Kawasaki Disease: Contemporary Clinical Approaches and Challenges

Abstract

Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis that mainly affects young children. It is the leading cause of acquired heart disease in the developed world and is unique among childhood vasculitides for its predilection toward coronary artery involvement. This review describes the clinical spectrum of KD, highlighting diagnostic difficulties, especially in atypical presentations, and the challenges of managing treatment resistance. While intravenous immunoglobulin and aspirin remain the standard of care, especially in reducing coronary inflammation, early recognition and prompt therapy are crucial to preventing lifelong cardiac complications. To support this, various clinical risk scores have been developed over the decades to predict coronary artery lesions and IVIG resistance, enabling earlier intensification of treatment to prevent cardiac complications. Although the etiopathogenesis of KD remains unknown, extensive and robust research is ongoing to identify biomarkers, including epigenetic markers, innate and adaptive immunity activation markers, cytokine profiles, and to explore the influence of external triggers and the gut microbiome–immunity interplay. This review attempts to provide a concise overview of KD, aiming to assist clinicians in understanding the complexity of the problem rather than addressing all issues in detail.

1. Introduction

In 1967, Dr. Tomisaku Kawasaki first described a group of 50 patients in Tokyo with a characteristic clinical feature of prolonged fever, erythema of lips and oral mucosa, skin rash, bilateral nonexudative conjunctivitis, and cervical lymphadenopathy [1]. The original article was presented in Japanese. Based on the cardinal features of this group of children, the disease was previously named acute febrile mucocutaneous lymph node syndrome. In 1974, Dr. Kawasaki published the report in English, and the disease began to be recognized widely in both eastern and western countries. The link between Kawasaki disease and coronary arteritis was also established [2,3,4]. As awareness grew, the disease was renamed Kawasaki disease (KD) in honor of Dr. Kawasaki, who played a key role in identifying it. Nowadays, KD has surpassed acute rheumatic fever as a major acquired heart disease in children. It is one of the most common childhood-onset systemic vasculitides, recognized as medium-sized vasculitis by the Chapel Hill Consensus Conference (CHCC) [5]. It differs from other pediatric vasculitides by its predilection for coronary arteries and its mucocutaneous features.

A distinct epidemiological pattern is observed in KD, with the highest incidence reported in Japan, where 265 cases per 100,000 children < 5 years old have been reported. The incidence was also high in Asian countries, including Korea (134.4 per 100,000), Hong Kong (74 per 100,000), and Taiwan (82.8 per 100,000). In North America, Australia, and Europe, the incidence of KD remains plateaued at around 4 to 25 in 100,000 children under 5 years old [6,7].

KD is usually self-limiting and characterized by high fever, which usually peaks at day 6 and lasts for 10–14 days, a skin rash, erythema of the lips and tongue, conjunctivitis, and cervical lymphadenopathy. Diagnosis is based on clinical criteria, and there is no definitive test to confirm the diagnosis. Clinical criteria are prone to error, and children with incomplete or atypical features may result in a delay in diagnosis, leading to serious complications in the long run. Cardiovascular sequelae of Kawasaki disease are the most significant complication. Coronary artery aneurysms have been reported in up to 25% of untreated patients and are one of the most common causes of acquired heart disease in children [8,9,10].

Kawasaki disease (KD) is thought to arise from a gene–environment interaction that triggers an exaggerated immune response in genetically susceptible children. An infectious or environmental stimulus activates innate immunity (i.e., neutrophils, monocytes, and inflammasomes), inducing the release of various cytokines, which then recruit and amplify adaptive immunity. This cytokine storm activates the inflammatory process, together with complement dysregulation and vascular remodeling, leading to coronary artery inflammation and aneurysm formation. Biomarkers that help in early diagnosis or prediction of IVIG resistance are particularly clinically important, as early treatment will dampen down the inflammatory process and avoid future complications. There has been enthusiastic research to identify useful biomarkers that help to make a definitive diagnosis, identify patients with higher risk of coronary artery lesions, and provide early treatment to halt the progression of inflammation.

Modern KD research integrates genomics, transcriptomics, proteomics, metabolomics, and microbiome data to create multi-dimensional biomarker panels. Although most of these biomarkers remain investigational, they may come into clinical use soon, especially for early diagnosis, risk stratification, IVIG resistance, and coronary artery outcome prediction. They may replace the traditional markers like CRP, ESR, and platelets as more precise indicators and guide customized treatment strategies.

2. Clinical Features of Kawasaki Disease

Kawasaki disease is a medium-sized vessel vasculitis. The diagnosis is based on a constellation of clinical features that appear in a typical temporal sequence, despite the diagnostic criteria for Kawasaki disease having been updated several times, both by the Joint Working Groups in Japan [11,12,13] and by the American Heart Association (AHA) [14,15,16]. The cardinal clinical features of Kawasaki disease remain similar (

Table 1. Diagnostic criteria of Kawasaki disease.

Kawasaki Disease Research Committee Guidelines (Japanese) 2002—The Fifth Revision [11]

AHA Guidelines for Diagnosis of Kawasaki Disease (2004) [14]

Five of the following six criteria: Fever persisting greater or equal to five days Bilateral conjunctival congestion Changes in lips and oral cavity Polymorphous exanthema Changes in peripheral extremities Acute non-purulent cervical lymphadenopathy

Fever persistent at least 5 days with at least four of the five principal clinical features Changes in extremities: erythema, edema, periungual peeling of fingers and toes Polymorphous exanthema Bilateral bulbar conjunctival injection without exudates Changes in lips and oral cavity Cervical lymphadenopathy and exclusion of other diseases with similar findings (e.g., scarlet fever, viral infections, Steven Johnson syndrome, toxic shock syndrome)

).

