Plain language summary
Using steroids to treat Kawasaki disease
We reviewed the use of a set of drugs known as steroids in children affected by Kawasaki disease for the reduction in the chance of future heart problems as well as the effect on the duration of fever, signs of infection in the blood and the number of days spent in hospital.
We currently have a limited understanding of Kawasaki disease and how best to manage it. This is important as one of the long-term consequences can involve the heart, putting the child at higher risk of life-shortening outcomes.
Evidence is current to November 2016. Male and female children diagnosed with Kawasaki disease were included in this review. We selected only randomised clinical trials. Trials compared the use of steroids against not using steroids. This review involves seven trials and 922 participants.
Steroids appear to reduce the risk of heart problems after Kawasaki disease without causing any important side effects. They also reduce the length of symptoms (fever and rash), length of hospital stay, and blood markers associated with being unwell. Certain groups, including those based in Asia, those with higher risk scores, and those receiving longer steroid treatment, may have greater benefit from steroid use, especially with decreasing rates of heart problems, but more tests are needed to answer these questions. More tests are also needed to obtain a more accurate marker of the risk of serious side effects and to determine if there is a lower chance of death when using steroids. Evidence presented in this review suggests that treatment with a long course of steroids should be considered for all children diagnosed with Kawasaki disease until further studies are performed.
Quality of the evidence
Evidence quality was graded according to the GRADE system. Evidence was considered high quality for serious adverse events, mortality and time for laboratory parameters to normalise. Evidence was considered moderate quality for the risk of future heart problems, duration of clinical symptoms (fever, rash) and length of hospital stay. This means that we are reasonably confident that the true effect is close to that estimated in this work.
Kortikosteroidi za liječenje Kawasakijeve bolesti u djece
U ovom Cochrane sustavnom pregledu analizirali smo djelotvornost niza lijekova poznatih kao steroidi za liječenje djece pogođene Kawasakijevom bolešću s ciljem smanjenja vjerojatnosti budućih srčanih problema, učinaka na trajanje temperature, znakove infekcije u krvi i broj dana provedenih u bolnici.
Trenutno imamo ograničeno razumijevanje Kawasakijeve bolesti i kako je najbolje liječiti. To je važno jer jedna od dugoročnih posljedica bolesti može zahvatiti srce, zbog čega dijete ima veći rizik kraćega života.
Obilježja uključenih istraživanja
Dokazi se temelje na literaturi objavljenoj do studenog 2016. Muška i ženska djeca kojima je dijagnosticirana Kawasakijeva bolest su bila uključena u ovaj pregled. Za analizu literature odabrali smo samo randomizirana klinička ispitivanja. Studije su uspoređivale korištenje steroida u odnosu na nekorištenje steroida. Ovaj pregled literature uključuje sedam studija i 922 sudionika.
Čini se da steroidi smanjuju rizik od srčanih problema nakon nastupa Kawasakijeve bolesti bez uzrokovanja značajnih nuspojava. Oni također smanjuju duljinu simptoma (povišenu temperaturu i osip), duljinu boravka u bolnici i krvne markere povezane s bolešću. Određene skupine, uključujući one u Aziji, one s visokom ocjenom rizika, i one koji su primali duže liječenje steroidima, mogu imati veću korist od upotrebe steroida, a posebno sa smanjenjem stope srčanih problema, ali potrebno je više studija za odgovoriti na t pitanja. Također je potrebno više istraživanja kako bi se dobio točniji pokazatelj rizika ozbiljnih nuspojava, a kako bi se utvrdilo postoji li manja vjerojatnost smrti kada se koriste steroidi. Dokazi prikazani u ovom pregledu literature predlažu da bi se u djece s Kawasakijevom bolesti trebalo razmotriti dugotrajno liječenje steroidima dok se ne provedu daljnja istraživanja.
