Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque ( Macaca mulatta ) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1β and tumor necrosis factor–α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.

BACKGROUND:Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments. OBJECTIVES:To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid. SEARCH METHODS:We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was  24 February 2021. SELECTION CRITERIA:We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration. DATA COLLECTION AND ANALYSIS:Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect. MAIN RESULTS:Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence). AUTHORS' CONCLUSIONS:Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.

The journey from prioritised reviews to publication (or not!). Poster presented at the 23rd Cochrane Colloquium, 3rd - 7th October 2015, Vienna, Austria.Cochrane Airways aims to publish the systematic reviews that are most important to today’s decision-makers. In this project, we used a prioritisation process to identify a set of reviews for updating over two years. Here, we describe our experience of publishing priority reviews and updates over the period 2013 to 2015.

SESSION TITLE: Wednesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Erdheim-Chester disease (ECD) is a rare neoplastic, histiocytic disorder characterized by abnormal growth and proliferation of activated myeloid progenitor cells carrying pathogenic mutations in the mitogen activated protein kinase (MAPK) pathway. The most commonly seen mutation in ECD is BRAF V600E, though other mutations in the MAPK pathway are also described. The relationship between cigarette smoke exposure and ECD has not been previously described CASE PRESENTATION: A 61-year-old female with chronic obstructive pulmonary disease, osteoporosis, and ongoing tobacco use was referred for further evaluation of reticulonodular lung infiltrates. Physical examination was unremarkable except for poor dentition and cachectic body habitus. Review of her prior laboratory work up revealed mildly abnormal anti-nuclear and anti-chromatin antibodies. The patient had undergone two video-assisted thoracoscopic (VATS)-guided surgical lung biopsies prior to being evaluated at our clinic. The initial biopsy showed necrotizing granulomas, lipoid pneumonia, and fibrous pleuritis. Cultures were negative for infectious etiologies. Subsequently, the patient was lost to follow up for 7 years. Imaging obtained upon her return revealed worsening reticulonodular infiltrates most prominent in bilateral upper lobes. A second VATS-guided lung biopsy revealed interstitial vacuolated macrophages and perivascular, septal, and diffuse parenchymal fibrosis with foamy macrophages. The macrophages stained positive for CD68 and Factor XIIIa, and were negative for S100 and CD1a staining. Upon further review, specimens from the prior lung biopsy and an interval joint replacement showed similar histologic features. Based on the characteristic histopathological features, the patient was diagnosed with ECD. Pharmacologic treatment was deferred until additional workup could confirm the diagnosis and determine the extent of systemic involvement. In the interim, our management focused on reducing her ongoing cigarette smoking. FDG-PET scan demonstrated increased uptake in the femoral diaphysis, consistent with long bone involvement from ECD. The patient declined additional testing to identify the underlying genetic mutation for her ECD. Repeat chest imaging obtained prior to the initiation of pharmacotherapy for ECD showed improvement in her pulmonary abnormalities. Pharmacologic treatment was deferred and the patient continued to improve with smoking reduction as sole therapy. DISCUSSION: The relationship between cigarette smoke exposure and ECD has not been previously described. Our case is the first description of a clinically meaningful therapeutic response to reduction in cigarette smoke exposure in a patient with histopathologically proven ECD. CONCLUSIONS: This case provides novel insight into the development of ECD and suggests a possible overlap in the pathogenesis of pulmonary Langerhans cell histiocytosis and ECD. Reference #1: Diamond, Eli L, et al. "Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease." Blood 2014; 124(4): 483-92. DISCLOSURES: No relevant relationships by Christopher Cates, source=Web Response no disclosure on file for Nishant Gupta

Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.

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.

Systematic reviewers conducting pairwise meta-analyses sometimes encounter multi-arm studies. To include these studies, and to avoid a unit-of-analysis error, often two or more arms are combined or the control arm is split. In this tutorial, we present 5 different approaches that can be used. Particularly, we present a novel approach (method 4) that to the best of our knowledge has not been presented before. We demonstrate their application on 3 selected data sets, discuss their scope of application and their advantages and limitations, and give recommendations.

