Psychological interventions for asthma in children and adolescents.

BACKGROUND: Rates of asthma are high in children and adolescents, and young people with asthma generally report poorer health outcomes than those without asthma. Young people with asthma experience a range of challenges that may contribute to psychological distress. This is compounded by the social, psychological, and developmental challenges experienced by all people during this life stage. Psychological interventions (such as behavioural therapies or cognitive therapies) have the potential to reduce psychological distress and thus improve behavioural outcomes such as self-efficacy and medication adherence. In turn, this may reduce medical contacts and asthma attacks. OBJECTIVES: To determine the efficacy of psychological interventions for modifying health and behavioural outcomes in children with asthma, compared with usual treatment, treatment with no psychological component, or no treatment. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (including CENTRAL, CRS, MEDLINE, Embase, PsycINFO, CINAHL EBSCO, AMED EBSCO), proceedings of major respiratory conferences, reference lists of included studies, and online clinical databases. The most recent search was conducted on 22 August 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing psychological interventions of any duration with usual care, active controls, or a waiting-list control in male and female children and adolescents (aged five to 18 years) with asthma. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. symptoms of anxiety and depression, 2. medical contacts, and 3. asthma attacks. Our secondary outcomes were 1. self-reported asthma symptoms, 2. medication use, 3. quality of life, and 4. adverse events/side effects. MAIN RESULTS: We included 24 studies (1639 participants) published between 1978 and 2021. Eleven studies were set in the USA, five in China, two in Sweden, three in Iran, and one each in the Netherlands, UK, and Germany. Participants' asthma severity ranged from mild to severe. Three studies included primary school-aged participants (five to 12 years), two included secondary school-aged participants (13 to 18 years), and 18 included both age groups, while one study was unclear on the age ranges. Durations of interventions ranged from three days to eight months. One intervention was conducted online and the rest were face-to-face. Meta-analysis was not possible due to clinical heterogeneity (interventions, populations, outcome tools and definitions, and length of follow-up). We tabulated and summarised the results narratively with reference to direction, magnitude, and certainty of effects. The certainty of the evidence was very low for all outcomes. A lack of information about scale metrics and minimal clinically important differences for the scales used to measure anxiety, depression, asthma symptoms, medication use, and quality of life made it difficult to judge clinical significance. Primary outcomes Four studies (327 participants) reported beneficial or mixed effects of psychological interventions versus controls for symptoms of anxiety, and one found little to no difference between groups (104 participants). Two studies (166 participants) that evaluated symptoms of depression both reported benefits of psychological interventions compared to controls. Three small studies (92 participants) reported a reduction in medical contacts, but two larger studies (544 participants) found little or no difference between groups in this outcome. Two studies (107 participants) found that the intervention had an important beneficial effect on number of asthma attacks, and one small study (22 participants) found little or no effect of the intervention for this outcome. Secondary outcomes Eleven studies (720 participants) assessed asthma symptoms; four (322 participants) reported beneficial effects of the intervention compared to control, five (257 participants) reported mixed or unclear findings, and two (131 participants) found little or no difference between groups. Eight studies (822 participants) reported a variety of medication use measures; six of these studies (670 participants) found a positive effect of the intervention versus control, and the other two (152 participants) found little or no difference between the groups. Across six studies (653 participants) reporting measures of quality of life, the largest three (522 participants) found little or no difference between the groups. Where findings were positive or mixed, there was evidence of selective reporting (2 studies, 131 participants). No studies provided data related to adverse effects. AUTHORS' CONCLUSIONS: Most studies that reported symptoms of anxiety, depression, asthma attacks, asthma symptoms, and medication use found a positive effect of psychological interventions versus control on at least one measure. However, some findings were mixed, it was difficult to judge clinical significance, and the evidence for all outcomes is very uncertain due to clinical heterogeneity, small sample sizes, incomplete reporting, and risk of bias. There is limited evidence to suggest that psychological interventions can reduce the need for medical contact or improve quality of life, and no studies reported adverse events. It was not possible to identify components of effective interventions and distinguish these from interventions showing no evidence of an effect due to substantial heterogeneity. Future investigations of evidence-based psychological techniques should consider standardising outcomes to support cross-comparison and better inform patient and policymaker decision-making.

Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease.

BACKGROUND: Long-acting beta-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and inhaled corticosteroids (ICSs) are inhaled medications used to manage chronic obstructive pulmonary disease (COPD). When two classes of medications are required, a LAMA plus an ICS (LABA+ICS) were previously recommended within a single inhaler as the first-line treatment for managing stable COPD in people in high-risk categories. However, updated international guidance recommends a LAMA plus a LABA (LAMA+LABA). This systematic review is an update of a Cochrane Review first published in 2017. OBJECTIVES: To compare the benefits and harms of LAMA+LABA versus LABA+ICS for treatment of people with stable COPD. SEARCH METHODS: We performed an electronic search of the Cochrane Airways Group Specialised Register, ClinicalTrials.gov, and the World Health Organization Clinical Trials Search Portal, followed by handsearches. Two review authors screened the selected articles. The most recent search was run on 10 September 2022. SELECTION CRITERIA: We included parallel or cross-over randomised controlled trials of at least one month's duration, comparing LAMA+LABA and LABA+ICS for stable COPD. We included studies conducted in an outpatient setting and irrespective of blinding. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and evaluated risk of bias. We resolved any discrepancies through discussion. We analysed dichotomous data as odds ratios (ORs), and continuous data as mean differences (MDs), with 95% confidence intervals (CIs) using Review Manager 5. Primary outcomes were: participants with one or more exacerbations of COPD; serious adverse events; quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score change from baseline; and trough forced expiratory volume in one second (FEV1). We used the GRADE framework to rate our certainty of the evidence in each meta-analysis as high, moderate, low or very low.  MAIN RESULTS: This review updates the first version of the review, published in 2017, and increases the number of included studies from 11 to 19 (22,354 participants). The median number of participants per study was 700. In each study, between 54% and 91% (median 70%) of participants were males. Study participants had an average age of 64 years and percentage predicted FEV1 of 51.5% (medians of study means). Included studies had a generally low risk of selection, performance, detection, attrition, and reporting biases. All but two studies were sponsored by pharmaceutical companies, which had varying levels of involvement in study design, conduct, and data analysis. Primary outcomes The odds of having an exacerbation were similar for LAMA+LABA compared with LABA+ICS (OR 0.91, 95% CI 0.78 to 1.06; I2 = 61%; 13 studies, 20,960 participants; moderate-certainty evidence). The odds of having a serious adverse event were also similar (OR 1.02, 95% CI 0.91 to 1.15; I2 = 20%; 18 studies, 23,183 participants; high-certainty evidence). Participants receiving LAMA+LABA had a similar improvement in quality of life, as measured by the SGRQ, to those receiving LABA+ICS (MD -0.57, 95% CI -1.36 to 0.21; I2 = 78%; 9 studies, 14,437 participants; moderate-certainty evidence) but showed a greater improvement in trough FEV1 (MD 0.07, 95% CI 0.05 to 0.08; I2 = 73%; 12 studies, 14,681 participants; moderate-certainty evidence).  Secondary outcomes LAMA+LABA decreased the odds of pneumonia compared with LABA+ICS from 5% to 3% (OR 0.61, 95% CI 0.52 to 0.72; I2 = 0%; 14 studies, 21,829 participants; high-certainty evidence) but increased the odds of all-cause death from 1% to 1.4% (OR 1.35, 95% CI 1.05 to 1.75; I2 = 0%; 15 studies, 21,510 participants; moderate-certainty evidence). The odds of achieving a minimal clinically important difference of four or more points on the SGRQ were similar between LAMA+LABA and LABA+ICS (OR 1.06, 95% CI 0.90 to 1.25; I2 = 77%; 4 studies, 13,614 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Combination LAMA+LABA therapy probably holds similar benefits to LABA+ICS for exacerbations and quality of life, as measured by the St George's Respiratory Questionnaire, for people with moderate to severe COPD, but offers a larger improvement in FEV1 and a slightly lower risk of pneumonia. There is little to no difference between LAMA+LABA and LAMA+ICS in the odds of having a serious adverse event. Whilst all-cause death may be lower with LABA+ICS, there was a very small number of events in the analysis, translating to a low absolute risk. Findings are based on moderate- to high-certainty evidence from heterogeneous trials with an observation period of less than one year. This review should be updated again in a few years.

Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children.

BACKGROUND: People with asthma may experience exacerbations, or 'attacks', during which their symptoms worsen and additional treatment is required. Written action plans sometimes advocate a short-term increase in the dose of inhaled corticosteroids (ICS) at the first sign of an exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. OBJECTIVES: To compare the clinical effectiveness and safety of increased versus stable doses of ICS as part of a patient-initiated action plan for the home management of exacerbations in children and adults with persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and handsearched abstracts to 20 December 2021. We also searched major trial registries for ongoing trials. SELECTION CRITERIA: We included parallel and cross-over randomised controlled trials (RCTs) that allocated people with persistent asthma to take a blinded inhaler in the event of an exacerbation which either increased their daily dose of ICS or kept it stable (placebo). DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, and extracted data. We reassessed risk of bias for all studies at the result level using the revised risk of bias tool for RCTs (Risk of Bias 2), and employed the GRADE approach to assess our confidence in the synthesised effect estimates. The primary outcome was treatment failure, defined as the need for rescue oral steroids in the randomised population. Secondary outcomes were treatment failure in the subset who initiated the study inhaler (treated population), unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, serious and non-serious adverse events, and duration of exacerbation. MAIN RESULTS: This review update added a new study that increased the number of people in the primary analysis from 1520 to 1774, and incorporates the most up-to-date methods to assess the likely impact of bias within the meta-analyses. The updated review now includes nine RCTs (1923 participants; seven parallel and two cross-over) conducted in Europe, North America, and Australasia and published between 1998 and 2018. Five studies evaluated adult populations (n = 1247; ≥ 15 years), and four studies evaluated child or adolescent populations (n = 676; < 15 years). All study participants had mild to moderate asthma. Studies varied in the dose of maintenance ICS, age, fold increase of ICS in the event of an exacerbation, criteria for initiating the study inhaler, and allowed medications. Approximately 50% of randomised participants initiated the study inhaler (range 23% to 100%), and the included studies reported treatment failure in a variety of ways, meaning assumptions were required to permit the combining of data. Participants randomised to increase their ICS dose at the first signs of an exacerbation had similar odds of needing rescue oral corticosteroids to those randomised to a placebo inhaler (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.76 to 1.25; 8 studies; 1774 participants; I2 = 0%; moderate quality evidence). We could draw no firm conclusions from subgroup analyses conducted to investigate the impact of age, time to treatment initiation, baseline dose, smoking history, and fold increase of ICS on the primary outcome. Results for the same outcome in the subset of participants who initiated the study inhaler were unchanged from the previous version, which provides a different point estimate with very low confidence due to heterogeneity, imprecision, and risk of bias (OR 0.84, 95% CI 0.54 to 1.30; 7 studies; 766 participants; I2 = 42%; random-effects model). Confidence was reduced due to risk of bias and assumptions that had to be made to include study data in the intention-to-treat and treated-population analyses. Sensitivity analyses that tested the impact of assumptions made for synthesis and to exclude cross-over studies, studies at overall high risk of bias, and those with commercial funding did not change our conclusions. Pooled effects for unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, and duration of exacerbation made it very difficult to determine where the true effect may lie, and confidence was reduced by risk of bias. Point estimates for both serious and non-serious adverse events favoured keeping ICS stable, but imprecision and risk of bias due to missing data and outcome measurement and reporting reduced our confidence in the effects (serious adverse events: OR 1.69, 95% CI 0.77 to 3.71; 2 studies; 394 participants; I² = 0%; non-serious adverse events: OR 2.15, 95% CI 0.68 to 6.73; 2 studies; 142 participants; I² = 0%). AUTHORS' CONCLUSIONS: Evidence from double-blind trials of adults and children with mild to moderate asthma suggests there is unlikely to be an important reduction in the need for oral steroids from increasing a patient's ICS dose at the first sign of an exacerbation. Other clinically important benefits and potential harms of increased doses of ICS compared with keeping the dose stable cannot be ruled out due to wide confidence intervals, risk of bias in the trials, and assumptions that had to be made for synthesis. Included studies conducted between 1998 and 2018 reflect evolving clinical practice and study methods, and the data do not support thorough investigation of effect modifiers such as baseline dose, fold increase, asthma severity and timing. The review does not include recent evidence from pragmatic, unblinded studies showing benefits of larger dose increases in those with poorly controlled asthma. A systematic review is warranted to examine the differences between the blinded and unblinded trials using robust methods for assessing risk of bias to present the most complete view of the evidence for decision makers.

Macrolides versus placebo for chronic asthma.

BACKGROUND: Asthma is a chronic disease in which inflammation of the airways causes symptomatic wheezing, coughing and difficult breathing. Macrolides are antibiotics with antimicrobial and anti-inflammatory activities that have been explored for the long-term control of asthma symptoms. OBJECTIVES: To assess the effects of macrolides compared with placebo for managing chronic asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register up to March 2021. We also manually searched bibliographies of previously published reviews and conference proceedings and contacted study authors. We included records published in any language in the search. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) involving both children and adults with asthma treated with macrolides versus placebo for four or more weeks. Primary outcomes were exacerbation requiring hospitalisation, severe exacerbations (exacerbations requiring emergency department (ED) visits or systemic steroids, or both), symptom scales, asthma control questionnaire (ACQ, score from 0 totally controlled, to 6 severely uncontrolled), Asthma Quality of Life Questionnaire (AQLQ, with score from 1 to 7 with higher scores indicating better QoL), rescue medication puffs per day, morning and evening peak expiratory flow (PEF; litres per minutes), forced expiratory volume in one second (FEV1; litres), bronchial hyperresponsiveness, and oral corticosteroid dose. Secondary outcomes were adverse events (including mortality), withdrawal, blood eosinophils, sputum eosinophils, eosinophil cationic protein (ECP) in serum, and ECP in sputum. DATA COLLECTION AND ANALYSIS: Two review authors independently examined all records identified in the searches then reviewed the full text of all potentially relevant articles before extracting data in duplicate from all included studies. As per protocol, we used a fixed-effect model. We conducted a sensitivity analysis for analyses with high heterogeneity (I2 greater than 30%). GRADE was used to assess the certainty of the body of evidence. MAIN RESULTS: Twenty-five studies met the inclusion criteria, randomising 1973 participants to receive macrolide or placebo for at least four weeks. Most of the included studies reported data from adults (mean age 21 to 61 years) with persistent or severe asthma, while four studies included children. All participants were recruited in outpatient settings. Inclusion criteria, interventions and outcomes were highly variable. The evidence suggests macrolides probably deliver a moderately sized reduction in exacerbations requiring hospitalisations compared to placebo (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.20 to 1.12; studies = 2, participants = 529; moderate-certainty evidence). Macrolides probably reduce exacerbations requiring ED visits and/or treatment with systemic steroids (rate ratio (RaR) 0.65, 95% CI 0.53 to 0.80; studies = 4, participants = 640; moderate-certainty evidence). Macrolides may reduce symptoms (as measured on symptom scales) (standardised mean difference (SMD) -0.46, 95% CI -0.81 to -0.11; studies = 4, participants = 136 ; very low-certainty evidence). Macrolides may result in a little improvement in ACQ (SMD -0.17, 95% CI -0.31 to -0.03; studies = 5, participants = 773; low-certainty evidence). Macrolides may have little to no effect on AQLQ (mean difference (MD) 0.24, 95% CI 0.12 to 0.35; studies = 6, participants = 802; very low-certainty evidence). For both the ACQ and the AQLQ the suggested effect of macrolides versus placebo did not reach a minimal clinically important difference (MCID, 0.5 for ACQ and AQLQ) (ACQ: low-certainty evidence; AQLQ: very low-certainty evidence). Due to high heterogeneity (I2 > 30%), we conducted sensitivity analyses on the above results, which reduced the size of the suggested effects by reducing the weighting on the large, high quality studies.  Macrolides may result in a small effect compared to placebo in reducing need for rescue medication (MD -0.43 puffs/day, 95% CI -0.81 to -0.04; studies = 4, participants = 314; low-certainty evidence). Macrolides may increase FEV1, but the effect is almost certainly below a level discernible to patients (MD 0.04 L, 95% CI 0 to 0.08; studies = 10, participants = 1046; low-certainty evidence). It was not possible to pool outcomes for non-specific bronchial hyperresponsiveness or lowest tolerated oral corticosteroid dose (in people requiring oral corticosteroids at baseline). There was no evidence of a difference in severe adverse events (including mortality), although less than half of the studies reported the outcome (OR 0.80, 95% CI 0.49 to 1.31; studies = 8, participants = 854; low-certainty evidence). Reporting of specific adverse effects was too inconsistent across studies for a meaningful analysis. AUTHORS' CONCLUSIONS: Existing evidence suggests an effect of macrolides compared with placebo on the rate of exacerbations requiring hospitalisation. Macrolides probably reduce severe exacerbations (requiring ED visit and/or treatment with systemic steroids) and may reduce symptoms. However, we cannot rule out the possibility of other benefits or harms because the evidence is of very low quality due to heterogeneity among patients and interventions, imprecision and reporting biases. The results were mostly driven by a well-designed, well powered RCT, indicating that azithromycin may reduce exacerbation rate and improve symptom scores in severe asthma. The review highlights the need for researchers to report outcomes accurately and according to standard definitions. Macrolides can reduce exacerbation rate in people with severe asthma. Future trials could evaluate if this effect is sustained across all the severe asthma phenotypes, the comparison with newer biological drugs, whether effects persist or wane after treatment cessation and whether effects are associated with infection biomarkers.