Kvaliteta dokaza se ocjenjivala prema GRADE sustavu. Smatralo se da su dokazi visoke kvalitete za ozbiljne nuspojave, smrtnost i vrijeme za normalizaciju laboratorijskih pokazatelja. Dokazi za rizik od budućih srčanih problema, trajanje kliničkih simptoma (temperatura, osip) i duljinu boravka u bolnici ocijenjeni su srednjom kvalitetom. To znači da smo prilično sigurni da je pravi učinak blizu onome procijenjenom u ovom radu.
Prevela: Ivana Sruk
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: firstname.lastname@example.org
Resumen en términos sencillos
Uso de corticosteroides para el tratamiento de la enfermedad de Kawasaki
Pregunta de la revisión
Se analizó la administración de un conjunto de fármacos conocidos como corticosteroides en los niños afectados por la enfermedad de Kawasaki para la reducción de las perspectivas de problemas cardíacos a futuro, así como el efecto sobre la duración de la fiebre, los signos de infección en la sangre y el número de días en el hospital.
Es limitada la comprensión actual sobre la enfermedad de Kawasaki y la mejor forma de tratamiento. Lo anterior es importante porque una de las consecuencias a largo plazo puede comprometer el corazón, lo que coloca al niño en un riesgo más alto de resultados que acortan la vida.
Características de los estudios
Las pruebas están actualizadas hasta noviembre 2016. Se incluyeron en esta revisión niños y niñas con diagnóstico de enfermedad de Kawasaki. Sólo se seleccionaron ensayos clínicos con asignación aleatoria. Los ensayos compararon la administración de corticosteroides con el no uso de corticosteroides. Esta revisión involucra siete ensayos con 922 participantes.
Los corticosteroides parecen reducir el riesgo de problemas cardíacos después de la enfermedad de Kawasaki sin causar ningún efecto secundario importante. También reducen la duración de los síntomas (fiebre y erupción cutánea), la duración de la estancia hospitalaria y los marcadores sanguíneos asociados con el malestar. Algunos grupos (como los residentes en Asia, los que presentan puntuaciones de riesgo más altas y lo que reciben tratamiento con corticosteroides por más tiempo) pueden obtener más beneficios con los corticosteroides, sobre todo en cuanto a una tasa más baja de problemas cardíacos, aunque se necesitan más exámenes para responder estas preguntas. Se necesitan también más pruebas para obtener un marcador más exacto del riesgo de efectos secundarios graves y determinar si hay menores perspectivas de muerte cuando se usan los corticosteroides. Las pruebas presentadas en esta revisión indican que el tratamiento con un ciclo prolongado de corticosteroides debe considerarse para todos los niños con diagnóstico de EK hasta que se realicen más estudios.
Calidad de la evidencia
La calidad de la evidencia se clasificó según el sistema GRADE. Las pruebas se consideraron de alta calidad para los eventos adversos graves, la mortalidad y el tiempo hasta la normalización de los parámetros de laboratorio. Las pruebas se consideraron de calidad moderada para el riesgo de problemas cardíacos a futuro, la duración de los síntomas clínicos (fiebre, erupción cutánea) y la duración de la estancia hospitalaria. Esto significa que es razonable confiar en que el verdadero efecto se acerca al calculado en este trabajo.
Notas de traducción
La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, email@example.com.
Резюме на простом языке
Применение стероидов для лечения болезни Кавасаки
Мы рассмотрели применение ряда препаратов, известных как стероиды, у детей с болезнью Кавасаки с целью снижения риска будущего поражения сердца, а также их влияние на продолжительность лихорадки, признаки инфекции в крови и число дней, проведенных в больнице.
В настоящее время понимание болезни Кавасаки и лучшего способа ее лечения ограничено. Этот вопрос важен, так как одним из долгосрочных последствий может быть поражение сердца, обусловливающее более высокий риск сокращения жизни у детей.
Доказательства актуальны на ноябрь 2016 года. В этот обзор были включены мальчики и девочки с диагностированной болезнью Кавасаки. Мы выбирали лишь рандомизированные клинические испытания. В испытаниях применение стероидов сравнивалось с их отсутствием. Этот обзор включает 7 испытаний с 922 участниками.
