Psychological therapies delivered remotely for the management of chronic pain (excluding headache) in adults.

BACKGROUND: Chronic pain (pain lasting three months or more) is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Common types (excluding headache) include back pain, fibromyalgia, and neuropathic pain. Access to traditional face-to-face therapies can be restricted by healthcare resources, geography, and cost. Remote technology-based delivery of psychological therapies has the potential to overcome treatment barriers. However, their therapeutic effectiveness compared to traditional delivery methods requires further investigation. OBJECTIVES: To determine the benefits and harms of remotely-delivered psychological therapies compared to active control, waiting list, or treatment as usual for the management of chronic pain in adults. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, Embase, and PsycINFO to 29 June 2022. We also searched clinical trials registers and reference lists. We conducted a citation search of included trials to identify any further eligible trials. SELECTION CRITERIA: We included RCTs in adults (≥ 18 years old) with chronic pain. Interventions included psychological therapies with recognisable psychotherapeutic content or based on psychological theory. Trials had to have delivered therapy remote from the therapist (e.g. Internet, smartphone application) and involve no more than 30% contact time with a clinician. Comparators included treatment as usual (including waiting-list controls) and active controls (e.g. education). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included 32 trials (4924 participants) in the analyses. Twenty-five studies delivered cognitive behavioural therapy (CBT) to participants, and seven delivered acceptance and commitment therapy (ACT). Participants had back pain, musculoskeletal pain, opioid-treated chronic pain, mixed chronic pain, hip or knee osteoarthritis, spinal cord injury, fibromyalgia, provoked vestibulodynia, or rheumatoid arthritis. We assessed 25 studies as having an unclear or high risk of bias for selective reporting. However, across studies overall, risk of bias was generally low. We downgraded evidence certainty for primary outcomes for inconsistency, imprecision, and study limitations. Certainty of evidence ranged from moderate to very low. Adverse events were inadequately reported or recorded across studies. We report results only for studies in CBT here. Cognitive behavioural therapy (CBT) versus treatment as usual (TAU) Pain intensity Immediately after treatment, CBT likely demonstrates a small beneficial effect compared to TAU (standardised mean difference (SMD) -0.28, 95% confidence interval (CI) -0.39 to -0.16; 20 studies, 3206 participants; moderate-certainty evidence). Participants receiving CBT are probably more likely to achieve a 30% improvement in pain intensity compared to TAU (23% versus 11%; risk ratio (RR) 2.15, 95% CI 1.62 to 2.85; 5 studies, 1347 participants; moderate-certainty evidence). They may also be more likely to achieve a 50% improvement in pain intensity (6% versus 2%; RR 2.31, 95% CI 1.14 to 4.66; 4 studies, 1229 participants), but the evidence is of low certainty. At follow-up, there is likely little to no difference in pain intensity between CBT and TAU (SMD -0.04, 95% CI -0.17 to 0.09; 8 studies, 959 participants; moderate-certainty evidence). The evidence comparing CBT to TAU on achieving a 30% improvement in pain is very uncertain (40% versus 24%; RR 1.70, 95% CI 0.82 to 3.53; 1 study, 69 participants). No evidence was available regarding a 50% improvement in pain. Functional disability Immediately after treatment, CBT may demonstrate a small beneficial improvement compared to TAU (SMD -0.38, 95% CI -0.53 to -0.22; 14 studies, 2672 participants; low-certainty evidence). At follow-up, there is likely little to no difference between treatments (SMD -0.05, 95% CI -0.23 to 0.14; 3 studies, 461 participants; moderate-certainty evidence). Quality of life Immediately after treatment, CBT may not have resulted in a beneficial effect on quality of life compared to TAU, but the evidence is very uncertain (SMD -0.16, 95% CI -0.43 to 0.11; 7 studies, 1423 participants). There is likely little to no difference between CBT and TAU on quality of life at follow-up (SMD -0.16, 95% CI -0.37 to 0.05; 3 studies, 352 participants; moderate-certainty evidence). Adverse events Immediately after treatment, evidence about the number of people experiencing adverse events is very uncertain (34% in TAU versus 6% in CBT; RR 6.00, 95% CI 2.2 to 16.40; 1 study, 140 participants). No evidence was available at follow-up. Cognitive behavioural therapy (CBT) versus active control Pain intensity Immediately after treatment, CBT likely demonstrates a small beneficial effect compared to active control (SMD -0.28, 95% CI -0.52 to -0.04; 3 studies, 261 participants; moderate-certainty evidence). The evidence at follow-up is very uncertain (mean difference (MD) 0.50, 95% CI -0.30 to 1.30; 1 study, 127 participants). No evidence was available for a 30% or 50% pain intensity improvement. Functional disability Immediately after treatment, there may be little to no difference between CBT and active control on functional disability (SMD -0.26, 95% CI -0.55 to 0.02; 2 studies, 189 participants; low-certainty evidence). The evidence at follow-up is very uncertain (MD 3.40, 95% CI -1.15 to 7.95; 1 study, 127 participants). Quality of life Immediately after treatment, there is likely little to no difference in CBT and active control (SMD -0.22, 95% CI -1.11 to 0.66; 3 studies, 261 participants; moderate-certainty evidence). The evidence at follow-up is very uncertain (MD 0.00, 95% CI -0.06 to 0.06; 1 study, 127 participants). Adverse events Immediately after treatment, the evidence comparing CBT to active control is very uncertain (2% versus 0%; RR 3.23, 95% CI 0.13 to 77.84; 1 study, 135 participants). No evidence was available at follow-up. AUTHORS' CONCLUSIONS: Currently, evidence about remotely-delivered psychological therapies is largely limited to Internet-based delivery of CBT. We found evidence that remotely-delivered CBT has small benefits for pain intensity (moderate certainty) and functional disability (moderate to low certainty) in adults experiencing chronic pain. Benefits were not maintained at follow-up. Our appraisal of quality of life and adverse events outcomes post-treatment were limited by study numbers, evidence certainty, or both. We found limited research (mostly low to very low certainty) exploring other psychological therapies (i.e. ACT). More high-quality studies are needed to assess the broad translatability of psychological therapies to remote delivery, the different delivery technologies, treatment longevity, comparison with active control, and adverse events.

