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Kawasaki disease

Kawasaki disease (KD) is an acute, self-limited vasculitis that primarily affects medium-sized blood vessels, with a particular predilection for the coronary arteries, and occurs most commonly in children under five years of age.^[1] It is characterized by prolonged fever lasting at least five days, along with at least four of five principal clinical features: bilateral conjunctival injection without exudate, changes in the oropharyngeal mucous membranes (such as red cracked lips or strawberry tongue), polymorphous rash, changes in the peripheral extremities (such as erythema of the palms or soles, or periungual desquamation), and cervical lymphadenopathy (usually unilateral).^[2] Also known as mucocutaneous lymph node syndrome, KD can lead to serious cardiac complications, including coronary artery aneurysms, if not treated promptly.^[3] The disease typically presents in three phases: an acute febrile phase lasting one to two weeks, a subacute phase from the second to fourth week marked by desquamation and potential coronary artery involvement, and a convalescent phase where symptoms resolve but cardiac risks persist.^[1] Incomplete or atypical KD, which does not meet all diagnostic criteria, is common in younger infants and still carries a high risk of coronary artery abnormalities.^[3] Diagnosis is primarily clinical, supported by laboratory findings such as elevated C-reactive protein, erythrocyte sedimentation rate, and supplemental tests like echocardiography to assess for coronary involvement.^[1] Early recognition is critical, as treatment within the first ten days of illness significantly reduces the risk of cardiac sequelae.^[3] The etiology of KD remains unknown, though it is thought to involve an excessive immune response possibly triggered by an infectious agent in genetically susceptible individuals, with recent research (as of 2025) providing compelling evidence for a single unidentified respiratory virus as a potential trigger, and no evidence of person-to-person transmission.^[1]^[4] Epidemiologically, KD is the leading cause of acquired heart disease in children in developed countries, with an incidence of 18 to 25 cases per 100,000 children under five in the United States and higher rates in Asian populations, such as over 200 per 100,000 in Japan (with recent estimates up to 370).^[5]^[6]^[7] Risk factors include age under five (peaking at 6 to 11 months), male sex (1.5:1 ratio), Asian or Pacific Islander ethnicity, and seasonal occurrence in winter and early spring in temperate climates.^[3]^[1] Treatment consists of intravenous immunoglobulin (IVIG) at 2 g/kg as a single infusion, combined with high-dose aspirin (80 to 100 mg/kg/day) during the acute phase, which reduces the incidence of coronary artery aneurysms from 25% in untreated cases to about 5%.^[1] For IVIG-resistant cases (occurring in 10 to 20%), additional therapies such as corticosteroids or infliximab may be used.^[1] Long-term management involves low-dose aspirin for antiplatelet effects and regular cardiac monitoring, particularly in those with aneurysms.^[5] With prompt treatment, the prognosis is excellent, and most children recover fully without long-term complications, though untreated or severe cases can result in myocardial infarction or sudden death.^[1]

Signs and symptoms

Mucocutaneous and systemic features

Kawasaki disease presents with a constellation of mucocutaneous and systemic features during its acute phase, with persistent fever serving as the hallmark symptom, typically lasting at least five days and often exceeding 39°C, showing minimal response to antipyretics.^[1] This fever is essential for diagnosis and usually persists for one to two weeks if untreated, up to three to four weeks in some cases.^[1]^[8] Mucosal changes are prominent early in the illness, appearing within the first five days of fever onset, and include bilateral nonexudative conjunctival injection, which is painless and limbic-sparing, affecting the bulbar conjunctiva without discharge.^[6]^[8] Oral mucosal involvement manifests as erythematous and cracked lips, often with fissuring, alongside a strawberry tongue characterized by prominent papillae on an erythematous base.^[1]^[6] These changes contribute to the diagnostic criteria and reflect the underlying vasculitis affecting small vessels in the mucosa.^[1] Skin manifestations are polymorphous, typically developing within the first five days and presenting as a diffuse maculopapular, morbilliform, or scarlatiniform rash on the trunk and extremities, sparing the perineal area in some cases.^[1]^[8] Erythema and indurative edema of the palms and soles occur early, followed by periungual desquamation in the subacute phase, starting around two to three weeks after fever onset and peaking in weeks two to four.^[1]^[8] This peeling is a characteristic feature that aids in confirming the diagnosis retrospectively.^[1] Cervical lymphadenopathy, usually unilateral and nonpurulent, affects approximately 50-75% of patients and involves nodes greater than 1.5 cm in diameter, often appearing early but sometimes as the last principal feature to develop.^[6]^[8] Systemic symptoms accompany these mucocutaneous signs and include irritability and anorexia, which are common and reflect the generalized inflammatory state.^[6]^[8] Additional manifestations occur in subsets of patients, such as arthralgia or arthritis in 15-50%, gastrointestinal symptoms like abdominal pain, vomiting, or diarrhea in about 20%, and aseptic meningitis in up to 25%, presenting with headache, neck stiffness, or cerebrospinal fluid pleocytosis without organisms.^[1] Respiratory symptoms, including rhinorrhea and cough, affect 20-30% of cases.^[1] The non-cardiac features evolve across distinct phases: the acute phase spans the first one to two weeks, dominated by high fever, rash, conjunctival injection, and mucosal changes; the subacute phase, from weeks two to four, features resolution of fever, onset of desquamation, and emerging thrombocytosis; and the convalescent phase, beginning around four weeks and lasting up to three months, involves gradual normalization of symptoms with persistent nail changes like Beau's lines appearing five to eight days after onset and resolving over two to four weeks.^[1]^[8]

