Kawasaki syndrome is an acute, self-limited, exanthematous febrile, vasculitic disease of young children, notable for its cardiac sequelae.
- Vasculitis affecting the coronary arteries can result in aneurysms or ectasia, further leading to myocardial infarction/ischemia or sudden death.
- System(s) affected: Cardiovascular; GI; Hematologic/Lymphatic/Immunologic; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
- Synonym(s): Mucocutaneous lymph node syndrome; infantile polyarteritis
Kawasaki syndrome should be considered in any child with extended high fever unresponsive to antibiotics or antipyretics, rash, and nonexudative conjunctivitis.
Incomplete or atypical cases that exhibit <4 clinical criteria often occur in infants ≤6 months old or older children/adolescents. In this subset of patients, the frequency of coronary artery aneurysms (CAAs) is often higher owing to missed diagnosis.
- Worldwide: Affects all races, but most prevalent in Japan, where incidence is ∼112/100,000 in children <5 years of age
- In the US, the annual incidence rate among children <5 years of age is 33/100,000 for Asian Americans, 17/100,000 for non-Hispanic blacks, 11/100,00 for Hispanics, and 9/100,000 for whites.
- Leading cause of acquired heart disease in children:
- Predominant age: 1–5 years (peak age in the US, 18–24 months; Japan, 6–11 months)
- 76% of the children <5 years of age and 50% <2 years of age
- Predominant sex: Male > Female (1.5–1.7:1 in US, 1.35:1 in Japan)
- Highest to lowest prevalence: Asians > blacks > Hispanics > whites
- Seasonal variation: Increased in winter and early spring and outbreaks at 2- to 3-year intervals
- Increased incidence of human leukocyte antigen (HLA) types B54, Bw15, Bw35, and Bw22 in Japanese patients; in US whites, HLA types Bw51, B5, and B44 are increased; in Israelis, HLA type Bw51
- The risk of occurrence in twins is ∼13%.
- Siblings of patients in Japan have been found to have a 10-fold relative risk.
- Parents and patients should be educated about the possibility of recurrence (4% in Japan, <1% in US).
- If cardiac problems are present, the need for continued care must be emphasized because Kawasaki syndrome is potentially fatal.
Acute Kawasaki syndrome most severely affects medium-sized arteries. The media of severely affected vessels are inflamed with necrosis of smooth muscle cells. 7–9 days after onset of fever, inflammatory cells secrete various cytokines, interleukins, and matrix metalloproteases that target vascular endothelial cells, resulting in fragmentation of the internal elastic lamina, leading to CAAs. During the period when greatest vascular damage occurs, there is a progressive increase in the serum platelet count. Over weeks to months, active inflammatory cells are replaced by fibroblasts and monocytes involved in tissue repair and remodeling. This process also can lead to progressive fibrosis and vascular stenosis.
Unknown; however, an infectious cause is favored owing to the acute, self-limited nature of Kawasaki syndrome. Community-wide outbreaks and seasonality point to a transmissible childhood disease.
Fever and ≥4 of following 5 principal clinical features or <4 features and presence of coronary artery disease on 2D echocardiography:
- Conjunctival injection
- Erythematous mouth and pharynx, tongue, and lips
- A polymorphous, generalized, erythematous rash
- Changes in the skin of the peripheral extremities
- Cervical lymphadenopathy
Prolonged fever without rash and treated with antibiotics may cause clinicians to believe that later rash development is due to a drug reaction.
Symptoms may not occur all at once.
- Fever for ≥5 days:
- Fever is high (103–105°F [39.4–40.5°C]) and unresponsive to antibiotics.