Telehealth interventions: remote monitoring and consultations for people with chronic obstructive pulmonary disease (COPD).

BACKGROUND: Chronic obstructive pulmonary disease (COPD, including bronchitis and emphysema) is a chronic condition causing shortness of breath, cough, and exacerbations leading to poor health outcomes. Face-to-face visits with health professionals can be hindered by severity of COPD or frailty, and by people living at a distance from their healthcare provider and having limited access to services. Telehealth technologies aimed at providing health care remotely through monitoring and consultations could help to improve health outcomes of people with COPD. OBJECTIVES: To assess the effectiveness of telehealth interventions that allow remote monitoring and consultation and multi-component interventions for reducing exacerbations and improving quality of life, while reducing dyspnoea symptoms, hospital service utilisation, and death among people with COPD. SEARCH METHODS: We identified studies from the Cochrane Airways Trials Register. Additional sources searched included the US National Institutes of Health Ongoing Trials Register, the World Health Organization International Clinical Trials Registry Platform, and the IEEEX Xplore Digital Library. The latest search was conducted in April 2020. We used the GRADE approach to judge the certainty of evidence for outcomes. SELECTION CRITERIA: Eligible randomised controlled trials (RCTs) included adults with diagnosed COPD. Asthma, cystic fibrosis, bronchiectasis, and other respiratory conditions were excluded. Interventions included remote monitoring or consultation plus usual care, remote monitoring or consultation alone, and mult-component interventions from all care settings. Quality of life scales included St George's Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT). The dyspnoea symptom scale used was the Chronic Respiratory Disease Questionnaire Self-Administered Standardized Scale (CRQ-SAS). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed confidence in the evidence for each primary outcome using the GRADE method. Primary outcomes were exacerbations, quality of life, dyspnoea symptoms, hospital service utilisation, and mortality; a secondary outcome consisted of adverse events. MAIN RESULTS: We included 29 studies in the review (5654 participants; male proportion 36% to 96%; female proportion 4% to 61%). Most remote monitoring interventions required participants to transfer measurements using a remote device and later health professional review (asynchronous). Only five interventions transferred data and allowed review by health professionals in real time (synchronous). Studies were at high risk of bias due to lack of blinding, and certainty of evidence ranged from moderate to very low. We found no evidence on comparison of remote consultations with or without usual care. Remote monitoring plus usual care (8 studies, 1033 participants) Very uncertain evidence suggests that remote monitoring plus usual care may have little to no effect on the number of people experiencing exacerbations at 26 weeks or 52 weeks. There may be little to no difference in effect on quality of life (SGRQ) at 26 weeks (very low to low certainty) or on hospitalisation (all-cause or COPD-related; very low certainty). COPD-related hospital re-admissions are probably reduced at 26 weeks (hazard ratio 0.42, 95% confidence interval (CI) 0.19 to 0.93; 106 participants; moderate certainty). There may be little to no difference in deaths between intervention and usual care (very low certainty). We found no evidence for dyspnoea symptoms or adverse events. Remote monitoring alone (10 studies, 2456 participants) Very uncertain evidence suggests that remote monitoring may result in little to no effect on the number of people experiencing exacerbations at 41 weeks (odds ratio 1.02, 95% CI 0.67 to 1.55). There may be little to no effect on quality of life (SGRQ total at 17 weeks, or CAT at 38 and 52 weeks; very low certainty). There may be little to no effect on dyspnoea symptoms on the CRQ-SAS at 26 weeks (low certainty). There may be no difference in effects on the number of people admitted to hospital (very low certainty) or on deaths (very low certainty). We found no evidence for adverse events. Multi-component interventions with remote monitoring or consultation component (11 studies, 2165 participants) Very uncertain evidence suggests that multi-component interventions may have little to no effect on the number of people experiencing exacerbations at 52 weeks. Quality of life at 13 weeks may improve as seen in SGRQ total score (mean difference -9.70, 95% CI -18.32 to -1.08; 38 participants; low certainty) but not at 26 or 52 weeks (very low certainty). COPD assessment test (CAT) scores may improve at a mean of 38 weeks, but evidence is very uncertain and interventions are varied. There may be little to no effect on the number of people admitted to hospital at 33 weeks (low certainty). Multi-component interventions are likely to result in fewer people re-admitted to hospital at a mean of 39 weeks (OR 0.50, 95% CI 0.31 to 0.81; 344 participants, 3 studies; moderate certainty). There may be little to no difference in death at a mean of 40 weeks (very low certainty). There may be little to no effect on people experiencing adverse events (very low certainty). We found no evidence for dyspnoea symptoms. AUTHORS' CONCLUSIONS: Remote monitoring plus usual care provided asynchronously may not be beneficial overall compared to usual care alone. Some benefit is seen in reduction of COPD-related hospital re-admissions, but moderate-certainty evidence is based on one study. We have not found any evidence for dyspnoea symptoms nor harms, and there is no difference in fatalities when remote monitoring is provided in addition to usual care. Remote monitoring interventions alone are no better than usual care overall for health outcomes. Multi-component interventions with asynchronous remote monitoring are no better than usual care but may provide short-term benefit for quality of life and may result in fewer re-admissions to hospital for any cause. We are uncertain whether remote monitoring is responsible for the positive impact on re-admissions, and we are unable to discern the long-term benefits of receiving remote monitoring as part of patient care. Owing to paucity of evidence, it is unclear which COPD severity subgroups would benefit from telehealth interventions. Given there is no evidence of harm, telehealth interventions may be beneficial as an additional health resource depending on individual needs based on professional assessment. Larger studies can determine long-term effects of these interventions.

Individual-level interventions to reduce personal exposure to outdoor air pollution and their effects on people with long-term respiratory conditions.

