Inhaled corticosteroids for sub‐acute cough in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy of inhaled corticosteroids in reducing the severity of cough in children with sub‐acute cough (defined as cough duration of two to four weeks).
Background
Cough is the most common symptom presenting to primary health care services in Australia (Britt 2009) and worldwide (Cherry 2008; Irwin 2006a). The symptom of cough is also one of the most frequent reasons for referrals to paediatricians and respiratory physicians (Chang 2006a). In the United States, the number of doctor visits per year for cough exceeds 27 million (Cherry 2008). Cough accounts for 6.8 of every 100 visits to general practitioners in Australia (Britt 2009). Cough in children is not only a common problem, but one that impacts at both an individual level with reduced quality of life (Marchant 2008), as well as at a population level due to the considerable expense of treatment (Irwin 2006a). Irrespective of the aetiology or cough duration, the symptom of cough in children is associated with significant morbidity to parents (Cornford 1993; Fuller 1998) and children as it disrupts usual daily activities including school and sleep (Faniran 1998). Cough was the most common reason for school absenteeism in a community‐based study (Doull 1996). In the United States, 1 in 10 children receive medication for their acute cough at any one time (Vernacchio 2008). This reflects the anxiety and distress to parents caused by the symptom of cough in their child (Cornford 1993). The use of unnecessary or inappropriate medications for cough is associated with adverse effects (Thomson 2002).
Description of the condition
Cough duration is variably defined. In the Australian and United States paediatric cough guidelines, sub‐acute cough is defined as cough lasting two to four weeks (Chang 2006a, Chang 2006b). Acute cough in children is defined as cough lasting less than two weeks, with chronic cough defined as cough duration longer than four weeks (Chang 2006a). The paediatric definitions are different to the adult definitions (with chronic cough defined as cough lasting longer than eight weeks), due to the natural history of acute upper respiratory tract infections in children (Hay 2002) and the knowledge that cough in children differs from cough in adults (Chang 2006b; Chang 2005). Cough related to an acute upper respiratory tract infection resolves within one to three weeks in most pre‐school aged children presenting to primary care, however cough persists for three to four weeks following an acute upper respiratory tract infection in 10 percent of children (Hay 2002).
Description of the intervention
Corticosteroids are a commonly used medication for eosinophilic dominated airway diseases like asthma. For asthma, oral corticosteroids are used predominantly during periods of exacerbations, while inhaled corticosteroids (ICS) are used mainly for maintenance or preventative therapy (BTS 2008). In children, ICS can be delivered via a metered dose inhaler (MDI) with or without a spacer, dry powder inhalation (DPI) or through nebulisation.
How the intervention might work
Short term treatment with ICS reduces cough frequency in adults with post‐infectious cough (Gillissen 2007). Cough is the dominant symptom of airway inflammation, and airway hyper‐reactivity is also associated with cough (Nair 2010). ICS can ameliorate airway inflammation and airway hyper‐reactivity (at least in some people) (Rytila 2008), thus ICS treatment can potentially reduce the severity of cough in children with sub‐acute cough.
Why it is important to do this review
ICS is recommended as an empirical treatment in guidelines on adults with chronic cough (Irwin 2006b). Although ICS is not recommended in children with isolated chronic cough (i.e. cough without any other symptoms) (Chang 2006b), many doctors continue to use ICS in children with cough of various durations. Evidence examining the use of ICS for chronic cough has been addressed in a Cochrane systematic review (Tomerak 2005) and a Cochrane review examining the use of ICS for acute cough (cough duration less than two weeks) is in preparation. Although physicians often think "it's only a cough", the symptom of cough is burdensome and substantially reduces the quality of life of parents (Marchant 2008). Due to the significant impact of cough in children, improvement from ICS treatment and other therapies would be beneficial. However as with all interventions, adverse events will also need to be considered. A systematic review of the benefits (or otherwise) of ICS on sub‐acute cough would therefore be useful to help guide clinical practice.
Objectives
To evaluate the efficacy of inhaled corticosteroids in reducing the severity of cough in children with sub‐acute cough (defined as cough duration of two to four weeks).
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials comparing inhaled corticosteroids with a control group for treatment of sub‐acute cough in children.
Types of participants
Children with sub‐acute cough (cough duration of two to four weeks).
Exclusion criteria: Participants with known chronic respiratory disease (such as cystic fibrosis, asthma, bronchiectasis, aspiration lung disease). Children with cough post acute respiratory infections such as croup will not be excluded.
Types of interventions
All randomised controlled comparisons of any type of ICS (MDI, DPI or nebulised). Trials comparing two or more medications without a placebo comparison group will not be included. Trials that include the use of other medications or interventions will only be included if all participants had equal access to such medications or interventions.
Types of outcome measures
Reporting of one or more outcomes of interest will not be an inclusion criteria.
