Kawasaki Disease (6 mo - 18 years) - Curbside
Kawasaki Disease (6 mo - 18 years)
Editors: Dan Imler, MD
Inclusion Criteria  (All criteria are present)
  • 5 days of fever > 38.0 C (100.4 F)
  • No identifiable source of fever
Exclusion Criteria
  • Immunosuppresed, cancer
  • History of rheumatologic disease

Contact Kawasaki disease expert (rheumatology or infectious disease)

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Evidence
Total Notes: 9
Evidence

1 Kawasaki disease

Kawasaki disease (KD) is a common vasculitis of childhood with unknown etiology. In the United States it has an incidence of 20 per 100,000 for all children younger than five years. However, it's incidence is very dependent on geographic location, age, gender, genetics and ethnicity. 

  • Japan - incidence 215 per 100,000
  • United States
    • Asians and Pacific Islanders - incidence 30 per 100,000
    • Non-Hispanic African Americans - incidence  17 per 100,000
    • Hispanics - incidence  16 per 100,000
    • Caucasians - incidence  12 per 100,000
  • Age
    • 80-90 percent occur before at 5
    • Uncommon before age 1
    • Rare in adults
  • Gender - Boys represent 60 percent of cases
  • Genetics - 10x increased risk if affected sibling, 2x increased risk of affected parent

KD affects medium sized arteries in the body, with the most profound and long term effects on the coronary arteries. Although the etiology remains unknown, many factors point to KD occurring as the result of an infectious or post-infectious process (ex. KD can occur in epidemics). Of note, KD if left untreated is a self-limiting illness with average fever length of 12 days. However, treatment may drastically decrease the risk of cardiac complications.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Kawasaki syndrome hospitalizations in the United States, 1997 and 2000.
    Holman RC, Curns AT, Belay ED, Steiner CA, Schonberger LB
    Pediatrics. 2003;112(3 Pt 1):495.
  4. Spatial and temporal clustering of Kawasaki syndrome cases.
    Kao AS, Getis A, Brodine S, Burns JC
    Pediatr Infect Dis J. 2008;27(11):981.
  5. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006.
    Son MB, Gauvreau K, Ma L, Baker AL, Sundel RP, Fulton DR, Newburger JW
    Pediatrics. 2009;124(1):1.
  6. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children
    Kawasaki T.
    Arerugi. 1967;16(3):178.
  7. Epidemiologic features of Kawasaki disease in Japan: results of the 2007-2008 nationwide survey.
    Nakamura Y, Yashiro M, Uehara R, Sadakane A, Chihara I, Aoyama Y, Kotani K, Yanagawa H
    J Epidemiol. 2010;20(4):302.
  8. Hospitalizations for Kawasaki syndrome among children in the United States, 1997-2007.
    Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA, Schonberger LB
    Pediatr Infect Dis J. 2010;29(6):483.
  9. Kawasaki syndrome in Denmark.
    Fischer TK, Holman RC, Yorita KL, Belay ED, Melbye M, Koch A
    Pediatr Infect Dis J. 2007;26(5):411.
  10. Epidemiologic features of Kawasaki disease in Taiwan, 2003-2006.
    Huang WC, Huang LM, Chang IS, Chang LY, Chiang BL, Chen PJ, Wu MH, Lue HC, Lee CY, Kawasaki Disease Research Group
    Pediatrics. 2009;123(3):e401.
  11. Epidemiologic pictures of Kawasaki disease in Japan: from the nationwide incidence survey in 1991 and 1992.
    Yanagawa H, Yashiro M, Nakamura Y, Kawasaki T, Kato H
    Pediatrics. 1995;95(4):475.
  12. Acute febrile mucocutaneous lymph node syndrome (Kawasaki disease) in adults: case report and review of the literature.
    Tomiyama J, Hasegawa Y, Kumagai Y, Adachi Y, Karasawa K
    Jpn J Med. 1991;30(3):285.
  13. Kawasaki disease in older children and adolescents.
    Stockheim JA, Innocentini N, Shulman ST
    J Pediatr. 2000;137(2):250.
  14. Characteristics of Kawasaki disease in older children.
    Cai Z, Zuo R, Liu Y
    Clin Pediatr (Phila). 2011;50(10):952.
  15. Kawasaki disease in adults: report of 10 cases.
    Gomard-Mennesson E, Landron C, Dauphin C, Epaulard O, Petit C, Green L, Roblot P, Lusson JR, Broussolle C, Sève P
    Medicine (Baltimore). 2010;89(3):149.
  16. Incidence rate of recurrent Kawasaki disease and related risk factors: from the results of nationwide surveys of Kawasaki disease in Japan.
    Hirata S, Nakamura Y, Yanagawa H
    Acta Paediatr. 2001;90(1):40.
  17. Kawasaki disease in parents and children.
    Uehara R, Yashiro M, Nakamura Y, Yanagawa H
    Acta Paediatr. 2003;92(6):694.
  18. Familial occurrence of Kawasaki syndrome in North America.
    Dergun M, Kao A, Hauger SB, Newburger JW, Burns JC
    Arch Pediatr Adolesc Med. 2005;159(9):876.
  19. Pathogenesis of Kawasaki disease.
    Takahashi K, Oharaseki T, Yokouchi Y
    Clin Exp Immunol. 2011;164 Suppl 1:20.
  20. Kawasaki disease: what is the epidemiology telling us about the etiology?
    Burgner D, Harnden A
    Int J Infect Dis. 2005;9(4):185.

