonary rehabilitation and regular physical activity are indicated in all severities of COPD and improve quality of life. Noninvasive ventilation is associated with improved quality of life. Long-term oxygen therapy improves mortality but only in hypoxic COPD patients. The choice of an inhaler device is a key component of COPD therapy and this requires more attention from physicians than perhaps we are aware of. Disease management programs, characterized as they are by patient centeredness, improve quality of life and decrease hospitalization rates. Most outcomes in COPD can be modified by interventions and these are well tolerated and have acceptable safety profiles.
PMCID: PMC2699821  PMID: 19554195
COPD; exacerbation; health burden; mortality; inhaled steroids; long-acting bronchodilators; long-acting antimuscarinic agents; macrolide; disease management program; tolerability; safety; pulmonary rehabilitation; exercise
18.  Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial 
Respiratory Research  2007;8(1):93.
Guidelines recommend inhaled corticosteroids (ICS) for patients with severe chronic obstructive pulmonary disease (COPD). Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity. The effect of withdrawing ICS from COPD patients in primary care is unknown.
In a pragmatic randomised, double-blind, placebo-controlled trial in 31 practices, 260 COPD patients stopped their usual ICS (median duration of use 8 years) and were allocated to 500 mcg fluticasone propionate twice daily (n = 128), or placebo (n = 132). Follow-up assessments took place at three monthly intervals for a year at the patients' practice. Our primary outcome was COPD exacerbation frequency. Secondary outcomes were time to first COPD exacerbation, reported symptoms, peak expiratory flow rate and reliever inhaler use, and lung function and health related quality of life.
In patients randomised to placebo, COPD exacerbation risk over one year was RR: 1.11 (CI: 0.91–1.36). Patients taking placebo were more likely to return to their usual ICS following exacerbation, placebo: 61/128 (48%); fluticasone: 34/132 (26%), OR: 2.35 (CI: 1.38–4.05). Exacerbation risk whilst taking randomised treatment was significantly raised in the placebo group 1.48 (CI: 1.17–1.86). Patients taking placebo exacerbated earlier (median time to first exacerbation: placebo (days): 44 (CI: 29–59); fluticasone: 63 (CI: 53–74), log rank 3.81, P = 0.05) and reported increased wheeze. In a post-hoc analysis, patients with mild COPD taking placebo had increased exacerbation risk RR: 1.94 (CI: 1.20–3.14).
Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration. Patients with mild COPD may be at increased risk of exacerbation after withdrawal.
Trial Registration NCT00440687
PMCID: PMC2245934  PMID: 18162137
19.  Acute exacerbations 
BMJ : British Medical Journal  2006;333(7558):87-89.
PMCID: PMC1489228  PMID: 16825232
20.  Effectiveness of innovations in nurse led chronic disease management for patients with chronic obstructive pulmonary disease: systematic review of evidence 
BMJ : British Medical Journal  2005;331(7515):485.
Objective To determine the effectiveness of innovations in management of chronic disease involving nurses for patients with chronic obstructive pulmonary disease (COPD).
Design Systematic review of randomised controlled trials.
Data sources 24 electronic databases searched for English or Dutch language studies published between January 1980 and January 2005.
Review methods Included studies described inpatient, outpatient, and community based interventions for chronic disease management that were led, coordinated, or delivered by nurses. Hospital at home and early discharge schemes for acute exacerbations of COPD were excluded.
Results We identified nine relevant randomised controlled trials, most of which had some potential methodological flaws. All the interventions seemed to be variations on a case management model. The interventions described could be divided into brief (one month) and longer term (around a year) or more intensive interventions. Only two studies examined the effect of brief interventions, these found little evidence of any benefit. Meta-analysis of the long term interventions failed to detect any influence on mortality at 9-12 months' follow-up (Peto odds ratio 0.85, 95% confidence interval 0.58 to 1.26). There was evidence that the long term interventions had not improved patients' health related quality of life, psychological wellbeing, disability, or pulmonary function. The evidence on whether long term interventions reduced readmissions to hospital was equivocal, but the only study exclusively directed at patients on long term oxygen therapy reported a reduction in readmission. We identified several outcomes where little or no evidence was available; these included patients' satisfaction, self management skills, adherence with treatment recommendations, the likelihood of smoking cessation, and the effect of the interventions on carers.
Conclusion There is little evidence to date to support the widespread implementation of nurse led management interventions for COPD, but the data are too sparse to exclude any clinically relevant benefit or harm arising from such interventions.
PMCID: PMC1199024  PMID: 16093253
21.  Hospital at home for patients with acute exacerbations of chronic obstructive pulmonary disease: systematic review of evidence 
BMJ : British Medical Journal  2004;329(7461):315.