The diagnostic criteria are fever, together with the 4 out of the 5 signs of mucocutaneous inflammation. Fever in KD is typically high spiking and remittent. The temperature is generally >39 °C, and in many cases, it exceeds 40 °C. Traditionally, the diagnosis required a fever lasting 5 or more days. In Japanese guidelines [12,13], fever is not required, and in the updated AHA guidelines [15,16], KD can be diagnosed within 4 days of fever if other clinical features are compatible. Other features include:

• Bilateral nonsuppurative conjunctivitis, which does not have any discharge. Conjunctivitis typically affects the bulbar region and spares the limbus of the conjunctiva.
• Mucosal changes, including cracked lips, strawberry tongue, or reddened oropharynx. Strawberry tongue refers to erythema and prominent fungiform papillae. There will be dryness, redness, fissuring, or cracking of the lips.
• Extremity changes, including swelling of the dorsal surfaces of the hands and feet, redness of the palms and/or soles. Periungual desquamation usually begins in the periungual region within 2 to 3 weeks after the onset of the fever.
• Polymorphous eruption. The rash may take various forms. The most common form is a nonspecific, diffuse maculopapular rash; occasionally, it may be urticarial, scarlatiniform, or erythema multiforme-like. The rash may occur in the body, extremities, and accentuation in the perineal region, where early desquamation may occur.
• Cervical lymphadenopathy, with one lymph node ≥ 1.5 cm in diameter. The lymph node is usually unilateral and is commonly in the anterior cervical triangle. The lymph nodes are firm, non-fluctuant, and usually non-tender.

3. Incomplete Kawasaki Disease

Incomplete KD describes patients who do not meet all the clinical criteria for KD. The American Heart Association (AHA) guidelines [15,16] have suggested that, in the presence of ≥4 principal clinical criteria, the diagnosis of KD may be made with only 4 days of fever. Since the clinical features may present during the illness and be resolved by the time of presentation, a careful history will help in making the diagnosis. Some patients may lack the full clinical features of classic KD, but if there are coronary artery abnormalities detected, the diagnosis of KD is considered confirmed. To assist in diagnosing KD in patients with incomplete or atypical clinical features, these guidelines have added several laboratory findings and specific features, such as the gallbladder hydrops and elevated BNP, or N-terminal proBNP, anemia, raised WBC and elevated inflammatory markers [14,15,16,17,18] (

Table 2. Clinical features, laboratory and echocardiographic findings of subtypes of Kawasaki disease [11,12,13,14,15].

Kawasaki Disease Types	Symptoms	Laboratory Findings
Classical/complete	Fever ≥ 5 days, and at least 4 of the following 5 symptoms: Oral mucosal changes Nonsuppurative conjunctival injection Polymorphous skin rash Changes in the extremities Cervical lymphadenopathy	Elevated inflammatory markers CRP ≥ 3.0 mg/dL +/− ESR ≥ 40 mm/h Anemia for age Platelet count of ≥450,000/mm3 after the 7th day of fever Albumin < 3.0 g/dL Elevated ALT WBC count ≥ 15,000/mm3 Urine ≥ 10 WBC/hpf (sterile pyuria)
Incomplete KD	Fever for ≥5 days and 2 or 3 of the symptoms of classic KD with or without the presence of coronary artery aneurysms
Atypical KD	Fever for ≥5 days and presentation of nontypical symptoms, such as renal impairment, unilateral peripheral facial nerve palsy, testicular swelling, pulmonary nodules ± infiltrates, pleural effusion, diarrhea, vomiting and abdominal pain, acute surgical abdomen, hemophagocytic lymphohistiocytosis (HLA) with or without the presence of coronary artery aneurysms.

). Patients may have incomplete features and may still warrant early IVIG treatment.

4. Special and Adjunct Features

Although there are no pathognomonic features of KD, several specific and supportive clinical signs can strengthen suspicion, especially in children with incomplete classical features.

BCG scar reactivation was observed in 30–50% of children in Asian countries such as Hong Kong and many others, where BCG vaccination is universal. The BCG inoculation site may become erythematous, indurated, or even ulcerated during the acute phase of KD. This usually appears in the first week of illness, along with the fever and rash. It was thought to reflect the immune activation and cross-reactivity at the site of prior BCG vaccination. This feature was included in some Japanese diagnostic guidelines [13]. Although BCG site reactivation is uncommon, it occurs primarily in infants with KD. A recent study has reported an eightfold higher risk of CAAs among infants with BCG site reactivation [19,20].

Perineal desquamation describes early skin peeling in the diaper area, often occurring before periungual peeling of the fingers and toes. It could be an early clue in diagnosing.

Striking irritability, which reflects central nervous system involvement, is common. Other adjunct clinical features include sterile pyuria, hepatic involvement, gastrointestinal symptoms mimicking appendicitis, and aseptic meningitis. Supportive laboratory features included elevated C-reactive protein, elevated ESR, leukocytosis, thrombocytosis after the first week, anemia, hypoalbuminemia, and hyponatremia. These help to diagnose “incomplete KD” [14,15,16,18,19].

Although coronary artery abnormalities are a major complication and morbidity of KD, they are never required as one of its diagnostic criteria. Because all the clinical features of KD may not present at the same time, it can be particularly difficult to make a timely diagnosis for intervention. These may result in serious complications like coronary artery aneurysms (CAAs) or even myocardial ischemia and infarction [21,22,23]. The group of patients below is at a high risk of delay in diagnosis:

• Infants < 6 months: high risk of complication but subtle presentation;
• Adolescent: atypical features may result in delayed diagnosis;
• Patients with incomplete Kawasaki features.

Clinical features of Kawasaki disease mimic and overlap with many other viral infections, which may confuse medical practitioners and delay referral and subsequent diagnosis.

5. Coronary Artery Lesions in Kawasaki Disease

KD is a self-limiting disease that resolves spontaneously within a mean of 12 days even without treatment. Coronary artery aneurysms (CAAs) or ectasia were reported to develop in 15–25% of untreated children and may lead to subsequent myocardial infarction or ischemic heart disease [8,9,10,24]. The period of fever indicates the acute inflammatory phase, during which coronary inflammation can begin very early, even if it may not be clinically detectable. During the acute phase of KD, all histological layers of the heart, that is, the pericardium, myocardium, and endocardium, the heart valves, and the coronary arteries, may all be involved. Early studies of Kawasaki disease (KD) showed that inflammation in the coronary arteries starts with neutrophils and then shifts to mononuclear cells as healing begins. This process breaks down collagen and elastin, causing the arteries to balloon and sometimes leading to thrombus formation [25]. More recent research by Shulman ST et al. [26] found that these processes actually link, rather than happening sequentially. Firstly, neutrophils drive necrotizing arteritis, which starts at the inner artery lining and causes damage throughout the vessel wall. This stage usually ends within two weeks after a child’s fever goes away. It can leave behind large aneurysms and blood clots when the endothelium, media, and adventitia layers are damaged. Secondly, subacute or chronic arteritis begins in the outer layer of the artery and moves inward, involving mostly lymphocytes, plasma cells, and eosinophils. The third stage is luminal myofibroblastic proliferation, causing narrowing of arteries over time.

