Kawasaki Disease

Kawasaki disease (KD) is an acute, febrile vasculitis of childhood that affects medium-sized arteries and carries a high risk of coronary artery aneurysms (CAA) if not treated. Intravenous immune globulin (IVIG) in combination with aspirin reduces the incidence of CAA (see treatment section below). KD is a self-limited inflammatory process of unknown etiology, but multiple environmental and infectious factors have been hypothesized as triggers. The majority (80%-90%) of cases occur in children younger than 5 years.

The diagnostic criteria for complete or typical KD are at least 5 days of fever plus four or more of the following:

• bilateral conjunctivitis

• mucous membrane changes

• peripheral extremity changes

• polymorphous rash

• cervical adenopathy (>1.5 cm).

Incomplete or atypical KD should be considered when less than four criteria are met but supplementary laboratory criteria (explained below) and/or coronary artery caliber changes are present. Incomplete KD is more common in infants younger than 6 months. It is important to note that KD is a transient vasculitis in which fever will self-resolve after an average of 2 weeks. However, treatment is aggressively pursued to decrease the risk of coronary artery aneurysms, which can occur in up to 25% of patients not treated within the first 10 days of fever onset.

When KD is a suspected diagnosis, subspecialists in Pediatric Infectious Disease and Cardiology as well as Rheumatology may be involved in the diagnosis, treatment, and follow-up care.

Clinical Manifestations and Diagnosis

Complete or Typical Kawasaki Disease

Classic presentation:

• 5 days of fever >101°F plus at least four of the following five criteria:

  • conjunctival injection: bilateral, bulbar (limbic sparing), nonpurulent and painless

  • peripheral extremity changes: edema (“sausage-like” digits) of the hands and feet, erythema of the palms/soles; periungual desquamation 2-3 weeks after fever onset

  • erythematous mucous membrane changes: injected oropharynx; dry, fissured, peeling, cracking lips; “strawberry” tongue

  • polymorphous rash: maculopapular, urticarial, morbilliform, scarlatiniform, or targetoid; prominence in groin area and groin desquamation may occur by end of first week

  • cervical adenopathy: ≥1.5 cm, generally unilateral and may be tender

(Source: Kawasaki Disease. N Engl J Med 1995.)

Atypical or Incomplete Kawasaki Disease

Recommendations from the American Heart Association (AHA) for diagnosis, treatment, and long-term management of Kawasaki disease were revised in 2004 to include evaluation and diagnosis of suspected incomplete or atypical KD in patients with 5+ days of fever but less than four of the five classic clinical symptoms. The updated 2017 AHA scientific statement incorporates new evidence regarding underlying pathological processes, along with an algorithm for the evaluation of suspected incomplete Kawasaki disease to ensure capture of incomplete KD during the effective window of therapy and guidance for evaluating children with less than five of the classic symptoms.

Other Clinical Manifestations

• coronary artery aneurysm (CAA): Treatment within 10 days of fever onset decreases incidence from 25% to less than 5%. Additional risk factors for CAA other than treatment delay include IVIG resistance, age <12 months, and male sex.

• aseptic meningitis: can lead to extreme irritability

• transient sensorineural hearing loss

• myocarditis, valvular disease

• arthritis of small and large joints

• urethritis

• uveitis

• gastrointestinal involvement (gallbladder hydrops, hepatitis, jaundice, hepatosplenomegaly)

• macrophage activation syndrome

• shock-like syndrome

Clinical Course

The three clinical phases of KD are as follows:

• acute febrile phase (7-14 days)

• subacute phase (14-24 days)

• convalescent phase (>24 days)

Evaluation

Laboratory Evaluation

• inflammatory markers: elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (Note: ESR is falsely elevated after IVIG therapy and is no longer clinically meaningful.)

• complete blood count (CBC) with differential: leukocytosis, normocytic anemia, thrombocytosis after the first week (platelet count can rise to 1,000,000/mm³)

• basic metabolic panel (BMP): typically, bland but can include mild hyponatremia

• liver function tests: mild elevation in transaminases, bilirubin, gamma-glutamyltransferase (GGT); hypoalbuminemia

• urinalysis: sterile pyuria (>10 leukocytes per high-powered field [HPF]) due to urethritis (clean catch required as catheter sample may miss it)

• cerebrospinal fluid (CSF): not routinely obtained unless concern for meningitis, can show pleocytosis with lymphocyte predominance

Echocardiogram

• Maximum echocardiogram coronary artery internal luminal diameters are converted to z scores (normalized for age, sex, and size) to stratify the severity of coronary artery ectasias or aneurysms and guide management.

  • Any coronary artery z score ≥ 2.5 is considered abnormal and requires escalation of therapy.

• Echocardiogram may assist in diagnosis of incomplete KD.

• Echocardiogram can show pericardial effusion, valvular abnormalities, or diminished ventricular function.

