Kawasaki Disease

Infectious and Environmental Triggers

Seasonal variation

• Peaks occur in winter and spring, particularly in Japan and the United States, suggesting an infectious or environmental influence.

Geographical clustering

• Temporal and spatial clusters have been reported worldwide.
• Certain regions of Japan show distinct “hot spots” with increased incidence.

Age distribution

• Around 80% of cases occur in children under five years of age.
• The rarity in infants younger than three months suggests protection through maternal antibodies.

Potential infectious agents

• No single causative pathogen has been identified.
• Studies have excluded parvovirus B19, retroviruses, Epstein-Barr virus, herpesviruses, measles, and human coronavirus NL-63.
• More than 40% of children with KD test positive for viral respiratory pathogens, suggesting a role for infection as a trigger.

Superantigen theory

• KD shares clinical features with staphylococcal and streptococcal toxic shock syndrome and scarlet fever.
• Case reports describe Staphylococcus aureus producing toxic shock syndrome toxins in KD patients with coronary aneurysms.
• It is hypothesised that bacterial or viral toxins may act as superantigens, though evidence remains inconclusive.

Environmental hypotheses

• Some theories suggest wind-borne or water-borne pathogens.
• Studies have not demonstrated consistent links with drugs, chemicals, or heavy metals such as mercury.

Genetic Susceptibility

Ethnic predisposition

• Higher incidence is observed among Asian populations, including those living outside Asia.

Familial risk

• Parents and siblings of affected children are at higher risk.
• Siblings have a 10–20 times greater likelihood of developing KD compared to the general population.

Polymorphisms

• Genome-wide association studies in Japan identify susceptibility variants such as FCGR2A (encoding a receptor for IgG) and ITPKC (inositol 1,4,5-triphosphate 3-kinase C).
• ITPKC variants are associated with resistance to intravenous immunoglobulin and greater risk of coronary artery aneurysm.

Other genetic markers

• Associations include HLA-B51, HLA-Bw22j2, CCR2–CCR5 haplotypes, and FCGR3A polymorphisms.
• A 2017 meta-analysis found 23 polymorphisms linked to KD susceptibility and 10 associated with coronary artery lesions.
• Many genes involve lymphocyte activation, cytokine and chemokine signalling, adhesion molecules, or vascular remodelling.

Early Vascular Changes

Endothelial and medial involvement

• In the earliest stage, vascular endothelial cells and the media become oedematous, while the internal elastic lamina initially remains intact.
• Within 7–9 days of fever onset, neutrophil infiltration occurs, followed rapidly by CD8+ cytotoxic lymphocytes and oligoclonal IgA-producing plasma cells.
• These inflammatory cells secrete cytokines such as tumour necrosis factor (TNF-α), vascular endothelial growth factor, monocyte chemotactic and activating factor, and interleukins (IL-1, IL-4, IL-6).
• Matrix metalloproteinases (MMP3 and MMP9) degrade the vascular matrix, causing fragmentation of the internal elastic lamina and medial necrosis of smooth muscle cells.

Immune-Mediated Cascade

Role of innate and adaptive immunity

• An infectious agent, likely respiratory in origin, is proposed to activate lymphocytes, macrophages, and monocytes.
• Aberrant activation of monocytes and macrophages appears unique to KD, pointing towards an innate immune dysregulation.
• Oligoclonal IgA plasma cells infiltrating both vascular tissue and the respiratory tract support the hypothesis of a respiratory trigger.
• This immune cascade drives coronary arteritis, myocarditis, and fibrinoid necrosis of the internal elastic lamina, leading to weak arterial walls and predisposition to aneurysm formation.

Progression of Vascular Damage

Transition to chronic changes

• Neutrophil-driven inflammation transitions to mononuclear infiltrates, fibroblasts, and myofibroblastic proliferation.
• Fibrous connective tissue replaces the intima and media, resulting in scarring, intimal thickening, and arterial stenosis.
• Arterial remodelling continues for years, particularly at the junctions between normal artery and aneurysmal segments.

Long-term outcomes

• Larger aneurysms persist and are more prone to thrombotic occlusion, stenosis, and myocardial infarction.
• Fibrotic changes within the myocardium suggest cardiac inflammation extends beyond the coronary arteries.
• Autopsy studies of children without acute coronary aneurysms have shown late coronary artery intimal thickening and medial fibrosis, raising the possibility of KD vasculopathy emerging independently of aneurysm formation.
• Thrombocytosis during convalescence marks the period of greatest risk for vascular thrombosis and sudden death.
• Small aneurysms may resolve in approximately 60% of cases once inflammatory markers normalise.

Age Distribution

• Peak incidence occurs between 13 and 24 months of age.
• 85–90% of cases present in children under five years old; 90–95% occur before age ten.
• KD is rare in infants under six months, likely reflecting protection from maternal antibodies, and is also uncommon in adolescents and adults.
• In the United States, incidence peaks between 18 and 24 months, while in Japan, the highest incidence occurs between 6 and 12 months.