Судя по всему, стероиды снижают риск поражения сердца после болезни Кавасаки, не вызывая каких-либо серьезных побочных эффектов. Они также сокращают продолжительность симптомов (лихорадки и сыпи), длительность госпитализации и уровень маркеров болезни в крови. Отдельные группы, включая группы из Азии, группы с высоким риском и получающие более длительное лечение стероидами, вероятно, получают большую пользу от стероидов, особенно в отношении частоты поражений сердца; однако, чтобы ответить на эти вопросы, необходимы дополнительные исследования. Дополнительные исследования также необходимы для получения более точного маркера риска серьезных побочных эффектов и проверки того факта, что стероиды снижают вероятность смерти. Доказательства, представленные в этом обзоре, позволяют предположить целесообразность длительного курса стероидов у всех детей с болезнью Кавасаки до получения результатов дальнейших исследований.
Качество доказательств оценивали в соответствии с системой GRADE. Качество доказательств по серьезным нежелательным явлениям, смертности и времени нормализации лабораторных показателей было высоким. Качество доказательств по риску будущего поражения сердца, продолжительности клинических симптомов (лихорадки, сыпи) и длительности госпитализации было умеренным. Это означает, что мы вполне уверены в том, что реальный эффект близок к отмеченному в этой работе.
Заметки по переводу
Перевод: Сапукова Юлия. Редактирование: Кукушкин Михаил Евгеньевич. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: firstname.lastname@example.org; email@example.com
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 by Kawasaki 1967, it is a medium vessel vasculitis of unclear aetiology that has been linked with an abnormal host response to an infectious trigger. Generally affecting children less than five years old, peak onset is between 18 and 24 months. The incidence in those aged under 5 years varies widely throughout the world, including 8.4 per 100,000 in the UK, 17.5 per 100,000 to 20.8 per 100,000 in the USA, and 239.6 per 100,000 in Japan (Gardner-Medwin 2002; Harnden 2002; Holman 2003; Nakamura 2012; Singh 2015). 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 infectious agents (Wood 2009).
KD is a multisystem vasculitis but its most important complication involves the predisposition for coronary artery vasculitis leading to aneurysms in up to 25% of untreated patients (Burns 1996). Such complications render the coronary vessels vulnerable to stenoses and thromboses, with subsequent risk of myocardial infarction and death (Daniels 2012). Furthermore, these thromboses act as focus for accelerated KD vasculopathy, increasing 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). Diagnosis is generally based on 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 of five diagnostic criteria are satisfied.
Description of the intervention
It is thought that the prompt and effective treatment of KD can decrease the incidence of its cardiac sequelae. Accepted and proven initial pharmacological management involves intravenous immunoglobulin (IVIG) at a dose of 2 g/kg in a single 12-hour infusion alongside 30 to 50 mg/kg of aspirin 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). Plasma exchange is also used 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 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, while specific, 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).
Resistance to IVIG.
Very young age of onset (< 12 months).
Severe inflammatory markers.
Clinical features of shock.
Existing arterial aneurysms.
Kobayashi score greater than or equal to five.
These high-risk patients have a higher prevalence of coronary aneurysms, especially giant aneurysms (> 8 mm), and have associated greater long-term cardiovascular morbidity and mortality (Tatara 1987). Current consensus on management recommends a repeat dose of IVIG which facilitates disease defervescence in approximately half of the patients (Hashino 2001b). 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 are 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, given steroids (Kato 1979).
There have been recent gains in knowledge regarding the use of corticosteroids in KD. The early use of steroids has been advocated, but only in high-risk patients (as defined above). This acknowledged, it remains unclear how best to use corticosteroids (Chen 2013). A recent editorial has highlighted some of the critical issues with current meta-analyses in this area (Levin 2013). Problems include varying inclusion criteria and populations, differing methodologies of included works and an overall lack of power with respect to data on side effects. It is not currently known which demographic groups show the greatest benefit with respect to coronary sequelae, or if there is the potential for 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. Research into the exact pathological mechanisms is ongoing and current theories of KD pathogenesis implicate immunological responses to infectious 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 and subsequent incidence of future cardiovascular sequelae (Levin 2013). It therefore remains important to ascertain the utility of IVS in KD.