Echocardiography is important in the acute phase to monitor cardiac complications. However, it is important to understand that a normal echocardiography examination does not rule out Kawasaki disease. Similarly, a normal baseline echocardiogram does not exclude the possibility of future development of coronary artery aneurysms. The initial criteria for CAAs were defined as an internal diameter > 3 mm in children < 5 years old and >4 mm in children > 5 years old. Subsequently, the AHA first proposed using Z-scores to define CAAs in 2004. An aneurysm is defined as an internal diameter Z-score > 2.5 (as per body surface area adjusted Z-score) [15,16,24,27] (

Table 3. Classification of coronary artery abnormalities in children with Kawasaki disease by z-score [14,27].

Classification	Size of Coronary Artery Abnormality
No coronary involvement	Z-score always <2 and no more than a 0.9 decrease in Z-score during follow up
Coronary artery dilatation	Z-score 2 to <2.5 or if initially <2, a >1 decrease in Z-score during follow up
Small aneurysm	Z-score ≥ 2.5 to <5
Medium aneurysm	Z-score of ≥5 to <10 and absolute internal diameter of <8 mm
Large aneurysm	Z-score ≥ 10 or absolute internal diameter ≥ 8 mm

The size of the coronary artery is classified according to the internal lumen diameter, normalized for body surface area as a Z-score or standard deviation units.

). The progression of coronary artery lesions depends on the load and severity of coronary inflammation; hence, serial echocardiography plays a vital role in monitoring and detecting the development of CAAs.

6. Risk Scores in Predicting the Outcome of Kawasaki Disease

There are several risks scores used in the clinical setting to predict children who are at higher risk of developing complications of Kawasaki disease. The most commonly used scores are derived from the Japanese population, such as Harada score [28], the Kobayashi score [29], the Egami score [30], and the Sano score [31]. Unlike Harada score, which predicts the risk of coronary artery aneurysm development, other Japanese scores predict IVIG resistance. However, these Japanese population-based scores have lower predictive accuracy in non-Japanese populations. The recent AHA 2024 guidelines [16] explicitly stated that these scores should not be used in North American practice due to their low predictive value and specificity when applied to diverse populations. However, in Japan and some Asian countries, pediatricians may like to use the scores to predict IVIG-resistant and guide early use of steroids. The North American risk score [32], updated in a recent recommendation, is also widely used as a predictive score. This score was developed to predict coronary artery aneurysm (CAA) risk and not IVIG resistance. It incorporates risk factors including age, ethnicity, C-reactive protein, and baseline coronary artery z-scores to estimate the likelihood of aneurysm formation (

Table 4. Summary of different risk assessment scores for Kawasaki disease.

Year Established/Population	Scoring System	Main Outcome Prediction	Key Risk Factors	Threshold for High Risk
1990 Japan [28]	Harada score (7 risk factors)	Development of CCA	Age ≤ 12 months, Illness ≤ 4 days at diagnosis, WBC ≥ 12,000/mm3, Platelet count ≤350,000/mm3, CRP ≥ 3 mg/dL, Hematocrit ≤ 35%, Serum albumin ≤ 3.5 g/dL.	High risk if they meet ≥4 of the following 7 criteria and guided early IVIG use.
2006 Japan [29]	Kobayashi score (total 7 risk factors with 10 points)	IVIG resistance	Age ≤ 12 months (1 point), CRP ≥ 10 mg/dL (1 point), ALT ≥ 100 IU/L (1 point), Sodium ≤ 133 mmol/L (2 points), Neutrophils count > 80% (2 points). This score incorporates serum sodium and neutrophil count as strong predictors for IVIG resistance	High risk if they meet ≥5 points, but score < 5, IVIG resistance can still occur. High risk may consider initial combination therapy of IVIG + steroid or other adjuncts).
2006 Japan [30]	Egami	IVIG resistance	Age ≤ 6 months (1 point), Illness ≤ 4 days at diagnosis (1 point), CRP ≥ 8 mg/dL (1 point), ALT ≥ 80 IU/L (2 points), Platelet count ≤ 300,000/mm3 (1 point). Younger infants with strong inflammatory makers/liver involvement are at most risk	Score ≥ 3 predicts high risk for IVIG resistance.
2007 Japan [31]	Sano	IVIG resistance	CRP ≥ 7 mg/dL (1 point), Total bilirubin ≥ 0.9 mg/dL (1 point) and AST ≥ 200 IU/L This score emphasizes liver derangement as predictors of poor IVIG response	Score ≥ 2 is at high risk for IVIG resistance.
2017 and 2024 update Mixed ethnicity [15,16,32]	North American risk score	Coronary aneurysm risk	Age ≤ 6 months, baseline LAD or RCA z-score ≥ 2.5, Asian race, CRP ≥ 13 mg/dL For risk stratification and treatment intensification	Patients meeting these criteria have a 16-fold increase in development of coronary artery aneurysm.

).

Despite their popularity for clinicians, these risk assessment scores have important limitations. Most risk scores are based on clinical features and laboratory parameters (CRP, ESR, white cell count, neutrophil counts and platelet counts, serum albumin, hemoglobin, and serum sodium) which reflect the severity of systemic inflammation [33,34,35]. However, these data can be influenced by patient’s age, fever duration, timing of presentation, organ involvement, and local practices, leading to variability in outcome prediction across countries. The initial high fever phase reflects intense systemic inflammation which usually peaks around day 6, then gradually subsiding as the patient enters the afebrile, convalescent stage. Therefore, differences in when patients present to medical attention can influence presenting laboratory results.

7. Special Clinical Challenges in Kawasaki Disease

7.1. Special Age Groups

Infants < 6 months and adolescents are age groups known to present with atypical features, leading to delayed diagnosis. Hence, with specific or adjunct features such as striking irritability, BCG scar reactivation, and perineal peeling, which are more commonly observed in infants, may help in the diagnosis. Children with atypical features may also benefit from laboratory testing.

7.2. Kawasaki Disease Shock Syndrome (KDSS)

This is a rare form of KD with vasodilatory shock syndrome with hypotension and poor perfusion with or without myocardial dysfunction. Children with KD shock will have serious hypotension and poor perfusion with or without myocardial dysfunction [36,37]. KDSS was particularly confusing during the COVID pandemic in 2020, and children presented with multisystemic inflammatory syndrome (MIS-C) showed similar features to KD [38].

