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Corticosteroides para el tratamiento de la enfermedad de Kawasaki en niños

Appendices

Appendix 1. Database search strategies

Source

Search strategy

Hits retrieved

CENTRAL via CRSO

#1 MESH DESCRIPTOR Mucocutaneous Lymph Node Syndrome EXPLODE ALL TREES 104

#2 kawasaki*:TI,AB,KY 313

#3 (mucocutaneous near5 syndrome):TI,AB,KY 189

#4 #1 OR #2 OR #3 331

#5 MESH DESCRIPTOR Glucocorticoids EXPLODE ALL TREES 19175

#6 steroid*:TI,AB,KY 29613

#7 (corticosteroid* or corticoid* or glucocorticoid*):TI,AB,KY 27108

#8 dexamethasone:TI,AB,KY 11715

#9 methylprednis*:TI,AB,KY 5330

#10 prednisone:TI,AB,KY 9443

#11 prednisolone:TI,AB,KY 7039

#12 hydroxycorticosteroid*:TI,AB,KY 112

#13 corticosterone:TI,AB,KY 136

#14 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 73042

#15 #4 AND #14 83

#16 01/01/2016 TO 08/02/2021:CD 858409

#17 #15 AND #16 43

Feb 2021: 43

Clinicaltrials.gov

Mucocutaneous Lymph Node Syndrome OR kawasaki

Feb 2021: 18

ICTRP Search Portal

Mucocutaneous Lymph Node Syndrome OR kawasaki

Feb 2021: 0

MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) 1946 to present

1 exp Mucocutaneous Lymph Node Syndrome/

2 kawasaki*.ti,ab.

3 (mucocutaneous adj5 syndrome).ti,ab.

4 or/1‐3

5 exp Glucocorticoids/

6 steroid*.ti,ab.

7 (corticosteroid* or corticoid* or glucocorticoid*).ti,ab.

8 dexamethasone.ti,ab.

9 methylprednis*.ti,ab.

10 prednisone.ti,ab.

11 prednisolone.ti,ab.

12 hydroxycorticosteroid*.ti,ab.

13 corticosterone.ti,ab.

14 or/5‐13

15 4 and 14

16 randomized controlled trial.pt.

17 controlled clinical trial.pt.

18 randomized.ab.

19 placebo.ab.

20 drug therapy.fs.

21 randomly.ab.

22 trial.ab.

23 groups.ab.

24 or/16‐23

25 exp animals/ not humans.sh.

26 24 not 25

27 15 and 26

28 (2016* or 2017* or 2018* or 2019* or 2020* or 2021*).ed.

29 27 and 28

Feb 2021: 85

Embase (Ovid)

1 exp mucocutaneous lymph node syndrome/

2 kawasaki*.ti,ab.

3 (mucocutaneous adj5 syndrome).ti,ab.

4 or/1‐3

5 exp glucocorticoid/

6 steroid*.ti,ab.

7 (corticosteroid* or corticoid* or glucocorticoid*).ti,ab.

8 dexamethasone.ti,ab.

9 methylprednis*.ti,ab.

10 prednisone.ti,ab.

11 prednisolone.ti,ab.

12 hydroxycorticosteroid*.ti,ab.

13 corticosterone.ti,ab.

14 or/5‐13

15 4 and 14

16 randomized controlled trial/

17 controlled clinical trial/

18 random$.ti,ab.

19 randomization/

20 intermethod comparison/

21 placebo.ti,ab.

22 (compare or compared or comparison).ti.

23 ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab.

24 (open adj label).ti,ab.

25 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.

26 double blind procedure/

27 parallel group$1.ti,ab.

28 (crossover or cross over).ti,ab.

29 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.

30 (assigned or allocated).ti,ab.

31 (controlled adj7 (study or design or trial)).ti,ab.

32 (volunteer or volunteers).ti,ab.

33 trial.ti.

34 or/16‐33

35 15 and 34

36 (2016* or 2017* or 2018* or 2019* or 2020* or 2021*).dc.

