Corticosteroids for the treatment of Kawasaki disease in children

  • Review
  • Intervention

Authors


Abstract

Background

Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in the developed world. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids.

Objectives

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 include 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.

Search methods

The Cochrane Vascular Information Specialist searched Cochrane Vascular's Specialised Register (25 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) in the Cochrane Library (searched 25 November 2016). Trial registries were also searched for details of ongoing or unpublished studies.

Selection criteria

We selected randomised trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroid and different durations of treatment.

Data collection and analysis

MJS and GMC independently selected studies, assessed evidence quality and extracted data. This process was overseen by AJW.

Main results

Seven trials consisting of 922 participants were included in this analysis. Trials ranged from 32 to 242 participants. On pooled analysis, corticosteroids reduced the subsequent occurrence of coronary artery abnormalities (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.18 to 0.46; 907 participants; 7 studies; I² = 55%) without resultant serious adverse events (no events, 737 participants) and mortality (no events, 915 participants). In addition, corticosteroids reduced the duration of fever (mean difference (MD) −1.65 days, 95% CI −3.31 to 0.00; 210 participants; 2 studies; I² = 88%), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD −2.80 days, 95% CI −4.38 to −1.22; 178 participants; 1 study) and length of hospital stay (MD −1.41 days, 95% CI −2.36 to −0.46; 39 participants; 1 study). No studies detailed outcomes beyond 24 weeks. Subgroup analysis showed some potential groups that may benefit more than others; however, further randomised controlled trials are required before this can be the basis for clinical action.

Evidence quality was graded according to the GRADE system. Evidence was considered high quality for the incidence of serious adverse events, mortality and time for laboratory parameters to normalise. Evidence was considered moderate for the incidence of coronary artery abnormalities due to potential inconsistencies in data geography and patient benefits according to grouping. Evidence was moderate for duration of clinical symptoms (fever, rash) due to potential subjectivity in measurement. Evidence was moderate for length of hospital stay as only one study recorded this outcome. This means that we are reasonably confident that the true effect is close to that estimated in this work.

Authors' conclusions

Moderate-quality evidence shows that use of steroids in the acute phase of KD can be associated with improved coronary artery abnormalities, shorter duration of hospital stay and a decreased duration of clinical symptoms. High-quality evidence shows reduced inflammatory marker levels. There were insufficient data available regarding incidence of adverse effects attributable to steroids, mortality and long-term (> 1 year) coronary morbidity. 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. Evidence presented in this study suggests that treatment with a long course of steroids should be considered for all children diagnosed with KD until further studies are performed.

Resumen

Corticosteroides para el tratamiento de la enfermedad de Kawasaki en niños

Antecedentes

La enfermedad Kawasaki (EK) o síndrome mucocutáneo es la principal causa de cardiopatía adquirida en la niñez en países desarrollados. Existe mucha polémica acerca del mejor tratamiento para los niños con EK y en particular quiénes pueden beneficiarse con el tratamiento adicional además de la inmunoglobulina intravenosa (IgIV) y la aspirina estándar, como el agregado de corticosteroides.

Objetivos

Evaluar la repercusión de la administración de corticosteroides en la incidencia de anomalías de la arteria coronaria en la EK como tratamiento de primera o segunda línea. Los corticosteroides pueden administrarse solos o con otros tratamientos aceptados para la EK. Los objetivos secundarios son: el efecto de los corticosteroides en la mortalidad, el tiempo hasta la normalización de los parámetros de laboratorio, la duración de los síntomas agudos (como la fiebre), la repercusión a largo plazo del uso de corticosteroides y la evaluación de la seguridad en la EK y la eficacia en subgrupos relevantes de la población.

Métodos de búsqueda

El especialista en información del Grupo Cochrane Vascular (Cochrane Vascular Information Specialist) buscó en el registro especializado del Grupo Cochrane Vascular (Cochrane Vascular's Specialised Register) (25 noviembre 2016) y en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; 2016, número 10) en la Cochrane Library (búsqueda 25 noviembre 2016). También se realizaron búsquedas en registros de ensayos para obtener detalles de estudios en curso o no publicados.

Criterios de selección

Se seleccionaron los ensayos aleatorios que incorporaron niños con EK de cualquier gravedad, tratados con corticosteroides, incluidos diferentes tipos de corticosteroides y diferentes duraciones de tratamiento.

Obtención y análisis de los datos

MJS y GMC de forma independiente, seleccionaron los estudios, evaluaron la calidad de las pruebas y extrajeron los datos. Este proceso fue supervisado por AJW.

Resultados principales

Se incluyeron en este análisis siete ensayos con 922 participantes. Los ensayos variaron de 32 a 242 participantes. En el análisis agrupado, los corticosteroides redujeron la aparición posterior de anomalías de la arteria coronaria (odds ratio [OR] 0,29; intervalo de confianza [IC] del 95%: 0,18 a 0,46; 907 participantes; siete estudios; I² = 55%) sin eventos adversos graves (ningún evento, 737 participantes) y mortalidad (ningún caso, 915 participantes). Además, los corticosteroides redujeron la duración de la fiebre (diferencia de medias [DM] −1,65 días, IC del 95%−3,31 a 0,00; 210 participantes; dos estudios; I² = 88%), el tiempo hasta la normalización de los parámetros de laboratorio (velocidad de eritrosedimentación [VES] y proteína C reactiva [PCR]) (DM −2,80 días, IC del 95%: −4,38 a −1,22; 178 participantes; 1 estudio) y la duración de la estancia hospitalaria (DM −1,41 días, IC del 95%: −2,36 a −0,46; 39 participantes; un estudio). Ningún estudio dio detalles sobre los resultados más allá de las 24 semanas. El análisis de subgrupos mostró algunos grupos potenciales que pueden beneficiarse más que otros; sin embargo, se necesitan más ensayos controlados aleatorios antes de que ésta pueda ser la base para la práctica clínica.

La calidad de la evidencia se clasificó según el sistema GRADE. Las pruebas se consideraron de alta calidad para la incidencia de eventos adversos graves, la mortalidad y el tiempo hasta la normalización de los parámetros de laboratorio. Las pruebas se consideraron moderadas para la incidencia de anomalías de la arteria coronaria debido a las incongruencias potenciales en la geografía de datos y los beneficios de los pacientes según el agrupamiento. Las pruebas fueron moderadas para la duración de los síntomas clínicos (fiebre, erupción cutánea) debido a la subjetividad potencial en la medición. Las pruebas fueron moderadas para la duración de la estancia hospitalaria ya que sólo un estudio registró este resultado. Esto significa que es razonable confiar en que el verdadero efecto se acerca al calculado en este trabajo.

Conclusiones de los autores

Las pruebas de calidad moderada indican que la administración de corticosteroides en la fase aguda de la EK puede asociarse con una mejoría en las anomalías de la arteria coronaria, una duración más corta de la estancia hospitalaria y una menor duración de los síntomas clínicos. Las pruebas de alta calidad muestran una reducción de los niveles de marcadores inflamatorios. Se disponía de datos insuficientes con respecto a la incidencia de los efectos adversos atribuibles a los corticosteroides, la mortalidad y la morbilidad coronaria a largo plazo (> 1 año). 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. Las pruebas presentadas en este estudio 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.