2 Clinical characteristics

As KD does not have a known etiology or diagnostic test, diagnosis is made with the presence of signs of systemic inflammation (fever) in combination with mucocutaneous inflammation (primary supportive criteria). KD may present in a wide variety of forms (even without fever in patients with other signs of KD). However, this pathway uses the criteria of at least 5 days of fever to be included. Four or more of the primary criteria qualify a patient for the classical diagnosis of KD. Two to three criteria places the patient into the situation of incomplete Kawasaki disease.

  • Fever is the most common symptom of KD. It is usually above 38.5 C (101.3 F) and responds minimally to NSAIDs
  • Oral mucous membrane changes often occur later in the course of KD. Ulcers and vesicles are less common with KD and point towards alternative diagnoses
  • The rash of KD usually occurs early in the course of KD and is polymorphous. It often starts with erythema that progress to a macular rash with desquamation.
  • Peripheral extremity changes are common with periungual desquamation occurring in 68-98 percent of patients
  • Cervical lymphadenopathy occurs in 50-75 percent of patients
  • Bilateral bulbar conjunctival injection without exudate occurs in 90 percent of KD patients and often spares the limbus. Patients may also develop anterior uveitis.

KD patients may present with many other complaints as well given the systemic nature of the inflammation. A high clinical suspicion is needed, especially in patients with more than 5 days of fever.

It should be noted that the classical KD criteria where created prior to the understanding of the association between KD and cardiovascular disease and were not developed to capture all patients with potential for cardiovascular complications. Up to 10 percent of patients who progress to coronary artery aneurysms never meet the criteria for KD.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. National surveillance of Kawasaki disease.
    Morens DM, Anderson LJ, Hurwitz ES
    Pediatrics. 1980;65(1):21.
  4. Associated symptoms in the ten days before diagnosis of Kawasaki disease.
    Baker AL, Lu M, Minich LL, Atz AM, Klein GL, Korsin R, Lambert L, Li JS, Mason W, Radojewski E, Vetter VL, Newburger JW, Pediatric Heart Network Investigators
    J Pediatr. 2009;154(4):592.
  5. Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. United States Multicenter Kawasaki Disease Study Group.
    Burns JC, Mason WH, Glode MP, Shulman ST, Melish ME, Meissner C, Bastian J, Beiser AS, Meyerson HM, Newburger JW
    J Pediatr. 1991;118(5):680.
  6. Clinical and epidemiological characteristics of children with Kawasaki disease in Turkey.
    Ozdemir H, Ciftçi E, Tapisiz A, Ince E, Tutar E, Atalay S, Dogru U
    J Trop Pediatr. 2010;56(4):260.
  7. Characteristics of Kawasaki disease in older children.
    Cai Z, Zuo R, Liu Y
    Clin Pediatr (Phila). 2011;50(10):952.
  8. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition).
    Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, Ishii M, Harada K, Kawasaki Disease Research Committee
    Pediatr Int. 2005;47(2):232.
  9. Lack of association of cervical lymphadenopathy and coronary artery complications in Kawasaki disease.
    Sung RY, Ng YM, Choi KC, Mok GC, Cheng YW, Ho MH, Hong Kong Kawasaki Disease Study Group
    Pediatr Infect Dis J. 2006;25(6):521.
  10. Anterior uveitis in Kawasaki disease.
    Germain BF, Moroney JD, Guggino GS, Cimino L, Rodriguez C, Bocanegra TS
    J Pediatr. 1980;97(5):780.
  11. Kawasaki syndrome and the eye.
    Smith LB, Newburger JW, Burns JC
    Pediatr Infect Dis J. 1989;8(2):116.
  12. Periungual desquamation in patients with Kawasaki disease.
    Wang S, Best BM, Burns JC
    Pediatr Infect Dis J. 2009;28(6):538.
  13. Kawasaki disease and cervical adenopathy.
    April MM, Burns JC, Newburger JW, Healy GB
    Arch Otolaryngol Head Neck Surg. 1989;115(4):512.
  14. Update on the treatment of Kawasaki disease in childhood.
    Sundel RP
    Curr Rheumatol Rep. 2002;4(6):474.

