Assessment of intravenous immunoglobulin non-responders in Kawasaki disease

Hwang, Ja Young; Lee, Kyung-Yil; Rhim, Jung Woo; Youn, You Sook; Oh, Jin Hee; Han, Jieun; Lee, Joon Sung; Burgner, David

doi:10.1136/adc.2010.184101

Cited by 52 publications

(40 citation statements)

References 7 publications

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“…Given that IVIG non-responders are still febrile with ongoing inflammation, we hypothesized a direct impact of IVIG on neutrophils instead of a secondary therapeutic effect of global inflammation reduction. This is consistent with previous smaller cohort observations [34, 35]. Neutrophils isolated from IVIG responders exhibit accelerated spontaneous apoptosis in vitro [36], suggesting that apoptosis may cause the reduction of neutrophils during IVIG treatment.…”

Section: Discussionsupporting

confidence: 93%

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness

Wang

et al. 2016

PLoS ONE

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BackgroundResistance to intravenous immunoglobulin (IVIG) occurs in 10–20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.MethodWe explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.ResultsThirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.ConclusionsGene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics.

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Section: Discussionsupporting

confidence: 93%

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness

Wang

et al. 2016

PLoS ONE

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“…However, some patients do not respond to IVIG. According to recent studies, 20–30% of KD patients have no response to IVIG , a rate that is much higher than the 11% reported a decade ago . In the present study, 18.2% of KD patients had no response to the first IVIG infusion.…”

Section: Discussioncontrasting

confidence: 59%

A Comprehensive Assessment of the Value of Laboratory Indices in Diagnosing Kawasaki Disease

Shao

Shang

et al. 2015

Arthritis & Rheumatology

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Objective Kawasaki disease (KD) is the primary cause of heart disease among children, but because its clinical symptoms are nonspecific, it is difficult to diagnose. The purpose of this study was to evaluate laboratory indices for possible use in the early diagnosis of KD and to determine which indices are predictive of a response to intravenous immunoglobulin (IVIG) and can be used to monitor the effects of treatment. Methods Three hundred thirty KD patients, 330 age‐matched children with KD‐like febrile disease, and 330 age‐matched healthy children (controls) were enrolled in this prospective study. Levels of N‐terminal pro–brain natriuretic peptide (NT‐proBNP), erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), and cytokines were determined in all study subjects. Results In the derivation cohort, 181 patients in the KD group were compared with 181 patients in the KD‐like febrile group. The following indices were found to be useful in the diagnosis of KD: NT‐proBNP (area under the curve [AUC] 0.923), ESR (AUC 0.909), CRP (AUC 0.834), and interleukin‐6 (IL‐6; AUC 0.678). The diagnostic efficiency of each index demonstrated in the derivation cohort was repeated in the 149 KD patients in the validation cohort. There were significant differences in NT‐proBNP levels between IVIG‐responsive KD patients (n = 270) and IVIG‐nonresponsive KD patients (n = 60), with higher NT‐proBNP levels in IVIG‐nonresponsive KD patients. The NT‐proBNP level can effectively distinguish IVIG‐responsive KD patients from IVIG‐nonresponsive patients, and its AUC was 0.73. There were also significant differences in the NT‐proBNP levels before and after treatment, with a significant decline after treatment. Conclusion Serum levels of NT‐proBNP can be used in the diagnosis of KD, the prediction of a patient's sensitivity to IVIG treatment, and the monitoring of the effects of IVIG treatment, but more attention must be paid to the scope of its application.

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“…The results of 20 studies were combined in this study comprising 18 Asian studies [4, 6, 9, 10, 13, 17, 19, 20, 22, 24–26, 29, 32, 33, 37, 41, 44] and 2 North American studies [18, 38]. Each subgroup analysis showed the results had statistical significance; however, Baek et al [2] reported that ESR and platelet count could not predict IVIG-resistant Kawasaki disease from their statistical meta-analysis, which is contrary to the results of the present study.…”

Section: Discussionmentioning

confidence: 99%

Predictors of intravenous immunoglobulin-resistant Kawasaki disease in children: a meta-analysis of 4442 cases

Chen

Tang

et al. 2018

Eur J Pediatr

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The purpose of this study was to identify the clinical features and laboratory factors that are predictive of intravenous immunoglobulin (IVIG)-resistant Kawasaki disease. Multiple databases were searched for relevant studies on IVIG-resistant Kawasaki disease published from January 2002 to April 2017. Eligible studies were retrieved by manual review of the references. Stata 12 was used for the meta-analysis. Weighted mean differences and odds ratios with 95% confidence intervals were calculated for several indices. Twenty-eight studies involving 26,260 patients comprising 4442 IVIG-resistant Kawasaki disease patients and 21,818 IVIG-sensitive Kawasaki disease patients were included. The meta-analysis showed that the erythrocyte sedimentation rate (ESR) in the IVIG-resistant group was significantly higher than that in the IVIG-sensitive group, and that platelet count and hemoglobin levels were significantly lower in the IVIG-resistant group. The patients with oral mucosa alterations, cervical lymphadenopathy, swelling of the extremities, polymorphous rash, and initial administration of IVIG ≤ 4.0 days after the onset of symptoms were more likely to be IVIG resistant.Conclusion: The initial administration of IVIG ≤ 4.0 days after the onset of symptoms increased ESR and decreased hemoglobin and platelet counts, oral mucosa alterations, cervical lymphadenopathy, swelling of the extremities, and polymorphous rash and are the risk factors for IVIG-resistant Kawasaki disease. What is Known: • Recent reports on this topic are about aspartate aminotransferase (AST), alanine aminotransferase (ALT), gammaglutamyl transferase, total bilirubin, white blood cells, platelets, erythrocyte sedimentation rate (ESR), polymorphonuclear leukocytes (PMN), C-reactive protein (CRP), pro-brain natriuretic peptide (BNP), albumin, and sodium as the risk factors in the IVIG-resistant Kawasaki disease; however, no studies have been published on clinical features as predictors of IVIG resistance. What is New: • This meta-analysis identified the clinical features, the initial administration of IVIG ≤ 4.0 days after the onset of symptoms, and much more comprehensive laboratory indicators, such as hemoglobin, as predictors of IVIG-resistant Kawasaki disease. Electronic supplementary materialThe online version of this article (10.1007/s00431-018-3182-2) contains supplementary material, which is available to authorized users.

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Assessment of intravenous immunoglobulin non-responders in Kawasaki disease

Cited by 52 publications

References 7 publications

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness

Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness

A Comprehensive Assessment of the Value of Laboratory Indices in Diagnosing Kawasaki Disease

Predictors of intravenous immunoglobulin-resistant Kawasaki disease in children: a meta-analysis of 4442 cases

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