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. 2023 Jan 25;1(1):CD014884.
doi: 10.1002/14651858.CD014884.pub2.

Intravenous immunoglobulin for the treatment of Kawasaki disease

Cathryn Broderick  1 , Shinobu Kobayashi  2 , Maiko Suto  3 , Shuichi Ito  4 , Tohru Kobayashi  5
Affiliations

Intravenous immunoglobulin for the treatment of Kawasaki disease

Cathryn Broderick et al. Cochrane Database Syst Rev. .

Abstract

Background: Kawasaki disease (KD) is an acute systemic vasculitis (inflammation of the blood vessels) that mainly affects children. Symptoms include fever, chapped lips, strawberry tongue, red eyes (bulbar conjunctival injection), rash, redness, swollen hands and feet or skin peeling; and enlarged cervical lymph nodes. High fevers and systemic inflammation characterise the acute phase. Inflammation of the coronary arteries causes the most serious complication of the disease, coronary artery abnormalities (CAAs). The primary treatment is intravenous immunoglobulin (IVIG) and acetylsalicylic acid (ASA/aspirin), with doses and regimens differing between institutions. It is important to know which regimens are the safest and most effective in preventing complications.

Objectives: To evaluate the efficacy and safety of IVIG in treating and preventing cardiac consequences of Kawasaki disease.

Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 26 April 2022.

Selection criteria: We included randomised controlled trials (RCTs) investigating the use of IVIG for the treatment of KD. We included studies involving treatment for initial or refractory KD, or both.

Data collection and analysis: We used standard Cochrane methods. Our primary outcomes were incidence of CAAs and incidence of any adverse effects after treatment. Our secondary outcomes were acute coronary syndromes, duration of fever, need for additional treatment, length of hospital stay, and mortality. We used GRADE to assess the certainty of the evidence for each outcome.

Main results: We identified 31 RCTs involving a total of 4609 participants with KD. Studies compared IVIG with ASA, another dose or regimen of IVIG, prednisolone, or infliximab. The majority of studies reported on primary treatment, so those results are reported below. A limited number of studies investigated secondary or tertiary treatment in IVIG-resistant patients. Doses and regimens of IVIG infusion varied between studies, and all studies had some concerns related to risk of bias. Primary treatment with IVIG compared to ASA for people with KD Compared to ASA treatment, IVIG probably reduces the incidence of CAAs in people with KD up to 30 days (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.41 to 0.87; 11 studies, 1437 participants; moderate-certainty evidence). The individual studies reported a range of adverse effects, but there was little to no difference in numbers of adverse effects between treatment groups (OR 0.57, 95% CI 0.17 to 1.89; 10 studies, 1376 participants; very low-certainty evidence). There was limited evidence for the incidence of acute coronary syndromes, so we are uncertain of any effects. Duration of fever days from treatment onset was probably shorter in the IVIG group (mean difference (MD) -4.00 days, 95% CI -5.06 to -2.93; 3 studies, 307 participants; moderate-certainty evidence). There was little or no difference between groups in need for additional treatment (OR 0.27, 95% CI 0.05 to 1.57; 3 studies, 272 participants; low-certainty evidence). No study reported length of hospital stay, and no deaths were reported in either group. Primary treatment with IVIG compared to different infusion regimens of IVIG for people with KD Higher-dose regimens of IVIG probably reduce the incidence of CAAs compared to medium- or lower-dose regimens of IVIG up to 30 days (OR 0.60, 95% CI 0.40 to 0.89; 8 studies, 1824 participants; moderate-certainty evidence). There was little to no difference in the number of adverse effects between groups (OR 1.11, 95% CI 0.52 to 2.37; 6 studies, 1659 participants; low-certainty evidence). No study reported on acute coronary syndromes. Higher-dose IVIG may reduce the duration of fever compared to medium- or lower-dose regimens (MD -0.71 days, 95% CI -1.36 to -0.06; 4 studies, 992 participants; low-certainty evidence). Higher-dose regimens may reduce the need for additional treatment (OR 0.29, 95% CI 0.10 to 0.88; 4 studies, 1125 participants; low-certainty evidence). We did not detect a clear difference in length of hospital stay between infusion regimens (MD -0.24, 95% CI -0.78 to 0.30; 3 studies, 752 participants; low-certainty evidence). One study reported mortality, and there was little to no difference detected between regimens (moderate-certainty evidence). Primary treatment with IVIG compared to prednisolone for people with KD The evidence comparing IVIG with prednisolone on incidence of CAA is very uncertain (OR 0.60, 95% CI 0.24 to 1.48; 2 studies, 140 participants; very low-certainty evidence), and there was little to no difference between groups in adverse effects (OR 4.18, 95% CI 0.19 to 89.48; 1 study; 90 participants; low-certainty evidence). We are very uncertain of the impact on duration of fever, as two studies reported this outcome differently and showed conflicting results. One study reported on acute coronary syndromes and mortality, finding little or no difference between groups (low-certainty evidence). No study reported the need for additional treatment or length of hospital stay.

