Kawasaki Disease

1. Clinical Overview

Summary

Kawasaki Disease (KD) is an acute, self-limiting systemic vasculitis affecting medium-sized arteries, predominantly occurring in children under 5 years. It is the leading cause of acquired heart disease in children in developed countries, surpassing acute rheumatic fever. [1,2]

The primary concern is the development of coronary artery aneurysms (CAAs), which occur in 15-25% of untreated cases but can be reduced to less than 5% with prompt treatment using intravenous immunoglobulin (IVIG) 2 g/kg. [1,3] Diagnosis is clinical, based on fever for ≥5 days plus ≥4 of 5 principal features (the "CREAM" criteria). Treatment must be initiated within 10 days of fever onset to maximise coronary protection. [1,4]

Despite decades of research since its first description by Tomisaku Kawasaki in 1967, the exact aetiology remains unknown, though current evidence suggests a genetically susceptible host encountering an infectious trigger leading to widespread immune activation and vascular inflammation. [5]

Clinical Pearls

"Fever = Clock Ticking": The 10-day treatment window is critical. Every day of untreated Kawasaki increases coronary artery aneurysm risk. The inflammatory cascade peaks during the second week of illness.

Incomplete Kawasaki is Still Kawasaki: Children with fever ≥5 days and only 2-3 criteria may have "incomplete" KD. Infants and young children are at highest risk for incomplete presentation and paradoxically have the worst outcomes. Have a low threshold to treat if inflammatory markers elevated and other causes excluded. [6]

"CREAM" Mnemonic: Conjunctivitis, Rash, Extremity changes, Adenopathy, Mucosal changes.

Aspirin in a Child: Kawasaki is one of the FEW paediatric conditions where Aspirin is used (risk of Reye's syndrome applies only in influenza/varicella context). However, evidence suggests aspirin may not add benefit beyond IVIG for preventing CAA. [7]

The Echo is Mandatory: Every suspected case requires baseline echocardiography. Do not delay treatment if echocardiography is not immediately available - treat first, image later. [1]

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2. Epidemiology

Demographics

• Age: Peak incidence at 18-24 months. 80% of cases occur in children less than 5 years old. Rare in adults (though recognition increasing). [8]
• Sex: Males affected more than females (1.5:1 ratio).
• Ethnicity: Highest incidence in Asian populations, particularly Japanese, Korean, and Taiwanese descent. Asian children living in Western countries maintain elevated risk, suggesting genetic predisposition. [8,9]
• Seasonality: Winter and spring peaks in temperate climates, suggesting infectious trigger. [5]

Incidence

Global incidence varies dramatically by ethnicity:

• Japan: ~300 per 100,000 children less than 5 years (highest globally). [9]
• Korea/Taiwan: 150-200 per 100,000 children less than 5 years.
• UK: ~8-9 per 100,000 children less than 5 years. [10]
• USA: ~20-25 per 100,000 children less than 5 years. [8]
• Recurrence: 1-3% of children experience recurrent episodes. [1]

Trends

Incidence has been increasing globally over the past 3-4 decades, likely due to improved recognition rather than true increase in disease burden. The COVID-19 pandemic saw emergence of MIS-C (Multisystem Inflammatory Syndrome in Children), a Kawasaki-like illness following SARS-CoV-2 infection. [11]

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1a. Clinical Significance & Urgency

Kawasaki Disease is a Medical Emergency. It is the only common paediatric vasculitis where a single therapeutic intervention (IVIG) can prevent lifelong cardiac disease.

The Window of Opportunity

IVIG is most effective when given within the first 10 days of illness. [1,4] Treatment started after day 10 still provides benefit, but coronary artery protection is reduced. The pathophysiology explains this:

• Days 0-10: Acute necrotising arteritis - vessel wall destruction is active
• Days 10-25: Subacute vasculitis - aneurysm formation occurs
• Beyond day 25: Chronic scarring and remodelling

IVIG works by modulating the immune response and reducing inflammation. Delaying treatment allows irreversible vascular damage to progress.

The Silent Killer

A child may appear "well" between fevers or after defervescence, creating false reassurance. However, coronary artery inflammation is ongoing and asymptomatic. Children do not experience angina. The first presentation of coronary involvement may be sudden death or myocardial infarction, sometimes years after the acute illness. [12]

The "Incomplete" Trap

The term "Atypical Kawasaki" is outdated and should not be used. Use "Incomplete KD". [1,6]

Critical Scenario: Infant less than 6 months with fever > 7 days and only red lips or sterile pyuria.

Risk: Infants have the highest risk of coronary aneurysms (up to 30-40% if untreated) yet often present with the fewest clinical signs. They may have only 1-2 features and still develop severe cardiac complications. [6]

Guideline: The AHA recommends mandatory echocardiography for any infant with unexplained fever lasting ≥7 days, even in the absence of other KD features. [1]

Kawasaki Shock Syndrome

A subset of patients (5-7%) present with haemodynamic instability and shock, often confused with septic shock or toxic shock syndrome. These children have severe myocardial dysfunction, higher rates of IVIG resistance, and increased aneurysm risk. Early recognition and aggressive treatment (IVIG + corticosteroids) is essential. [13]

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3. Aetiology: The "Perfect Storm" Hypothesis

Despite over 50 years of research since Kawasaki's original description, the exact cause remains elusive. The prevailing theory involves three components: [5]

1. Genetic Susceptibility

Ethnicity: Asian ancestry confers 10-50 fold higher risk compared to Caucasian populations, even when living in the same geographic area. [9]

Gene polymorphisms: Genome-wide association studies have identified susceptibility loci:

• ITPKC (Inositol 1,4,5-trisphosphate 3-kinase C): Regulates T-cell activation
• CASP3 (Caspase-3): Controls apoptosis
• BLK (B-lymphoid tyrosine kinase): B-cell signalling
• FCGR2A (Fc gamma receptor IIA): Response to IVIG [5]

Familial clustering: Siblings have 10-20 times higher risk. Studies of twins show 13% concordance in monozygotic vs 0% in dizygotic pairs.

2. Infectious Trigger

The clinical presentation resembles an infectious illness:

• Epidemics: Geographic and temporal clustering suggests person-to-person transmission
• Seasonality: Winter/spring peaks
• Age distribution: Rare in infants less than 3 months (protected by maternal antibodies), peak in toddlers
• Lack of recurrence: 97-99% of cases do not recur, suggesting acquired immunity [5]

Candidate pathogens investigated include:

• Coronaviruses (including novel betacoronaviruses)
• Superantigens from Staphylococcus and Streptococcus
• Candida species
• Respiratory RNA viruses

However, no single causative agent has been definitively identified. Current theory suggests multiple different triggers may lead to KD in genetically susceptible individuals.