Introduction and objectives Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind randomised placebo-controlled trials of this intervention is lacking. We conducted a Cochrane systematic review and meta-analysis to evaluate the efficacy of administration of vitamin D in reducing asthma exacerbations treated with systemic corticosteroids (primary outcome) and improving asthma symptom control. Methods Standard Cochrane collaboration procedures were followed. Double-blind randomised placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk and/or asthma symptom control were included. Results Seven trials involving a total of 435 children and two trials involving a total of 658 adults were included in the primary analysis. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (Rate Ratio 0.63, 95% CI: 0.45 to 0.88; 680 participants; 3 studies; high quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit and/or hospitalisation (Odds Ratio [OR] 0.39, 95% CI: 0.19 to 0.78; number needed to treat for one additional person to experience a beneficial outcome (NNTB), 27; 963 participants; 7 studies; high quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (Mean Difference [MD] 0.48, 95% CI: −0.93 to 1.89; 387 participants; 4 studies; high quality evidence) or Asthma Control Test scores (MD −0.08, 95% CI: −0.70 to 0.54; participants = 713; studies = 3; high quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI: 0.54 to 1.89; 879 participants; 5 studies; moderate quality evidence). No participant in any included trial suffered a fatal asthma exacerbation. Conclusions Meta-analysis of a modest number of trials in patients with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce the risk of severe asthma exacerbation and reduce health care use.

BackgroundPulmonary rehabilitation has become a cornerstone in the management of patients with stable Chronic Obstructive Pulmonary Disease (COPD). Systematic reviews have shown large and important clinical effects of pulmonary rehabilitation in these patients. However, in unstable COPD patients who have recently suffered an exacerbation, the effects of pulmonary rehabilitation are less established.ObjectivesTo assess the effects of pulmonary rehabilitation after COPD exacerbations on future hospital admissions (primary outcome) and other patient-important outcomes (mortality, health-related quality of life and exercise capacity).Search strategyTrials were identified from searches of CENTRAL, MEDLINE, EMBASE, PEDRO and the Cochrane Airways Group Register of Trials. Searches were current as of March 2010.Selection criteriaRandomized controlled trials comparing pulmonary rehabilitation of any duration after exacerbation of COPD with conventional care. Pulmonary rehabilitation programmes needed to include at least physical exercise. Control groups received conventional community care without rehabilitation.Data collection and analysisWe calculated pooled odds ratios and weighted mean differences (MD) using random-effects models. We requested missing data from the authors of the primary studies.Main resultsWe identified nine trials involving 432 patients. Pulmonary rehabilitation significantly reduced hospital admissions (pooled odds ratio 0.22 [95% CI 0.08 to 0.58], number needed to treat (NNT) 4 [95% CI 3 to 8], over 25 weeks) and mortality (OR 0.28; 95% CI 0.10 to 0.84), NNT 6 [95% CI 5 to 30] over 107 weeks). Effects of pulmonary rehabilitation on health-related quality of life were well above the minimal important difference when measured by the Chronic Respiratory Questionnaire (MD for dyspnea, fatigue, emotional function and mastery domains between 0.81 (fatigue; 95% CI 0.16 to 1.45) and 0.97 (dyspnea; 95% CI 0.35 to 1.58)) and the St. Georges Respiratory Questionnaire total score (MD -9.88; 95% CI -14.40 to -5.37); impacts domain (MD -13.94; 95% CI -20.37 to -7.51) and for activity limitation domain (MD -9.94; 95% CI -15.98 to -3.89)). The symptoms domain of the St. Georges Respiratory Questionnaire showed no significant improvement. Pulmonary rehabilitation significantly improved exercise capacity and the improvement was above the minimally important difference (six-minute walk test (MD 77.70 meters; 95% CI 12.21 to 143.20) and shuttle walk test (MD 64.35; 95% CI 41.28 to 87.43)). No adverse events were reported in three studies.Authors' conclusionsEvidence from nine small studies of moderate methodological quality, suggests that pulmonary rehabilitation is a highly effective and safe intervention to reduce hospital admissions and mortality and to improve health-related quality of life in COPD patients who have recently suffered an exacerbation of COPD.

