Jadwiga A. Wedzicha

Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) is characterised by both an accelerated decline in lung function and periods of acute deterioration in symptoms termed exacerbations. The aim of this study was to investigate whether these are related. Methods: Over 4 years, peak expiratory flow (PEF) and symptoms were measured at home daily by 109 patients with COPD (81 men; median (IQR) age 68.1 (63–74) years; arterial oxygen tension (Pao2) 9.00 (8.3–9.5) kPa, forced expiratory volume in 1 second (FEV1) 1.00 (0.7–1.3) l, forced vital capacity (FVC) 2.51 (1.9–3.0) l); of these, 32 (29 men) recorded daily FEV1. Exacerbations were identified from symptoms and the effect of frequent or infrequent exacerbations (> or < 2.92 per year) on lung function decline was examined using cross sectional, random effects models. Results: The 109 patients experienced 757 exacerbations. Patients with frequent exacerbations had a significantly faster decline in FEV1 and peak expiratory flow (PEF) of –40.1 ml/year (n=16) and –2.9 l/min/year (n=46) than infrequent exacerbators in whom FEV1 changed by –32.1 ml/year (n=16) and PEF by –0.7 l/min/year (n=63). Frequent exacerbators also had a greater decline in FEV1 if allowance was made for smoking status. Patients with frequent exacerbations were more often admitted to hospital with longer length of stay. Frequent exacerbations were a consistent feature within a patient, with their number positively correlated (between years 1 and 2, 2 and 3, 3 and 4). Conclusions: These results suggest that the frequency of exacerbations contributes to long term decline in lung function of patients with moderate to severe COPD.

Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease

BACKGROUND Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. METHODS We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patients recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. CONCLUSIONS Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)

Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease

BACKGROUND Methods of classifying chronic obstructive pulmonary disease (COPD) depend largely upon spirometric measurements but disability is only weakly related to measurements of lung function. With the increased use of pulmonary rehabilitation, a need has been identified for a simple and standardised method of categorising disability in COPD. This study examined the validity of the Medical Research Council (MRC) dyspnoea scale for this purpose. METHODS One hundred patients with COPD were recruited from an outpatient pulmonary rehabilitation programme. Assessments included the MRC dyspnoea scale, spirometric tests, blood gas tensions, a shuttle walking test, and Borg scores for perceived breathlessness before and after exercise. Health status was assessed using the St George’s Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ). The Nottingham Extended Activities of Daily Living (EADL) score and Hospital Anxiety and Depression (HAD) score were also measured. RESULTS Of the patients studied, 32 were classified as having MRC grade 3 dyspnoea, 34 MRC grade 4 dyspnoea, and 34 MRC grade 5 dyspnoea. Patients with MRC grades 1 and 2 dyspnoea were not included in the study. There was a significant association between MRC grade and shuttle distance, SGRQ and CRQ scores, mood state and EADL. Forced expiratory volume in one second (FEV1) was not associated with MRC grade. Multiple logistic regression showed that the determinants of disability appeared to vary with the level of disability. Between MRC grades 3 and 4 the significant covariates were exercise performance, SGRQ and depression score, whilst between grades 4 and 5 exercise performance and age were the major determinants. CONCLUSIONS The MRC dyspnoea scale is a simple and valid method of categorising patients with COPD in terms of their disability that could be used to complement FEV1 in the classification of COPD severity.

Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease

Acute exacerbations of chronic obstructive airways disease (COAD) are a common cause of admission to hospital, and have a high mortality. Nasal intermittent positive pressure ventilation (NIPPV) has been used successfully in patients with respiratory failure due to neuromuscular and skeletal disorders, but the outcome of treatment in patients with COAD is less well known. We carried out a prospective randomised controlled trial of conventional treatment versus conventional treatment plus NIPPV, in 60 patients with acute ventilatory failure due to exacerbations of COAD. For the NIPPV group there was a rise in pH, compared with a fall in the controls (mean difference of change between the groups 0.046 [95% CI 0.06-0.02, p < 0.001]), and a larger fall in PaCO2 (mean difference in change between the groups 1.2 kPa [95% CI 0.45 to 2.03, p < 0.01]). Median visual analogue scores over the first 3 days of admission showed less breathlessness in the NIPPV group (2.3 cm [range 0.1-5.5]) than in the control group (4.5 cm [range 0.9-8.8]) (p < 0.025). Survival rates at 30 days were compared for intention-to-treat and efficacy populations. In the efficacy mortality comparison, mortality in the NIPPV group was reduced: 1/26 vs 9/30 (relative risk = 0.13, CI = 0.02-0.95, p = 0.014). This effect was less in the intention-to-treat analysis: 3/30 vs 9/30 (relative risk = 0.33, CI = 0.10-1.11, p = 0.106). In patients with acute ventilatory failure due to COAD who received NIPPV there was a significant rise in pH, a reduction in PaCO2 and breathlessness, and reduced mortality.

Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis

Abstract Objectives: 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. Design: 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. Results: 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)). Conclusions: 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 topic Prospective 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 quality What this study adds Evidence from good quality, randomised controlled trials shows that NPPV is an effective treatment for acute exacerbations of COPD NPPV 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

Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations

BACKGROUND Although it is presumed that exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased airway inflammation, there is little information available on inflammatory markers during an exacerbation and the relationship with severity or time course of recovery. A study was undertaken to investigate the sputum cell and cytokine characteristics of COPD when stable and during an exacerbation. METHODS Induced sputum samples from 57 patients with moderate to severe COPD were analysed (44 samples were taken during a stable period and 37 during an exacerbation). The patients recorded daily symptoms on diary cards. Cell counts and sputum levels of interleukin (IL)-6 and IL-8 were measured. RESULTS Patients with ⩾3 exacerbations/year had higher median stable sputum levels of IL-6 (110 (95% CI 11 to 215) pg/ml) and IL-8 (6694 (95% CI 3120 to 11995) pg/ml) than those with ⩽2 exacerbations/year (22 (95% CI 12 to 93) and 1628 (95% CI 607 to 4812) pg/ml, respectively). Median IL-6 levels were increased during exacerbations compared with stable conditions. The levels of IL-6 during exacerbations were related to the presence of a cold and to the total cell count and eosinophil and lymphocyte numbers, while IL-8 was positively correlated with all sputum cell counts. Sputum cell counts and cytokine levels during an exacerbation did not predict the size and duration of lung function changes in the exacerbation. CONCLUSIONS Patients with more frequent exacerbations have higher baseline sputum cytokine levels, which may predict the frequency of future exacerbations.

Outcomes for COPD pharmacological trials: from lung function to biomarkers

The American Thoracic Society/European Respiratory Society jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations

Background: Patients with chronic obstructive pulmonary disease (COPD) are prone to frequent exacerbations which are a significant cause of morbidity and mortality. Stable COPD patients often have lower airway bacterial colonisation which may be an important stimulus to airway inflammation and thereby modulate exacerbation frequency. Methods: Twenty nine patients with COPD (21 men, 16 current smokers) of mean (SD) age 65.9 (7.84) years, forced expiratory volume in 1 second (FEV1) 1.06 (0.41) l, FEV1 % predicted 38.7 (15.2)%, FEV1/FVC 43.7 (14.1)%, inhaled steroid dosage 1.20 (0.66) mg/day completed daily diary cards for symptoms and peak flow over 18 months. Exacerbation frequency rates were determined from diary card data. Induced sputum was obtained from patients in the stable state, quantitative bacterial culture was performed, and cytokine levels were measured. Results: Fifteen of the 29 patients (51.7%) were colonised by a possible pathogen: Haemophilus influenzae (53.3%), Streptococcus pneumoniae (33.3%), Haemophilus parainfluenzae (20%), Branhamella catarrhalis (20%), Pseudomonas aeruginosa (20%). The presence of lower airway bacterial colonisation in the stable state was related to exacerbation frequency (p=0.023). Patients colonised by H influenzae in the stable state reported more symptoms and increased sputum purulence at exacerbation than those not colonised. The median (IQR) symptom count at exacerbation in those colonised by H influenzae was 2.00 (2.00–2.65) compared with 2.00 (1.00–2.00) in those not colonised (p=0.03). The occurrence of increased sputum purulence at exacerbation per patient was 0.92 (0.56–1.00) in those colonised with H influenzae and 0.33 (0.00–0.60) in those not colonised (p=0.02). Sputum interleukin (IL)-8 levels correlated with the total bacterial count (rho=0.459, p=0.02). Conclusion: Lower airway bacterial colonisation in the stable state modulates the character and frequency of COPD exacerbations.

COPD exacerbations: defining their cause and prevention

Summary Exacerbations of chronic obstructive pulmonary disease (COPD) are episodes of worsening of symptoms, leading to substantial morbidity and mortality. COPD exacerbations are associated with increased airway and systemic inflammation and physiological changes, especially the development of hyperinflation. They are triggered mainly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. Some patients are particularly susceptible to exacerbations, and show worse health status and faster disease progression than those who have infrequent exacerbations. Several pharmacological interventions are effective for the reduction of exacerbation frequency and severity in COPD such as inhaled steroids, long-acting bronchodilators, and their combinations. Non-pharmacological therapies such as pulmonary rehabilitation, self-management, and home ventilatory support are becoming increasingly important, but still need to be studied in controlled trials. The future of exacerbation prevention is in assessment of optimum combinations of pharmacological and non-pharmacological therapies that will result in improvement of health status, and reduction of hospital admission and mortality associated with COPD.

COPD exacerbations: definitions and classifications.

Chronic obstructive pulmonary disease (COPD) is defined independently of exacerbations, which are largely a feature of moderate-to-severe disease. This article is the result of a workshop that tried to define exacerbations of COPD for use in clinical, pharmacological and epidemiological studies. The conclusions represent the consensus of those present. This review describes definitions, ascertainment, severity assessments, duration and frequency, using varying sources of data including direct patient interview, healthcare databases and symptom diaries kept by patients in studies. The best general definition of a COPD exacerbation is the following: an exacerbation of COPD is a sustained worsening of the patients condition, from the stable state and beyond normal day-to-day variations that is acute in onset and may warrant additional treatment in a patient with underlying COPD. A more specific definition for studies where a bacteriological cause of exacerbation is being studied is included, as well as simpler definitions for retrospective identification from database sources. Prospective diary card assessments are best recorded as changes from an agreed baseline, rather than absolute symptom severities. Diary cards identify many unreported exacerbations, which on average have similar severities to reported exacerbations. A scale for exacerbation severity is proposed that incorporates in- and outpatient assessments. Exacerbation duration, which also relates to severity, is defined from diary card reports. Healthcare utilisation is not an adequate substitute for severity, depending on many unrelated social and comorbidity factors. It is an outcome in its own right.