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The therapeutic window of intravenous immunoglobulin (IVIG) and its correlation with clinical outcomes in Kawasaki disease: a systematic review and meta-analysis

Italian Journal of Pediatrics volume 49, Article number: 45 (2023) Cite this article

Abstract

Background

The optimal therapeutic window to start intravenous immunoglobulin (IVIG) for Kawasaki disease (KD) is highly debatable. We aimed to summarize the existing literature to evaluate the therapeutic window of IVIG treatment and its correlation with clinical outcomes in KD patients.

Methods

We searched the databases from inception to August 26, 2022, without language restrictions. The primary outcomes were initial IVIG resistance and coronary artery lesions (CALs) in acute phase. Secondary outcome was CALs during 1–2 months of follow-up.

Results

27 studies involving 41,139 patients were included in this study. Very low-quality evidence showed that the earlier IVIG treatment within 4 days had a higher IVIG-resistance rate (RR, 1.80; 95% CI, 1.50–2.15; P < .00001; I2 = 75%) than the late treatment. Very low-quality evidence showed that IVIG treatment for more than 7 days was associated with a higher risk of CALs in acute phase(RR, 0.57; 95% CI, 0.40–0.80; P = .001; I2 = 76%). There was a lower risk of CALs during 1–2 months follow-up for those who started IVIG administration within 10 days from the onset.

Conclusions

Overall, IVIG treatment within 7 days of illness seems to be the optimal therapeutic window of IVIG. IVIG treatment within 7 days is found to be effective for reducing the risk of coronary artery lesions and cardiac sequelae in KD patients. The early IVIG treatment within 4 days should be vigilant for the IVIG resistance although large multi-center randomized trials with well design are needed.

Background

Kawasaki disease (KD) is an acute, febrile vasculitis of unknown aetiology that primarily affecting children < 5 years of age [1]. Major classical features of KD include fever, conjunctivitis, erythema of the lips, oral mucosa, changes in extremities, rash, and cervical lymphadenopathy. KD has been reported in more than 60 countries worldwide since first described in Japan in 1974 [2]. The incidence of KD is increasing, and the highest relative risk is in Asian children, especially in eastern Asia [3]. KD has surpassed acute rheumatic fever as the most common cause of acquired heart disease in developed countries [4].

The most common sequel caused by KD is coronary artery lesions (CALs), including coronary artery dilatation and coronary artery aneurysm (CAA) [5]. CAA can develop in around 25% of untreated KD children [1]. Intravenous immunoglobulin (IVIG) in conjunction with aspirin remains the first-line drug therapy for KD patients [1]. The mortality rates of KD have been markedly decreased since the IVIG therapy was introduced in 1983 [6], and the incidence of CALs in those treated appropriately is dropped to 4% [1]. However, several latest clinical guidelines on the optimal timing of IVIG administration and if IVIG can be given earlier remain inconclusive [1, 7, 8]. Some previous retrospective studies reported that IVIG treatment within 5 days of illness reduces the risk of cardiac sequelae, suggesting the efficacy of the earlier initiation of IVIG treatment [9,10,11]. On the contrary, other studies reported that IVIG use at ≤ 4 days of illness had no benefit in preventing coronary complications but was instead associated with increased IVIG resistance [12, 13]. Therefore, the association between the earlier timing of IVIG administration of disease onset and the risk for IVIG unresponsiveness remains controversial and debatable [14].

Given this background, there is a need to qualitatively and critically appraise available evidence and evaluate where gaps exist. Thus, we conducted a systematic review and meta-analysis to investigate the optimal timing of IVIG administration in KD patients by comparing the clinical outcomes of early and conventional IVIG treatment.

Methods

This systematic review and meta-analysis aimed to critically appraise the therapeutic window of IVIG treatment and its correlation with clinical outcomes in KD patients. We performed this systematic review based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [15]. The protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42022356138).

Data sources and search strategy

We systematically searched databases, including PubMed (MEDLINE), Cochrane Library (CENTRAL), Embase, Web of Science, and Chinese Biomedical Literature database (CBM) from database inception to August 26, 2022, without language restrictions. An e-mail alert was received weekly based on a previously developed search strategy saved in PubMed for any new potential studies. For completed and ongoing trials, we also searched trial registries, including ClinicalTrials.gov and the international Clinical Trial registry platform (ICTRP). Finally, we hand-searched reference lists of identified articles for further eligible trials. A search strategy was built based on MeSH terms and free-text words based on the following terms: Mucocutaneous Lymph Node Syndrome, Kawasaki disease, intravenous immunoglobulin, and gamma-Globulins. A detailed search strategy can be seen in Supplementary Material, Appendix S1.

Eligibility criteria

Studies that met all of the following criteria were included: (a) Patients with KD (diagnosed using any recognized diagnostic criteria) undergoing early (≤ day 4), conventional (days 5–10) or late (>day 10) IVIG treatment; (b) study design: randomized controlled trials (RCTs), cross-sectional study, cohort, case-control; (c) with adequate data on necessary basic characteristics and outcomes.