7.3. Kawasaki Disease and Macrophage Activation Syndrome (KD-MAS)

Kawasaki disease with macrophage activation is a hyperinflammatory and life-threatening variant of the disease. It is characterized by cytopenia, hyperferritinemia, and organ dysfunction. This hyperinflammatory state was believed to result from uncontrolled activation of macrophages and T cells. The cytokines, especially IL-1, IL-6, TNF-α, and IFN-γ, are so excessive that they lead to hemophagocytosis and multi-organ dysfunction. Clinically, it overlaps with the features of secondary hemophagocytic lymphohistiocytosis (HLH), and the diagnosis is based on the HLH-2004 MAS-specific criteria, adapted from systemic-onset juvenile idiopathic arthritis (sJIA) [39]. Apart from supportive care for organ dysfunction, it requires immediate escalation of therapy, including IVIG with high-dose methylprednisolone. Biologics such as anakinra, infliximab, and cyclosporine may be required for severe or refractory cases. There is a higher coronary aneurysm risk in children with KD-MAS, likely related to severe and prolonged inflammation. Early recognition, prompt aggressive immunotherapy with organ support, and serial echocardiograms are important for timely patient management [40].

7.4. Recurrent Kawasaki Disease

Although rare, Kawasaki disease can recur. The incidence of recurrent KD was reported to be 1.7% in the USA and 3.5% in Japan [41]. Recurrent KD usually occurs in younger children, those with incomplete clinical features, or those with incomplete treatment. Hirata S et al. [42] studied a cohort of 10,679 patients over 2.95 years and reported a KD recurrence rate of 6.89 per 1000 observed children. The incidence was high among those under 3 years of age and those with cardiac sequelae during the first episode. Recurrent KD usually presents with similar or milder features. A longer duration of fever before IVIG treatment, a high AST level and low hemoglobin level [43], and a presenting age of <1 year with initial resistance to the initial dose of IVIG [44] were reported to be significantly related to its recurrence. Treatment of recurrent KD is the same as for the initial episode. The coronary risk remains significant in this patient group. Nakamura Y et al. [45] reported that giant coronary aneurysms in KD recurrent patients were twice as likely in men and 1.5 times in women than in the initial onset cases. As the recurrence of KD may imply a persistent inflammation that was not damped down completely, more aggressive treatment strategies in conjunction with IVIG may be indicated for the second episode of KD.

With the variety of clinical presentations, KD behaves as a heterogenous syndrome with variable phenotypes and severity of organ involvement. Understanding its pathogenesis is important to conclude whether these phenotypes represent the same disease.

8. Understanding the Etiopathogenesis

Although the etiology of KD remains unknown, it likely occurs in genetically predisposed children who are exposed to an environmental trigger that initiates an intense, dysregulated immune response, leading to the clinical phenotypes.

The incidence of KD is particularly higher in Japanese and southeast Asian populations, suggesting a genetic predisposition in these ethnic groups. Several candidate genes, including ITPKC, CASP3, BLK, CD40, HLA, FCGR2A, and ORAI, have been identified in genome-wide association studies (GWASs) and linkage studies as associated with KD over the past 15 years (

Table 5. Key genetic associations with Kawasaki disease [46,47,48,49].

Gene	Function	KD Association
ITPKC	Regulate calcium signaling in T cells Loss of function variants will cause excessive T cell activation and cytokine release	Linked to IVIG resistance and risk of coronary aneurysm
CASP3	Central in apoptosis pathways Variants may impair immune cell apoptosis and prolong inflammatory response	Linked to persistent fever and IVIG- non responsiveness
BLK	Involved in B cell receptor signaling	Linked to autoimmune predisposition and KD susceptibility
CD40	Co-stimulatory molecule on antigen presenting cells Variants enhance T cell activation and cytokine storm	Associated with coronary artery lesions
HLA	Certain HLA class II alleles (e.g., HLA-B, HLA-C, HLA-DR) confer KD susceptibility	May explain ethnical difference
FCGR2A	Fc receptor for IgG Regulates immune complex clearance	Variants linked to IVIG resistance
ORAI1	Control calcium influx in immune cells Variants lead to abnormal T-cell activation and cytokine release	Associated with KD susceptibility and severity

ITPKC: inositol-triphosphate 3-kinase C; CASP3: caspase-3; BLK: B-lymphoid tyrosine kinase; HLA: human leukocyte antigen; FCGR2A: Fc gamma receptor IIA; ORAI1: calcium release-activated calcium channel protein 1.

) [46,47,48]. These genes regulate immune activation, apoptosis, calcium signaling, and the Fc receptor pathway, not only in association with KD susceptibility but also with aneurysm risk and IVIG resistance [47,48]. However, the difference in incidence rates was not explained by the risk allele frequencies of the identified susceptibility genes, and the influence of each risk factor differs across ethnicities. Hence, the genetic factors underlying KD susceptibility are heterogeneous, and their effects across ethnicities vary [46,49]. Understanding how the genetic variants contribute to KD pathogenesis is essential for developing targeted therapies. Functional studies that investigate the molecular basis of these genetic variations help understand how these variants influence immune activation, inflammation intensity, and cardiovascular outcomes and may offer new avenues for future treatment.

While the results of genetic studies on KD have limited clinical implications because of no definitive genetic markers in diagnosis and no reproduction of genes in the population, looking for environmental factors is another window to explore the pathogenesis of KD.

Epidemiological observational studies, such as several epidemics of KD in Japan in 1979, 1982 and 1986, have suggested that the introduction of causative agents into genetically susceptible patients is correlated with the onset of KD [47,50]. The clinical features of KD, especially fever, conjunctivitis, and skin rash, have several similarities with those of many infectious diseases described in the literature. Its epidemiological features, age distribution, and occurrence of community outbreaks support an infectious origin, followed by an abnormal immune response induced by a possible “superantigen” or infective origins. However, over the decades, no single organism has been identified as the cause, and there is no evidence of person-to-person transmission [50,51,52]. The rarity of KD in the first few months of life and in adults may suggest that KD is an immune response to a trigger first encountered by the host. The upsurge of MIS-C during the COVID-19 pandemic likely explains the intensity of the host’s immune response to a newly encountered infectious agent [51,52].

