Kawasaki Disease: Pathophysiology, Clinical Manifestations, and Management

  • Victoria R. Dimitriades
  • Amanda G. Brown
  • Abraham Gedalia
Part of the following topical collections:
  1. Topical Collection on Vasculitis


Kawasaki Disease, a systemic vasculitis of unknown origin with specific predilection for the coronary arteries, is the most common cause of childhood-acquired heart disease in western countries. Despite its world-wide incidence, the pathophysiology of this enigmatic disease is still under investigation. Diagnosis is made on a clinical basis, with supportive laboratory evidence and imaging. Once identified, timely initiation of treatment is imperative in order to quell the inflammatory response and decrease the incidence of long-term sequelae, specifically coronary artery aneurysms. Finally, longitudinal follow-up should be implemented based on risk stratification and individualized to each patient.


Kawasaki disease Coronary artery Aneurysm Vasculitis Immunoglobulin Corticosteroids IVIg resistance Pathophysiology Clinical manifestations Management Treatment Etiology Diagnosis 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. 1967;16(3):178–222. Japanese.PubMedGoogle Scholar
  2. 2.
    Callinan LS, Holman RC, Vugia DJ, Schonberger LB, Belay ED. Kawasaki disease hospitalization rate among children younger than 5 years of age in California, 2003-2010. Pediatr Infect Dis J. 2014 Jan 24.Google Scholar
  3. 3.
    Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J Epidemiol. 2012;22(2):79–85.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Uehara R, Yashiro M, Nakamura Y, Yanagawa H. Parents with a history of Kawasaki disease whose child also had the same disease. Pediatr Int. 2011;53(4):511–4.PubMedCrossRefGoogle Scholar
  5. 5.•
    Onouchi Y. Genetics of Kawasaki Disease; what we know and don’t know. Circ J. 2012;76:1581–6. Review of genome-wide linkage studies to clarify the genetic background of patients as well as to delineate susceptibility factors for KD in relation to etiologic factors.PubMedCrossRefGoogle Scholar
  6. 6.
    Khor CC, Davila S, Breunis WB, et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki Disease. Nat Genet. 2011;43:1241–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Khor CC, Davila S, Shimisu C, et al. Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki Disease. J Med Genet. 2011;48:467–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Kuo HC, Chang WC. Genetic polymorphisms in Kawasaki disease. Acta Pharmacol Sin. 2011;32(10):1193–8.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.••
    Jaggi P, Kajon A, Mejias A, et al. Human Adenovirus infection in Kawasaki Disease: a confounding bystander? Clin Inf Dis. 2012;56:57–63. A study reporting on the rate of confounding and concomitant adenoviral infections in the setting of KD.Google Scholar
  10. 10.
    Burns JC, Herzog L, Fabri O, et al. Seasonality of Kawasaki disease: a global perspective. PLoS One. 2013;8(9):e74529.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Yaganawa H, Yashiro M, Nakamura Y, et al. Nationwide surveillance of Kawasaki disease in Japan. Pediatr Infect Dis J. 1995;14:69–71.Google Scholar
  12. 12.
    Gedalia A. Kawasaki disease: 40 years after the original report. Curr Rheumatol Rep. 2007;9(4):336–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Rowley A. Kawasaki disease: novel Insights into etiology and genetic susceptibility. Ann Rev Med. 2011;62:69–77.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Meissner HC, Leung DY. Superantigens, conventional antigens and etiology of Kawasaki syndrome. Ped Infect Dis J. 2000;19:91–4.CrossRefGoogle Scholar
  15. 15.•
    Rowley AH, Baker SC, Shulman ST, et al. Ultrastructural, immunofluorescence, and RNA evidence support the hypothesis of a "new" virus associated with Kawasaki disease. J Infect Dis. 2011;203(7):1021–30. Report on evidence of intracytoplasmic inclusion bodies in the ciliated epithelia of KD patients which are presumed to be virally induced by an unidentified strain of RNA virus.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Yeung RS. Kawasaki disease: update on pathogenesis. Curr Opin Rheumatol. 2010;22(5):551–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Jia S, Li C, Wang G, Yang J, Zu Y. The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease. Clin Exp Immunol. 2010;162(1):131–7.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Newburger JW, Takahashi M, Gerber MA. 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(6):1708–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Ha KS, Jang G, Lee J. Incomplete clinical manifestation as a risk factor for coronary artery abnormalities in Kawasaki disease: a meta-analysis. Eur J Pediatr. 2013;172(3):343–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Yellen ES, Gauvreau K, Takahashi M. Performance of 2004 American Heart Association recommendations for treatment of Kawasaki disease. Pediatrics. 2010;125(2):e234–41.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Scuccimarri R. Kawasaki disease. Pediatr Clin N Am. 2012;59:425–45.CrossRefGoogle Scholar
  22. 22.
    Jordan-Villegas A, Chang ML, Ramilo O, Mejías A. Concomitant respiratory viral infections in children with Kawasaki disease. Pediatr Infect Dis J. 2010;29(8):770–2.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Beiser AS, Takahasha M, Baker AL, et al. A predictive instrument for coronary artery aneurysms in Kawasaki disease. Am J Cardiol. 1998;81:1116–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149:237–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Kobayashi T, Inoue I, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–12.PubMedCrossRefGoogle Scholar