BACKGROUND: More than 90% of the global population lives in areas exceeding World Health Organization air quality limits. More than four million people each year are thought to die early due to air pollution, and poor air quality is thought to reduce an average European's life expectancy by one year. Individuals may be able to reduce health risks through interventions such as masks, behavioural changes and use of air quality alerts. To date, evidence is lacking about the efficacy and safety of such interventions for the general population and people with long-term respiratory conditions. This topic, and the review question relating to supporting evidence to avoid or lessen the effects of air pollution, emerged directly from a group of people with chronic obstructive pulmonary disease (COPD) in South London, UK. OBJECTIVES: 1. To assess the efficacy, safety and acceptability of individual-level interventions that aim to help people with or without chronic respiratory conditions to reduce their exposure to outdoor air pollution. 2. To assess the efficacy, safety and acceptability of individual-level interventions that aim to help people with chronic respiratory conditions reduce the personal impact of outdoor air pollution and improve health outcomes. SEARCH METHODS: We identified studies from the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials, and other major databases. We did not restrict our searches by date, language or publication type and included a search of the grey literature (e.g. unpublished information). We conducted the most recent search on 16 October 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies (NRS) that included a comparison treatment arm, in adults and children that investigated the effectiveness of an individual-level intervention to reduce risks of outdoor air pollution. We included studies in healthy individuals and those in people with long-term respiratory conditions. We excluded studies which focused on non-respiratory long-term conditions, such as cardiovascular disease. We did not restrict eligibility of studies based on outcomes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two review authors independently selected trials for inclusion, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane Risk of Bias tool for RCTs and the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) as appropriate. One review author entered data into the review; this was spot-checked by a second author. We planned to meta-analyse results from RCTs and NRS separately, using a random-effects model. This was not possible, so we presented evidence narratively. We assessed certainty of the evidence using the GRADE approach. Primary outcomes were: measures of air pollution exposure; exacerbation of respiratory conditions; hospital admissions; quality of life; and serious adverse events. MAIN RESULTS: We identified 11 studies (3372 participants) meeting our inclusion criteria (10 RCTs and one NRS). Participants' ages ranged from 18 to 74 years, and the duration of studies ranged from 24 hours to 104 weeks. Six cross-over studies recruited healthy adults and five parallel studies included either people with pre-existing conditions (three studies) or only pregnant women (two studies). Interventions included masks (e.g. an N95 mask designed to filter out airborne particles) (five studies), an alternative cycle route (one study), air quality alerts and education (five studies). Studies were set in Australia, China, Iran, the UK, and the USA. Due to the diversity of study designs, populations, interventions and outcomes, we did not perform any meta-analyses and instead summarised results narratively. We judged both RCTs and the NRS to be at risk of bias from lack of blinding and lack of clarity regarding selection methods. Many studies did not provide a prepublished protocol or trial registration. From five studies (184 participants), we found that masks or altered cycle routes may have little or no impact on physiological markers of air pollution exposure (e.g. blood pressure and heart rate variability), but we are very uncertain about this estimate using the GRADE approach. We found conflicting evidence regarding health care usage from three studies of air pollution alerts, with one non-randomised cross-over trial (35 participants) reporting an increase in emergency hospital attendances and admissions, but the other two randomised parallel trials (1553 participants) reporting little to no difference. We also gave the evidence for this outcome a very uncertain GRADE rating. None of our included trials reported respiratory exacerbations, quality of life or serious adverse events. Secondary outcomes were not well reported, but indicated inconsistent impacts of air quality alerts and education interventions on adherence, with some trials reporting improvements in the intervention groups and others reporting little or no difference. Symptoms were reported by three trials, with one randomised cross-over trial (15 participants) reporting a small increase in breathing difficulties associated with the mask intervention, one non-randomised cross-over trial (35 participants) reporting reduced throat and nasal irritation in the lower-pollution cycle route group (but no clear difference in other respiratory symptoms), and another randomised parallel trial (519 participants) reporting no clear difference in symptoms between those who received a smog warning and those who did not. AUTHORS' CONCLUSIONS: The lack of evidence and study diversity has limited the conclusions of this review. Using a mask or a lower-pollution cycle route may mitigate some of the physiological impacts from air pollution, but evidence was very uncertain. We found conflicting results for other outcomes, including health care usage, symptoms and adherence/behaviour change. We did not find evidence for adverse events. Funders should consider commissioning larger, longer studies, using high-quality and well-described methods, recruiting participants with pre-existing respiratory conditions. Studies should report outcomes of importance to people with respiratory conditions, such as exacerbations, hospital admissions, quality of life and adverse events.

