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. 2024 Feb;76(2):285-292.
doi: 10.1002/art.42680. Epub 2023 Nov 20.

Elevation of IL-17 Cytokines Distinguishes Kawasaki Disease From Other Pediatric Inflammatory Disorders

Kailey E Brodeur  1 , Meng Liu  2 , Daniel Ibanez  1 , Mareike J de Groot  3 , Liang Chen  1 , Yan Du  4 , Eman Seyal  1 , Raquel Laza-Briviesca  1 , Annette Baker  1 , Joyce C Chang  1 , Margaret H Chang  1 , Megan Day-Lewis  1 , Fatma Dedeoglu  1 , Audrey Dionne  1 , Sarah D de Ferranti  1 , Kevin G Friedman  1 , Olha Halyabar  1 , Mindy S Lo  1 , Esra Meidan  1 , Robert P Sundel  1 , Lauren A Henderson  1 , Peter A Nigrovic  5 , Jane W Newburger  1 , Mary Beth Son  1 , Pui Y Lee  1
Affiliations

Elevation of IL-17 Cytokines Distinguishes Kawasaki Disease From Other Pediatric Inflammatory Disorders

Kailey E Brodeur et al. Arthritis Rheumatol. 2024 Feb.

Abstract

Objective: Kawasaki disease (KD) is a systemic vasculitis of young children that can lead to development of coronary artery aneurysms. We aimed to identify diagnostic markers to distinguish KD from other pediatric inflammatory diseases.

Methods: We used the proximity extension assay to profile proinflammatory mediators in plasma samples from healthy pediatric controls (n = 30), febrile controls (n = 26), and patients with KD (n = 23), multisystem inflammatory syndrome in children (MIS-C; n = 25), macrophage activation syndrome (n = 13), systemic and nonsystemic juvenile idiopathic arthritis (n = 14 and n = 10, respectively), and juvenile dermatomyositis (n = 9). We validated the key findings using serum samples from additional patients with KD (n = 37) and febrile controls (n = 28).

Results: High-fidelity proteomic profiling revealed distinct patterns of cytokine and chemokine expression across pediatric inflammatory diseases. Although KD and MIS-C exhibited many similarities, KD differed from MIS-C and other febrile diseases in that most patients exhibited elevation in one or more members of the interleukin-17 (IL-17) cytokine family, IL-17A, IL-17C, and IL-17F. IL-17A was particularly sensitive and specific, discriminating KD from febrile controls with an area under the receiver operator characteristic curve of 0.95 (95% confidence interval 0.89-1.00) in the derivation set and 0.91 (0.85-0.98) in the validation set. Elevation of all three IL-17-family cytokines was observed in over 50% of KD patients, including 19 of 20 with coronary artery aneurysms, but was rare in all other comparator groups.

Conclusion: Elevation of IL-17 family cytokines is a hallmark of KD and may help distinguish KD from its clinical mimics.

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Conflict of interest statement

Conflict of interest statement:

The authors declare the following conflicts of interest related to this work:

FD is a consultant for Novartis and receives royalties from UpToDate.

AD receives sponsored research funding from Pfizer.

SDF receives royalties from UpToDate.

LAH is a consultant for Adaptive Biotech, Pfizer, and Sobi, receives sponsored research funding from BMS, and receives royalties from CARRA.

PAN is a consultant for BMS, Fresh Track Therapeutics, Exo Therapeutics, Merck, Novartis, Pfizer, Qiagen, and Sobi, receives sponsored research from BMS and Pfizer, and receives royalties from the American Academy of Pediatrics and UpToDate.

MBS receives royalties from UpToDate.

JWN receives sponsored research from Pfizer and BMS and receives royalties from UpToDate.

PYL is a consultant for Fresh Track Therapeutics and Exo Therapeutics and receives royalties from UpToDate.

The other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Profiling proinflammatory markers in pediatric inflammatory diseases using proximity extension assay (PEA).
A) Schematic illustrating the key steps of PEA. B) Hierarchical clustering and heatmap display of normalized PEA data in healthy controls (n=30), febrile controls (n=26), and patients with Kawasaki disease (KD; n=23), multisystem inflammatory syndrome in children (MIS-C; n=25), macrophage activation syndrome (MAS, n=13), systemic- and non-systemic juvenile idiopathic arthritis (n=14 and n=10, respectively), and juvenile dermatomyositis (n=9). C) Radar plots of median expression values of key cytokines and chemokines upregulated in KD, MAS, and MIS-C. Units represent pg/mL in panel C.
Figure 2.
Figure 2.. Identification of inflammatory mediators associated with KD.
A) Comparison of IL-17 cytokine levels in febrile controls (n=26 in derivation cohort; n=28 in validation cohort), patients with KD (n=23 in derivation cohort; n=37 in validation cohort), and patients with MIS-C (n=25). Median and interquartile range are displayed by blue lines. B) Receiver operator characteristics (ROC) curve analysis to evaluate the utility of IL-17A, IL-17C, and IL-17F in distinguishing KD from febrile controls (red line) and MIS-C (blue line). C) ROC curve of IL-17A, IL-17C, and IL-17F in the validation cohort of febrile controls (n=28) vs. patients with KD (n=37). D) Circle diagrams illustrating the proportion of patients with elevated levels of IL-17A, IL-17C, and/or IL-17F. Mann Whitney U test was used for statistical analysis in panel A. Chi square test was used for panel D. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p< 0.0001.
Figure 3.
Figure 3.. Clinical correlates of IL-17 levels in KD.
A) Comparison of IL-17A, IL-17C, and IL-17F levels in KD patients with (n=11 in derivation cohort; n=9 in validation cohort) or without coronary artery aneurysms (n=12 in derivation cohort; n=28 in validation cohort). B) Circle diagrams illustrating the proportion of patients with elevated levels of IL-17A, IL-17C and/or IL-17F in derivation and validation KD cohorts stratified by the presence or absence of CAA. C) Comparison of IL-1β, IL-6, and TNF levels in KD patients with (n=11 in derivation cohort; n=9 in validation cohort) or without coronary artery aneurysms (n=12 in derivation cohort; n=28 in validation cohort). Median and interquartile range are displayed in Panels A and C. Mann Whitney U test was used for statistical analysis. Chi square test was used for panel B.
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