Why it is important to do this review
There is much controversy regarding 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 markers used to indicate resistance to IVIG include very young age of onset (< 12 months), high inflammatory markers, clinical features of shock, existing arterial aneurysms, or a Kobayashi score greater than or equal to five. The utility of corticosteroids 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 corticosteroids the most, for example whether ethnic origin, severity of KD or pre-steroid treatment status may help define the optimum population. It is hoped that the whole group and subgroup analyses of this work will cast greater light on this issue.
To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. Corticosteroids may be given alone or in conjunction with other accepted KD treatments. Secondary objectives assess the effect of steroids on mortality, the time taken for laboratory parameters to normalise, the duration of acute symptoms (such as fever), the long-term impact of steroid use and evaluating their safety in KD and their efficacy in relevant population subgroups.
Criteria for considering studies for this review
Types of studies
We searched all randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation methods are not completely random, for example using alternation). Cross-over trials were not included as the response to steroid intervention may depend on timing and previous treatment state. We excluded all studies not conforming to the RCT format.
Types of participants
We included all children (less than 19 years old) diagnosed with KD worldwide in the analysis. The diagnosis of KD had to fulfil the Diagnostic Guidelines of the Japan KD Research Committee. This requires any five of the following (Ayusawa 2005).
Fever for more than five days, non-responsive to anti-pyrexial agents.
Conjunctivitis: bilateral bulbar, non-suppurative.
Lymphadenopathy: cervical, generally more than 1.5 cm.
Polymorphous exanthem, no crusts or vesicles.
Oral and perioral changes: strawberry tongue, cracked erythematous lips, diffuse oropharyngeal erythema.
Changes in the extremities, either acute (< 2 weeks): erythema and oedema of the palms and soles; or convalescent: desquamation at the fingertips.
An accepted exception to the above for a positive KD diagnosis exists if only four criteria are fulfilled but cardiac complications are found at echocardiography or angiography. We also accepted American Heart Association guideline definitions (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 could 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 had to be in parallel. Cross–over trials were not eligible for inclusion.
Participants with positive blood cultures were excluded.
Types of interventions
All forms of corticosteroid therapy in conjunction with any combination of no treatment, placebo, immunoglobulin, aspirin or infliximab for the treatment of KD were considered the intervention of interest. That stated, the use of corticosteroids had to be the only difference in management between trial arms.
Comparator groups included any of:
immunoglobulin and aspirin;
infliximab and immunoglobulin;
infliximab, immunoglobulin and aspirin.
Types of outcome measures
The incidence of coronary artery abnormalities (measured via diameter or z-scores; Boston scores (de Zorzi 1998)) per study group found at either cardiac angiography or echocardiography within three months of KD diagnosis. Coronary abnormality was defined using either the de Zorzi criteria (a coronary dimension that is ≥ 2.5 standard deviations (SDs) above the mean for body surface area) (de Zorzi 1998); or the Japanese Ministry of Health criteria (Research Committee on Kawasaki Disease 1984), as follows.
Lumen > 3 mm in children < 5 years old;
Lumen > 4 mm in children > 5 years old;
Internal diameter of a segment measuring ≥ 1.5 times that of an adjacent segment.
The incidence of any serious adverse effects per study group that is attributable to the administration of steroids at any point after treatment initiation. Known side effects of steroids in other diseases include, for example, immunosuppression with resultant opportunistic infection and avascular necrosis of the femoral head.
Duration of clinical symptoms: fever and rash.
Time for laboratory parameters to normalise: CRP and ESR.
Length of hospital stay.
Longer-term (greater than one-year post-disease onset) coronary morbidity (non-aneurysmal).
Search methods for identification of studies
We included studies reported as full-text or published as abstract only.
The Cochrane Vascular Information Specialist (CIS) searched the following databases for relevant trials:
The Cochrane Vascular Specialised Register (searched 25 November 2016);
The Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) in the Cochrane Library (searched 25 November 2016).
See Appendix 1 for details of the search strategy used to search CENTRAL.
