Current Infectious Disease Reports

, Volume 12, Issue 2, pp 96–102 | Cite as

Recent Advances in the Understanding and Management of Kawasaki Disease



Kawasaki disease (KD) is an acute systemic inflammatory illness of childhood that can result in coronary artery aneurysms, myocardial infarction, and sudden death. Clinical and epidemiologic data point to an unknown infectious agent as the cause. We discovered that an oligoclonal IgA immune response is present in arterial tissue in acute KD. Synthetic versions of prevalent IgA antibodies in the KD arterial wall identify cytoplasmic inclusion bodies in acute KD ciliated bronchial epithelium and other inflamed KD tissues. Light and electron microscopic studies show that the inclusion bodies are consistent with aggregates of viral protein and RNA, and are likely formed by the KD etiologic agent. KD susceptibility is likely to be polygenic. Treatment of gammaglobulin nonresponders usually consists of additional intravenous immunoglobulin, methylprednisolone, and/or infliximab. Additional data regarding KD pathogenesis are urgently needed to provide other targets for therapy for those patients at highest risk of developing coronary artery abnormalities.


IgA Inclusion bodies Intravenous immunoglobulin Coronary artery aneurysm 



No potential conflict of interest relevant to this article was reported.


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

  1. 1.
    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. Pediatrics 2004, 114:1708–1733.CrossRefPubMedGoogle Scholar
  2. 2.
    Rowley AH, Baker SC, Shulman ST, et al.: Detection of antigen in bronchial epithelium and macrophages in acute Kawasaki disease by use of synthetic antibody. J Infect Dis 2004, 190:856–865.CrossRefPubMedGoogle Scholar
  3. 3.
    Rowley AH: Incomplete (atypical) Kawasaki disease. Pediatr Infect Dis J 2002, 21:563–565.CrossRefPubMedGoogle Scholar
  4. 4.
    Newburger JW, Takahashi M, Beiser AS, et al.: A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991, 324:1633–1639.PubMedGoogle Scholar
  5. 5.
    Freeman AF, Shulman ST: Refractory Kawasaki disease. Pediatr Infect Dis J 2004, 23:463–464.CrossRefPubMedGoogle Scholar
  6. 6.
    Kawasaki T: [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. Arerugi 1967, 16:178–222.PubMedGoogle Scholar
  7. 7.
    Landing BH, Larson EJ: Are infantile periarteritis nodosa with coronary artery involvement and fatal mucocutaneous lymph node syndrome the same? Comparison of 20 patients from North America with patients from Hawaii and Japan. Pediatrics 1977, 59:651–662.PubMedGoogle Scholar
  8. 8.
    Amano S, Hazama F, Hamashima Y: Pathology of Kawasaki disease: I. Pathology and morphogenesis of the vascular changes. Jpn Circ J 1979, 43:633–643.PubMedGoogle Scholar
  9. 9.
    Amano S, Hazama F, Hamashima Y: Pathology of Kawasaki disease: II. Distribution and incidence of the vascular lesions. Jpn Circ J 1979, 43:741–748.PubMedGoogle Scholar
  10. 10.
    Amano S, Hazama F, Kubagawa H, et al.: General pathology of Kawasaki disease. On the morphological alterations corresponding to the clinical manifestations. Acta Pathol Jpn 1980, 30:681–694.PubMedGoogle Scholar
  11. 11.
    Fatica NS, Ichida F, Engle MA, Lesser ML: Rug shampoo and Kawasaki disease. Pediatrics 1989, 84:231–234.PubMedGoogle Scholar
  12. 12.
    Ohga K, Yamanaka R, Kinumaki H, et al.: Kawasaki disease and rug shampoo. Lancet 1983, 1:930.CrossRefPubMedGoogle Scholar
  13. 13.
    Nash MC, Shah V, Reader JA, Dillon MJ: Anti-neutrophil cytoplasmic antibodies and anti-endothelial cell antibodies are not increased in Kawasaki disease. Br J Rheumatol 1995, 34:882–887.CrossRefPubMedGoogle Scholar
  14. 14.
    Yanagawa H, Nakamura Y, Kawasaki T, Shigematsu I: Nationwide epidemic of Kawasaki disease in Japan during winter of 1985–86. Lancet 1986, 2:1138–1139.CrossRefPubMedGoogle Scholar