Differential Diagnosis

The following conditions are associated with clinical findings similar to KD:

• streptococcal or staphylococcal toxin disease

• viral illness including measles and adenovirus (a positive viral test does not exclude KD)

• drug reaction, Stevens-Johnson syndrome

• Rocky Mountain spotted fever (Rickettsia rickettsiae)

• leptospirosis

• multisystem inflammatory syndrome in children (MIS-C)

KD should be considered in the differential diagnosis of all children with prolonged fever without obvious source, but particularly in infants and children with the following characteristics:

• infants <6 months of age with prolonged fever

• infants with prolonged fever and aseptic meningitis

• infants and children with cervical lymphadenitis or phlegmon unresponsive to antibiotics

• infants with prolonged fever and unexplained culture-negative shock (Kawasaki disease shock syndrome)

MIS-C is a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests after SARS-CoV-2 infection. MIS-C and KD share overlapping clinical features, including conjunctival injection, mucocutaneous features, extremity swelling and erythema, and cervical lymphadenopathy. Although the symptoms of MIS-C are similar to those of KD, MIS-C appears to be a unique entity with the following differences:

• broader age range (MIS-C tends to affect children >5 years and adolescents)

• more prominent gastrointestinal and neurologic symptoms

• more frequent presentation in shock

• ventricular dysfunction is more likely (whereas CAA is more likely in KD)

• lower platelet counts (relative thrombocytopenia), lower absolute lymphocyte counts (lymphopenia), and higher C-reactive protein (CRP) levels than patients with KD

For more information on MIS-C, see acquired heart disease in the Pediatric Cardiology rotation guide and the American College of Rheumatology (ACR) clinical guidance for diagnosis and management of MIS-C in children.

Treatment

Early recognition of KD is critical to preventing sequelae. Intravenous immune globulin (IVIG) reduces the incidence of CAA. Studies in the 1980s demonstrated that IVIG administration (given over 4 days) reduced the incidence of CAA from 25% to 5%. Now, high-dose IVIG is administered as a single infusion together with aspirin, ideally within 10 days of fever onset for maximum benefit. The 2021 updated guidelines for the management of KD from the American College of Rheumatology and Vasculitis Foundation (ACR/VF) note that there is not evidence that high-dose aspirin is more effective than low-dose aspirin in the prevention of aneurysms in KD. Physicians may now choose between low-dose or high-dose aspirin for therapy. If choosing high dose, transitioning to low dose after an initial 24-72-hour period is still recommended.

Most patients with KD demonstrate rapid response following a single infusion of IVIG and initiation of aspirin. Approximately 10% to 15% of patients do not respond to the initial IVIG infusion or experience recurrence of fever following initial response. Other reasons for continued fever (incorrect diagnosis) or recurrent fever (reaction to IVIG) are important to consider when evaluating a child with fever following initial IVIG infusion.

For patients with acute KD who are resistant to IVIG, have CAA at diagnosis, or are at high risk of developing CAA, use of IVIG with adjunctive glucocorticoids as initial therapy is recommended over treatment with IVIG alone. Non-glucocorticoid immunomodulatory agents should also be considered. Risk factors for development of CAA include age <6 months or >9 years and significant elevation of inflammatory markers (C-reactive protein level ≥13 mg/dL), although further investigation is needed to clarify features of high-risk KD in a U.S. population.

Recommendation for initial treatment:

• age >6 months: IVIG and aspirin

• age <6 months (and at high-risk for CAA): IVIG and strongly consider adjunctive glucocorticoids; use low-dose aspirin only in combination with adjunctive glucocorticoids

  • IVIG: given over 10 to 12 hours in a single dose even if diagnosis is made after 10 days of illness

    • monitor for hemolytic anemia, a major adverse effect of IVIG

    • recommend repeat CBC 24-36 hours after IVIG in patients with pallor, tachycardia, or worsening fatigue

  • aspirin: strict guidelines for duration of high-dose aspirin treatment do not exist; if high-dose aspirin is chosen as initial therapy, clinically acceptable dosing regimens vary from 24 hours to 72 hours after resolution of fever before transition to low-dose aspirin

Recommendation for treatment of KD patients unresponsive to initial treatment, with abnormal echocardiogram (z score ≥2.5), or at high risk for poor outcomes:

• Conventional treatment is a second dose of IVIG if a patient is refractory to first infusion (see ACR/VF treatment algorithm).

• New data from the KIDCARE trial show that replacing a second IVIG treatment with a single infliximab infusion leads to shorter duration of fever, reduced need for additional therapy, less-severe anemia, and shorter hospitalization.

• Regardless of treatment with a second dose of IVIG or infliximab, consideration of adjunctive glucocorticoids is strongly recommended.

• Other nonsteroid immunomodulatory agents to consider:

  • anakinra (IL-1 receptor antagonist): The efficacy of anakinra in IVIG-resistant KD patients is being evaluated in an ongoing clinical trial.

  • cyclosporine: Effectiveness has been reported in case reports in IVIG-resistant KD.

• For treatment of large CAA, anticoagulants other than aspirin are often used in consultation with cardiology, hematology, or both.

Follow-up monitoring:

• Laboratory follow-up is generally not indicated in uncomplicated cases.

• Obtain echocardiogram at baseline and at 6-8 weeks after treatment (or sooner, depending on presence of CAA).

• Children with CAA should be followed longitudinally by cardiology for management of CAA or other abnormal findings.

• Follow up with pediatric rheumatologist recommended in refractory cases, including those requiring glucocorticoids (helpful to exclude other mimicking diagnoses after glucocorticoids are withdrawn), cases in which non-IVIG immunomodulatory agents were used, or both.

Immunizations:

• Seasonal influenza vaccine: If patient hasn’t received the vaccine, administer prior to hospital discharge if during appropriate season.

• Live vaccines (e.g., measles-mumps-rubella, and varicella): Defer for 11 months after receipt of high-dose IVIG due to decreased immunogenicity of these vaccines; children at high risk for measles infection may receive measles vaccine earlier and may be reimmunized 11 months after receipt of IVIG if they did not have a positive serologic response.