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

1Mucocutaneous lymph node syndrome is an acute vasculitis first described by Dr. Tomisaku Kawasaki in 1967. 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.

2Kawasaki 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. A considerably higher incidence is reported in Asian countries. 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. Most patients are 6 months to 5 years old, although cases in older children and adults also occur. The male/female ratio is approximately 1.5 to 1.

3The 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). 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. “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. 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. 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.

4Although 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.

5Multiple viral infectious triggers have been suggested, including coxsackie virus, parainfluenzavirus, respiratory syncytial virus, human metapneumovirus, chikungunya, and cytomegalovirus. In fact, two recent studies showed that up to about half of all KD patients had one of more respiratory viruses detected by PCR, but their etiological role is unproven. Also, the possibility of a respiratory RNA virus has been suggested by ultrastructural studies of autopsy specimens. However, no virus has repeatedly been confirmed in KD studies.

6Bacteria have also been suggested as the trigger of KD, with research mainly focusing on bacterial superantigens. Superantigens produced by several bacteria are able to stimulate a large percentage of T cells by binding to the Vβ region of T cell receptors and so stimulate the production of pro-inflammatory cytokines. One study looking at five superantigens (streptococcal pyrogenic exotoxin (SPE)-A, C, G, and J, and toxic shock syndrome toxin-1 (TSST-1)), found these in 70% of stool samples collected from acute KD patients as opposed to 27% in healthy controls visiting the same center for vaccinations. Another study found significantly increased IgM antibodies against five superantigens (staphylococcal enterotoxin A, B, and C, TSST-1, and SPE-A). Nevertheless, the role of superantigens in KD remains unclear.

7The encounter of a susceptible individual with the unknown agent probably leads to an (exaggerated) immune response involving innate and adaptive pathways. Multiple studies have been performed, both evaluating animal models and immune response in the peripheral blood as well as immune infiltration in the coronary arteries.

8The general paradigm of the immune response is an imbalance between pro-inflammatory and anti-inflammatory pathways. For example, regulatory T cells, a subset of T cells limiting inflammation, have been shown to be important in the vascular inflammation. Also, the IL-1 signaling pathway is upregulated, with upregulated IL-1 pathway genes and increased IL-1 concentrations in peripheral blood of KD patients during the acute phase. Recently, it has become clear that inflammasomes, multiproteins that are part of the innate immune system, are induced by the NLRP3 gene and promote the production of IL-1β and IL-18, play a role in KD.

9In the coronary arteries, immune infiltration of the arterial wall with neutrophils, CD8+ cytotoxic T cells, Ig-A producing plasma cells, and macrophages have been found, accompanied by pro-inflammatory cytokines which may vary in proportion and contribution over time.

10Genetics are considered to contribute to susceptibility to KD, and probably to CAA and response to treatment. A number of genome-wide association studies (GWAS) have been performed. 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.

11In 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. 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. 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. 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.

12From 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. 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. Alphonse et al. suggested that the role of ITPKC is not T cell-mediated but more monocyte/macrophage-dependent in its impact. 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).

13Other 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.

14The current treatment for KD is a high dose of 2 g/kg IVIG, given over 8–12 h. 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. Treatment with IVIG significantly reduces the incidence of CAA. IVIG is preferably given within the first 10 days after disease onset. Apart from IVIG, high-dose aspirin is advised by the AHA, although evidence for further risk reduction for CAA is lacking.

15The majority of patients respond rapidly to IVIG, yet approximately 10–20% of all patients do not respond or have recurrent fever within 36–48 h after IVIG. These children have a higher risk of developing CAA. In Japan, risk-scores have been developed to identify patients with a higher risk of IVIG resistance. Unfortunately, these risk-scores do not perform adequately in Western, ethnically mixed, and in Chinese populations. A possible method to decrease IVIG resistance is to intensify the initial treatment. A recent meta-analysis showed a beneficial effect of adding corticosteroids to the initial treatment with IVIG, yet this effect was only found in Japanese studies and not in two studies conducted in the USA. Burns et al. showed that adding infliximab to initial IVIG treatment did not decrease treatment resistance but did decrease the number of days with fever and inflammation parameters 24 h after treatment.

16Children who do not respond to IVIG require additional anti-inflammatory treatment. A second dose of IVIG is commonly advised, particularly in patients who have partially responded. Furthermore, corticosteroids are still commonly advised. The above-mentioned meta-analyses showed no significant benefit for either of these approaches when used as rescue treatment. In 2012, we published the first case report successfully using the IL-1 antagonist anakinra for refractory KD. Since then, additional clinical trials have been instigated to investigate both efficacy and safety of this IL-1 inhibitor. Other secondary treatment possibilities are infliximab (TNF-α inhibitor), cyclosporine (calcineurin inhibitor), and statins, yet efficacy remains to be investigated.

17After normalization of temperature, the AHA advises ongoing aspirin in a low dose until no evidence of CA dilation are present at by 4 to 6 weeks after the acute illness. If CAA are present and persisting around that time, aspirin is continued as anti-thrombotic therapy. In case of large (around a z-score ≥10) or complex abnormalities, additional anticoagulation therapy should be administered to prevent clotting due to turbulence in these pro-coagulatory large coronary artery lesions.