Plain language summary

Using steroids to treat Kawasaki disease

Review question

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.

Background

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.

Study characteristics

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.

Key results

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.

Laički sažetak

Kortikosteroidi za liječenje Kawasakijeve bolesti u djece

Istraživačko pitanje

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.

Dosadašnje spoznaje

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.

Ključni rezultati

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

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.

Bilješke prijevoda

Hrvatski Cochrane
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: cochrane_croatia@mefst.hr

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.

Antecedentes

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.

Resultados clave

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, cochrane@infoglobal-suport.com.

Резюме на простом языке

Применение стероидов для лечения болезни Кавасаки

Вопрос обзора

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.

Актуальность

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.

Характеристика исследований

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.

Основные результаты

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

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: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Summary of findings table: Corticosteroids versus no corticosteroid use for treatment if Kawasaki disease in children
  1. 1 Further investigation to reduce potential confounding required to explain inconsistencies in data (i.e. geographical variation), however overall effect unlikely to change (likely beneficial)
    2 Downgraded by one level: large group and effect size, however subgroup analysis suggests that those with low-risk scores or receiving single-dose treatment may not benefit
    3 Downgraded by one level: significant heterogeneity within the data, likely due to the subjective nature of the included outcome (i.e. rash)
    4 Downgraded by one level: length of hospital stay measured in one small study only (n = 39)

Corticosteroids versus no steroid use for the treatment of Kawasaki disease in children
Patient or population: children diagnosed with Kawasaki disease
Setting: hospital-based
Intervention: corticosteroids
Comparison: no corticosteroid use
OutcomesAnticipated absolute effects* (95% CI)Relative effect
(95% CI)
№ of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Risk with no corticosteroid useRisk with corticosteroids

Incidence of coronary artery abnormalities

Duration: 2 to 6 weeks

Study populationOR 0.29
(0.18 to 0.46)
907
(7 RCTs)
⊕⊕⊕⊝
MODERATE1, 2
 
168 per 100056 per 1000
(35 to 85)
Moderate
114 per 100036 per 1000
(23 to 56)

Incidence of serious adverse effects attributable to steroid use

Duration: 2 to 6 weeks

Study populationnot estimable737
(6 RCTs)
⊕⊕⊕⊕
HIGH
No cases of adverse events attributable to steroids use are recorded by the included studies
see comments

Mortality (all-cause)

Duration: 2 to 6 weeks

Study populationnot estimable915
(7 RCTs)
⊕⊕⊕⊕
HIGH
No deaths are recorded by the included studies
see comments

Duration of clinical symptoms: fever, rash (days)

Duration: N/A

-The mean duration of clinical symptoms (fever, rash) in the intervention group was 0.97 days fewer (1.2 fewer to 0.74 fewer)-210
(2 RCTs)
⊕⊕⊕⊝
MODERATE3
 

Time for laboratory parameters to normalise: CRP, ESR (days)

Duration: N/A

-The mean time for laboratory parameters (CRP, ESR) to normalise in the intervention group was 2.8 days fewer (4.38 fewer to 1.22 fewer)-178
(1 RCT)
⊕⊕⊕⊕
HIGH
 

Length of hospital stay (days)

Duration: N/A

-The mean length of hospital stay in the intervention group was 1.41 days fewer (2.36 fewer to 0.46 fewer)-39
(1 RCT)
⊕⊕⊕⊝
MODERATE4
 

Longer-term (> 1 year post disease onset) coronary morbidity (non-aneurysmal)

Duration: N/A

see commentsee commentsee commentsee commentNone of the included studies included data on outcomes (including coronary morbidity (non-aneurysmal) > 1 year after study enrolment
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; OR: Odds ratio; RCT: randomised controlled trial
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

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 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).

  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 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.

Objectives

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.

Methods

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).

  1. Fever for more than five days, non-responsive to anti-pyrexial agents.

  2. Conjunctivitis: bilateral bulbar, non-suppurative.

  3. Lymphadenopathy: cervical, generally more than 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 (< 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:

  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
  • 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.

    1. Lumen > 3 mm in children < 5 years old;

    2. Lumen > 4 mm in children > 5 years old;

    3. 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.

Secondary outcomes
  1. Mortality (all-cause).

  2. Duration of clinical symptoms: fever and rash.

  3. Time for laboratory parameters to normalise: CRP and 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

We included studies reported as full-text or published as abstract only.

Electronic searches

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.

  1. General study information: publication type.

  2. Fulfilment of eligibility criteria: study type, interventions, outcomes measured and reasons for exclusion.

  3. Study methods: allocations methods, study dates, duration, ethical approval and statistical methods.

  4. Participants: methods of recruitment, consent, total number, treatment groups, age, sex, race, KD severity, subgroup analyses reported and eligibility criteria.

  5. Intervention (steroids): number of participants, dosing, frequency, duration, delivery method, providers, compliance and 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 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:

  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 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.

Data synthesis

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:

  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 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.

Sensitivity analysis

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.

  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.

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.

Results

Description of studies

Results of the search

See Figure 1.

Figure 1.

Study flow diagram.

Included studies

See Characteristics of included studies.

After applying the aforementioned inclusion and exclusion criteria, we identified seven trials (14 reports) suitable for inclusion within this review (Ikeda 2006; Inoue 2006; Kobayashi 2012; Newburger 2007; Ogata 2012; Okada 2003; Sundel 2003). This process is summarised in a flow diagram (Figure 1). Full-text publications were obtained from the websites of the original source of publication. When studies had multiple publications, data were combined in order to give as complete an interpretation of available data as possible.

Two trials were conducted in North America (Newburger 2007; Sundel 2003); and five in Japan (Ikeda 2006; Inoue 2006; Kobayashi 2012; Ogata 2012; Okada 2003). Three trials were single centre (Ikeda 2006; Ogata 2012; Sundel 2003); and four trials were multicentre (Inoue 2006; Kobayashi 2012; Newburger 2007; Okada 2003).

The seven trials consisted of 922 participants and ranged from 32 to 242 participants. Three studies segmented high-risk participants using criteria as set out in Table 1 (Ikeda 2006; Kobayashi 2012; Ogata 2012).

Table 1. High-risk subjects' criteria
  1. ALT: alanine transaminase
    CRP: C-reactive protein
    IVIG: intravenous immunoglobulin
    KD: Kawasaki disease

StudyHigh risk criteria
Ikeda 2006Developed own risk score based upon IVIG unresponsiveness in a multiple logistic regression analysis. 42/178 randomly identified KD patients were deemed high risk.
Kobayashi 2012Kobayashi risk score of 5 or greater (≤ 4 days fever pre-diagnosis, ≤ 12 years old, CRP ≥ 10 mg/dL, ≤ 300 platelets, ALT ≥ 100, sodium ≤ 133, neutrophils ≥ 80%)
Ogata 2012Egami score of 3 or greater (≤ 6 months old, ≤ 4 days fever pre diagnosis, ≤ 300 platelets, CRP ≥ 7 mg/dL, ALT ≥ 80)

Coronary artery abnormality was the primary outcome in four studies (Ikeda 2006; Inoue 2006; Kobayashi 2012; Newburger 2007). Duration of fever was the primary outcome in two studies (Ogata 2012; Sundel 2003). Cytokine levels was the primary outcome in one study (Okada 2003).

