Simon Gompertz

Chronic obstructive pulmonary disease • 6: The aetiology of exacerbations of chronic obstructive pulmonary disease

Exacerbations of COPD are thought to be caused by interactions between host factors, bacteria, viruses, and changes in air quality to produce increased inflammation in the lower airway. The evidence for this and the potential mechanisms by which they result in the characteristic symptoms of exacerbations is reviewed. A better understanding of the causes and processes is needed for the appropriate use of existing treatments and the development of new ones. Future studies need to define populations clearly, stratify for known confounding factors, and should aim to identify clinical correlates so that clinical practice can be modified appropriately.

Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis

Background: Recent studies of the role of bacteria in chronic bronchitis have shown that bacterial colonisation is associated with enhanced inflammation and that purulent acute exacerbations of chronic bronchitis (AECB) are associated with bacteria and characterised by increased inflammation. Changes in bronchial inflammation in response to the success or failure of bacterial eradication following AECB were therefore studied. Methods: Bacterial quantitative culture and sputum markers of inflammation (myeloperoxidase (MPO), neutrophil elastase, leukotriene B4 (LTB4), sol:serum albumin ratio, and secretory leukoprotease inhibitor) were measured in patients presenting with culture positive purulent AECB and repeated 10 days and 2 months later. 41 patients provided sputum sufficient for both bacteriology and assessment of inflammation at baseline and day 10, and 46 provided sufficient sample for bacteriology, 40 of which could also be analysed for inflammation at 2 months (when clinically stable). Results: At day 10, 17 of the 41 patient samples had a positive bacterial culture. In the stable state, 18 of the 46 samples had a positive culture, but with a significantly lower bacterial load than at presentation. Although there was no difference between the groups at presentation, the concentration of MPO was lower (p<0.05) in those in whom bacteria were eradicated by day 10 than in those with persisting bacteria. The LTB4 concentration was similarly lower (p<0.001) in those in whom bacteria were eradicated than in those with persistent bacteria. In the stable clinical state the concentrations of both MPO and LTB4 were lower in those in whom bacteria were eradicated than in patients with persisting bacteria. Conclusion: Resolution of bronchial inflammation following AECB is related to bacterial eradication. Those in whom bacteria continue to be cultured in their sputum have partial resolution of inflammation which may reflect continued stimulation by the reduced bacterial load.

Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD

BACKGROUND Patients with more frequent exacerbations of chronic obstructive pulmonary disease (COPD) may have increased bronchial inflammation. Airway inflammation was measured in patients who had been thoroughly investigated with full pulmonary function testing, thoracic HRCT scanning, and sputum microbiology to examine further the relationship between exacerbation frequency and bronchial inflammation. METHODS Airway inflammation (spontaneous sputum sol phase myeloperoxidase (MPO), elastase, leukotriene (LT)B4, interleukin (IL)-8, secretory leukoprotenase inhibitor (SLPI), protein leakage) and serum levels of C reactive protein (CRP) were compared in 40 patients with stable, smoking related COPD, divided into those with frequent (⩾3/year) or infrequent (⩽2/year) exacerbations according to the number of primary care consultations during the preceding year. The comparisons were repeated after excluding eight otherwise clinically indistinguishable patients who had tubular bronchiectasis on the HRCT scan. RESULTS Patients with frequent (n=12) and infrequent (n=28) exacerbations were indistinguishable in terms of their clinical, pulmonary function, and sputum characteristics, CRP concentrations, and all of their bronchial inflammatory parameters (p>0.05). The patients without evidence of tubular bronchiectasis (n=32) were equally well matched but the sputum concentrations of SLPI were significantly lower in the frequent exacerbators (n=8) in this subset analysis (p<0.05). CONCLUSIONS There are several clinical features that directly influence bronchial inflammation in COPD. When these were carefully controlled for, patients with more frequent reported exacerbations had lower sputum concentrations of SLPI. This important antiproteinase is also known to possess antibacterial and antiviral activity. Further studies are required into the nature of recurrent exacerbations and, in particular, the regulation and role of SLPI in affected individuals.