What is CAR T-cell therapy?

The emergence of targeted and precision therapies has increased treatment options for people living with cancer. Of particular note is the development and approval of chimeric antigen receptor (CAR) T-cell therapies that involve the use of a patient's own immune system to treat cancers that have proven resistant to other approaches. Keeping abreast of treatment changes and practice guidelines is a challenge for all healthcare professionals, and the pressure of doing so becomes most acute with innovations in cancer therapeutics that have the potential to extend or save lives. Though uncommon, step changes like CAR T-cell therapy pose a challenge, often requiring completely new ways of thinking about efficacy evidence, basic science, ethics and service delivery. At a time when patients are able and empowered to readily access information about novel and exploratory treatments, healthcare professionals need to feel informed enough to help patients with life-changing or life-limiting cancers who approach them for advice. This article gives an overview of the basic principles of CAR T-cell therapy including how it is delivered, who is eligible to receive it in the UK, and a brief outline of current evidence of its efficacy and safety. The information is intended to provide healthcare professionals with an introduction to CAR T-cell therapy to help them advise potentially eligible patients or those already undergoing treatment about what to expect.

Sublingual immunotherapy for asthma.

BACKGROUND: Asthma is a common long-term respiratory disease affecting approximately 300 million people worldwide. Approximately half of people with asthma have an important allergic component to their disease, which may provide an opportunity for targeted treatment. Sublingual immunotherapy (SLIT) aims to reduce asthma symptoms by delivering increasing doses of an allergen (e.g. house dust mite, pollen extract) under the tongue to induce immune tolerance. Fifty-two studies were identified and synthesised in the original Cochrane Review in 2015, but questions remained about the safety and efficacy of sublingual immunotherapy for people with asthma. OBJECTIVES: To assess the efficacy and safety of sublingual immunotherapy compared with placebo or standard care for adults and children with asthma. SEARCH METHODS: The original searches for trials from the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, WHO ICTRP, and reference lists of all primary studies and review articles found trials up to 25 March 2015. The most recent search for trials for the current update was conducted on 29 October 2019. SELECTION CRITERIA: We included parallel randomised controlled trials, irrespective of blinding or duration, that evaluated sublingual immunotherapy versus placebo or as an add-on to standard asthma management. We included both adults and children with asthma of any severity and with any allergen-sensitisation pattern. We included studies that recruited participants with asthma, rhinitis, or both, providing at least 80% of trial participants had a diagnosis of asthma. We selected outcomes to reflect recommended outcomes for asthma clinical trials and those most important to people with asthma. Primary outcomes were asthma exacerbations requiring a visit to the emergency department (ED) or admission to hospital, validated measures of quality of life, and all-cause serious adverse events (SAEs). Secondary outcomes were asthma symptom scores, exacerbations requiring systemic corticosteroids, response to provocation tests, and dose of inhaled corticosteroids (ICS). DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results for included trials, extracted numerical data, and assessed risk of bias, all of which were cross-checked for accuracy. Any disagreements were resolved by discussion. We analysed dichotomous data as odds ratios (ORs) or risk differences (RDs) using study participants as the unit of analysis; we analysed continuous data as mean differences (MDs) or standardised mean differences (SMDs) using random-effects models. We considered the strength of evidence for all primary and secondary outcomes using the GRADE approach. MAIN RESULTS: Sixty-six studies met the inclusion criteria for this update, including 52 studies from the original review. Most studies were double-blind and placebo-controlled, varied in duration from one day to three years, and recruited participants with mild or intermittent asthma, often with comorbid allergic rhinitis. Twenty-three studies recruited adults and teenagers; 31 recruited only children; three recruited both; and nine did not specify. The pattern of reporting and results remained largely unchanged from the original review despite 14 further studies and a 50% increase in participants studied (5077 to 7944). Reporting of primary efficacy outcomes to measure the impact of SLIT on asthma exacerbations and quality of life was infrequent, and selective reporting may have had a serious effect on the completeness of the evidence; 16 studies did not contribute any data, and a further six studies could only be included in a post hoc analysis of all adverse events. Allocation procedures were generally not well described; about a quarter of the studies were at high risk of performance or detection bias (or both); and participant attrition was high or unknown in around half of the studies. The primary outcome in most studies did not align with those of interest to the review (mostly asthma or rhinitis symptoms), and only two small studies reported our primary outcome of exacerbations requiring an ED or hospital visit; the pooled estimate from these studies suggests SLIT may reduce exacerbations compared with placebo or usual care, but the evidence is very uncertain (OR 0.35, 95% confidence interval (CI) 0.10 to 1.20; n = 108; very low-certainty evidence). Nine studies reporting quality of life could not be combined in a meta-analysis and, whilst the direction of effect mostly favoured SLIT, the effects were often uncertain and small. SLIT likely does not increase SAEs compared with placebo or usual care, and analysis by risk difference suggests no more than 1 in 100 people taking SLIT will have a serious adverse event (RD -0.0004, 95% CI -0.0072 to 0.0064; participants = 4810; studies = 29; moderate-certainty evidence). Regarding secondary outcomes, asthma symptom and medication scores were mostly measured with non-validated scales, which precluded meaningful meta-analysis or interpretation, but there was a general trend of SLIT benefit over placebo. Changes in ICS use (MD -17.13 µg/d, 95% CI -61.19 to 26.93; low-certainty evidence), exacerbations requiring oral steroids (studies = 2; no events), and bronchial provocation (SMD 0.99, 95% CI 0.17 to 1.82; low-certainty evidence) were not often reported. Results were imprecise and included the possibility of important benefit or little effect and, in some cases, potential harm from SLIT. More people taking SLIT had adverse events of any kind compared with control (OR 1.99, 95% CI 1.49 to 2.67; high-certainty evidence; participants = 4251; studies = 27), but events were usually reported to be transient and mild. Lack of data prevented most of the planned subgroup and sensitivity analyses. AUTHORS' CONCLUSIONS: Despite continued study in the field, the evidence for important outcomes such as exacerbations and quality of life remains too limited to draw clinically useful conclusions about the efficacy of SLIT for people with asthma. Trials mostly recruited mixed populations with mild and intermittent asthma and/or rhinitis and focused on non-validated symptom and medication scores. The review findings suggest that SLIT may be a safe option for people with well-controlled mild-to-moderate asthma and rhinitis who are likely to be at low risk of serious harm, but the role of SLIT for people with uncontrolled asthma requires further evaluation.

Implantable cardiac monitors to detect atrial fibrillation after cryptogenic stroke: a systematic review and economic evaluation.