Further details including dosing and baseline characteristics can be found in Characteristics of included studies.

Excluded studies

See Characteristics of excluded studies.

Fourteen studies (17 reports) were excluded from the review (Asai 1985; Hashino 2001; ISRCTN74427627; Jibiki 2005; Kato 1979; Kusakawa 1983; Miura 2008; Nakamura 1985; Nonaka 1995; Ogata 2009; Sekine 2012; Seto 1983; Xu 2002; Yuan 2000).

Six studies did not assess the outcomes of this review (Jibiki 2005; Miura 2008; Nakamura 1985; Ogata 2009; Sekine 2012; Yuan 2000). Attempts were made to contact the study authors without success. For four studies, study outcome data were not available and again study authors were contacted without success (ISRCTN74427627; Kato 1979; Kusakawa 1983; Nonaka 1995). Hashino 2001 was excluded due to trial design affecting the comparability of results with the included works. Two studies combined steroids with an additional intervention meaning steroids were not the only differential factor between the trial arms (Asai 1985; Xu 2002).

One trial is ongoing and there are currently no suitable data available for review (JPRN-UMIN000009524).

Risk of bias in included studies

All included studies were assessed for bias as illustrated in Figure 2 and Figure 3 and Characteristics of included studies.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All included studies are randomised controlled trials (Ikeda 2006; Inoue 2006; Kobayashi 2012; Newburger 2007; Ogata 2012; Okada 2003; Sundel 2003).

Random sequence generation

Three studies were deemed to be of low risk of bias from random sequence generation due to the use of recognised and accepted approaches to this step (e.g. use of computer generation) (Kobayashi 2012; Ogata 2012; Okada 2003). Four studies were deemed to be of unclear risk of bias because although the use of random allocation was stated, there was no detail regarding the exact approach (Ikeda 2006; Inoue 2006; Newburger 2007; Sundel 2003).

Allocation concealment

Four studies were deemed of unclear bias for allocation concealment due to inadequate detail being published (Ikeda 2006; Newburger 2007; Ogata 2012; Sundel 2003). Three were regarded as low risk of allocation disclosure due to the use of centrally held databases (Inoue 2006; Kobayashi 2012; Ogata 2012).

Blinding

Five trials were non-blinded (Inoue 2006; Kobayashi 2012; Ogata 2012; Okada 2003; Sundel 2003); one trial was double blinded (Newburger 2007); and one trial did not state whether participants or investigators were blinded (Ikeda 2006). Therefore six studies were deemed at unclear risk of performance bias (Ikeda 2006; Inoue 2006; Kobayashi 2012; Ogata 2012; Okada 2003; Sundel 2003), and one study was deemed at low risk of performance bias (Newburger 2007).

Four studies had blinded outcome reporters and are coded as low risk of bias (Kobayashi 2012; Newburger 2007; Ogata 2012; Sundel 2003); one study had non-blinded outcome reporters (Inoue 2006); and two studies did not mention if outcome reporters were blinded and was therefore judged as 'unclear' for detection bias (Ikeda 2006; Okada 2003).

Incomplete outcome data

Intention-to-treat analysis was mentioned in two studies (Kobayashi 2012; Newburger 2007). Inoue 2006 reported key outcome variables as per protocol analysis with an intention-to-treat analysis also performed. Three further studies were able to account for all or most of the data (Ogata 2012; Okada 2003; Sundel 2003). These were all judged to be of low risk of bias. One study did not state how data were handled and was therefore coded as unclear risk of bias (Ikeda 2006).

All trials had a relatively short follow-up period, up to five weeks, so there was limited loss to follow-up, which is consistent throughout the studies. No study had a dropout rate exceeding 20%.

Selective reporting

The protocol for one study was published before initiation of the trial (Newburger 2007). The published methodology including outcome measures reported by the remainder of the trials was consistent with that reported in the respective results section (Ikeda 2006; Inoue 2006; Kobayashi 2012; Ogata 2012; Okada 2003; Sundel 2003). The risk of selective reporting bias for these studies has therefore been coded as low.

Other potential sources of bias

None noted.

Effects of interventions

See: Summary of findings for the main comparison Summary of findings table: Corticosteroids versus no corticosteroid use for treatment if Kawasaki disease in children

Primary outcomes

Incidence of coronary artery abnormality

Seven trials on 907 participants assessed incidence of coronary artery abnormality (Ikeda 2006; Inoue 2006; Kobayashi 2012; Newburger 2007; Ogata 2012; Okada 2003; Sundel 2003). The pooled data of steroid use versus no steroid use demonstrate an OR of 0.29 (95% CI 0.18 to 0.46, P < 0.00001) (Analysis 1.1). There was possible moderate heterogeneity of 55% and this was reduced in subgroup analysis (see below).

Incidence of serious adverse events attributable to steroid use

From six trials with 737 participants, no serious adverse events attributable to corticosteroid use were noted and the effects were deemed not estimable (Analysis 1.2) (Inoue 2006; Kobayashi 2012; Newburger 2007; Ogata 2012; Okada 2003; Sundel 2003). Ikeda 2006 did not disclose sufficient information for inclusion despite attempts to contact the authors.

Secondary outcomes

Mortality (all cause)

From the seven trials with 915 participants no deaths were recorded within the observed study period (Analysis 1.3) (Ikeda 2006; Inoue 2006; Kobayashi 2012; Newburger 2007; Ogata 2012; Okada 2003; Sundel 2003).

Duration of clinical symptoms: fever, rash

Two studies reported data on the duration of clinical symptoms (days), showing a significant reduction in time (MD −1.65 days, 95% CI −3.31 to 0.00; participants = 210; studies = 2; I² = 88%; P = 0.05) (Inoue 2006; Okada 2003). There was possible significant heterogeneity at 88% which was not explained by subgroup analysis for high- and low-risk scores (Analysis 4.2). In both studies a child was considered afebrile if their temperature was below 37.5 °C for more than 24 hours; Inoue 2006 measured axillary temperature and Okada 2003 simply measured "body temperature", but does not state the site. This may account for the heterogeneity as body temperature can vary depending on measurement site.

Time for laboratory parameters to normalise: CRP, ESR

One study involving 178 participants directly measured the time for laboratory parameters to normalise (Inoue 2006). Analysis showed a MD of −2.80 days (95% CI −4.38 to −1.22; P = 0.0005) in the steroid group versus the non-steroid group (Analysis 1.5).

Length of hospital stay

One study reported on the length of hospital stay with steroid use versus non-steroid use and demonstrated a reduction in days stayed in hospital (MD −1.41 days, 95% CI −2.36 to −0.46; participants = 39; P = 0.004) (Analysis 1.6) (Sundel 2003).

Longer-term (> 1 year post disease onset) coronary morbidity

None of the included studies included data on outcomes (including coronary morbidity (non-aneurysmal) more than 1 year after study enrolment.