Exclusion criteria were as follows: (a) KD patients complicated with severe infection, allergy, autoimmune diseases, or collagen disease; (b) case reports, reviews, guidelines, opinions, editorials, letters, animal studies, and comments.

Study selection

Study selection was managed using Covidence software (https://www.covidence.org/). Two independent reviewers (ZZ and XMZ) evaluated articles for potential inclusion by screening titles and abstracts. The full texts of those identified as being relevant would then be assessed to determine eligibility for final inclusion. The results would be discussed between each assessment to reach a consensus on the interpretation of the inclusion criteria. Any disagreements regarding study eligibility would be resolved by consensus, and a third reviewer (WT) was consulted if necessary. If the information required to assess eligibility were unavailable or unclear, the relevant study authors would be contacted for clarification. Duplicate publications were identified and removed using EndNote software version X7 (Clarivate Analytics). The identified publications were analyzed using criteria based on largest sample size, the maximum correspondence with the inclusion criteria, and a minimal risk of bias.

Data extraction

Two authors (JL and CMY) independently extracted data in duplicate using a predefined data extraction form (Excel, Microsoft Corporation, USA). We did a thorough pilot test before the formal data collection to ensure consistency in the data extraction process and that all necessary information was collected. The following data were extracted from the studies selected for inclusion, as follows: (a) general characteristics of the study (author names, publication date, study design, study period, setting, funding and country); (b) patient demographic features (including sample size, groups, age, gender, the proportion of complete KD cases, recurrent cases and patients who received IVIG treatment); (c) outcome measures and analyses; (d) IVIG treatment protocol and definitions of IVIG resistance.

The primary outcomes were the incidence of initial IVIG resistance and CALs in the acute phase. The secondary outcome was CALs during 1–2 months follow-up.

Risk of bias and grade certainty assessment

Two reviewers (GFP and HLL) independently assessed the risk of bias based on articles and protocols. Any discrepancies were solved by discussion and intervention of a third reviewer (QT) whenever necessary. We used the Risk of Bias Tool 2.0 (RoB 2.0) developed by the Cochrane Collaboration for randomized trials [16]. This tool evaluates five domains of bias: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results. The RoB 2.0 for each of the 5 domains is described as low, some concerns, or high. The risk of bias was assessed using the Newcastle-Ottawa scale (NOS) for observational cohort and case-control studies [17]. There were three grouping items as follows: selection, comparability, and exposure/outcomes. A study can be awarded a maximum of one star for each numbered item within the selection and outcome categories. A maximum of two stars can be given for comparability. More stars are equalling lower risk. The NOS scale awards a maximum of nine stars to each study. The summary score given to studies can be categorized as poor (0–3 points), fair (4–6 points), or high (≥ 7 points) quality. The quality of evidence of the included studies was assessed according to The Grading of Recommendations Assessment, Development and Evaluation (GRADEpro Guideline Development Tool, available online at gradepro.org) [18].

Statistical analysis

Results were assessed using forest plots and presented as RRs for the binary outcomes. Heterogeneity was assessed by I² tests, and substantial heterogeneity was defined as I² greater than 50%. An inverse variance, fixed-effects method was used if I² was less than 50%, and a random-effects method was used if I² was 50% or greater. We performed subgroup analyses based on research types, study location and type of CALs (coronary artery dilation or CAA). Sensitivity analysis was performed by evaluating the pooled estimate after omitting a study each time. Publication bias was assessed by visually inspecting a funnel plot and quantified by the Egger test. Statistical analyses were conducted using ReviewManager version 5.2 (RevMan; Copenhagen: The Nordic Cochrane Center, the Cochrane Collaboration, 2014, London, UK) and Stata statistical software version 14.0 (StataCorp, College Station, Texas) software. A two-sided p-value less than 0.05 was set as the threshold for statistical significance.

Results

Literature search and study selection.

We identified 8914 articles by the initial database search, including 201 from Pubmed, 4412 from Embase, 246 from the Cochrane database, 3710 from Web of Science, and 345 from CBM. After removing duplicates (n = 2692) and articles based on screening of the title and abstract screening (n = 6179), 43 full-text articles were assessed for eligibility. Furthermore, two articles were identified through citation searching. After screening of full texts, 18 articles that did not meet the inclusion criteria were excluded (reasons for exclusion are summarized in Supplementary Material, Appendix S2). A total of 27 studies [9,10,11,12,13, 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40] met the inclusion criteria and were analyzed for the systemic review and meta-analysis (Fig. 1).

Fig. 1
figure 1

PRISMA Flow Diagram

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Characteristics of the included studies

The included studies were all published from 2002 to 2022 and encompassed 41,139 patients. These studies originated from 7 countries, with sample sizes ranging from 31 to 20,845. Studies were published in English and Chinese. Most of the studies were observational. Eighteen (66.7%) were cohort studies [9, 10, 12, 13, 19,20,21,22,23,24,25,26,27,28,29,30,31,32], three (11.1%) were case-control studies [11, 33, 34], and six (22.2%) were RCTs [35,36,37,38,39,40]. The included articles showed that the clinical outcomes differed among four categories (start of IVIG therapy up to 4 days, 5 to 7 days, 8 to 10 days, and more than 10 days). The heterogeneity might be due to the participant characteristics, IVIG treatment protocol, the definition of IVIG resistance and the definition of CALs. The IVIG treatment protocol and specific definitions used for IVIG resistance were at the individual study investigators’ discretion (Supplementary Material, Appendix S3). Details of the included studies are described in Table 1.

