Corticosteroids for the treatment of Kawasaki disease in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the role of corticosteroids for a reduction in the incidence of coronary aneurysms in Kawasaki disease (KD), as either first‐line or second‐line treatment. Corticosteroids may be given alone or in conjunction with other accepted KD treatments. Secondary objectives will include to determine the effects of steroids on mortality, biochemical parameters and duration of acute symptoms including fever as well as evaluating their safety in KD and efficacy in relevant population subgroups.
Background
Description of the condition
Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood acquired heart disease in the developed world (Kato 1996). Originally described in 1967 by Tomiaski Kawasaki (Kawasaki 1967), it is a medium vessel vasculitis of unclear aetiology that has been linked with genetic immunological predispositions and bacterial supersensitivity. Generally affecting children less than five years old, peak onset is between 18 to 24 months. The incidence in those aged under five years varies widely throughout the world, including 8.1 per 100,000 in the UK; 17.1 per 100,000 in the USA; and 239.6 per 100,000 in Japan (Gardner‐Medwin 2002; Harnden 2002; Holman 2003; Nakamura 2012). Rate of recurrence is approximately 3600 per 100,000 whilst acute mortality occurred in just one of the 23,730 cases Nakamura analysed in the 2009 to 2010 period (Nakamura 2012). Such varied epidemiology has strengthened theories linking KD with genetics and one or more bacterial agents (Wood 2009).
KD is a multisystem vasculitis but its most important complication involves the predisposition for coronary abnormalities leading to aneurysms in up to 25% of untreated patients (Burns 1996). Such complications render the coronary vessels vulnerable to stenoses and thrombosis, with subsequent risk of myocardial infarction and patient mortality (Daniels 2012). Furthermore, these thromboses act as centres for accelerated atherosclerosis and therefore increase future cardiovascular risk.
There is no diagnostic test for KD but laboratory findings typically show a raised white cell count, erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP). Instead, diagnosis is generally made based upon clinical symptoms from one of two major sets of criteria. The Diagnostic Guidelines of the Japan KD Research Committee require any five from (1) fever longer than five days, (2) conjunctivitis, (3) lymphadenopathy, (4) polymorphous rash, (5) oral and perioral changes, and (6) changes in the extremities (Ayusawa 2005). The American Heart Association guidelines are similar, requiring a total of five of the aforementioned six but also stipulating that fever must feature (Newburger 2004). Diagnosis is complicated by these symptoms being prevalent in various common childhood viral exanthems. Symptoms may also occur sequentially rather than simultaneously. This variability leads to the idea of 'incomplete' KD, where KD is suspected but only three fifths of diagnostic criteria are satisfied.
Description of the intervention
It is thought that prompt and effective treatment of KD can prevent the cardiac sequelae. Accepted and proven initial pharmacological management involves intravenous immunoglobulin (IVIG) 2 g/kg in a single 12‐hour infusion alongside aspirin 30 to 50 mg/kg in four divided doses (Eleftheriou 2013). This has been shown to limit the duration of the acute phase of KD as well as reduce the long‐term coronary sequelae from 25% to 4.7% (Levin 1991). Both medications have already been subject to Cochrane reviews (Baumer 2006; Oates‐Whitehead 2003). There is also a limited but still of note use of plasma exchange for KD in certain institutions (Hokosaki 2012).
Patients do not always respond to the above regimen. A subset of KD patients, approximately 20%, have clinical symptoms that are resistant to the first dose of IVIG and aspirin measured after 48 hours. This group has been proven to be at higher risk for cardiac sequelae (Brogan 2002). Various systems for identifying this group have been formulated, including the Kobayashi score, however these have shown poor sensitivity in Western populations compared with the Japanese groups in which they were devised (Kobayashi 2008; Sleeper 2011). Currently accepted identifiers for this high‐risk group include the following (Eleftheriou 2013).
