Commissioning Brief - Background Information Sputum colour charts to guide antibiotic self-treatment of acute exacerbation of COPD HTA no 17/128 This background document provides further information to support applicants for this call. It is intended to summarize what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. Searches and information provided were up to date as of September 2017. Background information: Source of topic Primary Care Panel. Patient group Chronic obstructive pulmonary disease (COPD) is characterised by airflow obstruction which is the result of chronic inflammation. The airflow obstruction is usually progressive, not fully reversible and does not change markedly over several months. The disease is predominantly caused by smoking, but can also be caused by other noxious particles or gases. Significant airflow obstruction may be present before the individual is aware of it. The rate of COPD in the population is estimated at between 2% and 4%, representing between 982,000 and 1.96 million people in England. However, an estimated 2 million people are thought to have undiagnosed COPD, mostly at the milder end of the spectrum. There are around 1.4 million GP consultations for COPD each year, up to four times more than the number of consultations for angina. One in eight (130,000) emergency admissions to hospital is for COPD, making it the second largest cause of emergency admission in the UK, and one of the most costly inpatient conditions treated by the NHS. The direct cost of COPD to the UK healthcare system has been estimated to be between 810-930m per year. More than half of these costs relate to the provision of care in hospital. Acute exacerbations Exacerbation of COPD is defined as a sustained worsening of the patient's symptoms from their usual stable state, which is beyond normal day-to-day variations and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. Exacerbation may be caused by viral or bacterial infections, by common pollutants (e.g. air pollution, tobacco smoke), or by comorbidities such as heart failure. The majority of patients with symptomatic COPD experience exacerbations, typically one or two episodes per year. The frequency of acute exacerbations tends to increase as the severity of the underlying COPD increases. [Sources: NICE CG101; patient.info; DynaMed database]. Page 1 of 7
NICE and other guidance NICE CG101 Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Published June 2010. Last reviewed July 2014. Currently in update; publication expected in November 2018 Recommendation: Self-management Patients at risk of having an exacerbation of COPD should be given self-management advice that encourages them to respond promptly to the symptoms of an exacerbation by: starting oral corticosteroid therapy if their increased breathlessness interferes with activities of daily living (unless contraindicated); starting antibiotic therapy if their sputum is purulent; adjusting their bronchodilator therapy to control their symptoms. Patients at risk of having an exacerbation of COPD should be given a course of antibiotic and corticosteroid tablets to keep at home for use as part of a self-management strategy. The appropriate use of these tablets should be monitored. Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global Strategy for Diagnosis, Management, and Prevention of COPD 2016 Recommendations: Give antibiotics to patients with exacerbations who have all 3 cardinal symptoms (increased dyspnoea, increased sputum volume, and increased sputum purulence) or have 2 cardinal symptoms if increased purulence of sputum is one of the symptoms. The choice of the antibiotic should be based on the local bacterial resistance pattern. The GOLD strategy does not include a recommendation or statement on the use of rescue packs for self-initiated treatment of exacerbations. Current practice and proposed intervention Current practice Current practice includes the provision of rescue packs, usually containing oral corticosteroids and antibiotics, as per NICE guideline. This recommendation appears to be based on expert consensus with the intention to facilitate prompt treatment. The NICE guideline does not refer to any evidence supporting self-treatment, but the associated NICE pathway suggests that guidance on antibiotic stewardship should be taken into account when prescribing antibiotics for patient-initiated treatment. Patients should be advised to use antibiotics supplied for self-management of exacerbations only if the sputum is purulent. The GOLD strategy