Sex Distribution

• KD has a male predominance, with a male-to-female ratio ranging between 1.3:1 and 1.8:1, depending on population studied.
• Boys are more likely to develop coronary complications and have higher mortality compared to girls.
• Certain complications, such as arthritis, appear to be more common in females.

Ethnic and Racial Distribution

• The highest incidence is observed in Asian populations, particularly those of Japanese and Korean descent.
• Rates are intermediate in African Americans, Polynesians, and Filipinos, and lowest in Caucasians.
• In the United States, children of Asian/Pacific Islander ancestry have the highest risk (up to 50.4 per 100,000), followed by Black children (29.8) and White children (22.5).
• Recurrence in Japanese children is reported at around 3%.

Seasonal and Temporal Trends

• KD shows seasonal variation, with peaks in the winter and spring months in many regions.
• In Japan, a bimodal pattern has been documented, with incidence peaking in January and June/July.
• Temporal clustering has been described, with nationwide epidemics in Japan during 1979, 1982, and 1986.
• Case numbers declined during the COVID-19 pandemic in Japan, Korea, and elsewhere, though this was not attributed to delayed presentation.

Geographic Incidence

Japan

• Japan has the highest incidence worldwide, with reported rates between 243 and 265 per 100,000 children under five in recent years.
• Despite a declining birth rate, overall case numbers continue to rise, and nationwide surveillance shows long-term increases.

Other Asian Regions

• South Korea: approximately 105 per 100,000 children under five.
• Taiwan: around 55 per 100,000.
• Hong Kong: 25.4 per 100,000.
• China: 16.8–36.8 per 100,000 in Shanghai; 18.2–30.6 per 100,000 in Beijing.

North America

• United States: around 20–25 per 100,000 children under five, with an estimated 5,000 cases annually.
• Canada: 11–15 per 100,000, though rates are higher in Ontario (26.2 per 100,000).

Europe and Oceania

• United Kingdom: 8.1 per 100,000 in 1999–2000, though more recent surveys highlight increased recognition of incomplete KD.
• Australia: 3.6 per 100,000, among the lowest recorded incidence worldwide.

Outcomes and Complications

• Without treatment, 20–25% of patients develop coronary artery aneurysms.
• Even with intravenous immunoglobulin therapy, complications persist; in the UK, a survey found 19% of treated patients developed aneurysms, with rates rising to 39% in infants under one year.
• Long-term morbidity and mortality are linked to risks of coronary thrombosis, rupture, and myocardial infarction, underscoring the importance of early diagnosis and treatment.

Fever pattern and duration

• Prolonged fever: typically ≥5 days; often abrupt in onset and high-spiking (≈39–40 °C).
• Non-response to antibiotics if given.
• AHA diagnostic note: complete KD can be diagnosed on day 4 if ≥4 principal features are present; experienced clinicians may diagnose earlier; patients with coronary artery involvement may be diagnosed with ≥3 principal features.

Diagnostic completeness (complete vs incomplete)

Complete KD

• Fever plus ≥4 of the 5 principal clinical features (history-based items listed below).

Incomplete KD

• Persistent fever with fewer features; ask about any transient occurrence of features earlier in the illness (count towards diagnosis).

Rash (polymorphous)

• Typical: diffuse, maculopapular erythematous rash; may be scarlatiniform or erythema multiforme–like.
• Not consistent with KD: bullous, vesicular, or petechial rashes.
• Distribution/details to ask: trunk and extremities; groin erythema or desquamation; fine pustules over extensor surfaces.

Oropharyngeal and mucosal symptoms

• Lips: dryness, erythema, fissuring, bleeding/crusting.
• Tongue: “strawberry” tongue (prominent papillae).
• Mucosa: diffuse oropharyngeal erythema.
• Against KD: exudative pharyngitis or oral ulceration/Koplik spots.

Conjunctival symptoms

• Bilateral, painless, non-exudative conjunctival injection; often limbic-sparing.
• Less common: history suggestive of episcleritis or uveitis (anterior/posterior).
• Against KD: purulent conjunctivitis.

Extremity changes

• Acute: erythema and oedema of palms/soles (may impede walking/hand use).
• Subacute: periungual desquamation of fingers/toes (~2 weeks after fever onset).
• Later convalescence: Beau’s lines (deep transverse nail grooves) 1–2 months after fever onset.

Cervical lymphadenopathy

• Unilateral, non-purulent cervical node(s) ≥1.5 cm; may have overlying erythema.
• Poor response to antibiotics if they were prescribed.