BACKGROUND:Asthma remains a significant cause of avoidable morbidity and mortality. Regular check-ups with a healthcare professional are essential to monitor symptoms and adjust medication.Health services worldwide are considering telephone and internet technologies as a way to manage the rising number of people with asthma and other long-term health conditions. This may serve to improve health and reduce the burden on emergency and inpatient services. Remote check-ups may represent an unobtrusive and efficient way of maintaining contact with patients, but it is uncertain whether conducting check-ups in this way is effective or whether it may have unexpected negative consequences. OBJECTIVES:To assess the safety and efficacy of conducting asthma check-ups remotely versus usual face-to-face consultations. SEARCH METHODS:We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to 24 November 2015. We also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal, reference lists of other reviews and contacted trial authors for additional information. SELECTION CRITERIA:We included parallel randomised controlled trials (RCTs) of adults or children with asthma that compared remote check-ups conducted using any form of technology versus standard face-to-face consultations. We excluded studies that used automated telehealth interventions that did not include personalised contact with a health professional. We included studies reported as full-text articles, as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS:Two review authors screened the literature search results and independently extracted risk of bias and numerical data. We resolved any disagreements by consensus, and we contacted study authors for missing information.We analysed dichotomous data as odds ratios (ORs) using study participants as the unit of analysis, and continuous data as mean differences using the random-effects models. We rated all outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS:Six studies including a total of 2100 participants met the inclusion criteria: we pooled four studies including 792 people in the main efficacy analyses, and presented the results of a cluster implementation study (n = 1213) and an oral steroid tapering study (n = 95) separately. Baseline characteristics relating to asthma severity were variable, but studies generally recruited people with asthma taking regular medications and excluded those with COPD or severe asthma. One study compared the two types of check-up for oral steroid tapering in severe refractory asthma and we assessed it as a separate question. The studies could not be blinded and dropout was high in four of the six studies, which may have biased the results.We could not say whether more people who had a remote check-up needed oral corticosteroids for an asthma exacerbation than those who were seen face-to-face because the confidence intervals (CIs) were very wide (OR 1.74, 95% CI 0.41 to 7.44; 278 participants; one study; low quality evidence). In the face-to-face check-up groups, 21 participants out of 1000 had exacerbations that required oral steroids over three months, compared to 36 (95% CI nine to 139) out of 1000 for the remote check-up group. Exacerbations that needed treatment in the Emergency Department (ED), hospital admission or an unscheduled healthcare visit all happened too infrequently to detect whether remote check-ups are a safe alternative to face-to-face consultations. Serious adverse events were not reported separately from the exacerbation outcomes.There was no difference in asthma control measured by the Asthma Control Questionnaire (ACQ) or in quality of life measured on the Asthma Quality of Life Questionnaire (AQLQ) between remote and face-to-face check-ups. We could rule out significant harm of remote check-ups for these outcomes but we were less confident because these outcomes are more prone to bias from lack of blinding.The larger implementation study that compared two general practice populations demonstrated that offering telephone check-ups and proactively phoning participants increased the number of people with asthma who received a review. However, we do not know whether the additional participants who had a telephone check-up subsequently benefited in asthma outcomes. AUTHORS' CONCLUSIONS:Current randomised evidence does not demonstrate any important differences between face-to-face and remote asthma check-ups in terms of exacerbations, asthma control or quality of life. There is insufficient information to rule out differences in efficacy, or to say whether or not remote asthma check-ups are a safe alternative to being seen face-to-face.