1. Resistance to IVIG.
2. Very young age of onset (< 12 months).
3. Severe inflammatory markers.
4. Clinical features of shock.
5. Existing arterial aneurysms.
6. Kobayashi score greater or equal to five.
These high‐risk patients have a higher prevalence of coronary aneurysms, especially giant aneurysms (> 8 mm), and have a greater long‐term cardiovascular morbidity and mortality related to this (Tatara 1987). Current consensus on management recommends a repeat dose of IVIG, facilitating disease defervescence in approximately half of the patients (Hashino 2001). Measures to improve the success rate have been reviewed and the utility of intravenous steroids (IVS) with or without infliximab has shown mixed results. Current data on infliximab is insufficiently powered to draw conclusions (Davies 2013). IVS have long been used in vasculitides similar to KD, however their use in KD has been subject to long‐standing controversy due to earlier works showing a deleterious effect (Levin 2013). That stated, it is now widely believed that these studies were subject to significant selection bias with only the most severe cases bearing the greatest probability of a poor outcome when given IVS (Kato 1979).
There have been recent gains in knowledge regarding the use of IVS in KD. The early use of steroids has been advocated but only in high‐risk patients (as defined earlier). This acknowledged, it remains unclear how best to carry out corticosteroid treatment (Chen 2013). A recent editorial has highlighted some of the critical issues with current meta‐analyses in this area (Levin 2013). Problems highlighted have included varying inclusion criteria and populations, differing methodologies of included works and an overall lack of power with respect to side effects data. It is not currently known which demographic groups show the greatest benefit with respect to coronary sequelae, or if there is the potential for adverse complications with IVS treatment. Furthermore, the most effective types, frequencies and doses of steroid have not yet been clarified, nor whether steroids should be administered alongside IVIG, aspirin or infliximab (Levin 2013).
How the intervention might work
Steroid treatment is already utilised in a broad range of vasculitides to great effect. Furthermore, steroids were a key part of KD treatment prior to the advent of IVIG. Although the exact pathological mechanisms remain unclear, current theories of KD pathogenesis implicate immunological responses to bacterial agents (Eleftheriou 2013). Such reactions are thought to be controllable via steroid administration due to a reduction in inflammatory mediator transcription. In the context of KD, this may mean a reduction in fever as well as lower levels of inflammation, leading to a reduction in the formation of coronary abnormalities, which could lower the incidence of future cardiovascular sequelae (Levin 2013). Given the aforementioned, it remains important to ascertain the utility of IVS in KD.
Why it is important to do this review
There is much controversy on how best to identify the high‐risk patients who may benefit from additional treatment beyond the standard IVIG and aspirin. Furthermore, this situation is complicated by early reports of harmful effects of steroids in KD, although these conclusions are now considered to be the result of selection bias as only the sickest patients were investigated (Kato 1979). Current identifiers used include resistance to IVIG, very young age of onset (< 12 months), severe inflammatory markers, clinical features of shock, existing arterial aneurysms, or a Kobayashi score greater or equal to five. The utility of IVS in KD as a whole remains unclear, despite several meta‐analyses, and we seek to use this work to clarify the situation through a more targeted approach to analysis. In addition, it is unclear how best to define the patients that may benefit from IVS the most, for example ethnic origin, severity of KD or pre‐steroid treatment status. It is hoped that the whole group and subgroup analyses of this work will cast greater light on this issue.
Objectives
To assess the role of corticosteroids for a reduction in the incidence of coronary aneurysms in Kawasaki disease (KD), as either first‐line or second‐line treatment. Corticosteroids may be given alone or in conjunction with other accepted KD treatments. Secondary objectives will include to determine the effects of steroids on mortality, biochemical parameters and duration of acute symptoms including fever as well as evaluating their safety in KD and efficacy in relevant population subgroups.
Methods
Criteria for considering studies for this review
Types of studies
We will search for all randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation methods are not completely random, for example using alternation). Cross‐over trials will not be included as the response to steroid intervention may depend on timing and previous treatment status.
Types of participants
We will include all children (less than 19 years old) diagnosed with KD, worldwide, in the analysis. The diagnosis of KD must fulfil the Diagnostic Guidelines of the Japan KD Research Committee. This requires any five of the following (Ayusawa 2005).
