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

Wang, Yue; Li, Zhen; Hu, Guang; Hao, Shiying; Deng, Xin; Huang, Min; Miao, Ran; Jiang, Xiyuan; Kanegaye, John T.; Ha, Kee Soo; Lee, JungHwa; Li, Xiaofeng; Jiang, Xuejun; Yu, Yunxian; Tremoulet, Adriana H.; Burns, Jane C.; Whitin, John C.; Shin, Andrew; Sylvester, Karl G.; McElhinney, Doff B.; Cohen, Harvey J.; Ling, Xuefeng B.

doi:10.1371/journal.pone.0167434

Cited by 17 publications

(9 citation statements)

References 44 publications

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“…Identification of potential non-responders before IVIG treatment using genomic scores (MDTH) in an ethnically diverse population may potentially allow early use of adjunctive therapies in selected patients, which in turn could be associated with improved coronary outcomes [ 6 , 30 ]. Previous studies have utilized whole blood transcriptional patterns to identify specific transcripts that were over-expressed in patients with eventual IVIG resistance [ 36 , 37 ], as well as serum biomarkers and cytokines such as G-CSF and sTNFR1 that were correlated with lack of response to therapy. [ 38 , 39 ][ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease

Jaggi

Mejías

et al. 2018

PLoS ONE

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BackgroundEarly identification of children with Kawasaki Disease (KD) is key for timely initiation of intravenous immunoglobulin (IVIG) therapy. However, the diagnosis of the disease remains challenging, especially in children with an incomplete presentation (inKD). Moreover, we currently lack objective tools for identification of non-response (NR) to IVIG.MethodsChildren with KD were enrolled and samples obtained before IVIG treatment and sequentially at 24 h and 4–6 weeks post-IVIG in a subset of patients. We also enrolled children with other febrile illnesses [adenovirus (AdV); group A streptococcus (GAS)] and healthy controls (HC) for comparative analyses. Blood transcriptional profiles were analyzed to define: a) the cKD and inKD biosignature, b) compare the KD signature with other febrile illnesses and, c) identify biomarkers predictive of clinical outcomes.ResultsWe identified a cKD biosignature (n = 39; HC, n = 16) that was validated in two additional cohorts of children with cKD (n = 37; HC, n = 20) and inKD (n = 13; HC, n = 8) and was characterized by overexpression of inflammation, platelets, apoptosis and neutrophil genes, and underexpression of T and NK cell genes. Classifier genes discriminated KD from adenovirus with higher sensitivity and specificity (92% and 100%, respectively) than for GAS (75% and 87%, respectively). We identified a genomic score (MDTH) that was higher at baseline in IVIG-NR [median 12,290 vs. 5,572 in responders, p = 0.009] and independently predicted IVIG-NR.ConclusionA reproducible biosignature from KD patients was identified, and was similar in children with cKD and inKD. A genomic score allowed early identification of children at higher risk for non-response to IVIG.

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Section: Discussionmentioning

confidence: 99%

Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease

Jaggi

Mejías

et al. 2018

PLoS ONE

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“…Therefore, finding biomarkers that can predict IVIG resistance is an important area of current KD research. Neutrophils [14,[77][78][79][80][81], B cells [23], CD8+ T cells [82], and Th17 cells [32,33] in KD peripheral blood have all been reported to predict IVIG resistance, but the types of immune cells supported by different studies are not consistent. Our research did not identify immune cells that can accurately predict IVIG response in multiple datasets.…”