3 Incomplete KD

The clinical diagnosis of KD is not 100% sensitive with up to 10 percent of patients who went on to develop coronary artery aneurysms never meeting clinical criteria. This entity is referred to as incomplete KD and is more common in infants and adults presenting with KD. The most common missing criteria in patients diagnosed with incomplete KD are:

  • Cervical lymphadenopathy (90 percent)
  • Rash (50 percent)
  • Peripheral extremity changes (40 percent)
  • Mucous membrane changes (10 percent)

In order to identify patients at risk for coronary artery aneurysms, but who do not reach complete criteria for KD, the American Heart Association and the American Academy of Pediatrics developed a clinical pathway which is mirrored in the pathway shown here. This pathway uses laboratory studies and echocardiography to aid in the diagnosis of these patients and their need for treatment.

Given the complexity of diagnosis and multiple overlapping diagnoses, the provider may consider consultation with pediatric or rheumatologic experts in the workup of these patients.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Atypical and incomplete Kawasaki disease.
    Cimaz R, Sundel R
    Best Pract Res Clin Rheumatol. 2009;23(5):689.
  4. Incidence and clinical features of incomplete Kawasaki disease.
    Fukushige J, Takahashi N, Ueda Y, Ueda K
    Acta Paediatr. 1994;83(10):1057.
  5. Atypical and complicated Kawasaki disease in infants. Do we need criteria?
    Joffe A, Kabani A, Jadavji T
    West J Med. 1995;162(4):322.
  6. Kawasaki disease in adults: report of 10 cases.
    Gomard-Mennesson E, Landron C, Dauphin C, Epaulard O, Petit C, Green L, Roblot P, Lusson JR, Broussolle C, Sève P
    Medicine (Baltimore). 2010;89(3):149.
  7. Kawasaki disease in adult patients
    Sève P, Lega JC
    Rev Med Interne. 2011;32(1):17.
  8. Acute Kawasaki disease: not just for kids.
    Wolff AE, Hansen KE, Zakowski L
    J Gen Intern Med. 2007;22(5):681.
  9. Characteristics of Kawasaki disease in infants younger than six months of age.
    Chang FY, Hwang B, Chen SJ, Lee PC, Meng CC, Lu JH
    Pediatr Infect Dis J. 2006;25(3):241.
  10. Performance of 2004 American Heart Association recommendations for treatment of Kawasaki disease.
    Yellen ES, Gauvreau K, Takahashi M, Burns JC, Shulman S, Baker AL, Innocentini N, Zambetti C, Pancheri JM, Ostrow A, Frazer JR, Sundel RP, Fulton DR, Newburger JW
    Pediatrics. 2010;125(2):e234.