Table 1 Characteristics of the included studies
Full size table

Assessments of risk of bias

All observational studies were of fair-to-high quality, and all randomized studies were at some concerns. The results for each quality assessment by the study are presented in Supplementary Material, Appendix S4 and Supplementary Material, Appendix S5.

Certainty of the evidence

We rated the certainty of the evidence of primary outcomes using by GRADE approach. The analysis results showed that the overall quality of evidence was very low, mainly due to more observational designs we included and inconsistency (I2 > 50%). The outcomes and assessments were presented as a summary of findings in Supplementary Material, Appendix S6.

Primary outcomes

Initial IVIG resistance

Due to a lack of data, we did not include repeated IVIG resistance in our analysis. Of the 27 studies, 21 studies [9,10,11,12,13, 19, 21, 23,24,25, 28, 29, 31,32,33, 35,36,37,38,39,40] including 36,499 participants reported initial IVIG resistance, and 5764 had IVIG resistance (15.8%). Very low-quality evidence showed that, using day 4 of fever as the cut-off point, the early group ( ≦ 4 days) had a higher initial IVIG-resistance (RR, 1.80; 95% CI, 1.50–2.15; P < .00001; I2 = 75%) than the late group (>4 days), with 21.6% (2699 of 12,481) in the early group VS 12.2% (2720 of 22,277) in the late group (Fig. 2). Moreover, at the 7-day (RR, 1.28; 95% CI, 0.71–2.32; P = .41; I2 = 90%) and 10-day (RR, 0.86; 95% CI, 0.58–1.28; P = .46; I2 = 74%) cut-off point, the prevalence of IVIG resistance had no significant difference between the groups (Fig. 2).

Fig. 2
figure 2

Forest Plot of risk ratios for initial IVIG resistance for Early IVIG VS. Late IVIG.

Full size image

The occurrence of CALs in the acute phase

21 studies [9,10,11,12,13, 19, 21, 23,24,25, 28, 29, 31,32,33, 35,36,37,38,39,40] including 38,587 participants investigated the occurrence of CALs in the acute phase, and 4172 had CALs (10.8%). Very low-quality evidence showed that using day 4 of fever as the cut-off point, the two groups of KD patients had a similar likelihood of CALs in the acute phase (RR, 0.92; 95% CI, 0.77–1.10; P = .37; I2 = 70%) (Fig. 3). However, at the 7-day (RR, 0.57; 95% CI, 0.40–0.80; P = .001; I2 = 76%) and 10-day (RR, 0.53; 95% CI, 0.30–0.92; P = .03; I2 = 96%) cut-off point, the rate of CALs in the late group was significantly higher than the early group (Fig. 3).

Fig. 3
figure 3

Forest Plot of risk ratios for CALs in the acute phase for Early IVIG VS. Late IVIG.

Full size image

Secondary outcomes

CALs during 1–2 months follow-up

13 studies [9, 11, 12, 19,20,21,22,23, 25, 29, 31, 33, 39] reported CALs during 1–2 months follow-up (654 of 6652 [9.8%] vs. 696 of 6995 [9.9%]). The pooled analysis showed that delaying IVIG treatment for more than 10 days was associated with a higher risk of CALs during 1–2 months follow-up than the earlier treatment (OR, 0.49; 95% CI, 0.32–0.76; P = .002; I2 = 75%). However, at the 4-day (RR, 1.11; 95% CI, 0.81–1.52; P = .51; I2 = 52%) and 7-day (RR, 0.63; 95% CI, 0.23–1.67; P = .35; I2 = 86%) cut-off point, there was no difference between the groups (Supplementary Material, Appendix S7).

Sensitivity analysis

We conducted several sensitivity analyses to confirm the robustness of our findings. In the sensitivity analysis, the total findings did not change significantly. All sensitivity analyses indicated that the results of the meta-analysis were robust and the heterogeneity reduced to some extent (Supplementary Material, Appendix S8 and S9).

Subgroup analysis

Subgroup analyses were performed based on research types and the study location (Supplementary Material, Appendix S10 and S11). For the subgroup of research types, the pooled analysis of randomized trials, which had a broader confidence interval, smaller sample size and higher heterogeneity (RR, 1.97; 95% CI, 0.76–5.07; P = .16; I2 = 81%), showed that early initiation of IVIG treatment within 4 days was not associated with a higher risk of initial IVIG resistance. The pooled analysis from 13 observational studies showed that early IVIG treatment (≤ 4 days ) was associated with a higher risk of initial IVIG resistance (RR, 1.74; 95% CI, 1.45–2.09; P < .00001; I2 = 74%), but there was evidence of heterogeneity across the studies. The subgroup analyses of CALs in the acute phase showed similar findings based on research types. There were no significant differences in the occurrence of CALs (≤ 4 days VS > 4 days) in both RCTs (RR, 0.71; 95% CI, 0.38–1.33; P = .28; I2 = 0%) and observational studies (RR, 0.94; 95% CI, 0.78–1.14; P = .51; I2 = 74%).