Cardiac involvement

Cardiac involvement in Kawasaki disease primarily manifests during the acute phase, with myocarditis affecting nearly all patients to varying degrees, often presenting as sinus tachycardia, a gallop rhythm, and reduced ventricular function that can progress to congestive heart failure in severe cases.^[9]^[10] These myocardial changes, driven by inflammatory infiltration, typically resolve without long-term sequelae but underscore the need for vigilant monitoring in the initial illness phase, which coincides with persistent fever and rash.^[11] The most critical cardiovascular complication involves the coronary arteries, where inflammation leads to dilation and aneurysm formation, classified based on internal diameter or z-score measurements adjusted for body size.^[12] Small aneurysms are defined as having a z-score of 2.5 to less than 5 (or diameter 3-4 mm), medium aneurysms as z-score 5 to less than 10 (or 4-8 mm), and giant aneurysms as z-score 10 or greater (or absolute diameter greater than 8 mm), with the latter carrying the highest risk of thrombosis and stenosis.^[12]^[13] Per the 2024 American Heart Association guidelines, a coronary artery z-score of 2.5 or higher at diagnosis indicates abnormality, prompting intensified therapy to mitigate progression.^[14] Without prompt treatment, up to 25% of patients develop coronary artery aneurysms, a rate reduced to approximately 5% with timely intravenous immunoglobulin administration.^[12] In severe instances, pericardial effusion may occur, contributing to hemodynamic instability, while valvular involvement, such as mitral or aortic regurgitation, arises in about 1% of cases due to endothelial inflammation.^[15]^[16] During the subacute phase, patients with aneurysms face risks of silent myocardial ischemia or infarction, particularly from thrombus formation or stenotic lesions within or adjacent to aneurysms, which can lead to long-term ischemic heart disease if undetected.^[17]^[18]

Pathophysiology

Etiology and triggers

The etiology of Kawasaki disease (KD) remains idiopathic, with no single causative agent identified despite extensive research over five decades.^[19] Proposed triggers include infectious and environmental factors that likely interact with genetic susceptibility to initiate the disease in predisposed children.^[20] Although no definitive pathogen has been confirmed, the superantigen hypothesis posits that bacterial toxins, such as staphylococcal toxic shock syndrome toxin-1 (TSST-1) or streptococcal pyrogenic exotoxins, may drive massive T-cell activation leading to the inflammatory cascade observed in KD.^[21] However, recent analyses indicate that superantigens are unlikely to be the primary driver, as evidence from genomic and immunological studies has not consistently supported this mechanism.^[19] Infectious triggers, particularly respiratory viruses, have been implicated through temporal and epidemiological correlations. For instance, outbreaks of KD have coincided with peaks in infections from adenovirus, coronaviruses, and other common respiratory pathogens, suggesting these viruses may act as environmental precipitants in susceptible individuals.^[22] The emergence of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection has further highlighted potential viral roles, as MIS-C shares clinical overlaps with KD but is distinctly post-infectious, reinforcing the idea that coronaviruses could trigger similar vasculitic responses.^[23] Environmental exposures also contribute to KD risk, with seasonal patterns showing peaks in winter and spring in temperate climates, possibly linked to increased indoor activities or atmospheric changes.^[24] Associations have been reported between KD incidence and air pollution, particularly exposure to fine particulate matter (PM2.5) and nitrogen dioxide from urban traffic and agricultural sources, which may promote airway inflammation in genetically vulnerable children.^[25] Additionally, epidemiological studies have identified a potential link to recent household carpet cleaning, where aerosolized chemicals or dust might serve as irritants, though this remains correlative rather than causal.^[26] Genetic factors play a critical role in susceptibility, with KD incidence markedly higher in East Asian populations; for example, Japan reports rates of approximately 300 cases per 100,000 children under 5 years, compared to 20-25 per 100,000 in North America and Europe.^[27] Genome-wide association studies have identified variants in genes like ITPKC, CASP3, and ORAI1 that confer risk, particularly in Asian cohorts, indicating an inherited predisposition that amplifies responses to external triggers.^[28] Emerging 2024 research highlights microbiome dysbiosis as a potential susceptibility factor, with alterations in gut microbiota composition observed in KD patients, possibly exacerbated by prior antibiotic use and contributing to immune dysregulation.^[29] Similarly, aerosolized exposures, including wind-transported dust and ultrafine metal-rich particles, have been proposed as novel triggers based on spatiotemporal analyses linking atmospheric events to KD clusters.^[24] These findings suggest that such exposures may initiate the aberrant immune response characteristic of KD in genetically at-risk individuals.^[19]