3. Abnormal Immune Response

Instead of clearing the pathogen, the immune system launches an excessive, misdirected inflammatory response:

• Superantigen-mediated T-cell activation: Polyclonal activation of T-cells
• Cytokine storm: Massive elevation of TNF-α, IL-1, IL-6, IL-17
• Endothelial cell injury: Immune complexes and activated immune cells attack vascular endothelium
• Matrix metalloproteinase activation: Destruction of vessel wall integrity [5]

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4. Pathophysiology: From Inflammation to Aneurysm

The destruction of the coronary artery wall occurs in 4 pathological stages (Naoe and Takahashi Classification): [14]

Stage 1: Acute Necrotising Arteritis (Days 0-12)

• Neutrophil infiltration of the vessel wall (intima and media)
• Endothelial cell destruction - the protective inner lining is stripped away
• Internal elastic lamina fragmentation - loss of structural integrity
• Periarterial inflammation extends to surrounding tissues

Clinical correlation: High fever, acute rash, mucosal changes, extreme irritability

Stage 2: Subacute/Chronic Vasculitis (Days 12-25)

• Inflammation shifts to lymphocytes and plasma cells
• Panvasculitis - the entire vessel wall thickness is inflamed
• Myofibroblast proliferation - attempted healing response
• Loss of structural support - the weakened wall dilates under arterial pressure
• Aneurysm formation - focal or diffuse dilatation develops

Clinical correlation: Fever typically resolving, periungual desquamation, thrombocytosis (600-1,000 × 10⁹/L), highest risk period for sudden death

Stage 3: Luminal Myointimal Proliferation (Days 28-60)

• The body attempts to heal the injured vessel
• Smooth muscle cell proliferation within the lumen
• Intimal thickening - may lead to stenosis
• Thrombosis risk - sluggish flow in aneurysms promotes clot formation

Clinical correlation: Child appears well, but silent coronary remodelling occurring

Stage 4: Scarring and Calcification (Months to Years)

• Fibrosis leads to stiff, non-compliant vessels
• Aneurysms may regress in size (particularly small/medium) but vessel wall is never truly normal
• Calcification develops
• Premature atherosclerosis - lifelong increased cardiovascular risk even in those without persistent aneurysms [12,15]

Why the Coronary Arteries?

While KD is a systemic vasculitis affecting medium-sized arteries throughout the body, the coronary arteries are disproportionately affected:

Theories:

• High shear stress at coronary ostia
• Unique endothelial receptor expression
• Arterial bifurcation points particularly vulnerable
• Specific immune complex deposition patterns

Other affected vessels (less common):

• Axillary arteries
• Iliac arteries
• Renal arteries
• Brachial arteries

Involvement of non-coronary vessels may be detected on whole-body MR angiography but is rarely clinically significant.

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5. Clinical Features: The Diagnostic Criteria

Classic Diagnostic Criteria (AHA 2017) [1]

Diagnosis requires:

1. Fever ≥5 days (typically ≥39°C) AND
2. ≥4 of 5 principal features (CREAM):

The "CREAM" Criteria - Detailed

1. Conjunctivitis

Type: Bilateral, non-purulent bulbar conjunctival injection

Appearance:

• "Dry" conjunctivitis - no exudate or discharge
• Red, bloodshot eyes
• Limbic sparing - pathognomonic finding: a clear halo of white sclera immediately around the iris, distinguishing it from viral/bacterial conjunctivitis [1]

Associated findings:

• Anterior uveitis present in 70% (detected on slit-lamp examination)
• Photophobia uncommon
• Usually painless

Frequency: 85-90% of cases

Timing: Typically appears within first few days of fever

Differential: Viral conjunctivitis usually has discharge; allergic has itching

2. Rash

Appearance: Polymorphous - can look like almost anything, EXCEPT no vesicles or bullae

Morphology variations:

• Maculopapular (most common)
• Morbilliform (measles-like)
• Scarlatiniform (scarlet fever-like)
• Erythema multiforme-like
• Urticarial

Distribution: Generalised, often starting on trunk and extending to extremities

Pathognomonic signs:

• Perineal desquamation - early erythema and peeling in the nappy/groin area. Often the first sign, appearing before other criteria. [1]
• BCG scar reactivation - induration and erythema at the old BCG vaccination site (highly specific in vaccinated populations, particularly Asian children). [16]

Frequency: 90% of cases

Timing: Usually appears within 5 days of fever onset

3. Extremity Changes

Acute phase (Week 1):

• Erythema of palms and soles - bright fuchsia red colour, unlike the pink of scarlet fever
• Indurated oedema of hands and feet - painful, brawny swelling
• Child refuses to walk or hold objects due to discomfort
• Knuckles and joints appear "full"

Subacute/convalescent phase (Week 2-3):

• Periungual desquamation - the hallmark sign
• Skin peels in sheets from fingertips and toes
• Begins at the junction of nail and skin
• Diagnostic even if seen after fever has resolved

Late finding (Weeks-Months):

• Beau's lines - transverse grooves across fingernails, marking the timing of severe illness

Frequency: 70-90% (acute); 95% (desquamation if looked for in weeks 2-3)

Clinical tip: If you see a child in week 1 without extremity changes, arrange review in week 2-3 to look for desquamation

4. Adenopathy (Cervical Lymphadenopathy)

Character:

• Unilateral in 75% of cases
• Anterior cervical triangle location
• ≥1.5 cm diameter (single node or cluster)
• Firm, non-fluctuant consistency
• Usually non-tender or mildly tender

Frequency: 50-75% - this is the LEAST common of the 5 principal features [1]

Differential diagnosis:

• Bacterial lymphadenitis - usually more tender, may be fluctuant, responds to antibiotics
• EBV - generalised lymphadenopathy, hepatosplenomegaly
• TB - chronic, may be fluctuant, systemic symptoms

Clinical trap: Children are often started on antibiotics for "bacterial adenitis" before KD is recognised

5. Mucosal Changes

Lips:

• Bright red, often described as "cherry red"
• Cracked and fissured - vertical fissures
• Bleeding from fissured areas
• Swollen appearance

Tongue:

• "Strawberry tongue" - identical to scarlet fever
• Hypertrophy of fungiform papillae on an erythematous base
• May have white coating initially, then red

Oral mucosa:

• Diffuse oropharyngeal erythema
• Dry, cracked appearance

Crucial exclusions (NOT seen in KD):

• NO ulcers (think herpes, Behçet's)
• NO exudate (think streptococcal pharyngitis, EBV)
• NO vesicles (think hand-foot-mouth disease, chickenpox)

Frequency: 90-95% of cases

Clinical pearl: The oral changes combined with the conjunctivitis create the characteristic "miserable-looking child with red eyes and red mouth"

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5a. Incomplete Kawasaki Disease - The Critical Algorithm

Definition: Fever ≥5 days + 2 or 3 principal criteria (not meeting the full classic definition) [1,6]

Importance:

• Accounts for 15-30% of all KD cases
• Highest risk in infants less than 6 months and children > 5 years
• SAME risk for coronary aneurysms as classic KD if untreated
• Often leads to delayed diagnosis and treatment

AHA Algorithm for Incomplete KD (2017) [1]

Step 1: Clinical Suspicion

• Child with fever ≥5 days and 2 or 3 compatible clinical features
• OR infant with fever ≥7 days regardless of other features

Step 2: Assess for Alternative Diagnosis

• Could this be sepsis, bacterial infection, viral exanthem, drug reaction?
• If clear alternative diagnosis, treat that condition but maintain vigilance
• If no alternative diagnosis OR fever persists despite treatment, proceed

Step 3: Laboratory Assessment

Check inflammatory markers:

• CRP and ESR

If CRP less than 30 mg/L AND ESR less than 40 mm/hr:

• Follow daily
• Repeat laboratory tests if fever persists

If CRP ≥30 mg/L OR ESR ≥40 mm/hr:

• Proceed to Supplemental Laboratory Criteria

Step 4: Supplemental Laboratory Criteria

Assess for ≥3 of the following:

1. Albumin less than 30 g/L (hypoalbuminaemia from capillary leak)
2. Anaemia for age (normocytic, due to chronic inflammation)
3. Elevated ALT (hepatic involvement)
4. Platelets ≥450 × 10⁹/L (after day 7 of illness - thrombocytosis is a late finding)
5. WBC ≥15 × 10⁹/L (leukocytosis)
6. Urine WBC ≥10 per high-power field (sterile pyuria from urethritis)

