Basics
Description
- Kawasaki disease (KD) is a medium vessel vasculitis of early childhood with a predilection for the coronary arteries, which can result in dilatation, aneurysms, thrombosis, and stenosis.
- No diagnostic test exists, and incomplete presentations are common. Prompt recognition and treatment can reduce risk of coronary artery involvement from 25% to 5%.
Epidemiology
- Worldwide with highest incidence in Japan
- Peak of hospitalizations December " March
- 76% of children with KD are <5 years old.
Incidence
- U.S. hospitalization data (1997 " 2007) demonstrate an annual incidence of 17.1 " 20.8/100,000 children aged <5 years.
- KD is more common in boys than girls. In 2006, the hospitalization rate for boys was 24.2/100,000 versus 16.8/100,000 in girls.
- More common in Asian/Pacific Islanders, with highest rates in Japan
- Ethnic predisposition persists in different geographic locations, with highest incidence in the United States in Asian/Pacific Islander children <5 years of age (30.3/100,000).
- Rates are higher in black and Hispanic children compared to white children.
Prevalence
- 5,523 reported cases of KD in the United States in 2006
Risk Factors
- Asian/Pacific Islander descent
- Young age
Genetics
- Siblings have 10 " 30-fold higher risk of KD.
- Genome-wide linkage studies suggest single nucleotide polymorphisms in the ITPKC gene confer susceptibility to KD.
Pathophysiology
- Generalized vasculitis with early neutrophilic infiltrate, with later transition to lymphocyte infiltration, and lastly to luminal myofibroblastic proliferation
- Can very rarely result in destruction of the endothelium through to the adventitia resulting in aneurysms and rupture
Etiology
- Etiology is unknown.
- Infectious cause suggested by the following:
- Abrupt onset and resolution of symptoms without recurrence
- Clusters and epidemics
- Age of affected patients
- Seasonal predominance
- Oligoclonal IgA plasma cells noted in KD tissues, which bind to cytoplasmic inclusion bodies found in affected tissues
- Data suggest that KD is caused by a previously unrecognized ubiquitous RNA virus that causes disease in an immunologically susceptible population.
- No supporting evidence for multiple proposed etiologic agents: toxic shock toxin, rug shampoo, retrovirus, bocavirus, coronavirus, mercury, EBV/CMV.
Diagnosis
- KD is a clinical diagnosis.
- Current diagnostic criteria: fever for ≥5 days and ≥4 of 5 clinical findings, which need not be present at the same time
- Extremity changes (erythema of palms, soles, and/or edema of hands, feet)
- Polymorphous exanthema (frequently in perineal region with early desquamation)
- Nonexudative bilateral bulbar conjunctivitis (with limbic sparing)
- Mucosal changes (erythema of lips and oropharyngeal mucosa, strawberry tongue, cracked/swollen lips)
- Unilateral cervical lymphadenopathy (>1.5 cm in diameter)
- Incomplete KD
- If patient has characteristics consistent with KD along with fever for ≥5 days with 2 or 3 clinical criteria and CRP ≥3 and/or ESR ≥40, obtain echocardiogram (ECHO). If patient with ≥3 supplemental lab criteria, treat for KD.
- Supplemental lab criteria for incomplete KD: albumin ≤3, platelets (after 7 days) ≥450,000/ ΌL, WBC ≥15,000/ ΌL, urine ≥10 WBC/HPF, anemia for age, ALT elevation
Alert
Young infants with KD often present with few, if any, clinical characteristics of KD. Maintain a high index of suspicion for KD in young infants with prolonged fever.
History
- High-spiking fevers usually greater than 39 °C can persist up to 3 " 4 weeks (mean 11 days).
- In addition to the clinical criteria above, the following complaints are sometimes seen:
- Irritability
- Abdominal pain/emesis/diarrhea
- Refusal to ambulate or pain with ambulation
- Poor appetite
Physical Exam
- Extremity changes with palmar/plantar erythema and/or hand/foot swelling
- Periungual desquamation of hands and feet within 2 " 3 weeks of fever onset
- Beau lines (transverse grooves across nails) within 1 " 2 months of fever onset
- Polymorphous rash
- Usually, diffuse maculopapular rash
- Often, perineal rash with desquamation
- Also seen: erythema multiforme, erythroderma, urticaria, scarlatiniform
- Not vesicular or bullous
- Bilateral nonexudative conjunctivitis
- Bulbar, with limbic sparing
- Painless
- Anterior uveitis/iridocyclitis can be seen.