For the subgroup of the study location, we found that the studies performed in Japan (RR, 1.79; 95% CI, 1.56–2.05; P < .00001; I2 = 60%) and Korea (RR, 2.38; 95% CI, 1.94–2.92; P < .00001) showed an increased risk in the occurrence of initial IVIG resistance with early IVIG treatment within 4 days. Meanwhile, studies conducted in China (RR, 1.43; 95% CI, 0.85–2.42; P = .18; I2 = 81%) and Canada (RR, 1.40; 95% CI, 0.66–2.98; P = .38) showed that early IVIG treatment within 4 days is not associated with a higher risk of initial IVIG resistance. The subgroup analyses of CALs in the acute phase showed similar findings based on the study location. There were no significant differences in the incidence of CAL (≤ 4 days VS > 4 days) regardless of the study location (China: RR, 0.79; 95% CI, 0.58–1.08; P = .14; I2 = 46%; Japan: RR, 1.17; 95% CI, 0.95–1.44; P = .13; I2 = 63%; Canada: RR, 0.86; 95% CI, 0.59–1.26; P = .44). It was worth to note only one study [27] conducted in the United States showed that early treatment with IVIG within 4 days was a protective factor against the developing CAL (RR, 0.67; 95% CI, 0.52–0.86; P = .002).

For the subgroup of the type of CALs (coronary artery dilation or CAA), eight non-randomized studies [9,10,11, 25, 29, 32,33,34] and two randomized trials [35, 36] with a sample size of 4122 participants, reported the outcomes of CAA in the acute phase (34 of 608 vs. 312 of 3514). Eight non-randomized studies [9, 11, 20, 22, 25, 29, 33, 34] with a sample size of 4235 participants reported the outcomes of CAA during 1–2 months follow-up (71 of 1625 vs. 126 of 2610). Both in the acute phase (RR, 0.23; 95% CI, 0.14–0.39; P < .00001; I2 = 65%) and during 1–2 months follow-up (RR, 0.20; 95% CI, 0.13–0.31; P < .00001; I2 = 43%), the pooled results showed that a significantly increased incidence of CAA was observed in the late IVIG (≥ 10 days) treatment compared with the earlier treatment (<10 days). Furthermore, the incidence of CAA was lower in the early group than in the late group but without statistical significance (acute phase: RR, 0.42; 95% CI, 0.16–1.11; P = .08; I2 = 90%; follow-up: RR, 0.28; 95% CI, 0.07–1.14; P = .08; I2 = 75%) when using the 7-day as the cut-off point. At the 4-day cut-off point, the incidence of CAAs was similar between the two groups (acute phase: RR, 0.91; 95% CI, 0.35–2.35; P = .84; I2 = 70%, follow-up: RR, 1.18; 95% CI, 0.52–2.65; P = .69; I2 = 24%). The detailed information can be seen in Supplementary Material, Appendix S12 and Supplementary Material, Appendix S13.

Eight non-randomized studies [9,10,11, 25, 29, 30, 32, 33] and three randomized trials [35, 36, 38] with a sample size of 4146 participants reported the outcomes of coronary artery dilation in the acute phase (89 of 637 vs. 553 of 3509). Six non-randomized studies [9, 11, 20, 25, 29, 33] with a sample size of 2907 participants reported the outcomes of coronary artery dilation during 1–2 months follow-up (41 of 502 vs. 229 of 2405). Both in the acute phase (RR, 0.64; 95% CI, 0.53–0.77; P < .00001; I2 = 0%) and during 1–2 months follow-up (RR, 0.51; 95% CI, 0.34–0.79; P = .002; I2 = 15%), the pooled analysis showed that delaying IVIG treatment for more than 10 days had a higher risk of coronary artery dilation than the earlier treatment within 10 days. There was no evidence of heterogeneity within the subgroups. Meanwhile, the incidence of coronary artery dilation in patients who were treated with IVIG within 4 days (acute phase: RR, 0.86; 95% CI, 0.67–1.10; P = .23; I2 = 0%, follow-up: RR, 0.80; 95% CI, 0.55–1.15; P = .22; I2 = 0%) or 7 days (acute phase: RR, 0.64; 95% CI, 0.40–1.02; P = .06; I2 = 50%, follow-up: RR, 0.79; 95% CI, 0.37–1.70; P = .55; I2 = 66%) of symptom onset was lower than the late IVIG treatment but without statistical significance. The results can be seen in Supplementary Material, Appendix S14 and S15.

Publication Bias

Funnel plots were generated for outcomes with 10 or more studies to evaluate publication bias (Supplementary Material, Appendix S16 and Supplementary Material, Appendix S17). The Egger test did not demonstrate significant publication bias for initial IVIG resistance (4-day cut-off point: P = .36, 10-day cut-off point: P = .90) and CALs in the acute phase (4-day cut-off point: P = .25, 10-day cut-off point: P = .57).