Among bacterial infections, scarlet fever (SF) and acute rheumatic fever (ARF) are notable diseases that share similarities with Kawasaki Disease (KD); both SF and ARF are associated with Group A streptococcal (GAS) infection but present with distinct clinical features. Scarlet fever and toxic shock syndrome are more consistent with the “Superantigen model,” in which bacterial exotoxins cause widespread, nonspecific cross-linking of T cell receptors and MHC class II molecules. This process results in a systemic cytokine storm and subsequent localized vascular injury [47,53]. In contrast, Rowley et al. [54] proposed the “RNA virus theory” after postmortem examinations of KD patients showed infiltration by numerous mononuclear cells, CD8+ lymphocytes, and IgA-producing plasma cells. Despite these findings, decades of research have failed to identify a definitive bacterial or viral cause for KD.

The “Protein-Homeostasis System (PHS)” hypothesis, proposed by Lee et al. [55], presents a distinct perspective on hyperinflammatory syndromes. The authors suggest that the immunopathogenesis of KD closely resembles that of acute rheumatic fever (ARF) and acute post-streptococcal glomerulonephritis (APSGN). According to this hypothesis, all three diseases arise when the body fails to eliminate toxic proteins derived from pathogens or damaged host cells. These toxic proteins selectively bind to specific target organs: coronary arteries in KD, heart and joints in ARF, and kidneys in APSGN. The accumulation of these proteins triggers an intense immune clearance response, resulting in a profound cytokine storm. In KD, toxic proteins may bind directly to coronary endothelial cells, initiating coronary artery involvement even before systemic inflammation peaks. The PHS model contrasts with the traditional superantigen model and offers a framework for understanding how changes in gut microbiota and environmental factors might influence disease development [55,56].

Pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharides (LPS), flagellin, and viral DNA, are foreign molecules derived from infectious agents. Damage-associated molecular patterns (DAMPs), including extracellular ATP, heat shock proteins, nuclear DNA, and uric acid, are endogenous signals released from injured or stressed cells. Both PAMPs and DAMPs are recognized by innate immune receptors like Toll-like receptors (TLRs) and NOD-like receptors (NLRs), which then activate the host’s innate immune response. Infectious agents supply PAMPs that engage pattern recognition receptors (PRRs) on neutrophils, monocytes, and dendritic cells, leading to the secretion of inflammatory cytokines such as IL-1, IL-6, and TNF-α. This inflammatory response damages endothelial cells, prompting the release of DAMPs and further amplifying inflammation in a self-perpetuating cycle of sterile inflammation. In addition to exogenous triggers, alterations in the host’s gut microbiota due to environmental factors have been proposed as an etiological factor in KD. Epidemiological evidence suggests that KD “agents” may be related to shifts in normal flora influenced by environmental changes [55,56]. Gut dysbiosis may activate the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [57,58], increasing cytokine levels and contributing to vascular injury.

Innate immune activation dominates the acute phase of Kawasaki disease (KD). Neutrophils infiltrate coronary arteries, releasing reactive oxygen species (ROS) and proteolytic enzymes. Children with KD who exhibit higher brain natriuretic peptide (BNP) levels and an elevated neutrophil-to-lymphocyte ratio (NLR) are at increased risk for coronary artery aneurysm (CAA) formation. Subsequent infiltration of monocytes and macrophages further amplifies inflammation, as these cells are early drivers that release pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α [55,59].

Tumor necrosis factor-alpha (TNF-α) levels are markedly increased during the acute phase of KD, particularly in patients who develop coronary artery aneurysms (CAAs). Through its soluble receptors, TNFR1 and TNFR2, TNF-α enhances matrix metalloproteinase (MMP) activity, leading to elastin degradation and a heightened risk of CAA formation [59,60,61].

Activated macrophages, monocytes, and neutrophils release interleukin-1 (IL-1) in response to PAMPs and DAMPs. IL-1 is the primary upstream initiator at the very top of the cytokines cascade. It stimulates endothelial activation, upregulating adhesion molecules and recruiting additional immune cells to the coronary arteries. It amplifies the cytokine cascade by inducing the production of IL-6, TNF-α, and various chemokines. IL-1 is a key mediator of fever, acute-phase response (notably C-reactive protein [CRP]), and systemic symptoms. Furthermore, it promotes MMP activation, resulting in vascular wall degradation and contributing to the development of coronary artery aneurysms [61].

Interleukin-6 (IL-6) is a prominent cytokine in the acute phase of KD. Elevated IL-6 levels are observed in patients with Kawasaki disease shock syndrome (KDSS), macrophage activation syndrome (KD-MAS), and those who develop CAAs. IL-6 also promotes megakaryocyte maturation, potentially contributing to the thrombocytosis seen during the convalescent stage of KD. Other inflammatory cytokines associated with KD complications include interferon-gamma (IFN-γ), IL-17, and IL-18. As research progresses, the array of cytokines and chemokines implicated in the pathogenesis of KD continues to grow [59]. While intravenous immunoglobulin (IVIG) therapy helps restore and modulate the hyperactive immune response, a deeper understanding of these cytokines will inform the use of targeted anti-cytokine biologics in patients resistant to IVIG [59,60,61,62,63].

The role of adaptive immunity in acute KD remains less defined. CD8+ T cells and various T-helper cell subsets accumulate in the coronary arteries. Regulatory T cells (Tregs) are functionally impaired, failing to suppress excessive inflammation. Adaptive immune responses interact with innate immunity, amplifying the inflammatory cascade and creating a feed-forward loop. This interplay helps explain why KD can result in prolonged inflammation, persisting even after the initial triggering agents are no longer present [62,63,64].

Given the complexity of its pathogenesis, KD may be better described as a syndrome rather than a single disease with a single etiologic agent [65]. Whether the different subgroups in KD represent manifestations of children with different genetic susceptibilities that shape their diverse immune responses to an external agent, a “super-antigen,” or a disturbed Protein-Homeostasis System remains unresolved. A single theory may not answer etiopathogenesis.

9. Use of Biomarkers in Kawasaki Disease

Traditional inflammatory markers in KD include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocytosis, thrombocytosis, anemia, hypoalbuminemia, elevated liver enzymes, and ferritin. These markers are nonspecific. In recent years, there has been a concerted effort to develop and identify biomarkers that can serve as effective diagnostic tools to rule out conditions that mimic KD and to help predict risk. These biomarkers include multi-omics integration, non-coding RNAs, cytokine and inflammatory profiles, and gingival crevicular fluid proteomics [66,67,68].

Over the decades, researchers have tried to identify biomarkers that are more specific for diagnosing KD and guiding treatment. Genomic studies have gone beyond finding risk genes to also identify microRNAs, which influence gene activity and may help tell KD apart from other febrile illnesses, especially in the first week. Proteomics research aims to discover new proteins linked to KD’s disease process. Studies of metabolism and the gut microbiome look at changes like reduced short-chain fatty acids (SCFAs) and higher stress metabolites, which can help predict resistance to IVIG treatment and the risk of coronary artery abnormalities.