Immune and vascular mechanisms

Kawasaki disease involves hyperactivation of the innate immune system, primarily through Toll-like receptors (TLRs) and the NLRP3 inflammasome, which recognize damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) following an environmental trigger.^[30] This activation leads to caspase-1 cleavage, promoting the release of proinflammatory cytokines such as IL-1β and IL-18. The resulting cytokine storm features markedly elevated levels of IL-1, IL-6, and TNF-α, which amplify systemic inflammation and contribute to endothelial injury in the acute phase.^[30] These cytokines drive pyroptosis in immune cells, exacerbating vascular damage through reactive oxygen species (ROS) production and neutrophil extracellular trap (NET) formation. Adaptive immunity plays a secondary but significant role, characterized by oligoclonal expansion of T cells, particularly CD8+ subsets, as identified through single-cell T-cell receptor sequencing in affected tissues. This expansion occurs in coronary artery lesions, where CD8+ T cells outnumber CD4+ T cells by a factor of 4-5, releasing cytotoxic mediators like perforin, granzyme, IFN-γ, and TNF-α that target vascular endothelium. Concurrently, B cells produce autoantibodies against endothelial cells, forming immune complexes that deposit in vessel walls and perpetuate inflammation via complement activation.^[31] A Th17/Treg imbalance further sustains this response, with elevated IL-17 promoting IVIG resistance in susceptible individuals. Vascular pathology in Kawasaki disease manifests as endothelial dysfunction in medium-sized arteries, particularly the coronaries, driven by cytokine-induced oxidative stress and ROS accumulation. This leads to increased permeability, leukocyte adhesion, and apoptosis of endothelial cells, initiating necrotizing arteritis. Subsequent smooth muscle cell proliferation and myofibroblast transformation in the arterial intima cause luminal narrowing and aneurysm formation, with oxidized low-density lipoprotein (oxLDL) via LOX-1 receptor exacerbating these changes.^[31] Thrombosis arises from platelet activation and fibrin deposition on damaged endothelium, posing a risk for myocardial infarction in aneurysmal segments. Genetic factors modulate these immune and vascular processes, with polymorphisms in FCGR2A (rs1801274), ITPKC (rs28493229), and CASP3 (rs72689236) associated with increased disease susceptibility and coronary artery aneurysm risk.^[32] The FCGR2A A allele enhances Fcγ receptor-mediated inflammation in Asian populations, while ITPKC variants impair calcium signaling to boost IL-2 production and T-cell activation.^[32] CASP3 polymorphisms promote apoptosis in endothelial cells, linking to more severe vasculitis; these loci also correlate with IVIG non-response rates of up to 20-25% in affected cohorts.^[32] Recent 2024-2025 genomic studies, including whole-exome sequencing, highlight additional variants in genes like EIF2AK4 and MYH14, refining the polygenic risk landscape for immune dysregulation and therapeutic resistance. MicroRNAs (miRNAs) serve as key biomarkers reflecting immune dysregulation and aneurysm predisposition in Kawasaki disease.^[33] For instance, upregulated miR-155 disrupts Treg function via the STAT-5 pathway, impairing FoxP3 expression and promoting unchecked inflammation.^[33] miR-223-3p targets IL6ST to mitigate endothelial injury but, when dysregulated, contributes to pyroptosis and cytokine amplification.^[33] In aneurysm formation, miR-125a-5p induces endothelial apoptosis through Bax/Bcl-2/caspase-3 activation, while miR-27b inhibits TGF-β-mediated endothelial-to-mesenchymal transition to protect vessel integrity.^[33] Circulating miRNA profiles, such as those in exosomes, correlate with disease severity and offer potential for early detection of high-risk vascular complications.^[33]