Supervised maintenance programmes following pulmonary rehabilitation compared to usual care for chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation benefits patients with chronic obstructive pulmonary disease (COPD), but gains are not maintained over time. Maintenance pulmonary rehabilitation has been defined as ongoing supervised exercise at a lower frequency than the initial pulmonary rehabilitation programme. It is not yet known whether a maintenance programme can preserve the benefits of pulmonary rehabilitation over time. Studies of maintenance programmes following pulmonary rehabilitation are heterogeneous, especially regarding supervision frequency. Furthermore, new maintenance models (remote and home-based) are emerging. OBJECTIVES: To determine whether supervised pulmonary rehabilitation maintenance programmes improve health-related quality of life (HRQoL), exercise performance, and health care utilisation in COPD patients compared with usual care. Secondly, to examine in subgroup analyses the impact of supervision frequency and model (remote or in-person) during the supervised maintenance programme. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, PEDro, and two additional trial registries platforms up to 31 March 2020, without restriction by language or type of publication. We screened the reference lists of all primary studies for additional references. We also hand-searched conference abstracts and grey literature through the Cochrane Airways Trials Register and CENTRAL. SELECTION CRITERIA: We included only randomised trials comparing pulmonary rehabilitation maintenance for COPD with attention control or usual care. The primary outcomes were HRQoL, exercise capacity and hospitalisation; the secondary outcomes were exacerbation rate, mortality, direct costs of care, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, extracted data, and assessed the risk of bias. Results data that were similar enough to be pooled were meta-analysed using a random-effects model, and those that could not be pooled were reported in narrative form. Subgroup analyses were undertaken for frequency of supervision (programmes offered monthly or less frequently, versus more frequently) and those using remote supervision (e.g. telerehabilitation versus face-to-face supervision). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 21 studies (39 reports) with 1799 COPD patients. Participants ranged in age from 52 years to 88 years. Disease severity ranged from 24% to 88% of the predicted forced expiratory volume in one second. Programme duration ranged from four weeks to 36 months. In-person supervision was provided in 12 studies, and remote supervision was provided in six studies (telephone or web platform). Four studies provided a combination of in-person and remote supervision. Most studies had a high risk of performance bias due to lack of blinding of participants, and high risk of detection, attrition, and reporting bias. Low- to moderate-certainty evidence showed that supervised maintenance programmes may improve health-related quality of life at six to 12 months following pulmonary rehabilitation compared to usual care (Chronic Respiratory Questionnaire total score mean difference (MD) 0.54 points, 95% confidence interval (CI) 0.04 to 1.03, 258 participants, four studies), with a mean difference that exceeded the minimal important difference of 0.5 points for this outcome. It is possible that supervised maintenance could improve six-minute walk distance, but this is uncertain (MD 26 metres (m), 95% CI -1.04 to 52.84, 639 participants, 10 studies). There was little to no difference between the maintenance programme and the usual care group in exacerbations or all-cause hospitalizations, or the chance of death (odds ratio (OR) for mortality 0.73, 95% CI 0.36 to 1.51, 755 participants, six studies). Insufficient data were available to understand the impact of the frequency of supervision, or of remote versus in-person supervision. No adverse events were reported. AUTHORS' CONCLUSIONS: This review suggests that supervised maintenance programmes for COPD patients after pulmonary rehabilitation are not associated with increased adverse events, may improve health-related quality of life, and could possibly improve exercise capacity at six to 12 months. Effects on exacerbations, hospitalisation and mortality are similar to those of usual care. However, the strength of evidence was limited because most included studies had a high risk of bias and small sample size. The optimal supervision frequency and models for supervised maintenance programmes are still unclear.

Tailored or adapted interventions for adults with chronic obstructive pulmonary disease and at least one other long-term condition: a mixed methods review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by shortness of breath, cough and recurrent exacerbations. People with COPD often live with one or more co-existing long-term health conditions (comorbidities). People with more severe COPD often have a higher number of comorbidities, putting them at greater risk of morbidity and mortality. OBJECTIVES: To assess the effectiveness of any single intervention for COPD adapted or tailored to their comorbidity(s) compared to any other intervention for people with COPD and one or more common comorbidities (quantitative data, RCTs) in terms of the following outcomes: Quality of life, exacerbations, functional status, all-cause and respiratory-related hospital admissions, mortality, pain, and depression and anxiety. To assess the effectiveness of an adapted or tailored single COPD intervention (simple or complex) that is aimed at changing the management of people with COPD and one or more common comorbidities (quantitative data, RCTs) compared to usual care in terms of the following outcomes: Quality of life, exacerbations, functional status, all-cause and respiratory-related hospital admissions, mortality, pain, and depression and anxiety. To identify emerging themes that describe the views and experiences of patients, carers and healthcare professionals when receiving or providing care to manage multimorbidities (qualitative data). SEARCH METHODS: We searched multiple databases including the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, and CINAHL, to identify relevant randomised and qualitative studies. We also searched trial registries and conducted citation searches. The latest search was conducted in January 2021. SELECTION CRITERIA: Eligible randomised controlled trials (RCTs) compared a) any single intervention for COPD adapted or tailored to their comorbidity(s) compared to any other intervention, or b) any adapted or tailored single COPD intervention (simple or complex) that is aimed at changing the management of people with COPD and one or more comorbidities, compared to usual care. We included qualitative studies or mixed-methods studies to identify themes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for analysis of the RCTs. We used Cochrane's risk of bias tool for the RCTs and the CASP checklist for the qualitative studies. We planned to use the Mixed Methods Appraisal tool (MMAT) to assess the risk of bias in mixed-methods studies, but we found none. We used GRADE and CERQual to assess the quality of the quantitative and qualitative evidence respectively. The primary outcome measures for this review were quality of life and exacerbations. MAIN RESULTS: Quantitative studies We included seven studies (1197 participants) in the quantitative analyses, with interventions including telemonitoring, pulmonary rehabilitation, treatment optimisation, water-based exercise training and case management. Interventions were either compared with usual care or with an active comparator (such as land-based exercise training). Duration of trials ranged from 4 to 52 weeks. Mean age of participants ranged from 64 to 72 years and COPD severity ranged from mild to very severe. Trials included either people with COPD and a specific comorbidity (including cardiovascular disease, metabolic syndrome, lung cancer, head or neck cancer, and musculoskeletal conditions), or with one or more comorbidities of any type. Overall, we judged the evidence presented to be of moderate to very low certainty (GRADE), mainly due to the methodological quality of included trials and imprecision of effect estimates. Intervention versus usual care Quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) total score may improve with tailored pulmonary rehabilitation compared to usual care at 52 weeks (mean difference (MD) -10.85, 95% confidence interval (CI) -12.66 to -9.04; 1 study, 70 participants; low-certainty evidence). Tailored pulmonary rehabilitation is likely to improve COPD assessment test (CAT) scores compared with usual care at 52 weeks (MD -8.02, 95% CI -9.44 to -6.60; 1 study, 70 participants, moderate-certainty evidence) and with a multicomponent telehealth intervention at 52 weeks (MD -6.90, 95% CI -9.56 to -4.24; moderate-certainty evidence). Evidence is uncertain about effects of pharmacotherapy optimisation or telemonitoring interventions on CAT improvement compared with usual care. There may be little to no difference in the number of people experiencing exacerbations, or mean exacerbations with case management compared with usual care (OR 1.09, 95% CI 0.75 to 1.57; 1 study, 470 participants; very low-certainty evidence). For secondary outcomes, six-minute walk distance (6MWD) may improve with pulmonary rehabilitation, water-based exercise or multicomponent interventions at 38 to 52 weeks (low-certainty evidence). A multicomponent intervention may result in fewer people being admitted to hospital at 17 weeks, although there may be little to no difference in a telemonitoring intervention. There may be little to no difference between intervention and usual care for mortality. Intervention versus active comparator We included one study comparing water-based and land-based exercise (30 participants). We found no evidence for quality of life or exacerbations. There may be little to no difference between water- and land-based exercise for 6MWD (MD 5 metres, 95% CI -22 to 32; 38 participants; very low-certainty evidence). Qualitative studies One nested qualitative study (21 participants) explored perceptions and experiences of people with COPD and long-term conditions, and of researchers and health professionals who were involved in an RCT of telemonitoring equipment. Several themes were identified, including health status, beliefs and concerns, reliability of equipment, self-efficacy, perceived ease of use, factors affecting usefulness and perceived usefulness, attitudes and intention, self-management and changes in healthcare use. We judged the qualitative evidence presented as of very low certainty overall. AUTHORS' CONCLUSIONS: Owing to a paucity of eligible trials, as well as diversity in the intervention type, comorbidities and the outcome measures reported, we were unable to provide a robust synthesis of data. Pulmonary rehabilitation or multicomponent interventions may improve quality of life and functional status (6MWD), but the evidence is too limited to draw a robust conclusion. The key take-home message from this review is the lack of data from RCTs on treatments for people living with COPD and comorbidities. Given the variation in number and type of comorbidity(s) an individual may have, and severity of COPD, larger studies reporting individual patient data are required to determine these effects.

