Kawasaki disease

Kawasaki disease (KD) is an acute, necrotizing vasculitis of unknown etiology. The condition primarily affects children under the age of five and is more common among those of Asian descent. KD is characterized by high fever, desquamative rash, conjunctivitis, mucositis (e.g., strawberry tongue), cervical lymphadenopathy, as well as erythema and edema of the distal extremities. The most concerning manifestation is coronary artery aneurysms, which can lead to myocardial infarction or arrhythmias. KD is a clinical diagnosis that is supported by findings such as elevated ESR or evidence of cardiac involvement on echocardiography. Treatment with intravenous immunoglobulins (IVIG) and aspirin is essential and should be initiated as soon as possible after diagnosis.

• Sex: ♂ > ♀ (1.5:1) ^[1]
• Age: : primarily children < 5 years (most common cause of acquired coronary artery disease in children) ^[2][3]
• Peak incidence: occurs mostly in late winter and spring
• Prevalence ^[2]
  • Approx. 20 per 100,000 children
  • Highest rate in children of Asian and Pacific-Islander descent
• Mortality: < 0.5% ^[4]

Epidemiological data refers to the US, unless otherwise specified.

• The exact cause of Kawasaki disease remains uncertain.
• However, it is associated with infectious and genetic factors (the prevalence is higher in patients of Asian descent and in siblings of affected children). ^[5]

Principal clinical features of Kawasaki disease ^[6]

• Fever ≥ 5 days
  • Usually > 39°C
  • Required for diagnosis
  • Resolution of fever does not exclude KD.
• Oropharyngeal mucositis, e.g.,
  • Strawberry tongue: erythema and swelling of the tongue
  • Cracked and red lips
  • Diffuse oropharyngeal erythema
• Painless bilateral conjunctivitis without exudate
• Polymorphous rash originating on the trunk
• Erythema and edema of hands and feet, including the palms and soles (the first week) with possible desquamation of fingertips and toes after 2–3 weeks
• Cervical lymphadenopathy ≥ 1.5 cm (often unilateral)

Fever must last ≥ 5 days to fulfill the diagnostic criteria for KD. ^[6]

“CRASH and BURN”: Conjunctivitis, Rash, Adenopathy, Strawberry tongue, Hands and feet, and BURN (fever ≥ 5 days) are the most common features of KD.

Maintain a high index of suspicion for KD in infants (especially < 6 months old) and children with prolonged fever and any of the following: irritability, aseptic meningitis, unexplained shock (e.g., negative blood cultures), and lymphadenopathy or deep neck infections resistant to antibiotics. ^[6]

Other clinical features ^[6]

• Cardiovascular
  • Clinical features of myocarditis
  • Clinical features of pericarditis
  • Clinical features of acute heart failure
  • Clinical features of peripheral vascular disease including gangrene
  • Cardiac murmurs
• Respiratory: retropharyngeal or parapharyngeal swelling
• Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, jaundice
• Musculoskeletal: arthralgias and other clinical features of arthritis
• Neurological: severe irritability, facial nerve palsy, hearing loss
• Genitourinary: groin rash, urethritis, scrotal swelling
• Ocular: cells and flare on slit lamp examination

Children with KD may present with cardiogenic shock requiring fluids and vasopressors. ^[6]

Approach ^[6][7]

• Determine if the patient meets diagnostic criteria for classic KD.
• If diagnostic criteria for classic KD are not met, apply the diagnostic criteria for incomplete KD.
• If the diagnosis remains uncertain:
  • Perform serial clinical and laboratory evaluations. ^[6]
  • Perform echocardiography if periungual desquamation develops.
  • Treat empirically if the diagnostic criteria for classic KD are met or the diagnostic criteria for incomplete KD is fulfilled on subsequent evaluation.

Diagnostic criteria for classic KD ^[6][7]

• Fever lasting ≥ 5 days
• Presence of ≥ 4 other principal clinical features of KD at any time during illness

Diagnostic criteria for incomplete KD ^[6][7]

The following criteria are consistent with recommendations from the 2017 AHA scientific statement on diagnosis, treatment, and long-term management of KD and the 2021 American College of Rheumatologists/Vasculitis Foundation guidelines for the management of KD.

• Unexplained fever, e.g., ≥ 5 days in patients with suggestive clinical features or ≥ 7 days in infants with no other identifiable cause
• < 4 other principal clinical features of KD at any time during illness
• Elevated ESR and/or CRP in combination with either of the following:
  • ≥ 3 other characteristic laboratory findings (e.g., anemia, thrombocytosis)
  • Positive echocardiographic findings (e.g., coronary artery aneurysm)

Take a thorough history, as one or more principal clinical features of KD may have resolved by the time of evaluation. ^[6]

Characteristic laboratory findings ^[6][7]

Experts consider the following to correlate more strongly with KD than other laboratory findings:

• Elevated ESR and/or CRP
  • ESR ≥ 40 mm/hour
  • CRP ≥ 3.0 mg/dL
• Anemia: See the “WHO criteria for anemia” for age-based cutoffs in children.
• Leukocytosis: WBC ≥ 15,000/mm³
• Thrombocytosis: platelets ≥ 450,000/mm³ 1 week after fever onset
• Elevated ALT level
• Low albumin (≤ 3 g/dL)
• Elevated urine WBC count (≥ 10 cells/hpf)

KD is less likely if inflammatory markers are normal 7 days after illness onset. ^[6]

Echocardiography ^[6][7]

• Indications
  • Workup of incomplete KD
  • Screening for coronary disease as soon as KD is diagnosed
  • Unexplained shock in children
  • Baseline measurements, monitoring, and follow-up of all patients with KD
• Findings ^[6]
  • Coronary artery aneurysm or dilatation
  • LV dysfunction
  • Mitral regurgitation
  • Pericardial effusion