- Mucosal changes
- Cracked, red, swollen lips
- Strawberry tongue with erythema and prominent papillae
- Buccal and pharyngeal mucosa erythema
- Unilateral cervical lymphadenopathy of one or more nodes that are >1.5 cm in diameter
- Can be misdiagnosed as bacterial lymphadenitis
- Usually without overlying erythema
- Least common clinical finding in KD
- Other clinical findings
- Myocarditis with tachycardia, gallop, innocent flow murmur
- Shock and hypotension
- Arthritis and arthralgias (early can be multiple joints, later is usually weight-bearing joints)
- Urethritis, meatitis
- Rare findings: transient hearing loss
Alert
In a patient with ongoing fever and nonsuppurative lymphadenitis despite adequate antibacterial therapy, consider KD.
Diagnostic Tests & Interpretation
- No definitive diagnostic test
- The presence of ancillary lab findings can support diagnosis of KD and be helpful in identifying those patients with incomplete KD.
Lab
- Elevated ESR and/or CRP
- CBC
- WBC normal to elevated with left shift
- Anemia (normocytic/normochromic)
- Platelets usually normal in the 1st week of illness and increase over the next 2 " 3 weeks, sometimes to >1,000,000/mm3
- Chemistries
- Hypoalbuminemia
- Hyponatremia
- Transaminitis and elevated GGT
- Hyperbilirubinemia
- Aseptic meningitis with CSF pleocytosis
- Sterile pyuria
- Synovial fluid leukocytosis
- Elevated triglycerides and LDL, low HDL
Alert
ESR is artifactually elevated after administration of IVIG and therefore not useful in this scenario.
Imaging
- Chest x-ray
- ECHO
- Aneurysms or ectasias of the epicardial coronary arteries that evolve over time
- Z-score corrects for variations in body surface area among children.
- Larger aneurysms with higher risk of thrombosis and death
- Decreased myocardial contractility
- Mitral or aortic (rare) regurgitation
- Pericardial effusion
- Rarely, aneurysms of other medium sized vessels, including iliac and axillary
- Abdominal ultrasound
- Hydrops of the gallbladder
Differential Diagnosis
- Viral infections
- Measles, adenovirus, Epstein-Barr virus
- Bacterial infections
- Scarlet fever
- Streptococcal or staphylococcal toxic shock
- Staphylococcal scalded-skin syndrome
- Leptospirosis
- Rocky Mountain spotted fever
- Cervical lymphadenitis
- Rheumatologic conditions
- Juvenile idiopathic arthritis, especially systemic onset
- Drug reactions
- Mercury hypersensitivity
Treatment
Medication
- Combination therapy with IV immunoglobulin (IVIG) and aspirin
- Proven efficacy in reducing coronary artery aneurysms when given by 10th day of illness
- Clinical benefit to therapy after 10th day, although prevention of coronary aneurysms unclear
- IVIG dose: 2 g/kg given over 10 " 12 hours
- Aspirin dose: 80 " 100 mg/kg/24 h PO divided q6h until acute-phase reactants normalize and patient defervesces, or until 14th day of illness, at which time the dose is reduced to 3 " 5 mg/kg once daily
- Treatment of refractory KD
- 5 " 15% of patients do not respond to the first dose of IVIG.
- 70 " 80% of nonresponders will respond to a second dose of IVIG.
- Limited evidence to support a treatment recommendation for those not responding to 2nd IVIG dose, but salvage therapy with a 3rd dose of IVIG, IV corticosteroids, infliximab, cyclophosphamide, and methotrexate has been reported.
- Corticosteroids as adjunctive therapy
- Primary adjunctive corticosteroid therapy appears to reduce the incidence of coronary artery disease in a subset of high-risk Japanese patients.
- Some data support adjunctive corticosteroids for IVIG-refractory patients to reduce coronary artery disease risk.
- Optimal dose, duration, and formulation of steroid has not been established.
- Antithrombotic therapy for aneurysms
- Consider addition of antiplatelet therapy or anticoagulation in consultation with cardiology depending on size and extent of aneurysms.
Additional Therapies
- Surgical therapy for life-threatening aneurysms
- Coronary artery bypass
- Heart transplantation (rarely)
General Measures
- Rapid diagnosis and treatment can decrease the risk of coronary artery aneurysms.