states that the use of antibiotics in exacerbations remains controversial, due to poor quality of evidence. However, the strategy points out that there is evidence supporting the use of antibiotics in exacerbations when patients have clinical signs of a bacterial infection. The authors state, The presence of purulent sputum during an exacerbation can be sufficient indication for starting empirical antibiotic treatment. However, some patients are known to use multiple rescue packs per year, and there is concern that this may be an indicator of over-use. Proposed intervention Purulent sputum is typically yellow or green, and it is assumed that green or yellow sputum is associated with presence of bacteria. A Birmingham-based team has demonstrated high sensitivity and specificity of purulent sputum as an indicator of high bacterial load in exacerbation of COPD (Stockley 2000). 1 The authors used a standardised chart of eight colours, and sputum colour was assessed by laboratory staff. Cultures of 84% of the purulent sputum samples contained bacteria (as compared to 38% of the mucoid samples). High bacterial load was present in 94.4% of the green sputum samples, and absent in 77.0% of samples that were not green, making the presence of green sputum a predictor for high bacterial load, where antibiotic treatment may be indicated. These findings were in part confirmed in a more recent retrospective pooled analysis of data from six randomized trials, where green or yellow sputum was associated with 94.7% sensitivity for the presence of bacteria. However, bacteria were also detected in a large proportion of white sputum samples; only Page 2 of 7
15% of the white samples did not contain potentially pathological bacteria (Miravitlles 2012). 2 Unlike the Birmingham study, this retrospective analysis did not use a standardised colour chart. Various sputum colour charts are available. These may vary in the number of colours presented and in the target groups or conditions. Of note are the following. BronkoTest In their studies, the Birmingham team appeared to use different colour charts, with different numbers of colours. The charts are based on the presence of neutrophils in purulent sputum of people with bacterial airway infection. Neutrophils contain myeloperidoxidase, a green protein, which causes the sputum colour. This colour may serve as a guide to presence of bacteria, bacterial load, and inflammation. Sputum colour is therefore considered a potentially useful guide to determine the need for antibiotic therapy and in monitoring treatment response. A five-colour version, the BronkoTest, is now commercially available for use in COPD and bronchiectasis exacerbations (http://www.bronkotest.co.uk/). It is marketed as 'part of a selfmanagement and action tool for both HCP [healthcare professionals] and patients.' When used as part of the BronkoTest COPD Monitoring Pack, patients and clinicians are thought be able to identify changes in the patient's health state, and use the information provided in management decisions. The company claims that some UK primary care trusts have implemented the BronkoTest colour chart in their COPD self-management plans. There are also claims of a reduction in emergency admissions and in use of antibiotics in areas of the UK where the chart was used in the management of patients with COPD (data on file, but no reference to publicly available data is provided). The BronkoTest was used in various trials in a range of lung conditions for monitoring and for the assessment of treatment outcomes. No formal validation of the BronkoTest was identified where the colour card was use by patients with the intention to self-manage antibiotic treatment. Alternative charts were developed, but these were either not validated, or they were shown not to be sufficiently accurate, such as the Colorimetric scale for sputum colour and purulence evaluation. This ten-colour scale (strip) was developed by an Italian team, but was shown to be too complex in clinical practice, and there was insufficient agreement between physicians' and patients' colour ratings (Allegra 2005). 3 The Cleveland Clinic 'colour of snot' chart A frequently featured chart for nasal mucus was published by the Cleveland clinic. This is a generic seven-colour chart for use by the general public, developed in the context of antibiotic stewardship (https://health.clevelandclinic.org/2014/11/whatthe-color-of-your-snot-really-means-infographic/). There is no indication that it has been validated in clinical trials. It does not specifically target patients with lung conditions. Page 3 of 7
