Samuel Chen

Background: Kawasaki disease is an inflammatory disease seen in young children (5 years and younger). The disease was first described by Tomisaku Kawasaki, a Japanese pediatrician, in 1967 ^[1]. It is now one of the leading causes of acquired heart disease in Europe, Japan, and North America, with cardiovascular sequelae extending into adulthood ^[2]. Coronary arteritis and coronary artery aneurysms occur in up to 30% of children who are not properly treated ^2,3. The disease causes release of pro-inflammatory cytokines, like IL-1B, IL-18, TNF, which promote vascular endothelial damage ^1,2.  Clinical diagnosis of Kawasaki disease is based on set criteria, including mucosal changes, conjunctivitis, polymorphous rash, extremity changes, and   lymphadenopathy ^1,2.  Current treatment of Kawasaki disease is intravenous immunoglobulin (IVIG) therapy and aspirin ^1,2, and administration of IVIG reduces risk of CAA from 30% to 5-7% ^1,2. However, over 10% of KD patients exhibit IVIG resistance, which leads to increased risk of other complications, and the mechanism of resistance remains relatively unexplored. ⁴ In addition, other treatments for IVIG resistant KD are in trial.

Objectives: In this review, the mechanisms of Kawasaki Disease inflammation and IVIG resistance were explored, as well as alternative treatments to IVIG resistant KD.

Search Methods: An online search in the PubMed database was conducted from 2018-2023 with the following keywords: “Kawasaki Disease,” “Kawasaki disease mechanism,” “IVIG resistance,” “IVIG treatment.”

Results: Current studies have shown that PTX3 can be used as a biomarker of IVIG-resistant KD. ⁴ A study of 60 patients (20 with IVIG resistant KD, 18 with IVIG responsive KD, and 22 healthy patients) determined that PTX3 was elevated in patients with IVIG resistance using qRT-PCR and ELISA. ⁴ The study determined that PTX3’s mechanism of action inhibited p105 phosphorylation and increased p50 and p65 levels. P65 activates the NF-kB pathway and promotes endothelial injury. ⁴ In addition, this study demonstrated that PTX3 knockout inhibited the endothelial damage commonly seen with IVIG resistant KD. As seen in previous studies, IL-1 is required for development of coronary vasculitis. Specifically targeting the IL-1 receptor using an IL-1 receptor antagonist is a potential way to prevent coronary aneurysms and associated heart defects seen in IVIG-resistant KD. ⁵  Anakinra is an IL-1Ra (receptor antagonist) that has been explored and tested to treat IVIG-resistant KD patients.⁶  Lactobacillus casei cell wall extract (LCWE) was injected into mice to induce KD vasculitis, and anakinra was given to mice before injection to day 5. The study used MRI to determine heart functioning, assessing ejection fraction, diastolic volume, and systolic volume.⁶ Echocardiography also was used to determine ejection fraction and interventricular wall thickness. ⁶ Following one week of LCWE injection, mice that were treated with anakinra showed improved EF compared to mice untreated with anakinra. ⁶ EDV and ESV was also improved in the anakinra trial group 35 days after injection. ⁶   In addition, TNF plays a role in cardiac inflammation seen in KD vasculitis.⁵  Infliximab is a TNF blocker that is currently being trialed for IVIG resistant KD.⁵ A 2021 study provided a randomized controlled trial that compared second IVIG infusion versus infliximab in children with IVIG resistant KD. ⁷ The study showed that Infliximab can result in faster fever dissipation and less risk of anemia in first round IVIG resistant KD patients. ⁷

Conclusions: TNF blockers are proven through clinical trials to treat IVIG resistant patients. However, the mechanism on how IVIG resistance develops remains relatively unexplored, and the etiology of the disease remains unknown. A full understanding of both these topics will allow for researchers and physicians to better treat, and potentially prevent Kawasaki disease.

Works Cited

1. Rife E, Gedalia A. Kawasaki Disease: an Update. Curr Rheumatol Rep.          2020;22(10):75. Published 2020 Sep 13. doi:10.1007/s11926-020-00941-4
2. Noval Rivas M, Arditi M. Kawasaki disease: pathophysiology and insights from mouse models. Nat Rev Rheumatol. 2020;16(7):391-405. doi:10.1038/s41584-020-0426-0
3. Seki M, Minami T. Kawasaki Disease: Pathology, Risks, and Management. Vasc Health Risk Manag. 2022;18:407-416. Published 2022 Jun 10. doi:10.2147/VHRM.S291762
4. Sun Y, Liu L, Yang R. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway. Open Life Sci. 2023;18(1):20220735. Published 2023 Oct 24. doi:10.1515/biol-2022-0735
5. Stock AT, Jama HA, Hansen JA, Wicks IP. TNF and IL-1 Play Essential but Temporally Distinct Roles in Driving Cardiac Inflammation in a Murine Model of Kawasaki Disease. J Immunol. 2019;202(11):3151-3160. doi:10.4049/jimmunol.1801593
6. Gorelik M, Lee Y, Abe M, et al. IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis. Clin Exp Immunol. 2019;198(1):101-110. doi:10.1111/cei.13314
7. Burns JC, Roberts SC, Tremoulet AH, et al. Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial [published correction appears in Lancet Child Adolesc Health. 2022 Feb;6(2):e5]. Lancet Child Adolesc Health. 2021;5(12):852-861. doi:10.1016/S2352-4642(21)00270-

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