Step 5: Echocardiography

If ≥3 supplemental criteria: Treat as Kawasaki Disease (IVIG + aspirin)

If less than 3 supplemental criteria:

• Perform echocardiogram
• If echo shows coronary artery abnormalities (Z-score ≥2.5) → Treat as KD
• If echo negative but clinical suspicion remains high → Consider treatment or close follow-up with repeat echo

Special Populations at High Risk for Incomplete Presentation

Infants less than 6 months: [6]

• Highest risk group for aneurysms
• Often present with minimal features (sometimes only prolonged fever + irritability)
• May have only sterile pyuria
• Mandatory echo for ANY infant with fever ≥7 days

Children > 8 years:

• Less likely to have all features
• Higher index of suspicion needed

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5b. Other Clinical Features - Systemic Vasculitis

Kawasaki affects multiple organ systems beyond the classic CREAM criteria:

Cardiovascular (Non-Coronary)

Myocarditis: 50-70% have some degree of myocardial inflammation [1]

• Elevated troponin, BNP
• Decreased ventricular function on echo
• Arrhythmias (usually benign - sinus tachycardia, first-degree heart block)
• Gallop rhythm

Pericarditis: Pericardial effusion in 15-30%

• Usually small, asymptomatic
• Rarely causes tamponade

Valvulitis:

• Mitral regurgitation most common (1-2%)
• Aortic regurgitation less common
• Usually mild and self-limiting

Kawasaki Shock Syndrome: 5-7% of cases [13]

• Hypotension, poor perfusion
• Severe myocardial dysfunction
• Often confused with septic shock or toxic shock syndrome
• Higher IVIG resistance rates
• Requires ICU support, consider early steroids

Gastrointestinal

Common symptoms:

• Diarrhoea (25-30%) - often leads to misdiagnosis as gastroenteritis
• Vomiting (20%)
• Abdominal pain (15-20%)

Hepatic involvement:

• Mild transaminitis (40-60%)
• Hypoalbuminaemia

Gallbladder hydrops (5-15%):

• Acute distension without stones
• Presents with right upper quadrant pain, palpable mass
• Diagnosed on ultrasound
• Usually resolves spontaneously

Pancreatitis: Rare

Neurological

Extreme irritability: One of the most characteristic features [1]

• Out of proportion to degree of illness
• Inconsolable crying
• Child cannot be comforted

Aseptic meningitis: 50% if lumbar puncture performed

• CSF shows pleocytosis (elevated white cells)
• Negative Gram stain and culture
• Protein and glucose usually normal

Other: Sensorineural hearing loss (rare, usually transient), facial nerve palsy (rare)

Musculoskeletal

Arthritis/Arthralgia: 10-15%

• Small joints (fingers, toes) > large joints
• Usually self-limiting

Genitourinary

Sterile pyuria: 60-80% if looked for [1]

• Urethritis causing white cells in urine
• Urine culture is STERILE (negative)
• Often leads to misdiagnosis as urinary tract infection

Clinical trap: Child with fever + pyuria → diagnosed as UTI → given antibiotics → fever persists → delayed KD diagnosis

Meatal erythema: Red, swollen urethral opening

Respiratory

Rhinorrhoea, cough: May be present, but prominent respiratory symptoms should prompt consideration of alternative diagnosis

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6. Investigations

Laboratory Investigations - Markers of Inflammation

No specific diagnostic test exists for Kawasaki Disease. Laboratory findings are non-specific markers of systemic inflammation:

Key clinical pearls:

• Thrombocytosis peaks in week 2-3 and is one of the most characteristic findings. Platelet count can exceed 1,000 × 10⁹/L.
• Normal ESR/CRP makes KD very unlikely (but can be normal in first 24-48 hours)
• Hyponatraemia is common and associated with IVIG resistance [17]

Other laboratory markers:

• BNP/NT-proBNP: Elevated in myocarditis, marker of cardiac involvement
• Troponin: May be elevated in severe cases
• Ferritin: Extremely high ferritin (> 500 μg/L) suggests macrophage activation syndrome (rare, life-threatening complication)
• D-dimer: Elevated, reflects prothrombotic state

Echocardiography - The Essential Investigation [1,18]

Echocardiography is MANDATORY in all suspected and confirmed cases.

Timing:

• At diagnosis: Baseline assessment of coronary arteries
• At 2 weeks: Peak inflammation period - assess for developing aneurysms
• At 6-8 weeks: Assess for persistence or regression
• Ongoing surveillance based on initial findings

Views required:

• Parasternal short-axis view (proximal coronary segments)
• Parasternal long-axis view
• Apical views
• Subcostal views

Coronary arteries assessed:

• Left Main Coronary Artery (LMCA)
• Left Anterior Descending (LAD)
• Left Circumflex (LCx)
• Right Coronary Artery (RCA)

Measurement:

• Absolute internal diameter measured
• Z-score calculated: Number of standard deviations from normal for body surface area
• Z-scores account for body size differences in children

Other findings:

• Myocardial function (ejection fraction, wall motion abnormalities)
• Pericardial effusion
• Mitral regurgitation
• Aortic root dimensions

Advanced imaging (if baseline echo abnormal or high-risk features):

• CT angiography: Better visualisation of distal coronary segments
• Cardiac MRI: Assessment of myocarditis, late gadolinium enhancement
• Invasive angiography: If stenotic lesions suspected

Classification of Coronary Artery Abnormalities (AHA 2017) [1]

Morphology:

• Fusiform: Symmetric dilatation of segment
• Saccular: Asymmetric focal outpouching - higher thrombosis risk

Prognosis by size:

• Small aneurysms: 50-70% regress within 1-2 years [1]
• Medium aneurysms: 10-20% regress
• Giant aneurysms: Rarely regress, permanent structural abnormality, high risk of thrombosis and stenosis [12]

Other Investigations

Microbiological:

• Blood cultures (rule out bacteraemia)
• Throat swab (rule out streptococcal infection)
• Viral studies if indicated
• Urine culture (will be sterile despite pyuria)

Lumbar puncture:

• If meningitis suspected
• Will show aseptic meningitis if KD

ECG:

• Usually shows sinus tachycardia
• May show prolonged PR interval, low voltages
• Arrhythmias rare
• Look for ischaemic changes in severe cases (rare in acute phase)

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7. Differential Diagnosis - "The Febrile Child with Rash"

Kawasaki Disease must be differentiated from other causes of prolonged fever and rash in children:

Other Important Differentials

Viral Exanthems:

• Adenovirus: Pharyngoconjunctival fever, less severe
• EBV (Infectious Mononucleosis): Generalised lymphadenopathy, hepatosplenomegaly, atypical lymphocytes
• Enterovirus: Hand-foot-mouth disease has vesicles

Drug Reactions:

• DRESS syndrome: Facial oedema, eosinophilia, drug exposure history
• Stevens-Johnson syndrome: Mucosal erosions and bullae (not seen in KD)

Systemic JIA (Still's Disease):

• Quotidian fever (daily spike then returns to normal - different from KD's remittent fever)
• Salmon-pink evanescent rash
• Arthritis prominent
• Older age group (though can occur in toddlers)

Leptospirosis:

• Exposure to contaminated water
• Conjunctival suffusion (not injection)
• Renal/hepatic involvement

Rocky Mountain Spotted Fever:

• Tick exposure
• Rash starts on extremities, moves centrally (opposite of viral exanthems)

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8. Management

Immediate Assessment and Stabilisation

All suspected cases should be admitted for:

• Cardiac monitoring
• Intravenous access
• Baseline investigations including echocardiography

If Kawasaki Shock Syndrome (hypotension, poor perfusion):

• ICU admission
• Fluid resuscitation
• Inotropic support as needed
• Early echocardiography
• Consider early addition of corticosteroids

First-Line Treatment - IVIG + Aspirin [1,4,7]

Intravenous Immunoglobulin (IVIG)

Dose: 2 g/kg as a SINGLE infusion [1,3]

Example calculation: 10 kg child receives 20 g (typically 4 bottles of 5 g IVIG)

Administration:

• Infuse over 10-12 hours
• Start at slow rate (0.01 mL/kg/min) for first 30 minutes
• Monitor for infusion reactions (fever, chills, hypotension, anaphylaxis)
• Gradually increase rate as tolerated
• Pre-medications usually not required

Mechanism of action (incompletely understood):

• Fc receptor blockade on macrophages
• Neutralisation of superantigens
• Anti-idiotypic antibodies
• Suppression of cytokine production (TNF-α, IL-1, IL-6)
• Modulation of T-cell and B-cell function [4]

Efficacy:

• Rapidly reduces fever - typically defervescence within 24-48 hours
• Reduces coronary artery aneurysm risk from 25% to less than 5% [3]
• Most effective when given within 10 days of fever onset [1,4]

Contraindications (relative):

• IgA deficiency (risk of anaphylaxis - use IgA-depleted products)
• Volume overload/heart failure (infuse more slowly)

Side effects:

• Aseptic meningitis (common) - severe headache 12-24 hours after infusion, photophobia. Self-limiting.
• Haemolytic anaemia (usually mild)
• Transfusion reactions
• Thrombotic events (rare)

Important counselling point: IVIG interferes with live vaccines

• Defer MMR, varicella, rotavirus for 11 months after IVIG administration [1]
• Inactivated vaccines can be given as per schedule

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Aspirin

The role of aspirin in KD has been debated. Recent evidence suggests aspirin does not reduce coronary aneurysm risk beyond IVIG alone, but it continues to be recommended in most guidelines. [7]

High-Dose Phase (Anti-inflammatory):

• Dose: 30-50 mg/kg/day divided into 4 doses (QDS)
• Duration: Until afebrile for 48-72 hours
• Purpose: Anti-inflammatory effect (though IVIG does the heavy lifting)

Low-Dose Phase (Antiplatelet):

• Dose: 3-5 mg/kg/day (maximum 75-81 mg) once daily
• Duration: 6-8 weeks (if normal coronaries on follow-up echo, then stop)
• Duration if CAA present: Continue indefinitely
• Purpose: Antiplatelet effect - prevents thrombosis in inflamed/dilated coronaries

Monitoring:

• Salicylate levels if high-dose aspirin continued > 3 days (risk of salicylism, especially in young infants)
• Signs of toxicity: tinnitus, hyperventilation, vomiting

Reye's Syndrome Warning:

• Risk applies when aspirin used during influenza or varicella infection
• If child develops influenza or chickenpox while on aspirin:
  • Stop aspirin
  • Switch to alternative antiplatelet (clopidogrel 1 mg/kg/day) if CAA present
  • Consider influenza and varicella vaccination prior to KD season (if child not acutely ill)

Alternative to aspirin:

• Some centres use no aspirin (IVIG alone) or only low-dose aspirin from the start
• Clopidogrel can be used if aspirin contraindicated

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IVIG-Resistant Kawasaki Disease [1,17,19]

Definition: Persistent or recurrent fever (≥38°C) at least 36 hours after completion of first IVIG infusion

Incidence: 10-20% of cases

Risk factors for IVIG resistance:

• Young age (less than 6 months)
• Asian ethnicity
• Male sex
• Higher inflammatory markers (CRP, ESR, neutrophils)
• Hyponatraemia
• Elevated ALT, bilirubin
• Lower platelet count at presentation
• Higher coronary artery Z-scores at diagnosis

Predictive scores: Kobayashi score, Egami score (developed in Japanese populations, less accurate in non-Asian populations) [17]

Significance: IVIG resistance associated with higher risk of coronary aneurysms (up to 40-50%)

Management options (evidence quality varies):

1. Second dose of IVIG (first-line in most centres):

• 2 g/kg repeat infusion
• 60-70% respond to second dose [19]

2. Intravenous Methylprednisolone:

• Dose: 30 mg/kg IV (maximum 1 g) given over 2-3 hours, once daily for 1-3 days
• OR Pulse-dose: 10-30 mg/kg/day for 3 days
• OR Longer course: 2 mg/kg/day for 5-7 days, then taper
• Increasing evidence supports steroids as rescue therapy [19]

3. Infliximab (Anti-TNF-α monoclonal antibody):

• Dose: 5 mg/kg IV single infusion
• Mechanism: Blocks TNF-α, a key cytokine in KD pathogenesis
• Rapidly gaining acceptance, particularly in USA [1,19]
• Well-tolerated, effective in ~80% of IVIG-resistant cases
• Screen for tuberculosis before use (reactivation risk)

4. Other biological agents (for refractory cases):

• Anakinra (IL-1 receptor antagonist)
• Tocilizumab (IL-6 receptor antagonist)
• Etanercept (TNF-α inhibitor)

5. Cyclosporine:

• For highly refractory cases
• Requires specialist guidance

6. Plasma exchange:

• Rarely used, for critically ill refractory patients

Approach to IVIG resistance:

• Confirm true IVIG resistance (fever ≥38°C, no alternative cause)
• Urgent repeat echocardiography
• Second-line options: Second IVIG OR Infliximab OR IV methylprednisolone
• Consider combination therapy for severe cases
• Escalate to paediatric rheumatology/cardiology

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Adjunctive Therapies

Primary Corticosteroid Therapy (With Initial IVIG):

Recent trials have explored adding steroids to initial treatment for high-risk patients:

• RAISE trial (Japan): Adding IV methylprednisolone to initial IVIG in high-risk patients (Kobayashi score ≥5) reduced IVIG resistance [20]
• Not universally recommended - consider in high-risk patients or discuss with specialist

Indications for considering primary steroids:

• High-risk scores for IVIG resistance
• Kawasaki shock syndrome
• Severe cardiac involvement at presentation

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Management of Coronary Artery Aneurysms [1,18]

Treatment is risk-stratified based on aneurysm size:

Long-term cardiac medications (for Risk Levels III-V):

• Beta-blockers (e.g., atenolol, metoprolol): Reduce myocardial oxygen demand
• ACE inhibitors: If ventricular dysfunction
• Calcium channel blockers: Prevent coronary vasospasm
• Statins: For premature atherosclerosis risk

Surgical/Interventional options (for severe stenosis or ischaemia):

• Percutaneous coronary intervention (PCI): Balloon angioplasty ± stenting
• Coronary artery bypass grafting (CABG): For significant stenosis
  • Internal mammary artery grafts preferred (grow with child)
  • "Challenges: Vessels may be small, friable, calcified"

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Follow-Up and Surveillance [1]

All patients:

• 2 weeks: Clinical review + echocardiography
• 6-8 weeks: Clinical review + echocardiography

If no coronary involvement (Risk Level I):

• No further cardiac follow-up required
• Counsel regarding lifelong cardiovascular risk (slightly elevated compared to general population)
• Encourage healthy lifestyle

If coronary abnormalities (Risk Levels II-V):

• Ongoing cardiology follow-up (frequency based on risk level)
• Serial echocardiography: Every 3-6 months initially, then annually
• Stress testing (older children/adolescents): Assess for inducible ischaemia
• CT angiography or cardiac MRI: For better visualisation of aneurysms/stenosis
• Invasive angiography: If stenosis suspected or before intervention

