Kawasaki Disease, Pediatric

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Kawasaki Disease, Pediatric

Basics

Description

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.

In a patient with ongoing fever and nonsuppurative lymphadenitis despite adequate antibacterial therapy, consider KD.

ESR is artifactually elevated after administration of IVIG and therefore not useful in this scenario.

• 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.

• 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 JapanEthnic 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.

• 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.

• 5,523 reported cases of KD in the United States in 2006

Risk Factors

• Asian/Pacific Islander descent
• Young age

• 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 recurrenceClusters and epidemicsAge of affected patientsSeasonal predominanceOligoclonal 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.

• 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

• 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 timeExtremity 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 KDIf 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/ Ž ΌL, WBC ≥15,000/ Ž ΌL, urine ≥10 WBC/HPF, anemia for age, ALT elevation

• 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)

• 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/ Ž ΌL, WBC ≥15,000/ Ž ΌL, urine ≥10 WBC/HPF, anemia for age, ALT elevation

Alert

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:IrritabilityAbdominal pain/emesis/diarrheaRefusal to ambulate or pain with ambulationPoor appetite

• 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 swellingPeriungual desquamation of hands and feet within 2 " “3 weeks of fever onsetBeau lines (transverse grooves across nails) within 1 " “2 months of fever onset
• Polymorphous rashUsually, diffuse maculopapular rashOften, perineal rash with desquamationAlso seen: erythema multiforme, erythroderma, urticaria, scarlatiniformNot vesicular or bullous
• Bilateral nonexudative conjunctivitisBulbar, with limbic sparingPainlessAnterior uveitis/iridocyclitis can be seen.
• Mucosal changesCracked, red, swollen lipsStrawberry tongue with erythema and prominent papillaeBuccal and pharyngeal mucosa erythema
• Unilateral cervical lymphadenopathy of one or more nodes that are >1.5 cm in diameterCan be misdiagnosed as bacterial lymphadenitisUsually without overlying erythemaLeast common clinical finding in KD
• Other clinical findingsMyocarditis with tachycardia, gallop, innocent flow murmurShock and hypotensionArthritis and arthralgias (early can be multiple joints, later is usually weight-bearing joints)Urethritis, meatitisRare findings: transient hearing loss

• 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

• Usually, diffuse maculopapular rash
• Often, perineal rash with desquamation
• Also seen: erythema multiforme, erythroderma, urticaria, scarlatiniform
• Not vesicular or bullous

• Bulbar, with limbic sparing
• Painless
• Anterior uveitis/iridocyclitis can be seen.

• Cracked, red, swollen lips
• Strawberry tongue with erythema and prominent papillae
• Buccal and pharyngeal mucosa erythema

• Can be misdiagnosed as bacterial lymphadenitis
• Usually without overlying erythema
• Least common clinical finding in KD

• 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

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.

• Elevated ESR and/or CRP
• CBCWBC normal to elevated with left shiftAnemia (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
• ChemistriesHypoalbuminemiaHyponatremiaTransaminitis and elevated GGTHyperbilirubinemia
• Aseptic meningitis with CSF pleocytosis
• Sterile pyuria
• Synovial fluid leukocytosis
• Elevated triglycerides and LDL, low HDL

• 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

• Hypoalbuminemia
• Hyponatremia
• Transaminitis and elevated GGT
• Hyperbilirubinemia

• Chest x-rayInterstitial pneumonitis
• ECHOAneurysms or ectasias of the epicardial coronary arteries that evolve over timeZ-score corrects for variations in body surface area among children.Larger aneurysms with higher risk of thrombosis and deathDecreased myocardial contractilityMitral or aortic (rare) regurgitationPericardial effusionRarely, aneurysms of other medium sized vessels, including iliac and axillary
• Abdominal ultrasoundHydrops of the gallbladder

• Interstitial pneumonitis

• Aneurysms or ectasias of the epicardial coronary arteries that evolve over timeZ-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

• Z-score corrects for variations in body surface area among children.
• Larger aneurysms with higher risk of thrombosis and death

• Hydrops of the gallbladder

Differential Diagnosis

• Viral infectionsMeasles, adenovirus, Epstein-Barr virus
• Bacterial infectionsScarlet feverStreptococcal or staphylococcal toxic shockStaphylococcal scalded-skin syndromeLeptospirosisRocky Mountain spotted feverCervical lymphadenitis
• Rheumatologic conditionsJuvenile idiopathic arthritis, especially systemic onset
• Drug reactionsStevens-Johnson syndrome
• Mercury hypersensitivity

• Measles, adenovirus, Epstein-Barr virus

• Scarlet fever
• Streptococcal or staphylococcal toxic shock
• Staphylococcal scalded-skin syndrome
• Leptospirosis
• Rocky Mountain spotted fever
• Cervical lymphadenitis

• Juvenile idiopathic arthritis, especially systemic onset

• Stevens-Johnson syndrome

Treatment

Medication

• Combination therapy with IV immunoglobulin (IVIG) and aspirinProven efficacy in reducing coronary artery aneurysms when given by 10th day of illnessClinical benefit to therapy after 10th day, although prevention of coronary aneurysms unclearIVIG dose: 2 g/kg given over 10 " “12 hoursAspirin 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 KD5 " “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 therapyPrimary 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 aneurysmsConsider addition of antiplatelet therapy or anticoagulation in consultation with cardiology depending on size and extent of aneurysms.

• 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

• 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.

• 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.

• 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 aneurysmsCoronary artery bypassHeart transplantation (rarely)

• Coronary artery bypass
• Heart transplantation (rarely)

• 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

• Prolonged fever and clinical and laboratory findings suggestive of KD

• Frequent vital signs and monitoring during IVIG administration
• Patient education

• 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.

• 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 ’ ˆ 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)