Amelie‐Benoist/BSIP/Science Photo Library Despite being one of the most common long‐term diseases worldwide[1], asthma is notoriously difficult to get under control for many people with the condition. Changes to an individual's treatment regimen are usually made using a stepwise approach, guided by factors such as frequency of symptoms, rescue medication use, and asthma attacks.[2, 3] Treatment is stepped up if control is deemed to be inadequate and stepped down if control is good. However, even in countries with high levels of access to health care that is free at the point of need, control remains poor. A recent survey of approximately 8000 people with asthma in 11 European countries found that nearly half of the respondents had uncontrolled asthma, and for a further third their asthma was only partially controlled.[4] Conversely, there is evidence that some people with asthma are being overtreated, or even misdiagnosed, and are therefore exposed unnecessarily to the side effects associated with therapy.[5, 6] As a result of this mismatch between the therapy people with asthma need and the therapy they receive, there is growing interest in objective measures to guide both diagnosis and management of asthma. One such strategy involves measuring the amount of a specific gas, nitric oxide (NO), when a person exhales. This is known as the fractional exhaled nitric oxide (FeNO). FeNO is a marker of airway inflammation caused by eosinophils and associated with allergy.[7] Eosinophilic airway inflammation accounts for over 50% of asthma cases (allergic asthma), and this type of asthma responds better to treatment with steroids.[7] FeNO may offer a simple non‐invasive method for diagnosing eosinophilic asthma and for guiding the stepping‐up and ‐down of inhaled corticosteroids (ICS), the mainstay of asthma treatment. In 2011 the American Thoracic Society issued strong guidance to healthcare professionals in the United States advocating the clinical use of FeNO, at the time based on only low‐to‐moderate‐quality evidence.[8] In 2006, 2008, and 2009 Cochrane Airways produced and updated a Cochrane Review examining the evidence from randomized controlled trials investigating whether using FeNO to guide asthma management is more effective than the established methods, such as clinical guidelines. More recently, this review has been split to look at adults and children separately. The review in adults has been published and includes seven trials, which compare the use of FeNO with clinical guidelines, the Asthma Control Questionnaire score, or a combination of symptoms, lung function, and physical examination.[9] Despite five years passing since the American Thoracic Society recommendation, the evidence from trials remains somewhat inconclusive. Pooled data from five studies involving over 1000 adults showed that the number of participants experiencing an asthma attack was lower in the FeNO group (odds ratio 0.60, 95% confidence interval 0.43 to 0.84). However, severe exacerbations requiring hospitalization occurred so rarely in the included trials that the authors could not be sure whether the use of FeNO to guide management had an impact on these most serious and costly exacerbations. In addition, no clear between‐group difference was detected for asthma control, health‐related quality of life, symptoms, or final dose of ICS. Different FeNO thresholds and dose adjustment algorithms were used in the trials, hampering interpretation, and some trials implemented a ceiling dose of ICS to prevent relentless increases in response to persistently elevated FeNO, perhaps due to concurrent atopy. Importantly, the authors also noted that the included studies did not report any cost analysis of using FeNO. So, what can we conclude? The crucial question is whether FeNO offers an advantage over using symptoms and measures such as peak flow to tailor asthma treatment. Can FeNO improve control for some, by triggering an appropriate ICS dose increase, while reducing over‐treatment for others? Arguably the case is not yet closed. Tailoring treatment on the basis of FeNO measurement is only going to have an impact if the myriad other obstacles to good control, including adherence to inhaled steroids, inhaler technique, and appropriate self‐management, are tackled and improved simultaneously.

BACKGROUND:Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind, randomised, placebo-controlled trials of this intervention is lacking. OBJECTIVES:To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. SEARCH METHODS:We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016. SELECTION CRITERIA:Double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both. DATA COLLECTION AND ANALYSIS:Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). MAIN RESULTS:We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.63, 95% CI 0.45 to 0.88; 680 participants; 3 studies; high-quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high-quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI -0.93 to 1.89; 387 participants; 4 studies; high-quality evidence) or Asthma Control Test scores (MD -0.08, 95% CI -0.70 to 0.54; 713 participants; 3 studies; high-quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate-quality evidence). One trial comparing low-dose versus high-dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above. AUTHORS' CONCLUSIONS:Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use. It is as yet unclear whether these effects are confined to people with lower baseline vitamin D status; further research, including individual patient data meta-analysis of existing datasets, is needed to clarify this issue. Children and people with frequent severe asthma exacerbations were under-represented; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups.

