Pathophysiology of Kawasaki Disease

  • Anne H. RowleyEmail author
  • Stanford T. Shulman
  • Jan M. Orenstein


Kawasaki Disease (KD) vasculopathy, which most significantly affects the coronary arteries, is characterized by three linked pathological processes: necrotizing arteritis, subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). Necrotizing arteritis (NA), initiated at the endothelial luminal surface, leads to giant aneurysms that can rupture or thrombose. SA/C vasculitis begins in the adventitia and is closely associated with LMP. LMP consists of actively proliferating smooth muscle cell-derived myofibroblasts and their matrix products, and can result in progressive arterial luminal stenosis. All three processes begin in the first 2 weeks after fever onset. NA subsides in the first 2 weeks, while subacute/chronic vasculitis and LMP can persist for months or years. The clinical and epidemiological features of KD are best explained by infection with an as-yet-unidentified ubiquitous agent, likely a virus entering via the respiratory route. Recent advances in genomics and RNA sequencing are beginning to reveal specific immune response dysfunction in KD that could lead to new diagnostics and therapeutics for this important childhood illness.


Necrotizing arteritis Subacute/chronic vasculitis Luminal myofibroblastic proliferation Pathology Gene expression 


  1. 1.
    Orenstein JM, Shulman ST, Fox LM, Baker SC, Takahashi M, Bhatti TR, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One. 2012;7(6):e38998. PMID:22723916.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Fujiwara H, Hamashima Y. Pathology of the heart in Kawasaki disease. Pediatrics. 1978;61(1):100–7. PMID:263836.PubMedGoogle Scholar
  3. 3.
    Amano S, Hazama F, Hamashima Y. Pathology of Kawasaki disease: I. Pathology and morphogenesis of the vascular changes. Jpn Circ J. 1979;43(7):633–43. PMID:41111.CrossRefPubMedGoogle Scholar
  4. 4.
    Kuijpers TW, Biezeveld M, Achterhuis A, Kuipers I, Lam J, Hack CE, et al. Longstanding obliterative panarteritis in Kawasaki disease: lack of cyclosporin A effect. Pediatrics. 2003;112(4):986–92. PMID:14523200.CrossRefPubMedGoogle Scholar
  5. 5.
    Burke AP, Virmani R, Perry LW, Li L, King TM, Smialek J. Fatal Kawasaki disease with coronary arteritis and no coronary aneurysms. Pediatrics. 1998;101(1 Pt 1):108–12. PMID:9417162.CrossRefPubMedGoogle Scholar
  6. 6.
    Satoda M, Tatsukawa H, Katoh S. Images in cardiovascular medicine. Sudden death due to rupture of coronary aneurysm in a 26-year-old man. Circulation. 1998;97(7):705–6. PMID:9495308.CrossRefPubMedGoogle Scholar
  7. 7.
    Heaton P, Wilson N. Fatal Kawasaki disease caused by early occlusive coronary artery disease. Arch Dis Child. 2002;87(2):145–6. PMID:12138067.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ozawa J, Suzuki H, Hasegawa S, Numano F, Haniu H, Watanabe K, et al. Two cases of new coronary aneurysms that developed in the late period after Kawasaki disease. Pediatr Cardiol. 2013;34(8):1992–5. PMID:23052675.CrossRefPubMedGoogle Scholar
  9. 9.
    Toyono M, Shimada S, Aoki-Okazaki M, Kubota H, Oyamada J, Tamura M, et al. Expanding coronary aneurysm in the late phase of Kawasaki disease. Pediatr Int. 2012;54(1):155–8. PMID:22335330.CrossRefPubMedGoogle Scholar
  10. 10.