Long-term considerations:

• Transition to adult cardiology services
• Cardiovascular risk factor modification (lipids, BP, smoking, obesity)
• Pregnancy planning (for women with CAA)
• Considerations for contact sports (restricted if significant CAA)

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9. Complications

Cardiac Complications

Non-Cardiac Complications

Macrophage Activation Syndrome (MAS): less than 1% but life-threatening

• Cytokine storm leading to haemophagocytosis
• Features: Extremely high ferritin (> 10,000 μg/L), cytopenias, hepatosplenomegaly, coagulopathy
• Requires aggressive immunosuppression (steroids, cyclosporine, etoposide)

Peripheral artery aneurysms: Rare

• Axillary, iliac, femoral arteries
• Usually asymptomatic

Gangrene: Very rare

• Digital or limb ischaemia from thrombosis

Hearing loss: Rare

• Usually sensorineural, may be transient

Neurological sequelae: Rare

• Facial nerve palsy, sensorineural hearing loss

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10. Prognosis and Long-Term Outcomes

Acute Phase

• With early treatment (less than 10 days): Excellent prognosis, CAA risk less than 5% [1,3,4]
• Without treatment: CAA risk 25%, high morbidity and mortality
• Mortality in acute phase: less than 0.1% in developed countries with access to IVIG [1]

Regression of Aneurysms

Small aneurysms (Z-score 2.5-less than 5):

• 50-70% regress within 1-2 years on echocardiography [1]
• However, vessel wall is never truly normal - intimal thickening and dysfunction persist

Medium aneurysms (Z-score 5-less than 10):

• 10-20% regress in size
• Higher rates of persistent abnormality

Giant aneurysms (Z-score ≥10):

• Rarely regress (less than 5%)
• Permanent structural abnormality
• Highest risk for thrombosis, stenosis, MI [12]

Long-Term Cardiovascular Risk [15]

Even children with no aneurysms have:

• Endothelial dysfunction
• Increased carotid intima-media thickness
• Elevated cardiovascular risk markers
• Possible increased risk of premature coronary artery disease in adulthood

Children with a history of CAA:

• Lifelong increased risk of myocardial infarction, even if aneurysms regress
• Require ongoing cardiology surveillance
• Need aggressive cardiovascular risk factor management
• May require revascularisation (PCI or CABG) if stenosis develops

Myocardial infarction after KD: [12]

• Can occur years or decades after acute illness
• 50% occur in first year after KD
• May be silent (no chest pain) - requires high index of suspicion
• Often presents as sudden death, heart failure, or arrhythmia

Quality of Life

• Most children with no CAA have normal quality of life
• Those with persistent CAA may have:
  • Activity restrictions
  • Need for lifelong anticoagulation
  • Psychological impact of chronic disease
  • Challenges with school sports, insurance, employment

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11. Prevention and Future Directions

Primary Prevention

• No vaccine exists
• No proven measures to prevent KD (aetiology unknown)
• Public health focus on early recognition and treatment

Secondary Prevention

• Early diagnosis and treatment prevents CAA
• Education of healthcare providers to recognise incomplete KD
• Public awareness campaigns in high-incidence areas

Research Directions

• Aetiological agent identification: Ongoing search for causative pathogen(s)
• Genetic studies: Identifying susceptibility genes to understand pathogenesis
• Biomarkers: Develop diagnostic tests to replace clinical criteria
• Optimal treatment regimens: Trials comparing IVIG + steroids vs IVIG alone, biologics as first-line therapy
• Long-term outcomes: Cohort studies following KD patients into adulthood
• Risk stratification: Better tools to predict IVIG resistance and CAA development

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12. Key Guidelines and Evidence Base

Major Guidelines

American Heart Association (2017): [1]

• Diagnostic criteria: Fever ≥5 days + ≥4/5 CREAM features, or incomplete KD algorithm
• Treatment: IVIG 2 g/kg + aspirin
• Echocardiography: Baseline, 2 weeks, 6-8 weeks minimum
• Long-term management: Risk-stratified based on coronary status

Japanese Circulation Society (2020): [21]

• Similar diagnostic criteria with modifications for Japanese population
• Emphasis on risk scores (Kobayashi, Egami) for IVIG resistance prediction
• Early consideration of primary steroid therapy in high-risk patients

European Guidelines:

• Generally align with AHA recommendations
• Some variation in aspirin use (some centres do not use high-dose aspirin)

Landmark Evidence

Newburger et al. (1986): [3]

• First RCT showing IVIG reduces CAA risk from 20% to 4%
• Established IVIG as first-line therapy

Newburger et al. (1991): [4]

• Confirmed 2 g/kg single dose superior to 400 mg/kg × 4 days
• Reduced CAA risk from 23% to 8%

RAISE trial (2012): [20]

• Adding IV methylprednisolone to IVIG in high-risk patients reduced IVIG resistance
• Validated Kobayashi score for risk stratification in Japanese population

Burns et al. (2020): [7]

• Meta-analysis showing aspirin does not reduce CAA risk beyond IVIG alone
• Challenged routine use of high-dose aspirin

Tremoulet et al. (2014): [19]

• Infliximab effective for IVIG-resistant KD
• ~80% response rate

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13. Examination Focus - OSCE, Vivas, Written Exams

Common OSCE Stations

Station 1: Parental Counselling - IVIG Consent

Scenario: You are the paediatric registrar. A 3-year-old child has been diagnosed with Kawasaki Disease. Explain the diagnosis and obtain consent for IVIG treatment.

Key Points:

1. Explain the disease:

   • "Kawasaki Disease is an illness where blood vessels throughout the body, particularly those supplying the heart, become inflamed."
   • "We don't know the exact cause, but it behaves like an infection triggering an immune reaction."
   • "It mainly affects young children under 5."

2. Explain the risk:

   • "The main concern is that inflammation can weaken the coronary arteries - the vessels that supply blood to the heart muscle."
   • "Without treatment, 1 in 4 children develop aneurysms - bulges in these arteries."
   • "These aneurysms can lead to heart problems later in life."

3. Explain the treatment (IVIG):

   • "The treatment is called Immunoglobulin - it's a concentrated form of antibodies collected from thousands of blood donors."
   • "We give a high dose through a drip over about 10-12 hours."
   • "It works by calming down the immune system and reducing inflammation."
   • "This treatment reduces the risk of aneurysms from 1 in 4 down to less than 1 in 20."

4. Explain aspirin:

   • "We also give aspirin - unusual for a child, but this is one of the few conditions where it's beneficial."
   • "High dose initially to reduce inflammation, then low dose to prevent blood clots."

5. Risks of IVIG:

   • "It's generally very safe."
   • "Common side effects: headache about 24 hours after (from temporary inflammation in the lining of the brain - not dangerous)."
   • "Rare allergic reactions - we monitor closely during the infusion."
   • "Very rare: severe allergic reaction - we have emergency medications ready."

6. Effect on vaccines:

   • "The immunoglobulin will interfere with some vaccines like MMR and chickenpox vaccine."
   • "These will need to be delayed for 11 months."

7. Follow-up:

   • "Your child will need heart scans (echocardiograms) to check the coronary arteries."
   • "These will be done now, in 2 weeks, and again in 6-8 weeks."
   • "Most children recover completely with no long-term problems."

8. Prognosis:

   • "With early treatment, the outlook is excellent."
   • "The fever usually settles within 24-48 hours of the immunoglobulin."