BACKGROUND: Cryptogenic stroke is a stroke for which no cause is identified after standard diagnostic tests. Long-term implantable cardiac monitors may be better at diagnosing atrial fibrillation and provide an opportunity to reduce the risk of stroke recurrence with anticoagulants. OBJECTIVES: The objectives were to assess the diagnostic test accuracy, clinical effectiveness and cost-effectiveness of three implantable monitors [BioMonitor 2-AF™ (Biotronik SE & Co. KG, Berlin, Germany), Confirm Rx™ (Abbott Laboratories, Lake Bluff, IL, USA) and Reveal LINQ™ (Medtronic plc, Minneapolis, MN, USA)] in patients who have had a cryptogenic stroke and for whom no atrial fibrillation is detected after 24 hours of external electrocardiographic monitoring. DATA SOURCES: MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of Reviews of Effects and Health Technology Assessment databases were searched from inception until September 2018. REVIEW METHODS: A systematic review was undertaken. Two reviewers agreed on studies for inclusion and performed quality assessment using the Cochrane Risk of Bias 2.0 tool. Results were discussed narratively because there were insufficient data for synthesis. A two-stage de novo economic model was developed: (1) a short-term patient flow model to identify cryptogenic stroke patients who have had atrial fibrillation detected and been prescribed anticoagulation treatment (rather than remaining on antiplatelet treatment) and (2) a long-term Markov model that captured the lifetime costs and benefits of patients on either anticoagulation or antiplatelet treatment. RESULTS: One randomised controlled trial, Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL-AF) (Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478-86), was identified, and no diagnostic test accuracy study was identified. The CRYSTAL-AF trial compared the Reveal™ XT (a Reveal LINQ predecessor) (Medtronic plc) monitor with standard of care monitoring. Twenty-six single-arm observational studies for the Reveal devices were also identified. The only data for BioMonitor 2-AF or Confirm Rx were from mixed population studies supplied by the companies. Atrial fibrillation detection in the CRYSTAL-AF trial was higher with the Reveal XT than with standard monitoring at all time points. By 36 months, atrial fibrillation was detected in 19% of patients with an implantable cardiac monitor and in 2.3% of patients receiving conventional follow-up. The 26 observational studies demonstrated that, even in a cryptogenic stroke population, atrial fibrillation detection rates are highly variable and most cases are asymptomatic; therefore, they probably would not have been picked up without an implantable cardiac monitor. Device-related adverse events, such as pain and infection, were low in all studies. The de novo economic model produced incremental cost effectiveness ratios comparing implantable cardiac monitors with standard of care monitoring to detect atrial fibrillation in cryptogenic stroke patients based on data for the Reveal XT device, which can be related to Reveal LINQ. The BioMonitor 2-AF and Confirm RX were included in the analysis by making a strong assumption of equivalence with Reveal LINQ. The results indicate that implantable cardiac monitors could be considered cost-effective at a £20,000-30,000 threshold. When each device is compared incrementally, BioMonitor 2-AF dominates Reveal LINQ and Confirm RX. LIMITATIONS: The cost-effectiveness analysis for implantable cardiac monitors is based on a strong assumption of clinical equivalence and should be interpreted with caution. CONCLUSIONS: All three implantable cardiac monitors could be considered cost-effective at a £20,000-30,000 threshold, compared with standard of care monitoring, for cryptogenic stroke patients with no atrial fibrillation detected after 24 hours of external electrocardiographic monitoring; however, further clinical studies are required to confirm their efficacy in cryptogenic stroke patients. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018109216. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 5. See the NIHR Journals Library website for further project information.

An abnormal heart rhythm (atrial fibrillation) is an important cause of stroke. Clots form in the heart, break off, pass into blood vessels in the head and block the blood supply to parts of the brain. This is important to diagnose because atrial fibrillation can be treated with blood-thinning drugs, which can prevent further stroke. For this reason, all patients with stroke are tested for atrial fibrillation. Unfortunately, the standard tests, which include 24 hours of outpatient external heart monitoring, may miss the condition. Implantable cardiac monitors, which are small devices placed beneath the skin of the chest that can monitor the heart for up to 4 years, may be better than the standard tests. This study compared three different implantable cardiac monitors [BioMonitor 2-AF™ (Biotronik SE & Co. KG, Berlin, Germany), Confirm Rx™ (Abbott Laboratories, Lake Bluff, IL, USA) and Reveal LINQ™ (Medtronic plc, Minneapolis, MN, USA)] to determine how effective they are at detecting atrial fibrillation in people who have had a cryptogenic stroke (a stroke for which no cause is identified), whether or not they are better than standard monitoring and whether or not they offer good value for money. No evidence was found that directly compared the three implantable monitors in cryptogenic stroke patients. The limited evidence found suggested that all three monitors had few side effects; only one monitor (Reveal LINQ) had evidence that it was better than standard monitoring. By 36 months, 19% of patients had atrial fibrillation detected by Reveal LINQ compared with only 2.3% with conventional monitoring. There was insufficient information for the other monitors. Overall, implantable monitors offer value for money when compared with standard monitoring for people who have had a cryptogenic stroke and for whom atrial fibrillation has not been detected with standard tests.

Targeted therapies for previously treated advanced or metastatic renal cell carcinoma: systematic review and network meta-analysis.

OBJECTIVE: To compare the effectiveness and safety of treatments for advanced or metastatic renal cell carcinoma (amRCC) after treatment with vascular endothelial growth factor (VEGF)-targeted treatment. DESIGN: Systematic review and network meta-analysis of randomised controlled trials (RCTs) and comparative observational studies. MEDLINE, EMBASE and Cochrane Library were searched up to January 2018. PARTICIPANTS: People with amRCC requiring treatment after VEGF-targeted treatment. INTERVENTIONS: Axitinib, cabozantinib, everolimus, lenvatinib with everolimus, nivolumab, sorafenib and best supportive care (BSC). OUTCOMES: Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were objective response rate (ORR), adverse events, and health-related quality of life (HRQoL). RESULTS: Twelve studies were included (n=5144): five RCTs and seven observational studies. Lenvatinib with everolimus significantly increased OS and PFS over everolimus (HR 0.61, 95% Credible Interval [95%CrI]: 0.36 to 0.96 and 0.47, 95%CrI: 0.26 to 0.77, respectively) as did cabozantinib (HR 0.66, 95%CrI: 0.53 to 0.82 and 0.51, 95%CrI: 0.41 to 0.63, respectively). This remained the case when observational evidence was included. Nivolumab also significantly improved OS versus everolimus (HR 0.74, 95%CrI: 0.57 to 0.93). OS sensitivity analysis, including observational studies, indicates everolimus being more effective than axitinib and sorafenib. However, inconsistency was identified in the OS sensitivity analysis. PFS sensitivity analysis suggests axitinib is more effective than everolimus, which may be more effective than sorafenib. The results for ORR supported the OS and PFS analyses. Nivolumab is associated with fewer grade 3 or grade 4 adverse events than lenvatinib with everolimus or cabozantinib. HRQoL could not be analysed due to differences in tools used. CONCLUSIONS: Lenvatinib with everolimus, cabozantinib and nivolumab are effective in prolonging the survival for people with amRCC subsequent to VEGF-targeted treatment, but there is considerable uncertainty about how they compare to each other and how much better they are than axitinib and sorafenib. PROSPERO REGISTRATION NUMBER: CRD42017071540.

Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis.