Interventions to improve adherence to pharmacological therapy for chronic obstructive pulmonary disease (COPD).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic lung condition characterised by persistent respiratory symptoms and limited lung airflow, dyspnoea and recurrent exacerbations. Suboptimal therapy or non-adherence may result in limited effectiveness of pharmacological treatments and subsequently poor health outcomes. OBJECTIVES: To determine the efficacy and safety of interventions intended to improve adherence to single or combined pharmacological treatments compared with usual care or interventions that are not intended to improve adherence in people with COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register, CENTRAL, MEDLINE and Embase (search date 1 May 2020). We also searched web-based clinical trial registers. SELECTION CRITERIA: RCTs included adults with COPD diagnosed by established criteria (e.g. Global Initiative for Obstructive Lung Disease). Interventions included change to pharmacological treatment regimens, adherence aids, education, behavioural or psychological interventions (e.g. cognitive behavioural therapy), communication or follow-up by a health professional (e.g. telephone, text message or face-to-face), multi-component interventions, and interventions to improve inhaler technique. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Working in pairs, four review authors independently selected trials for inclusion, extracted data and assessed risk of bias. We assessed confidence in the evidence for each primary outcome using GRADE. Primary outcomes were adherence, quality of life and hospital service utilisation. Adherence measures included the Adherence among Patients with Chronic Disease questionnaire (APCD). Quality of life measures included the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ). MAIN RESULTS: We included 14 trials (2191 participants) in the analysis with follow-up ranging from six to 52 weeks. Age ranged from 54 to 75 years, and COPD severity ranged from mild to very severe. Trials were conducted in the USA, Spain, Germany, Japan, Jordan, Northern Ireland, Iran, South Korea, China and Belgium. Risk of bias was high due to lack of blinding. Evidence certainty was downgraded due to imprecision and small participant numbers. Single component interventions Six studies (55 to 212 participants) reported single component interventions including changes to pharmacological treatment (different roflumilast doses or different inhaler types), adherence aids (Bluetooth inhaler reminder device), educational (comprehensive verbal instruction), behavioural or psychological (motivational interview). Change in dose of roflumilast may result in little to no difference in adherence (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.22 to 1.99; studies = 1, participants = 55; low certainty). A Bluetooth inhaler reminder device did not improve adherence, but comprehensive verbal instruction from a health professional did improve mean adherence (prescription refills) (mean difference (MD) 1.00, 95% CI 0.46 to 1.54). Motivational interview improved mean adherence scores on the APCD scale (MD 22.22, 95% CI 8.42 to 36.02). Use of a single inhaler compared to two separate inhalers may have little to no impact on quality of life (SGRQ; MD 0.80, 95% CI -3.12 to 4.72; very low certainty). A Bluetooth inhaler monitoring device may provide a small improvement in quality of life on the CCQ (MD 0.40, 95% CI 0.07 to 0.73; very low certainty). Single inhaler use may have little to no impact on the number of people admitted to hospital compared to two separate inhalers (OR 1.47, 95% CI 0.75 to 2.90; very low certainty). Single component interventions may have little to no impact on the number of people expereincing adverse events (very low certainty evidence from studies of a change in pharmacotherapy or use of adherence aids). A change in pharmacotherapy may have little to no impact on exacerbations or deaths (very low certainty). Multi-component interventions Eight studies (30 to 734 participants) reported multi-component interventions including tailored care package that included adherence support as a key component or included inhaler technique as a component. A multi-component intervention may result in more people adhering to pharmacotherapy compared to control at 40.5 weeks (risk ratio (RR) 1.37, 95% CI 1.18 to 1.59; studies = 4, participants = 446; I2 = 0%; low certainty). There may be little to no impact on quality of life (SGRQ, Chronic Respiratory Disease Questionnaire, CAT) (studies = 3; low to very low certainty). Multi-component interventions may help to reduce the number of people admitted to hospital for any cause (OR 0.37, 95% CI 0.22 to 0.63; studies = 2, participants = 877; low certainty), or COPD-related hospitalisations (OR 0.15, 95% CI 0.07 to 0.34; studies = 2, participants = 220; moderate certainty). There may be a small benefit on people experiencing severe exacerbations. There may be little to no effect on adverse events, serious adverse events or deaths, but events were infrequently reported and were rare (low to very certainty). AUTHORS' CONCLUSIONS: Single component interventions (e.g. education or motivational interviewing provided by a health professional) can help to improve adherence to pharmacotherapy (low to very low certainty). There were slight improvements in quality of life with a Bluetooth inhaler device, but evidence is from one study and very low certainty. Change to pharmacotherapy (e.g. single inhaler instead of two, or different doses of roflumilast) has little impact on hospitalisations or exacerbations (very low certainty). There is no difference in people experiencing adverse events (all-cause or COPD-related), or deaths (very low certainty). Multi-component interventions may improve adherence with education, motivational or behavioural components delivered by health professionals (low certainty). There is little to no impact on quality of life (low to very low certainty). They may help reduce the number of people admitted to hospital overall (specifically pharmacist-led approaches) (low certainty), and fewer people may have COPD-related hospital admissions (moderately certainty). There may be a small reduction in people experiencing severe exacerbations, but evidence is from one study (low certainty). Limited evidence found no difference in people experiencing adverse events, serious adverse events or deaths (low to very low certainty). The evidence presented should be interpreted with caution. Larger studies with more intervention types, especially single interventions, are needed. It is unclear which specific COPD subgroups would benefit, therefore discussions between health professionals and patients may help to determine whether they will help to improve health outcomes.