Authors' conclusions: The included RCTs investigated a variety of comparisons, and the small number of events observed during the study periods limited detection of effects. The certainty of the evidence ranged from moderate to very low due to concerns related to risk of bias, imprecision, and inconsistency. The available evidence indicated that high-dose IVIG regimens are probably associated with a reduced risk of CAA formation compared to ASA or medium- or low-dose IVIG regimens. There were no clinically significant differences in incidence of adverse effects, which suggests there is little concern about the safety of IVIG. Compared to ASA, high-dose IVIG probably reduced the duration of fever, but there was little or no difference detected in the need for additional treatment. Compared to medium- or low-dose IVIG, there may be reduced duration of fever and reduced need for additional treatment. We were unable to draw any conclusions regarding acute coronary syndromes, mortality, or length of hospital stay, or for the comparison IVIG versus prednisolone. Our findings are in keeping with current guideline recommendations and evidence from long-term epidemiology studies.

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Conflict of interest statement

CB: none known. As CB is based within Cochrane Vascular, editorial tasks for this review update were carried out by other members of the Cochrane Vascular editorial team. SK: none known MS: none known SI: none known TK: declares that his institution received a scholarship grant from Japan Blood Products Organization (total amount JPY 300,000 in 2021). This does not conflict with his work on this review. TK also reports payments for lectures from Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nihon Pharmaceutical, and Teijin Pharma.