- May be prolonged (2–3 weeks, with mean duration of 11 days)
- Bilateral nonpurulent conjunctival injection without exudate
- Changes in lips and oral cavity:
- Reddening of lips in the acute stage, which crack, fissure, and bleed in the subacute phase
- Strawberry or erythematous tongue
- Diffuse injection of oral and pharyngeal mucosa without exudate
- Extensive polymorphous rash:
- May be maculopapular, scarlatiniform, morbilliform, resemble erythema multiforme, or rarely micropustular
- Perineal desquamation
- Extremity changes:
- Reddened palms and soles on days 3–5
- Edema of hands and feet on days 4–7
- Periungual desquamation of fingers and toes at 2–3 weeks
- Acute, unilateral cervical lymphadenopathy:
- Lymph nodes >1.5 cm and nontender
- Generalized lymphadenopathy usually absent
- Cardiac exam: Tachycardia, gallop rhythms, hyperdynamic precordium, innocent flow murmurs
- Skin exam: Rash involving both trunk and extremities; erythema/induration at bacille Calmette-Guérin (BCG) vaccination site, if applicable
- Other organ system involvement:
- Cardiovascular: Myocarditis; pericarditis (often subclinical), coronary artery and other medium-sized arterial aneurysms
- GI: Anorexia, abdominal pain, vomiting or diarrhea, acute gallbladder hydrops
- Renal: Nephritis, urethritis
- Respiratory: Pneumonitis, atelectasis or pleural effusion, cough
- Joints: Polyarthritis of small joints in acute phase; weight-bearing joints affected after 10th day from onset of fever
- Neurologic: Irritability, aseptic meningitis, peripheral neuropathy, transient sensorineural hearing loss
Diagnostic Tests & Interpretation
- Initial workup should include appropriate testing to rule out sepsis: Complete blood count (CBC) with differential, urine analysis and culture, blood culture; lumbar puncture if <4 months of age
- Leukocytosis (12,000–40,000 cells/mm3) with immature forms and neutrophilia
- Anemia (normochromic, normocytic)
- Thrombocytosis (500,000 to >1,000,000 cells/mm3) in 2nd and 3rd weeks
- Elevated CRP, ESR, and α1-antitrypsin concentrations
- ESR can be artificially high after immune globulin IV (IVIG) therapy.
- Mildly elevated AST, ALT, GGT, and bilirubin
- Decreased albumin
- Abnormal plasma lipids: Decreased cholesterol, high-density lipoprotein (HDL), and apo-AI
- CSF pleocytosis may be seen.
- Sterile pyuria (in 33% of patients)
- Once Kawasaki syndrome is suspected, all patients need a cardiac evaluation, including ECG and echocardiogram.
- ECG may show arrhythmias, prolonged PR interval, and ST/T-wave changes.
- Echocardiogram may show perivascular brightening, ectasia, decreased left ventricular (LV) contractility, pericardial effusion, or aneurysms. Echocardiography has a high sensitivity and specificity for detection of abnormalities of proximal LMCA and RCA (1)C].
- CXR for baseline; may show pleural effusion, atelectasis, and congestive heart failure (CHF)
- MRI and MR angiography for aneurysms in both coronary and peripheral arteries
- No laboratory study proves diagnosis; the diagnosis rests on clinical features and exclusion of other illnesses in differential diagnosis.
- Patients with complex coronary artery lesions may benefit from coronary angiography after the acute inflammatory process has resolved; generally recommended in 6–12 months (1)[C].
- 7–9 days after onset, neutrophilic infiltrates involve the pericardium, myocardium, endocardium, and vascular endothelium.
- Necrosis may develop and result in aneurysmal dilatation of medium-sized arteries.
- Mononuclear infiltration predominates in the 2nd week of illness, gradually resolving with or without fibrosis.
- In addition to cardiac involvement, arteritis may also develop in lungs, kidneys, gastrointestinal tract, and other organs.
- Staphylococcal scalded-skin syndrome
- Toxic shock syndrome
- Stevens-Johnson syndrome
- Viral syndromes (i.e., measles, adenovirus)
- Scarlet fever
- Juvenile rheumatoid arthritis
- Reiter syndrome
- Epstein-Barr virus infections
- Mycoplasma infection
- Lyme disease
- Rocky Mountain spotted fever
- Acrodynia (mercury hypersensitivity)
- Drug reactions
- Other vasculitides
- Since diagnosis is often not initially clear, consider evaluation for sepsis as part of workup.
- Inpatient care with IV access and cardiac monitoring until stable
- Optimal therapy is 2 g/kg IVIG with high-dose aspirin as soon as possible after diagnosis during the acute febrile phase of illness, followed by low-dose aspirin until follow-up echocardiograms indicate a lack of coronary abnormalities (2).
- IV immune globulin (IVIG) 2 g/kg IV over 12 hours at the time diagnosis is made lowers the risk of coronary artery aneurysms and may shorten the duration (3)[A]. Retreatment if clinical response is incomplete or fever persists/returns 48 hours after start of IVIG treatment (1)[C].
- Aspirin, 80–100 mg/kg/d in 4 doses beginning with IVIG administration (1)[A]. Switch to low-dose aspirin (3–5 mg/kg/d) when child is afebrile for 48–72 hours or after 2 weeks. Maintain this dose for 6–8 weeks until follow-up echocardiogram is normal (1)[C]. Continue salicylate regimen in children with coronary abnormalities long term or until documented regression of aneurysm (1)[B].