4 Echocardiography

Echocardiography should be performed soon after the diagnosis of KD (including incomplete KD) to assess for coronary artery aneurysms and other cardiac abnormalities associated with KD. This will also provide a baseline for future imaging that will be required 2 to 6 weeks later. One in five patients with untreated KD will go on to develop coronary artery aneurysms. ECG may show some changes associated with coronary artery aneurysms, but is not routine recommended as echocardiography is highly sensitive and will need to be performed in all patients.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Sensitivity, specificity and predictive value of two-dimensional echocardiography in detecting coronary artery aneurysms in patients with Kawasaki disease.
    Capannari TE, Daniels SR, Meyer RA, Schwartz DC, Kaplan S
    J Am Coll Cardiol. 1986;7(2):355.
  4. Coronary artery dimensions may be misclassified as normal in Kawasaki disease.
    de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW
    J Pediatr. 1998;133(2):254.
  5. Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements.
    McCrindle BW, Li JS, Minich LL, Colan SD, Atz AM, Takahashi M, Vetter VL, Gersony WM, Mitchell PD, Newburger JW, Pediatric Heart Network Investigators
    Circulation. 2007;116(2):174.
  6. Kawasaki disease thirty years on.
    Curtis N, Levin M
    Curr Opin Pediatr. 1998;10(1):24.
  7. Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease.
    Nakamura Y, Yashiro M, Uehara R, Watanabe M, Tajimi M, Oki I, Ojima T, Sonobe T, Yanagawa H
    Pediatr Int. 2004;46(1):33.
  8. Kawasaki disease: review of risk factors for coronary aneurysms.
    Koren G, Lavi S, Rose V, Rowe R
    J Pediatr. 1986;108(3):388.
  9. A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group.
    Beiser AS, Takahashi M, Baker AL, Sundel RP, Newburger JW
    Am J Cardiol. 1998;81(9):1116.
  10. Kawasaki syndrome and risk factors for coronary artery abnormalities: United States, 1994-2003.
    Belay ED, Maddox RA, Holman RC, Curns AT, Ballah K, Schonberger LB
    Pediatr Infect Dis J. 2006;25(3):245.

5 Intravenous Immunoglobulin

Intravenous Immunoglobulin (IVIG) is the mainstay treatment of KD and has been shown to be highly cost-effective. It works by decreasing the systemic inflammatory response intrinsic to KD and limiting the likelihood of cardiac complications. It should be given as a single infusion over 8 to 12 hours at a dose of 2g/kg. Patient's maximally benefit if IVIG is given within day 7-10 of fever onset. If the diagnosis is made after day 10, IVIG still may provide benefit.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease.
    Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, Kobayashi T, Morikawa A
    Circulation. 2006;113(22):2606.
  4. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease.
    Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, Matsuishi T
    J Pediatr. 2006;149(2):237.
  5. Performance of 2004 American Heart Association recommendations for treatment of Kawasaki disease.
    Yellen ES, Gauvreau K, Takahashi M, Burns JC, Shulman S, Baker AL, Innocentini N, Zambetti C, Pancheri JM, Ostrow A, Frazer JR, Sundel RP, Fulton DR, Newburger JW
    Pediatrics. 2010;125(2):e234.
  6. High-dose intravenous gammaglobulin for Kawasaki disease.
    Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, Tamura T, Hirose O, Manabe Y, Yokoyama T
    Lancet. 1984;2(8411):1055.
  7. The treatment of Kawasaki syndrome with intravenous gamma globulin.
    Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP
    N Engl J Med. 1986;315(6):341.
  8. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.
    Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, Colan SD, Duffy CE, Fulton DR, Glode MP
    N Engl J Med. 1991;324(23):1633.
  9. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment.
    Durongpisitkul K, Gururaj VJ, Park JM, Martin CF
    Pediatrics. 1995;96(6):1057.
  10. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose.
    Terai M, Shulman ST
    J Pediatr. 1997;131(6):888.
  11. Intravenous immunoglobulin for the treatment of Kawasaki disease in children.
    Oates-Whitehead RM, Baumer JH, Haines L, Love S, Maconochie IK, Gupta A, Roman K, Dua JS, Flynn I
    Cochrane Database Syst Rev. 2003;(4):CD004000.
  12. Economic evaluation of intravenous immune globulin therapy for Kawasaki syndrome.
    Klassen TP, Rowe PC, Gafni A
    J Pediatr. 1993;122(4):538.
  13. Treatment of acute Kawasaki disease: aspirin's role in the febrile stage revisited.
    Hsieh KS, Weng KP, Lin CC, Huang TC, Lee CL, Huang SM
    Pediatrics. 2004;114(6):e689.
  14. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease.
    Tse SM, Silverman ED, McCrindle BW, Yeung RS
    J Pediatr. 2002;140(4):450.
  15. Factors relating to the cardiac sequelae of Kawasaki disease one month after initial onset.
    Zhang T, Yanagawa H, Oki I, Nakamura Y
    Acta Paediatr. 2002;91(5):517.
  16. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan.
    Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, Nakamura Y, Yanagawa H, Matsuishi T
    J Pediatr. 2004;144(4):496.
  17. Late intravenous gamma globulin treatment in infants and children with Kawasaki disease and coronary artery abnormalities.
    Marasini M, Pongiglione G, Gazzolo D, Campelli A, Ribaldone D, Caponnetto S
    Am J Cardiol. 1991;68(8):796.
  18. Late intravenous immunoglobulin treatment in patients with Kawasaki disease.
    Muta H, Ishii M, Yashiro M, Uehara R, Nakamura Y
    Pediatrics. 2012;129(2):e291.