Subgroup analysis

Planned subgroup analyses are listed below with comments on the ability for them to be performed.

  1. Type of steroid used: this subgroup analysis was performed for the outcome coronary artery abnormalities in six of the included studies (Inoue 2006; Kobayashi 2012; Newburger 2007; Ogata 2012; Okada 2003; Sundel 2003), where the type and duration of steroid used was stated. When looking at the use of steroids as a single intravenous (IV) dose there was no evidence of effect with regards to coronary artery abnormalities (OR 0.56, 95% CI 0.29 to 1.08; participants = 277; studies = 3; I² = 36%) (Newburger 2007; Okada 2003; Sundel 2003). When this was followed with an oral course of steroids fewer coronary artery abnormalities were identified in the corticosteroid group (OR 0.13, 95% CI 0.05 to 0.32; participants = 452; studies = 3; I² = 0%) (Inoue 2006; Kobayashi 2012; Okada 2003). The P value for the test for subgroup differences is 0.009. Subgroupings explained the heterogeneity identified for the combined analysis (Analysis 2.1).

  2. Steroid dosing: this subgroup analysis was not applicable as steroid dosing was broadly classed into one-off IV methylprednisolone, or a longer tapering course of prednisolone, and the subgroup analysis for this was performed in the subgroup analysis 1 above.

  3. Steroid treatment frequency: this subgroup analysis was not applicable as steroid dosing was broadly classed into one-off IV methylprednisolone, or a longer tapering course of prednisolone, and the subgroup analysis for this was performed in the subgroup analysis 1 above.

  4. Total steroid treatment duration: this subgroup analysis was not applicable as steroid dosing was broadly classed into one-off IV methylprednisolone, or a longer tapering course of prednisolone, and the subgroup analysis for this was performed in the subgroup analysis 1 above.

  5. Steroid route of administration: this subgroup analysis was not applicable as steroid dosing was broadly classed into one-off IV methylprednisolone, or a longer tapering course of prednisolone. All steroids in the initial phase were given intravenously, and the subgroup analysis for this was performed in the subgroup analysis 1 above.

  6. First-line versus second-line management: there were insufficient data to perform this subgroup analysis.

  7. Geographical distribution of trial participants, ethnicity: this subgroup analysis found that the use of steroids appears to have an increased beneficial effect on coronary artery abnormalities in the studies conducted in Japan (Ikeda 2006; Inoue 2006; Kobayashi 2012; Ogata 2012; Okada 2003; OR 0.14, 95% CI 0.07 to 0.29, 678 participants) versus no evidence of benefit in North America (Newburger 2007; Sundel 2003; OR 0.77, 95% CI 0.37 to 1.59, 229 participants). The P value for test for subgroup differences is 0.001; however it is important to note that this analysis is vulnerable to confounding as most participants who received a one-off dose of steroid were from the North American cohorts (Analysis 3.1).

  8. KD severity (non-high risk versus high risk as detailed earlier): on analysis of high-risk participants only there is strong evidence of effect (OR 0.13, 95% CI 0.06 to 0.29; participants = 377; studies = 3; I² = 0%) (Ikeda 2006; Kobayashi 2012; Ogata 2012). When looking at low-risk participants alone the benefit was weaker and potentially lost (OR 0.53, 95% CI 0.29 to 1.00; participants = 530; studies = 5; I² = 6%) (Ikeda 2006; Inoue 2006; Newburger 2007; Okada 2003; Sundel 2003). These groups proved to be significantly different (P = 0.007). In both subgroups heterogeneity was reduced to negligible levels (Analysis 4.1).

  9. Recognised concomitant treatments for KD (as detailed earlier in the text): there were insufficient data to perform this subgroup analysis.

Sensitivity analysis and reporting bias

A sensitivity analysis was not required for this review as all studies were randomised controlled trials, no studies were found to have a significant risk of bias and dropout rates were not significantly different between studies.

As there were only seven trials included in this Cochrane Review, we have not screened for publication and reporting bias by assessing funnel plot asymmetry using tests as outlined in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Discussion

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).

Authors' conclusions

Implications for practice

Moderate-quality evidence shows that use of steroids in the acute phase of KD can be associated with improved coronary artery abnormalities, shorter duration of hospital stay and a decreased duration of clinical symptoms. High-quality evidence shows improved rates of reduced inflammatory markers with the use of steroids. There were insufficient data available regarding incidence of adverse effects attributable to steroids, mortality and long-term (> 1 year) coronary morbidity during the study periods included in this analysis.

There appears to be an increased benefit to patients of Japanese origin, higher risk score and receiving a prolonged course of steroids. That stated, there is a risk of confounding in these conclusions. Therefore more tests are needed to answer these questions. Evidence presented in this study suggests that treatment with a long course of steroids should be considered for all children diagnosed with KD until further studies are performed.

Implications for research

This meta-analysis partially answers the question of the utility of steroids in the treatment of the acute phase of KD. However, the follow-up periods were generally short and data are lacking to ascertain the long-term benefit for patients.

Further trials and increased follow-up of previous trials is required to evaluate the longer-term implications of steroid use in KD. More trials outside Japan of appropriate steroid use and treatment duration are also required.

Data and analyses

Download statistical data

Comparison 1. Corticosteroids vs no corticosteroid use
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of coronary artery abnormalities7907Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.18, 0.46]
2 Incidence of serious adverse effects attributable to steroid use6737Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Mortality (all-cause)7915Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Duration of clinical symptoms: fever, rash2210Mean Difference (IV, Random, 95% CI)-1.65 [-3.31, 0.00]
5 Time for laboratory parameters to normalise: CRP, ESR1178Mean Difference (IV, Fixed, 95% CI)-2.80 [-4.38, -1.22]
6 Length of hospital stay139Mean Difference (IV, Fixed, 95% CI)-1.41 [-2.36, -0.46]
Analysis 1.1.

Comparison 1 Corticosteroids vs no corticosteroid use, Outcome 1 Incidence of coronary artery abnormalities.

Analysis 1.2.

Comparison 1 Corticosteroids vs no corticosteroid use, Outcome 2 Incidence of serious adverse effects attributable to steroid use.

Analysis 1.3.

Comparison 1 Corticosteroids vs no corticosteroid use, Outcome 3 Mortality (all-cause).

Analysis 1.4.

Comparison 1 Corticosteroids vs no corticosteroid use, Outcome 4 Duration of clinical symptoms: fever, rash.

Analysis 1.5.

Comparison 1 Corticosteroids vs no corticosteroid use, Outcome 5 Time for laboratory parameters to normalise: CRP, ESR.

Analysis 1.6.

Comparison 1 Corticosteroids vs no corticosteroid use, Outcome 6 Length of hospital stay.

Comparison 2. Subgroup: One-off steroid use vs longer course of steroids
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Coronary artery abnormalities6729Odds Ratio (M-H, Fixed, 95% CI)0.30 [0.18, 0.50]
1.1 One-off steroid use3277Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.29, 1.08]
1.2 Longer course of steroids3452Odds Ratio (M-H, Fixed, 95% CI)0.13 [0.05, 0.32]
Analysis 2.1.

