> Table of Contents > Kawasaki Syndrome
Kawasaki Syndrome
Alicia D. Evans, MD
Scott P. Grogan, DO, MBA, FAAFP
image BASICS
DESCRIPTION
  • Kawasaki syndrome (KS) is a self-limited acute, febrile, systemic vasculitis of small- and medium-sized arteries that predominantly affects patients age 6 months to 5 years and is the most prominent cause of acquired coronary artery disease in pediatric populations.
    • Vasculitis of coronary arteries resulting in aneurysms/ectasia, further leading to myocardial infarction (MI)/ischemia or sudden death
  • System(s) affected: cardiovascular, gastrointestinal, hematologic/lymphatic/immunologic, musculoskeletal, nervous, pulmonary, renal/urologic, skin/exocrine
  • Synonym(s): mucocutaneous lymph node syndrome (MCLS), infantile polyarteritis, Kawasaki disease
EPIDEMIOLOGY
Incidence
  • Worldwide: affects all races but most prevalent in Asia; Japan annual incidence rate 216/100,000 in children <5 years of age
  • In the United States, the annual incidence in children <5 years is 19/100,000. In comparison to Caucasians, African Americans have a 1.5 times risk, and Asian Americans have a 2.5 times increased risk. Highest state incidence is in Hawaii.
  • Leading cause of acquired heart disease in children in developed countries
    • Predominant age: 1 to 5 years
    • 85% of cases are children <5 years of age and 50% <2 years of age.
    • Male-to-female ratio = 1.5:1
Prevalence
  • Highest to lowest prevalence: Asians > African Americans > Hispanics > Caucasians
  • Seasonal variation: increased in winter and early spring in temperate places, summer in Asia, and outbreaks at 2- to 3-year intervals
ETIOLOGY AND PATHOPHYSIOLOGY
  • Acute KS causes inflammation in the smooth muscle layer of medium extraparenchymal arteries, especially the coronary arteries.
  • Inflammatory cells in the media secrete cytokines (TNF-&agr;), interleukins, and matrix metalloproteases that cause fragmentation of the internal elastic lamina.
  • A prominence of IgA plasma cells and IgA deposits are characteristic features and may be found in the lungs.
  • As the process resolves, active inflammatory cells are replaced by fibroblasts and monocytes; tissue repair/remodeling may cause vascular fibrosis and stenosis.
  • Unknown; believed to be an exaggerated immune response to infectious agent due to the acute, self-limited nature; community-wide outbreaks; age distribution; seasonality; and laboratory features indicating respiratory route of entry
Genetics
  • Siblings of patients in Japan have a 10- to 30-fold increased risk, and >50% develop KS within 10 days of first case. Increased occurrence of KS in children whose parents also had illness in childhood.
  • Populations at higher risk and family link suggest a genetic predisposition.
GENERAL PREVENTION
No preventive measures available
image DIAGNOSIS
≥5 days of fever and ≥4 of the following 5 principal clinical features; or <4 features and presence of coronary artery disease on 2D echocardiography:
  • Bilateral conjunctival injection with limbic sparing
  • Erythematous mouth and pharynx, tongue, and lips
  • A polymorphous, generalized, erythematous rash
  • Changes in the skin of the peripheral extremities
  • Cervical lymphadenopathy
Pediatric Considerations
  • Prolonged fever without rash and treated with antibiotics may cause clinicians to believe that later rash development is due to a drug reaction.
  • Can be diagnosed on day 4 of illness if ≥4 principal features are present
  • Incomplete KS
    • ≥5 days of fever, 2 to 3 principal clinical features, labs indicating systemic inflammation, and exclusion of other diseases
    • Incomplete cases that exhibit <4 clinical criteria often occur in infants ≤6 months of age or older children/adolescents. The frequency of coronary artery aneurysms (CAAs) is often higher in patients with missed diagnosis/delayed treatment. Therefore, in infants with prolonged fever and few or no clinical features, consider echocardiography and inflammatory labs.
PHYSICAL EXAM
  • High-spiking and remittent fever for ≥5 days
    • Fever is high (102-105°F [39.4-40.5°C]) and unresponsive to antibiotics.
    • May be prolonged up to 3 to 4 weeks
    • Extreme irritability is a very common feature.
  • Bilateral, painless, nonpurulent, conjunctival injection without corneal ulceration or edema. Limbic sparing is usually seen.