BACKGROUND Asthma is a chronic disease that causes reversible narrowing of the airways due to bronchoconstriction, inflammation and mucus production. Asthma continues to be associated with significant avoidable morbidity and mortality. Self management facilitated by a healthcare professional is important to keep symptoms controlled and to prevent exacerbations.Telephone and Internet technologies can now be used by patients to measure lung function and asthma symptoms at home. Patients can then share this information electronically with their healthcare provider, who can provide feedback between clinic visits. Technology can be used in this manner to improve health outcomes and prevent the need for emergency treatment for people with asthma and other long-term health conditions. OBJECTIVES To assess the efficacy and safety of home telemonitoring with healthcare professional feedback between clinic visits, compared with usual care. SEARCH METHODS We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to May 2016. We also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal and reference lists of other reviews, and we contacted trial authors to ask for additional information. SELECTION CRITERIA We included parallel randomised controlled trials (RCTs) of adults or children with asthma in which any form of technology was used to measure and share asthma monitoring data with a healthcare provider between clinic visits, compared with other monitoring or usual care. We excluded trials in which technologies were used for monitoring with no input from a doctor or nurse. 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 and independently extracted risk of bias and numerical data, resolving disagreements by consensus.We analysed dichotomous data as odds ratios (ORs) while using study participants as the unit of analysis, and continuous data as mean differences (MDs) while using random-effects models. We rated evidence for all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach. MAIN RESULTS We found 18 studies including 2268 participants: 12 in adults, 5 in children and one in individuals from both age groups. Studies generally recruited people with mild to moderate persistent asthma and followed them for between three and 12 months. People in the intervention group were given one of a variety of technologies to record and share their symptoms (text messaging, Web systems or phone calls), compared with a group of people who received usual care or a control intervention.Evidence from these studies did not show clearly whether asthma telemonitoring with feedback from a healthcare professional increases or decreases the odds of exacerbations that require a course of oral steroids (OR 0.93, 95% confidence Interval (CI) 0.60 to 1.44; 466 participants; four studies), a visit to the emergency department (OR 0.75, 95% CI 0.36 to 1.58; 1018 participants; eight studies) or a stay in hospital (OR 0.56, 95% CI 0.21 to 1.49; 1042 participants; 10 studies) compared with usual care. Our confidence was limited by imprecision in all three primary outcomes. Evidence quality ratings ranged from moderate to very low. None of the studies recorded serious or non-serious adverse events separately from asthma exacerbations.Evidence for measures of asthma control was imprecise and inconsistent, revealing possible benefit over usual care for quality of life (MD 0.23, 95% CI 0.01 to 0.45; 796 participants; six studies; I(2) = 54%), but the effect was small and study results varied. Telemonitoring interventions may provide additional benefit for two measures of lung function. AUTHORS' CONCLUSIONS Current evidence does not support the widespread implementation of telemonitoring with healthcare provider feedback between asthma clinic visits. Studies have not yet proven that additional telemonitoring strategies lead to better symptom control or reduced need for oral steroids over usual asthma care, nor have they ruled out unintended harms. Investigators noted small benefits for quality of life, but these are subject to risk of bias, as the studies were unblinded. Similarly, some benefits for lung function are uncertain owing to possible attrition bias.Larger pragmatic studies in children and adults could better determine the real-world benefits of these interventions for preventing exacerbations and avoiding harms; it is difficult to generalise results from this review because benefits may be explained at least in part by the increased attention participants receive by taking part in clinical trials. Qualitative studies could inform future research by focusing on patient and provider preferences, or by identifying subgroups of patients who are more likely to attain benefit from closer monitoring, such as those who have frequent asthma attacks.

