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

Mucocutaneous lymph node syndrome is an acute vasculitis first described by Dr. Tomisaku Kawasaki in 1967 [60]. This condition, now known as “Kawasaki disease (KD),” is increasingly recognized in Western countries but has a greatly increased incidence in Japan and Asia. The main complication is coronary artery damage or coronary artery aneurysms (CAA) and KD is the leading cause of pediatric acquired heart disease in asset-rich countries.

Kawasaki disease is commonest in infants and young children. The incidence varies markedly between ethnic groups. The incidence of KD in recent European studies is 5–10 per 100,000 children under the age of 5 years [45, 55, 105, 120]. A considerably higher incidence is reported in Asian countries [14, 44]. The highest incidence is found in Japan; the most recent nationwide survey reported an incidence of 265/100,000 children under the age of 5 in 2012, and suggested that the incidence of KD is still rising [78]. Most patients are 6 months to 5 years old, although cases in older children and adults also occur [36]. The male/female ratio is approximately 1.5 to 1 [120].

The diagnosis of KD is based on the presence of clinical features of persistent fever in combination with a polymorphous exanthema, cervical lymphadenopathy, non-purulent conjunctival injection, changes of the lips and oral cavity (including strawberry tongue, cracked lips, redness of the mucosae), and changes in extremities (swelling and redness of the palms, desquamation in the subacute phase) [83]. In the most recent American Heart Association (AHA) guidelines, persistent fever is classified as ≥5 days, but in the presence of four or more symptoms, the diagnosis can be made with only 4 days of fever [83, 99]. “Complete” KD is defined as fever and ≥4 out of the 5 symptoms. It is important to appreciate that criteria may present successively instead of simultaneously. The AHA has created an algorithm to increase the possibility of “incomplete” KD in case ≤3 criteria are present. This algorithm includes CA abnormalities on echocardiography and/or laboratory abnormalities [83]. There is no diagnostic test for KD, and the diagnosis may be delayed or overlooked. To improve diagnosis, multiple new biomarkers have been studied, but none has so far proved specific for KD [96]. Classification tools have been developed to aid in the differentiation between KD and other febrile illness, although the utility as a point-of-care diagnostic test remains unproven [46, 74].

Although the etiology of KD is unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. An infectious etiology is suspected due to the symptomatology of KD resembling common childhood infections, once-in-a-lifetime occurrence at young age (although second manifestations do occur), spatial and temporal clustering, and the clear seasonal pattern in high-incidence countries [57, 78].

Genetics are considered to contribute to susceptibility to KD, and probably to CAA and response to treatment [91, 132]. A number of genome-wide association studies (GWAS) have been performed [7, 63, 69, 72, 92, 94, 126]. Apart from the GWAS, multiple studies have identified specific single nucleotide polymorphisms (SNPs) in several genes. Most of these candidate genes have an immune regulatory function. Table 1 shows some of the key pathways and SNPs associated with KD susceptibility, CAA development, and intravenous immunoglobulin (IVIG) resistance.

In the first GWAS that resulted in a significant correlation with susceptibility to KD, we identified the major activating IgG receptor FcgRIIa (CD32a) on immune cells and platelets, encoded by the FCGR2A gene at the FCGR2/3 gene cluster at chromosome 1q23 [7]. Following this study, Japanese and Taiwanese studies also confirmed this genetic association while at the same time characterizing CD40 and BLK, respectively, as being associated with KD, as confirmed for BLK in Caucasian KD patients in a subsequent meta-analysis [12, 72, 94]. CD40 is a protein expressed on antigen-presenting cells, such as dendritic cells, macrophages, and B cells, and interacts with CD40L which is primarily expressed by activated T cells and platelets [49]. The function of FAM167A and BLK gene is yet to be investigated. The BLK gene encodes for tyrosine kinase, which is presumed to play a role in B cell signal transduction [100].

From alternative genetic studies (non-GWAS), other pathways were found to be involved, such as vascular endothelial growth factor (VEGF) and angiopoietin (ANGPT). ANGPT1 and angiopoietin receptor (TIE-2) promote cell survival and induce anti-inflammatory signals in contrast to ANGPT2 and TIE-2, which have a pro-inflammatory effect with VEGF acting as a co-factor. Also the transcription growth factor beta (TGF-β) pathway may play an important role. TGF-β is important in T cell activation and cardiovascular remodeling. One of the more recent and promising pathways involves the inositol-triphosphate 3-kinase (ITPKC) gene. ITPKC expression is part of a transmembrane signaling pathway with release of Ca²⁺ from intracellular storage [48]. Initially, nuclear factor of activated T cells (NFAT) was suggested to be involved in regulating the immune response in KD. The NFAT pathway is calcium-dependent, and when these cytosolic proteins become dephosphorylated, they translocate from the cytoplasm to the nucleus to initiate transcription of downstream target genes including for cytokines such as IL-2, IL-10, and IFNγ. Stimulation of T lymphocytes accommodates the release of inositol-triphosphate (IP3), which increases intracellular Ca²⁺ through the endoplasmic reticulum (Fig. 1). ITPKC serves as a negative regulator of the Ca²⁺/NFAT pathway and—at the same time—is also believed to act as a key second messenger in T cell receptor signaling. This would make ITPKC responsible for a greater and more prolonged expansion of inflammation, thus creating an increased risk of KD and/or leading to disease severity [76]. Alphonse et al. suggested that the role of ITPKC is not T cell-mediated but more monocyte/macrophage-dependent in its impact [2]. They showed that ITPKC influences NLRP3 activation through intracellular calcium levels leading to an increased IL-1β and IL-18 production. Khor et al. performed a global meta-analysis of SNP rs28493229 in ITPKC of all performed studies, including GWAS data, showing strong evidence for association with KD (p = 8.28 × 10⁻²²) [61].

