Protocol for a systematic review to identify and weight the indicators of risk of asthma exacerbations in children aged 5–12 years

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all been associated with increased risk of exacerbations. Other factors described in adults and teenagers (such as socioeconomic status, 28 ethnicity, 29 upper airways disease, 30 blood eosinophilia, 31 obesity 32,33 and non-attendance for review appointments 4 ) may also be relevant as predictors of exacerbations in young children. There is thus a need to identify and weight risk factors in children aged 5-12 years from factors identified in a systematic review, which can be further tested and validated in this population group.
The focus of this systematic review will be factors that increase a child's propensity to asthma exacerbations, rather than immediate triggers for exacerbations, e.g., respiratory tract infections, exposure to airborne pollutants or allergens, physical or emotional exertion.

AIMS
To undertake a systematic review of the literature to: 1. Identify factors associated with the risk of asthma exacerbations in children aged 5-12 years. 2. Quantify their importance to inform the assessment of risk in children.

METHODS
We will follow the systematic review procedures described in the Cochrane Handbook for Systematic Reviews of Interventions. 34 'PICOS' criteria The PICOS criteria and study designs of interest are given in Table 1. We will include both controlled trials of interventions that aim to reduce exacerbation risk and observational studies, which seek to identify risk factors. We are interested in factors that contribute to future risk as opposed to immediate triggers (such as contracting an upper respiratory tract infection, or events such as thunderstorms). We will not include trials of pharmacological efficacy, or studies of unusual events or factors that cannot be routinely measured/tested or those that are not routinely available. Studies investigating risk factors for incidence/ prevalence of asthma, asthma symptoms or objective measures of asthma activity (lung function, symptom scores, medication usage, health care utilisation) will not be included.

Outcome measures
Our primary outcome will be severe exacerbations of asthma: asthma symptoms and/or objective evidence of airways obstruction outside the patients' normal variation necessitating (a) a short course (at least 3 days) of oral corticosteroids and/or (b) a hospitalisation or emergency department visit requiring systemic corticosteroids. 5 In addition, we are interested in risk factors for, and predictors of moderate exacerbations. 5 See Table 1 for definitions.

Identification of studies
The following electronic databases will be searched: MEDLINE, EMBASE, CINAHL, AMED, PsycINFO and CENTRAL. Unpublished and in-progress studies will be identified by the following: (a) searching internet-based trial registries, i.e., ClinicalTrials.gov (http://www. clinicaltrials.gov) and Current Controlled Trials (www.controlledtrials.com), and (b) contacting experts in the field. See Appendix 1 for an example of the search strategy developed for the MEDLINE database that will be adapted to search other databases. Papers included in related systematic reviews in adults will be checked to identify reports on children, 35 and forward and backward citation checks will be undertaken on the included papers. In addition, our expert advisors will be asked to identify known and anticipated risk factors for asthma exacerbations in children as a reality check to ensure we have captured all likely predictors.
No language or publication time restrictions will be imposed. Translations will be undertaken where necessary, and papers for which translation is not feasible will be noted.
Study selection and data extraction Independently, two reviewers (NT or Audrey Buelo (AB) and SMcL) will perform the following: • Review titles and abstracts of papers identified from the literature searches and select potentially relevant studies. • Assess retrieved full texts of all potentially eligible studies against the review inclusion/exclusion criteria.
• Extract data using a customised data extraction form, piloted on a subsample to ensure the form is easily and consistently interpreted and captures all relevant information (including PICOS criteria, definitions used and outcomes).
Disagreements at each stage of the review will be resolved by discussion between the reviewers (NT/AB and SMcL) or, if necessary, arbitration by a third reviewer (HP). Unresolved issues relating to interpretation of inclusion/exclusion criteria will be referred to the Steering Group.
We will attempt to contact authors of the papers with missing or unclear essential information. Multiple publications from the same study will be treated as a single study, but draw on all the relevant publications.
The selection process will be summarised using a PRISMA flow diagram. 36 Assessment of the methodological quality Two reviewers (AB and SMcL) will independently assess the methodological quality of the included papers. Using the Cochrane Risk of Bias Tool, 34 randomised trials will be assessed for bias. Each individual domain (selection, performance, detection, attrition, reporting and other bias) will independently be judged by two reviewers (AB and SMcL) to be at low, unclear or high risk of bias. A summary assessment will include the overall risk of bias. Non-randomised studies will be assessed using the Newcastle-Ottawa checklist, 37 which covers selection, comparability and outcome domains and is customised for crosssectional, case-control and cohort studies. Authors will be contacted for unpublished information. 38 Data analysis and synthesis We will provide a descriptive summary of the factors associated with a significant risk of exacerbation of asthma in children aged 5-12 years in detailed tables, and undertake a narrative synthesis of the data. We anticipate substantial heterogeneity of the studies and so do not plan to undertake a formal quantitative meta- Intervention (if applicable) Any intervention that aims to reduce exacerbation risk, specifically excluding trials of pharmacological efficacy as robust reviews are in existence for these. Examples might include interventions to improve medicationrelated behaviour (adherence, inhaler technique), social or lifestyle adaptation, improve residential environment (reduce housing damp/mould, improve indoor air quality) and reduce stress in mothers and children). Observational studies (cohort, case-control and cross-sectional) without a specific intervention that seek to identify relevant risk factors will also be included.