BACKGROUND: Asthma guidelines guide health practitioners to adjust treatments to the minimum level required for asthma control. As many people with asthma have an eosinophilic endotype, tailoring asthma medications based on airway eosinophilic levels (sputum eosinophils or exhaled nitric oxide, FeNO) may improve asthma outcomes. OBJECTIVE: To synthesise the evidence from our updated Cochrane systematic reviews, for tailoring asthma medication based on eosinophilic inflammatory markers (sputum analysis and FeNO) for improving asthma-related outcomes in children and adults. DATA SOURCES: Cochrane reviews with standardised searches up to February 2017. STUDY SELECTION: The Cochrane reviews included randomised controlled comparisons of tailoring asthma medications based on sputum analysis or FeNO compared with controls (primarily clinical symptoms and/or spirometry/peak flow). RESULTS: The 16 included studies of FeNO-based management (seven in adults) and 6 of sputum-based management (five in adults) were clinically heterogeneous. On follow-up, participants randomised to the sputum eosinophils strategy (compared with controls) were significantly less likely to have exacerbations (62 vs 82/100 participants with ≥1 exacerbation; OR 0.36, 95% CI 0.21 to 0.62). For the FeNO strategy, the respective numbers were adults OR 0.60 (95% CI 0.43 to 0.84) and children 0.58 (95% CI 0.45 to 0.75). However, there were no significant group differences for either strategy on daily inhaled corticosteroids dose (at end of study), asthma control or lung function. CONCLUSION: Adjusting treatment based on airway eosinophilic markers reduced the likelihood of asthma exacerbations but had no significant impact on asthma control or lung function.

Axitinib, cabozantinib, everolimus, nivolumab, sunitinib and best supportive care in previously treated renal cell carcinoma: a systematic review and economic evaluation.

BACKGROUND: Several therapies have recently been approved for use in the NHS for pretreated advanced or metastatic renal cell carcinoma (amRCC), but there is a lack of comparative evidence to guide decisions between them. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of axitinib (Inlyta®, Pfizer Inc., NY, USA), cabozantinib (Cabometyx®, Ipsen, Slough, UK), everolimus (Afinitor®, Novartis, Basel, Switzerland), nivolumab (Opdivo®, Bristol-Myers Squibb, NY, USA), sunitinib (Sutent®, Pfizer, Inc., NY, USA) and best supportive care (BSC) for people with amRCC who were previously treated with vascular endothelial growth factor (VEGF)-targeted therapy. DATA SOURCES: A systematic review and mixed-treatment comparison (MTC) of randomised controlled trials (RCTs) and non-RCTs. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were objective response rates (ORRs), adverse events (AEs) and health-related quality of life (HRQoL). MEDLINE, EMBASE and The Cochrane Library were searched from inception to January and June 2016 for RCTs and non-RCTs, respectively. Two reviewers abstracted data and performed critical appraisals. REVIEW METHODS: A fixed-effects MTC was conducted for OS, PFS [hazard ratios (HRs)] and ORR (odds ratios), and all were presented with 95% credible intervals (CrIs). The RCT data formed the primary analyses, with non-RCTs and studies rated as being at a high risk of bias included in sensitivity analyses (SAs). HRQoL and AE data were summarised narratively. A partitioned survival model with health states for pre progression, post progression and death was developed to perform a cost-utility analysis. Survival curves were fitted to the PFS and OS results from the MTC. A systematic review of HRQoL was undertaken to identify sources of health state utility values. RESULTS: Four RCTs (n = 2618) and eight non-RCTs (n = 1526) were included. The results show that cabozantinib has longer PFS than everolimus (HR 0.51, 95% CrI 0.41 to 0.63) and both treatments are better than BSC. Both cabozantinib (HR 0.66, 95% CrI 0.53 to 0.82) and nivolumab (HR 0.73, 95% CrI 0.60 to 0.89) have longer OS than everolimus. SAs were consistent with the primary analyses. The economic analysis, using drug list prices, shows that everolimus may be more cost-effective than BSC with an incremental cost-effectiveness ratio (ICER) of £45,000 per quality-adjusted life-year (QALY), as it is likely to be considered an end-of-life treatment. Cabozantinib has an ICER of £126,000 per QALY compared with everolimus and is unlikely to be cost-effective. Nivolumab was dominated by cabozantinib (i.e. more costly and less effective) and axitinib was dominated by everolimus. LIMITATIONS: Treatment comparisons were limited by the small number of RCTs. However, the key limitation of the analysis is the absence of the drug prices paid by the NHS, which was a limitation that could not be avoided owing to the confidentiality of discounts given to the NHS. CONCLUSIONS: The RCT evidence suggests that cabozantinib is likely to be the most effective for PFS and OS, closely followed by nivolumab. All treatments appear to delay disease progression and prolong survival compared with BSC, although the results are heterogeneous. The economic analysis shows that at list price everolimus could be recommended as the other drugs are much more expensive with insufficient incremental benefit. The applicability of these findings to the NHS is somewhat limited because existing confidential patient access schemes could not be used in the analysis. Future work using the discounted prices at which these drugs are provided to the NHS would better inform estimates of their relative cost-effectiveness. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016042384. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Shared decision-making for people with asthma.

BACKGROUND: Asthma is a chronic inflammatory disease that affects the airways and is common in both adults and children. It is characterised by symptoms including wheeze, shortness of breath, chest tightness, and cough. People with asthma may be helped to manage their condition through shared decision-making (SDM). SDM involves at least two participants (the medical practitioner and the patient) and mutual sharing of information, including the patient's values and preferences, to build consensus about favoured treatment that culminates in an agreed action. Effective self-management is particularly important for people with asthma, and SDM may improve clinical outcomes and quality of life by educating patients and empowering them to be actively involved in their own health. OBJECTIVES: To assess benefits and potential harms of shared decision-making for adults and children with asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, which contains studies identified in several sources including CENTRAL, MEDLINE, and Embase. We also searched clinical trials registries and checked the reference lists of included studies. We conducted the most recent searches on 29 November 2016. SELECTION CRITERIA: We included studies of individual or cluster parallel randomised controlled design conducted to compare an SDM intervention for adults and children with asthma versus a control intervention. We included studies available as full-text reports, those published as abstracts only, and unpublished data, and we placed no restrictions on place, date, or language of publication. We included interventions targeting healthcare professionals or patients, their families or care-givers, or both. We included studies that compared the intervention versus usual care or a minimal control intervention, and those that compared an SDM intervention against another active intervention. We excluded studies of interventions that involved multiple components other than the SDM intervention unless the control group also received these interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened searches, extracted data from included studies, and assessed risk of bias. Primary outcomes were asthma-related quality of life, patient/parent satisfaction, and medication adherence. Secondary outcomes included exacerbations of asthma, asthma control, acceptability/feasibility from the perspective of healthcare professionals, and all adverse events. We graded and presented evidence in a 'Summary of findings' table.We were unable to pool any of the extracted outcome data owing to clinical and methodological heterogeneity but presented findings in forest plots when possible. We narratively described skewed data. MAIN RESULTS: We included four studies that compared SDM versus control and included a total of 1342 participants. Three studies recruited children with asthma and their care-givers, and one recruited adults with asthma. Three studies took place in the United States, and one in the Netherlands. Trial duration was between 6 and 24 months. One trial delivered the SDM intervention to the medical practitioner, and three trials delivered the SDM intervention directly to the participant. Two paediatric studies involved use of an online portal, followed by face-to-face consultations. One study delivered an SDM intervention or a clinical decision-making intervention through a mixture of face-to-face consultations and telephone calls. The final study randomised paediatric general practice physicians to receive a seminar programme promoting application of SDM principles. All trials were open-label, although one study, which delivered the intervention to physicians, stated that participants were unaware of their physicians' involvement in the trial. We had concerns about selection and attrition bias and selective reporting, and we noted that one study substantially under-recruited participants. The four included studies used different approaches to measure fidelity/intervention adherence and to report study findings.One study involving adults with poorly controlled asthma reported improved quality of life (QOL) for the SDM group compared with the control group, using the Asthma Quality of Life Questionnaire (AQLQ) for assessment (mean difference (MD) 1.90, 95% confidence interval (CI) 1.24 to 2.91), but two other trials did not identify a benefit. Patient/parent satisfaction with the performance of paediatricians was greater in the SDM group in one trial involving children. Medication adherence was better in the SDM group in two studies - one involving adults and one involving children (all medication adherence: MD 0.21, 95% CI 0.11 to 0.31; mean number of controlled medication prescriptions over 26 weeks: 1.1 in the SDM group (n = 26) and 0.7 in the control group (n = 27)). In one study, asthma-related visit rates were lower in the SDM group than in the usual care group (1.0/y vs 1.4/y; P = 0.016), but two other studies did not report a difference in exacerbations nor in prescriptions for short courses of oral steroids. Finally, one study described better odds of reporting no asthma problems in the SDM group than in the usual care group (odds ratio (OR) 1.90, 95% CI 1.26 to 2.87), although two other studies reporting asthma control did not identify a benefit with SDM. We found no information about acceptability of the intervention to the healthcare professional and no information on adverse events. Overall, our confidence in study results ranged from very low to moderate, and we downgraded outcomes owing to risk of bias, imprecision, and indirectness. AUTHORS' CONCLUSIONS: Substantial differences between the four included randomised controlled trials (RCTs) indicate that we cannot provide meaningful overall conclusions. Individual studies demonstrated some benefits of SDM over control, in terms of quality of life; patient and parent satisfaction; adherence to prescribed medication; reduction in asthma-related healthcare visits; and improved asthma control. Our confidence in the findings of these individual studies ranges from moderate to very low, and it is important to note that studies did not measure or report adverse events.Future trials should be adequately powered and of sufficient duration to detect differences in patient-important outcomes such as exacerbations and hospitalisations. Use of core asthma outcomes and validated scales when possible would facilitate future meta-analysis. Studies conducted in lower-income settings and including an economic evaluation would be of interest. Investigators should systematically record adverse events, even if none are anticipated. Studies identified to date have not included adolescents; future trials should consider their inclusion. Measuring and reporting of intervention fidelity is also recommended.