37 35 and 36

Feb 2021: 75

CINAHL (EBSCO)

S33 S31 AND S32

S32 EM 2016 OR EM 2017 OR EM 2018 OR EM 2019 OR EM 2020 OR EM 2021

S31 S15 AND S30

S30 S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29

S29 MH "Random Assignment"

S28 MH "Triple‐Blind Studies"

S27 MH "Double‐Blind Studies"

S26 MH "Single‐Blind Studies"

S25 MH "Crossover Design"

S24 MH "Factorial Design"

S23 MH "Placebos"

S22 MH "Clinical Trials"

S21 TX "multi‐centre study" OR "multi‐center study" OR "multicentre study" OR "multicenter study" OR "multi‐site study"

S20 TX crossover OR "cross‐over"

S19 AB placebo*

S18 TX random*

S17 TX trial*

S16 TX "latin square"

S15 S4 AND S14

S14 S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13

S13 corticosterone

S12 TX hydroxycorticosteroid*

S11 TX prednisolone

S10 TX prednisone

S9 TX methylprednis*

S8 TX dexamethasone

S7 TX corticosteroid* or corticoid* or glucocorticoid*

S6 TX steroid*

S5 (MH "Glucocorticoids+")

S4 S1 OR S2 OR S3

S3 TX mucocutaneous N5 syndrome

S2 TX kawasaki*.

S1 (MH "Mucocutaneous Lymph Node Syndrome")

Feb 2021: 24

Appendix 2. Glossary of terms

Term

Definition

Aetiology

Cause of a condition

Defervesence

The abatement of a fever

Deleterious

Negative effect

Desquamation

Loss of the outermost layer of a surface

Erythematous

Reddening ‐ a term generally reserved for the skin

Exanthem

A virus known to be associated with a rash

Mucocutanoeous

Type of bodily surface, such as that inside the mouth

Oropharyngeal

Area of the body encompassing the mouth and throat

Polymorphous rash

Rash of varying appearance

Sequelae

Consequence

Stenosis

Restriction in the diameter of a vessel

Thrombosis

The formation of a blood clot within a blood vessel

Flow diagram for studies in 2021 updated review

Figuras y tablas -
Figure 1

Flow diagram for studies in 2021 updated review

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

Figuras y tablas -
Figure 2

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

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

Figuras y tablas -
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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Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 1: Incidence of coronary artery abnormalities

Figuras y tablas -
Analysis 1.1

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

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

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

Figuras y tablas -
Analysis 1.3

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

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

Figuras y tablas -
Analysis 1.4

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

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

Figuras y tablas -
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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Comparison 1: Corticosteroids versus no corticosteroid use, Outcome 6: Length of hospital stay

Figuras y tablas -
Analysis 1.6

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

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

Figuras y tablas -
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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Comparison 3: Subgroup: geography, Outcome 1: Coronary artery abnormalities

Figuras y tablas -
Analysis 3.1

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

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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 1: Coronary artery abnormalities

Figuras y tablas -
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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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

Figuras y tablas -
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

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 usea

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with no corticosteroid use

Risk with corticosteroids

Incidence of coronary artery abnormalities
Follow‐up: range 2–6 weeks

Study population

OR 0.32
(0.14 to 0.75)

986
(8 RCTs)

⊕⊕⊕⊝
Moderateb

—

167 per 1000

60 per 1000
(27 to 131)

Incidence of any serious adverse effects attributable to the administration of corticosteroids
Follow‐up: range 2–6 weeks

Study population

—

737
(6 RCTs)

⊕⊕⊕⊝
Moderatec

0 cases of serious adverse events attributable to corticosteroids use recorded by the included studies.

See comment

See comment

Mortality (all‐cause)
follow‐up: range 2–6 weeks

Study population

—

1075
(8 RCTs)

⊕⊕⊕⊝
Moderatec

0 deaths recorded by the included studies.

See comment

See comment

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)

⊕⊕⊝⊝
Lowd

—

Time for laboratory parameters to normalise: CRP, ESRe

(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)

⊕⊕⊕⊝
Moderatef

—

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)

⊕⊕⊕⊝
Moderateg

—

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).

Figuras y tablas -
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

Figuras y tablas -
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]
Figuras y tablas -
Comparison 1. Corticosteroids versus no corticosteroid use
Ir a la tabla de la revisión
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]
Figuras y tablas -
Comparison 2. Subgroup: single, pulse dose corticosteroid use versus longer course of corticosteroids
Ir a la tabla de la revisión
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]
Figuras y tablas -
Comparison 3. Subgroup: geography
Ir a la tabla de la revisión
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]
Figuras y tablas -
Comparison 4. Subgroup: high‐risk scores versus lower‐risk scores or all participants if risk score not calculated in study
Ir a la tabla de la revisión