Other pathways and candidate genes have, sometimes inconsistently, been implicated including ATP-binding cassette, subfamily C, member 4 (ABCC4), interleukin-4, interleukin-10 and interleukin-18, chemokine receptors, tumor necrosis factor-α and, even more variably, different regions of the human leukocyte antigen (HLA) region.

The current treatment for KD is a high dose of 2 g/kg IVIG, given over 8–12 h [86]. The main goal of treatment is prevention of the development of CAA. Hypothesis on the mechanisms of efficacy of IVIG include immune modulation of T regulatory cells, neutralization of the etiologic agent, and reduction of cytokine production [8]. Treatment with IVIG significantly reduces the incidence of CAA [124]. IVIG is preferably given within the first 10 days after disease onset [83]. Apart from IVIG, high-dose aspirin is advised by the AHA, although evidence for further risk reduction for CAA is lacking [34, 124].

Multiple criteria have been used for diagnosis of CAA. The criteria of the Japanese Circulation Society (JSC) state that an aneurysm is an artery of >3 mm in a child under the age of 5 and an artery of >4 mm in a child ≥5 years or when an arterial segment is 1.5 times its adjacent segment [31]. A giant CAA is classified as ≥8 mm or >4 times its adjacent segment [42]. Conversely, over the past years, it has become clear that z-scores, diameters adjusted for basal-surface-area, may be better indication of abnormality [25]. Multiple z-score classifications exist [23, 79, 82, 90]. Unfortunately, the z-scores using different classifications can vary, mainly at larger dimensions [101]. The threshold for abnormality is a z-score ≥2.5, although a z-score between 2 and 2.5 can be classified as a dilation [83]. A small-sized CAA has a z-score of 2.5–5, a medium-sized CAA of 5–10, and a giant CAA of ≥10 [79].

Risk factors for CAA have been inconsistently reported but include a male gender, a young age (<1 year), an incomplete disease presentation, IVIG resistance, and the duration of fever [43, 64, 113, 114].

Apart from the increased cardiovascular risk due to persisting or regressed CAA, it is uncertain whether the vasculitis itself causes an increased cardiovascular or atherosclerotic risk at a later age. As most patients have not been followed long enough to evaluate the long-term natural course of the disease, multiple studies have focused on the use of surrogate markers for cardiovascular disease such as flow-mediated dilation, stiffness index, and carotid intima-media thickness (cIMT) [17, 89, 107]. Two reviews showed that most of these studies are small, lacking quality and there was significantly heterogeneity between studies [15, 27]. Nevertheless, results suggested that surrogate markers were increased in CAA-positive but not in CAA-negative patients. In a follow-up study evaluating cIMT, we found that patients with giant CAA have a trend towards an increased cIMT at a later age, whereas in children without any coronary artery enlargement, their cIMT was initially increased but normalized to control values over time [26]. The results suggest that long-term effects of KD are not caused by atherosclerosis, as one would expect the differences in cIMT to increase compared with control measurements. This is in concordance with a postmortem study in which multiple growth factors were seen in the smooth muscle cells and intima layer of the coronary arteries, but no fatty streaks as seen atherosclerosis, distinguishing “KD vasculopathy” from atherosclerosis [118].

Multiple studies have investigated the cognitive and behavioral outcome after KD. Baker et al. studied 110 KD children, and found similar psychosocial and physical summary scores as an US population sample using a parent-completed questionnaire [3]. Only patients with giant CAA had a lower mean physical score. Parents did however report lower health perception. King et al. studied 38 KD patients and found no effect on cognitive or academic performance, but parents rated their children as having more internalizing and attentional behavior problems than controls [65]. Carlton-Conway et al. found that 40% of their patients showed internalizing scores in the clinical range as reported by parents, which was significantly more than their hospital controls who stayed in the hospital for a short period and had undergone cardiac catheterization [11]. Nishad et al. found no difference in social adaption, cognitive function, and behavioral function in 20 children [88]. Muta et al. studied 250 adolescents and young adults, including 19 patients with giant CAA and found significantly higher health-related quality of life (HRQOL) scores compared to national norms [85]. Two studies from our center showed significantly lower scores on several HRQOL scales in children under 5, when reported by their parents. However, self-report by the older KD children did not show any significant difference with controls. Moreover, parental perceptions of child vulnerability were significantly increased when compared to reference groups of Dutch parents [121, 129].

Although many aspects of KD are still unknown, there is increasing knowledge on the origin and treatment of KD as well as the development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up, with appropriate imaging modalities and awareness of the long-term effects, is increasingly important.