  15. 15.
    Rowley AH, Shulman ST, Spike BT, et al.: Oligoclonal IgA response in the vascular wall in acute Kawasaki disease. J Immunol 2001, 166:1334–1343.PubMedGoogle Scholar
  16. 16.
    Lee HH, Shin JS, Kim DS: Immunoglobulin V(H) chain gene analysis of peripheral blood IgM-producing B cells in patients with Kawasaki disease. Yonsei Med J 2009, 50:493–504.CrossRefPubMedGoogle Scholar
  17. 17.
    Choi IH, Chwae YJ, Shim WS, et al.: Clonal expansion of CD8+ T cells in Kawasaki disease. J Immunol 1997, 159:481–486.PubMedGoogle Scholar
  18. 18.
    Suenaga T, Suzuki H, Shibuta S, et al.: Detection of multiple superantigen genes in stools of patients with Kawasaki disease. J Pediatr 2009, 155:266–270.CrossRefPubMedGoogle Scholar
  19. 19.
    •• Rowley AH, Baker SC, Orenstein JM, Shulman ST: Searching for the cause of Kawasaki disease—cytoplasmic inclusion bodies provide new insight. Nat Rev Microbiol 2008, 6:394–401. This article reviews etiologic, pathologic, and immunologic studies in KD, including the discovery that viral-like cytoplasmic inclusion bodies are present in KD tissues, and proposes a model of KD pathogenesis.Google Scholar
  20. 20.
    Rowley AH, Eckerley CA, Jack HM, et al.: IgA plasma cells in vascular tissue of patients with Kawasaki syndrome. J Immunol 1997, 159:5946–5955.PubMedGoogle Scholar
  21. 21.
    Rowley AH, Shulman ST, Mask CA, et al.: IgA plasma cell infiltration of proximal respiratory tract, pancreas, kidney, and coronary artery in acute Kawasaki disease. J Infect Dis 2000, 182:1183–1191.CrossRefPubMedGoogle Scholar
  22. 22.
    Brown TJ, Crawford SE, Cornwall ML, et al.: CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. J Infect Dis 2001, 184:940–943.CrossRefPubMedGoogle Scholar
  23. 23.
    Rowley AH, Shulman ST, Garcia FL, et al.: Cloning the arterial IgA antibody response during acute Kawasaki disease. J Immunol 2005, 175:8386–8391.PubMedGoogle Scholar
  24. 24.
    Rowley AH, Baker SC, Shulman ST, et al.: Cytoplasmic inclusion bodies are detected by synthetic antibody in ciliated bronchial epithelium during acute Kawasaki disease. J Infect Dis 2005, 192:1757–1766.CrossRefPubMedGoogle Scholar
  25. 25.
    • Rowley AH, Baker SC, Shulman ST, et al.: RNA-containing cytoplasmic inclusion bodies in ciliated bronchial epithelium months to years after acute Kawasaki disease. PLoS ONE 2008, 3:e1582. This article describes a study demonstrating the presence of RNA-containing cytoplasmic inclusion bodies in 85% of acute and late-stage KD fatalities, and in 25% of adult controls, consistent with the hypothesis that KD is the result of infection with a previously unidentified, ubiquitous, persistent RNA virus.Google Scholar
  26. 26.
    Holman RC, Curns AT, Belay ED, et al.: Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics 2003, 112(3 Pt 1):495–501.CrossRefPubMedGoogle Scholar
  27. 27.
    Nakamura Y, Yashiro M, Uehara R, et al.: Epidemiologic features of Kawasaki disease in Japan: results from the nationwide survey in 2005–2006. J Epidemiol 2008, 18:167–172.CrossRefPubMedGoogle Scholar
  28. 28.
    Onouchi Y, Tamari M, Takahashi A, et al.: A genomewide linkage analysis of Kawasaki disease: evidence for linkage to chromosome 12. J Hum Genet 2007, 52:179–190.CrossRefPubMedGoogle Scholar
  29. 29.
    • Onouchi Y, Gunji T, Burns JC, et al.: ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 2008, 40:35–42. This study shows an association between a polymorphism of ITPKC that results in inefficient downregulation of T-lymphocyte activation and susceptibility both to KD and to the development of coronary artery abnormalities.Google Scholar
  30. 30.