Figures

1
1
PRISMA flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Chronological changes of proportion of intravenous immunoglobulin (IVIG) administration and incidence of coronary artery abnormalities (CAAs) from the Nationwide Survey of Kawasaki Disease in Japan. Created by review author (TK) with data from the Nationwide Survey (with permission from the Director of the Nationwide Survey Kawasaki Disease in Japan).
1.1
1.1. Analysis
Comparison 1: Primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 1: CAA: total dose of IVIG subgrouped by single or multiple infusion (up to 30 days)
1.2
1.2. Analysis
Comparison 1: Primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 2: CAA: total dose of IVIG subgrouped by single or multiple infusion (≥ 6 months)
1.3
1.3. Analysis
Comparison 1: Primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 3: Adverse effects: total dose of IVIG subgrouped by single or multiple infusion
1.4
1.4. Analysis
Comparison 1: Primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 4: Duration of fever from treatment onset (days): total dose of IVIG subgrouped by single or multiple infusion
1.5
1.5. Analysis
Comparison 1: Primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 5: Duration of fever from KD onset (days): total dose of IVIG subgrouped by single or multiple infusion
1.6
1.6. Analysis
Comparison 1: Primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 6: Need for additional treatment: total dose of IVIG subgrouped by single or multiple infusion
2.1
2.1. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 1: CAA: high‐dose regimens vs medium‐ or low‐dose regimens
2.2
2.2. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 2: CAA: higher‐dose single‐infusion regimens vs lower‐dose single‐infusion regimens
2.3
2.3. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 3: CAA: higher‐dose multiple‐infusion regimens vs lower‐dose multiple‐infusion regimens
2.4
2.4. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 4: CAA: single‐infusion regimens vs multiple‐infusion regimens
2.5
2.5. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 5: Adverse effects: high‐dose regimens vs medium‐ or low‐dose regimens
2.6
2.6. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 6: Adverse effects: higher‐dose single‐infusion regimens vs lower‐dose single‐infusion regimens
2.7
2.7. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 7: Adverse effects: higher‐dose multiple‐infusion regimens vs lower‐dose multiple‐infusion regimens
2.8
2.8. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 8: Adverse effects: single‐infusion regimens vs multiple‐infusion regimens
2.9
2.9. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 9: Duration of fever (days): high‐dose regimens vs medium‐ or low‐dose regimens
2.10
2.10. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 10: Duration of fever (days): higher‐dose single‐infusion regimens vs lower‐dose single‐infusion regimens
2.11
2.11. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 11: Duration of fever (days): higher‐dose multiple‐infusion regimens vs lower‐dose multiple‐infusion regimens
2.12
2.12. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 12: Duration of fever (days): single‐infusion regimens vs multiple‐infusion regimens
2.13
2.13. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 13: Need for additional treatment: high‐dose regimens vs medium‐ or low‐dose regimens
2.14
2.14. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 14: Need for additional treatment: higher‐dose single‐infusion regimens vs lower‐dose single‐infusion regimens
2.15
2.15. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 15: Need for additional treatment: higher‐dose multiple‐infusion regimens vs lower‐dose multiple‐infusion regimens
2.16
2.16. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 16: Need for additional treatment: single‐infusion regimens vs multiple‐infusion regimens
2.17
2.17. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 17: Length of hospital stay (days): high‐dose regimens vs medium‐ or low‐dose regimens
2.18
2.18. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 18: Length of hospital stay (days): higher‐dose single‐infusion regimens vs lower‐dose single‐infusion regimens
2.19
2.19. Analysis
Comparison 2: Primary treatment ‐ IVIG versus IVIG, Outcome 19: Length of hospital stay (days): single‐infusion regimens vs multiple‐infusion regimens
3.1
3.1. Analysis
Comparison 3: Primary treatment ‐ IVIG versus prednisolone, Outcome 1: CAA: total dose of IVIG vs total dose of IV prednisolone
3.2
3.2. Analysis
Comparison 3: Primary treatment ‐ IVIG versus prednisolone, Outcome 2: Adverse events: total dose of IVIG vs total dose of IV prednisolone
3.3
3.3. Analysis
Comparison 3: Primary treatment ‐ IVIG versus prednisolone, Outcome 3: Duration of fever (days) : total dose of IVIG vs total dose of IV prednisolone
4.1
4.1. Analysis
Comparison 4: Secondary treatment ‐ IVIG versus infliximab, Outcome 1: CAA: total dose of single IVIG vs single infliximab
4.2
4.2. Analysis
Comparison 4: Secondary treatment ‐ IVIG versus infliximab, Outcome 2: Adverse effects: total dose of single IVIG vs single infliximab
4.3
4.3. Analysis
Comparison 4: Secondary treatment ‐ IVIG versus infliximab, Outcome 3: Need for additional treatment: total dose of single IVIG vs single infliximab
5.1
5.1. Analysis
Comparison 5: Secondary treatment ‐ IVIG versus prednisolone, Outcome 1: CAA: single IVIG vs multiple prednisolone
5.2
5.2. Analysis
Comparison 5: Secondary treatment ‐ IVIG versus prednisolone, Outcome 2: Adverse effects: IVIG vs multiple prednisolone
6.1
6.1. Analysis
Comparison 6: Tertiary treatment ‐ IVIG versus prednisolone, Outcome 1: CAA: IVIG vs prednisolone
6.2
6.2. Analysis
Comparison 6: Tertiary treatment ‐ IVIG versus prednisolone, Outcome 2: Duration of fever (days): IVIG vs prednisolone
7.1
7.1. Analysis
Comparison 7: Additional subgroup analysis: primary treatment ‐ IVIG (and ASA) versus ASA, Outcome 1: Analysis 1.1 subgrouped by geographic distribution
8.1
8.1. Analysis
Comparison 8: Additional subgroup analysis: primary treatment ‐ IVIG versus IVG, Outcome 1: Analysis 2.1.1 subgrouped by geographical distribution
8.2
8.2. Analysis
Comparison 8: Additional subgroup analysis: primary treatment ‐ IVIG versus IVG, Outcome 2: Analysis 2.2 subgrouped by geographical distribution
8.3
8.3. Analysis
Comparison 8: Additional subgroup analysis: primary treatment ‐ IVIG versus IVG, Outcome 3: Analysis 2.4 subgrouped by geographical distribution
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References