Discussion

This systematic review and meta-analysis of 27 studies, including 41,139 participants, comprehensively summarized the available published literature and focused on the optimal therapeutic window of IVIG treatment across a wide range of populations. There are several main findings of our study. First, very low-quality evidence showed that the early IVIG treatment (≤ 4 days) had a higher IVIG resistance rate than the late treatment (≥ 5 days). Further subgroup analysis with heterogeneity from observational studies showed similar results. However, the pooled results of the RCTs subgroup showed that early IVIG treatment within 4 days was not associated with a higher risk of initial IVIG resistance. In contrast to the studies performed in China and Canada that found no significant difference in IVIG resistance, studies conducted in Japan and South Korea showed an increased risk of IVIG resistance with early IVIG treatment within 4 days. Second, early IVIG treatment within 7 days was associated with a lower occurrence of CALs in the acute phase in the overall estimate. Third, for the secondary outcomes, there was a lower risk of CALs during 1–2 months follow-up for those who started IVIG administration within 10 days from the onset.

IVIG is the first-line treatment of KD with well-established therapeutic effects in preventing coronary artery abnormalities [41]. However, the criteria for when to provide IVIG are unclear and differ from the latest guidelines. The latest 2017 American Heart Association (AHA) and 2018 Italian Society of Pediatrics guidelines recommend that IVIG be administered to KD patients within the first 10 days of illness and, if possible, within the first seven days of illness because the rate at which KD patients develop aneurysms increases significantly after the ninth day of illness [1, 7]. Similarly, the 2020 Japanese Circulation Society stated that IVIG was most frequently administered on the 5th day of illness [8]. There is no suggestion on the optimal timing of IVIG and if it can be given earlier. Our study showed that IVIG treatment within 4 days of illness was associated with increased initial IVIG resistance, which is in line with the results of a previous meta-analysis [42]. It is worth noting that subgroup analyses for the RCTs revealed that early IVIG treatment (≤ 4 days) was not associated with a higher risk of initial IVIG resistance. Meanwhile, the pooled results from observational studies with heterogeneity showed that early IVIG therapy (≤ 4 days ) was associated with a higher risk of IVIG resistance. Thus, these results must be interpreted cautiously since most of the observational studies were retrospective, with potential selection and information bias. More large, well-conducted RCT evaluating the relationship between the early IVIG treatment and IVIG resistance would answer this question.

In the nationwide surveys of KD in Japan, patients treated early (≤ day 4 of illness) were more likely to require retreatment with IVIG [12]. Several studies conducted in Japan showed similar results [13, 21]. On the other hand, recent studies [9, 10] showed that Chinese KD patients who had earlier IVIG treatment administration within 4 days might not increase the higher incidence of IVIG resistance. Further subgroup analyses confirmed that unlike the studies performed in China that found no significant difference in IVIG resistance, studies conducted in Japan showed an increased risk in the rate of IVIG resistance with early IVIG treatment within 4 days. One possible explanation is that the early group showed a higher rate of IVIG resistance because there might be more patients with severe inflammation or atypical clinical course, respectively. Another reason for the difference may be that KD’s characteristics vary between ethnicities.

The most common sequela of KD is CAL, which is speculated to be caused by acute systemic inflammation [43]. The early prevention of CALs is important to improve outcomes in KD patients, as CALs severely impair the life quality of KD patients. It is not surprising that our results showed that patients treated earlier (≤ 7 days) had a lower rate of occurrence of CALs in the acute phase. Furthermore, KD patients who received IVIG therapy more than 10 days after the onset had a higher incidence of CALs during 1–2 months of follow-up. Our study highlights the importance of early intervention to prevent coronary artery complications in treating KD. To minimize cardiac sequelae, avoiding any delay in IVIG treatment is crucial because earlier inflammatory suppression may contribute to avoiding developing CAA [44].

Strengths and Limitations

Our study had strengths: First, we used standard Cochrane protocols and had the largest cumulative sample size to date compared to the previous reports. Second, we analyzed long-term follow-up data on primary and secondary outcomes and included all IVIG infusion time points. Third, no language limit was applied; we included studies published in English and Chinese. Fourth, the GRADEpro approach was used to rate the certainty of evidence.

This study had several limitations to be noted. First, Most of the articles we included were retrospective observational studies with potential selection and information bias. In addition, the sample size of included RCTs was small, and all were carried out in China. Second, the clinical heterogeneity of studies, particularly the participant characteristics, IVIG treatment protocol, and the diagnostic criteria of IVIG resistance and CALs, was quite varied, potentially leading to substantial heterogeneity. Finally, the certainty of the evidence for all outcomes was very low.

Conclusion

The findings of this systematic review and meta-analysis pooling data from multiple countries demonstrate that IVIG therapy within 7 days of illness may be the optimal therapeutic window of IVIG. IVIG treatment within 7 days is found to be effective for reducing the risk of coronary artery lesions and cardiac sequelae in KD patients. The early IVIG treatment within 4 days should be vigilant for the IVIG resistance although large multi-center randomized trials with well design are needed.