Comparison 2 Subgroup: One-off steroid use vs longer course of steroids, Outcome 1 Coronary artery abnormalities.

Comparison 3. Subgroup: Geography
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Coronary artery abnormalities7907Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.18, 0.46]
1.1 Centres in Japan5678Odds Ratio (M-H, Fixed, 95% CI)0.14 [0.07, 0.29]
1.2 Centres in North America2229Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.37, 1.59]
Analysis 3.1.

Comparison 3 Subgroup: Geography, Outcome 1 Coronary artery abnormalities.

Comparison 4. Subgroup: High-risk scores vs lower-risk scores or all participants if risk score not calculated in study
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Coronary artery abnormalities7907Odds Ratio (M-H, Fixed, 95% CI)0.29 [0.18, 0.46]
1.1 High-risk scores3377Odds Ratio (M-H, Fixed, 95% CI)0.13 [0.06, 0.29]
1.2 Lower-risk scores or all participants in study if risk score not calculated5530Odds Ratio (M-H, Fixed, 95% CI)0.53 [0.29, 1.00]
2 Duration of clinical symptoms2210Mean Difference (IV, Random, 95% CI)-1.65 [-3.31, 0.00]
2.1 High-risk scores132Mean Difference (IV, Random, 95% CI)-2.6 [-3.74, -1.46]
2.2 Lower-risk scores or all participants in study if risk score not calculated1178Mean Difference (IV, Random, 95% CI)-0.9 [-1.13, -0.67]
Analysis 4.1.

Comparison 4 Subgroup: High-risk scores vs lower-risk scores or all participants if risk score not calculated in study, Outcome 1 Coronary artery abnormalities.

Analysis 4.2.

Comparison 4 Subgroup: High-risk scores vs lower-risk scores or all participants if risk score not calculated in study, Outcome 2 Duration of clinical symptoms.

Appendices

Appendix 1. CENTRAL search strategy

#1MESH DESCRIPTOR Mucocutaneous Lymph Node Syndrome EXPLODE ALL TREES74
#2kawasaki*:TI,AB,KY182
#3(mucocutaneous near5 syndrome):TI,AB,KY121
#4#1 OR #2 OR #3193
#5MESH DESCRIPTOR Glucocorticoids EXPLODE ALL TREES13302
#6steroid*:TI,AB,KY19295
#7(corticosteroid* or corticoid* or glucocorticoid*):TI,AB,KY15794
#8dexamethasone :TI,AB,KY5923
#9methylprednis*:TI,AB,KY3345
#10prednisone:TI,AB,KY6256
#11prednisolone:TI,AB,KY4294
#12hydroxycorticosteroid*:TI,AB,KY113
#13corticosterone:TI,AB,KY84
#14#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #1344334
#15#4 AND #1448

Appendix 2. Trials' registries searches

WHO

69 records for 65 trials found Kawasaki clinical trials in children

Clinicaltrials.gov

86 studies found for Kawasaki/Child

ISRCTN

4 results found for Kawasaki

Appendix 3. Glossary of terms

TermDefinition
AetiologyCause of a condition
DefervesenceThe abatement of a fever
DeleteriousNegative effect
DesquamationLoss of the outermost layer of a surface
ErythematousReddening - a term generally reserved for the skin
ExanthemA virus known to be associated with a rash
MucocutanoeousType of bodily surface, such as that inside the mouth
OropharyngealArea of the body encompassing the mouth and throat
Polymorphous rashRash of varying appearance
SequelaeConsequence
StenosisRestriction in the diameter of a vessel
ThrombosisThe 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

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

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.

Notes

This review replaces the withdrawn protocol 'Steroid hormone treatment for Kawasaki disease in children' (Jones 2014).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ikeda 2006

Methods

Participants "randomly assigned" and stratified into high- or low-risk groups

Unclear how many centres

Participants

178 with a diagnosis of KD were randomly assigned

No statement of baseline characteristics at enrolment between groups

90 assigned to steroid, 88 to control and they were divided as follows:

Low risk:

  • Steroid = 45 participants

  • Control = 46 participants

High risk:

  • Steroid = 45 participants

  • Control = 42 participants

Interventions

Participants given control (IVIG) or treatment (IVIG + prednisolone)

No information on route, duration or dose of steroid used

Outcomes

Coronary artery abnormalities

Unclear at what time point outcome measure assessed

Notes

No statement of blinding participants or researchers

No clear dose, route or duration of steroid use

Uncear source of funding

No clear definition of "coronary artery abnormalities"

No indication of when measurements were taken after treatment

Undertaken at Gunma Children's Medical Centre, Japan

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Randomly assigned"

Comment: unclear how this was done

Allocation concealment (selection bias)Unclear risk

Not stated

Comment: impossible to know if participants or physicians were blinded to the allocation

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Not stated

Comment: impossible to know if participants or physicians were blinded to the study treatment

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Not stated

Comment: impossible to know if there was any blinding of outcome assessors

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll data present
Selective reporting (reporting bias)Low riskPublished methodology consistent with that reported in published results
Other biasLow riskNone identified

Inoue 2006

Methods

Mulitcenter (12 centres in Gunma and Saitama, Japan) prospective non-blinded randomised.

September 2000 to March 2005.

Participants

588 children referred to the medical institutions. 410 found to be ineligible (389 because parents decided against participation, 17 because of a previous diagnosis of KD, and 4 because a coronary artery abnormality was present before randomisation)

178 participants who were all diagnosed with KD (had at least 5 of the following: fever (> 38 °C), non-exudative conjunctival injection, changes in the oropharynx (including mucosal erythema; dry, cracked lips; and "strawberry tongue"), changes in the extremities (including palmar and plantar erythema), oedema of the hands and feet or periungual desquamination, rash and cervical lymphadenopathy

Groups well balanced in respect of baseline demographic and clinical characteristics, alongside risk score. All participants followed up for at least 2 months (range 2 to 50 months).

Control: 88

Steroid: 90

Interventions

Control:

  • IVIG 1 g/kg/day for 2 days given over 12 h

  • Aspirin 30 mg/kg/day decreased to 5 mg/kg/day once CRP resolved

Treatment:

  • IVIG 1 g/kg/day for 2 days given over 12 h

  • Aspirin 30 mg/kg/day decreased to 5 mg/kg/day once CRP resolved

  • Prednisolone sodium succinate 2 mg/kg/day in 3 divided doses, intravenous until fever resolved, then given orally until CRP normalised. Once CRP normalised prednisolone was given orally in tapering doses over 15 days in 5-day steps (2 mg/kg/day for 5 days, 1 mg/kg/day for 5 days, then 0.5 mg/kg/day for 5 days). If there was difficulty with oral delivery, doses were given IV

Excluding 1 participant whose steroid treatment was discontinued at the discretion of the treating physician, duration of steroid treatment 18 to 100 days (median 23 days). Total dose of prednisolone ranged from 23.5 to 90 mg/kg (median 32 mg/kg)

Outcomes

Primary:

  • Detection of coronary artery abnormality (luminal diameter > 3.0 mm in a child < 5 yrs, or > 4.0 mm in a child > 5 yrs, when the internal diameter of a segment was at least 1.5 times that of an adjacent segment, or when a luminal contour was clearly irregular)