Outcomes
Our primary outcome is severe exacerbations of asthma defined according to the ATS/ERS Task Force: asthma symptoms and/or objective evidence of obstruction outside the normal variation for the patient necessitating (a) a short course (at least 3 days) of oral corticosteroids and/or (b) a hospitalisation or emergency department visit requiring systemic corticosteroids. 5 Moderate exacerbations as defined by the ATS/ERS task force (asthma symptoms and/or airflow obstruction) outside the normal variation for the patient prompting a temporary change of treatment (excluding systemic steroids) to prevent a severe exacerbation. 5

Setting Any setting
Study designs Randomised controlled trials, controlled clinical trials, interrupted time series, controlled before-and-after studies, cohort and case-controlled studies (but not case studies or case series).
Indicators of risk of asthma exacerbations N Tagiyeva et al analysis, but will weight identified factors as conferring slightly, moderately or greatly increased risk, based on the observed effect size and confidence intervals and the quality of the included papers, which will be interpreted in the light of biological plausibility. The weighting will be done independently by two raters. Disagreements will be resolved by discussion with a third rater arbitrating if necessary The results across studies will be explored graphically and through summary measures to investigate whether the heterogeneity of effect can be accounted for by known factors. Severity of asthma and co-morbid rhinitis are part of the causal pathway for the outcome and are likely to be predictors in the final model and so will be investigated in an exploratory way.
The protocol is registered with PROSPERO International Prospective Register of Systematic Reviews (CRD42016037464), and the findings will be summarised and published in a peerreviewed journal.

DISCUSSION
The key aim of the management of asthma in children (and all ages) is to reduce the burden of disease both by achieving good control of day-to-day symptoms and by reducing the risk of troublesome, and potentially serious asthma attacks. Targeting those at risk, has the potential to facilitate care commensurate with need and improve outcomes for those at highest risk. Likely risk factors include markers of severe disease and historical poor control (including previous exacerbations), as well as allergic sensitisation, exposure to environmental factors (including parental smoking), especially, the combination of infection and allergen exposure in sensitised children, 24 and poor adherence to preventer medication and non-attendance for review appointments. Identification and weighting of these features of children and their family/environment will allow clinicians to identify 'at-risk' children, and inform discussions with parents about the need for regular 'preventer' treatment.
The vision is that risk assessment will have application both clinically for assessing individual children's asthma control and thus focussing additional care on those at high risk, as well as for assessing control within populations and targeting care at high-risk populations.