Corticosteroids for the treatment of Kawasaki disease in children

Jessica Green; Andrew J Wardle; Robert MR Tulloh

doi:10.1002/14651858.CD011188.pub3

Cochrane Database of Systematic Reviews

Corticosteroides para el tratamiento de la enfermedad de Kawasaki en niños

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DOI:

https://doi.org/10.1002/14651858.CD011188.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

27 mayo 2022see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Vascular

Copyright:

Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Jessica Green

Children's & Adolescent Services, Whiston Hospital, St Helens and Knowsley Teaching Hospitals NHS Trust, Prescot, Merseyside, UK
Andrew J Wardle

Correspondencia a: Cardiology, Hammersmith Hospital, Imperial College London, London, UK

[email protected]
Robert MR Tulloh

Congenital Heart Disease, Bristol Royal Hospital for Children and Bristol Heart Institute, Bristol, UK

Contributions of authors

JG: study selection, assessing risk of bias, data extraction and analysis, updating review.

AJW: final reviewing and drafting of the review update, guarantor of the review.

RMRT: study selection, assessing risk of bias, data extraction and analysis, updating review.

Sources of support

Internal sources

No sources of support provided

External sources

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

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

Declarations of interest

JG: none.

AJW: none.

RMRT: none.

Acknowledgements

The review authors would like to thank Georgia M Connolly and Matthew J Seager for their contributions to previous versions of this review.

The review authors and the Cochrane Vascular editorial base are grateful to the following peer reviewers for their time and comments: Dr Mamoru Ayusawa, Nihon University School of Medicine & Itabashi Hospital, Tokyo, Japan; Prof Kevin Friedman, Boston Children's Hospital, Boston, USA; Prof Michael A Portman, Seattle Children’s Hospital, Seattle, USA.

Version history

Published

Title

Stage

Authors

Version

2022 May 27

Corticosteroids for the treatment of Kawasaki disease in children

Review

Jessica Green, Andrew J Wardle, Robert MR Tulloh

https://doi.org/10.1002/14651858.CD011188.pub3

2017 Jan 27

Corticosteroids for the treatment of Kawasaki disease in children

Review

Andrew J Wardle, Georgia M Connolly, Matthew J Seager, Robert MR Tulloh

https://doi.org/10.1002/14651858.CD011188.pub2

2014 Aug 04

Corticosteroids for the treatment of Kawasaki disease in children

Protocol

Andrew J Wardle, Harriet C Kiddy, Matthew J Seager, Robert MR Tulloh, Michael Levin

https://doi.org/10.1002/14651858.CD011188

Differences between protocol and review

2021

We carried out additional subgroup analyses based on first‐ or second‐line corticosteroid treatment to investigate if this had any impact on the results. The previous version of the review only included studies using first‐line treatment.

2016

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.

We used odds ratio 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 effects we intended to study.

Notes

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

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Child; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Flow diagram for studies in 2021 updated review

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Figure 2

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

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Figure 3

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

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Analysis 1.1

Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 1: Incidence of coronary artery abnormalities

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Analysis 1.2

Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 2: Incidence of any serious adverse effects attributable to the administration of corticosteroids

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Analysis 1.3

Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 3: Mortality (all‐cause)

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Analysis 1.4

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

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Analysis 1.5

Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 5: Time for laboratory parameters to normalise: CRP and ESR (days)

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Analysis 1.6

Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 6: Length of hospital stay

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Analysis 2.1

Comparison 2: Subgroup: single, pulse dose corticosteroid use versus longer course of corticosteroids, Outcome 1: Coronary artery abnormalities

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Analysis 3.1

Comparison 3: Subgroup: geography, Outcome 1: Coronary artery abnormalities

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Analysis 4.1

Comparison 4: Subgroup: high‐risk scores versus lower‐risk scores or all participants if risk score not calculated in study, Outcome 1: Coronary artery abnormalities

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Analysis 4.2

Comparison 4: Subgroup: high‐risk scores versus lower‐risk scores or all participants if risk score not calculated in study, Outcome 2: Duration of clinical symptoms