Data Availability

The datasets used and/or analyzed during the current study are available within the manuscript.

Abbreviations

KD:

Kawasaki disease

IVIG:

Intravenous immunoglobulin

CALs:

Coronary artery lesions

CAA:

Coronary artery aneurysm

RCTs:

Randomized controlled trials

NOS:

Newcastle-Ottawa scale

RoB:

Risk of Bias Tool

AHA:

American Heart Association

References

  1. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki Disease: A Scientific Statement for Health Professionals from the American Heart Association. Circulation. 2017;135:e927–99.

    Article  PubMed  Google Scholar 

  2. Zhang Y, Wang X, Cai J, Yang Y, Liu Y, Liao Y, et al. Status and influencing factors of medication literacy among chinese caregivers of discharged children with Kawasaki disease. Front Public Health. 2022;10:960913.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lucas R, Dennington P, Wood E, Murray KJ, Cheng A, Burgner D, et al. Epidemiology of Kawasaki disease in Australia using two nationally complete datasets. J Paediatr Child Health. 2022;58:674–82.

    Article  PubMed  Google Scholar 

  4. Matsubara Y, Matsubara D, Ae R, Kosami K, Aoyama Y, Yashiro M, et al. Cumulative incidence of Kawasaki disease with cardiac sequelae in Japan. Pediatr Int. 2020;62:444–50.

    Article  PubMed  Google Scholar 

  5. Masuda H, Ae R, Koshimizu TA, Matsumura M, Kosami K, Hayashida K, et al. Epidemiology and risk factors for giant coronary artery aneurysms identified after Acute Kawasaki Disease. Pediatr Cardiol. 2021;42:969–77.

    Article  PubMed  Google Scholar 

  6. Takahashi K, Oharaseki T, Yokouchi Y, Yamada H, Shibuya K, Naoe S. A half-century of autopsy results–incidence of pediatric vasculitis syndromes, especially Kawasaki disease. Circ J. 2012;76:964–70.

    Article  PubMed  Google Scholar 

  7. Marchesi A, Tarissi de Jacobis I, Rigante D, Rimini A, Malorni W, Corsello G, et al. Kawasaki disease: guidelines of the italian society of Pediatrics, part I - definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase. Ital J Pediatr. 2018;44:102.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fukazawa R, Kobayashi J, Ayusawa M, Hamada H, Miura M, Mitani Y, et al. JCS/JSCS 2020 Guideline on diagnosis and management of Cardiovascular Sequelae in Kawasaki Disease. Circ J. 2020;84:1348–407.

    Article  CAS  PubMed  Google Scholar 

  9. Li W, He X, Zhang L, Wang Z, Wang Y, Lin H, et al. A Retrospective Cohort Study of Intravenous Immunoglobulin Therapy in the Acute phase of Kawasaki Disease: the earlier, the Better? Cardiovasc Ther. 2021;2021:6660407.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cai JH, Tang M, Zhang HX, Dan Luo E, Zhang R, Shuai SP, et al. Therapeutic window of Intravenous Immunoglobulin (IVIG) and its correlation with IVIG-resistant in Kawasaki Disease: a retrospective study. J Pediatr (Rio J). 2023;99(2):161–7.

    Article  PubMed  Google Scholar 

  11. Tse SM, Silverman ED, McCrindle BW, Yeung RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr. 2002;140:450–5.

    Article  CAS  PubMed  Google Scholar 

  12. Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9.

    Article  CAS  PubMed  Google Scholar 

  13. Kuwabara M, Yashiro M, Ae R, Yanagawa H, Nakamura Y. The effects of early intravenous immunoglobulin therapy for Kawasaki disease: the 22nd nationwide survey in Japan. Int J Cardiol. 2018;269:334–8.

    Article  PubMed  Google Scholar 

  14. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–12.

    Article  PubMed  Google Scholar 

  15. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.

    Article  PubMed  Google Scholar 

  17. Wells G, Shea B, O’Connell D, Robertson J, Peterson J, Welch V et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-analyses. http://www3.med.unipmn.it/dispense_ebm/2009-2010/Corso%20Perfezionamento%20EBM_Faggiano/NOS_oxford.pdf. Accessed 12 January 2023.

  18. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64:383–94.

    Article  PubMed  Google Scholar 

  19. Karimi Yazdi A, Akbariasbagh P, Aghighi Y, Raeeskarami SR, Toomaj K, Heidari S, et al. Impact of early treatment with high-dose intravenous immunoglobulin on incidence of Kawasaki Disease Complications in Iranian Children. J Family Reprod Health. 2021;15:242–7.

    PubMed  PubMed Central  Google Scholar 

  20. Ha KS, Lee J, Lee KC. Prediction of intravenous immunoglobulin resistance in patients with Kawasaki disease according to the duration of illness prior to treatment. Eur J Pediatr. 2020;179:257–64.

    Article  CAS  PubMed  Google Scholar 

  21. Shiozawa Y, Inuzuka R, Shindo T, Mafune R, Hayashi T, Hirata Y, et al. Effect of i.v. immunoglobulin in the first 4 days of illness in Kawasaki disease. Pediatr Int. 2018;60:334–41.