Dear Sirs, We read with interest the paper by Ho et al,1 which used the AMSTAR tool to assess the methodological quality of systematic reviews (SRs) on chronic obstructive pulmonary disease (COPD). As staff at the Cochrane Airways Group with the responsibility of producing high-quality SRs for airway conditions, including COPD, we are always happy to hear how we could improve. However, there are some methodological issues within the study. The abstract states that the methodological quality of the reviews was disappointing and emphasises the more negative findings, neglecting the positive results (e.g., a priori design in 67% SRs, comprehensive literature search in 97% and scientific quality assessed and documented in 85%). The authors did not complete the AMSTAR ratings in duplicate; yet, duplicate data extraction is a mark of a good SR. Our experience with this tool is that the discussion between two or more people helps reach a fair judgement.2 It would have been helpful to see the AMSTAR ratings per review so that the work could be replicated and evaluated. We noted the lack of discussion about the choice to limit the study to SRs that include a meta-analysis. Choosing not to perform a meta-analysis when there is a lot of heterogeneity between studies is a valid decision. The authors highlighted that non-English databases were searched infrequently. This is not an AMSTAR criterion; have the authors suggested that this be incorporated in any update of the tool? Cochrane does not require that non-English language databases be searched and this is usually done only when we expect that this will yield additional relevant trials. We agree that multilingual SR teams are advantageous and we would be grateful if people who wish to translate the trial reports for inclusion in Cochrane reviews contact us. We take the authors’ point about being clearer about reviewers’ support, and making a statement about publication bias in the results section as well as the methods section when there are too few studies to permit a funnel plot. As highlighted in the paper, the quality of SRs has improved significantly in recent years through the development of methods and improved implementation.3,4 It would have been helpful to highlight this important point in the conclusions and abstract.

Christopher Cates and Charlotta Karner argue that information about individual patient responses should be included in the clinical assessment of treatments

BackgroundIndacaterol is an inhaled long-acting beta(2)-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain.ObjectivesTo compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta(2)-agonists for the treatment of patients with stable COPD.Search methodsWe identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014.Selection criteriaWe included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta(2)-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD.Data collection and analysisTwo review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC).Main resultsA total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta(2)-agonist comparison. The comparator beta(2)-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data that could be used in this review. Two trials included both indacaterol versus placebo and indacaterol versus twice-daily beta(2)-agonist comparisons. Trials were between 12 weeks and 52 weeks in duration. Overall the quality of the evidence was strong, and risk of significant bias was minimal in most of the included studies. Enrolled participants had stable COPD across a range of spirometric severities. Forced expiratory volume in 1 second (FEV1) was generally between 30% and 80% predicted, and a mean FEV1 of approximately 50% was predicted in most studies. Patients with concurrent respiratory disease, including asthma, were excluded. Concomitant use of inhaled corticosteroids was permitted.The primary objectives were to compare trough FEV1 at the end of dosing, exacerbation rates and quality of life. Significant adverse events, mortality and dyspnoea were included as secondary outcomes. Compared with placebo, a significant and clinically relevant improvement in trough FEV1 was noted with indacaterol (mean difference (MD) 149.11, 95% confidence interval (CI) 137.09 to 161.12). In addition, compared with placebo, a significant improvement in mean St George Respiratory Questionaire (SGRQ) score (MD -3.60, 95% CI -4.36 to -2.83) was reported, and the proportion of participants experiencing clinically relevant improvement in SGRQ score was significantly greater (odds ratio (OR) 1.63, 95% CI 1.46 to 1.84). Compared with twice-daily beta(2)-agonists, a small but statistically significant increase in trough FEV1 was seen with indacaterol (MD 61.71 mL, 95% CI 41.24 to 82.17). Differences between indacaterol and twice-daily beta(2)-agonists in mean SGRQ scores (MD -0.81, 95% CI -2.28 to 0.66) and in the proportions of participants achieving clinically relevant improvements in SGRQ scores (OR 1.07, 95% CI 0.87 to 1.32) were not statistically significant, but the confidence intervals are too wide to permit the conclusion that the treatments were equivalent. Data were insufficient for analysis of differences in exacerbation rates for both placebo and twice-daily beta(2)-agonist comparisons.Authors' conclusionsFor patients with stable COPD, use of indacaterol versus placebo results in statistically significant and clinically meaningful improvements in lung function and quality of life. The clinical benefit for lung function is at least as good as that seen with twice-daily longacting beta(2)-agonists. The comparative effect on quality of life remains uncertain, as important differences cannot be excluded.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the efficacy and safety of using technology with health professional feedback to remotely monitor asthma control versus monitoring without feedback.