Secondary:

  • Duration of fever after initial treatment

  • Time to normalisation of CRP level (< 5 mg/dL)

  • Incidence of treatment failure and recurrence

Notes

Study terminated on 31 March 2005 by data monitoring committee at the time of the deadline despite a lower enrolment rate than expected

Unclear source of funding

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "centre randomly assigned the patient"

Comment: no clear statement of mechanism for random assignment

Allocation concealment (selection bias)Low risk

Quote: "Centrally maintained table of random numbers"

Comment: likely adequate

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Non-blinded

Comment: unclear how this would have influenced results

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Echocardioraphy operators were non-blinded

Quote: "findings reviewed in a non blinded manner"

Unclear if laboratory team processing blood samples were blinded

Comment: unclear how this would have influenced results

Incomplete outcome data (attrition bias)
All outcomes
Low riskKey outcome variables are reported as per protocol analysis with intention-to-treat analysis variable performed
Selective reporting (reporting bias)Low riskPublished methodology consistent with that reported in published results
Other biasLow riskNone identified

Kobayashi 2012

Methods

Multicentre (74 hospitals in Japan), prospective, randomised, blinded end points

29 September 2008 to 2 December 2010

Participants

Eligible participants had a diagnosis of KD (Japanese diagnostic guidelines) and a risk score of 5 points or higher, which emphasised the positive predictive value of no response to initial treatment with IVIG (2 points for each of the following: blood sodium < 133, < 4 days of fever at diagnosis, AST > 100, neutrophils > 80% of total WCC; 1 point for each of the following: platelet count < 30 x 104, CRP > 100, age < 12 months)

Excluded were children with a history of KD, those diagnosed on or after day 9 of fever, those with coronary artery abnormalities prior to enrolment, those who were afebrile prior to enrolment, those who had received steroids in the previous 30 days before the study, those who had received IVIG in the previous 180 days before the study, those with concomitant severe medical disorders, or those with suspected infectious disease

2014 children assessed for eligibility. 1547 did not meet inclusion criteria (1436 had low risk scores, 44 had previous diagnosis of KD, 24 had defervescence, 16 had suspected infectious disease, 12 had presence of coronary artery abnormality at diagnosis, 10 had illness for > 9 days, 3 had pre-existing severe disease, 1 had a history of IVIG use, 1 had history of steroid use, 219 declined to participate.

248 participants randomly assigned.

Steroid group: 125 (4 excluded: 1 withdrew consent, 2 had presence of coronary artery abnormality, 1 had misdiagnosis of KD)

Control group: 123 (2 excluded: 1 had presence of coronary artery abnormalities at enrolment, 1 did not receive IVIG)

No significant differences between groups at baseline

Interventions

Control:

  • IVIG 2 g/kg over 24 h

  • Aspirin 30 mg/kg/day until afebrile, then 3 to 5 mg/kg/day for at least 28 days from fever onset

Steroid group:

  • IVIG 2 g/kg over 24 h

  • Aspirin 30 mg/kg/day until afebrile, then 3 to 5 mg/kg/day for at least 28 days from fever onset

  • IV prednisolone 2 mg/kg/day in 3 divided doses for 5 days, or until fever resolved, if longer. When CRP normalised (< 5mg/L) prednisolone doses were tapered in 5 day steps over 15 days, from 2 mg/kg/day, to 1 mg/kg/day to 0.5 mg/kg/day

  • 0.5 mg/kg/day H2 blocker famotidine whilst on prednisolone

Outcomes

Primary end point:

  • Detection of coronary artery abnormality during study period (luminal diameter > 3.0 mm in a child < 5 years, or > 4.0 mm in a child > 5 yrs, when the internal diameter of a segment was at least 1.5 times that of an adjacent segment, or when a luminal contour was clearly irregular)

Secondary end point:

  • Incidence of coronary artery abnormality at week 4 after enrolment

  • Incidence of need for additional rescue treatment

  • CRP concentrations at 1 and 2 weeks after enrolment

  • Incidence of serious adverse events

Notes

Funding source: Japanese Ministry of Health, Labour and Welfare – had no role in study design, data collection, data analysis, data interpretation or writing of the report

RASIE study. Registered with University Hospital Medical Information Network clinical trials registry, number UMIN000000940

Pre-planned interim analysis after enrolment of the 200th participant in June 2010 demonstrated significance difference in the incidence of coronary artery abnormalities between the 2 treatment groups (P < 0.0001), therefore independent data and safety monitoring committee recommended termination of the study. Study terminated on 2 December 2010

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Computer generated randomisation sequence"

Comment: likely adequate and performed

Allocation concealment (selection bias)Low risk

Quote: "Centrally maintained table of random numbers"

Comment: likely adequate

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Quote: "Participant and treating physician non-blinded"

Comment: unclear how this would have influenced results

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "Blinded end point"

Echocardiography assessors blinded

Comment: appears adequate

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Intention to treat analysis used"

Comment: appears adequate

Selective reporting (reporting bias)Low riskPublished methodology consistent with that reported in published results
Other biasLow riskNone identified

Newburger 2007

Methods

Multicentre (8 centres in North America), randomised, double-blind, placebo-controlled trial.

December 2002 to December 2004

Participants

All participants between day 4 and day 10 of illness

Inclusion criteria:

  • Child met > 4 of principal clinical criteria.

  • Coronary artery z-score of > 2.5 (RCA or LAD) and met 2 principal clinical criteria if < 6 months, 3 criteria if > 6 months

  • Presence of a coronary artery aneurysm and met at least 1 clinical criterion

Exclusion criteria:

  • Previous treatment with IVIG

  • Oral steroid use in preceding 2 weeks

  • Presence of a disease known to mimic KD

  • Contraindications to steroid use

  • Allergy to aspirin

589 children identified. 276 were ineligible (185 met at least 1 exclusion criterion. 95 did not meet inclusion criteria)

313 considered eligible, of these 199 parents granted consent

199 children randomised

Treatment: 101 participants

Control: 98 participants

No significant differences between groups at baseline randomisation

Interventions

Control:

  • 1 mg/kg diphenhydramine

  • IVIG 2 g/kg over 10 h

  • Aspirin 80 to 100 mg/kg/day until they were afebrile for 48 h, then 3 to 5 mg/kg/day aspirin until study completion

Treatment:

  • One-off dose of 30mg/kg intravenous methyl prednisolone

  • 1 mg/kg diphenhydramine

  • IVIG 2 g/kg over 10 h

  • Aspirin 80 to 100 mg/kg/day until they were afebrile for 48 h, then 3 to 5 mg/kg/day aspirin until study completion

If children had recurrent fever > 36 h after the initial infusion (and no alternative source was found) then a further dose of IVIG 2 mg/kg, then if they remained pyrexial after a further 36 h another dose of IVIG 2 mg/kg was administered

Outcomes

Primary outcome:

  • Detection of coronary artery abnormality during study period (luminal diameter > 3.0 mm in a child < 5 yrs, or > 4.0 mm in a child > 5 yrs, when the internal diameter of a segment was at least 1.5 times that of an adjacent segment, or when a luminal contour was clearly irregular, of a z-score of > 2.5)

Secondary outcomes:

  • Duration of fever

  • Number of days spent in hospital until first discharge

  • Number of total days spent in hospital during study period

  • Number of episodes of re-treatment with IVIG

  • Incidence of adverse events

  • Laboratory data at week 1 and 5 after randomisation

Notes

ClinicalTrials.gov number: NCT00132080

Funding: National Institutes of Health and Higgins Family Cardiology Research Fund

No relevant potential conflict of interest reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Randomly assigned" with use of "dynamic balancing" at each centre

Comment: no information of what "dynamic balancing" entailed

Allocation concealment (selection bias)Unclear risk

Not stated

Comment: impossible to know if participants or physicians were blinded to the allocation

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "double blind"

Comment: appears adequate

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "double blind"

Comment: appears adequate

Incomplete outcome data (attrition bias)
All outcomes
Low risk

"Interim analysis reviewed by an independent data and safety monitoring board."