Novel biomarkers such as N-terminal pro-brain natriuretic peptide (NT-proBNP) [69], plasma clusterin [70], troponin, creatinine kinase, and neutrophil inducible nitric oxide synthesis (iNOS) [64] are promising tools for early diagnosis, cardiac risk assessment, and monitoring vascular inflammation in KD. These structural proteins, immune regulators, and proteases may contribute to vascular inflammation and immune dysregulation. Kim et al. [71] reviewed biomarkers relevant to KD and categorized them into the following three groups: biomarkers related to KD diagnosis, coronary artery lesion incidence, and IVIG resistance. Ferritin, N-terminal pro BNP (NT-proBNP), non-coding RNA (ncRNA), and microRNA (miRNA) help in the diagnosis of KD, prognostic nutritional index (PNI) and ncRNA for incidence of coronary artery lesion, and prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), CRP, and ncRNA for IVIG resistance.

High-accuracy mass spectrometric analysis of urinary proteomes in children has also been developed and reported to improve the diagnostic accuracy of children with suspected KD [72]. These tests for urine proteome profiles are non-invasive. They detect markers for endothelial cell injury, such as filamin and talin, complement dysregulation biomarkers like complement regulator (CUB) and Sushi multiple domains 3 (CSMD3), immune pattern recognition receptor like muclin, and immune cytokine protease meprin A. While still experimental, they may become part of multi-omics panels for early KD detection, risk stratification, and coronary outcome prediction.

Table 6. Summary of different types of biomarkers studied in Kawasaki disease [59,60,61,69,70,71].

	Origins/Function and Pathway Involvement	Significance in KD
Inflammatory markers
CRP, ESR	Acute phase reactants from the liver	Elevated in acute KD, correlates with disease activity
White blood cells (WBCs)	Innate immune activation	Raised in acute phase with neutrophils dominance
Platelets	Megakaryocyte activation	Thrombocytosis usually noted after day 7 and is a marker for subacute inflammation
IL-1, IL-6, TNF-α	Cytokines from macrophages, neutrophils	Important cytokine profiles which drive fever, vascular inflammation and account for IVIG resistance
HMGB1, S100A12	DMAPs from damaged cells	May associate with CCA risk
Immunological Markers
Th1 cytokines (IFN-γ, IL-2)	CD4+ T cells	Activate macrophages and perpetuate vascular inflammation
Th17 cytokines (IL17, IL-22)	CD4+ T cells	Recruit neutrophils and sustain inflammatory process
Treg dysregulation	Regulatory T cells	Loss of immune suppression and prolonging the inflammatory process
Complement activation (C3, C4, CSMD3)	Plasma proteins	Amplify vascular damage and immune complex deposition
Proteomic markers
NT-proBNP	Cardiac stress peptide	Has diagnostic and prognostic markers for myocardial involvement
Clusterin	Endothelial protection, apoptosis regulation	Elevated in KD and is a marker of vascular stress
Filamin, Talin	Cytoskeletal remodeling	Reflect endothelial cell injury and repair
Meprin A, MMPs	Extracellular matrix degradation	Linked to aneurysm formation
CSMD3	Complement regulation	Indicate immune dysregulation
Muclin, Meprin A	Innate immune system activation	Distinguish KD from viral infections

HMGB1: High Mobility Group Box 1. This is a nuclear protein that acts as a potent DAMP when released extracellularly. S100A12: S100 calcium-binding protein A12. It is also known as calgranulin C and is a small calcium-binding protein from the S100 family. Activated neutrophils mainly produce it, and it is a damage-associated molecular pattern (DAMP) which plays a major role in amplifying inflammation. CSMD3: CUB and Sushi multiple domains 3. It is a large membrane-associated protein that belongs to the CSMD family of complement regulatory proteins. It plays a role in modulating the complement system. NT-proBNP: N-terminal pro–B-type natriuretic peptide. This is an inactive fragment of the precursor molecule proBNP, which is released from the heart when the ventricles are under stress. It is widely used as a biomarker of cardiac strain.

summarizes and categorizes the more commonly studied biomarkers for easy reference. The list has expanded over the years and is not exhaustive.

10. Contemporary Management

10.1. First-Line Therapy: IVIG and Aspirin Approach

The aim of treatment in KD is to reduce inflammation, especially in the coronary arteries, and prevent the development of coronary artery disease. Kato et al. in 1979 [73] first showed the effectiveness of aspirin in reducing the incidence of CAAs in KD. The incidence was only 11% in the aspirin-treated group, compared with 64.7% in the steroid-treated group. The study suggested that the use of steroids might adversely affect the progression of coronary lesions in KD. This unfavorable outcome of corticosteroids paved the way for the exploration of another immune modulator, IVIG, which has several immune-modulating effects [74], making it a viable option.

In 1984, Furusho et al. [75] published their study in the Lancet. They performed a multicenter controlled trial on the use of IVIG in KD patients by comparing the use of aspirin at a dose of 10–30 mg/kg/day for 3 months in the control group, versus the use of IVIG at 400 mg/kg/day for 5 days in the study group. None of the patients in the IVIG group developed CAAs, whereas 17% of those in the control group did. In 1986, another landmark study [76] published in the New England Journal of Medicine established that high-dose intravenous gamma globulin (IVIG), combined with aspirin, administered early in the acute phase of Kawasaki disease, significantly reduces the incidence of coronary artery abnormalities from approximately 20–25% to just 3–8%. In this study, Newburger JW et al. [76] compared the efficacy of intravenous gamma globulin plus aspirin with aspirin alone in reducing the frequency of coronary artery abnormalities (CAAs) in children with Kawasaki disease in a multicenter, randomized trial. The studied patients were randomly assigned to the IVIG group, who received intravenous gamma globulin at 400 mg/kg per day, for four consecutive days; both treatment groups received aspirin at 100 mg/kg per day, through the first fourteen days of illness, then to aspirin at 3 to 5 mg/kg per day. At two weeks, coronary artery abnormalities were present in 23% in the aspirin group, as compared with 8% in the gamma globulin group (p = 0.01). Seven weeks after enrollment, coronary artery abnormalities were present in 18% in the aspirin group versus 4% in the gamma globulin group (p = 0.005). In 1991, Furusho et al. [77] studied the effects of aspirin and IVIG on the development of coronary artery lesions in KD using three different protocols. They demonstrated that a dose of IVIG at 1000 mg/kg or more not only significantly reduces the occurrence of coronary arterial lesions in patients treated with IVIG but also results in a reduction in the residual coronary artery lesions for 2 years compared with the group treated with aspirin alone. These studies laid the foundation for the beneficial effect of early IVIG in the treatment of children with KD.