The Cochrane Vascular Specialised Register is maintained by the CIS and is constructed from weekly electronic searches of MEDLINE Ovid, Embase Ovid, 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 Vascular module in the Cochrane Library (www.cochranelibrary.com).
The CIS searched the following trial registries for details of ongoing and unpublished studies;
See Appendix 2 for details of the search strategies used.
Searching other resources
We contacted the authors of trials that met the eligibility criteria identified by the searches as ongoing or unpublished trials. We also searched reference lists of relevant trials for further publications.
Data collection and analysis
Selection of studies
Two review authors (MJS and GMC) independently applied the selection criteria to the studies identified by the search strategy. This included independently assessing whether the studies fulfilled the inclusion and exclusion criteria. If insufficient information was available to decide whether a study was truly eligible we contacted the study authors to request further information. A third review author (AJW) resolved disagreements.
Data extraction and management
Two review authors (MJS and GMC) independently extracted data using a modified version of the Cochrane Vascular standard data extraction form. These data were then brought together and monitored for discrepancies by a third review author (AJW), before being entered into Review Manager 5 software (RevMan 2014). We contacted study authors for any required information that was not included in the published works. The key information gathered in the data collection form included the following.
General study information: publication type.
Fulfilment of eligibility criteria: study type, interventions, outcomes measured and reasons for exclusion.
Study methods: allocations methods, study dates, duration, ethical approval and statistical methods.
Participants: methods of recruitment, consent, total number, treatment groups, age, sex, race, KD severity, subgroup analyses reported and eligibility criteria.
Intervention (steroids): number of participants, dosing, frequency, duration, delivery method, providers, compliance and concomitant treatment.
Outcomes: coronary diameters (acute), coronary diameter z-scores (acute), coronary abnormality (long term), duration of clinical symptoms (e.g. fever), adverse effects, duration of laboratory parameter abnormality (e.g. CRP) and duration of hospital stay.
Assessment of risk of bias in included studies
Risk of bias was assessed using the recommended Cochrane tool as described in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors (MJS and GMC) performed this independently, and resolved any disagreements by discussion with a third review author (AJW). The domains assessed included:
sequence generation (selection bias);
allocation sequence concealment (selection bias);
blinding of participants and personnel (performance bias);
blinding of outcome assessment (detection bias);
incomplete outcome data (attrition bias);
selective outcome reporting (reporting bias);
Measures of treatment effect
The effect measure of choice for dichotomous data was the odds ratio (OR) with a 95% confidence interval (CI). This is a ratio between the corticosteroid intervention group and its parallel comparator group.
We managed continuous data, including time-to-event data, using mean differences (MD) and 95% CIs. If necessary, we planned to use a standardised mean difference (SMD) for studies that measured the same outcome but used different methods.
Unit of analysis issues
The unit of analysis was each participant recruited into a trial.
Dealing with missing data
We accounted for all missing data due to dropouts via an intention-to-treat (ITT) analysis. We reported if the individual trials carried this out. If they did not then we have endeavoured to apply an ITT analysis. In the event that we have been unable to do this then we utilised a per protocol analysis. We have explained all post-allocation dropouts. We have followed up any data missing from the published document with the study’s original authors. If data still remain absent then we have considered this in the 'Risk of bias' assessments.
Assessment of heterogeneity
We took heterogeneity into account using the I² statistic for quantification of variability (< 40% = likely low heterogeneity; 40% to 60% = possible moderate heterogeneity; > 60% = possible significant heterogeneity). We also used the Chi² test (limit = degrees of freedom) and P values (10% significance threshold). Where heterogeneity exceeded generally accepted limits (> 60% heterogeneity) we subgrouped the analysis in a logical manner to explain these differences and reduce remaining heterogeneity. These methods were reinforced by visual recognition on forest plots to assess for overlapping CIs.
Assessment of reporting biases
Had there been more than eight trials, we planned to screen for publication and reporting bias using funnel plot asymmetry and measure using tests as outlined in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For smaller studies, we took 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 also tried 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 has taken into account selective outcome reporting.