Lay-led and peer support interventions for adolescents with asthma.

BACKGROUND: Adolescents with asthma are at high risk of poor adherence with treatment. This may be compounded by activities that worsen asthma, in particular smoking. Additional support above and beyond routine care has the potential to encourage good self-management. We wanted to find out whether sessions led by their peers or by lay leaders help to reduce these risks and improve asthma outcomes among adolescents. OBJECTIVES: To assess the safety and efficacy of lay-led and peer support interventions for adolescents with asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains reports of randomised trials obtained from multiple electronic and handsearched sources, and we searched trial registries and reference lists of primary studies. We conducted the most recent searches on 25 November 2016. SELECTION CRITERIA: Eligible studies randomised adolescents with asthma to an intervention led by lay people or peers or to a control. We included parallel randomised controlled trials with individual or cluster designs. We included studies reported as full text, those published as abstract only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors screened the searches, extracted numerical data and study characteristics and assessed each included study for risk of bias. Primary outcomes were asthma-related quality of life and exacerbations requiring at least a course of oral steroids. We graded the analyses and presented evidence in a 'Summary of findings' table.We analysed dichotomous data as odds ratios, and continuous data as mean differences (MD) or standardised mean differences, all with a random-effects model. We assessed clinical, methodological and statistical heterogeneity when performing meta-analyses, and we described skewed data narratively. MAIN RESULTS: Five studies including a total of 1146 participants met the inclusion criteria for this review. As ever with systematic reviews of complex interventions, studies varied by design (cluster and individually randomised), duration (2.5 to 9 months), setting (school, day camp, primary care) and intervention content. Most risk of bias concerns were related to blinding and incomplete reporting, which limited the meta-analyses that could be performed. Studies generally controlled well for selection and attrition biases.All participants were between 11 and 17 years of age. Asthma diagnosis and severity varied, as did smoking prevalence. Three studies used the Triple A programme; one of these studies tested the addition of a smoke-free pledge; another delivered peer support group sessions and mp3 messaging to encourage adherence; and the third compared a peer-led asthma day camp with an equivalent camp led by healthcare practitioners.We had low confidence in all findings owing to risk of bias, inconsistency and imprecision. Results from an analysis of asthma-related quality of life based on the prespecified random-effects model were imprecise and showed no differences (MD 0.40, 95% confidence interval (CI) -0.02 to 0.81); a sensitivity analysis based on a fixed-effect model and a responder analysis suggested small benefit may be derived for this outcome. Most other results were summarised narratively and did not show an important benefit of the intervention; studies provided no analysable data on asthma exacerbations or unscheduled visits (data were skewed), and one study measuring adherence reported a drop in both groups. Effects on asthma control favoured the intervention but findings were not statistically significant. Results from two studies with high levels of baseline smoking showed some promise for self-efficacy to stop smoking, but overall nicotine dependence and smoking-related knowledge were not significantly better in the intervention group. Investigators did not report adverse events. AUTHORS' CONCLUSIONS: Although weak evidence suggests that lay-led and peer support interventions could lead to a small improvement in asthma-related quality of life for adolescents, benefits for asthma control, exacerbations and medication adherence remain unproven. Current evidence is insufficient to reveal whether routine use of lay-led or peer support programmes is beneficial for adolescents receiving asthma care.Ongoing and future research may help to identify target populations for lay-led and peer support interventions, along with attributes that constitute a successful programme.

Asthma education for school staff.

BACKGROUND: Teachers and school staff should be competent in managing asthma in schools. Demonstrated low levels of asthma knowledge mean that staff may not know how best to protect a child with asthma in their care, or may fail to take appropriate action in the event of a serious attack. Education about asthma could help to improve this knowledge and lead to better asthma outcomes for children. OBJECTIVES: To assess the effectiveness and safety of asthma education programmes for school staff, and to identify content and attributes underpinning them. SEARCH METHODS: We conducted the most recent searches on 29 November 2016. SELECTION CRITERIA: We included randomised controlled trials comparing an intervention to educate school staff about asthma versus a control group. We included studies reported as full text, those published as abstract only and unpublished data. DATA COLLECTION AND ANALYSIS: At least two review authors screened the searches, extracted outcome data and intervention characteristics from included studies and assessed risk of bias. Primary outcomes for the quantitative synthesis were emergency department (ED) or hospital visits, mortality and asthma control; we graded the main results and presented evidence in a 'Summary of findings' table. We planned a qualitative synthesis of intervention characteristics, but study authors were unable to provide the necessary information.We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all with a random-effects model. We assessed clinical, methodological and statistical heterogeneity when performing meta-analyses, and we narratively described skewed data. MAIN RESULTS: Five cluster-RCTs of 111 schools met the review eligibility criteria. Investigators measured outcomes in participating staff and often in children or parents, most often at between 1 and 12 months.All interventions were educational programmes but duration, content and delivery varied; some involved elements of training for pupils or primary care providers. We noted risk of selection, performance, detection and attrition biases, although to a differing extent across studies and outcomes.Quanitative and qualitative analyses were limited. Only one study reported visits to the ED or hospital and provided data that were too skewed for analysis. No studies reported any deaths or adverse events. Studies did not report asthma control consistently, but results showed no difference between groups on the paediatric asthma quality of life questionnaire (mean difference (MD) 0.14, 95% confidence interval (CI) -0.03 to 0.31; 1005 participants; we downgraded the quality of evidence to low for risk of bias and indirectness). Data for symptom days, night-time awakenings, restricted activities of daily living and school absences were skewed or could not be analysed; some mean scores were better in the trained group, but most differences between groups were small and did not persist to 24 months.Schools that received asthma education were more adherent to asthma policies, and staff were better prepared; more schools that had received staff asthma training had written asthma policies compared with control schools, more intervention schools showed improvement in measures taken to prevent or manage exercise-induced asthma attacks and more staff at intervention schools reported that they felt able to administer salbutamol via a spacer. However, the quality of the evidence was low; results show imbalances at baseline, and confidence in the evidence was limited by risk of bias and imprecision. Staff knowledge was higher in groups that had received asthma education, although results were inconsistent and difficult to interpret owing to differences between scales (low quality).Available information about the interventions was insufficient for review authors to conduct a meaningful qualitative synthesis of the content that led to a successful intervention, or of the resources required to replicate results accurately. AUTHORS' CONCLUSIONS: Asthma education for school staff increases asthma knowledge and preparedness, but studies vary and all available evidence is of low quality. Studies have not yet captured whether this improvement in knowledge has led to appreciable benefits over the short term or the longer term for the safety and health of children with asthma in school. Randomised evidence does not contribute to our knowledge of content or attributes of interventions that lead to the best outcomes, or of resources required for successful implementation.Complete reporting of the content and resources of educational interventions is essential for assessment of their effectiveness and feasibility for implementation. This applies to both randomised and non-randomised studies, although the latter may be better placed to observe important clinical outcomes such as exacerbations and mortality in the longer term.