Data excluded for "6 patients who were discovered to have met an exclusion criteria, for 2 patients who did not receive IV steroid despite randomisation into this group, and 8 patients who were enrolled because they had coronary abnormalities but did not meet the classic criteria for KD."

Selective reporting (reporting bias)Low riskPre-trial protocol published on ClinicalTrials.gov and consistent with methodology and results published
Other biasLow riskNone identified

Ogata 2012

Methods

Single centre in Japan (Kitasato University Hospital), unblinded with stratification of participants into high- and low-risk groups. Participants were then randomly assigned to each treatment group

April 2007 to November 2010

Participants

Incluson criteria:

  • 5 of 6 clinical criteria for KD

Exclusion criteria:

  • Previous diagnosis of KD

  • Presence of a coronary artery abnormality before treatment

  • Use of steroid treatment before recruitment

122 participants enrolled into the study - all Japanese

100% consent rate for parents

High-risk group (Egami score > 3): aspirin + IVIG = 26, aspirin + IVIG + steroid = 22

Low-risk group (Egami score < 2; Table 1): aspirin alone = 6, aspirin + IVIG = 62

No significant differences at baseline between groups in the high-risk group

Interventions

Low risk group:

Treatment:

  • Aspirin 30 mg/kg 3 times daily until afebrile for 36 h, then 5 mg/kg/day

  • IVIG 2 g/kg over 24 h

Control:

  • Aspirin 30 mg/kg 3 times daily until afebrile for 36 h, then 5 mg/kg/day

High risk group:

Treatment:

  • Aspirin 30 mg/kg 3 times daily until afebrile for 36 h, then 5 mg/kg/day

  • IVIG 2 g/kg over 24 h

  • One-off dose of intravenous methyl prednisolone 30mg/kg over 2 h

Control:

  • Aspirin 30 mg/kg 3 times daily until afebrile for 36 h, then 5 mg/kg/day

  • IVIG 2 g/kg over 24 h

Outcomes

Primary outcome:

  • Treatment resistance (temperature > 37.5 °C) at 36 h

Secondary outcomes:

  • Duration of fever

  • Laboratory markers of vasculitic markers

  • Z-scores of coronary arteries

Notes

Trial number: UMIN000005021

No conflict of interest reported

Grant-in-aid for scientific research from Ministry of Education, Culture, Sports, Science and Technology; a Parents' Association Grant at Kitasato University School of Medicine, and a grant-in-aid from the Kawasaki Disease Research Centre in Japan

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: Randomly assigned using a "random number list"

Comment: appears adequate

Allocation concealment (selection bias)Unclear risk

Not stated

Comment: impossible to know if participants or physicians were blinded to the allocation

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Non-blinded

Comment: unclear how this would have influenced results

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "double-blinded"

Comment: appears adequate

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll data included in analysis
Selective reporting (reporting bias)Low riskPublished methodology consistent with that reported in published results
Other biasLow riskNone identified

Okada 2003

Methods

Multicentre (9 centres in Gunma Prefecture, Japan), prospective, randomised. Once participants identified, randomised into treatment groups

June 2001 to May 2002

Participants

Inclusion criteria:

  • At least 5 of the following: fever (> 38 °C), non-exudative conjunctival injection, changes in the oropharynx (including mucosal erythema; dry, cracked lips; and strawberry tongue), changes in extremities (palmar and plantar erythema, oedema of the hands and feet, or periungual desquamation in subacute phase of the disease), rash, cervical lymphadenopathy

  • Enrolled within 9 days of onset of fever

32 participants recruited:

  • Steroid treatment group: 14

  • Control: 18

Age, sex distribution, and severity score were similar in the 2 groups

Interventions

Control:

  • IVIG 1 g/kg for 2 days

  • Aspirin 30 mg/kg per day throughout the study period

  • Dipyridamole 2 mg/kg throughout the study period

Treatment:

  • IVIG 1 g/kg/day for 2 days

  • Prednisolone intravenous 2 mg/kg 3 times daily until resolution of fever, then oral prednisolone 2 mg/kg 3 times daily until CRP normalised, then a reducing regime of prednisolone was used, 1 mg/kg 2 times daily for 5 days, then 0.5 mg/kg once daily for 5 days

  • Aspirin 30 mg/kg per day throughout the study period

  • Dipyridamole 2 mg/kg throughout the study period

Outcomes

Primary outcome:

  • Cytokine levels pre-treatment, post IVIG dose, day 7 and day 14

Secondary outcomes:

  • Average duration of fever

  • Time to normalisation of CRP

  • Coronary artery abnormality (luminal diameter > 3.0 mm in a child < 5 yrs, or > 4.0 mm in a child > 5 yrs, when the internal diameter of a segment was at least 1.5 times that of an adjacent segment, or when a luminal contour was clearly irregular)

  • Adverse effects

NotesUnclear source of funding
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Randomised via a controller in the registration centre"

Comment: appears adequate

Allocation concealment (selection bias)Low risk

Quote: "Controller in the registration centre"

Comment: efforts made to separate randomisation from the study trial, reducing chance of information spread

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Non-blinded

Comment: unclear how this would have influenced results

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk

Unclear if blinded

Comment: unclear how this would have influenced results

Incomplete outcome data (attrition bias)
All outcomes
Low riskData for all participants appears in analysis
Selective reporting (reporting bias)Low riskPublished methodology consistent with that reported in published results
Other biasLow riskNone identified

Sundel 2003

  1. a

    AST: aspartate aminotransferase
    CRP: C-reactive protein
    ECHO: cardiac echocardiogram
    IV: intravenous
    IVIG: intravenous immunoglobulin
    KD: Kawasaki disease
    LAD: left anterior descending
    RCA: right coronary artery
    WCC: white cell count

Methods

Single centre (Boston, North America). Prospective randomised trial. Once recruited participants were randomised to each treatment group

February 1998 to November 2000

Participants

Inclusion criteria:

  • Fever < 10 days

  • 4 out of 5 clinical criteria

Exclusion criteria:

  • Previous diagnosis of KD

  • Presence of coronary artery aneurysm

  • Possible infection

  • Known hypersensitivity to IVIG

  • Contra-indications to steroid therapy

71 met eligibility criteria. 10 declined consent. 20 not enrolled due to insufficient time prior to IVIG infusion. 2 excluded due to coronary artery abnormalities