Station 2: History Taking - Prolonged Fever in a Child

Scenario: 2-year-old with 7 days of fever. Take a focused history.

Key Questions:

Fever characteristics:

• How high? (expect > 39°C)
• Pattern? (remittent, doesn't touch baseline vs quotidian in JIA)
• Response to paracetamol/ibuprofen? (minimal in KD)

CREAM features:

• C: Red eyes? Any discharge?
• R: Any rash? Where? What does it look like? Peeling skin?
• E: Red/swollen hands or feet? Refusing to walk/hold objects?
• A: Lumps in neck? One side or both?
• M: Cracked lips? Red tongue? Sore throat?

Systemic features:

• Irritability (key feature)
• Feeding/drinking
• Vomiting/diarrhoea
• Urinary symptoms

Red flags:

• Breathing difficulty (pneumonia, myocarditis)
• Chest pain (rare in young children, but suggests cardiac involvement)
• Lethargy, reduced consciousness

Travel and contacts:

• Recent travel (measles, leptospirosis)
• Unwell contacts
• Vaccination status (measles)

Previous treatment:

• Antibiotics given? (often given for presumed bacterial infection before KD recognised)

Station 3: Examination - Spot Diagnosis

Scenario: Examine this child who has been unwell for 10 days.

Findings:

• General: Irritable, miserable-looking child
• Hands: Peeling skin at fingertips (periungual desquamation) - diagnostic
• Skin: Fading rash, perineal erythema
• Eyes: Bilateral conjunctival injection without discharge
• Mouth: Cracked red lips, strawberry tongue
• Neck: Unilateral cervical lymph node
• CVS: Tachycardia, may have gallop rhythm

Presentation: "This child has features consistent with the convalescent phase of Kawasaki Disease, evidenced by the pathognomonic periungual desquamation, along with persistent conjunctival injection, oral mucosal changes, and cervical lymphadenopathy. Given the 10-day history, urgent assessment of coronary artery status with echocardiography is required, along with initiation of IVIG therapy if not already given."

Viva Questions and Model Answers

Q1: What are the diagnostic criteria for Kawasaki Disease?

Model Answer: "Kawasaki Disease is diagnosed clinically using the American Heart Association criteria. It requires fever persisting for at least 5 days, plus at least 4 of 5 principal features - easily remembered by the mnemonic CREAM:

• Conjunctivitis - bilateral, non-purulent, with characteristic limbic sparing
• Rash - polymorphous, generalised, notably perineal involvement
• Extremity changes - acute phase with erythema and oedema of hands/feet, then convalescent periungual desquamation
• Adenopathy - cervical, usually unilateral, at least 1.5 cm
• Mucosal changes - red cracked lips, strawberry tongue, pharyngeal erythema

Importantly, children with fewer than 4 criteria can have incomplete Kawasaki Disease and still require treatment if inflammatory markers are elevated and echocardiography shows coronary involvement." [1]

Q2: How does IVIG work in Kawasaki Disease?

Model Answer: "The exact mechanism is incompletely understood, but several theories exist. IVIG likely works through multiple mechanisms:

• Fc receptor blockade on macrophages and other immune cells, preventing them from causing tissue damage
• Neutralisation of superantigens or other pathogenic triggers
• Suppression of cytokine production, particularly TNF-alpha, IL-1, and IL-6
• Modulation of T-cell and B-cell function
• Provision of anti-inflammatory antibodies

The key clinical point is that IVIG at 2 g/kg given as a single infusion reduces coronary artery aneurysm risk from 25% to less than 5%, and is most effective when given within the first 10 days of illness." [1,3,4]

Q3: Describe your approach to incomplete Kawasaki Disease.

Model Answer: "Incomplete Kawasaki Disease is defined as fever for at least 5 days with only 2 or 3 principal features. This accounts for 15-30% of cases and is particularly common in infants under 6 months and children over 5 years.

My approach follows the AHA algorithm:

First, I assess whether there's an alternative explanation for the fever. If no clear alternative diagnosis exists, or if fever persists despite treatment of another condition, I proceed with evaluation.

Second, I check inflammatory markers - CRP and ESR. If both are low (CRP less than 30 mg/L and ESR less than 40 mm/hr), I follow the child closely with daily monitoring. If either is elevated, I proceed.

Third, I assess supplemental laboratory criteria, looking for at least 3 of: hypoalbuminaemia, anaemia, elevated ALT, thrombocytosis after day 7, leukocytosis, or sterile pyuria.

If 3 or more supplemental criteria are present, I treat as Kawasaki Disease with IVIG and aspirin.

If fewer than 3, I arrange urgent echocardiography. If this shows coronary abnormalities with Z-score ≥2.5, I treat. If negative but clinical suspicion remains high, I discuss with paediatric cardiology regarding treatment versus very close follow-up.

The key principle is that incomplete KD carries the same risk for coronary aneurysms as classic KD, so we must maintain a high index of suspicion, particularly in high-risk groups like infants." [1,6]

Q4: What would you do for a child with persistent fever 48 hours after completing IVIG?

Model Answer: "This represents IVIG-resistant Kawasaki Disease, which occurs in 10-20% of cases and carries a higher risk of coronary aneurysms, up to 40-50%.

My immediate steps would be:

First, confirm true IVIG resistance - ensure the fever is genuinely ≥38°C and at least 36 hours have passed since completing the first IVIG dose. I'd exclude other causes of fever such as intercurrent infection or IVIG-related aseptic meningitis.

Second, arrange urgent repeat echocardiography to assess coronary artery status.

Third, initiate second-line therapy. The main options are:

• Second dose of IVIG (2 g/kg) - about 60-70% respond
• IV methylprednisolone - 30 mg/kg (max 1 g) for 1-3 days
• Infliximab - 5 mg/kg as a single infusion, increasingly used with good results

The choice depends on local protocols and individual patient factors. I would likely give a second dose of IVIG while discussing with paediatric cardiology and rheumatology regarding addition of steroids or infliximab.

Fourth, ensure low-dose aspirin continues and arrange close monitoring.

If the child fails to respond to second-line therapy, third-line options include biological agents like anakinra or tocilizumab, or cyclosporine, in consultation with specialists." [1,17,19]

Q5: Describe the long-term management of a child with a giant coronary artery aneurysm.

Model Answer: "Giant coronary artery aneurysms, defined as Z-score ≥10 or absolute diameter ≥8 mm, represent the highest risk category and require lifelong management.

Antiplatelet and anticoagulation:

• Aspirin 3-5 mg/kg/day indefinitely
• Clopidogrel 1 mg/kg/day
• Warfarin targeting INR 2.0-3.0, OR low molecular weight heparin with anti-Xa 0.5-1.0

Additional cardiac medications:

• Beta-blockers to reduce myocardial oxygen demand
• Consider calcium channel blockers to prevent vasospasm
• ACE inhibitors if ventricular dysfunction
• Statins for premature atherosclerosis prevention

Surveillance and monitoring:

• Regular paediatric cardiology follow-up, transitioning to adult cardiology
• Echocardiography every 3-6 months initially, then at least annually
• Exercise stress testing (in older children/adolescents) to detect inducible ischaemia
• CT angiography or cardiac MRI for detailed visualisation of aneurysm morphology and stenosis
• Consider invasive coronary angiography to assess for stenosis

Activity restrictions:

• No competitive or contact sports
• Limit high-intensity exercise
• Develop individualised exercise plan with cardiology

Monitoring for complications:

• Education regarding symptoms of myocardial infarction (though may be silent)
• Regular ECGs
• High index of suspicion for coronary thrombosis or ischaemia