Completed research Evidence Synthesis The following Cochrane review is included for completeness, but does not answer the research question. An update of this review is in progress. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Review. Vollenweider (2012). 4 The objective of this review was to assess the effects of antibiotics in the management of acute COPD exacerbations on treatment failure (primary outcome) and on other patient-important outcomes (mortality, adverse events, length of hospital stay). Searches up to September 2012. Eligibility criteria: Randomised controlled trials (RCTs) in people with acute COPD exacerbations comparing antibiotic therapy and placebo with a follow-up of at least seven days. Main results: Sixteen trials with 2068 participants were included. Antibiotics for COPD exacerbations showed large and consistent beneficial effects across outcomes of patients admitted to an intensive care unit. However, for outpatients and inpatients the results were inconsistent. The risk for treatment failure was significantly reduced in both inpatients and outpatients when all trials (1957 to 2012) were included but not when the analysis for outpatients was restricted to currently used antibiotics. Antibiotics had no statistically significant effect on mortality and length of hospital stay in inpatients and almost no data on patient-reported outcomes exist. Sputum colour and bacteria in chronic bronchitis exacerbations: a pooled analysis. Miravitlles (2012). Spain. 2 This is a retrospective analysis of pooled data from six RCTs. The purpose of the study was to investigate the correlation between sputum colour and presence of potentially pathogenic' bacteria in patients with acute exacerbation of chronic bronchitis. 4,089 sputum samples were included, and colour was reported in 4,003 samples. Bacteria were found in the cultures of 1,898 (46.4%) samples. There was 95% probability that people with infectious exacerbation of COPD had yellow or green sputum (sensitivity of yellow/green sputum = 95%). Only 5% of people with infection did not have yellow/green sputum. There was 15% probability that people without infection did not have yellow or green sputum (specificity of yellow/green sputum = 15%). However, yellow/green sputum was present in 85% of people without infection. There was 53% probability that people with yellow or green sputum had infectious exacerbation of COPD. If the decision to start antibiotics was solely based on the presence of yellow/green sputum, then just under half of those patients with yellow/green sputum would take antibiotics even though they may not have infection. (Positive predictive value of yellow/green sputum = 53%) There was 75% probability that people who did not have yellow or green sputum had no infection. If the decision to start antibiotics was solely based on the absence of yellow/green sputum, then 25% of patient of patients without yellow/green sputum would not take antibiotics, even though they may have infection. (Negative predictive value of yellow/green sputum = 75%) It should be noted though, that no standardised colour charts were used in the included studies, which may affect the accuracy of these findings. This may explain, why the Birmingham study summarised in the primary research section below found higher diagnostic accuracy when using a standardised colour chart. However, the Birmingham study only reported the accuracy of green sputum for the detection of infection (not yellow or green as is the case in this pooled analysis), and bacterial load may be higher in green sputum, compared to yellow sputum. Sputum test Positive (yellow or green sputum present) Negative (no yellow/green sputum) Infective exacerbation of COPD Yes No Total 95 (true 5 (false 85 (false 15 (true Total 100 100 200 180 PPV = 53% 20 NPV = 75% Page 4 of 7