Following these, numerous studies were conducted to compare various IVIG regimens to establish the optimal dosage and duration of IVIG use, for example, IVIG at 400 mg/kg/day for 5 days versus IVIG at 1 g/kg in a single dose (Barron 1990 [78]); 400 mg/kg/day for 4 days versus 2 gm/kg in a single dose (Newburger 1991 [79]), IVIG at 200 mg/kg/day versus 400 mg/kg/day (Morikawas in 1994 [80]), (Onouchi 1995 [81]), and (Sato 1995, 1999 [82]). A dose-comparison meta-analysis [83] showed that a single high-dose IVIG regimen significantly reduced the duration of fever and hospitalization. There was no statistically significant difference between different preparations of IVIG, and no significant difference in adverse effects. Nowadays, the single high dose of IVIG at 2 g/kg has also become the standard therapy of IVIG in KD children. The effectiveness of IVIG as an immune modulator is closely linked to the severity of systemic inflammation. Patients who do not respond to IVIG typically exhibit higher pre-treatment inflammatory markers, indicating more severe inflammation [84]. Assessing treatment response requires monitoring both clinical features and serial inflammatory markers, such as CRP, WBC, and platelet counts, to help guide decisions regarding additional IVIG dosing or other adjuvant therapies [85]. In cases of IVIG hypersensitivity, reducing the infusion rate or administering premedication with antihistamines and hydrocortisone may be necessary.

10.2. Salicylic Acid

Aspirin inhibits the cyclo-oxygenase pathway of arachidonic acid. In lower-dose aspirin (LDA) at 3–5 mg/kg/day, it exerts an anti-thrombotic effect by inhibiting platelet-derived thromboxane A2. At a high-dose aspirin (HDA) of 80–100 mg/kg/day, it exhibits its anti-inflammatory effect.

Before recognizing IVIG as an effective treatment modality, the first line of treatment was using acetylsalicylic acid (aspirin) at high doses. Koren et al. [86] reported in 1985 that there were significantly more cases of coronary abnormalities in the untreated group than in the salicylate-treated group, and of coronary aneurysm, the difference is 39% in the untreated group versus 3% in the salicylate-treated group. They concluded that, despite the difficulty of achieving a therapeutic salicylate serum concentration, a dose as high as 100 mg/kg/day can prevent coronary artery disease in KD children. In the AAP/AHA guideline in 2004 [14], IVIG, together with high-dose aspirin at 80–100 mg/kg/day, was used as the initial treatment, whereas the Japanese guideline [87,88] recommended an initial aspirin dose of 30–50 mg/kg as an initial anti-inflammatory agent. After the fever resolves, both guidelines recommend switching to a low-dose aspirin of 3–5 mg/kg/day. With the efficacy of high-dose IVIG becoming more evident, the initial aspirin dose was lowered to 30 mg/kg/day as the initial adjuvant therapy, as in the Japanese guideline [87,88]. Studies have examined the optimal aspirin dose or even removed it from the initial treatment regimen. Akagi et al. [89] evaluated the therapeutic efficacy of high dose at 100 mg/kg per day versus low dose at 30 mg/kg/day and found no difference in the incidence of coronary artery disease, suggesting high-dose salicylate therapy may be disadvantageous, and the dose at 30 mg/kg/day was safe in the acute stage of KD.

An early systematic review in 2006 [90] identified only one RCT from Japan in 1991 and found no clear benefit of adding salicylate to immunoglobulin treatment on the rate of CAA at up to 30 days. Dallaire et al. [91] demonstrated in a multicenter retrospective study that, in combination with IVIG, low-dose aspirin was not inferior to high-dose aspirin for reducing the risk of CAAs in acute KD. There was a trend toward re-examining the aspirin dose in treating the acute phase of KD. A systematic review by Safar et al. [92] identified only 12 studies that met the PICO criteria after a preliminary search of 1169 records. The studies included eleven retrospective cohort studies and one RCT for further analysis. There was no significant difference in CAAs during the acute phase of KD with IVIG treatment between the no- or low-dose aspirin group and the high-dose aspirin group. The incidence of IVIG resistance and the duration of fever also did not differ between no- or low-dose aspirin and high-dose aspirin [92].

Due to the potential harmful effects of high-dose aspirin and its weaker anti-inflammatory action compared to high-dose IVIG and corticosteroids (CSs), low-dose aspirin (3–5 mg/kg/day) combined with IVIG is generally sufficient during the acute phase of KD. The decision to use aspirin, given its antiplatelet properties in the convalescent phase, should be individualized, and the duration of therapy should be based on the severity of thrombocytosis and the extent of coronary abnormalities [93].

10.3. Management of IVIG-Resistant KD: Steroid and Beyond

Patients with persistent or recrudescent fever ≥ 36 h after completion of the initial IVIG infusion are arbitrarily defined as IVIG-resistant. However, this is no universal consensus among researchers on IVIG-non-responsiveness or refractory KD. Most guidelines suggested giving a second dose of IVIG at the same dosage for non-responsive patients. Unlike older guidelines, newer guidelines [14,15,16,87,88,94,95] with updated data support the use of first-line corticosteroids in “high-risk” patients. Steroids can be given as high-dose pulse methylprednisolone (IVMP), up to 30 mg/kg/day, either as a single dose or for 3 consecutive days, or as oral prednisolone at 2 mg/kg/day for a longer course, gradually tapered after normalization of inflammatory markers and resolution of symptoms.

Corticosteroids (CSs), once avoided due to concerns about delaying vascular healing, have recently been reappraised for their potential to reduce inflammation in Kawasaki disease [96,97]. CS is now incorporated into the initial round of IVIG treatment for children identified as high risk for CCAs by risk-scoring systems or used as a second-line rescue option when fever and elevated inflammatory markers persist after the first IVIG dose [98]. A Cochrane database review [99] demonstrated that corticosteroids in the acute phase can lower the incidence of CCAs, speed up the normalization of inflammatory markers, shorten hospital stays, and reduce symptom duration. However, most studies have examined their use in combination with IVIG, and there is a paucity of research on corticosteroids as sole primary therapy in the IVIG era. Given their anti-inflammatory effects and widespread use in other childhood vasculitides, further studies are warranted—especially considering the possibility of IVIG shortages and its high cost, which make it unaffordable in many low-income countries.