Interventional/surgical planning:

• If stenosis develops: percutaneous coronary intervention or coronary artery bypass grafting
• Internal mammary artery grafts preferred (grow with child)

Psychosocial support:

• Psychological support for child and family
• School liaison regarding activity restrictions
• Transition planning to adult services

Cardiovascular risk factor management:

• Lipid screening and management
• Blood pressure monitoring
• Smoking prevention
• Healthy diet and weight management

The key message is that these children require lifelong specialist cardiac care and have significantly elevated lifetime risk of myocardial infarction and sudden death." [1,12,18]

Common Mistakes (What Gets You Failed)

❌ Missing incomplete Kawasaki Disease in an infant with prolonged fever and minimal signs

• Always consider KD in any infant with fever ≥7 days

❌ Delaying treatment waiting for echocardiography

• Treat first if high suspicion, image later - don't wait for echo

❌ Not recognising that aspirin doesn't prevent aneurysms - it's the IVIG that does

• IVIG is the critical treatment; aspirin role is adjunctive

❌ Assuming regressed aneurysms mean "cured"

• Vessel wall is never normal; lifelong cardiovascular risk remains

❌ Missing IVIG resistance and not escalating therapy

• Persistent fever ≥36 hours after IVIG requires second-line treatment

❌ Forgetting to counsel about vaccine delay

• Live vaccines must be deferred 11 months after IVIG

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14. Clinical Case Studies

Case 1: Classic Presentation - The "CREAM" Child

Presentation: 3-year-old girl, 6 days of high fever (39-40°C), not responding to paracetamol. Seen by GP on day 3, given amoxicillin for "tonsillitis"

• no improvement.

Examination:

• Irritable, miserable-looking child
• Temperature 39.8°C
• Bilateral non-purulent conjunctivitis with limbic sparing
• Bright red cracked lips, strawberry tongue
• Polymorphous rash on trunk and limbs, perineal erythema
• Erythema and oedema of hands and feet - refuses to walk
• Right-sided cervical lymph node 2 cm
• Old BCG scar on left arm is red and indurated

Investigations:

• WBC 18 × 10⁹/L, neutrophils 14 × 10⁹/L
• Platelets 250 × 10⁹/L (normal at this stage)
• CRP 150 mg/L, ESR 90 mm/hr
• Albumin 28 g/L
• ALT 80 U/L
• Urine: WBC 30/hpf, culture negative (sterile pyuria)

Echocardiography: Normal coronary arteries, trivial pericardial effusion

Diagnosis: Classic Kawasaki Disease - meets all 5 CREAM criteria plus fever ≥5 days

Management:

• Admitted, IV access obtained
• IVIG 2 g/kg (12 kg child → 24 g over 12 hours)
• Aspirin 30 mg/kg/day divided QDS
• Fever resolved within 6 hours of completing IVIG ("Lazarus effect")
• Switched to low-dose aspirin (3 mg/kg/day) on day 3

Follow-up:

• Echo at 2 weeks: Normal coronaries
• Echo at 6 weeks: Normal coronaries, Z-scores all less than 2.0
• Aspirin stopped
• Periungual desquamation noted at week 2 (diagnostic)
• No further cardiac follow-up required

Learning Points:

• Antibiotics do not affect KD fever
• BCG reactivation is highly specific
• Sterile pyuria is a trap - often misdiagnosed as UTI
• Early treatment (day 6) resulted in excellent outcome

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Case 2: Incomplete KD - The High-Risk Infant

Presentation: 5-month-old boy, 9 days of fever. Seen in ED on day 4, diagnosed with "viral illness" and sent home. Re-presented day 9 with persistent fever and parental concern.

Examination:

• Extremely irritable
• Temperature 38.5°C
• Red lips
• No rash
• No conjunctivitis
• No lymphadenopathy
• Hands and feet appear normal

Initial Assessment: Infant with fever ≥7 days → incomplete KD must be considered

Investigations:

• WBC 22 × 10⁹/L
• Platelets 680 × 10⁹/L (thrombocytosis - late finding)
• CRP 180 mg/L, ESR 110 mm/hr
• Albumin 25 g/L
• ALT 120 U/L
• Haemoglobin 90 g/L (normocytic anaemia)
• Urine: WBC 50/hpf, culture negative

Supplemental criteria met: 4/6 (hypoalbuminaemia, anaemia, elevated ALT, thrombocytosis)

Echocardiography (urgent): Dilated left anterior descending artery, Z-score +4.5 (medium aneurysm)

Diagnosis: Incomplete Kawasaki Disease with coronary artery aneurysm

Management:

• IVIG 2 g/kg started immediately (day 9)
• Aspirin 30 mg/kg/day
• Fever resolved 48 hours post-IVIG
• Switched to low-dose aspirin (3 mg/kg/day) + clopidogrel 1 mg/kg/day

Follow-up:

• Echo at 2 weeks: LAD aneurysm Z-score +5.2 (slight increase)
• Echo at 6 weeks: LAD Z-score +4.8 (stable)
• Echo at 6 months: LAD Z-score +3.5 (partial regression)
• Echo at 1 year: LAD Z-score +2.8 (small aneurysm)
• Ongoing cardiology follow-up
• Continues on aspirin + clopidogrel

Learning Points:

• Infants less than 6 months have highest risk for aneurysms despite minimal clinical signs
• ANY infant with fever ≥7 days needs KD workup including echo
• Sterile pyuria in isolation should trigger KD consideration
• Treatment on day 9 was too late - damage already done
• Partial regression occurred but vessel never normal
• Requires lifelong antiplatelet therapy and monitoring

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Case 3: Kawasaki Shock Syndrome

Presentation: 4-year-old boy, 5 days of fever, brought to ED by ambulance - parents report he "became floppy and grey."

Examination:

• Unwell, lethargic child
• Temperature 40°C
• Hypotensive: BP 70/40 (low for age)
• Tachycardic: HR 180 bpm
• Poor perfusion: Mottled skin, capillary refill 5 seconds, weak pulses
• Polymorphous rash
• Red eyes
• Strawberry tongue

Initial Management: Suspected septic shock vs Kawasaki shock syndrome

• Fluid bolus 20 mL/kg × 2
• Blood cultures, full septic screen
• IV ceftriaxone started
• PICU admission

Investigations:

• Lactate 4.5 mmol/L
• WBC 25 × 10⁹/L
• CRP 220 mg/L
• Troponin 450 ng/L (elevated - myocardial injury)
• BNP 2,500 pg/mL (very high)
• Blood cultures: No growth

Echocardiography (urgent): Severely impaired LV function (EF 30%), dilated coronaries (LMCA Z-score +3.5, LAD +4.0), moderate pericardial effusion

Revised Diagnosis: Kawasaki Shock Syndrome

Management:

• IVIG 2 g/kg started within 4 hours of presentation
• IV methylprednisolone 30 mg/kg added given shock presentation
• High-dose aspirin
• Inotropic support (dobutamine)
• Antibiotics continued pending culture results (then stopped at 48 hours)

Response:

• Fever resolved 12 hours post-IVIG
• Haemodynamics improved over 24 hours, weaned off inotropes
• Repeat echo day 3: LV function improved to EF 50%

Follow-up:

• Echo at 2 weeks: LV function normalised (EF 60%), coronary aneurysms stable (LAD Z-score +4.2 - medium aneurysm)
• Echo at 6 weeks: Aneurysms persist
• Continues on aspirin + clopidogrel
• Close cardiology follow-up

Learning Points:

• Kawasaki Shock Syndrome is a severe presentation mimicking septic shock
• 5-7% of KD cases, higher IVIG resistance, worse outcomes
• Severe myocardial dysfunction is the cause of shock
• Early recognition and aggressive treatment (IVIG + steroids) is key
• These patients need PICU care
• Higher risk for coronary aneurysms

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Case 4: IVIG-Resistant KD

Presentation: 2-year-old girl diagnosed with classic KD on day 7 of fever, treated with IVIG 2 g/kg + aspirin.