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References to studies excluded from this review

ChiCTR2000035163 {published data only}
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Hamada 2019 {published data only}
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    1. Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, et al. Efficacy of primary treatment with immunoglobulin plus cyclosporine for prevention of coronary artery abnormalities in Kawasaki disease patients predicted to be at increased risk of IVIG non-response (KAICA study): a controlled, phase 3, randomised, open-label, blinded-endpoints trial. Rheumatology 2019;58(Suppl 2):kez063-031. [DOI: 10.1093/rheumatology/kez063.031] - DOI - PubMed
ISRCTN71987471 {published data only}
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JPRN‐UMIN000014665 {published data only}
    1. JPRN-UMIN000014665. The investigation of the therapeutic efficacy of rapid intravenous immunoglobulin injection for acute phase Kawasaki disease. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-UMIN000014665 (first received 30 October 2014).
Lee 1996 {published data only}
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Lin 2021 {published data only}
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Nanishi 2017 {published data only}
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Portman 2019 {published data only}
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    1. Portman MA, Dahdah NS, Slee A, Olson AK, Choueiter NF, Soriano BD, et al. Etanercept with IVIg for acute Kawasaki disease: a randomized controlled trial. Pediatrics 2019;143:6. [DOI: 10.1542/peds.2018-3675] - DOI - PMC - PubMed
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References to studies awaiting assessment

Chang 2007 {published data only}
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Chang 2008 {published data only}
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Chen 2006 {published data only}
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Ho 2003 {published data only}
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Ho 2004 {published data only}
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Juan 2003 {published data only}
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Juan 2005 {published data only}
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Juan 2006 {published data only}
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Li 2008 {published data only}
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Li 2009 {published data only}
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Liao 2007 {published data only}
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Liu 2009 {published data only}
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Lu 2003 {published data only}
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Teng 2005 {published data only}
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Yao 2009 {published data only}
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Yuan 2009 {published data only}
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Yueh 2006 {published data only}
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References to ongoing studies

ChiCTR1900027954 {published data only}
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EUCTR2020‐003194‐22‐FR {published data only}
    1. EUCTR2020-003194-22-FR. A randomized phase III multicentre trial comparing the efficacy and safety of Anakinra versus intravenous immunoglobulin (IVIG) retreatment, in patients with Kawasaki disease who failed to respond to initial standard IVIG treatment (ANACOMP) [Essai multicentrique randomisé de phase III comparant l'efficacité et la sécurité de l'anakinra au retraitement par immunoglobulines intraveineuses (IVIG), chez des patients atteints de la maladie de Kawasaki qui n'ont pas répondu au traitement initial standard par IVIG]. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-003194-22-FR (first received 7 September 2020).
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References to other published versions of this review

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