  • Changes in lips and oral cavity
    • Redness and swelling of lips in the acute stage; cracking, fissuring, bleeding in subacute phase
    • Strawberry/erythematous tongue
  • Extensive erythematous polymorphous rash: within 5 days of fever
    • Morbilliform is most common. May be maculopapular, scarlatiniform; can resemble erythema multiforme, erythroderma, urticarial exanthem; rarely micropustular
    • Perineal desquamation, especially in skin folds
  • Extremity changes
    • Reddened palms and soles on days 3 to 5
    • Edema of hands and feet on days 4 to 7; painful induration
    • Desquamation of fingers and toes that begins in periungual area at 2 to 3 weeks
  • Acute, unilateral cervical lymphadenopathy (least common symptom)
    • ≥1 lymph nodes >1.5 cm, firm, nonfluctuant, and usually with no to slight tenderness
  • Cardiac exam: tachycardia, gallop rhythms, hyperdynamic precordium, innocent flow murmurs, depressed contractility
  • Other organ system involvement
    • Cardiovascular: myocarditis; pericarditis (often subclinical), CAAs, and other medium-sized arterial aneurysms
    • Gastrointestinal: anorexia, abdominal pain, vomiting/diarrhea, acute gallbladder hydrops, hepatic enlargement, jaundice
    • Renal: proteinuria, sterile pyuria
    • 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 (unilateral facial palsy), transient high-frequency hearing loss
DIFFERENTIAL DIAGNOSIS
  • Bacterial: staphylococcal scalded-skin syndrome, toxic shock syndrome, scarlet fever, bacterial cervical lymphadenitis, Mycoplasma infection, leptospirosis, Lyme disease, Rocky Mountain spotted fever
  • Viral: measles, adenovirus, Epstein-Barr virus
  • Toxoplasmosis
  • Reiter syndrome
  • Hypersensitivity drug reactions (erythema multiforme minor, Stevens-Johnson syndrome)
  • Juvenile rheumatoid arthritis
  • Acrodynia (mercury poisoning)
DIAGNOSTIC TESTS & INTERPRETATION
  • Initial workup: CBC with differential, urinalysis (UA)/culture, blood culture; lumbar puncture if signs of meningitis or if <90 days old
    • Leukocytosis (12,000 to 40,000 cells/mm3) with immature and mature granulocytes
    • Anemia: normochromic, normocytic
    • Thrombocytosis (500,000 to >1,000,000/mm3) in second and third week. Thrombocytopenia during acute phase is associated with CAA and MI.
  • Elevated C-reactive protein (CRP) (>35 mg/L in 80% cases), erythrocyte sedimentation rate (ESR) (>60 mm/hr in 60% cases), and &agr;1-antitrypsin
  • Hyponatremia
  • Moderately elevated AST, ALT, GGT, and bilirubin
  • Decreased albumin and protein
  • CSF pleocytosis may be seen (lymphocytic with normal protein and glucose).
  • N-terminal brain natriuretic peptide might be elevated in acute phase.
  • Sterile pyuria but not seen in suprapubic collection
  • Nasal swab to rule out adenovirus
Initial Tests (lab, imaging)
  • If KS is suspected, obtain ECG and echocardiogram.
    • ECG may show arrhythmias, prolonged PR interval, and ST/T wave changes.
    • Echocardiography has a high sensitivity and specificity for detection of abnormalities of proximal left main coronary artery, and right coronary artery may show perivascular brightening, ectasia, decreased left ventricular contractility, pericardial effusion, or aneurysms.
    • Cardiac stress test if CAA seen on echocardiogram
  • Baseline chest x-ray (CXR): may show pleural effusion, atelectasis, and congestive heart failure (CHF)
  • P.575

  • Hydrops of the gallbladder may be associated with abdominal pain or may be asymptomatic.
Diagnostic Procedures/Other
  • No laboratory study is diagnostic; diagnosis rests on constellation of clinical features and exclusion of other illnesses.
  • Magnetic resonance coronary angiography is noninvasive modality to visualize coronary arteries for stenosis, thrombi, and intimal thickening (1).
  • Patients with complex coronary artery lesions may benefit from coronary angiography after the acute inflammatory process has resolved; generally recommended in 6 to 12 months
image TREATMENT
GENERAL MEASURES
Use antibiotics until bacterial etiologies are excluded (e.g., sepsis or meningitis).
MEDICATION
  • Optimal therapy is IVIG 2 g/kg IV over 10 to 12 hours with high-dose aspirin preferably within 7 to 10 days of fever, followed by low-dose aspirin until follow-up echocardiograms indicate a lack of coronary abnormalities.
    • IVIG lowers the risk of CAA and may shorten fever duration.
    • The extreme irritability often resolves very quickly after IVIG is given.
  • Retreatment with IVIG if clinical response is incomplete or fever persists/returns >36 hours after start of IVIG treatment.
    • ≥10% of patients do not respond to initial IVIG treatment. 2/3 of nonresponders respond to the second dose of IVIG.
    • Nonresponders tend to have ↑ bands, ↓ albumin, and an abnormal echo.
  • Aspirin, 80 to 100 mg/kg/day in 4 doses beginning with IVIG administration. Switch to low-dose aspirin (3 to 5 mg/kg/day) when afebrile for 48 to 72 hours, or continue until day 14 of illness. Maintain low dose for 6 to 8 weeks until follow-up echocardiogram is normal and CRP and/or ESR are normal. Continue salicylate regimen in children with coronary abnormalities long term or until documented regression of aneurysm (2)[C].