Digital interventions for the management of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with dyspnoea, cough or sputum production (or both) and affects quality of life and functional status. More efficient approaches to alternative management that may include patients themselves managing their condition need further exploration in order to reduce the impact on both patients and healthcare services. Digital interventions may potentially impact on health behaviours and encourage patient engagement. OBJECTIVES: To assess benefits and harms of digital interventions for managing COPD and apply Behaviour Change Technique (BCT) taxonomy to describe and explore intervention content. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 28 April 2020). We found other trials at web-based clinical trials registers. SELECTION CRITERIA: We included RCTs comparing digital technology interventions with or without routine supported self-management to usual care, or control treatment for self-management. Multi-component interventions (of which one component was digital self-management) compared with usual care, standard care or control treatment were included. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two review authors independently selected trials for inclusion, extracted data, and assessed risk of bias. Discrepancies were resolved with a third review author. We assessed certainty of the evidence using the GRADE approach. Primary outcomes were impact on health behaviours, self-efficacy, exacerbations and quality of life, including the St George's Respiratory Questionnaire (SGRQ). The minimally important difference (MID) for the SGRQ is 4 points. Two review authors independently applied BCT taxonomy to identify mechanisms in the digital interventions that influence behaviours. MAIN RESULTS: Fourteen studies were included in the meta-analyses (1518 participants) ranging from 13 to 52 weeks duration. Participants had mild to very severe COPD. Risk of bias was high due to lack of blinding. GRADE ratings were low to very low certainty due to lack of blinding and imprecision. Common BCT clusters identified as behaviour change mechanisms in interventions were goals and planning, feedback and monitoring, social support, shaping knowledge and antecedents. Digital technology intervention with or without routine supported self-management Interventions included mobile phone (three studies), smartphone applications (one study), and web or Internet-based (five studies). Evidence is very uncertain about effects on impact on health behaviours as measured by six-minute walk distance (6MWD) at 13 weeks (mean difference (MD) 26.20, 95% confidence interval (CI) -21.70 to 74.10; participants = 122; studies = 2) or 23 to 26 weeks (MD 14.31, 95% CI -19.41 to 48.03; participants = 164; studies = 3). There may be improvement in 6MWD at 52 weeks (MD 54.33 95% CI -35.47 to 144.12; participants = 204; studies = 2) but studies were varied (very low certainty). There may be no difference in self-efficacy on managing Chronic Disease Scale (SEMCD) or pulmonary rehabilitation adapted index of self-efficacy tool (PRAISE). Evidence is very uncertain. Quality of life may be slightly improved on the chronic respiratory disease questionnaire (CRQ) at 13 weeks (MD 0.45, 95% CI 0.01 to 0.90; participants = 123; studies = 2; low certainty), but is not clinically important (MID 0.5). There may be little or no difference at 23 or 52 weeks (low to very low certainty). There may be a clinical improvement on SGRQ total at 52 weeks (MD -26.57, 95% CI -34.09 to -19.05; participants = 120; studies = 1; low certainty). Evidence for COPD assessment test (CAT) and Clinical COPD Questionnaire (CCQ) is very uncertain. There may be little or no difference in dyspnoea symptoms (CRQ dyspnoea) at 13, 23 weeks or 52 weeks (low to very low certainty evidence) or mean number of exacerbations at 26 weeks (low-certainty evidence). There was no evidence for the number of people experiencing adverse events. Multi-component interventions Digital components included mobile phone (one study), and web or internet-based (four studies). Evidence is very uncertain about effects on impact on health behaviour (6MWD) at 13 weeks (MD 99.60, 95% CI -15.23 to 214.43; participants = 20; studies = 1). No evidence was found for self-efficacy. Four studies reported effects on quality of life (SGRQ and CCQ scales). The evidence is very uncertain. There may be no difference in the number of people experiencing exacerbations or mean days to first exacerbation at 52 weeks with a multi-component intervention compared to standard care. Evidence is very uncertain about effects on the number of people experiencing adverse events at 52 weeks. AUTHORS' CONCLUSIONS: There is insufficient evidence to demonstrate a clear benefit or harm of digital technology interventions with or without supported self-management, or multi-component interventions compared to usual care in improving the 6MWD or self-efficacy. We found there may be some short-term improvement in quality of life with digital interventions, but there is no evidence about whether the effect is sustained long term. Dyspnoea symptoms may improve over a longer duration of digital intervention use. The evidence for multi-component interventions is very uncertain and as there is little or no evidence for adverse events, we cannot determine the benefit or harm of these interventions. The evidence base is predominantly of very low certainty with concerns around high risk of bias due to lack of blinding. Given that variation of interventions and blinding is likely to be a concern, future, larger studies are needed taking these limitations in consideration. Future studies are needed to determine whether the small improvements observed in this review can be applied to the general COPD population. A clear understanding of behaviour change through the BCT classification is important to gauge uptake of digital interventions and health outcomes in people with varying severity of COPD. Currently there is no guidance for interpreting BCT components of a digital intervention for changes to health outcomes. We could not interpret the BCT findings to the health outcomes we were investigating due to limited evidence that was of very low certainty. In future research, standardised approaches need to be considered when designing protocols to investigate effectiveness of digital interventions by including a standardised approach to BCT classification in addition to validated behavioural outcome measures that may reflect changes in behaviour.

Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by persistent respiratory symptoms and airflow limitation. Acute exacerbations punctuate the natural history of COPD and are associated with increased morbidity and mortality and disease progression. Chronic airflow limitation is caused by a combination of small airways (bronchitis) and parenchymal destruction (emphysema), which can impact day-to-day activities and overall quality of life. In carefully selected patients with COPD, long-term, prophylactic use of antibiotics may reduce bacterial load, inflammation of the airways, and the frequency of exacerbations. OBJECTIVES: To assess effects of different prophylactic antibiotics on exacerbations, quality of life, and serious adverse events in people with COPD in three separate network meta-analyses (NMAs), and to provide rankings of identified antibiotics. SEARCH METHODS: To identify eligible randomised controlled trials (RCTs), we searched the Cochrane Airways Group Specialised Register of trials and clinical trials registries. We conducted the most recent search on 22 January 2020. SELECTION CRITERIA: We included RCTs with a parallel design of at least 12 weeks' duration evaluating long-term administration of antibiotics prophylactically compared with other antibiotics, or placebo, for patients with COPD. DATA COLLECTION AND ANALYSIS: This Cochrane Review collected and updated pair-wise data from two previous Cochrane Reviews. Searches were updated and additional studies included. We conducted three separate network meta-analyses (NMAs) within a Bayesian framework to assess three outcomes: exacerbations, quality of life, and serious adverse events. For quality of life, we collected data from St George's Respiratory Questionnaire (SGRQ). Using previously validated methods, we selected the simplest model that could adequately fit the data for every analysis. We used threshold analysis to indicate which results were robust to potential biases, taking into account each study's contributions to the overall results and network structure. Probability ranking was performed for each antibiotic class for exacerbations, quality of life, and serious adverse events. MAIN RESULTS: Characteristics of studies and participants Eight trials were conducted at multiple sites that included hospital clinics or academic health centres. Seven were single-centre trials conducted in hospital clinics. Two trials did not report settings. Trials durations ranged from 12 to 52 weeks. Most participants had moderate to severe disease. Mean age ranged from 64 years to 73 years, and more males were recruited (51% to 100%). Forced expiratory volume in one second (FEV1) ranged from 0.935 to 1.36 L. Most participants had previous exacerbations. Data from 12 studies were included in the NMAs (3405 participants; 16 treatment arms including placebo). Prophylactic antibiotics evaluated were macrolides (azithromycin and erythromycin), tetracyclines (doxycyclines), quinolones (moxifloxacin) and macrolides plus tetracyclines (roxithromycin plus doxycycline). Risk of bias and threshold analysis Most studies were at low risk across domains, except detection bias, for which only seven studies were judged at low risk. In the threshold analysis for exacerbations, all comparisons in which one antibiotic was compared with another were robust to sampling variation, especially macrolide comparisons. Comparisons of classes with placebo were sensitive to potential bias, especially macrolide versus placebo, therefore, any bias in the comparison was likely to favour the active class, so any adjustment would bring the estimated relative effect closer to the null value, thus quinolone may become the best class to prevent exacerbations. Exacerbations Nine studies were included (2732 participants) in this NMA (exacerbations analysed as time to first exacerbation or people with one or more exacerbations). Macrolides and quinolones reduced exacerbations. Macrolides had a greater effect in reducing exacerbations compared with placebo (macrolides: hazard ratio (HR) 0.67, 95% credible interval (CrI) 0.60 to 0.75; quinolones: HR 0.89, 95% CrI 0.75 to 1.04), resulting in 127 fewer people per 1000 experiencing exacerbations on macrolides. The difference in exacerbations between tetracyclines and placebo was uncertain (HR 1.29, 95% CrI 0.66 to 2.41). Macrolides ranked first (95% CrI first to second), with quinolones ranked second (95% CrI second to third). Tetracyclines ranked fourth, which was lower than placebo (ranked third). Contributing studies were considered as low risk of bias in a threshold analysis. Quality of life (SGRQ) Seven studies were included (2237 participants) in this NMA. SGRQ scores improved with macrolide treatment compared with placebo (fixed effect-fixed class effect: mean difference (MD) -2.30, 95% CrI -3.61 to -0.99), but the mean difference did not reach the minimally clinical important difference (MCID) of 4 points. Tetracyclines and quinolones did not improve quality of life any more than placebo, and we did not detect a difference between antibiotic classes. Serious adverse events Nine studies were included (3180 participants) in the NMA. Macrolides reduced the odds of a serious adverse event compared with placebo (fixed effect-fixed class effect: odds ratio (OR) 0.76, 95% CrI 0.62 to 0.93). There was probably little to no difference in the effect of quinolone compared with placebo or tetracycline plus macrolide compared with placebo. There was probably little to no difference in serious adverse events between quinolones or tetracycline plus macrolide. With macrolide treatment 49 fewer people per 1000 experienced a serious adverse event compared with those given placebo. Macrolides ranked first, followed by quinolones. Tetracycline did not rank better than placebo. Drug resistance Ten studies reported drug resistance. Results were not combined due to variation in outcome measures. All studies concluded that prophylactic antibiotic administration was associated with the development of antimicrobial resistance. AUTHORS' CONCLUSIONS: This NMA evaluated the safety and efficacy of different antibiotics used prophylactically for COPD patients. Compared to placebo, prolonged administration of macrolides (ranked first) appeared beneficial in prolonging the time to next exacerbation, improving quality of life, and reducing serious adverse events. No clear benefits were associated with use of quinolones or tetracyclines. In addition, antibiotic resistance was a concern and could not be thoroughly assessed in this review. Given the trade-off between effectiveness, safety, and risk of antibiotic resistance, prophylactic administration of antibiotics may be best reserved for selected patients, such as those experiencing frequent exacerbations. However, none of the eligible studies excluded patients with previously isolated non-tuberculous mycobacteria, which would contraindicate prophylactic administration of antibiotics, due to the risk of developing resistant non-tuberculous mycobacteria.