  26. 26.
    Sano T, Kurotobi S, Matsuzaki K, et al. Prediction of nonresponsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr. 2007;166:131–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Sleeper LA, Minich LL, McCrindle BM, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr. 2011;158:831–835.e3.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.•
    Dominquez SR, Anderson MS. Advances in the treatment of Kawasaki Disease. Curr Opin Pediatr. 2013;25(1):103–9. A thorough review of recent evolution of treatment strategies and risk stratification systems used in the management of KD.CrossRefGoogle Scholar
  29. 29.
    Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gammaglobulin as compared with four infusions in treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324:1633–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Kato H, Koike S, Yokoyama T. Kawasaki disease: effect of treatment on coronary artery involvement. Pediatrics. 1979;63:175–9.PubMedGoogle Scholar
  31. 31.
    Inoue Y, Okada Y, Shinohara M, et al. Multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr. 2006;149:336–41.PubMedCrossRefGoogle Scholar
  32. 32.
    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;356:663–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Ogata S, Ogihara Y, Honda T, et al. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial. Pediatrics. 2012;129:e17–23.PubMedCrossRefGoogle Scholar
  34. 34.••
    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 randomized, open-label, blinded-endpoints trial. Lancet. 2012;379:1613–20. A randomized study looking at use of corticosteroids at lower doses but for longer times as an adjunct to IVIg/aspirin in high risk groups in Japan. This study showed a lower incidence of retreatment as well as a lower rate of coronary abnormalities in the steroid treatment group.PubMedCrossRefGoogle Scholar
  35. 35.
    Son MD, Newburger JW. Management of Kawasaki disease: corticosteroids revisited. Lancet. 2012;379:1571–2.PubMedCrossRefGoogle Scholar
  36. 36.
    Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr. 2005;146:662–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Son MB, Gauvreau K, Burns J, et al. Infliximab for intravenous immunoglobulin resistance in Kawasaki disease: a retrospective study. J Pediatr. 2011;158:644–649.e1.PubMedCrossRefGoogle Scholar
  38. 38.
    Son MB, Gauvreau K, Ma L, et al. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics. 2009;124:1–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Matsubara T, Furunkawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions. Clin Immunol Immunopathol. 1990;56(1):29–36.PubMedCrossRefGoogle Scholar
  40. 40.•
    Tremoulet AH, Jain S, Jaggi P, et al. Infliximab for intensification of primary therapy for Kawasaki Disease: a phase 3 randomized, double-blind, placebo-controlled trial. Lancet. 2014 Feb 24, pub online. This study showed that adding a dose of infliximab prior to the IVIG treatment did not reduce the IVIG treatment resistance as measured by coronary artery z scores at 5 weeks, although reduction of fever and inflammatory markers were significantly more pronounced in the infliximab group.Google Scholar
  41. 41.
    Choueiter NF, Olson AK, Shen DD, et al. Prospective open-label trial of etanercept as adjunctive therapy for kawasaki disease. J Pediatr. 2010;157(6):960–966.e1.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Portman MA, Olson A, Soriano B, et al. Etanercept as adjunctive treatment for acute Kawasaki disease: study design and rationale. Am Heart J. 2011;161(3):494–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Tremoulet AH, Pancoast P, Franco A, et al. Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. 2012;161:506–12.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Hokosaki T, Mori M, Nishizawa T, et al. Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease. Pedaiatr Int. 2012;54:99–103.CrossRefGoogle Scholar
  45. 45.
    Sauvaget E, Bonello B, David M, et al. Resistant Kawasaki disease treated with anti-CD 20. J Pediatr. 2012;160:875–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Sonoda K, Mori M, Hokosaki T, et al. Infliximab plus plasma exchange rescue therapy in Kawasaki Disease. J Pediatrics. 2014 Feb 19, pub onlineGoogle Scholar
  47. 47.
    Eleftheriou D, Levin M, Shingadia D, et al. Management of Kawasaki disease. Arch Dis Child. 2014;99:74–83.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Kavey RE, Allada V, Daniels SR. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114(24):2710–38.PubMedCrossRefGoogle Scholar
  49. 49.
    Nakamura Y, Aso E, Yashiro M, et al. Mortality among Japanese with a history of Kawasaki disease: results at the end of 2009. J Epidemiol. 2013;23(6):429–34.PubMedCrossRefGoogle Scholar
  50. 50.••
    Manlhiot C, Niedra E, McCrindle BW. Long-term management of Kawasaki disease: implications for the adult patient. Pediatr Neonatol. 2013;54(1):12–21. A review of the current recommendations for long-term follow-up of KD patients based on risk. Also reviewed are use of newer modalities of imaging which are less invasive and may be more tolerated for frequent evaluations in patients at higher risk.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Victoria R. Dimitriades
    • 1
  • Amanda G. Brown
    • 1
  • Abraham Gedalia
    • 1
    • 2
  1. 1.Division of Pediatric Rheumatology, Departments of PediatricsLSU Health Sciences Center and Children’s HospitalNew OrleansUSA
  2. 2.Department of Pediatrics/RheumatologyChildren’s HospitalNew OrleansUSA

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