  • Aspirin does not appear to reduce CAA (3)[B].
  • Contraindications
    • IVIG: documented hypersensitivity, IgA deficiency, anti-IgE/IgG antibodies, severe thrombocytopenia, coagulation disorders
    • Aspirin: vitamin K deficiency, bleeding disorders, liver damage, documented hypersensitivity, hypoprothrombinemia
  • Precautions
    • No statistically significant difference is noted between different preparations of IVIG.
    • High-dose aspirin therapy can result in tinnitus, decrease of renal function, and increased transaminases.
    • Do not use ibuprofen in children with CAAs who are taking aspirin for antiplatelet effects.
    • Significant possible interactions: Aspirin therapy has been 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. Delay any live vaccines for 11 months after IVIG treatment.
Second Line
  • Corticosteroids should be used only if ≥2 IVIG treatments have failed. The addition of corticosteroids to IVIG and aspirin during initial treatment might improve CAA outcomes but lacks consistent evidence (4)[C].
  • In patients refractory to IVIG and steroids, consider infliximab or cyclosporine (5)[B].
  • Plasma exchange may decrease likelihood of CAA in IVIG nonresponders (6)[B].
ISSUES FOR REFERRAL
Pediatric cardiologist if abnormalities on echo or if extensive stenosis
ADDITIONAL THERAPIES
  • Treatment and prevention of thrombosis are crucial.
  • Antiplatelet agents (clopidogrel, dipyridamole), heparin, low-molecular-weight heparin, or warfarin are sometimes added to the low-dose aspirin regimen, depending on severity of coronary involvement.
SURGERY/OTHER PROCEDURES
  • Rarely needed; coronary artery bypass grafting for severe obstruction/recurrent MI. Younger patients have a higher mortality rate.
  • Coronary revascularization via percutaneous coronary intervention for patients with evidence of ischemia on stress testing
INPATIENT CONSIDERATIONS
IV Fluids
Normal saline (NS) for rehydration and 1/2 NS for maintenance
Discharge Criteria
Discharge if afebrile after IVIG treatment for 24 hours.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
With aneurysms, contact and high-risk sports should be avoided.
Patient Monitoring
  • Repeat ECG and echocardiogram at 6 to 8 weeks. If abnormal, repeat at 6 to 12 months.
  • Patients with complex coronary artery lesions may benefit from coronary angiography at 6 to 12 months.
PROGNOSIS
  • Usually self-limited
  • Moderate-sized aneurysms usually regress in 1 to 2 years, resolving in 50-66% of cases.
  • Recurrence (3% in Japan, <1% in the United States)
  • Sudden death in early adulthood (rare)
REFERENCES
1. JCS Joint Working Group. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008)—digest version. Circ J. 2010;74(9):1989-2020.
2. Baumer JH, Love SJ, Gupta A, et al. Salicylate for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2006;(4):CD004175.
3. Lee G, Lee SE, Hong YM, et al. Is high-dose aspirin necessary in the acute phase of Kawasaki disease? Korean Circ J. 2013;43(3):182-186.
4. Chen S, Dong Y, Yin Y, et al. Intravenous immunoglobulin plus corticosteroid to prevent coronary artery abnormalities in Kawasaki disease: a metaanalysis. Heart. 2013;99(2):76-82.
5. Patel RM, Shulman ST. Kawasaki disease: a comprehensive review of treatment options. J Clin Pharm Ther. 2015;40(6):620-625.
6. Hokosaki T, Mori M, Nishizawa T, et al. Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease. Pediatr Int. 2012;54(1):99-103.
Additional Reading
&NA;
  • Huang SK, Lin MT, Chen HC, et al. Epidemiology of Kawasaki disease: prevalence from national database and future trends projection by system dynamics modeling. J Pediatr. 2013;163(1):126.e1-131.e1.
  • 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.
  • 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. Circulation. 2004;110(17):2747-2771.
  • Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2003;(4):CD004000.
  • Rowley AH, Shulman ST. Pathogenesis and management of Kawasaki disease. Expert Rev Anti Infect Ther. 2010;8(2):197-203.
  • Takahashi K, Oharaseki T, Yokouchi Y. Update on etio and immunopathogenesis of Kawasaki disease. Curr Opin Rheumatol. 2014;26(1):31-36.
  • Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J Epidemiol. 2012;22(2):79-85.
Codes
&NA;
ICD10
M30.3 Mucocutaneous lymph node syndrome [Kawasaki]
Clinical Pearls
&NA;
  • The diagnosis of KS rests on a constellation of clinical features.
  • Once KS is suspected, all patients need an inpatient cardiac evaluation, including ECG and echocardiogram.
  • Expert recommendations for optimal therapy is IVIG 2 g/kg IV over 10 hours, with high-dose aspirin 80 to 100 mg/kg/day in 4 doses.