Phosphodiesterase-4 inhibitors for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020. OBJECTIVES: To evaluate the efficacy and safety of oral PDE4 inhibitors for management of stable COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers. SELECTION CRITERIA: We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations). MAIN RESULTS: We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE4 inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV1) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE4 inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials. AUTHORS' CONCLUSIONS: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE4 inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE4 inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation, or mortality in COPD.

Inhaled steroids with and without regular formoterol for asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019. SELECTION CRITERIA: We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events. MAIN RESULTS: We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.

Head-to-head oral prophylactic antibiotic therapy for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD; including chronic bronchitis and emphysema) is a chronic respiratory condition characterised by shortness of breath, cough and recurrent exacerbations. Long-term antibiotic use may reduce both bacterial load and inflammation in the airways. Studies have shown a reduction of exacerbations with antibiotics in comparison to placebo in people with COPD, but there are concerns about antibiotic resistance and safety. OBJECTIVES: To compare the safety and efficacy of different classes of antibiotics (continuous, intermittent or pulsed) for prophylaxis of exacerbations in patients with COPD. SEARCH METHODS: We searched the Cochrane Airways Group Trials Register and bibliographies of relevant studies. The latest literature search was conducted on 6 February 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) were selected that compared one prophylactic antibiotic with another in patients with COPD. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data and assessed risk of bias. Discrepancies were resolved by involving a third review author. MAIN RESULTS: We included two RCTs, both published in 2015 involving a total of 391 participants with treatment duration of 12 to 13 weeks. One RCT compared a quinolone (moxifloxacin pulsed, for 5 days every 4 weeks), with a tetracycline (doxycycline continuous) or a macrolide (azithromycin intermittent).The second RCT compared a tetracycline (doxycycline continuous) plus a macrolide (roxithromycin continuous), with roxithromycin (continuous) alone.The trials recruited participants with a mean age of 68 years, with moderate-severity COPD. Both trials included participants who had between two and five exacerbations in the previous one to two years. In one trial, 17% of patients had previously been using inhaled corticosteroids. In the other study, all patients were positive for Chlamydophila pneumoniae (C pneumoniae).Overall, we judged the evidence presented to be of very low-certainty, mainly due to imprecision, but we also had concerns about indirectness and methodological quality of the included studies. The primary outcome measures for this review included exacerbations, quality of life, drug resistance and serious adverse events.Macrolide + tetracycline versus macrolide There was no clear difference between treatments in improvement in quality of life as assessed by the Chronic Respiratory Questionnaire (CRQ). The CRQ scale ranges from 0 to 10 and higher scores on the scale indicate better quality of life. CRQ sub-scales for dyspnoea (mean difference (MD) 0.58, 95% confidence interval (CI) -0.84 to 2.00; 187 participants; very low-certainty evidence), fatigue (MD 0.02, 95% CI -1.08 to 1.12; 187 participants; very low-certainty evidence), emotional function (MD -0.37, 95% CI -1.74 to 1.00; 187 participants; very low-certainty evidence), or mastery (MD -0.79, 95% CI -1.86 to 0.28; 187 participants; very low-certainty evidence) at 12 weeks. For serious adverse events, it was uncertain if there was a difference between combined roxithromycin and doxycycline versus roxithromycin alone at 48 weeks follow-up after active treatment of 12 weeks (odds ratio (OR) 1.00, 95% CI 0.52 to 1.93; 198 participants; very low-certainty evidence). There were five deaths reported in the combined treatment arm, versus three in the single treatment arm at 48 weeks follow-up after active treatment of 12 weeks (OR 1.63, 95% CI 0.38 to 7.02; 198 participants; very low-certainty evidence).Quinolone versus tetracycline There was no clear difference between moxifloxacin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants, very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes.Quinolone versus macrolide There was no clear difference between moxifloxacin and azithromycin for the number of participants experiencing one or more exacerbations (OR 1.00, 95% CI 0.32 to 3.10; 50 participants; very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes.Marcolide versus tetracycline There was no clear difference between azithromycin and doxycycline for the number of participants experiencing one or more exacerbations (OR 0.44, 95% CI 0.14 to 1.38; 50 participants; very low-certainty evidence) at 13 weeks. There were no serious adverse events or deaths reported in either treatment groups. We did not identify any evidence for our other primary outcomes.We did not find head-to-head evidence for impact of antibiotics on drug resistance. AUTHORS' CONCLUSIONS: It is not clear from the evidence included in this review whether there is a difference in efficacy or safety between different classes or regimens of prophylactic antibiotic, given for 12 to 13 weeks to people with COPD. Whilst no head-to-head comparisons of antibiotic resistance were identified, concerns about this continue. The sample size in this review is small and both included studies are of short duration. Thus, there is considerable uncertainty in effects observed and the effects of different prophylactic antibiotics requires further research.

The cardioprotective agent urocortin induces expression of CT-1.

The corticotrophin-releasing hormone-related factor, urocortin (Ucn) and the interleukin (IL)-6 family cytokine cardiotrophin-1 (CT-1) are both cardioprotective agents able to protect the heart from ischemic damage. In both cases the protective effect involves activation of the p42/p44 MAPK and PI-3 kinase/Akt pathways, but the protective effect of Ucn requires de novo protein synthesis whereas that of CT-1 does not. In this study, we show that Ucn induces enhanced expression of CT-1 at both the mRNA and protein levels. This effect is mediated by activation of the CT-1 gene promoter and requires the transcription factor C/EBPbeta/NF-IL6. Hence, a specific cardioprotective factor can induce enhanced expression of another cardioprotective factor belonging to an unrelated protein family.