    Article  CAS  PubMed  Google Scholar 

  22. Downie ML, Manlhiot C, Collins TH, Chahal N, Yeung RSM, McCrindle BW. Factors associated with development of coronary artery aneurysms after Kawasaki disease are similar for those treated promptly and those with delayed or no treatment. Int J Cardiol. 2017;236:157–61.

    Article  PubMed  Google Scholar 

  23. Mohammadzadeh I, Noei S, Babazadeh K, Zamani H, Barari-Savadkoohi R, Alizadeh-Navaei R. Comparison of early and late intravenous gamma globulin treatment of Kawasaki disease on fever and cardiovascular complications. Casp J Intern Med. 2016;7:211–6.

    Google Scholar 

  24. Chen JJ, Ma XJ, Liu F, Yan WL, Huang MR, Huang M, et al. Epidemiologic features of Kawasaki Disease in Shanghai from 2008 through 2012. Pediatr Infect Dis J. 2016;35:7–12.

    Article  CAS  PubMed  Google Scholar 

  25. Bal AK, Prasad D, Umali Pamintuan MA, Mammen-Prasad E, Petrova A. Timing of intravenous immunoglobulin treatment and risk of coronary artery abnormalities in children with Kawasaki disease. Pediatr Neonatol. 2014;55:387–92.

    Article  PubMed  Google Scholar 

  26. Wang H. Clinical Observation of Drug Resistance of Gamma Globulin in the treatment of Kawasaki Disease. J Liaoning Med Univ. 2014;35:51–3.

    Google Scholar 

  27. Callinan LS, Tabnak F, Holman RC, Maddox RA, Kim JJ, Schonberger LB, et al. Kawasaki syndrome and factors associated with coronary artery abnormalities in California. Pediatr Infect Dis J. 2012;31:894–8.

    Article  PubMed  Google Scholar 

  28. Sittiwangkul R, Pongprot Y, Silvilairat S, Phornphutkul C. Delayed diagnosis of Kawasaki disease: risk factors and outcome of treatment. Ann Trop Paediatr. 2011;31:109–14.

    Article  CAS  PubMed  Google Scholar 

  29. Du ZD, Di Z, Du JB, Lu S, Yi JM, Hou AC, et al. [Comparison of efficacy among early, conventional and late intravenous gamma globulin treatment of Kawasaki disease]. Zhonghua Yi Xue Za Zhi. 2009;89:1841–3.

    PubMed  Google Scholar 

  30. Li T, Fu P, Wang K, Sun Y, Hu Y, Wang Z, et al. Evaluation of the efficacy of intraveous γ-globulin and anspirin for Kawasaki disease within five days. J Fujian Med Univ. 2006;40:258–82.

    Google Scholar 

  31. Hsieh KS, Weng KP, Lin CC, Huang TC, Lee CL, Huang SM. Treatment of acute Kawasaki disease: aspirin’s role in the febrile stage revisited. Pediatrics. 2004;114:e689–93.

    Article  PubMed  Google Scholar 

  32. Nomura Y, Masuda K, Yoshinaga M, Sameshima K, Miyata K. Patients diagnosed with Kawasaki disease before the fifth day of illness have a higher risk of coronary artery aneurysm. Pediatr Int. 2002;44:353–7.

    Article  PubMed  Google Scholar 

  33. Muta H, Ishii M, Yashiro M, Uehara R, Nakamura Y. Late intravenous immunoglobulin treatment in patients with Kawasaki disease. Pediatrics. 2012;129:e291–7.

    Article  PubMed  Google Scholar 

  34. Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the efficacy of treatment of Kawasaki disease before day 5 of illness. Pediatr Cardiol. 2004;25:31–4.

    Article  CAS  PubMed  Google Scholar 

  35. Kong Z, Liao Q, Zhao J. The effect of gamma globulin application time on the antipyretic time and coronary artery injury in children with Kawasaki disease. J Med Theory Pract. 2021;34:1375–7.

    Google Scholar 

  36. Wu Q. Comparison of Therapeutic Effects of Gamma Globulin on Kawasaki Disease at different time. World Latest Medicine Information. 2019;19:125–6.

    Google Scholar 

  37. Xiong Y. Effect of Gamma Globulin Application Time on Antipyretic Time and Coronary Artery Injury in Children with Kawasaki Disease. Chin Foreign Med Res. 2019;17:30–2.

    Google Scholar 

  38. Shao Y. Comparison of the therapeutic effect of gamma globulin on children with atypical Kawasaki disease at different times. Contemp Med Forum. 2018;16:126–7.

    Google Scholar 

  39. An N, Yao X, Guo J, Xing L, Lv N, Bo J. The effect of gamma globulin application time on the antipyretic time and coronary artery injury in children with Kawasaki disease. Lab Med Clin. 2017;14:2437–9.

    CAS  Google Scholar 

  40. Li J. Different methods of intravenous gamma globulin treatment for Kawasaki disease analysis. Jilin Med J. 2013;34:4207–8.

