Dataset Information

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

ABSTRACT: Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.

SUBMITTER: Zandstra J

PROVIDER: S-EPMC7388698 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

Zandstra Judith J van de Geer Annemarie A Tanck Michael W T MWT van Stijn-Bringas Dimitriades Diana D Aarts Cathelijn E M CEM Dietz Sanne M SM van Bruggen Robin R Schweintzger Nina A NA Zenz Werner W Emonts Marieke M Zavadska Dace D Pokorn Marko M Usuf Effua E Moll Henriette A HA Schlapbach Luregn J LJ Carrol Enitan D ED Paulus Stephane S Tsolia Maria M Fink Colin C Yeung Shunmay S Shimizu Chisato C Tremoulet Adriana A Galassini Rachel R Wright Victoria J VJ Martinón-Torres Federico F Herberg Jethro J Burns Jane J Levin Michael M Kuijpers Taco W TW

Frontiers in pediatrics 20200722

<b>Background:</b> Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additio ...[more]

PMID: 32775314

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Project description:Background: Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood. Results: In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness. Conclusions: Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses. Whole blood (PAXgene tubes) was obtained from 64 Kawasaki disease patients prior to treatment. RNA was amplified using the MessageAmp kit (Ambion), and reverse transcribed. Each sample was labelled with Cy5, and hybridized to a Lymphochip cDNA array along with amplified human reference RNA labelled with Cy3(Universal Human Reference RNA, Stratagene). Analysis was restricted to those array elements (LUIDs) with signal intensity/background of at least 2.5 in either channel for at least 80% of the samples, and a regression correlation of 0.6. Patterns of gene expression were correlated with clinical parameters, including subsequent response to treatment with intravenous immunoglobulin (IVIG). A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Phenotype: Patient responded (R) or not (NR) to IVIG therapy. Some patients were not classified because they were treated more than 10 days after onset of fever Keywords: disease_state_design

Project description:Kawasaki disease (KD) is characterized by disorder of immune response with unknown etiology. Immune cells may be closely related to the onset of KD. The focus of this research was to evaluate the significance of the infiltration of immune cells for this disease and find possible diagnostic biomarkers for KD. The Gene Expression Omnibus database was utilized to retrieve two freely accessible gene expression patterns (GSE68004 and GSE18606 datasets) from human KD and control specimens. 114 KD, as well as 46 control specimens, were searched for obtaining differentially expressed genes (DEGs). Candidate biological markers were determined utilizing the support vector machine recursive feature elimination and the least absolute shrinkage and selection operator regression model analysis. To assess discriminating capacity, the area under the receiver operating characteristic curve (AUC) was computed. The GSE73461 dataset was utilized to observe the biomarkers' expression levels and diagnostic significance in KD (78 KD patients and 55 controls). CIBERSORT was employed to assess the composition profiles of the 22 subtypes of immune cell fraction in KD on the basis of combined cohorts. 37 genes were discovered. The DEGs identified were predominantly involved in arteriosclerotic cardiovascular disease, atherosclerosis, autoimmune disease of the urogenital tract, and bacterial infectious disease. Gene sets related to complement and coagulation cascades, Toll-like receptor signaling pathway, Fc gamma R-mediated phagocytosis, NOD-like receptor signaling pathway, and regulation of actin cytoskeleton underwent differential activation in KD as opposed to the controls. KD diagnostic biomarkers, including the alkaline phosphatase (ALPL), endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2), and histone cluster 2 (HIST2H2BE), were discovered (AUC = 1.000) and verified utilizing the GSE73461 dataset (AUC = 1.000). Analyses of immune cell infiltration demonstrated that ALPL, EDEM2, and HIST2H2BE were linked to CD4 memory resting T cells, monocytes, M0 macrophages, CD8 T cells, neutrophils, and memory CD4 T cells. ALPL, EDEM2, and HIST2H2BE could be utilized as KD diagnostic indicators, and they can also deliver useful information for future research on the disease's incidence and molecular processes.

Dataset Information

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

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Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

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