Diagnosis

Clinical criteria and case definition

Kawasaki disease (KD) is diagnosed clinically based on the presence of persistent fever and specific mucocutaneous features, as outlined in the American Heart Association (AHA) guidelines. The classic or complete form requires fever lasting at least 5 days, accompanied by at least 4 of 5 principal clinical criteria: (1) bilateral bulbar conjunctival injection without exudate; (2) changes in the oropharyngeal mucous membranes, such as injected or fissured lips, strawberry tongue, or injected pharynx; (3) changes in the peripheral extremities, including erythema of the palms or soles, edema of the hands or feet, or periungual desquamation in the subacute phase; (4) polymorphous exanthem; and (5) cervical lymphadenopathy, typically unilateral and greater than 1.5 cm in diameter.^[6] Experienced clinicians may establish the diagnosis earlier, with fever of 4 days or even 3 days if supported by the clinical features, to facilitate timely treatment.^[6] Incomplete KD applies to patients with prolonged fever (at least 5 days) but fewer than 4 principal criteria, particularly in cases where early recognition is challenging, such as in infants younger than 6 months who may present atypically.^[6] Diagnosis in these instances relies on an evaluative algorithm that incorporates supplemental laboratory findings after initial assessment, including elevated C-reactive protein (CRP ≥3.0 mg/dL) and/or erythrocyte sedimentation rate (ESR ≥40 mm/h), alongside other supportive indicators such as anemia (for age), thrombocytosis (platelet count ≥450,000/mm³ after 7 days of fever), leukocytosis, elevated alanine aminotransferase, hypoalbuminemia, and sterile pyuria.^[6] If laboratory criteria are met, further evaluation with echocardiography is recommended to assess for coronary artery abnormalities, which can confirm the diagnosis when clinical features are insufficient.^[6] The 2024 AHA scientific statement refines the identification of high-risk patients at diagnosis to guide intensified management, defining high-risk KD as occurring in infants aged 6 months or younger or those with a coronary artery z-score of 2.5 or greater in the left anterior descending or right coronary artery on initial evaluation.^[6] This update, derived from North American population data including the Son risk score (which incorporates age <6 months, Asian race/ethnicity, CRP >13 mg/dL, and initial coronary z-score >2), predicts a higher likelihood of coronary artery aneurysms, with infants under 6 months showing up to 68% prevalence of such complications.^[6] The diagnostic algorithm for suspected incomplete KD emphasizes exclusion of alternative diagnoses early in the process, such as infections (e.g., scarlet fever, measles), other vasculitides, or multisystem inflammatory syndrome in children (MIS-C), which may mimic KD but feature distinct elements like gastrointestinal symptoms, thrombocytopenia, or cardiac dysfunction.^[6] Features inconsistent with KD, including exudative conjunctivitis, unilateral eye involvement, vesicular rash, or oral ulcerations, should prompt consideration of other conditions.^[6] Prompt diagnosis within 10 days of fever onset, ideally by days 4 to 5 for complete cases, remains critical to mitigate risks.^[6]

Laboratory and imaging investigations

Laboratory investigations play a supportive role in the diagnosis of Kawasaki disease (KD), particularly in incomplete cases where clinical criteria are not fully met, by demonstrating systemic inflammation and other characteristic abnormalities. Common findings include elevated C-reactive protein (CRP) levels, often exceeding 3 mg/dL, and markedly increased erythrocyte sedimentation rate (ESR), typically greater than 40 mm/h, reflecting the acute inflammatory state.^[12] Leukocytosis with a predominance of neutrophils and immature forms is frequently observed during the acute phase, alongside normocytic normochromic anemia and hypoalbuminemia, which correlate with disease severity and duration.^[12] Thrombocytosis emerges later, usually after the first week, with platelet counts surpassing 450,000/mm³ and peaking around 700,000/mm³ by the third week, contributing to the prothrombotic risk.^[12] Sterile pyuria, detected in up to 80% of cases via urinalysis, indicates urethral involvement without bacterial infection.^[12] In cases with neurological symptoms, cerebrospinal fluid (CSF) analysis may confirm aseptic meningitis, showing pleocytosis with a mononuclear cell predominance in approximately 30% of patients, alongside normal glucose and protein levels.^[12] No single biomarker provides definitive diagnostic confirmation for KD; instead, these laboratory abnormalities aid in supporting the diagnosis when aligned with clinical criteria for incomplete KD and help monitor treatment response.^[12] Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) can indicate myocardial involvement but lacks established cutoffs for routine use.^[12] Echocardiography serves as the first-line imaging modality for assessing coronary artery involvement in KD, enabling early detection of dilation (defined by z-scores ≥2.5), aneurysms, pericardial effusion, and valvular regurgitation.^[12] Serial echocardiograms are recommended, typically at diagnosis, 1 to 2 weeks after treatment initiation, and 4 to 6 weeks post-onset for normalization assessment, with more frequent monitoring (e.g., twice weekly) if initial z-scores exceed 2.5.^[12] This approach classifies coronary abnormalities—such as small (z-score 2.5 to <5), medium (z-score 5 to <10 or diameter 5 to <8 mm), or giant (z-score ≥10 or diameter ≥8 mm) aneurysms—and evaluates ventricular function and myocardial performance.^[12] For complex cases involving giant aneurysms or inadequate visualization of distal coronary segments, advanced imaging with computed tomography (CT) angiography or magnetic resonance imaging (MRI) is employed to delineate stenosis, thrombosis, and involvement of non-coronary arteries.^[12] CT angiography provides high-resolution assessment of all coronary segments, while contrast-enhanced MRI evaluates myocardial perfusion, fibrosis, and ischemia without ionizing radiation.^[12] Recent advancements, as noted in the 2024 American Heart Association update, highlight optical coherence tomography (OCT) for detailed endothelial assessment in research settings, though its clinical role remains investigational due to procedural requirements like blood clearance for optimal imaging.^[6]