Statistical analysis took place using a fixed-effect model if there was low heterogeneity, and a random-effects model if there was significant heterogeneity (I² > 60%). We undertook outcome analyses using an ITT model. Two-sided P values less than or equal to 0.05 were considered significant and all analyses were undertaken using Review Manager 5 (RevMan 2014).
Subgroup analysis and investigation of heterogeneity
Planned subgroup analyses (data permitting) included:
type of steroid used;
steroid treatment frequency;
total steroid treatment duration;
steroid route of administration;
first-line versus second-line management;
geographical distribution of trial participants, ethnicity;
KD severity (non-high risk versus high risk as detailed earlier);
recognised concomitant treatments for KD (as detailed earlier in the text).
We also looked at employing further subgroup analyses if heterogeneity remained significant (I² > 60%). These subgroups were tested using a Chi² P value threshold of 0.05.
We planned to perform a sensitivity analysis to explore causes of heterogeneity and the robustness of the results if there were sufficient data available. We planned to include the following factors in the sensitivity analysis.
Type of study design (RCT versus quasi-RCT).
Low risk of bias trials versus high risk of bias trials.
Rates of dropouts for each treatment group.
Summary of findings
We presented the main findings of the review results concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the outcomes (Types of outcome measures) in a 'Summary of findings' table, according to the GRADE principles as described by Higgins 2011 and Atkins 2004. We used the GRADEpro (GRADEproGDT) software (www.guidelinedevelopment.org/) to assist in the preparation of the 'Summary of findings' table.
Summary of main results
Pooled data show that the use of steroids in the acute phase of KD in children can lead to reduced incidence of coronary artery aneurysms, duration of clinical symptoms (fever, rash), time for laboratory parameters to normalise (CRP, ESR) and length of hospital stay. There were insufficient data available regarding incidence of adverse effects attributable to steroids, mortality and long-term (> 1 year) coronary morbidity.
Subgroup analysis demonstrated that with respect to coronary abnormality:
the greatest benefit was in children in Japan versus those in North America, but the use of different regimens may have contributed to the different outcomes in Japanese and American studies;
the greatest benefit was in children with high-risk scores versus those with low-risk scores, although both display benefit;
there is a benefit of steroids if taken over a prolonged course versus the potential for no benefit if steroids are given as a one-off dose.
However, potential confounding of the subgroup analyses must be noted here – those studies completed in North America are both considered part of the lower-risk group and employed single-dose regimens (Newburger 2007; Sundel 2003).
Subgroup analysis demonstrated that with respect to duration of clinical symptoms both groups with high- and low-risk scores benefit from steroid treatment, with the greatest benefit in those with high-risk scores although the numbers of studies and participants on which this is based are small.
Overall completeness and applicability of evidence
All studies in this review collected data on the stated primary outcomes of this review: coronary artery abnormalities and serious adverse events attributable to steroids use. All relevant participants, interventions and outcomes have been investigated. Overall, the evidence collected is highly applicable to this review. The evidence demonstrates that steroids have some benefit in the acute treatment of KD in the populations studied in this review. That stated, further data looking at different ethnicity subgroups, disease risk scores, and duration of steroid use are required for a more complete guide. In particular, an investigation outside Japan employing risk stratification and IV steroid treatment followed by oral doses would be beneficial.
None of the studies demonstrated any serious adverse events during their follow-up periods due to the use of steroids.
Difficulties remain with the application of the results of this review to Western populations, where there is no comparable severity risk score. The identification of groups who might gain the greatest benefit from steroids will remain problematic until a reliable risk stratification score is developed for this group.
Overall the results of this review are applicable to the majority of children worldwide diagnosed with KD, and should serve as a guide to the treating clinician.
Quality of the evidence
See Summary of findings for the main comparison
All studies included in this meta-analysis were randomised trials, with variable incidence in the blinding of participants and outcome assessors. However, we do not believe the risks of bias identified in this work would affect the direction of the reported outcome variables. Trials reported data using a mixture of per protocol and intention-to-treat analyses. The overall quality of the current evidence can be considered moderate. This is represented by several inconsistencies in the different findings incorporated within this review.