18Multiple 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. A giant CAA is classified as ≥8 mm or >4 times its adjacent segment. Conversely, over the past years, it has become clear that z-scores, diameters adjusted for basal-surface-area, may be better indication of abnormality. Multiple z-score classifications exist. Unfortunately, the z-scores using different classifications can vary, mainly at larger dimensions. 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. 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.

19Risk 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.

20Multiple imaging techniques exist for the follow-up of patients after KD and in particular children with CAA. Echocardiography is a non-invasive method to image the coronary arteries, used in the acute phase of KD as well as during follow-up. With this non-invasive method, it is possible to evaluate the anatomy of the coronary arteries, myocardial function, and valve abnormalities. Nevertheless, it is impossible to visualize the distal coronary arteries with echocardiography. The gold standard for coronary anatomy is a conventional angiography, though this technique is invasive and exposes the patient to radiation. The role of cardiac MRI (cMRI) has been established over the past years. Using this modality, evaluation of the anatomy as well as cardiac function is possible. The disadvantage of cMRI is the need for anesthesia in younger children. CT angiography is an alternative. Although conventional CT angiography carries a high burden of radiation exposure, the new low-radiation dose CT scanning machines are becoming more widely available, which decreases the radiation burden significantly showing good resolution capacity in a small study. In Fig. 2, a MRI and CT image of a normal and a giant CAA are depicted.

21The AHA and JCS have both published guidelines on the follow-up of patients after KD. Recently, we proposed a pathway to follow-up patients after KD based on the worst-ever z-score. This pathway includes a cMRI (with or without adenosine stress testing according to the CAA status) during adolescence for all patients to visualize the complete coronary tree and a more intensive follow-up for patients with CAA (Fig. 3).

22Many CAA regress to a normal-sized lumen, mainly within the first 5 years. The likelihood of regression seems to be highly dependent on the original CAA size. While the lumen diameter may return to normal, it has become apparent that the vascular wall is often still damaged. Studies have shown persistent impaired dilation upon increased cardiac demand. Also, changes in the coronary artery wall structure are seen, such as intimal hyperplasia. The remodeling of the coronary wall can cause potentially life-threatening situations as was shown by a case series of three adult patients who were released from follow-up care after normalization of the lumen but presented with chronic heart failure, unstable angina, and acute myocardial infarction.

23(Giant) CAA may have serious long-term consequences. Apart from thrombosis within the CAA and perfusion abnormalities after the CAA, there is an increased risk of stenosis just proximal or distal to the CAA.

24In a large study of 245 Japanese patients with giant CAA (≥8 mm), Tsuda et al. found 10-, 20-, and 30-year event-free survival rates of 64, 48, and 36%, respectively. Fifteen patients died during follow-up. In another study of 76 Asian patients with giant CAA (≥8 mm), 10-, 20-, and 30-year survival rates of 95, 88, and 88% were reported. In a recent study by Friedman et al., 21 major adverse cardiac events (MACE) took place in 90 patients with giant CAA at diagnosis (z-score ≥10). This indicates that patients with giant CAA are at considerable risk for MACE and risk continues to exist years after the acute phase of KD.

25The risk for patients with small-medium-sized CAA is less clear. In a study by Chih et al., only 1/51 patients with medium-sized CAA (>4–8 mm) experienced ischemia during a median follow-up time of 47 months, although an additional 8 patients had stenosis and 4 patients developed calcification. No patients with small-sized (localized dilatation with ≤4 mm diameter) CAA experienced MI. In the study by Friedman et al., no patients with small- (z-score 2.5–5) or medium-sized CAA (z-score 5–10) experienced any MACE. However, longer term studies will be needed to establish the long-term event rate in patients with small- or medium-sized CAA.

26In patients with persisting CAA, calcifications are likely to develop as shown by a recent study looking at CT calcium scoring. The data suggested this only occurs from approximately 10 years onwards following KD.

27If thrombosis, stenosis, or abnormal blood flow in the CAA leads to a cardiac event or signs of ischemia, KD patients may need cardiac intervention. Thrombolytic treatment has been reported to be effective in treating fresh thrombus within giant CAA and in emergency management of ischemia due to thrombus.

28Percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) can be used to revascularize the artery when stenotic lesions are present. CABG is used more often in multi-vessel disease. Percutaneous transluminal angioplasty may be complicated by the need of high balloon pressures in patients who have already developed calcification. Two studies evaluating the difference between these two methods found that reinterventions were significantly higher in the PCI group.

29Available data are scarce on risk during pregnancy for women after KD. In a case series including 10 women who delivered 21 babies, none of the women experienced cardiovascular complications during pregnancy, including 4 women with CAA, MI, and CABG in the past. In a following comprehensive review, 56 women with 81 deliveries were described and cardiovascular complications were reported in 7 cases, including 2 MIs during pregnancy.

30Longer term studies will be needed to define the long term risk of CAA. However, the significant proportion of patients developing thrombosis within giant CAA, or suffering ischemic events due to stenosis, suggests that all patients with significant aneurysms following KD need life time follow-up and are at risk of cardiac complications long term.

31Apart 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). Two reviews showed that most of these studies are small, lacking quality and there was significantly heterogeneity between studies. 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. 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.

32Multiple 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. 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. 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. Nishad et al. found no difference in social adaption, cognitive function, and behavioral function in 20 children. 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. 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.

33Although 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.