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Summary of findings 1. Corticosteroids compared to no corticosteroid use for the treatment of Kawasaki disease in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Corticosteroids compared to no corticosteroid use for the treatment of Kawasaki disease in children
Patient or population: children diagnosed with Kawasaki disease Setting: hospital Intervention: corticosteroids Comparison: no corticosteroid use^a
Outcomes	Risk with no corticosteroid use	Risk with corticosteroids	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Incidence of coronary artery abnormalities Follow‐up: range 2–6 weeks	Study population		OR 0.32 (0.14 to 0.75)	986 (8 RCTs)	⊕⊕⊕⊝ Moderate^b	—
	167 per 1000	60 per 1000 (27 to 131)	OR 0.32 (0.14 to 0.75)	986 (8 RCTs)	⊕⊕⊕⊝ Moderate^b	—
Incidence of any serious adverse effects attributable to the administration of corticosteroids Follow‐up: range 2–6 weeks	Study population		—	737 (6 RCTs)	⊕⊕⊕⊝ Moderate^c	0 cases of serious adverse events attributable to corticosteroids use recorded by the included studies.
	See comment	See comment	—	737 (6 RCTs)	⊕⊕⊕⊝ Moderate^c
Mortality (all‐cause) follow‐up: range 2–6 weeks	Study population		—	1075 (8 RCTs)	⊕⊕⊕⊝ Moderate^c	0 deaths recorded by the included studies.
Mortality (all‐cause) follow‐up: range 2–6 weeks	See comment	See comment	—	1075 (8 RCTs)	⊕⊕⊕⊝ Moderate^c	0 deaths recorded by the included studies.
Duration of clinical symptoms: fever and rash (days) Follow‐up: range 2–6 weeks	The mean duration of clinical symptoms (fever and rash) across the control groups ranged from 1.5 to 11.2 days.	The mean duration of clinical symptoms (fever and rash) was1.34 days lower (2.24 lower to 0.45 lower).	—	290 (3 RCTs)	⊕⊕⊝⊝ Low^d	—
Time for laboratory parameters to normalise: CRP, ESR^e (days)	The mean time for laboratory parameters (CRP, ESR) to normalise was 11.2 days.	The mean time for laboratory parameters (CRP, ESR) to normalise was 2.8 days lower (4.38 lower to 1.22 lower).	—	178 (1 RCT)	⊕⊕⊕⊝ Moderate^f	—
Length of hospital stay (days)	The mean length of hospital stay across the control groups ranged from 3.31 to 6.7 days.	The mean length of hospital stay was1.01 days lower (1.72 lower to 0.30 lower).	—	119 (2 RCTs)	⊕⊕⊕⊝ Moderate^g	—
Longer term (> 1 year after disease onset) coronary morbidity (non‐aneurysmal)	Study population		—	—	—	0 studies included data on outcomes (including coronary morbidity (non‐aneurysmal)) > 1 year after study enrolment.
	See comment	See comment	—	—	—
*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; MD: mean difference; OR: odds ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aThese comprised alternative treatments such as intravenous immunoglobulin, aspirin and diphenhydramine. See Characteristics of included studies for more details. ^bDowngraded one level for inconsistency: large group and effect size; however, subgroup analysis suggests that those with low‐risk scores or receiving single‐dose treatment may not benefit. Further investigation to reduce potential confounding is required to explain inconsistencies in data (i.e. geographical variation, first‐line versus second‐line treatment). However, overall effect is unlikely to change (likely beneficial). ^cDowngraded one level for imprecision: small overall number of participants or events (for very rare events large number of participants needed). ^dDowngraded one level for inconsistency: significant heterogeneity within the data, likely due to the subjective nature of the included outcome (i.e. rash). Downgraded one level for indirectness: some indirectness of treatment effect since one study used corticosteroids as second‐line treatment. ^eLower numbers and a downward trend are generally better. A low result might be acceptable, rather than a completely negative result. The definitions of normal CRP can range slightly. The definition of a normal ESR range depends on age and sex. ^fDowngraded one level for imprecision due to only one study with a relatively small number of participants. ^gDowngraded one level for indirectness of treatment effect (participants in one of two studies received corticosteroids as second‐line treatment) and imprecision (small number of participants).

