Dissecting Kawasaki disease: a state-of-the-art review

Abstract

Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10-20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself.

Conclusion: Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk.

Keywords: Coronary artery aneurysms; Genetics; Intravenous immunoglobulins; Kawasaki disease.

Fig. 1

The role of IP3 and ITPKC in calcium signaling. (a) ITPKC phosphorylates IP3 to IP4 and modulates the abundance of IP3 and influences the calcium signaling. (b) Nuclear factor of activated T cells (NFAT) are regulated by calcium signaling and enter the nucleus when dephosphorylated, there it activates cytokine transcription namely IL-2, IFNγ in T cells and Pro-IL1, IL-10, Pro-IL18 in macrophages. Footnote: Inositol triphosphate receptor (IP3R) forms a bridge between the endoplasmatic reticulum (ER) and mitochondria creating a site of contact between the ER and mitochondria called the mitochondria-associated ER membrane (MAM). NLRP3 is an inflammasome that forms at or close to the MAM upon cellular activation and ER stress and plays a pivotal role (by activating caspase-1) in the cleavage of pro-IL1b into IL1b and its subsequent secretion. The ER releases calcium into the cytosol and into mitochondria through (a.o.) the IP3R, which is a calcium channel, to which IP3 as an agonist binds to induce calcium release. IP3R binds via glucose-regulated protein 75 (GRP75) with the mitochondrial voltage-dependent anion channel 1 (VDAC1) which may cause mitochondrial stress and leakage off reactive oxygen species (ROS), both important for inflammasome activation. Macrophages activate via their Toll-like receptors (TLRs) or G-protein coupled receptors several signaling pathways, that result in IP3 formation, NF-kB activation, and/or ER stress.

Fig. 2

Imaging techniques used for Kawasaki disease. a, b, d, e display coronaries of the same patient with different imaging techniques. a Curved multi-planar reformat of the coronary computed tomography angiography (cCTA) scan shows an aneurysm of the right coronary artery. b A giant aneurysm of the left anterior descending artery. c A normal left anterior descending artery. d Thin slab maximum intensity projection of the aneurysmatic proximal right coronary artery and left anterior descending artery. e A clearly depicted giant aneurysm of the left anterior descending artery, visualized with coronary angiography

Fig. 3

Flow diagram of the monitoring of Kawasaki disease using different imaging modalities. Footnote: Originally published in: Insights into imaging: Dietz SM, Tacke CEA, Kuipers IM, Wiegman A, de Winter RJ, Burns RC, Gordon RB, Groenink M, Kuijpers TW, Cardiovascular imaging in children and adults following Kawasaki disease, Insights into Imaging, 2015;6:697 (adapted version). ^aWhen information is lacking about coronary arterial aneurysms (CAA) status, calcium score may be indicated as a screening method. If positive, a CMRI with adenosine should be performed. ^bLong-term follow-up (cardiovascular counseling) of risk group 1 may be dictated by national health care policies and future studies. ^cAccording to the availability and experience of a center with (low-dose) CT angiography. ^dWhich of the different revascularization options improves prognosis best is unclear to date. ^eAdditional tests to evaluate for progression to stenotic lesions