Kawasaki Disease

Essentials of Diagnosis

• Fever, conjunctivitis, oral mucosal changes, rash, cervical lymphadenopathy, peripheral extremity changes

• Elevated ESR and CRP levels

• Risk for coronary arteritis and aneurysms

General Considerations

• An acute, self-limiting, mucocutaneous vasculitis

• Characterized by the infiltration of vessel walls with mononuclear cells and later by IgA secreting plasma cells that can result in the destruction of the tunica media and aneurysm formation

• Cause remains unknown

• Occurs mainly in children between the ages of 3 months and 5 years but can occur occasionally in adults as well

• Multisystem inflammatory syndrome in children (MIS-C)

  • Appears to affect older children (median age 9–11 years) than Kawasaki disease

  • Seems to be more severe than Kawasaki disease

  • Reports of this syndrome came during the peak time of the SARS-CoV-2 pandemic in Bergano (mid-February 2020 to mid-April 2020)

  • Since these initial reports, there have been multiple reports of similar disease from the United States and other European countries

  • This new syndrome raises the question of whether MIS-C is an immune response to SARS-CoV-2

Demographics

• Kawasaki disease occurs most often in Asians or native Pacific Islanders

• Its incidence in Japan is twice that of the United States, and it occurs among siblings at twice the incidence of cases and at higher rates among parents of cases

Symptoms and Signs

• A clinical diagnosis of classic or "complete" Kawasaki disease requires the presence of at least 5 days of fever, usually high-grade (over 39°C to 40°C) and four of the following five criteria:

  • Bilateral nonexudative conjunctivitis (begins shortly after the onset of fever)

  • Oral changes of erythema and cracking of lips, strawberry tongue, and erythema of oral and pharyngeal mucosa; (ulcers and pharyngeal exudates are not consistent with Kawasaki disease)

  • Peripheral extremity changes (erythema and edema of the hands and feet in the acute phase, and/or periungual desquamation within 2–3 weeks after the onset of fever)

  • Polymorphous rash

  • Cervical lymphadenopathy (>1.5 cm, usually unilateral; least common of the clinical features)

• The revised case definition allows the diagnosis on day 4 in the presence of more than four principal clinical criteria, particularly when redness and swelling of the hands and feet are present

• A diagnosis of atypical or "incomplete" Kawasaki disease could be diagnosed in patients with unexplained fever and fewer than four principal criteria if accompanied by compatible laboratory or findings of aneurysms detected by echocardiography or angiography

• The CDC's case definition of MIS-C includes patients younger than 21 years who have had

  • Fever (higher than 38.0°C for at least 24 hours, or report of subjective fever lasting at least 24 hours)

  • Laboratory evidence of inflammation

  • Evidence of clinically severe illness that requires hospitalization, with multisystem (more than two) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurologic)

  • No alternative plausible diagnosis

Differential Diagnosis

• Measles

• Adenovirus

• Scarlet fever

• Toxic shock syndrome

• Rickettsial infections

• Leptospirosis

• Drug hypersensitivity reactions

Laboratory Findings

• Leukocytosis with neutrophilic predominance

• Anemia

• Elevated ESR and CRP

• High platelet counts

• N-terminal moiety of B-type natriuretic peptide (NT-proBNP), likely indicative of myocardial involvement, may be elevated in some patients with Kawasaki disease

• MIS-C

  • Positivity for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test (or known COVID-19 exposure within the 4 weeks prior to the onset of symptoms)

  • Evidence of inflammation, including one or more of the following:

    • Elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, interleukin 6 (IL-6), or neutrophils

    • Reduced lymphocytes or albumin

• Should be started as soon as the diagnosis is suspected to reduce inflammation and arterial damage

• A single dose of IVIG should be given in the first 10 days of the illness

• Patients in whom the diagnosis was made later than the tenth day may still benefit from IVIG treatment if they have elevated inflammatory markers (ESR or CRP), with persistent fever or have coronary artery aneurysms

• Concomitant aspirin with IVIG

  • Should be started at 80–100 mg/kg/day orally (divided into four doses and not exceeding 4 g/day) until the patient is afebrile for 48 hours

  • Then, reduce to 3–5 mg/kg/day until markers of acute inflammation normalize

• Low-dose aspirin (3–5 mg/kg/day) may be as effective as high-dose aspirin (30 mg/kg/day or more) for the initial treatment of Kawasaki disease

• The use of corticosteroids for children with Kawasaki disease is controversial

• However, a course of corticosteroid therapy with tapering over 2–3 weeks could be considered in addition to IVIG and aspirin for patients at high-risk for not responding to IVIG

• Options for refractory cases include

  • A second dose of IVIG

  • High-dose pulse corticosteroids over 3 days with or without a subsequent oral taper course

  • Longer oral tapering course of corticosteroids over 2–3 weeks together with IVIG and aspirin

  • TNF-alpha blockers such as infliximab

  • The anti-inflammatory interleukin 1 receptor antagonist anakinra

  • Low-dose methotrexate

  • Cyclosporine

• Immunomodulatory monoclonal antibody therapy and cytotoxic agents, or (rarely) plasma exchange should be considered only in highly refractory cases in which other therapy has failed

Follow-Up

• Follow-up is especially needed among the subset of patients with neutropenia who have been treated with IVIG

• The frequency of clinical follow-up, diagnostic testing, reproductive counseling, indications for medical therapy (beta-blockers, statins), and thromboprophylaxis (aspirin and anticoagulation) depends on the individual's risk assessment

Complications

• Thrombotic occlusion of a coronary artery aneurysm leading to myocardial infarction or sudden death

• Arteritis and aneurysms of the coronary vessels

• Coronary complications are more common among

  • Patients older than 6 years or younger than 1 year of age

  • Males

  • Patients unresponsive to IVIG, those who received a smaller dose of IVIG, or those who did not receive treatment within 10 days of symptom onset

• While myocarditis can be found in all patients with Kawasaki disease on histologic specimens and is prominent during the acute stage, only a small percentage of patients are clinically symptomatic

• Cardiac complications include left ventricular dysfunction and mitral regurgitation

• Kawasaki shock syndrome

Prognosis

• The reported recurrence rate is 3% in one study from Japan

• The highest risk of recurrence occurs in the first 2 years after the first episode

• Mortality peaks between 15 and 45 days after the onset of fever, at the time of coronary artery vasculitis, thrombocytosis, and a hypercoagulable state

When to Refer

• All cases of Kawasaki disease merit referral to specialists

• Suspected cases of MIS-C in patients younger than 21 years should be reported to local or state health departments