Summary of findings 1. Corticosteroids compared to no corticosteroid use for the treatment of Kawasaki disease in children

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Table 1. Criteria of high‐risk participants

Study	High‐risk criteria
Ikeda 2006	Developed own risk score based upon IVIG unresponsiveness in a multiple logistic regression analysis. 42/178 randomly identified KD participants were deemed high risk.
Kobayashi 2012	Kobayashi risk score of ≥ 5 (≤ 4 days fever prediagnosis, aged ≤ 12 years, CRP ≥ 100 mg/L, ≤ 300 × 10³/μL platelets, ALT ≥ 100 units/L, sodium ≤ 133 mmol/L, neutrophils ≥ 80%)
Ogata 2012	Egami score ≥ 3 (aged ≤ 6 months, ≤ 4 days fever prediagnosis, ≤ 300 × 10³/μL platelets, CRP ≥ 7 mg/dL, ALT ≥ 80 units/L)
ALT: alanine transaminase; CRP: C‐reactive protein; IVIG: intravenous immunoglobulin; KD: Kawasaki disease

Table 1. Criteria of high‐risk participants

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Comparison 1. Corticosteroids versus no corticosteroid use

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Incidence of coronary artery abnormalities Show forest plot	8	986	Odds Ratio (M‐H, Random, 95% CI)	0.32 [0.14, 0.75]

1.1.1 First‐line treatment	7	907	Odds Ratio (M‐H, Random, 95% CI)	0.25 [0.10, 0.58]
1.1.2 Second‐line treatment	1	79	Odds Ratio (M‐H, Random, 95% CI)	1.38 [0.43, 4.41]
1.2 Incidence of any serious adverse effects attributable to the administration of corticosteroids Show forest plot	6	737	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable

1.2.1 First‐line treatment	6	737	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3 Mortality (all‐cause) Show forest plot	8	995	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable

1.3.1 First‐line treatment	7	915	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.2 Second‐line treatment	1	80	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4 Duration of clinical symptoms: fever and rash Show forest plot	3	290	Mean Difference (IV, Random, 95% CI)	‐1.34 [‐2.24, ‐0.45]

1.4.1 First‐line treatment	2	210	Mean Difference (IV, Random, 95% CI)	‐1.65 [‐3.31, 0.00]
1.4.2 Second‐line treatment	1	80	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.84, 0.04]
1.5 Time for laboratory parameters to normalise: CRP and ESR (days) Show forest plot	1	178	Mean Difference (IV, Fixed, 95% CI)	‐2.80 [‐4.38, ‐1.22]

1.6 Length of hospital stay Show forest plot	2	119	Mean Difference (IV, Fixed, 95% CI)	‐1.01 [‐1.72, ‐0.30]

1.6.1 First‐line treatment	1	39	Mean Difference (IV, Fixed, 95% CI)	‐1.41 [‐2.36, ‐0.46]
1.6.2 Second‐line treatment	1	80	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐1.58, 0.58]

Comparison 1. Corticosteroids versus no corticosteroid use

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Comparison 2. Subgroup: single, pulse dose corticosteroid use versus longer course of corticosteroids

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Coronary artery abnormalities Show forest plot	7	808	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.24, 0.60]

2.1.1 Single, pulse dose corticosteroid use	4	356	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.40, 1.22]
2.1.2 Longer course of corticosteroids	3	452	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.05, 0.32]

Comparison 2. Subgroup: single, pulse dose corticosteroid use versus longer course of corticosteroids

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Comparison 3. Subgroup: geography

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Coronary artery abnormalities Show forest plot	8	986	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.23, 0.55]

3.1.1 Centres in Japan	5	678	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.07, 0.29]
3.1.2 Centres in North America	2	229	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.37, 1.59]
3.1.3 Centres in China	1	79	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.43, 4.41]

Comparison 3. Subgroup: geography

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Comparison 4. Subgroup: high‐risk scores versus lower‐risk scores or all participants if risk score not calculated in study

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Coronary artery abnormalities Show forest plot	8	986	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.23, 0.55]

4.1.1 High‐risk scores	3	377	Odds Ratio (M‐H, Fixed, 95% CI)	0.13 [0.06, 0.29]
4.1.2 Lower‐risk scores or all participants in study if risk score not calculated	6	609	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.38, 1.13]
4.2 Duration of clinical symptoms Show forest plot	3	290	Mean Difference (IV, Random, 95% CI)	‐1.34 [‐2.24, ‐0.45]

4.2.1 High‐risk scores	1	32	Mean Difference (IV, Random, 95% CI)	‐2.60 [‐3.74, ‐1.46]
4.2.2 Lower‐risk scores or all participants in study if risk score not calculated	2	258	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.13, ‐0.67]

Comparison 4. Subgroup: high‐risk scores versus lower‐risk scores or all participants if risk score not calculated in study

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Corticosteroides para el tratamiento de la enfermedad de Kawasaki en niños

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