Factors influencing airway inflammation in chronic obstructive pulmonary disease

Airway inflammation in chronic obstructive pulmonary disease (COPD) is currently the subject of rapidly increasing research interest, investigating both the nature of the inflammatory cells and the cytokines present. The data are being used to define and assess the severity, cause, prognosis, and response to treatment of this disease. The collection of spontaneous sputum or the induction of sputum has been used to study inflammation in the larger airways. It remains unclear, however, how these data relate to the pathological processes at the site of airflow obstruction (the small airways and alveolar region). Nevertheless, even the interpretation of the results from the large airways depends on the many factors that will influence the inflammation. The initial process of sputum collection, sample processing, and the performance of assays in the biological fluids being tested may all influence the results. In addition, airways inflammation may be altered by the patients clinical state, current treatment, and the nature of the disease (asthma, COPD, or bronchiectasis). Other factors including smoking, α1-antitrypsin (AAT) deficiency, and bacterial colonisation may also affect airways inflammation. Despite these many factors that may influence airways inflammation, many papers currently in the literature do not address them. The purpose of this review is to indicate the influence of these factors on airways inflammation to assist interpretation of the data currently in the literature. ### EOSINOPHIL Airway inflammation in asthma is classically related to the eosinophil. Eosinophil granules contain a variety of mediators capable of causing inflammatory damage to the airway epithelium including eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil cationic protein (ECP), metalloproteinases, platelet activating factor, and cysteinyl leukotrienes.1 In addition, the immunological basis of asthma is distinct and reflected in the nature of the cytokines released into the airway. However, there is some overlap with COPD which may …

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial

BackgroundChronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that ‘low dose’ theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of ‘low dose’ theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD.Method/DesignTWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either ‘low dose’ theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1–5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period.DiscussionThe demonstration that ‘low dose’ theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally.Trial registrationCurrent Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial

Importance Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, −0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration isrctn.org Identifier: ISRCTN27066620

P210 Implementation of electronic copd discharge care bundles: a quality improvement project

Background and aims Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for 115,000 emergency admissions to hospital p.a.; one-third of patients are re-admitted within 90 days. COPD discharge care bundles reduce re-admission rate.1 Paper-based COPD discharge bundles were implemented in our trust (a large tertiary centre in the West Midlands) in 2013, with disappointing completion rates. In order to improve compliance, an electronic bundle (e-bundle) was introduced This uses a novel system (Figure 1) that electronically alerts our multidisciplinary respiratory support team to potential AECOPD patients when medications for AECOPD are electronically prescribed (e-prescribed). The aim of this audit was to see whether completion of COPD discharge bundles in this trust has improved since the e-prescribing alert system and e-bundle implementation in 2015. Methods Admissions coded as AECOPD were retrospectively identified using ICD-10 codes for a three-month continuous period in 2015. Discharge summaries and e-bundles for each patient were accessed via online records, and in patients who were bundle-appropriate, data were collected on the presence or absence of a bundle, and completion of its 10 individual elements. Results In 2015, 125 admissions coded as AECOPD were identified; 93 were bundle-appropriate. 80% of these had a COPD discharge bundle in the electronic record; a significant improvement on the 38% bundle completion in bundle-appropriate patients in 2013 (p < 0.0001). Percentage completion was >90% for seven of the ten elements included in the 2015 e-bundle. Direct comparison of the six points included in both the 2013 paper bundle and the 2015 e-bundle, revealed that more patients were assessed for pulmonary rehabilitation in 2013 (100% vs 92%, p = 0.0417); all other elements had no significant change in completion rates. Conclusions Introduction of an e-bundle and e-prescribing alerts to respiratory support team members more than doubled completion of COPD discharge bundles. This clearly shows the benefit conferred by use of an electronic system for prescribing, referrals and bundle proformas. We advocate the increased use of e-bundles as electronic prescribing and information systems are introduced across trusts. Reference Hopkinson NS, et al. Designing and implementing a COPD care discharge bundle. Thorax 2012;67:90–92. Abstract P210 Figure 1 Flow diagram showing pathway leading to COPD discharge bundle completion

Diagnosis of asthma

Asthma is a common and potentially life-threatening respiratory condition, which often presents in early childhood and can be a lifelong chronic health problem. Over a patient’s life, they will attend primary care for regular monitoring of their chronic disease, for repeat prescriptions and during acute exacerbations. The current national UK guidelines on the management of asthma produced by the Scottish Intercollegiate Guidelines Network and British Thoracic Society were updated in 2014. This article will focus on the diagnosis of asthma in adults and children and is directly applicable to primary care.

Inflammatory Mediators in Spontaneously Produced Sputum

Airway inflammation is currently the subject of intense research interest concerning both the nature of the inflammatory cells, proteins, and cytokines present. These data are being used to define and assess the severity, cause, prognosis, and response to treatment of airway inflammatory disease. Spontaneous sputum is a useful method for studying inflammation in the larger airways, in diseases such as asthma, bronchitis, and bronchiectasis.