Distinctive serum lipidomic profile of IVIG-resistant Kawasaki disease children before and after treatment

Abstract

Kawasaki Disease (KD) is an acute inflammatory disorder associated with systemic vasculitis. Intravenous immunoglobulin (IVIG) is an effective therapy for KD, yet, about 20% of cases show IVIG resistance with persistent inflammation. The lipid profile in IVIG-resistant KD patients and the relationship between lipid characteristics and IVIG resistance remain unknown. In this study, serum samples from twenty KD patients with different IVIG responses (sensitive, intermediate, or resistant) were collected both before and after treatment, and lipidomic analysis was performed using high-performance liquid chromatography-mass spectrometry. As a result, before treatment, six lipid species were found as the most variant features, in which all the top decreased lipids in the IVIG-resistant group were lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), suggesting the potential to be IVIG-resistant markers in pretreatment diagnosis. During treatment, lipidomic changes showed a weaker response in the IVIG-resistant group. After treatment, LPC and LPE species exhibited lower in the IVIG-resistant group and negative correlation with the inflammatory markers, indicating that the unique metabolism may occur among IVIG-responsiveness. These results might contribute to diagnosing IVIG-resistant patients more accurately for alternative therapy and to a better understanding of how lipid metabolism is associated with IVIG sensitiveness/resistance in KD.

Fig 1

Percentage (A) and concentration (B) of every lipid class in the KD serum before and after treatment among IVIG-sensitive, -intermediate, and -resistant groups. ** P < 0.01.

Fig 2

The Nightingale’s rose diagram of the top differentiated lipid species (A) and the comparison of the distinguished lipid species (B) between IVIG-sensitive + intermediate and IVIG-resistant groups before treatment.

Fig 3

(A) ROC curves of these lipid species for diagnosing IVIG resistance, with AUC, P-value of the curve, and the best cut-off. (B) The histograms of IVIG-sensitive + intermediate (blue) and IVIG-resistant (red) patients based on Gunma scoring, lipid scoring, and combined scoring, respectively. The purple dashed line indicates the referred cut-off of Gunma score, and the green dashed lines indicate the best cut-off calculated for the current samples. (C) ROC curves of Gunma scoring, lipid scoring, and combined scoring for IVIG resistance diagnosis.

Fig 4

(A) Volcano plots for the lipid changes after treatment in IVIG-sensitive, IVIG-intermediate, and IVIG-resistant groups. The lipid species with a change fold of more than 50% and a P value less than 0.05 were considered significant changing features and annotated in color. (B) The concentration of significantly changed LPE and LPC species among the three IVIG-response groups. Scatters in red and cyan stand for the samples before and the samples after treatment, respectively. Solid lines connecting two points indicate the same patient.

Fig 5

(A) Heatmap for the relative changes of TG and FFA species during KD treatment. (B) Changes of each fatty acyl in TG for Sen (blue), Int (green), and Res (red) groups between the before- and after-treatment groups.

Fig 6

(A) Comparison of WBC and CRP among IVIG-sensitive, IVIG-intermediate, and IVIG-resistant groups after treatment. (B) Comparison of the most variant lipid species among IVIG-sensitive, IVIG-intermediate, and IVIG-resistant groups after treatment. (C) Correlation between the top relevant lipid species (LPE20:4, LPE22:6, PI36:2, LPC16:0, LPC18:1, PC36:3) and clinical features (WBC and CRP).