Initial Response: Fever settled for 24 hours, child seemed improved.

Day 9 (48 hours post-IVIG): Fever recurred - temperature 39.5°C.

Assessment: IVIG-Resistant Kawasaki Disease

Repeat Investigations:

• CRP 150 mg/L (still elevated)
• Repeat echo: New left main coronary artery dilatation, Z-score +3.0 (small aneurysm)

Management:

• Second dose IVIG 2 g/kg
• IV methylprednisolone 30 mg/kg for 3 days
• Continue aspirin

Response:

• Fever resolved 24 hours after second IVIG
• No further fever
• Inflammatory markers improved

Follow-up:

• Echo at 2 weeks (day 16 overall): LMCA Z-score +3.5 (stable small aneurysm)
• Echo at 6 weeks: LMCA Z-score +2.8 (partial regression)
• Continues on low-dose aspirin
• Ongoing cardiology follow-up

Learning Points:

• 10-20% of patients are IVIG-resistant
• Persistent/recurrent fever ≥36 hours after IVIG is the definition
• IVIG resistance carries higher aneurysm risk
• Urgent repeat echo is essential
• Second-line therapy should be initiated promptly
• Combination therapy (repeat IVIG + steroids) often used

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15. Patient and Layperson Explanation

What is Kawasaki Disease?

Kawasaki Disease is an illness that causes inflammation (swelling and irritation) of blood vessels throughout the body, particularly those that supply the heart muscle (coronary arteries). It mainly affects young children, especially those under 5 years old.

What causes it?

We don't know exactly what causes Kawasaki Disease. It seems to happen when a child's immune system reacts too strongly to something, possibly an infection. It's not contagious - your child can't catch it from other children, and other children can't catch it from your child.

What are the symptoms?

The main symptoms are:

• High fever lasting at least 5 days that doesn't respond well to paracetamol or ibuprofen
• Red eyes (without sticky discharge)
• Rash on the body
• Red, cracked lips and red tongue (often called "strawberry tongue")
• Swollen, red hands and feet - your child might not want to walk or hold things
• Swollen glands in the neck
• Your child will likely be very irritable and miserable

After about 2 weeks, the skin may start to peel from the fingertips and toes.

Why is it serious?

The inflammation can weaken and stretch the walls of the coronary arteries (the blood vessels that feed the heart). This can cause them to bulge out (called aneurysms). If this happens:

• The blood flow to the heart muscle might be affected
• Blood clots might form
• This could cause heart problems later in life

However, with early treatment, we can prevent this in most children.

How is it diagnosed?

There's no single test for Kawasaki Disease. Doctors diagnose it based on the symptoms. Your child will have:

• Blood tests (to look for signs of inflammation)
• A heart ultrasound scan (echocardiogram) to check the coronary arteries

How is it treated?

The main treatment is:

Immunoglobulin (IVIG):

• This is a medicine made from antibodies donated by thousands of people
• It's given through a drip into a vein over about 10-12 hours
• It works by calming down the immune system and stopping the inflammation
• The fever usually settles within 1-2 days of this treatment
• This treatment reduces the risk of heart problems from 1 in 4 to less than 1 in 20

Aspirin:

• Yes, we do give aspirin to children with Kawasaki Disease (this is unusual, but it's safe and helpful for this condition)
• High dose at first to reduce inflammation
• Lower dose later to prevent blood clots
• Your child will take this for at least 6-8 weeks

What if my child doesn't get better with the first treatment?

About 1 in 10 children don't fully respond to the first treatment. If this happens, we have other treatments available, including:

• A second dose of immunoglobulin
• Steroid medicines
• Other special medicines

Will my child need to stay in hospital?

Yes, children with Kawasaki Disease are admitted to hospital for:

• The immunoglobulin treatment
• Monitoring
• Heart scans
• Usually stay for 3-5 days

What about vaccines?

The immunoglobulin treatment interferes with some vaccines. Your child will need to wait 11 months before having:

• MMR vaccine
• Chickenpox vaccine

Other vaccines can be given as normal.

What happens after treatment?

Your child will need heart scans (echocardiograms) to check the coronary arteries:

• One scan now
• Another in 2 weeks
• Another in 6-8 weeks

If the heart scans are normal:

• Most children make a complete recovery
• The aspirin can be stopped after 6-8 weeks
• No further heart scans needed
• Your child can return to normal activities

If there are any changes in the coronary arteries:

• Your child will need more regular heart scans
• May need to take aspirin or other medicines for longer
• Will see a heart specialist (paediatric cardiologist) regularly

What is the outlook?

With early treatment:

• Most children (more than 95%) do NOT develop heart problems
• Most make a complete recovery
• They can grow up to live normal, healthy lives

The most important thing is getting treatment quickly - within the first 10 days of fever.

When should I worry?

Call your doctor or return to hospital if:

• The fever comes back after treatment
• Your child becomes very unwell
• Your child develops chest pain or difficulty breathing
• You have any concerns

Questions parents often ask

Can my child go to school/nursery?

• Not while they're unwell and having treatment
• Once the fever has settled and they're feeling better, they can return (usually 1-2 weeks)
• It's not contagious

Will it happen again?

• Very rare - only about 1-3% of children get Kawasaki Disease more than once

Is it genetic? Will my other children get it?

• There is a slightly higher risk in brothers and sisters, but it's still uncommon
• It's not a genetic disease that's passed down in families

Can my child have the MMR vaccine if they're due for it now?

• No - it must wait 11 months after immunoglobulin treatment
• This is because the immunoglobulin would stop the vaccine from working

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16. Glossary

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17. References

1. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e999. doi:10.1161/CIR.0000000000000484

2. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. 1967;16(3):178-222. (Original description, Japanese)

3. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315(6):341-347. doi:10.1056/NEJM198608073150601

4. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324(23):1633-1639. doi:10.1056/NEJM199106063242305

5. Rowley AH, Shulman ST. The epidemiology and pathogenesis of Kawasaki disease. Front Pediatr. 2018;6:374. doi:10.3389/fped.2018.00374

6. Sonobe T, Kiyosawa N, Tsuchiya K, et al. Prevalence of coronary artery abnormality in incomplete Kawasaki disease. Pediatr Int. 2007;49(4):421-426. doi:10.1111/j.1442-200X.2007.02396.x

7. Burns JC, Capparelli EV, Brown JA, et al. Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. Pediatr Infect Dis J. 1998;17(12):1144-1148. doi:10.1097/00006454-199812000-00009

8. Holman RC, Belay ED, Christensen KY, et al. Hospitalizations for Kawasaki syndrome among children in the United States, 1997-2007. Pediatr Infect Dis J. 2010;29(6):483-488. doi:10.1097/INF.0b013e3181cf8705

9. Makino N, Nakamura Y, Yashiro M, et al. Descriptive epidemiology of Kawasaki disease in Japan, 2011-2012: from the results of the 22nd nationwide survey. J Epidemiol. 2015;25(3):239-245. doi:10.2188/jea.JE20140089

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11. Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19. JAMA. 2021;325(11):1074-1087. doi:10.1001/jama.2021.2091

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• Last Updated: 10 January 2026
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