Systems review by illness phase

Acute febrile phase (≈days 1–14)

• Marked irritability (often out of proportion to fever).
• Neurological: headache, photophobia, meningism (aseptic meningitis), seizures (rare).
• Ocular: anterior uveitis symptoms (photophobia, eye discomfort).
• ENT: otitis media symptoms.
• Cardiorespiratory: chest discomfort, dyspnoea, tachycardia; myocarditis/pericarditis may be suggested by reduced activity tolerance.
• Respiratory: cough/rhinorrhoea in 20–30%.
• Gastrointestinal/hepatic: abdominal pain, nausea, vomiting, diarrhoea; jaundice, dark urine or pale stools suggesting hepatitis/cholestasis; abdominal distension (hydrops of gallbladder).
• Genitourinary: dysuria/irritative symptoms (sterile pyuria), meatitis/urethritis; orchitis or vulvitis.
• Dermatological: perianal erythema/desquamation.
• Immunisation clue: erythema/induration at prior BCG inoculation site (commonly reported in Japan).

Subacute phase (≈weeks 2–6; after fever settles)

• Desquamation of digits.
• Arthralgia/arthritis (often large, weight-bearing joints; 20–40%).
• Persistent irritability, anorexia, lethargy.
• Warning sign: recrudescent fever beyond 2–3 weeks suggests ongoing disease activity and higher cardiac risk.

Convalescent phase (up to ≈3 months)

• Resolution of overt symptoms.
• Nail changes: Beau’s lines becoming apparent.
• Counsel that new aneurysms after week 8 are unusual if previous echocardiograms were normal, but historical symptoms (e.g., exertional chest pain, syncope) should still be queried.

Less common (but relevant) historical features

• Gastrointestinal: vomiting/diarrhoea (~20%), pseudo-obstruction, pancreatitis, intussusception.
• Hepatobiliary: hepatitis, obstructive jaundice, gallbladder hydrops.
• Cardiovascular: palpitations, syncope; history suggestive of ischaemia (rare in young children but important if present).
• Dermatological: erythema multiforme–like lesions, peripheral gangrene (rare).

Features arguing against KD (helpful differentials)

• Purulent conjunctivitis.
• Exudative pharyngitis.
• Bullous/vesicular/petechial rashes.
• Generalised lymphadenopathy or fluctuant/purulent neck nodes.

Risk modifiers to obtain from the history

• Age: <5 years (peak 13–24 months); rare <3 months and in adolescents/adults.
• Sex: male predominance (~1.3–1.8:1); boys at higher risk for serious complications.
• Ethnicity: Asian ancestry (especially Japanese/Korean) increases risk.
• Family history/previous KD: familial clustering and recurrence (ask about siblings and parental history).
• Timing/season: winter–spring peaks; prior incomplete presentations.

General and vital signs

• High, persistent fever (often ≥39 °C); appears ill and markedly irritable on observation.
• Tachycardia out of proportion to temperature; consider gallop rhythm suggesting myocarditis.

Skin and peripheral extremities

• Acute phase: erythema and indurated oedema of palms and soles; swelling of hands/feet (may impede use/ambulation).
• Subacute phase: periungual desquamation of fingers/toes (sheet-like peeling).
• Nails: Beau’s lines (transverse grooves) emerging 1–2 months after fever onset.
• Rash: generalised polymorphous eruption (commonly maculopapular; may be scarlatiniform or targetoid); perineal erythema with early desquamation is typical.
• Less common: erythema multiforme–like lesions, peripheral gangrene (severe disease).

Mucosal and oropharyngeal findings

• Lips: cracked, erythematous, fissured; may bleed/crust.
• Tongue: strawberry tongue with prominent fungiform papillae.
• Oral mucosa: diffuse erythema without exudate.

Conjunctival and ocular findings

• Bilateral, non-exudative bulbar conjunctival injection with limbal sparing (often striking “brilliant red”).
• Photophobia; anterior uveitis may be detectable (slit-lamp if available).
• Rare: vitreous opacities, papilloedema, subconjunctival haemorrhage.

Cervical lymph nodes

• Unilateral, non-purulent cervical lymphadenopathy; usually ≥1.5 cm over the anterior chain/sternocleidomastoid.
• Overlying skin may be erythematous; nodes firm, non-fluctuant.

Cardiovascular

• Soft gallop and tachycardia (myocarditis); small pericardial effusions may be suggested by muffled heart sounds (tamponade rare).
• Signs of coronary involvement are usually not evident early on exam; maintain high suspicion in irritable, tachycardic children.

Respiratory

• Generally clear chest; consider tachypnoea if myocarditis or pneumonitis is present.

Abdominal and hepatobiliary

• Right upper quadrant tenderness; hepatomegaly may be present.
• Hydrops of the gallbladder (may have palpable tenderness/fullness; typically resolves after IVIG).
• Rare: paralytic ileus; features of cholestasis.

Genitourinary

• Meatitis/urethritis (boys); vulvitis (girls).
• No discharge; consider sterile pyuria on urinalysis (supportive, not an exam sign).

Musculoskeletal

• Arthralgia/arthritis (often oligo- or polyarthritis of large weight-bearing joints); warmth, effusion, limited range of motion.

Neurological

• Irritability disproportionate to fever; meningism may be present (aseptic meningitis).
• Rare focal deficits; assess for altered behaviour in older children.

Inoculation site reaction

• BCG scar: erythema/induration is a supportive sign in settings where BCG is routinely administered.