Differential diagnosis

Kawasaki disease (KD) is a clinical diagnosis based on characteristic features, but its presentation overlaps with numerous infectious, inflammatory, and hypersensitivity conditions, necessitating exclusion of mimics through history, physical examination, laboratory tests, and imaging.^[1] No single diagnostic test exists for KD; instead, differentiation relies on the incomplete KD algorithm, which incorporates supportive laboratory criteria (e.g., elevated C-reactive protein and erythrocyte sedimentation rate) and echocardiography to assess for coronary artery abnormalities when fewer than four principal criteria are present.^[6] Infectious mimics include scarlet fever caused by group A Streptococcus, which features a sandpaper-like rash, strawberry tongue, and pharyngitis but lacks the bilateral conjunctival injection and extremity changes of KD; diagnosis is confirmed by positive throat culture or elevated antistreptolysin O (ASO) titer, typically rising 1-3 weeks post-infection.^[34] Measles presents with fever, cough, coryza, and a maculopapular rash starting on the face, distinguished by Koplik spots, viral exanthema, and positive serology or PCR, without the mucosal and extremity involvement seen in KD.^[1] Adenoviral infections often cause exudative conjunctivitis, upper respiratory symptoms, and fever with rash, but lack nonexudative bilateral conjunctival injection and respond to supportive care; viral PCR aids identification, though a positive result does not exclude KD.^[34] Epstein-Barr virus (EBV) infection mimicking KD through pharyngitis and rash is differentiated by mononucleosis features like splenomegaly, atypical lymphocytosis, and positive heterophile or EBV-specific antibody testing.^[1] Rheumatic and hypersensitivity disorders also feature prominently in the differential. Juvenile idiopathic arthritis (JIA) may present with prolonged fever and rash but is characterized by chronic symmetric polyarthritis and lacks the acute mucocutaneous changes of KD; rheumatoid factor and antinuclear antibody testing support JIA.^[35] Stevens-Johnson syndrome (SJS) involves severe mucocutaneous erosions, often triggered by drugs or infections, with targetoid lesions and epidermal necrosis absent in KD; a history of precipitant and skin biopsy confirm SJS.^[35] Toxic shock syndrome (TSS), due to staphylococcal or streptococcal toxins, causes fever, rash, and shock but features hypotension, multiorgan failure, and positive blood cultures, contrasting with KD's vasculitis focus.^[34] A Kawasaki disease-like illness associated with COVID-19, known as multisystem inflammatory syndrome in children (MIS-C), emerged in 2020 and shares features like prolonged fever, rash, conjunctivitis, and mucositis, but is distinguished by SARS-CoV-2 positivity (via PCR or serology), prominent gastrointestinal involvement (e.g., abdominal pain, diarrhea), shock, thrombocytopenia, lymphopenia, and elevated cardiac markers (troponin, BNP).^[6] MIS-C incidence peaked in 2020-2021 (up to 5-10 cases per 100,000 children in affected regions) but declined sharply by 2023-2024 due to population immunity and viral variants, with lower rates of coronary artery aneurysms (≈10-20%) compared to KD (≈25%).^[36] Intravenous immunoglobulin (IVIG) response in MIS-C is generally favorable but often requires adjunctive therapies like glucocorticoids more frequently than in KD.^[6] Other rare mimics include drug hypersensitivity reactions, identified by temporal association with medication exposure and eosinophilia on complete blood count, and mercury poisoning (acrodynia), which presents with pink papules, desquamation, and irritability due to environmental exposure; urine mercury levels confirm the latter.^[37] Echocardiography plays a supportive role in ruling out cardiac manifestations of mimics while confirming KD-specific coronary involvement.^[6]

Treatment

Acute phase therapy

The acute phase of Kawasaki disease treatment focuses on rapidly reducing systemic inflammation and preventing coronary artery damage, typically initiated within the first 10 days of fever onset to optimize outcomes.^[6] The cornerstone of therapy is intravenous immunoglobulin (IVIG), administered as a single infusion of 2 g/kg over 8 to 12 hours, which significantly lowers the risk of coronary artery aneurysms from approximately 25% without treatment to 5% with timely administration.^[6]00270-4/fulltext) This intervention modulates the immune response and is most effective when given early, ideally before day 10 of illness.^[38] High-dose aspirin is used concurrently with IVIG for its anti-inflammatory and antiplatelet effects during the febrile phase, dosed at 80 to 100 mg/kg per day in divided doses until the patient is afebrile for 48 to 72 hours.^[6]^[39] After defervescence, aspirin is tapered to a low dose of 3 to 5 mg/kg per day to provide ongoing antiplatelet protection, typically continued for 6 to 8 weeks or until coronary artery dimensions normalize on echocardiography.^[6]^[40] For high-risk patients—identified by risk stratification at diagnosis as those aged 6 months or younger or with a baseline coronary artery Z-score of 2.5 or greater—the 2024 American Heart Association (AHA) guidelines recommend adjunctive therapy with corticosteroids, such as oral prednisolone at 2 mg/kg per day for 5 days followed by a taper, or infliximab at 10 mg/kg intravenously, in addition to standard IVIG and aspirin.^[6] These additions aim to further mitigate inflammation in cases prone to poorer response.^[6] Patients are monitored in the hospital for treatment response, with fever resolution expected within 36 hours of IVIG initiation; persistent or recurrent fever prompts evaluation for additional interventions.^[6]^[41] Supportive care includes ensuring adequate hydration and nutrition to support recovery and facilitate IVIG administration.^[6]^[42]