Primary outcomes
Attempts will be made to obtain data on at least one of the following outcome measures:
Primary outcome:
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Proportion of participants who were not cured or not substantially improved (> 70% reduction in cough severity measure) at follow up (clinical failure)
The following hierarchy of assessment measures for cough severity will be used (i.e. where two or more assessment measures are reported in the same study, the outcome measure that is listed first in the hierarchy will be used):
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Objective measurements of cough indices (cough frequency, cough receptor sensitivity)
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Symptomatic (Quality of life, Likert scale, visual analogue scale, level of interference of cough, cough diary) ‐ assessed by the patient (child)
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Symptomatic (Quality of life, Likert scale, visual analogue scale, level of interference of cough, cough diary) ‐ assessed by the parents/carers
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Symptomatic (Likert scale, visual analogue scale, level of interference of cough, cough diary) ‐ assessed by clinicians
Secondary outcomes
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Proportion of participants who were not cured at follow up
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Proportion of participants who were not substantially improved at follow up
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Mean difference in cough indices (cough diary, cough frequency, cough scores, quality of life)
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Proportion of participants experiencing adverse effects of the intervention
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Proportion of participants experiencing complications (e.g. requirement for medication change)
The same hierarchy of assessment measures for cough severity will be used for secondary outcomes one and two.
Search methods for identification of studies
Electronic searches
Randomised controlled trials will be identified using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts (please see the Airways Group Module for further details).
All records in the Specialised Register coded as 'cough' will be searched using the following terms:
((steroid* or corticosteroid* or glucocorticosteroid* or glucocorticoid* or corticoid*) AND (inhal*)) or (beclomethasone or budesonide or fluticasone or ciclesonide or mometasone or flunisolide or mometasone)
Additional searches of CENTRAL, MEDLINE and EMBASE will also be conducted. The proposed search strategy for CENTRAL is in Appendix 1. This will be adapted for use in the other databases.
Searching other resources
We will handsearch references from identified papers and reviews for further references. We will contact authors to request their identification of any unpublished or missed trials.
Data collection and analysis
Selection of studies
Two review authors (SA, AC) will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, adjudication by a third reviewer (KO).
Data extraction and management
We will review trials that satisfy the inclusion criteria and record the following information: study setting, year of study, source of funding, participant recruitment details (including number of eligible people), inclusion and exclusion criteria, other symptoms, randomisation and allocation concealment method, number of participants randomised, blinding (masking) of participants, care providers and outcome assessors, duration of intervention, co‐interventions, number of participants not followed up, reasons for withdrawals from study protocol (clinical, side‐effects, refusal and other), details on side‐effects of therapy, and whether intention‐to‐treat analyses were possible. We will extract data for the outcomes described above and we will seek any follow‐up data provided in following four weeks post intervention. We will request further information from the authors where required.
Assessment of risk of bias in included studies
Two review authors (SA, AC) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreement will be resolved by discussion or by involving a third assessor. We will assess the risk of bias according to the following domains:
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Allocation sequence generation
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Concealment of allocation
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Blinding of participants and investigators
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Incomplete outcome data
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Selective outcome reporting
We will also note other sources of bias. Each potential source of bias will be graded as yes, no or unclear, relating to whether the potential for bias was low, high or unknown respectively.
Measures of treatment effect
An initial qualitative comparison of all the individually analysed studies will examine whether pooling of results (meta‐analysis) is reasonable. We will take into account differences in study populations, inclusion and exclusion criteria, interventions and outcome assessment. The results from studies that meet the inclusion criteria and report any of the outcomes of interest will be included in the subsequent meta‐analyses.
For the dichotomous outcome variables of each individual study, we will calculate the odds ratio (OR) and 95% confidence intervals (CIs) using a modified intention‐to‐treat analysis (modified if there are missing values due to drop outs). We will use the Cochrane statistical package Review Manager 5. Numbers needed to treat (NNT) will be calculated from the pooled OR and its 95% CI applied to a specified baseline risk (from the control group) using an online calculator (Cates 2003).
For continuous outcomes we will calculate the mean difference and 95% CIs using Review Manager 5. If studies report outcomes using different measurement scales, the standardised mean difference will be estimated.
Unit of analysis issues
Cross‐over trials are not appropriate for this intervention duration and thus will not be included in any meta‐analysis but will be described in the text.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity we will explore it by using pre‐specified subgroup analysis. We will describe any heterogeneity between the study results and test this to see if it reached statistical significance using the chi‐squared test. We will consider heterogeneity to be significant when the P value is less than 0.10 (Higgins 2008). We will categorise heterogeneity such that a value of under 25% is considered low, around 50% is considered moderate and over 75% is considered a high degree of heterogeneity.
Assessment of reporting biases
Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.
If combination of data and meta‐analysis (with at least five studies) is possible, we will assess publication bias using a funnel plot. We will try and identify and report on any selective reporting in the included trials, ideally by comparing the trial protocol with the final published paper, but alternatively by comparing the 'Methods' and 'Results' sections of the published studies.
Data synthesis
We will determine the summary OR and mean differences with their 95% CIs using a fixed‐effect model. We will use a random‐effects model whenever there are concerns about statistical heterogeneity.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses (for the primary outcome):
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Type of control arm (placebo/no treatment)
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Children in different age groups (younger than 6 years, 6 to 14 years and 15 years and above) (as older children are more likely to have adult‐like cough responses)
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Doses of ICS (low to moderate defined as < 800 μg/day budesonide equivalent versus high defined as > 800 μg/day budesonide equivalent)
Sensitivity analysis
Sensitivity analyses are also planned to assess the impact of the potentially important factors on the overall outcomes:
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Variation in the inclusion criteria
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Risk of bias in the included studies (i.e. double versus single blinded or unblinded; allocation clearly concealed versus unclear or no concealment)
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Analysis using random‐effects model
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Analysis by "treatment received" or "intention‐to‐treat"
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Nebulised ICS versus metered dose inhalers