6 Aspirin

Aspirin is recommended in all patients with KD given its antiplatelet and anti-inflammatory effects. It is unclear if aspirin has any effects on coronary artery aneurysms (CAA), but since all IVIG studies that showed decreased incidence of CAA included aspirin, this question as yet cannot be answered (although with retrospective data analysis benefit from aspirin appears unlikely).

The regimen recommended for KD involves a high dose aspirin until the patient has been fever free for 48 hours and then low dose aspirin for 2-3 months. It has been associated with rare complications such as salicylate toxicity and Reye's syndrome, however, the regimen recommended has been optimized to provide maximum benefit with minimum risk of these complications.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Efficacies and risks of aspirin in the treatment of the Kawasaki disease.
    Kusakawa S, Tatara K
    Prog Clin Biol Res. 1987;250:401.
  4. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.
    Brogan PA, Bose A, Burgner D, Shingadia D, Tulloh R, Michie C, Klein N, Booy R, Levin M, Dillon MJ
    Arch Dis Child. 2002;86(4):286.
  5. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association.
    Giglia TM, Massicotte MP, Tweddell JS, Barst RJ, Bauman M, Erickson CC, Feltes TF, Foster E, Hinoki K, Ichord RN, Kreutzer J, McCrindle BW, Newburger JW, Tabbutt S, Todd JL, Webb CL, American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, and Stroke Council
    Circulation. 2013;128(24):2622.
  6. The treatment of Kawasaki syndrome with intravenous gamma globulin.
    Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP
    N Engl J Med. 1986;315(6):341.
  7. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome.
    Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, Colan SD, Duffy CE, Fulton DR, Glode MP
    N Engl J Med. 1991;324(23):1633.
  8. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.
    Brogan PA, Bose A, Burgner D, Shingadia D, Tulloh R, Michie C, Klein N, Booy R, Levin M, Dillon MJ
    Arch Dis Child. 2002;86(4):286.
  9. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose.
    Terai M, Shulman ST
    J Pediatr. 1997;131(6):888.
  10. Treatment of acute Kawasaki disease: aspirin's role in the febrile stage revisited.
    Hsieh KS, Weng KP, Lin CC, Huang TC, Lee CL, Huang SM
    Pediatrics. 2004;114(6):e689.
  11. Hemolytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases.
    Berard R, Whittemore B, Scuccimarri R
    Pediatr Rheumatol Online J. 2012;10(1):10.
  12. Decreased protein binding of salicylates in Kawasaki disease.
    Koren G, Silverman E, Sundel R, Edney P, Newburger JW, Klein J, Robieux I, Laxer R, Giesbrecht E, Burns JC
    J Pediatr. 1991;118(3):456.
  13. Kawasaki disease with Reye syndrome: report of one case.
    Lee JH, Hung HY, Huang FY
    Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1992 Jan-Feb;33(1):67-71.
  14. Reye's syndrome developing in an infant on treatment of Kawasaki syndrome.
    Wei CM, Chen HL, Lee PI, Chen CM, Ma CY, Hwu WL
    J Paediatr Child Health. 2005;41(5-6):303.

7 Refractory KD

10 to 15 percent of patients treated for KD will have return of fever within 48 hours. Generally, refractory KD is suspected with fever (of any magnitute) returns after 36 hours until 2 weeks after the treatment for KD has begun. These patients have an increased risk of developing coronary artery abnormalities if not retreated with IVIG. 