Features on examination that argue against KD

• Purulent conjunctivitis.
• Exudative pharyngitis or tonsillar exudates.
• Bullous, vesicular, or petechial rashes.
• Fluctuant/purulent cervical nodes or generalised lymphadenopathy.

Diagnostic Approach

Clinical diagnosis first

• Complete KD is primarily a clinical diagnosis; investigations are not required to confirm.
• Investigations become critical in incomplete KD or when ruling out mimics.

Role in incomplete KD

• Laboratory and imaging studies are particularly useful when patients do not meet the full diagnostic criteria.
• Findings can provide sufficient supportive evidence to justify treatment.

Concurrent illness

• KD may coexist with intercurrent infections that mimic its features.
• Normal results do not exclude KD but help narrow differential diagnoses.

Echocardiography

• Mandatory once KD is suspected or diagnosed.
• Detects coronary artery abnormalities and other cardiac complications.

Baseline laboratory panel

Full blood count

• Acute stage – mild to moderate normochromic anaemia and leukocytosis with left shift.
• Subacute stage – thrombocytosis from week 2, often >1,000,000/µL.
• Thrombocytopenia is rare but indicates severe coronary disease, MI, or DIC

Biochemistry and proteins

• Hypoalbuminaemia is linked with severe or prolonged illness.
• ALT raised in ~40% of cases; bilirubin raised in ~10%.

Inflammatory markers

• ESR, CRP, and ferritin usually elevated at presentation.
• CRP normalises faster than ESR, which may remain raised into convalescence.

Urinalysis

• Sterile pyuria due to urethral inflammation occurs in ~50%.
• Abnormal urinalysis should always be cultured to rule out UTI.

Novel and research biomarkers

Urinary proteins

• Meprin A and filamin C identified as potential urinary biomarkers for KD.
• Meprin A regulates immunity; filamin C reflects endothelial and myocardial injury.

Cytokine profiling

• IL-17 family cytokines (IL-17A, IL-17C, IL-17F) are commonly elevated in KD.
• IL-17A shows high specificity in distinguishing KD from MIS-C and other febrile illnesses.

Cardiac biomarkers

• NT-proBNP and troponin I levels are generally higher in MIS-C than in KD.
• Thresholds: NT-proBNP ≥1500 ng/L and TnI ≥20 ng/L show good specificity.

Cardiac investigations

Echocardiography

• First-line investigation for coronary involvement.
• Baseline study at diagnosis, repeated at 1–2 weeks and again at 5–6 weeks.
• More frequent scans in high-risk patients or those with aneurysms.
• Can reveal proximal coronary dilatation, reduced LV function, mitral regurgitation, pericardial effusion, or aortic root dilatation.
• Diffuse coronary dilatation may be present in 50% of untreated patients by day 10.

Electrocardiography

• May show tachycardia, prolonged PR interval, ST–T wave changes, reduced R wave voltages.
• Q waves or ST changes may indicate myocardial infarction.

Cardiac enzymes

• CK and troponin elevated in cases of myocardial infarction.

Advanced imaging

• Coronary CT angiography (CTA) and MR angiography (MRA) useful for detailed evaluation.
• Cardiac catheterisation and angiography reserved for large/giant aneurysms; higher risk if done in acute phase.

Additional and selected studies

Abdominal ultrasound

• Detects hepatomegaly or gallbladder hydrops (~15% of patients).
• Hydrops usually resolves without surgical intervention.

Scrotal ultrasound

• Used if epididymitis suspected; KD-related cases may occur in younger boys.

Chest X-ray

• Can show cardiomegaly (pericarditis, myocarditis) or rarely pneumonitis.

Arthrocentesis

• Consider to rule out septic arthritis if joints are involved.
• Fluid typically sterile with WBC 125,000–300,000/µL, normal glucose.

Lumbar puncture

• May show aseptic meningitis in ~50% of patients sampled.
• CSF usually has mononuclear pleocytosis, normal glucose and protein.

Incomplete Kawasaki disease

Definition

• Prolonged fever (≥5 days) plus 2–3 principal features without another explanation.

Initial approach

• Measure ESR and CRP.
• CRP <3 mg/dL and ESR <40 mm/hr → monitor clinically.
• CRP ≥3 mg/dL or ESR ≥40 mm/hr → obtain supplemental laboratory tests.

Supplemental laboratory criteria

• Albumin ≤3 g/dL
• Anaemia for age
• ALT elevation
• Platelets ≥450,000 after 7 days
• WBC ≥15,000/mm³
• Urine WBC ≥10/hpf

Interpretation

• ≥3 positive criteria → diagnose and treat as KD; obtain echocardiogram.
• Fewer than 3 positive criteria → monitor clinically; repeat labs if fever persists.
• Echocardiogram abnormalities alone (e.g., aneurysms) warrant treatment regardless of labs.

Special populations

• Infants <6 months and adolescents may present with prolonged fever but few KD features.
• These groups are at higher risk of coronary complications; clinicians should have a low threshold for treatment.