Objectives To evaluate the efficacy of hospital at home schemes compared with inpatient care in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD).
Design A systematic review of randomised controlled trials.
Main outcome measure Mortality and readmission to hospital.
Results Seven trials with 754 patients were included in the review. Hospital readmission and mortality were not significantly different when hospital at home schemes were compared with inpatient care (relative risk 0.89, 95% confidence interval 0.72 to 1.12, and 0.61, 0.36 to 1.05, respectively). However, compared with inpatient care, hospital at home schemes were associated with substantial cost savings as well as freeing up hospital inpatient beds.
Conclusions Hospital at home schemes can be safely used to care for patients with acute exacerbations of COPD who would otherwise be admitted to hospital. Clinicians should consider this form of management, especially as there is increasing pressure for inpatient beds in the United Kingdom.
PMCID: PMC506849  PMID: 15242868
22.  Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis 
BMJ : British Medical Journal  2003;326(7382):185.
To determine the effectiveness of non-invasive positive pressure ventilation (NPPV) in the management of respiratory failure secondary to acute exacerbation of chronic obstructive pulmonary disease.
Systematic review of randomised controlled trials that compared NPPV and usual medical care with usual medical care alone in patients admitted to hospital with respiratory failure resulting from an exacerbation of chronic obstructive pulmonary disease and with PaCO2 >6 kPa.
The eight studies included in the review showed that, compared with usual care alone, NPPV as an adjunct to usual care was associated with a lower mortality (relative risk 0.41 (95% confidence interval 0.26 to 0.64)), a lower need for intubation (relative risk 0.42 (0.31 to 0.59)), lower likelihood of treatment failure (relative risk 0.51 (0.38 to 0.67)), and greater improvements at 1 hour in pH (weighted mean difference 0.03 (0.02 to 0.04)), PaCO2 (weighted mean difference −0.40 kPa (−0.78 to −0.03)), and respiratory rate (weighted mean difference −3.08 breaths per minute (−4.26 to −1.89)). NPPV resulted in fewer complications associated with treatment (relative risk 0.32 (0.18 to 0.56)) and shorter duration of stay in hospital (weighted mean difference −3.24 days (−4.42 to −2.06)).
NPPV should be the first line intervention in addition to usual medical care to manage respiratory failure secondary to an acute exacerbation of chronic obstructive pulmonary disease in all suitable patients. NPPV should be tried early in the course of respiratory failure and before severe acidosis, to reduce mortality, avoid endotracheal intubation, and decrease treatment failure.
What is already known on this topicProspective studies, especially the larger studies, have shown that non-invasive positive pressure ventilation (NPPV) reduces the need for intubation, improves survival, and reduces complications in patients with respiratory failure resulting from exacerbation of chronic obstructive pulmonary disease (COPD)A previous meta-analysis showed NPPV to be an effective intervention, including for acute exacerbations of COPD, but some studies in this meta-analysis contained mixed groups of patients and were not of good qualityWhat this study addsEvidence from good quality, randomised controlled trials shows that NPPV is an effective treatment for acute exacerbations of COPDNPPV should be considered early in the course of respiratory failure and before severe acidosis ensues, to avoid the need for endotracheal intubation and reduce mortality in patients with COPD
PMCID: PMC140272  PMID: 12543832
23.  The role of bronchodilator treatment in the prevention of exacerbations of COPD 
The European Respiratory Journal  2012;40(6):1545-1554.
Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea. These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD. Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (≥2 per year) independently of disease severity. Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis.
The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting β2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS). While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance. Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation. Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations.
Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations.
PMCID: PMC3511775  PMID: 22835613
Bronchodilator; chronic obstructive pulmonary disease; dyspnoea; exacerbations; long-acting anti-muscarinic agent; long-acting β2-agonists
24.  Community-based recruitment of patients with COPD into clinical research 
Thorax  2014;69(10):951-952.
Identifying subjects for clinical trials is difficult and the evidence base for recruitment strategies is limited, particularly in the field of COPD. We compared the efficiency and patient characteristics of different community-based recruitment strategies during a non-commercial COPD trial in the UK. Recruiting from general practice COPD registers was less efficient and identified patients with significantly milder disease than recruiting through pulmonary rehabilitation and patient groups. We report our experience and propose that pulmonary rehabilitation and patient groups may represent an enriched pool of COPD patients to recruit into clinical trials.
Trial registration number:
EudraCT 2011-001063-43
PMCID: PMC4174139  PMID: 24595667
COPD Epidemiology; Pulmonary Rehabilitation

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