Providers should be alert for other causes of persistant fever, including missed infectious diagnosis, macrophage activating syndrome (associated with KD) or other rheumatologic disease processess.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Intravenous gamma-globulin treatment and retreatment in Kawasaki disease. US/Canadian Kawasaki Syndrome Study Group.
    Burns JC, Capparelli EV, Brown JA, Newburger JW, Glode MP
    Pediatr Infect Dis J. 1998;17(12):1144.
  4. Late development of coronary artery abnormalities could be associated with persistence of non-fever symptoms in Kawasaki disease.
    Fukuda S, Ito S, Oana S, Sakai H, Kato H, Abe J, Ito R, Saitoh A, Takayama JI
    Pediatr Rheumatol Online J. 2013;11(1):28.
  5. Re-treatment for immune globulin-resistant Kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy.
    Hashino K, Ishii M, Iemura M, Akagi T, Kato H
    Pediatr Int. 2001;43(3):211.
  6. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan.
    Uehara R, Belay ED, Maddox RA, Holman RC, Nakamura Y, Yashiro M, Oki I, Ogino H, Schonberger LB, Yanagawa H
    Pediatr Infect Dis J. 2008;27(2):155.
  7. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease.
    Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, Matsuishi T
    J Pediatr. 2006;149(2):237.
  8. Resistance to intravenous immunoglobulin in children with Kawasaki disease.
    Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, Martin DD, Newburger JW, Burns JC
    J Pediatr. 2008;153(1):117.
  9. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease.
    Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, Kobayashi T, Morikawa A
    Circulation. 2006;113(22):2606.
  10. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance.
    Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, Atz AM, Printz BF, Baker A, Vetter VL, Newburger JW, Pediatric Heart Network Investigators
    J Pediatr. 2011 May;158(5):831-835.e3.
  11. Trial of prevention of coronary aneurysm in Kawasaki's disease using plasma exchange or infusion of immunoglobulins
    Villain E, Kachaner J, Sidi D, Blaysat G, Piéchaud JF, Pedroni E
    Arch Fr Pediatr. 1987;44(2):79.
  12. Risk factors for nonresponse to therapy in Kawasaki disease.
    Ashouri N, Takahashi M, Dorey F, Mason W
    J Pediatr. 2008;153(3):365.
  13. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006.
    Son MB, Gauvreau K, Ma L, Baker AL, Sundel RP, Fulton DR, Newburger JW
    Pediatrics. 2009;124(1):1.

8 Adjunct therapies

Several other agents have been found useful in patients with refractory KD, however they appear to not significantly decrease the risk of coronary artery abnormalities in patients responsive to IVIG. The most commonly studied (steroids) have shown benefit in patients resistant to IVIG. Steroids are not routinely recommended for initial treatment of patients with KD. Given the complexity and potential side effects of these treatments, an expert in KD (rheumatology, ID, etc.) should be consulted prior to initiating these modalities.