Refractory and long-term management

Approximately 10-20% of patients with Kawasaki disease exhibit resistance to initial intravenous immunoglobulin (IVIG) therapy, defined as persistent or recrudescent fever lasting 36 hours or more after completion of the initial 2 g/kg IVIG infusion.^[43]^[6] For these refractory cases, a second dose of IVIG (2 g/kg) is often administered, though alternatives such as infliximab (10 mg/kg IV), cyclosporine (5 mg/kg per day orally for 5 days), or anakinra (2-6 mg/kg per day subcutaneously) may be used to achieve defervescence and reduce coronary artery abnormalities.^[6] Etanercept (0.8 mg/kg subcutaneously weekly for 3 doses) serves as an adjunctive biologic agent, potentially aiding in steroid-sparing regimens for persistent inflammation.^[6] Recent evidence from 2023-2024 supports infliximab as superior to a second IVIG dose in refractory cases, demonstrating faster fever resolution and lower rates of additional treatment needs.^[44] Infliximab at 10 mg/kg has shown greater efficacy in reducing coronary artery lesions compared to 5 mg/kg dosing in these patients.^[45] Long-term management focuses on preventing thrombosis and ischemia in patients with coronary artery aneurysms. Low-dose aspirin (3-5 mg/kg per day) is continued indefinitely for those with persistent aneurysms to provide antiplatelet effects.^[39] For giant aneurysms (Z-score ≥10), anticoagulation with warfarin, low-molecular-weight heparin, or direct oral anticoagulants (such as apixaban) is added alongside aspirin to mitigate thrombotic risk.^[6] Beta-blockers or angiotensin-converting enzyme inhibitors may be prescribed for patients with evidence of myocardial ischemia.^[6] Surgical interventions, such as aneurysmectomy or coronary artery bypass grafting, are rare (occurring in less than 1% of cases) and reserved for severe stenosis or complications like myocardial infarction, managed by a multidisciplinary team.^[6] Ongoing monitoring includes annual echocardiography for all patients with a history of aneurysms, with more frequent imaging (e.g., computed tomography angiography) for giant or progressive lesions; exercise stress testing is recommended in adults to assess for inducible ischemia.^[6]

Prognosis and complications

Short-term outcomes

With prompt administration of intravenous immunoglobulin (IVIG) at 2 g/kg alongside high-dose aspirin, approximately 80-90% of children with Kawasaki disease experience defervescence and resolution of acute symptoms, such as fever, rash, and mucosal inflammation, within 2-3 days of treatment initiation.^[46]^[47] This rapid response significantly mitigates the risk of early vascular inflammation, though 10-20% of cases demonstrate IVIG resistance, defined as persistent or recrudescent fever at least 36 hours after completion of the infusion, often necessitating readmission for adjunct therapies like corticosteroids or infliximab.^[39]^[48] Early treatment also substantially reduces the incidence of coronary artery abnormalities in the acute phase. Without intervention, up to 25% of patients develop coronary dilation or aneurysms, but with timely IVIG, only about 5% exhibit transient ectasia, and 1-2% progress to persistent medium or large aneurysms detectable by echocardiography within the first month.^[6]^[49] Hospital stays are typically brief, averaging 3-5 days for responsive cases, allowing for outpatient monitoring once afebrile and clinically stable.^[50] Early diagnosis plays a key role in achieving these favorable short-term results by enabling intervention before significant endothelial damage occurs.^[6] In high-risk subgroups, such as infants under 6 months or those with elevated baseline coronary z-scores (≥2.5), short-term complication rates remain elevated at 15-20% higher than in standard cases, even with adjunctive therapies, primarily due to increased susceptibility to coronary artery dilation despite IVIG.^[6] Overall short-term mortality is rare, occurring in less than 0.2% of cases within 90 days, and is most often attributable to acute myocarditis or cardiogenic shock in untreated or refractory patients.^[51]

Long-term cardiovascular risks

Kawasaki disease poses significant long-term cardiovascular risks primarily due to coronary artery aneurysms (CAAs) that develop during the acute phase, which can persist or regress variably and lead to complications such as thrombosis, stenosis, and accelerated atherosclerosis. Smaller CAAs (z-score 2.5 to <5) regress in approximately 87% of cases within 2 years and nearly 99% over 10 years, though residual coronary stenosis may occur in some cases even after apparent resolution, contributing to ongoing vascular abnormalities. In contrast, giant CAAs (z-score ≥10) rarely regress fully and carry a substantial risk of adverse events; for instance, one large cohort study found that 23% of patients with giant aneurysms experienced at least one myocardial infarction within 20 years of disease onset, often due to thrombosis within the aneurysm, with 14% major adverse cardiac events over 10 years per 2024 AHA guidelines.^[52]^[53]^[54]^[6] Patients with a history of Kawasaki disease, particularly those with persistent CAAs, face an elevated risk of early atherosclerosis and ischemic heart disease in adulthood. Risks vary by aneurysm persistence; no events in those with normalized arteries over 30 years, but up to 6% in males with medium aneurysms (z-score ≥5 to <10) and higher (25-48%) in giant aneurysms, driven by endothelial dysfunction and accelerated plaque formation in previously inflamed coronary segments. The 2024 American Heart Association (AHA) scientific statement emphasizes lifelong cardiology follow-up for all patients with coronary involvement, including regular surveillance imaging (such as coronary computed tomography angiography or cardiac magnetic resonance) tailored to aneurysm severity, along with screening for traditional cardiovascular risk factors like dyslipidemia to mitigate atherosclerosis progression. For those with severe cases, such as giant aneurysms, exercise restrictions may be advised based on stress testing results to avoid inducible ischemia.^[55]^[6]^[6] Special considerations apply to female patients with residual aneurysms contemplating pregnancy, as they represent a high-risk group for cardiovascular complications. The 2024 AHA guidelines recommend multidisciplinary care involving high-risk obstetrics and cardiology for women with giant CAAs, particularly those on anticoagulation therapy, due to the potential for thrombosis or myocardial infarction exacerbated by hemodynamic changes during gestation and delivery. Antiplatelet or anticoagulant management must be carefully balanced against bleeding risks, with vaginal delivery often feasible if cardiovascular status is stable, though cesarean section may be preferred in severe cases to minimize stress on aneurysmal vessels.^[6]^[56]