    •• Onouchi Y: Molecular genetics of Kawasaki disease. Pediatr Res 2009, 65(5 Pt 2):46R–54R. This article is an outstanding review of the history of genetics studies in KD, and a discussion of future research in this area.Google Scholar
  31. 31.
    Burgner D, Davila S, Breunis WB, et al.: A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet 2009, 5:e1000319.CrossRefPubMedGoogle Scholar
  32. 32.
    Newburger JW, Takahashi M, Burns JC, et al.: The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986, 315:341–347.PubMedCrossRefGoogle Scholar
  33. 33.
    •• 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, 356:663–675. This study demonstrated a lack of efficacy of intravenous methylprednisolone with IVIG and aspirin as compared with IVIG and aspirin alone as primary therapy of KD.Google Scholar
  34. 34.
    Asai T: Evaluation method for the degree of seriousness in Kawasaki disease. Acta Paediatr Jpn 1983, 25:170–175.Google Scholar
  35. 35.
    Sundel RP, Burns JC, Baker A, et al.: Gamma globulin re-treatment in Kawasaki disease. J Pediatr 1993, 123:657–659.CrossRefPubMedGoogle Scholar
  36. 36.
    Wallace CA, French JW, Kahn SJ, Sherry DD: Initial intravenous gammaglobulin treatment failure in Kawasaki disease. Pediatrics 2000, 105:E78.CrossRefPubMedGoogle Scholar
  37. 37.
    Kusakawa S, Tatara K: Efficacies and risks of aspirin in the treatment of the Kawasaki disease. Prog Clin Biol Res 1987, 250:401–413.PubMedGoogle Scholar
  38. 38.
    Furukawa T, Kishiro M, Akimoto K, et al.: Effects of steroid pulse therapy on immunoglobulin-resistant Kawasaki disease. Arch Dis Child 2008, 93:142–146.CrossRefPubMedGoogle Scholar
  39. 39.
    Lang BA, Yeung RS, Oen KG, et al.: Corticosteroid treatment of refractory Kawasaki disease. J Rheumatol 2006, 33:803–809.PubMedGoogle Scholar
  40. 40.
    Wright DA, Newburger JW, Baker A, Sundel RP: Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids. J Pediatr 1996, 128:146–149.CrossRefPubMedGoogle Scholar
  41. 41.
    Hashino K, Ishii M, Iemura M, et al.: Re-treatment for immune globulin-resistant Kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy. Pediatr Int 2001, 43:211–217.CrossRefPubMedGoogle Scholar
  42. 42.
    Maury CP, Salo E, Pelkonen P: Elevated circulating tumor necrosis factor-alpha in patients with Kawasaki disease. J Lab Clin Med 1989, 113:651–654.PubMedGoogle Scholar
  43. 43.
    Matsubara T, Furukawa 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, 56:29–36.CrossRefPubMedGoogle Scholar
  44. 44.
    Burns JC, Mason WH, Hauger SB, et al.: Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005, 146:662–667.CrossRefPubMedGoogle Scholar
  45. 45.
    Burns JC, Best BM, Mejias A, et al.: Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr 2008, 153:833–838.CrossRefPubMedGoogle Scholar
  46. 46.
    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.CrossRefPubMedGoogle Scholar
  47. 47.
    Lee TJ, Kim KH, Chun JK, Kim DS: Low-dose methotrexate therapy for intravenous immunoglobulin-resistant Kawasaki disease. Yonsei Med J 2008, 49:714–718.CrossRefPubMedGoogle Scholar
  48. 48.
    Mori M, Imagawa T, Katakura S, et al.: Efficacy of plasma exchange therapy for Kawasaki disease intractable to intravenous gamma-globulin. Mod Rheumatol 2004, 14:43–47.CrossRefPubMedGoogle Scholar
  49. 49.
    Terai M, Kohno Y, Niwa K, et al.: Imbalance among T-cell subsets in patients with coronary arterial aneurysms in Kawasaki disease. Am J Cardiol 1987, 60:555–559.CrossRefPubMedGoogle Scholar
  50. 50.
    Terai M, Yasukawa K, Honda T, et al.: Peripheral blood eosinophilia and eosinophil accumulation in coronary microvessels in acute Kawasaki disease. Pediatr Infect Dis J 2002, 21:777–781.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of PediatricsNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.The Division of Infectious DiseasesThe Children’s Memorial HospitalChicagoUSA

Personalised recommendations