Histological findings

Early

• Neutrophilic infiltration with media destruction and loss of elastic fibres.

Subacute

• Lymphocytes, monocytes, and fibroblasts replace acute infiltrate.
• Arterial remodelling begins.

Chronic

• Intimal proliferation, neoangiogenesis, and vascular occlusion develop.

Microvasculature

• Endothelial cell injury, platelet aggregation, thrombosis, microvascular dilatation.
• Progressive fibrosis leads to stenosis and reduced perfusion.

Bacterial infections

Staphylococcal or streptococcal infections

• Can present with fever, rash, and lymphadenitis mimicking KD.
• Response to antibiotics and presence of purulent tonsillitis, pneumonia, septic arthritis, or skin lesions favour bacterial aetiology.
• Ultrasound of a node may show a solitary hypoechoic core typical of bacterial lymphadenitis.

Scarlet fever

• Febrile illness due to group A streptococcus.
• Rash is diffuse, fine papular, with circumoral pallor; lips are spared.
• Conjunctivitis is absent.
• Desquamation begins on the face and moves downward.
• Diagnosis supported by throat culture or positive serological testing.

Acute rheumatic fever

• Occurs 3–4 weeks after streptococcal pharyngitis.
• Presents with migratory polyarthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules.
• Does not cause coronary aneurysms.
• Positive streptococcal serology confirms diagnosis.

Toxic shock syndrome (TSS)

• Acute febrile illness with vomiting, diarrhoea, myalgia, strawberry tongue, and diffuse erythematous rash.
• Often complicated by hypotension and shock.
• Caused by staphylococcal or streptococcal toxin-producing strains.
• Diagnosis is clinical; supported by isolation of toxin-producing organisms.

Staphylococcal scalded skin syndrome (SSSS)

• Caused by staphylococcal exfoliative toxins.
• Generalised erythema followed by sterile blisters, erosions, and crusting around eyes, nose, and mouth.
• Positive Nikolsky’s sign.
• Confirmed by identifying toxin-producing strains in cultures.

Retropharyngeal or peritonsillar abscess

• May mimic KD with fever and cervical swelling.
• KD can cause retropharyngeal oedema but without pus or abnormal imaging changes.
• True abscess shows systemic symptoms and radiographic abnormalities.

Viral infections

Adenovirus

• Both KD and adenovirus present with fever, rash, and conjunctival injection.
• Adenovirus typically causes conjunctival exudates, unlike KD.

Enterovirus and parvovirus B19

• May mimic febrile rash illness but usually associated with pharyngitis, exanthema, or haematological abnormalities.

Measles

• Distinguished by exudative conjunctivitis, Koplik’s spots, and rash beginning behind the ears.
• Confirmed by serology or PCR.

Epstein-Barr virus (mononucleosis)

• Features include exudative pharyngitis, generalised lymphadenopathy, and hepatosplenomegaly.
• Unlike KD, coronary artery changes do not occur.

COVID-19 associated MIS-C

• Shares features with KD (fever, mucosal changes, rash, conjunctival injection, lymphadenopathy, cardiac involvement).
• Compared with KD:
  • MIS-C more often includes gastrointestinal and neurological symptoms.
  • Arrhythmias, ventricular dysfunction, and shock are more frequent.
  • Affects older children as well as young; broader age range.
  • Higher CRP, lower platelets and lymphocytes.
• Epidemiological link with recent COVID-19 infection or exposure is key.

Immunological and inflammatory disorders

Juvenile idiopathic arthritis (systemic JIA)

• Presents with fever, rash, lymphadenopathy, hepatosplenomegaly, serositis, and arthritis.
• Rash is evanescent, salmon-pink, and appears with fever spikes.
• Very high acute-phase markers, but no coronary aneurysms.

Infantile polyarteritis nodosa

• A medium-vessel vasculitis that overlaps clinically with KD.
• Distinguished by more widespread systemic vasculitis, often chronic.

Systemic lupus erythematosus

• Can mimic KD with fever, rash, mucosal involvement, and arthritis.
• Differentiated by chronic course, serological markers (ANA, anti-dsDNA), and multi-system autoimmunity.

Drug hypersensitivity reactions

• May mimic KD with fever and rash.
• History of drug exposure, oral ulcers, and periorbital oedema favour drug reaction.
• Acute-phase markers are usually much lower than in KD.

Stevens-Johnson syndrome / Toxic epidermal necrolysis

• Severe bullous mucocutaneous disorders.
• Marked mucosal erosions, widespread bullae, and systemic symptoms distinguish them from KD.
• No coronary aneurysm development.

Other mimics

Rocky Mountain spotted fever

• Tick-borne rickettsial illness with fever, abdominal pain, headache, and myalgia.
• Rash starts on extremities, involves palms and soles, and becomes petechial.
• May cause myocarditis, renal, or hepatic failure.
• Confirmed by serology or indirect fluorescent antibody test.