Epidemiology

Incidence and prevalence

Kawasaki disease (KD) primarily affects children under 5 years of age, with annual incidence rates varying significantly by region. In North America, the incidence is estimated at 17.5 to 20.8 cases per 100,000 children under 5 years, while in Europe, it ranges from 10 to 15 per 100,000 in the same age group.^[57]^[58] In Japan, the incidence exceeds 300 cases per 100,000 children under 5 years, with a record high of 426.7 per 100,000 reported in 2023 following the relaxation of COVID-19 restrictions, representing the highest reported rates worldwide.^[59] These figures underscore KD as a leading cause of acquired heart disease in children in developed countries.^[38] The disease shows a higher prevalence among males, with a male-to-female ratio of approximately 1.5:1 observed across multiple populations.^[60] Children of Asian and Pacific Islander descent experience elevated rates, with incidence up to 30.3 per 100,000 under 5 years in these groups in the United States, compared to lower rates in other ethnicities.^[12] Genetic factors contribute to this disparity, particularly in populations of East Asian ancestry.^[61] In the United States, annual KD cases are estimated at 4,000 to 5,000, based on national surveillance data.^[62] However, underreporting remains a challenge in developing countries, where misdiagnosis as infectious diseases leads to underestimation of true burden.^[63] Recent data indicate fluctuations in KD incidence following the COVID-19 pandemic, with a decline during restrictions and resurgence afterward; potential masking of cases due to overlap with multisystem inflammatory syndrome in children (MIS-C), which shares clinical features like fever and rash.^[64]^[65] KD exhibits seasonal variation, with peaks in winter months observed globally in the Northern Hemisphere, including January through March, and a nadir in late summer to early fall.^[66]^[67]

Demographic and geographic variations

Kawasaki disease exhibits marked geographic variations in incidence, with the highest rates observed in East Asian countries. In Japan, the annual incidence exceeds 300 cases per 100,000 children under 5 years of age, while in South Korea, it ranges from 113 to 238 per 100,000 in the same age group.^[59]^[68]^[69] In contrast, the lowest incidences are reported in Africa, particularly sub-Saharan Africa, where rates are under 1 per 100,000 children under 5 years, reflecting underdiagnosis and true rarity.^[70]^[71] Ethnic disparities are prominent, with Asian populations experiencing elevated risk compared to others. Among children in the United States, Asian Americans have an incidence 2 to 3 times higher than Caucasians, at approximately 33 per 100,000 versus 10 to 15 per 100,000 under 5 years. Familial clustering occurs in 1% to 2% of cases, with sibling recurrence rates up to 2.1% in Japanese cohorts, suggesting genetic susceptibility.^[72]^[8]^[73]^[74] The disease predominantly affects young children, with approximately 80% of cases occurring in those under 5 years of age and extreme rarity in adults, with approximately 100 cases reported worldwide as of 2018, mostly between 18 and 30 years. Infants younger than 6 months face heightened risk of coronary artery aneurysms, with rates up to 19% compared to 8.6% in older children under 5 years.^[75]^[8]^[76]^[77] Recent analyses highlight urban-rural differences, with higher incidence in urban areas potentially linked to increased pollution exposure, such as fine particulate matter and ozone, which correlate with disease onset in cohort studies. Migration studies demonstrate that Asian diaspora populations retain elevated risk; for instance, children of Asian origin in the United Kingdom and Spain show incidences 2 to 5 times higher than white peers, consistent with patterns in Hawaii's Asian and Pacific Islander communities.^[78]^[79]^[58]^[80]