References:
  1. Kawasaki syndrome.
    Burns JC, Glodé MP.
    Lancet. 2004;364(9433):533.
  2. 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.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA, Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association, American Academy of Pediatrics
    Circulation. 2004;110(17):2747.
  3. Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids.
    Wright DA, Newburger JW, Baker A, Sundel RP
    J Pediatr. 1996;128(1):146.
  4. Kawasaki disease resistant to immunoglobulin G therapy.
    Venugopalan P, Jaya S, Al-Azri MA, Piopongco E
    Ann Trop Paediatr. 2003;23(3):187.
  5. Response of refractory Kawasaki disease to pulse steroid and cyclosporin A therapy.
    Raman V, Kim J, Sharkey A, Chatila T
    Pediatr Infect Dis J. 2001;20(6):635.
  6. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006.
    Son MB, Gauvreau K, Ma L, Baker AL, Sundel RP, Fulton DR, Newburger JW
    Pediatrics. 2009;124(1):1.
  7. Massive lymphadenopathy and airway obstruction in a child with Kawasaki disease: success with pulse steroid therapy.
    Shetty AK, Homsi O, Ward K, Gedalia A
    J Rheumatol. 1998;25(6):1215.
  8. Re-treatment for immune globulin-resistant Kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy.
    Hashino K, Ishii M, Iemura M, Akagi T, Kato H
    Pediatr Int. 2001;43(3):211.
  9. Effects of steroid pulse therapy on immunoglobulin-resistant Kawasaki disease.
    Furukawa T, Kishiro M, Akimoto K, Nagata S, Shimizu T, Yamashiro Y
    Arch Dis Child. 2008;93(2):142.
  10. Steroid pulse therapy for children with intravenous immunoglobulin therapy-resistant Kawasaki disease: a prospective study.
    Teraguchi M, Ogino H, Yoshimura K, Taniuchi S, Kino M, Okazaki H, Kaneko K
    Pediatr Cardiol. 2013 Apr;34(4):959-63.
  11. Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor alpha among patients with Kawasaki disease.
    Lin CY, Lin CC, Hwang B, Chiang B
    J Pediatr. 1992;121(6):924.
  12. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease.
    Burns JC, Best BM, Mejias A, Mahony L, Fixler DE, Jafri HS, Melish ME, Jackson MA, Asmar BI, Lang DJ, Connor JD, Capparelli EV, Keen ML, Mamun K, Keenan GF, Ramilo O
    J Pediatr. 2008;153(6):833.
  13. Infliximab for intravenous immunoglobulin resistance in Kawasaki disease: a retrospective study.
    Son MB, Gauvreau K, Burns JC, Corinaldesi E, Tremoulet AH, Watson VE, Baker A, Fulton DR, Sundel RP, Newburger JW
    J Pediatr. 2011;158(4):644.
  14. Infliximab plus plasma exchange rescue therapy in Kawasaki disease.
    Sonoda K, Mori M, Hokosaki T, Yokota S
    J Pediatr. 2014;164(5):1128.
  15. Infliximab reduces the cytokine-mediated inflammation but does not suppress cellular infiltration of the vessel wall in refractory Kawasaki disease.
    Hirono K, Kemmotsu Y, Wittkowski H, Foell D, Saito K, Ibuki K, Watanabe K, Watanabe S, Uese K, Kanegane H, Origasa H, Ichida F, Roth J, Miyawaki T, Saji T
    Pediatr Res. 2009;65(6):696.
  16. Catastrophic Kawasaki disease unresponsive to IVIG in a 3-month-old infant: a diagnostic and therapeutic challenge.
    de Magalhães CM, Alves NR, de Melo AV, Junior CA, Nόbrega YK, Gandolfi L, Pratesi R
    Pediatr Rheumatol Online J. 2012;10(1):28.
  17. Pentoxifylline and intravenous gamma globulin combination therapy for acute Kawasaki disease.
    Furukawa S, Matsubara T, Umezawa Y, Motohashi T, Ino T, Yabuta K
    Eur J Pediatr. 1994;153(9):663.
  18. Trial of prevention of coronary aneurysm in Kawasaki's disease using plasma exchange or infusion of immunoglobulins
    Villain E, Kachaner J, Sidi D, Blaysat G, Piéchaud JF, Pedroni E
    Arch Fr Pediatr. 1987;44(2):79.
  19. Exchange transfusion in a case of Kawasaki syndrome
    Netter JC, Fries F, Rajon AM, Carrière JP, Dalous A
    Arch Fr Pediatr. 1982;39(9):699.
  20. Plasma exchange for refractory Kawasaki disease.
    Imagawa T, Mori M, Miyamae T, Ito S, Nakamura T, Yasui K, Kimura H, Yokota S
    Eur J Pediatr. 2004;163(4-5):263.
  21. Initial intravenous gammaglobulin treatment failure in Kawasaki disease.
    Wallace CA, French JW, Kahn SJ, Sherry DD
    Pediatrics. 2000;105(6):E78.
  22. Cyclosporin A treatment for Kawasaki disease refractory to initial and additional intravenous immunoglobulin.
    Suzuki H, Terai M, Hamada H, Honda T, Suenaga T, Takeuchi T, Yoshikawa N, Shibuta S, Miyawaki M, Oishi K, Yamaga H, Aoyagi N, Iwahashi S, Miyashita R, Onouchi Y, Sasago K, Suzuki Y, Hata A
    Pediatr Infect Dis J. 2011 Oct;30(10):871-6.
  23. Resistant Kawasaki disease treated with anti-CD20.
    Sauvaget E, Bonello B, David M, Chabrol B, Dubus JC, Bosdure E
    J Pediatr. 2012;160(5):875.

9 Concurrent Respiratory Viruses

Studies show no differences in clinical presentations or outcomes in children with KD stratified according to positive or negative respiratory viral PCR testing.



References:
  1. Concurrent Respiratory Viruses and Kawasaki Disease.
    Turnier JL, Anderson MS, Heizer HR, Jone PN, Glodé MP, Dominguez SR.
    Pediatrics. 2015 Sep;136(3):e609-14.
  2. Detection rate and clinical impact of respiratory viruses in children with Kawasaki disease.
    Kim JH, Yu JJ, Lee J, Kim MN, Ko HK, Choi HS, Kim YH, Ko JK,
    Korean J Pediatr 2012 Dec;55(12):470-3.