Do not delay treatment for echocardiography if clinical suspicion is high. ^[6]

Procedural sedation may be required to optimize image quality in very young or irritable children. ^[6]

Other investigations ^[6]

Clinical features of KD vary; the following findings may be present:

• Other laboratory studies: hyperbilirubinemia, elevated lipase or amylase
• Other cardiovascular imaging (e.g., cardiac MRI): abnormalities of coronary arteries and/or aortic root
• Nonspecific ECG changes
• Chest imaging: infiltrates, pulmonary nodules
• CSF analysis: pleocytosis, negative cultures
• Neck imaging: retropharyngeal or parapharyngeal mass

• Pediatric viral exanthems, e.g., measles, rubella, Coxsackie virus infection
• Other common viral infections, e.g., adenovirus, rhinovirus
• Toxin-mediated diseases, e.g., scarlet fever, toxic shock syndrome, staphylococcal scalded skin syndrome ^[6][8]
• Allergic reactions, e.g., urticaria, anaphylaxis
• Drug hypersensitivity reactions, e.g., Stevens-Johnson syndrome
• IgA vasculitis
• Erythema multiforme
• Multisystem inflammatory syndrome in children ^[8]
• Systemic lupus erythematosus ^[9]
• Systemic-onset juvenile idiopathic arthritis ^[8]
• In endemic areas: Rocky Mountain spotted fever, leptospirosis ^[6]
• See “Rash” for more conditions.

The differential diagnoses listed here are not exhaustive.

Approach ^[6][7]

Initiate treatment for all patients with classic or incomplete KD and admit them for further workup and management, including consultation with pediatric cardiology and rheumatology.

• Initial management
  • Initiate treatment with IVIG and ASA for patients with classic or incomplete KD.
  • Consider adjunctive therapy for patients at high risk of IVIG resistance or developing coronary artery aneurysms in consultation with a specialist
• Ongoing management
  • Persistent or recurrent fever > 36 hours after IVIG infusion
    • Repeat IVIG infusion.
    • Consider adjunctive therapy in consultation with a specialist.
  • Fever resolved: Monitor temperatures daily for 1–2 weeks.
• Outpatient management: Arrange repeat echocardiography 1–2 weeks and 4–6 weeks after treatment.

IV immunoglobulin (IVIG) ^[6][7][10]

• High single-dose IVIG infusion (off-label) is indicated for all patients with classic or incomplete KD. ^[6][7]
• Administer as soon as possible (preferably within 10 days of onset) to reduce the risk of coronary artery aneurysms.
• A second IVIG infusion is indicated for patients with recurrent or persistent fever > 36 hours after initial IVIG infusion.

Avoid administering live vaccines to patients within 11 months of IVIG treatment because of the risk of reduced vaccine efficacy. ^[11]

Aspirin (ASA) ^[6][7]

• Indicated for all patients with classic or incomplete KD, irrespective of age
• Dosage in acute KD can vary by institution; consult local protocols.
  • High-dose ASA (off-label) is often given until the patient is afebrile for 48–72 hours. ^[6][7]
  • Moderate-dose ASA (off-label) or low-dose ASA (off-label) can be given instead of high-dose ASA. ^[6][7]
• Low-dose ASA is often continued for 6–8 weeks. ^[6][7]

ASA is indicated in young children with KD. The benefit of treatment is considered to outweigh the risk of ASA-induced Reye syndrome in these patients. ^[6][7]

Adjunctive therapy ^[6][7]

• Consider in consultation with a specialist for the following:
  • High risk of IVIG resistance
  • High risk of developing coronary artery aneurysms
  • Refractory disease
• Options include:
  • Corticosteroids (e.g., prednisolone, methylprednisone) ^[12]
  • Immunomodulators (e.g., infliximab, cyclosporine, anakinra)

• Follow the ABCDE approach.
• Begin immediate hemodynamic support in patients with cardiogenic shock.
• Rule out mimics of KD (see “Differential diagnoses”).
• If clinical criteria for classic KD are not met, follow the diagnostic criteria for incomplete KD.
• Consult pediatric cardiology and rheumatology.
• Obtain laboratory studies: ESR, CRP, CBC, LFTs, albumin, and urinalysis.
• Obtain an echocardiogram as soon as possible.
• Initiate treatment with IVIG and ASA for patients with classic or incomplete KD.
• Consider adjunctive therapy under specialist guidance for high risk patients or refractory disease.
• If diagnostic criteria for incomplete KD is inconclusive, perform serial examination and obtain laboratory studies and follow-up echocardiography.
• Monitor for complications of KD.
• Admit patients for ongoing workup, monitoring, and management.

• Coronary artery aneurysm ; ^[6]
  • The risk of aneurysms is highest during the second and third weeks following symptom onset. ^[6]
  • Rupture or thrombosis of the aneurysm can be lethal.
• Myocardial infarction
• Myocarditis
• Ventricular dysfunction
  • Most commonly occurs within the first 2 weeks of onset of KD ^[13]
  • Often seen in infants with untreated KD ^[14]
  • Most commonly associated with lymphocytic myocarditis ^[13][15]
  • Manifests with symptoms (e.g., tachypnea or diaphoresis with feeding, exertional dyspnea) and physical examination findings of congestive heart failure (e.g., hepatomegaly, S₃ gallop, rales or crackles on lung auscultation) ^[16]
  • Increased risk of sudden death ^[14]
• Arrhythmias

We list the most important complications. The selection is not exhaustive.