    Google Scholar 

  41. Takekoshi N, Kitano N, Takeuchi T, Suenaga T, Kakimoto N, Suzuki T, et al. Analysis of age, sex, lack of response to Intravenous Immunoglobulin, and Development of Coronary Artery Abnormalities in Children with Kawasaki Disease in Japan. JAMA Netw Open. 2022;5:e2216642.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yan F, Zhang H, Xiong R, Cheng X, Chen Y, Zhang F. Effect of early intravenous immunoglobulin therapy in Kawasaki Disease: a systematic review and Meta-analysis. Front Pediatr. 2020;8:593435.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chen S, Dong Y, Kiuchi MG, Wang J, Li R, Ling Z, et al. Coronary artery complication in Kawasaki Disease and the importance of early intervention: a systematic review and Meta-analysis. JAMA Pediatr. 2016;170:1156–63.

    Article  PubMed  Google Scholar 

  44. Abrams JY, Belay ED, Uehara R, Maddox RA, Schonberger LB, Nakamura Y. Cardiac complications, earlier treatment, and initial Disease Severity in Kawasaki Disease. J Pediatr. 2017;188:64–9.

    Article  PubMed  Google Scholar 

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Acknowledgements

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Funding

This manuscript was supported by STI 2030-Major Projects [2022ZD0208500], Chengdu High-level Key Clinical Specialty Construction Project [GSPZX2022-03] and Chengdu University of Traditional Chinese Medicine “Xinglin Scholar” [FSYY204].

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Author notes

  1. Zheng Li, Jianghui Cai, Jing Lu and Mingju Wang contributed equally to this work and shared the first authorship.

Authors and Affiliations

  1. Department of Neurology, The Second Clinical Medical College, Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Chengdu Fifth People’s Hospital, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611130, China

    Zheng Li, Jing Lu, Mingju Wang, Chenmei Yang, Zheng Zeng, Qian Tang, Jianhong Li, Wen Tang, Huiling Luo, Gaofeng Pan & Xingmao Zeng

  2. Department of Pharmacy, School of Medicine, Chengdu Women’s and Children’s Central Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China

    Jianghui Cai

  3. Department of Neurology, The Second Clinical Medical College, Geriatric Diseases Institute of Chengdu/Cancer Prevention and Treatment Institute of Chengdu, Chengdu Fifth People’s Hospital, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine), No.33 Mashi Street, Wenjiang District, Chengdu city, 611100, China

    Xingmao Zeng

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Contributions

Dr. Zeng had full access to all of the data in the study and takes responsibility for the integrity of the data. ZL, JHC, JL and MJW drafted the manuscript. ZL and JHC contributed to the design of the search strategy. ZZ, XMZ and WT did the study selection. JL and CMY collected the data. QT, GFP and HLL assessed the risk of bias. MJW and JHL did the statistical analysis. All authors read, provided feedback and approved the final version.

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Correspondence to Xingmao Zeng.

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13052_2023_1451_MOESM1_ESM.docx

Supplementary appendix file: Supplementary Material, Appendix S1. Search strategies. Supplementary Material, Appendix S2. List of references with final exclusion reasons. Supplementary Material, Appendix S3. IVIG treatment protocol and definitions of IVIG resistance. Supplementary Material, Appendix S4. Newcastle-Ottawa scale to rate risk of bias for cohort and case-control study. Supplementary Material, Appendix S5. Cochrane Risk of Bias tool 2.0 (RoB 2) to rate risk of bias for randomised trials. Supplementary Material, Appendix S6. Evidence profiles. Supplementary Material, Appendix S7. Forest Plot of risk ratios (RR) for CALs during 1–2 months follow-up for Early IVIG VS Late IVIG. Supplementary Material, Appendix S8. Sensitivity analysis of initial IVIG resistance. Supplementary Material, Appendix S9. Sensitivity analysis of CALs in acute phase. Supplementary Material, Appendix S10. Subgroup analysis of initial IVIG resistance. Supplementary Material, Appendix S11. Subgroup analysis of CALs in acute phase. Supplementary Material, Appendix S12. Subgroup analysis of CAA in the acute phase for Early IVIG VS Late IVIG. Supplementary Material, Appendix S13. Subgroup analysis of CAA during 1–2 months follow-up for Early IVIG VS Late IVIG. Supplementary Material, Appendix S14. Subgroup analysis of coronary artery dilation in acute phase for Early IVIG VS Late IVIG. Supplementary Material, Appendix S15. Subgroup analysis of coronary artery dilation during 1–2 months follow-up for Early IVIG VS Late IVIG. Supplementary Material, Appendix S16. Funnel plot of initial IVIG resistance. Supplementary Material, Appendix S17. Funnel plot of CALs in acute phase.

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Li, Z., Cai, J., Lu, J. et al. The therapeutic window of intravenous immunoglobulin (IVIG) and its correlation with clinical outcomes in Kawasaki disease: a systematic review and meta-analysis. Ital J Pediatr 49, 45 (2023). https://doi.org/10.1186/s13052-023-01451-6

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Keywords

Italian Journal of Pediatrics

ISSN: 1824-7288

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