Leptospirosis

• Zoonotic febrile illness with jaundice, conjunctival suffusion, and myalgia.
• Distinguished by exposure history and positive serological testing.

Lyme disease

• Tick-borne illness with erythema migrans rash, arthritis, and neurological involvement.
• Absent coronary complications.

Goals

• Prevent coronary artery aneurysms (CAAs) and other cardiac complications by suppressing inflammation early.
• Treat the acute illness, shorten fever duration, and reduce inpatient stay.

Risk factors for complications

• Severe inflammation (e.g., CRP >100 mg/L), persistent/recurrent fever after treatment, or persistently raised CRP.

Initial therapy (presentation ≤10 days; or >10 days with ongoing inflammation)

Intravenous immunoglobulin (IVIG)

• Single infusion early (ideally within 10 days of fever onset) for complete or incomplete KD.
• Indicated after day 10 if there is ongoing inflammation or coronary involvement, even if afebrile.
• Reduces prevalence of CAAs from ~20–25% to 2–4% and shortens fever duration.
• Live vaccines (e.g., MMR, varicella) should be deferred after IVIG; if measles risk is high, immunise and repeat ≥11 months later.

Aspirin

• Use with IVIG: anti-inflammatory dose initially, then antiplatelet dose.
• Dose reduction practice varies:
  • Either 48–72 h after defervescence, or
  • Day 14 after symptom onset and afebrile ≥48–72 h.
• Continue low-dose aspirin for 6–8 weeks if echocardiogram remains normal.
• Meta-analysis suggests low-dose or no high-dose aspirin with IVIG may reduce CAA risk vs high-dose (requires prospective confirmation).

Monitoring response to treatment

Therapeutic target

• Aim for “zero fever, zero CRP.”

Early trajectory (first 48 h post-IVIG)

• Expect afebrile state and CRP <10 mg/L, or CRP halving every ~24 h (CRP half-life ≈18 h when hepatic production stops).
• Do not rely on fever resolution alone; track clinical trend + CRP.

Refractory to IVIG (IVIG resistance)

Definition and risk

• Persistent/recurrent fever 36–48 h after IVIG; some extend to ongoing systemic inflammation within 48 h.
• Occurs in ~10–20%; associated with higher CAA risk.

Second-line strategy

• Second IVIG infusion recommended by some guidelines as next step.
• Corticosteroids may be added with the second IVIG (per European guidance) or used in high-risk patients as initial adjunct.

Predictors of resistance (outside Japan; scores perform suboptimally)

• Age <12 months, low sodium/haemoglobin/albumin, high ALT/CRP/bilirubin, features of shock or macrophage activation syndrome.
• ITPKC polymorphisms associated with IVIG resistance and CAAs.

Corticosteroids

When to use

• First-line adjunct in severe disease (e.g., CRP >100 mg/L, persistent CRP, anaemia, hypoalbuminaemia, liver dysfunction, MAS, shock), evolving CAAs, or IVIG failure.
• High-risk of IVIG resistance/CAA (e.g., initial coronary Z-score ≥2.5, age <6 months): consider IVIG + steroids up-front.

Evidence summary

• Cochrane 2022: steroids in acute KD associated with reduced CAAs, shorter hospital stay, and lower inflammatory markers; regimens are heterogeneous.
• Use pulse IV methylprednisolone or systemic corticosteroids in refractory or life-threatening disease where benefits outweigh risks.

TNF-α antagonists and other immunomodulators

Infliximab (TNF-α antagonist)

• Option for IVIG-refractory cases; can reduce fever duration.
• Trials show no consistent reduction in CAAs vs second IVIG; evidence for second-line use weaker than steroids.

Other agents (selected)

• Anakinra (IL-1 blockade): supports inflammation control in refractory KD; effect may take ~2 weeks; ongoing trials needed.
• Ciclosporin or cyclophosphamide: consider in specialist centres for multi-refractory disease.
• Plasma exchange (rare): rescue option after failure of IVIG, steroids, and infliximab; observational data suggest benefit but randomised trials lacking.

Network/meta-analyses (interpret with caution)

• Some suggest combinations (e.g., IVIG + steroids or IVIG + ciclosporin) may shorten fever and lower CAA incidence; underlying study heterogeneity limits certainty.

Late presenters (>10 days from onset)

Without ongoing inflammation

• If afebrile and ESR/CRP normal and echocardiograms normal, treat with low-dose aspirin until 6–8 weeks; stop if 8-week echo normal.

With ongoing inflammation or coronary abnormalities

• Treat as active KD (IVIG ± adjuncts as above), regardless of day of illness.

Long-term management

General principles

• Any history of CAA warrants lifelong cardiology follow-up in a specialist service; risk of future events scales with maximum/ current Z-scores.
• At each visit: lifestyle counselling, cardiovascular risk assessment (BP, lipids, BMI/waist, diet, activity, smoking).
• Exercise: tailor to ischaemia testing and arrhythmia risk; restrict contact sports if on dual antiplatelet/anticoagulation.
• Antiplatelet alternatives: clopidogrel if aspirin-intolerant; dipyridamole no longer recommended for thromboprophylaxis.
• Pregnancy/contraception: caution with oestrogen-containing contraceptives in patients with current/past significant aneurysms; manage pregnancy with multidisciplinary team, adjust antithrombotics.