Interventions to improve adherence to inhaled steroids for asthma.

BACKGROUND: Despite its proven efficacy in improving symptoms and reducing exacerbations, many patients with asthma are not fully adherent to their steroid inhaler. Suboptimal adherence leads to poorer clinical outcomes and increased health service utilisation, and has been identified as a contributing factor to a third of asthma deaths in the UK. Reasons for non-adherence vary, and a variety of interventions have been proposed to help people improve treatment adherence. OBJECTIVES: To assess the efficacy and safety of interventions intended to improve adherence to inhaled corticosteroids among people with asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted the most recent searches on 18 November 2016. SELECTION CRITERIA: We included parallel and cluster randomised controlled trials of any duration conducted in any setting. We included studies reported as full-text articles, those published as abstracts only and unpublished data. We included trials of adults and children with asthma and a current prescription for an inhaled corticosteroid (ICS) (as monotherapy or in combination with a long-acting beta2-agonist (LABA)). Eligible trials compared an intervention primarily aimed at improving adherence to ICS versus usual care or an alternative intervention. DATA COLLECTION AND ANALYSIS: Two review authors screened the searches, extracted study characteristics and outcome data from included studies and assessed risk of bias. Primary outcomes were adherence to ICS, exacerbations requiring at least oral corticosteroids and asthma control. We graded results and presented evidence in 'Summary of findings' tables for each comparison.We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all using a random-effects model. We described skewed data narratively. We made no a priori assumptions about how trials would be categorised but conducted meta-analyses only if treatments, participants and the underlying clinical question were similar enough for pooling to make sense. MAIN RESULTS: We included 39 parallel randomised controlled trials (RCTs) involving adults and children with asthma, 28 of which (n = 16,303) contributed data to at least one meta-analysis. Follow-up ranged from two months to two years (median six months), and trials were conducted mainly in high-income countries. Most studies reported some measure of adherence to ICS and a variety of other outcomes such as quality of life and asthma control. Studies generally were at low or unclear risk of selection bias and at high risk of biases associated with blinding. We considered around half the studies to be at high risk for attrition bias and selective outcome reporting.We classified studies into four comparisons: adherence education versus control (20 studies); electronic trackers or reminders versus control (11 studies); simplified drug regimens versus usual drug regimens (four studies); and school-based directly observed therapy (three studies). Two studies are described separately.All pooled results for adherence education, electronic trackers or reminders and simplified regimens showed better adherence than controls. Analyses limited to studies using objective measures revealed that adherence education showed a benefit of 20 percentage points over control (95% confidence interval (CI) 7.52 to 32.74; five studies; low-quality evidence); electronic trackers or reminders led to better adherence of 19 percentage points (95% CI 14.47 to 25.26; six studies; moderate-quality evidence); and simplified regimens led to better adherence of 4 percentage points (95% CI 1.88 to 6.16; three studies; moderate-quality evidence). Our confidence in the evidence was reduced by risk of bias and inconsistency.Improvements in adherence were not consistently translated into observable benefit for clinical outcomes in our pooled analyses. None of the intervention types showed clear benefit for our primary clinical outcomes - exacerbations requiring an oral corticosteroid (OCS) (evidence of very low to low quality) and asthma control (evidence of low to moderate quality); nor for our secondary outcomes - unscheduled visits (evidence of very low to moderate quality) and quality of life (evidence of low to moderate quality). However, some individual studies reported observed benefits for OCS and use of healthcare services. Most school or work absence data were skewed and were difficult to interpret (evidence of low quality, when graded), and most studies did not specifically measure or report adverse events.Studies investigating the possible benefit of administering ICS at school did not measure adherence, exacerbations requiring OCS, asthma control or adverse events. One study showed fewer unscheduled visits, and another found no differences; data could not be combined. AUTHORS' CONCLUSIONS: Pooled results suggest that a variety of interventions can improve adherence. The clinical relevance of this improvement, highlighted by uncertain and inconsistent impact on clinical outcomes such as quality of life and asthma control, is less clear. We have low to moderate confidence in these findings owing to concerns about risk of bias and inconsistency. Future studies would benefit from predefining an evidence-based 'cut-off' for acceptable adherence and using objective adherence measures and validated tools and questionnaires. When possible, covert monitoring and some form of blinding or active control may help disentangle effects of the intervention from effects of inclusion in an adherence trial.

Interventions to improve inhaler technique for people with asthma.

BACKGROUND: Asthma is a common chronic disease worldwide. Inhalers are often prescribed to help control asthma symptoms, improve quality of life and reduce the risk of exacerbations or flare-ups. However, evidence suggests that many people with asthma do not use their inhaler correctly. It is therefore important to evaluate whether interventions aimed specifically at improving technique are effective and safe, and whether use of these interventions translates into improved clinical outcomes. OBJECTIVES: To assess the impact of interventions to improve inhaler technique on clinical outcomes and safety in adults and children with asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, which contains records compiled from multiple electronic and handsearched resources. We also searched trial registries and reference lists of primary studies. We conducted the most recent search on 23 November 2016. SELECTION CRITERIA: We included studies comparing a group of adults or children with asthma receiving an inhaler technique intervention versus a group receiving a control or alternative intervention. We included parallel and cluster-randomised trials of any duration conducted in any setting, and planned to include only the first phase of any cross-over trials identified. We included studies reported as full-text articles, those published as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors screened the search results for eligible studies. We extracted outcome data, assessed risk of bias in duplicate and resolved discrepancies by involving another review author. We grouped studies making similar comparisons by consensus (e.g. all those comparing enhanced inhaler technique education vs usual care) and conducted meta-analyses only if treatments, participants and the underlying clinical question were similar enough for pooling to make sense. We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all with random-effects models. We described skewed data narratively. We graded the results and presented evidence in 'Summary of findings' tables for each comparison. Primary outcomes were inhaler technique, asthma control and exacerbations requiring at least oral corticosteroids (OCS). MAIN RESULTS: This review includes 29 parallel randomised controlled trials (RCTs) (n = 2210), although not all reported relevant or useable data. All participants had asthma, and follow-up ranged from 2 to 26 weeks. Most studies were at low or unclear risk of selection and attrition biases and at high risk for biases associated with blinding. We considered most of the evidence to be of low quality owing to these biases and to imprecision in the estimates of effect.We classified studies into three comparisons: enhanced face-to-face training session(s), multi-media-delivered inhaler training (e.g. DVD, computer app or game) and technique feedback devices. Differences between interventions, populations and outcome measures limited quantitative analyses, particularly for exacerbations, adverse events, unscheduled visits to a healthcare provider and absenteeism from work or school.Enhanced inhaler technique education and multi-media training improved technique in most studies immediately after the intervention and at follow-up, although the variety of checklists used meant that this was difficult to assess reliably. For both adults and children, how and when inhaler technique was assessed appeared to affect whether inhaler technique improved and by how much.Analyses of the numbers of people who demonstrated correct or 'good enough' technique were generally more useful than checklist scores. Adult studies of enhanced education showed benefit when this metric was used at 2 to 26 weeks' follow-up (odds ratio (OR) 5.00, 95% confidence interval (CI) 1.83 to 13.65; 258 participants; three studies; 31 per 100 with correct technique in the control group compared with 69 (95% CI 45 to 86) in the education group; moderate-quality evidence). A similar result was seen in studies looking at feedback devices at four weeks' follow-up (OR 4.80, 95% CI 1.87 to 12.33; 97 participants; one study; 51 per 100 with correct technique in the control group compared with 83 (95% CI 66 to 93) in the feedback group; low-quality evidence). However, the benefit of multi-media training for adults even immediately after the intervention was uncertain (OR 2.15, 95% CI 0.84 to 5.50; 164 participants; two studies; I² = 49%; 30 per 100 in the control group with correct technique compared with 47 (95% CI 26 to 70) in the multi-media group; moderate-quality evidence). Evidence tended to be less clear for children, usually because results were based on fewer and smaller studies.Some studies did not report exacerbations in a way that allowed meta-analysis; others provided inconclusive results. Inhaler technique interventions provided some benefit for asthma control and quality of life but generally did not lead to consistent or important clinical benefits for adults or children. Confidence intervals included no difference or did not reach a threshold that could be considered clinically important. Responder analyses sometimes showed improvement among more people in the intervention groups, even though the mean difference between groups was small. We found no evidence about harms. AUTHORS' CONCLUSIONS: Although interventions to improve inhaler technique may work in some circumstances, the variety of interventions and measurement methods used hampered our ability to perform meta-analyses and led to low to moderate confidence in our findings. Most included studies did not report important improvement in clinical outcomes. Guidelines consistently recommend that clinicians check regularly the inhaler technique of their patients; what is not clear is how clinicians can most effectively intervene if they find a patient's technique to be inadequate, and whether such interventions will have a discernible impact on clinical outcomes.

