Kawasaki Disease

Background

• Second most common vasculitis in childhood after Henoch-Schönlein purpura (HSP)
• Most common cause of acquired heart disease in children in high-income countries
• Lack of appropriate treatment leads to coronary artery aneurysms (CAA) in ~25% of cases
• Worldwide distribution, more common in Asian children
• ~75% of cases occur in children under 5 years of age
• Less common in children <6 months and >5 years; these age groups are more likely to develop CAA
• Can present without all diagnostic criteria, posing a significant diagnostic challenge

Assessment

Epidemiology

• Kawasaki Disease (KD) is reported globally, affecting all ethnicities, but is most common in Japan.
  • Japan: Incidence is approximately 240/100,000 children under 4 years of age.
  • North America (USA): Incidence is around 17/100,000.
  • Caucasian populations: Incidence ranges around 9/100,000.
• Age Distribution:
  • Approximately 85% of KD patients are younger than 5 years, with an average age of about 2 years.
  • Cases have been reported in both younger and older individuals.
  • Increased Risk in Young Patients:
    • Children under 12 months have an increased risk of developing coronary artery aneurysms (up to 60% if untreated).
    • Younger patients often present with “incomplete” disease, leading to frequent misdiagnosis.

Etiology and Pathogenesis

• Etiology:
  • The exact cause of KD is unknown.
  • Familial clusters and higher incidence in Asian populations suggest a genetic component.
• Genetic Associations:
  • Various genetic variants linked to KD have been identified in different populations.
  • European KD Patients:
    • Genetic variants in the transforming growth factor (TGF) pathway (TGFβ2, TGFβR2, SMAD3) are associated with an increased risk of coronary aneurysms.
  • General Findings:
    • Genetic risk may involve several genes connected to immunological pathways.
    • Susceptibility to KD and coronary aneurysms may vary between populations, potentially explaining higher incidences in Asian populations.

Clinical Presentation

• Initial Symptoms:
  • Acute-onset high fever
  • Reduced general condition and cooperativity in children, complicating physical examination
• Further Symptoms:
  • Generalized polymorphic exanthema (>90%)
  • Palmoplantar erythema (80%)
  • Symmetric non-purulent conjunctivitis (80-90%)
  • Unilateral cervical lymphadenopathy (>1.5 cm; 50%)
  • Mucosal enanthema with red and/or chapped lips (80-90%)
  • Anterior uveitis (up to 80%)
  • Arthritis of small joints (up to 15%)
• Late Symptoms (after several weeks):
  • Periungual and/or perianal desquamation
  • Nail anomalies (Beau lines)

Diagnostic Criteria

• Fever for at least 5 days plus 4 out of 5 of the following:
  1. Bilateral bulbar conjunctival injection
  2. Oral mucous membrane changes:
     • Injected or fissured lips, strawberry tongue, injected pharynx
  3. Peripheral extremity changes:
     • Erythema, edema, desquamation
  4. Polymorphous rash
  5. Cervical lymphadenopathy
• A diagnosis can be made earlier than 5 days with a typical presentation in consultation with an experienced clinician.
• KD can be diagnosed with fewer than four criteria if coronary artery abnormalities are present.

Kawasaki disease: Diagnostic criteria Fever persisting for 5 days, PLUS 4 of the 5 following criteria:  A diagnosis earlier than 5 days can be made with a typical presentation in consultation with an experienced clinician KD can be diagnosed with less than four of the following features if coronary artery abnormalities are present
Criterion	Features
Conjunctival injection	Bilateral, non-exudative, painless.  Often with limbic sparing (zone around the iris is clear)
Rash	Erythematous polymorphous rash occurs in the first few days, involving trunk and extremities Variable presentations most commonly maculopapular, erythema multiforme-like or scarlatiniform Bullous, vesicular, or petechial rashes are not typical in KD
Oral Changes	Strawberry tongueErythema, dryness, cracking and bleeding of the lips Diffuse oropharyngeal erythema Exudates are not typical of KD
Extremity changes	Hyperaemia and painful oedema of hands and feet progresses to desquamation from the second week of illness
Lymphadenopathy	Cervical, most commonly unilateral, tender.  At least one node >1.5cm. Less common feature and seen in older children

Differential Diagnosis

• Group A streptococcal infections:
  • Tonsillitis
  • Scarlet fever
  • Acute rheumatic fever
• Viral infections:
  • Epstein-Barr Virus (EBV)
  • Cytomegalovirus (CMV)
  • Adenovirus
  • Human Herpesvirus 6 (HHV-6)
  • SARS-CoV-2
• Systemic juvenile idiopathic arthritis (JIA)
• Sepsis
• Toxic shock syndrome (staphylococcal or streptococcal)
• Stevens-Johnson syndrome
• Drug reaction
• Malignancy

Management

Investigations

• Echocardiogram:
  • Discuss timing with cardiology
  • Suggested schedule:
    • At presentation (do not delay treatment)
    • 2 weeks
    • 6 weeks
  • Coronary artery lesions management in consultation with paediatric cardiology and haematology services
• In all patients, consider:
  • Full Blood Examination (FBE)
  • C-Reactive Protein (CRP)
  • Erythrocyte Sedimentation Rate (ESR)
  • Urea, Electrolytes, and Creatinine (UEC)
  • Liver Function Tests (LFT) (Note: ESR unreliable after IVIg administration)
  • Blood culture
  • Antistreptolysin O Titre (ASOT)
  • Serum to store (prior to IVIg administration)
  • Urinalysis and culture (sterile pyuria)
  • COVID-19 swab
  • Electrocardiogram (ECG)
    • Common abnormalities include elevated ESR, CRP, neutrophils, and thrombocytosis in the second week of illness.

Treatment

• Intravenous Immunoglobulin (IVIg):
  • 2 g/kg as a single IV infusion on diagnosis
  • Administer within the first 10 days of illness; also to children diagnosed after 10 days if ongoing fever/inflammation
  • Second dose of 2 g/kg IVIg for non-responders to the first dose (persistent/recurrent fevers 36 hours post-infusion); seek specialist advice
  • Coordinate and authorise via the National Blood Authority and BloodSTAR
  • Haemolytic anaemia as a rare adverse effect, typically occurring up to a week post-infusion
  • Post-IVIg vaccination: defer live vaccines (e.g., measles, varicella); see National Immunisation Handbook; if high risk of measles, vaccinate and re-vaccinate after the appropriate period
• Aspirin:
  • 3-5 mg/kg orally as a daily dose until normal echo on follow-up (minimum 6 weeks)
  • Minimal risk of Reye syndrome with low-dose aspirin
  • Avoid non-steroidal anti-inflammatory medications while on aspirin
• Corticosteroids:
  • Limited evidence for indication and optimal dose/duration
  • Consider use with specialist advice
  • High-risk groups include:
    • Age <12 months, Asian ethnicity
    • Investigation abnormalities: ALT >100 IU/L, albumin ≤30 g/L, sodium ≤133 mmol/L, platelets ≤30 x 10^9/L, CRP >100 mg/L, anaemia for age
    • Cardiac or coronary artery involvement on echo at presentation
• Additional Treatments:
  • Biological medicines such as infliximab for non-responders to initial IVIg (consult local paediatric specialists)
  • Consult local paediatric team when Kawasaki disease is suspected or the child does not respond to initial treatment

Complications

• affects the coronary arteries – ischaemic heart disease, enurysms, ectasia
• Needs treatment with immunoglobulins, aspirin, steroids under specialist guidance
• Aspirin should continue for 6 weeks (5mg/kg daily)
• Differentials – measles, JRA, staph/.strep, viral exanthems, drug reactions