Risk-stratified follow-up (by coronary status; Z-scores)

No involvement (Z always <2)

• Low-dose aspirin for 4–6 weeks, then discontinue.
• Discharge from cardiology at 4–6 weeks (up to 12 months by preference).
• One-off cardiovascular risk assessment (ideally within a year).

Dilation only (Z ≥2.0 to <2.5, or Z decrease ≥1)

• Low-dose aspirin for 4–6 weeks; discharge if normalised; if persistent dilation, follow up to 12 months.
• If dilation persists beyond a year but represents a dominant branch, consider spaced follow-up (every 2–5 years).

Small aneurysms (Z ≥2.5 to <5.0)

• Persistent small aneurysms: low-dose aspirin; follow up at 4–6 weeks, 6 months, 1 year, then annually.
• Assess CV risks (add fasting lipids).
• Ischaemia testing every 2–3 years or earlier if symptomatic/ventricular dysfunction; angiography every 3–5 years as indicated.
• If regressed to normal Z or dilation only: consider stopping aspirin; review every 1–3 years; reserve echo/ischaemia testing for symptoms or abnormal tests.

Medium aneurysms (Z ≥5 to <10; absolute <8 mm)

• Current/persistent: low-dose aspirin; consider dual antiplatelet therapy.
• Follow up: 4–6 weeks, then 3, 6, 12 months, then every 6–12 months.
• Ischaemia testing every 1–3 years; angiography every 2–5 years as needed.
• Sport restrictions if on dual therapy.
• If regressed to small: continue aspirin ± second agent; annual follow up; ischaemia testing every 2–3 years; angiography every 3–5 years.
• If regressed to normal/dilation only: aspirin alone; follow up every 1–2 years; ischaemia testing every 2–4 years as indicated.

Large/giant aneurysms (Z ≥10 or absolute ≥8 mm)

• Current/persistent:
  • Low-dose aspirin + anticoagulation (warfarin INR 2–3 or LMWH anti-Xa 0.5–1.0).
  • Consider dual antiplatelet in extensive/distal aneurysms or prior thrombosis; consider β-blocker.
  • Follow up at 1, 2, 3, 6, 9, 12 months in year 1; then every 3–6 months.
  • Ischaemia testing every 6–12 months; angiography within year 1 and then every 1–5 years as indicated.
  • Modify sport participation; manage pregnancy/contraception carefully.
• Regression to medium: stop anticoagulant → add second antiplatelet with aspirin; consider β-blocker; follow up 6–12 monthly; ischaemia testing annually; angiography every 2–5 years.
• Regression to small: aspirin ± β-blocker; follow up 6–12 monthly; ischaemia testing every 1–2 years; angiography every 2–5 years.
• Regression to normal/dilation only: aspirin; follow up 1–2 yearly; ischaemia testing every 2–5 years if indicated.

Echocardiography and imaging follow-up

Echo schedule

• At diagnosis, then 1–2 weeks, and 5–6 weeks after onset.
• Weekly if active inflammation or abnormal initial echo until stabilisation.
• Every 3–6 months in patients with CAA (frequency by severity).

Additional imaging

• As indicated: stress echo/MRI/nuclear/PET for inducible ischaemia; CT/MR angiography or invasive angiography for anatomy/flow assessment.

Overall outlook

• Self-limiting illness with markedly improved immediate outcomes since routine intravenous immunoglobulin (IVIG).
• Mortality <0.5%, with the highest risk within the first year after disease onset.
• Aneurysm prevalence falls from ~20–25% untreated to ~3–5% when IVIG is given within 10 days of fever onset.

Cardiac morbidity and mortality

• Prognosis is driven by the extent and severity of coronary involvement.
• Major cardiovascular complications include coronary ectasia/aneurysms (including giant aneurysms), myocardial infarction, myocarditis, valvulitis (usually mitral; ~1%), and pericarditis with small effusions (~25% in the acute phase).
• Deaths are essentially due to cardiac events, typically acute MI in giant aneurysms; aneurysm rupture is rare and usually occurs within months of the acute illness.

Risk factors for coronary artery aneurysms (CAAs)

• Prolonged fever >8 days (strongest predictor).
• Recrudescent fever after ≥48 hours afebrile.
• Male sex, age <1 year, Asian/Pacific Islander and Hispanic ethnicity.
• Cardiomegaly on assessment.
• Incomplete KD and delayed diagnosis independently increase CAA risk.

Effect of treatment timing

• Early IVIG (ideally ≤7–10 days) markedly reduces CAAs and improves outcomes.
• Delayed recognition, especially in very young infants and in incomplete KD, is associated with higher aneurysm risk and worse prognosis.