Section: Discussionmentioning

confidence: 99%

Atlas of Circulating Immune Cells in Kawasaki Disease

Z¹,

Huang²,

X³

et al. 2021

Preprint

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Increased evidence shows that the pathogenesis of Kawasaki disease (KD) is caused by abnormal and unbalanced innate and adaptive immune responses. However, the changes in and functions of adaptive immune cells in KD peripheral blood are still controversial. In this study, three different methods, CIBERSORT, Immune Cell Abundance Identifier (ImmuCellAI), and immune cell markers, were used to evaluate the proportions and abundances of immune cells in eight KD datasets (GSE9863, GSE9864, GSE18606, GSE63881, GSE68004, GSE73461, GSE73463, and GSE64486; a total of 1,251 samples). Compared with those in normal controls and convalescent KD samples, the proportions and abundances of innate immune cells such as neutrophils, monocytes, and macrophages in acute KD peripheral blood samples were significantly increased, while those of adaptive immune cells such as B and T cells were significantly decreased. The change tendency of these immune cells was similar to that seen in other febrile illnesses but more dramatic. However, in the coronary artery tissue of KD patients, adaptive immune cells, especially B cells and CD8+ T cell subsets, were significantly increased. This result suggests that adaptive immune cells are selectively recruited from peripheral blood into the coronary arteries. In addition, we found that elevated neutrophils in peripheral blood could be used as a biomarker to assist in the differential diagnosis of KD, but we did not find immune cells that can accurately predict intravenous immunoglobulin (IVIG) response in multiple datasets.

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“…IVIG resistant patients have higher levels of N%, CRP, NT-proBNP, TBIL, ALT, AST and lower levels of L%, PLT. Several previous studies reported that CRP, ESR, ALT, γ-GT and NT-proBNP could be used for predicting resistance to IVIG therapy and patients who are at high risk for CALs [4,[31][32][33][34]. To predict the ability of response to IVIG before initial therapy, would allow clinicians to identify those potential IVIG resistant patients and give them more aggressive treatments [35].…”

Section: Discussionmentioning

confidence: 99%

Association of HMGB1, S100A12 and IL-17A Expression with IVIG-Resistant Kawasaki Disease and Treatment Options

Liu¹,

Liu²,

Liu³

et al. 2020

Preprint

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Background: Kawasaki disease (KD) is a medium vessel vasculitis of unknown aetiology that predominantly affecting coronary arteries. The damage-associated molecular pattern molecules (DAMPs) such as HMGB1, S100A12 and IL-17A have been reported to predict poor response to IVIG. Here, we explored the the role of HMGB1, S100A12 and IL-17A in the detection of intravenous immunoglobulin (IVIG)-resistant in KD patients, and to investigate the value of different adjunctive therapy.Method: 126 KD patients and as well as age- and sex-matched 16 febrile control subjects were enrolled in our study. The fresh peripheral blood were collected from KD patients and febrile controls, analyzed the demographic or clinical data and various laboratory parameters. We also measured changes in serum levels of IL-17A and mRNA expression levels of HMGB1 and S100A12 were tested in IVIG-resistant KD patients. Further we explored the association between coronary arteries lesions and different treatment options about IVIG retreatment, methylprednisolone and infliximab for IVIG-resistant KD patients. Result: Regarding laboratory parameters, KD individuals were found to have lower levels of lymphocyte(L)%, prealbumin, CD4+, CD8+ and higher levels of WBC, neutrophil (N)%, CRP, ESR, NT-proBNP, ALT, CD4+/CD8+ (P<0.05 or P<0.01). For KD group, the 53 IVIG-resistant patients had significantly higher levels of S100A12, HMGB1, serum IL-17A, N%, CRP, NT-proBNP, TBIL, ALT, AST and lower levels of L%, PLT (P<0.05 or P<0.01) in comparison to the IVIG-responsive patients. For patients with IVIG-resistant, IVIG retreatment, methylprednisolone or infliximab were used. Methylprednisolone showed better in improving clinical symptoms and CRP than the IVIG retreatment and infliximab (P> 0.05).Conclusion: IVIG-resistant was associated with overreaction of inflammation.The levels of HMGB1,S100A12 and IL-17A suggested to be reliable predictors for IVIG-resistant in KD. In addition, the adjunctive therapy of methylprednisolone and infliximab showed more effective in relieving clinical symptoms than IVIG retreatment.

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

Cited by 17 publications

References 44 publications

Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease

Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease

Atlas of Circulating Immune Cells in Kawasaki Disease

Association of HMGB1, S100A12 and IL-17A Expression with IVIG-Resistant Kawasaki Disease and Treatment Options

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