History

Discovery and early descriptions

Kawasaki disease was first described by Japanese pediatrician Tomisaku Kawasaki in 1967, who observed the condition in children at the Red Cross Hospital in Tokyo.^[81] His initial report detailed 50 cases among Japanese children, characterized by persistent fever lasting at least five days, polymorphous rash, bilateral conjunctival injection, changes in the oral mucous membranes, alterations in the extremities such as redness and swelling, and cervical lymphadenopathy.^[82] Kawasaki initially termed the illness "mucocutaneous lymph node syndrome" (also known as acute febrile mucocutaneous lymph node syndrome), viewing it as a distinct pediatric entity with a self-limited course.^[81] At this stage, the potential for cardiac complications was not yet emphasized, as the focus was on the mucocutaneous and lymph node manifestations.^[83] Kawasaki died on June 5, 2020, at the age of 95.^[84] In the early 1970s, further investigations revealed the disease's vasculitic pathology. A nationwide survey in Japan in 1970 identified 10 autopsy cases of sudden cardiac death in affected children, confirming widespread vasculitis and the formation of coronary artery aneurysms as key features.^[81] These findings linked Kawasaki disease to previously reported cases of infantile polyarteritis nodosa, resolving debates about whether it represented a new syndrome or a variant of known vasculitides.^[83] The recognition of these severe cardiac sequelae shifted understanding from a benign condition to one with potentially life-threatening outcomes.^[84] The disease achieved global recognition following Kawasaki's publication of the 50 cases in English in 1974, which detailed the clinical criteria and pathology, including the vasculitis confirmed through autopsies.^[83] This report, appearing in Pediatrics, facilitated international studies and established the syndrome's identity beyond Japan.^[81] Early misconceptions portrayed it primarily as an infectious process, given the fever and rash, leading to initial treatments with antibiotics despite the absence of identifiable pathogens.^[83] By the mid-1970s, however, it was increasingly accepted as a non-infectious vasculitis, paving the way for targeted research.^[84]

Key research advancements

In the 1980s, randomized controlled trials established the efficacy of intravenous immunoglobulin (IVIG) therapy for Kawasaki disease, demonstrating a significant reduction in coronary artery aneurysms from approximately 25% in untreated cases to 4-5% with high-dose IVIG administration within 10 days of fever onset.^[85] Key studies included a Japanese multicenter trial in 1988 that confirmed IVIG's role in suppressing inflammation and preventing cardiac sequelae, and a U.S. collaborative effort that further validated single-dose regimens over multiple infusions.^[86] During the 1990s and 2000s, genetic research identified susceptibility loci associated with Kawasaki disease, such as the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2, where functional polymorphisms were linked to increased disease risk by modulating immune activation.^[87] Concurrently, the American Heart Association (AHA) formalized diagnostic and management guidelines, with the 1993 statement emphasizing early IVIG and aspirin use, followed by updates in 2004 that refined risk stratification for coronary involvement based on echocardiographic findings.^[9] In the 2010s, predictive risk scores for IVIG resistance emerged, notably the Kobayashi score developed in 2006, which incorporates clinical factors like age, platelet count, and C-reactive protein levels to identify high-risk patients with up to 76% sensitivity in Japanese cohorts.^[88] The COVID-19 pandemic in 2020 highlighted links between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease, with observational studies revealing overlapping vasculitic features and immune dysregulation triggered by SARS-CoV-2, prompting comparative analyses of treatment responses.^[89] The 2024 AHA scientific statement updated high-risk definitions to include infants under 6 months or those with coronary z-scores ≥2.5 in the left anterior descending or right coronary arteries at diagnosis, incorporating advanced imaging like optical coherence tomography for precise aneurysm assessment and recommending biologics such as anakinra for refractory cases based on emerging trial data.^[6] Ongoing genome-wide association studies, as reviewed in 2024, have identified over 10 susceptibility genes beyond ITPKC, including CASP3 and FCGR2A, underscoring polygenic contributions to immune dysregulation and coronary complications in diverse populations.^[90]

References

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May 31, 2024 · Kawasaki Disease (KD) is characterized by a fever plus one or more other symptoms commonly associated with KD.
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Nov 8, 2023 · Kawasaki disease causes swelling, called inflammation, in the walls of small to medium-sized blood vessels that carry blood throughout the body.
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May 31, 2024 · Kawasaki disease (KD) can cause heart and blood vessel damage. It occurs mostly in children younger than 5 years old.
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Cardiac auscultation of the infant or child with Kawasaki disease in the acute phase often reveals a hyperdynamic precordium, tachycardia, a gallop rhythm, and ...<|separator|>
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The severity of myocarditis seems unrelated to coronary artery abnormalities. Clinical findings include sinus tachycardia, gallop rhythm, cardiomegaly ...
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Feb 7, 2022 · These findings suggest that viral infections, especially those caused by respiratory viruses, may be associated with triggering Kawasaki disease.
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Sep 1, 2015 · The condition is 10 to 20 times more common in East Asia, including Japan, Korea, and Taiwan.
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Aug 30, 2021 · These younger patients presented with a higher proportion of coronary aneurysms as well (19 vs 8.6%, p < 0.001). Shock at diagnosis (9.5 vs 1.9% ...
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We describe a short history of Kawasaki disease. In 1967, we published a paper entitled 'Infantile acute febrile mucocutaneous lymph node syndrome.
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Tomisaku Kawasaki published the first English-language report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading ...
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Kawasaki disease (KD) is an acute, self-limiting vasculitis that primarily affects children, especially those of East Asian descent. It is now considered to be ...<|separator|>