Primary Research We did not identify any studies that investigate the use of a sputum colour chart as a guide to antibiotic self-treatment by patients. However, various projects in this research area demonstrated links between sputum colour, purulence, use of antibiotics and patient outcomes. A qualitative study concluded that sputum colour is commonly used by patients to assess COPD exacerbation (among other objective and subjective criteria). Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Stockley (2000). Birmingham, UK. 1 In this longitudinal study, patients with acute exacerbation of COPD were offered antibiotics on the basis of green, purulent sputum. (N=121; 89 produced a sputum sample suitable for analysis; setting: primary care with specialist follow-up; follow-up: 2 months). People with clear or white sputum did not receive antibiotics. Bacterial culture was positive in 84% of the purulent samples, compared to 38% of nonpurulent samples (p < 0.0001). Participants with purulent sputum also had raised CRP levels (p<0.0001). In this study, a chart of eight colours was used to assess participants' sputum. The lead author, together with other colleagues, later developed a five-colour chart, which is marketed as the BronkoTest (see above). It should also be noted that only the diagnostic accuracy of green sputum was reported (not green or yellow as in the pooled analysis summarised above). There was 94% probability that people with infectious exacerbation of COPD had green sputum (sensitivity of green sputum = 94%). Only 6% of people with infection did not have green sputum. There was 77% probability that people without infection did not have green sputum (specificity of green sputum = 77%). However, 23% of people without infection had green sputum. There was 80% probability that people with green sputum had infectious exacerbation of COPD. If the decision to start antibiotics was solely based on the presence of green sputum, then around 20% those patients would take antibiotics even though they may not have infection. (Positive predictive value of yellow/green sputum = 80%) There was 93% probability that people who did not have green sputum had no infection. If the decision to start antibiotics was solely based on the absence of green sputum, then 7% of patient would not start antibiotics, even though they may have infection. (Negative predictive value of yellow/green sputum = 93%). Sputum test Positive (green sputum present) Negative (no green sputum) Infective exacerbation of COPD Yes No Total 94 (true 6 (false 23 (false 77 (true Total 100 100 200 117 PPV = 80% 83 NPV = 93% Patients' experience of identifying and managing exacerbations in COPD: a qualitative study. Williams (2014). Oxford, UK. 5 This study aimed to explore patients understanding and experience of the self-management of COPD exacerbations. Forty-four patients with moderate-to-very-severe COPD were interviewed in 2012-2013. Patients were found to use both objective markers (e.g. cough, sputum) and subjective symptoms (e.g. chest sensations and bodily knowledge ) in their self-assessment and -management. Selfmanagement strategies included self-medication (antibiotics, steroids). Contact to healthcare professionals was sought when patients felt no longer able to self-manage their exacerbation. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Miravitlles (2013). Spain. 6 This study aimed to evaluate predictors of outcomes in exacerbations of mild to moderate COPD not treated with antibiotics. The researchers used data from 152 patients of the placebo arm of a randomized trial of amoxicillin/clavulanate for exacerbations of mild to moderate COPD. Main results: Clinical failure without antibiotics was 19.9% compared with 9.5% with amoxicillin/clavulanate (p=0.022). The only factors significantly associated with an increased risk of failure without antibiotics were the increase in sputum purulence and increased C-reactive protein concentration ( 40 mg/l). When both factors were present, the probability of treatment failure without Page 5 of 7
antibiotics was 63.7%. The authors suggest that these factors may be useful in identifying patients with mild to moderate COPD exacerbation who can be safely treated without antibiotics in an ambulatory setting. Research in progress No planned or ongoing studies were identified that investigate the use of sputum colour charts. NIHR Evaluation Trials and Studies (NETS) research NETS have funded a number of projects in this disease area. None of these answers the research question specified in this brief. Completed Projects HTA 01/15/10 A randomised 2 x 2 trial of community versus hospital pulmonary rehabilitation for chronic obstructive pulmonary disease followed by telephone or conventional follow-up. Waterhouse et al., Health Technology Assessment Volume 14 Issue 6, 2010. HTA 03/13/06 A randomised controlled equivalence trial to determine the effectiveness and costutility of manual chest physiotherapy techniques in the management of exacerbations of chronic obstructive pulmonary disease (MATREX). Cross et al., Health Technology Assessment Volume 14 Issue 23, 2010. HTA 10/44/01 Supported self-management