Course of aneurysms and long-term vascular change

• Among those who develop CAAs, severity dictates prognosis.
• >50% of aneurysms resolve within ~2 years.
• Even after apparent angiographic resolution, intimal thickening and abnormal flow can persist, implying a risk of premature coronary atherosclerosis.
• Children without aneurysms can still show transient LV dysfunction and/or mild valvular regurgitation on echocardiography (reported in up to ~50%).

Late interventions and outcomes

• Thromboprophylaxis and vigilant surveillance for progressive stenoses are central to management of large/giant aneurysms.
• Selected patients may require revascularisation (e.g., CABG or PCI).
• Long-term series after paediatric CABG report excellent survival (~95% at 20–25 years), with some requiring redo CABG or percutaneous reintervention; transplant is rare but considered when revascularisation is not feasible.

Recurrence

• Uncommon: approximately 3% in Japan and ~1% in North America.
• Most relapses occur within 2 years of the first episode and are more frequent in younger children and those with initial cardiac sequelae.

Age-related prognosis

• Outcomes are generally better for children aged 6 months to 9 years than for younger infants or older children/adolescents, likely reflecting earlier diagnosis when classic features are present.

Practical implication

• Early diagnosis and rapid escalation when there is no prompt response to IVIG are critical to limit cardiac damage.
• The role of adjunctive anti-inflammatory and biologic therapies in further improving long-term outcomes continues to evolve.

Cardiac (acute phase)

Myocarditis

• Very common in the acute phase (reported in ~50–70% on biopsy/echo surrogates); usually mild, responding to IVIG; chronic heart failure is uncommon.

Pericarditis/pericardial effusion

• Small effusions occur in roughly a quarter of acutely unwell patients pre-IVIG; typically resolve with treatment.

Valvulitis

• Usually mitral; uncommon (~1%); valve replacement rarely required.

Arrhythmias / KD shock syndrome

• Tachycardia out of proportion to fever; consider low-output state and vasoplegia in KD shock syndrome.

Coronary artery involvement

Coronary artery aneurysms (CAA)

• Untreated KD: ~15–25% develop CAAs. With timely IVIG (≤10 days), aneurysms in ~3–5%.
• Size definitions (childhood echocardiography):
  • Dilatation: Z-score 2 to <2.5.
  • Small aneurysm: Z ≥2.5 to <5 (or internal luminal diameter <5 mm).
  • Medium aneurysm: Z ≥5 to <10 (absolute <8 mm).
  • Giant aneurysm: Z ≥10 or ≥8 mm absolute diameter.

Natural history

• Small aneurysms can resolve within ~2 years; giant aneurysms carry the highest morbidity and mortality.
• Giant aneurysms have a high risk of early thrombosis (especially in year 1) and MI.
• Even after apparent angiographic resolution, intimal thickening and endothelial dysfunction may persist, with concern for premature coronary atherosclerosis.

Clinical expression

• MI at rest/sleep reported; vasospasm may contribute.

Risk factors for CAA

• Fever >8 days, recrudescent fever, male sex, age <1 year or >8 years, Asian/Pacific Islander or Hispanic ethnicity, cardiomegaly.
• Laboratory predictors: lower IgG, raised NT-proBNP, high TNF-α, thrombocytopenia, persistent inflammation post-IVIG, hyponatraemia.
• Black ethnicity may confer relative protection.

Management implications

• Add a second antiplatelet agent (e.g., clopidogrel) in confirmed CAA and ensure specialist cardiology follow-up.

Longer-term cardiac complications

Coronary thrombosis

• Can occur despite antithrombotic therapy in giant aneurysms; managed per ACS protocols adapted for children (thrombolysis ± heparin/aspirin; urgent review of antithrombotic plan).

Acute coronary syndromes / MI

• Major cause of late morbidity/mortality; risk highest in first 2 years post-diagnosis and greatest with bilateral giant CAAs.
• Diagnosis challenging due to atypical symptoms; urgent imaging essential if unwell or chest pain.
• PCI feasible in selected cases but complicated by vascular injury/anatomy.

Rupture of giant CAA

• Extremely rare; may cause haemopericardium and sudden death.

Systemic arterial aneurysms

• Rare, involving peripheral medium-sized arteries; require cardiology/vascular surveillance.

Non-cardiac complications

Arthritis/arthralgia

• Typically oligo-/polyarticular; improves with IVIG; NSAIDs can be used post-IVIG if symptomatic.

Hepatic dysfunction

• Mild transaminase rise in 10–30%; jaundice uncommon; responds to IVIG.

Gallbladder hydrops

• Occurs in <10%; usually resolves without surgical intervention.

Pneumonitis

• Responds to IVIG.

Aseptic meningitis

• May occur as a KD feature or IVIG side effect; resolves spontaneously.

Macrophage activation syndrome (secondary HLH)

• Rare but life-threatening; consider with persistent fever, splenomegaly, high ferritin, thrombocytopenia, raised AST.

Peripheral gangrene / bowel ischaemia

• Extremely rare; surgical referral required.

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