- Limited evidence from underpowered studies shows no demonstrable reduction of CAAs with aspirin therapy (4).
- IVIG: Documented hypersensitivity, IgA deficiency, anti-IgE/IgG antibodies, severe thrombocytopenia, or coagulation disorders
- Aspirin: Vitamin K deficiency, bleeding disorders, liver damage, documented hypersensitivity, hypoprothrombinemia
- No statistically significant difference noted between different preparations of IVIG (3)[A]
- High-dose aspirin therapy can result in tinnitus and decrease of renal function.
- Significant possible interactions: Aspirin therapy is associated with Reye syndrome in children who develop viral infections, especially influenza B and varicella. Yearly influenza vaccination thus is recommended for children requiring long-term treatment with aspirin (1)[C].
- Children fulfilling the diagnostic criteria for Kawasaki syndrome should be treated with high-dose IVIG (2 g/kg single dose) within 10 days of onset of symptoms because treatment with IVIG has a generalized anti-inflammatory effect (3)[A].
- Antibiotics are given until bacterial etiologies are excluded (e.g., sepsis or meningitis).
Issues for Referral
- Referral to pediatric cardiologist if coronary abnormalities suspected on echo
- Referral to pediatric cardiac surgeon if extensive stenosis/pathology is suspected
- Coronary artery bypass grafting (CABG) for severe obstruction (>75%) of LCA or high-grade obstructions in 2 of 3 coronary arteries or after recurrent myocardial infarction (1)[C]. Younger patients have a higher mortality rate.
- Coronary revascularization via percutaneous coronary intervention for patients with evidence of ischemia on stress testing (1)[C]
All children with suspected Kawasaki syndrome
- Normal saline (NS) for rehydration in cardiogenic shock
- 1/2 NS for maintenance therapy
Children are usually discharged after 24–48 hours of remaining afebrile after IVIG treatment.
Limited in acute phase; longer with cardiac involvement; with giant or multiple aneurysms, contact and high-risk sports should be avoided.
- Repeat ECG and echo at 6–8 weeks. If abnormal, repeat at 6–12 months (5)[C].
- Children who have little/no cardiac abnormalities on follow-up echo should have a cardiovascular assessment every 3 years (1)[C].
- Usually self-limited
- Moderate-sized aneurysms usually regress in 1–2 years, resolving in 50–66% of cases.
- Sudden death is possible in early adulthood.
- 15–25% of untreated patients develop coronary artery aneurysms in convalescent phase.
- 2–7% of treated patients develop aneurysms.
- Risk factors for aneurysm:
- Male, age <1 year old, high ESR >4 weeks
- Fever >2 weeks in treated patients, fever >48 hours after IVIG treatment
- Mortality of 0.08–0.17% is due to sequelae.
1. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114:1708–33.
2. Rowley AH, Shulman ST et al. Pathogenesis and management of Kawasaki disease. Expert Rev Anti Infect Ther. 2010;8:197–203.
3. Oates-Whitehead RM, Baumer JH, Haines L, Love S, Maconochie IK, Gupta A, Roman K, Dua JS, Flynn I. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database of Systematic Reviews. 2003, Issue 4. Art. No.: CD004000. DOI:10.1002/14651858.CD004000.
4. Baumer JH, Love S, Gupta A, Haines L, Maconochie IK, Dua JS. Salicylate for the treatment of Kawasaki disease in children. Cochrane Database of Systematic Reviews. 2009, Issue 1. Art. No.: CD004175. DOI:10.1002/14651858.CD004175.pub2.
5. McMorrow Tuohy AM, Tani LY, Cetta F, et al. How many echocardiograms are necessary for follow-up evaluation of patients with Kawasaki disease? Am J Cardiol. 2001;88:328–30.
Inoue Y, Okada Y, et al. A multicenter, randomized trial of corticosteroids in primary therapy for Kawasaki disease: Clinical course and coronary artery outcome. Pediatrics. 2006;149:336–341e1.
446.1 Acute febrile mucocutaneous lymph node syndrome (MCLS)
75053002 acute febrile mucocutaneous lymph node syndrome (disorder)
- A child treated for Kawasaki syndrome should wait 11 months before receiving live vaccines, specifically varicella or measles, owing to IVIG interaction. If there is a measles outbreak, the child should be vaccinated twice—once at the time of possible exposure and 11 months later.
- If the child is currently on aspirin for coronary aneurysm, ibuprofen should be avoided because it inhibits the antiplatelet effects of aspirin.