BackgroundLong-acting bronchodilators, comprising long-acting beta(2)-agonists (LABA) and long-acting anti-muscarinic agents (LAMA, principally tiotropium), are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and LABAs for the treatment of COPD are unclear.ObjectivesTo compare the relative effects on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in people with COPD randomised to LABA plus tiotropium versus tiotropium alone; or LABA plus tiotropium versus LABA alone.Search methodsWe searched the Cochrane Airways Group Specialised Register of trials and ClinicalTrials.gov up to July 2015.Selection criteriaWe included parallel-group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to LABA against tiotropium or LABA alone for people with COPD.Data collection and analysisTwo review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.Main resultsThis review included 10 trials on 10,894 participants, mostly recruiting participants with moderate or severe COPD. All of the trials compared tiotropium in addition to LABA to tiotropium alone, and four trials additionally compared LAMA plus LABA with LABA alone. Four studies used the LABA olodaterol, three used indacaterol, two used formoterol, and one used salmeterol.Compared to tiotropium alone, treatment with tiotropium plus LABA resulted in a slightly larger improvement in mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) (mean difference (MD) -1.34, 95% confidence interval (CI) -1.87 to -0.80; 6709 participants; 5 studies). The MD was smaller than the four units that is considered clinically important, but a responder analysis indicated that 7% more participants receiving tiotropium plus LABA had a noticeable benefit (greater than four units) from treatment in comparison to tiotropium alone. In the control arm in one study, which was tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with tiotropium plus LABA the improvement was a fall of a further 1.3 units (on average). Most of the data came from studies using olodaterol. High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator forced expiratory volume in one second (FEV1) showed a small mean increase with the addition of LABA over the control arm (MD 0.06, 95% CI 0.05 to 0.07; 9573 participants; 10 studies), which showed a change from baseline ranging from 0.03 L to 0.13 L with tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There was moderate heterogeneity for both exacerbations and withdrawals.This review included data on four LABAs: two administered twice daily (salmeterol, formoterol) and two once daily (indacaterol, olodaterol). The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.Comparing LABA plus tiotropium treatment with LABA alone, there was a small but significant improvement in SGRQ (MD -1.25, 95% CI -2.14 to -0.37; 3378 participants; 4 studies). The data came mostly from studies using olodaterol and, although the difference was smaller than four units, this still represented an increase of 10 people with a clinically important improvement for 100 treated. There was also an improvement in FEV1 (MD 0.07, 95% CI 0.06 to 0.09; 3513 participants; 4 studies), and in addition an improvement in exacerbation rates (odds ratio (OR) 0.80, 95% CI 0.69 to 0.93; 3514 participants; 3 studies).Authors' conclusionsThe results from this review indicated a small mean improvement in health-related quality of life and FEV1 for participants on a combination of tiotropium and LABA compared to either agent alone, and this translated into a small increase in the number of responders on combination treatment. In addition, adding tiotropium to LABA reduced exacerbations, although adding LABA to tiotropium did not. Hospital admission and mortality were not altered by adding LABA to tiotropium, although there may not be enough data. While it is possible that this is affected by higher attrition in the tiotropium group, one would expect that participants withdrawn from the study would have had less favourable outcomes; this means that the expected direction of attrition bias would be to reduce the estimated benefit of the combination treatment. The results were largely from studies of olodaterol and there was insufficient information to assess whether the other LABAs were equivalent to olodaterol or each other.