1. Fever for > 5 days, non‐responsive to antipyrexial agents.
2. Conjunctivitis: bilateral bulbar, non‐suppurative.
3. Lymphadenopathy: cervical, generally > 1.5 cm.
4. Polymorphous exanthem, no crusts or vesicles.
5. Oral and perioral changes: strawberry tongue, cracked erythematous lips, diffuse oropharyngeal erythema.
6. Changes in the extremities, either acute: erythema and oedema of palms and soles; or convalescent: desquamation at fingertips.
An accepted exception to the above for a positive KD diagnosis exists if only four criteria are fulfilled but cardiac complications are found with echocardiography or an angiogram. We will also accept American Heart Association guidelines (Newburger 2004). These are similar, requiring a total of five of the above six, but stipulating that fever must feature. Therefore fulfilment of the American criteria automatically fulfils the Japanese criteria.
Corticosteroids may be part of the initial treatment for KD or form part of the second‐line treatment after failure of first‐line treatment that did not include steroids. The comparison group must be in parallel. Cross–over trials are not eligible for inclusion.
Participants with positive blood cultures will be excluded.
Types of interventions
All forms of corticosteroid therapy in conjunction with any combination of placebo or no treatment, immunoglobulin, aspirin or infliximab for the treatment of KD will be considered as the intervention of interest. That stated, corticosteroids will be the only difference in management between the trial arms.
Comparator groups will include any of:
1. placebo;
2. immunoglobulin only;
3. aspirin only;
4. immunoglobulin and aspirin;
5. infliximab only;
6. infliximab and immunoglobulin;
7. infliximab, immunoglobulin and aspirin.
Types of outcome measures
Primary outcomes
1. The incidence of aneurysmal coronary abnormalities (measured via diameter or z‐scores) per study group found at either coronary angiogram or echocardiography within three months of KD diagnosis. Coronary abnormality must by definition be either via the de Zrozi criteria (a coronary dimension that is ≥ 2.5 standard deviations (SDs) above the mean for that body surface area) or as defined within the Japanese Ministry of Health criteria:
a. lumen > 3 mm in children < 5 years old;
b. lumen > 4 mm in children > 5 years old;
c. internal diameter of a segment measuring ≥ 1.5 times that of an adjacent segment.
2. The incidence of any adverse effects per study group that are attributable to the administration of steroids at any point after treatment initiation. Known side effects of steroids in other diseases include immunosuppression with resultant opportunistic infection and vascular necrosis of the femoral head.
Secondary outcomes
1. Mortality (all‐cause)
2. Duration of clinical symptoms: fever, rash
3. Time for biochemical parameters to normalise: CRP, ESR
4. Length of hospital stay
5. Longer‐term (greater than one year post‐disease onset) coronary morbidity (non‐aneurysmal)
Search methods for identification of studies
Electronic searches
The Cochrane Peripheral Vascular Diseases Group Trials Search Co‐ordinator (TSC) will search the Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy which will be used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).
The following trial databases will be searched by the TSC for details of ongoing and unpublished studies:
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World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/);
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ClinicalTrials.gov (http://clinicaltrials.gov/);
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Current Controlled Trials (http://www.controlled‐trials.com/).
Searching other resources
We will contact the authors of trials that meet the eligibility criteria and are found in the ongoing or unpublished trial searches. Reference lists of relevant trials will be searched for further publications.
Data collection and analysis
Selection of studies
Two review authors (MJS and HCK) will independently apply the selection criteria to the studies identified by the search strategy. This includes independently assessing if the studies fulfil the inclusion and exclusion criteria. If insufficient information is available to decide whether a study is truly eligible the study authors will be contacted to request further information. Disagreements will be resolved by a third review author (AJW).
Data extraction and management
Two review authors (MJS and HCK) will independently extract data using a modified version of the Cochrane Peripheral Vascular Diseases Group standard data extraction form. These data will then be brought together and monitored for discrepancies by a third review author (AJW) before being entered into Review Manager 5.3 software (RevMan 2014). We will contact study authors for any required information not included in the published works. The key information gathered in the data collection form will include the following.
1. General study information: publication type.
2. Fulfilment of eligibility criteria: study type, interventions, outcomes measured, reasons for exclusion.
3. Study methods: allocations methods, study dates, duration, ethical approval, statistical methods.
4. Participants: methods of recruitment, consent, total number, treatment groups, age, sex, race, KD severity, subgroup analyses reported, eligibility criteria.