- Close follow-up and monitoring for the development of aneurysms after discharge
Inpatient Considerations
Admission Criteria
- Prolonged fever and clinical and laboratory findings suggestive of KD
Nursing
- Frequent vital signs and monitoring during IVIG administration
- Patient education
Discharge Criteria
- Resolution of fever for 24 hours after completion of IVIG administration
- Improvement in clinical symptoms
- Patients should have ECHO completed and interpreted prior to discharge, with additional therapy, monitoring, and prolonged hospital stay as indicated.
Ongoing Care
Follow-up Recommendations
- Low-dose aspirin should be continued until follow-up ECHO at 2 weeks and 6 " 8 weeks after discharge are normal.
- Some centers perform ECHO at 6 " 12 months after discharge.
- Inflammatory markers and CBC should be followed until normalized.
- More frequent follow-up and monitoring for those with coronary abnormalities; advise to monitor for emesis, irritability, and nonspecific symptoms of myocardial ischemia.
Patient Monitoring
- No coronary abnormalities: routine pediatric care after follow-up ECHOs complete
- Transient coronary arteritis that resolves by 6 " 8 weeks: low-dose aspirin until ECHO normalizes, follow-up every 3 " 5 years
- Isolated small- to medium-sized (3 " 6 mm) aneurysm: low-dose aspirin until regression is documented on annual follow-up ECHOs. Biennial stress test or myocardial perfusion assay for patients 11 years or older. Perform angiography if stenosis or is ischemia suggested.
- One or more large (>6 mm) or giant (>8 mm) aneurysm/multiple smaller or complex aneurysms: long-term antiplatelet therapy or clopidogrel indefinitely, with anticoagulation with warfarin or subcutaneous low-molecular-weight heparin. ECHO and ECG q6 months, stress testing yearly. Angiography 6 " 12 months after diagnosis and repeated if concerns for myocardial ischemia; no strenuous activity, additional limits on activity based on stress testing
- Evidence of stenosis or obstruction: emergent referral for cardiovascular surgical evaluation and thrombolytic therapy
Prognosis
- The process of resolution of aneurysms is incompletely understood. Some histopathologic changes in the arterial lumen likely persist despite angiographic regression.
- Smaller aneurysms are more likely to resolve than larger aneurysms.
- Resolution of aneurysms (by angiography) is reported in ’ Ό50 " 67% of vessels.
- Improved prognosis with age <1 year, fusiform rather than saccular aneurysm, distal location
- Giant aneurysms with worst prognosis: higher likelihood of thrombosis and stenosis
- Cause of death usually myocardial infarction due to thrombosis
- Long-term implications for cardiovascular health unclear, even when no aneurysms
Complications
- Aneurysmal rupture (very rare)
- Myocardial infarction
- Coronary artery stenosis years after onset
- Rare association with hemophagocytic syndrome
- Recurrence rate <1%, higher in Asian populations
Additional Reading
- Burns JC, Glode MP. Kawasaki syndrome. Lancet. 2004;364(9433):533 " 544. [View Abstract]
- Freeman AF, Shulman ST. Refractory Kawasaki disease. Pediatr Infect Dis J. 2004;23(5):463 " 464. [View Abstract]
- Holman RC, Belay ED, Christensen KY, et al. Hospitalizations for Kawasaki syndrome among children in the United States, 1997 " 2007. Pediatr Infect Dis J. 2010;29(6):483 " 488. [View Abstract]
- Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012;379(9826):1613 " 1620. [View Abstract]
- Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. 2007;356(7):663 " 675. [View Abstract]
- Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of patients with Kawasaki disease. Pediatrics. 2004;114(6):1708 " 1733. [View Abstract]
- Pinna GS, Kafetzis DA, Tselkas OI, et al. Kawasaki disease: an overview. Curr Opin Infect Dis. 2008;21(3):263 " 270. [View Abstract]
- Rowley A. Kawasaki disease: novel insights into etiology and genetic susceptibility. Annu Rev Med. 2011;62:69 " 77. [View Abstract]
- Rowley A, Shulman ST. Pathogenesis and management of Kawasaki disease. Expert Rev Anti Infect Ther. 2010;8(2):197 " 203. [View Abstract]
Codes
ICD09
- 446.1 Acute febrile mucocutaneous lymph node syndrome [MCLS]
ICD10
- M30.3 Mucocutaneous lymph node syndrome [Kawasaki]
SNOMED
- 75053002 Acute febrile mucocutaneous lymph node syndrome (disorder)