We graded evidence quality according to the GRADE system. We considered evidence was high quality for the incidence of adverse events, mortality and time for laboratory parameters to normalise. We considered evidence was moderate for the incidence of coronary artery abnormalities, duration of clinical symptoms (fever, rash) and length of hospital stay. We downgraded coronary artery abnormality evidence as subgroup analysis suggests that those with low-risk scores or receiving single-dose treatment may not have benefit. We downgraded 'duration of clinical symptoms' due to the large heterogeneity. We downgraded 'length of hospital stay' as only one very small study recorded this outcome. Subgroup analysis suggests that those with low-risk scores or receiving single-dose treatment may not have benefit.
Overall, this means that we are reasonably confident that the true effect is close to that estimated in this work.
Potential biases in the review process
There are no known biases to disclose in the implementation of this review. There were no limitations within the search and this study followed the predefined protocol following Cochrane guidelines.
Agreements and disagreements with other studies or reviews
The results of this review reflect the shifting paradigm regarding the use of steroids in KD and show that steroids are beneficial in the treatment of KD, fitting with their use in other vasculitic diseases. The included studies suggest that steroids enhance the resolution of fever and inflammatory markers and are associated with improved coronary artery outcomes. This is thought to be due to suppression of the inflammatory reaction in KD that causes the coronary artery abnormalities (influx of neutrophils, large mononuclear cells and lymphocytes which destroy the internal elastic lamina, followed by myofibroblast proliferation causing a coronary aneurysm (Eleftheriou 2013)). In addition, other recent systematic reviews on this question have come to similar conclusions on the efficacy of steroids for KD (Chen 2013; Zhu 2012).
Appendix 1. CENTRAL search strategy
|#1||MESH DESCRIPTOR Mucocutaneous Lymph Node Syndrome EXPLODE ALL TREES||74|
|#3||(mucocutaneous near5 syndrome):TI,AB,KY||121|
|#4||#1 OR #2 OR #3||193|
|#5||MESH DESCRIPTOR Glucocorticoids EXPLODE ALL TREES||13302|
|#7||(corticosteroid* or corticoid* or glucocorticoid*):TI,AB,KY||15794|
|#14||#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13||44334|
|#15||#4 AND #14||48|
Appendix 2. Trials' registries searches
69 records for 65 trials found Kawasaki clinical trials in children
86 studies found for Kawasaki/Child
4 results found for Kawasaki
Appendix 3. Glossary of terms
|Aetiology||Cause of a condition|
|Defervesence||The abatement of a fever|
|Desquamation||Loss of the outermost layer of a surface|
|Erythematous||Reddening - a term generally reserved for the skin|
|Exanthem||A virus known to be associated with a rash|
|Mucocutanoeous||Type of bodily surface, such as that inside the mouth|
|Oropharyngeal||Area of the body encompassing the mouth and throat|
|Polymorphous rash||Rash of varying appearance|
|Stenosis||Restriction in the diameter of a vessel|
|Thrombosis||The formation of a blood clot within a blood vessel|
Contributions of authors
AJW was involved in the conception, creation and reviewing of the protocol. AJW is the guarantor of the review. AJW and MJS were involved in the drafting of the protocol and identification of studies. GMC and AJW performed the analysis. RMRT was involved in the final reviewing and re-drafting of the review for submission.
Declarations of interest
AJW: none known
GMC: none known
MJS: none known
RMRT: none known
Differences between protocol and review
In conducting this study it was decided that we would refer to coronary 'aneurysms' in the context of coronary 'abnormalities'. This is due to a wide variation in the literature, including trials included in this review, as to what the definition of an aneurysm is.
Odds ratio was used instead of risk ratio to report dichotomous data, in line with standard statistical analysis.
We renamed the outcome 'incidence of any adverse effects...' to 'incidence of serious adverse events' to reflect more accurately the side effects we intended to study.
This review replaces the withdrawn protocol 'Steroid hormone treatment for Kawasaki disease in children' (Jones 2014).