5. Intervention (steroids): number of participants, dosing, frequency, duration, delivery method, providers, compliance, concomitant treatment.
6. Outcomes: coronary diameters (acute), coronary diameter z‐scores (acute), coronary abnormality (long‐term), duration of clinical symptoms (e.g. fever), adverse effects, duration of biochemical parameter abnormality (e.g. CRP), duration of hospital stay.
Assessment of risk of bias in included studies
Risk of bias will be assessed using the recommended Cochrane Collaboration tool as described in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This will be performed independently by two authors (MJS and HCK) with any disagreements resolved by discussion with the third review author (AJW). The domains assessed will include:
1. sequence generation (selection bias);
2. allocation sequence concealment (selection bias);
3. blinding of participants and personnel (performance bias);
4. blinding of outcome assessment (detection bias);
5. incomplete outcome data (attrition bias);
6. selective outcome reporting (reporting bias);
7. other bias.
Measures of treatment effect
The effect measure of choice for dichotomous data will be risk ratio (RR) with its 95% confidence interval (CI). This will be a ratio between the corticosteroid intervention group and its parallel comparator group.
Continuous data, including time to event data, will be managed using mean differences (MD) and 95% CIs. A standardised mean difference (SMD) will be used if different studies measure the same outcome but use alternative measures.
Unit of analysis issues
The unit of analysis will be each patient recruited into a trial.
Dealing with missing data
All missing data due to dropouts will be accounted for via an intention‐to‐treat (ITT) analysis. We will report if the individual trials carry this out. If they do not then we will endeavour to apply an ITT analysis. In the event we are unable to do this then we will utilise a per protocol analysis. Any dropouts post‐allocation will be explained. Any data missing from the published document will be followed up with the study’s original authors; if data still remain absent then this will be taken into account in the 'risk of bias' assessments.
Assessment of heterogeneity
Heterogeneity will be taken into account using the I2 statistic for quantification of variability (< 40% = likely low heterogeneity; 40% to 60% = possible moderate heterogeneity; > 60% = possible significant heterogeneity). The Chi2 test (limit = degrees of freedom) and P values (10% significance threshold) will also be utilised. Where heterogeneity exceeds generally accepted limits (> 60% heterogeneity) the analysis will be subgrouped in a logical manner to explain these differences and reduce remaining heterogeneity. These methods will be reinforced by visual recognition on forest plots, looking for overlapping CIs.
Assessment of reporting biases
If there are more than eight trials, publication and reporting bias will be screened for using funnel plot asymmetry and measured using tests as outlined in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For smaller studies, we will take into account 'the small study effect', where smaller studies can show larger treatment effects due to poor methodology, heterogeneity, selection bias, chance or artefact. We shall also seek to find eligible studies that have been registered and should have been completed but are without available published data. It should be noted that the risk of bias assessment will take into account selective outcome reporting.
Data synthesis
Statistical analysis will take place using a fixed‐effect model if there is low heterogeneity and a random‐effects model if there is significant heterogeneity (I2 > 60%). We will undertake outcome analyses using an ITT model. Two‐sided P values ≤ 0.05 will be considered and all analyses will be undertaken using Review Manager 5.3 (RevMan 2014).
Subgroup analysis and investigation of heterogeneity
Planned subgroup analyses (data permitting) will include:
1. type of steroid used;
2. steroid dosing;
3. steroid treatment frequency;
4. total steroid treatment duration;
5. steroid route of administration;
6. first‐line versus second‐line management;
7. geographical distribution of trial participants, ethnicity;
8. KD severity (non‐high risk versus high risk as detailed earlier);
9. recognised concomitant treatments for KD (as detailed earlier in the text).
We will also look at employing further subgroup analyses if heterogeneity remains significant (I2 > 60%). These subgroups will be tested using a Chi2 P value threshold of 0.05.
Sensitivity analysis
We will perform a sensitivity analysis to explore causes of heterogeneity and the robustness of the results if there are sufficient data available. We will include the following factors in the sensitivity analysis:
1. type of study design (RCT versus quasi‐RCT);
2. low risk of bias trials versus high risk of bias trials;
3. rates of dropouts for each treatment group.