Exhaled nitric oxide levels to guide treatment for children with asthma.

BACKGROUND: Asthma guidelines aim to guide health practitioners to optimise treatment for patients to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise health using minimum doses. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation and tailoring asthma medications in accordance to airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations, or both. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on fractional exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is, management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines (or both), for asthma-related outcomes in children. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and reference lists of articles. The last searches were in June 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on FeNO levels compared to those not using FeNO, that is, management based on clinical symptoms or asthma guidelines (or both) involving children. DATA COLLECTION AND ANALYSIS: We reviewed results of searches against predetermined criteria for inclusion. Two review authors independently selected relevant studies, assessed trial quality and extracted data. We contacted study authors for further information with responses provided from three. MAIN RESULTS: The review included nine studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut-off levels used (12 parts per billion (ppb) to 30 ppb), the way in which FeNO was used to adjust therapy and duration of study (6 to 12 months). Of 1426 children randomised, 1329 completed the studies. The inclusion criteria for the participants in each study varied but all had a diagnosis of asthma. There was a significant difference in the number of children having one or more asthma exacerbations over the study period, they were significantly lower in the FeNO group in comparison to the control group (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.45 to 0.75; 1279 participants; 8 studies). The number needed to treat for an additional beneficial outcome (NNTB) over 52 weeks was 9 (95% CI 6 to 15). There was no difference between the groups when comparing exacerbation rates (mean difference (MD) -0.37, 95% CI -0.8 to 0.06; 736 participants; 4 studies; I2 = 67%). The number of children in the FeNO group requiring oral corticosteroid courses was lower in comparison to the children in the control group (OR 0.63, 95% CI 0.48 to 0.83; 1169 participants; 7 studies; I2 = 0%). There was no statistically significant difference between the groups for exacerbations requiring hospitalisation (OR 0.75, 95% CI 0.41 to 1.36; 1110 participants; 6 studies; I2 = 0%). There were no significant differences between the groups for any of the secondary outcomes (forced expiratory volume in one second (FEV1), FeNO levels, symptom scores or inhaled corticosteroid doses at final visit). The included studies recorded no adverse events.Three studies had inadequate blinding and were thus considered to have a high risk of bias. However, when these studies were removed in subgroup analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'Number of participants who had one or more exacerbations over the study period') to very low (for the outcome 'Exacerbation rates'), based on lack of blinding, statistical heterogeneity and imprecision. AUTHORS' CONCLUSIONS: In this updated review with five new included studies, tailoring asthma medications based on FeNO levels (in comparison with primarily guideline management) significantly decreased the number of children who had one or more exacerbations over the study period but did not impact on the day-to-day clinical symptoms or inhaled corticosteroid doses. Therefore, the use of FeNO to guide asthma therapy in children may be beneficial in a subset of children, it cannot be universally recommended for all children with asthma.Further RCTs need to be conducted and these should encompass different asthma severities, different settings including primary care and less affluent settings, and consider different FeNO cut-offs.

Cognitive behavioural therapy (CBT) for adults and adolescents with asthma.

BACKGROUND: People with asthma have a higher prevalence of anxiety and depression than the general population. This is associated with poorer asthma control, medication adherence, and health outcomes. Cognitive behavioural therapy (CBT) may be a way to improve the quality of life of people with asthma by addressing associated psychological issues, which may lead to a lower risk of exacerbations and better asthma control. OBJECTIVES: To assess the efficacy of CBT for asthma compared with usual care. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). We also searched reference lists of all primary studies and review articles and contacted authors for unpublished data. The most recent searches were conducted in August 2016. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) comparing any cognitive behavioural intervention to usual care or no intervention. We included studies of adults or adolescents with asthma, with or without comorbid anxiety or depression. We included studies reported as full text, those published as abstract only, and unpublished data. DATA COLLECTION AND ANALYSIS: Two or more review authors independently screened the search results, extracted data, and assessed included studies for risk of bias. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMD) where scales varied across studies, all using a random-effects model. The primary outcomes were asthma-related quality of life and exacerbations requiring at least a course of oral steroids. We rated all outcomes using GRADE and presented our confidence in the results in a 'Summary of findings' table. MAIN RESULTS: We included nine RCTs involving 407 adults with asthma in this review; no studies included adolescents under 18. Study size ranged from 10 to 94 (median 40), and mean age ranged from 39 to 53. Study populations generally had persistent asthma, but severity and diagnostic measures varied. Three studies recruited participants with psychological symptomatology, although with different criteria. Interventions ranged from 4 to 15 sessions, and primary measurements were taken at a mean of 3 months (range 1.2 to 12 months).Participants given CBT had improved scores on the Asthma Quality of Life Questionnaire (AQLQ) (MD 0.55, 95% confidence interval (CI) 0.17 to 0.93; participants = 214; studies = 6; I2 = 53%) and on measures of asthma control (SMD -0.98, 95% CI -1.76 to -0.20; participants = 95; studies = 3; I2 = 68%) compared to people getting usual care. The AQLQ effect appeared to be sustained up to a year after treatment, but due to its low quality this evidence must be interpreted with caution. As asthma exacerbations requiring at least a course of oral steroids were not consistently reported, we could not perform a meta-analysis.Anxiety scores were difficult to pool but showed a benefit of CBT compared with usual care (SMD -0.38, 95% CI -0.73 to -0.03), although this depended on the analysis used. The confidence intervals for the effect on depression scales included no difference between CBT and usual care when measured as change from baseline (SMD -0.33, 95% CI -0.70 to 0.05) or endpoint scores (SMD -0.41, 95% CI -0.87 to 0.05); the same was true for medication adherence (MD -1.40, 95% CI -2.94 to 0.14; participants = 23; studies = 1; I2 = 0%).Subgroup analyses conducted on the AQLQ outcome did not suggest a clear difference between individual and group CBT, baseline psychological status, or CBT model. The small number of studies and the variation between their designs, populations, and other intervention characteristics limited the conclusions that could be drawn about these possibly moderating factors.The inability to blind participants and investigators to group allocation introduced significant potential bias, and overall we had low confidence in the evidence. AUTHORS' CONCLUSIONS: For adults with persistent asthma, CBT may improve quality of life, asthma control, and anxiety levels compared with usual care. Risks of bias, imprecision of effects, and inconsistency between results reduced our confidence in the results to low, and evidence was lacking regarding the effect of CBT on asthma exacerbations, unscheduled contacts, depression, and medication adherence. There was much variation between studies in how CBT was delivered and what constituted usual care, meaning the most optimal method of CBT delivery, format, and target population requires further investigation. There is currently no evidence for the use of CBT in adolescents with asthma.

Exhaled nitric oxide levels to guide treatment for adults with asthma.

BACKGROUND: Asthma guidelines aim to guide health practitioners to optimise treatment for patients so as to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise good health outcomes using minimum medications. Asthma maintenance therapies reduce airway inflammation that is usually eosinophilic. Tailoring asthma medications in accordance with airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations or both. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation, and as it is easy to measure, has an advantage over other measurements of eosinophilic inflammation (for example sputum eosinophils). OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both, for asthma-related outcomes in adults. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of articles. The last searches were undertaken in June 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on exhaled nitric oxide levels compared to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both. DATA COLLECTION AND ANALYSIS: We reviewed results of searches against predetermined criteria for inclusion. We independently selected relevant studies in duplicate. Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information, receiving responses from four. MAIN RESULTS: We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit).We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. AUTHORS' CONCLUSIONS: With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.