    Tsuda E, Kamiya T, Ono Y, Kimura K, Echigo S. Dilated coronary arterial lesions in the late period after Kawasaki disease. Heart. 2005;91(2):177–82. PMID:15657227.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kobayashi T, Sone K, Shinohara M, Kosuda T, Kobayashi T. Images in cardiovascular medicine. Giant coronary aneurysm of Kawasaki disease developing during postacute phase. Circulation. 1998;98(1):92–3. PMID:9665066.CrossRefPubMedGoogle Scholar
  12. 12.
    Kawai H, Takakuwa Y, Naruse H, Sarai M, Motoyama S, Ito H, et al. Two cases with past Kawasaki disease developing acute myocardial infarction in their thirties, despite being regarded as at low risk for coronary events. Heart Vessels. 2014. PMID:24985931.
  13. 13.
    Tsuda E, Hanatani A, Kurosaki K, Naito H, Echigo S. Two young adults who had acute coronary syndrome after regression of coronary aneurysms caused by Kawasaki disease in infancy. Pediatr Cardiol. 2006;27(3):372–5. PMID:16565902.CrossRefPubMedGoogle Scholar
  14. 14.
    Brown TJ, Crawford SE, Cornwall ML, Garcia F, Shulman ST, Rowley AH. CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. J Infect Dis. 2001;184(7):940–3. PMID:11528596.CrossRefPubMedGoogle Scholar
  15. 15.
    Rowley AH, Eckerley CA, Jäck HM, Shulman ST, Baker SC. IgA plasma cells in vascular tissue of patients with Kawasaki syndrome. J Immunol. 1997;159(12):5946–55. PMID:9550392.PubMedGoogle Scholar
  16. 16.
    Rowley AH, Shulman ST, Mask CA, Finn LS, Terai M, Baker SC, et al. IgA plasma cell infiltration of proximal respiratory tract, pancreas, kidney, and coronary artery in acute Kawasaki disease. J Infect Dis. 2000;182(4):1183–91. PMID:10979916.CrossRefPubMedGoogle Scholar
  17. 17.
    Greil GF, Seeger A, Miller S, Claussen CD, Hofbeck M, Botnar RM, et al. Coronary magnetic resonance angiography and vessel wall imaging in children with Kawasaki disease. Pediatr Radiol. 2007;37(7):666–73. PMID:17541574.CrossRefPubMedGoogle Scholar
  18. 18.
    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(5):394–401. PMID:18364728.CrossRefPubMedGoogle Scholar
  19. 19.
    Rowley AH, Baker SC, Shulman ST, Rand KH, Tretiakova MS, Perlman EJ, 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. PMID:21402552.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Onouchi Y. Genetics of Kawasaki disease: what we know and don’t know. Circ J. 2012;76(7):1581–6. PMID:22789975.CrossRefPubMedGoogle Scholar
  21. 21.
    Reindel R, Baker SC, Kim KY, Rowley CA, Shulman ST, Orenstein JM, et al. Integrins α4 and αM, collagen1A1, and matrix metalloproteinase 7 are upregulated in acute Kawasaki disease vasculopathy. Pediatr Res. 2013;73(3):332–6. PMID:23344661.CrossRefPubMedGoogle Scholar
  22. 22.
    Reindel R, Bischof J, Kim KY, Orenstein JM, Soares MB, Baker SC, et al. CD84 is markedly up-regulated in Kawasaki disease arteriopathy. Clin Exp Immunol. 2014;177(1):203–11. PMID:24635044.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Reindel R, Kim KY, Baker SC, Shulman ST, Perlman EJ, Lingen MW, et al. Periostin is upregulated in coronary arteriopathy in Kawasaki disease and is a potential diagnostic biomarker. Pediatr Infect Dis J. 2014;33(6):659–61. PMID:24476956.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Japan 2017

Authors and Affiliations

  • Anne H. Rowley
    • 1
    • 2
    Email author
  • Stanford T. Shulman
    • 1
    • 2
  • Jan M. Orenstein
    • 3
  1. 1.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.The Division of Infectious DiseasesThe Ann & Robert H. Lurie Children’s Hospital of ChicagoChicagoUSA
  3. 3.Research Emeritus Professor of PathologyThe George Washington University School of MedicineWashington, DCUSA

Personalised recommendations