for patients with moderate to severe chronic obstructive pulmonary disease (COPD): an evidence synthesis and economic analysis. Published. Jordan et al., Health Technology Assessment Volume 19 Issue 36, 2015. HTA 11/27/01 The cost-effectiveness of domiciliary non-invasive ventilation in patients with endstage chronic obstructive pulmonary disease: a systematic review and economic evaluation. Dretzke et al., Health Technology Assessment Volume 19 Issue 81, 2015. HTA 97/23/02 Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature. Brocklebank et al., Health Technology Assessment Volume 5 Issue 26, 2001. NICE TAR 10/06/01: Roflumilast for chronic obstructive pulmonary disease. Complete. NICE TAR 16/56/16: Rofluminast for the treatment of chronic obstructive pulmonary disease (Review of TA244). Single Technology Appraisal. Rob Riemsma. Kleijnen Systematic Reviews Ltd. Complete. HS&DR 08/1205/037: Evaluating the effectiveness of innovations involving nurses for people with chronic obstructive airways disease. Published. SRP 14/175/05: Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Christopher Ecclestone. Complete (Cochrane review). 14/175 SRPCIA Cochrane Incentive Awards Scheme 2014. Ongoing projects - HTA 11/58/15: A randomised, double-blind placebo controlled trial of the effectiveness of low dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease. Active. Expected completion: 31/12/2017. HTA 12/33/12: Primary care use of a C-Reactive Protein (CRP) Point of Care Test (POCT) to help target antibiotic prescribing to patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) who are most likely to benefit (The PACE Study). Active. Expected completion: 31/01/2018. HTA 13/03/25: Vitamin D supplementation to prevent acute respiratory infection: individual patient data meta-analysis of randomised controlled trials. Adrian Martineau. Queen Mary University of London. In Editorial. Expected publication: 24/04/2018. HTA 13/146/02: A tailored, psychological intervention for mild to moderate anxiety or depression in people with chronic obstructive pulmonary disease (COPD) (TANDEM Tailored intervention for ANxiety and DEpression Management in COPD). Post-contract setup. Expected completion: 30/06/2020. HTA 13/24/03: Pulmonary Rehabilitation and ACTIvity after COPD Exacerbations- The PRACTICE Trial. In Editorial. Expected publication: 19/03/2018. HTA 15/130/20: A randomised, double-blind placebo controlled trial of the effectiveness of the betablocker bisoprolol in preventing exacerbations of chronic obstructive pulmonary disease. Graham Devereux. University Court of the University of Aberdeen. Post contract set-up. Expected completion: 31/05/2022. Page 6 of 7
HTA 15/80/28: Real World Effects of Medications for Chronic Obstructive Pulmonary Disease. Decision to proceed. Ian Douglas. London School of Hygiene & Tropical Medicine. Post contract set-up. Expected completion: 31/01/2020. HS&DR 12/130/53: An evaluation of the effectiveness of 'care bundles' as a means of improving hospital care and reducing hospital re-admission for patients with chronic obstructive pulmonary disease (COPD). In Editorial. Expected publication: July 2018. HS&DR 14/19/50: What are the determinants of variations in emergency readmission rates and oneyear mortality in patients hospitalized with heart failure or chronic obstructive pulmonary disease? In Editorial. Expected publication: 17/04/2018. References 1. Stockley RA, O'Brien C, Pye A, et al. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000;117(6):1638-45. doi: DOI 10.1378/chest.117.6.1638 2. Miravitlles M, Kruesmann F, Haverstock D, et al. Sputum colour and bacteria in chronic bronchitis exacerbations: a pooled analysis. Eur Respir J 2012;39(6):1354-60. doi: 10.1183/09031936.00042111 3. Allegra L, Blasi F, Diano PL, et al. Sputum color as a marker of acute bacterial exacerbations of chronic obstructive pulmonary disease. Respir Med 2005;99(6):742-47. doi: 10.1016/j.rmed.2004.10.020 4. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. The Cochrane database of systematic reviews 2012;12:CD010257. doi: 10.1002/14651858.CD010257 5. Williams V, Hardinge M, Ryan S, et al. Patients' experience of identifying and managing exacerbations in COPD: a qualitative study. NPJ Prim Care Respir Med 2014;24 doi: ARTN 14062 10.1038/npjpcrm.2014.62 6. Miravitlles M, Moragas A, Hernandez S, et al. Is It Possible to Identify Exacerbations of Mild to Moderate COPD That Do Not Require Antibiotic Treatment. Chest 2013;144(5):1571-77. doi: 10.1378/chest.13-0518 Page 7 of 7