39 participants recruited:

  • Control = 21

  • Treatment = 18

No significant differences in demographic data at enrolment

Interventions

Control:

  • IVIG 2 g/kg over 10 h

  • Aspirin 20 to 25 mg/kg every 6 h until afebrile for 48 h, then 3 to 5 mg/kg/day for the duration of the study

  • Diphenhydramine pretreatment prior to IVIG

Treatment:

  • IVIG 2 g/kg over 10 h

  • Aspirin 20 to 25 mg/kg every 6 h until afebrile for 48 h, then 3 to 5 mg/kg/day for the duration of the study

  • Diphenhydramine pretreatment prior to IVIG

  • One-off dose of IV methyl prednisolone 30 mg/kg (max dose 1.5 g) 3 h before IVIG

Outcomes

Primary outcome:

  • Duration of fever

Secondary outcomes:

  • Length of hospital stay

  • Inflammatory markers at 6 weeks

  • Coronary artery abnormalities

  • Incidence of adverse events

NotesUnclear funding source
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Randomly assigned"

Comment: unclear how this was done

Allocation concealment (selection bias)Unclear risk

Not stated

Comment: impossible to know if participants or physicians were blinded to the allocation

Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Quote: "Participants and investigators were not blinded to treatment assignment"

Comment: unclear risk

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Outcome markers were generally measured objectively (e.g. temp, laboratory values), or were read by blinded observers unaware of patients' treatment status (echocardiograms)."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

95% of children had ECHO at 2 weeks

93% of children had ECHO at 6 weeks (1 in treatment group, 2 in control group)

Selective reporting (reporting bias)Low riskPublished methodology consistent with that reported in published results
Other biasLow riskNone identified

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    IVIG: intravenous immunoglobulin

Asai 1985Intervention included dipyridamole as well as prednisolone as the difference between the groups. Effect of steroids therefore not ascertainable. Furthermore primary outcome— arterial changes — poorly defined
Hashino 2001

Steroids only used if children were non-responders to 2 treatments with IVIG. These IVIG non-responsive children were then divided into groups allocated to receiving steroid (9 children) and those who received another dose of IVIG (8 children). This caused a significant delay in the administration of any steroids

Due to the steroid treatment group being classed as non-responders to IVIG, and the delay in receiving treatment, this study was not included as it is not comparable to any of the other studies used in this review

ISRCTN74427627Study outcome data not available despite attempts to contact author
Jibiki 2005Outcome not as per inclusion criteria of the review. Investigators assessed the laboratory mechanism of action of IVIG and steroid therapy in KD
Kato 1979Study outcome data not available despite attempts to contact author. Available outcome information does not provide objective data but categorises into aneurysm vs no aneurysm with inadequate detail on exact approach
Kusakawa 1983Study outcome data not available despite attempts to contact author. Available outcome information does not provide objective data but categorises into aneurysm versus no aneurysm with inadequate detail on exact approach
Miura 2008Outcome not as per inclusion criteria. Investigators assessed the laboratory mechanism of action of IVIG and steroid therapy in KD
Nakamura 1985Outcome not as per inclusion criteria of the review. The outcome of this study was regarding platelet laboratory processes, which was not an outcome measure of this review
Nonaka 1995Study outcome data not available despite attempts to contact author. Available outcome information does not provide objective data but categorises into aneurysm vs no aneurysm with inadequate detail on exact approach
Ogata 2009Outcome not as per inclusion criteria of the review. Investigators assessed the molecular mechanism of action of IVIG and steroid therapy in KD
Sekine 2012Outcome not as per inclusion criteria of the review. The outcome of this study was oxidative stress, which was not an outcome measure of this review
Seto 1983Inadequate information on methodology for validation, specifically no evidence of randomisation
Xu 2002Interventions included immunoglobulin versus steroids, meaning steroids were not the only differential factor between the groups and therefore their effect cannot be clearly defined. Inadequate information on methodology, specifically around randomisation, despite contacting authors
Yuan 2000Outcome not as per inclusion criteria of the review. Study does not clearly define coronary aneurysm or how this was measured

Characteristics of ongoing studies [ordered by study ID]

JPRN-UMIN000009524

  1. a

    IVIG: Intravenous immunoglobulin

Trial name or titleA prospective randomised controlled trial of immunoglobulin plus prednisolone for KD patients with high risk for coronary abnormalities
Methods

Parallel, assessor-blinded study

Control group:

Intravenous immunoglobulin (2 g/kg) over 24 h with aspirin (30 mg/kg/day). The dosage of aspirin can be reduced to 5 mg/kg/day after resolution of fever

Treatment group:

Intravenous immunoglobulin (2 g/kg) over 24 h plus intravenous prednisolone (2 mg/kg/day) with aspirin (30 mg/kg/day). The dosage of aspirin can be reduced to 5 mg/kg/day after resolution of fever
Prednisolone will be given intravenously for 3 days at least and then can be given orally after resolution of fever. When concentration of C-reactive protein becomes 1.0 mg/dL or less, the dose of prednisolone will be tapered over 9 days

Participants

Target sample size 240

Inclusion criteria:

1. Severe KD patients of risk score 4 points or more
2. Written informed consent is obtained from patients or their parents
3. Streptococcus, Epstein-Barr virus, adenovirus, or yersinia infection, or measles, or Stevens-Johnson syndrome is ruled out

Exclusion criteria:

1. Patients with past histories of KD
2. Patients diagnosed as KD on the ninth day of illness or later
3. KD patients with coronary artery lesions before treatment
4. KD patients with defervescence before treatment
5. Patients given steroids within 28 days before treatment
6. Patients given IVIG within 180 days before treatment
7. Patients with severe underlining diseases
8. Patients with a concurrent infection

Interventions

Control group:

Intravenous immunoglobulin (2 g/kg) over 24 h with aspirin (30 mg/kg/day). The dosage of aspirin can be reduced to 5 mg/kg/day after resolution of fever

Treatment group:

Intravenous immunoglobulin (2 g/kg) over 24 h plus intravenous prednisolone (2 mg/kg/day) with aspirin (30 mg/kg/day). The dosage of aspirin can be reduced to 5 mg/kg/day after resolution of fever
Prednisolone will be given intravenously for 3 days at least and then can be given orally after resolution of fever. When concentration of C-reactive protein becomes 1.0 mg/dL or less, the dose of prednisolone will be tapered over 9 days

Outcomes

Primary outcome:

Incidence of coronary artery lesions within 4 weeks after primary treatment

Secondary outcome:

Incidence of coronary artery lesions at 4 weeks after primary treatment, z-score of coronary artery diameters, incidence of resistance to primary treatment or relapse, duration of fever after primary treatment, serum concentrations of C-reactive protein at 1 week and 2 weeks after primary treatment, and incidence of adverse events

Starting date17 December 2012
Contact information

Taichi Kato

Nagoya University Graduate School of Medicine

Department of Pediatrics

65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan

+81-52-744-2298

ktaichi@med.nagoya-u.ac.jp

Notes 

Ancillary