In 2004, Weiss et al. [100] first reported their experience with the effectiveness of infliximab in treating KD in a patient who was non-responsive to IVIG and IVMP treatment. Subsequently, more reports [101] supported its effectiveness in suppressing inflammation, and it is a safe alternative. Although there were reports of etanercept at 0.8 mg/kg per dose, infliximab at 5–10 mg/kg given intravenously over 2 h was most widely reported and was recommended as a second-line therapy for patients with IVIG-resistant disease.

Other biologics, including anakinra (IL-1 receptor antagonist) at 10 mg/kg/day either subcutaneous or intravenous [102,103] and Tocilizumab (IL-6 inhibitor) [103,104], have been increasingly reported to be useful in refractory disease. Calcineurin inhibitors, which target T-cell activation, especially cyclosporin A at 5 mg/kg/day in two divided doses, have been used in Japan for severe refractory disease [87,88,105,106]. Cyclophosphamide or plasma exchange may be useful in life-threatening KD, especially in patients with MAS or refractory coronary aneurysm [95,107,108]. Treatment algorithm for KD has changed over the past decades. Recent updated guidelines based on new evidence provide useful information for pediatricians to support prompt diagnosis and early intervention (

Table 7. Highlights in updated acute management of Kawasaki disease [13,14,94,95,96,97,103].

The mandatory “5-day fever” rule is no longer required; emphasis is now on a holistic review of the principal diagnosis.

The new guidelines aim to empower pediatricians to achieve early diagnosis and timely intervention.

Early echocardiograms and the use of coronary artery Z-scores help assess the risk of coronary complications.

Risk assessment scores have been developed, allowing for intensified therapy in high-risk patients, but we have to be aware of their potential limitations.

Adjunctive corticosteroids or infliximab, in addition to IVIG and aspirin, are recommended for high-risk patients.

For severe or refractory cases, multi-drug strategies combining IVIG with prednisolone, infliximab, or cyclosporine are recommended [94,95,96].

For the most severe cases, plasma exchange is a recognized therapy [95].

The follow-up plan is based on risk stratification. Children with medium or giant coronary aneurysms require lifelong assessment. In addition to serial echocardiograms, CT angiograms and stress electrocardiograms are necessary.

The use of anticoagulants, such as Direct Oral Anticoagulants (DOACs), is recognized as a safe alternative for children.

). Conventional immunosuppressive agents and biologics are commonly used to control acute inflammation or act as corticosteroid-sparing agents in many childhood vasculitides and inflammatory diseases. However, these therapies are generally reserved for KD patients who are refractory to standard treatment or develop giant coronary aneurysms. Because of the variation in time of onset of these immunosuppressive agents, their role in controlling systemic inflammation during the acute phase varies. Long-term use of these agents may benefit patients with ongoing or slow progressive coronary inflammation, but such cases are rare and often challenging to identify. As anti-cytokine therapy is expensive, these conventional second-line immunosuppressive agents are valuable in managing refractory KD in countries where expensive anti-cytokine therapy is not easily available.

11. Long-Term Follow-Up

A long-term follow-up plan for KD is important, as even after the resolution of the acute inflammatory state, the risk of development of CCAs and other cardiac complications remains. Both the updated AHA [14] and Japanese guidelines [94,95] recommended risk-stratified surveillance based on the severity of coronary artery involvement. In general, patients with no coronary involvement have the lowest risk, but they still require periodic short-term follow-up. Patients with transient coronary dilatation need closer monitoring in the first year at least. For those who have persistent small aneurysms, ongoing surveillance with imaging and antiplatelet therapy like low-dose aspirin is recommended. Patients with medium to large aneurysms have the highest coronary artery risk. In addition to a regular echocardiogram, advanced cardiac imaging, such as MRI and CT angiogram, and stress testing with ECG, are necessary. Use of anticoagulation therapy, like warfarin and Direct Oral Anticoagulants (DOACs), is indicated in patients with significant coronary aneurysm. In the long run, this group of patients is encouraged to have lifestyle medication to reduce cardiovascular risk.

12. Unresolved Questions and Controversies

Dr. Kawasaki first described and named KD as “acute febrile mucocutaneous lymph node syndrome, with the surface of incomplete KD, atypical KD, KDSS, and Kawasaki-like syndrome (MIS-C) as a complication of COVID-19”. KD behaves as a spectrum of phenotypes with variable severity. Its diagnosis cannot be confirmed by genetic study or laboratory markers. Hence, should KD be better renamed as Kawasaki syndrome, instead of Kawasaki disease? The mild phenotype of KD may present early at 2–4 days of fever. Because of its self-limiting clinical course, investigation at this early presentation may not detect the peak of inflammation, resulting in underdiagnosis. On the contrary, with incomplete and atypical clinical features, overdiagnosis of patients, especially those without coronary involvement, is not uncommon in daily practice.

Clinical risk scores have been developed to segregate high-risk and IVIG-resistant patients; however, these scores based on clinical variables have their limitations, and their validity across countries is questionable.

The etiopathogenesis of KD remains unclear; biomarkers have been extensively investigated from various perspectives, such as genomics, proteomics, microbiome, and metabolomics. However, we are not certain about the significance of these biomarkers, especially how they best relate to the time frame of the disease process. Which biomarkers indicate early disease or an early coronary insult? None of these biomarkers are specific for KD diagnosis and explain the predilection for coronary artery disease involvement. Most of these studied biomarkers are not easily available in clinical practice; hence, their clinical application and significance become questionable.

Current treatment options remain nonspecific immune modulators like IVIG, aspirin, and steroids. Although specific anti-cytokine therapy is in the pipeline, controlled acute inflammation may not stop the aftermath of coronary inflammation and arrest progressive damage to the coronary arteries. With more understanding of the roles of specific biomarkers, more targeted therapies may emerge in the future.

13. Conclusions

Kawasaki disease sits at the intersection of infectious triggers, immune dysregulation, and possible severe cardiac injury. The clinical course could be complicated and challenging in both diagnosis and treatment, especially in those with IVIG-resistant and life-threatening phenotypes. Advances in identifying new biomarkers may help uncover the unknown; however, their clinical applications are still uncertain. Understanding the pathogenesis will help guide specific treatment and prevent long-term coronary artery disease.