Kawasaki disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR


[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Pathogenesis

  • The exact pathogenesis of Kawasaki disease is not fully understood.

Genetics

In independent cohort studies the genes which are suspected in susceptibility to Kawasaki disease with replication are:[1]

Adapted from the AHA Scientific Statement on the diagnosis, treatment, and long term management of Kawasaki disease[1]
Gene Chromosome Location Genetic Methods Validation Populations Potential Significance Reference and Year
FCGR2A 1q23 GWAS European descent, Taiwanese, Koreans, Han Chinese Low-affinity receptor for Fc fragment of IgG; risk allele has lower binding affinity Khor et al[2]2011
CASP3 4q34-35 Linkage analysis

Candidate gene study

Japanese, Taiwanese, Koreans, Chinese, Euro-Americans Mediates apoptosis in immune cells and cardiomyocytes

Risk allele decreases gene transcription

Onouchi et al[3] 2010
HLAclass II 6p21.3 GWAS Japanese, Taiwanese, Koreans Activation marker for immune cells; antigen presentation Onouchi et al[4] 2012
BLK 8p23-22 GWAS Japanese, Taiwanese, Koreans B-cell receptor signal transduction Onouchi et al[5] 2012
IPTKC 19q13.2 Linkage analysis

TDT

Japanese, Taiwanese, Koreans, Chinese, Euro- Americans Negative regulator of calcineurin-NFAT signaling pathway; risk allele increases signaling Onouchi et al[6] 2008
CD40 20q12-13.2 GWAS Japanese, Taiwanese, Koreans Risk alleles associated with increased translation Onouchi et al[7] 2012
BLK indicates B-cell lymphoid kinase; CASP3, caspase 3; FCGR, Fcγ receptor; GWAS, genome-wide association study; HLA, human leukocyte antigen; IgG, immunoglobulin G; ITPKC, inositol 1,4,5-trisphosphate kinase-C; KD, Kawasaki disease; NFAT, nuclear factor of activated T cells; and TDT, transmission disequilibrium test.

Associated Conditions

  • Inflammation of the coronary arteries lead to most important clinical outcomes.
  • Kawasaki disease is defined by the systemic inflammation of the medium sized arteries and in multiple organs and tissues.
  • The systemic inflammation of the medium sized arteries organs and tissues can lead to the following associated conditions:[8][9]
Organ and Tissue Associated conditions
Liver Hepatitis
Lung Interstitial pneumonitis
Gastrointestinal tract Abdominal pain

Diarrhea

Vomiting

Gallbladder hydrops

Meninges Aseptic meningitis

Irritability

Heart Myocarditis

Pericarditis

Valvulitis

Urinary tract Pyuria
Pancreas Pancreatitis
Lymph nodes Lymphadenopathy

Gross Pathology

  • On gross pathology, large or giant coronary artery aneurysms, thrombi containing aneurysms, decreases luminal diamieter, stenosis of the lumen and chronic inflamation are the usual findings of Kawasaki disease.[1]
  • The Kawasaki disease mainly involved the muscular arteries and is characterized by the following processes:
  • Necrotizing arteritis
  • Subacute vasculitis
  • Chronic Vasculitis
  • Luminal myofibroblastic proliferation

Microscopic Pathology

  • On microscopic histopathological analysis of autopsied cases of Kawasaki disease, intracytoplasmic inclusion bodies are frequently observed in ciliated bronchial epithelial cells.[10]

References

  1. 1.0 1.1 1.2 McCrindle, Brian W.; Rowley, Anne H.; Newburger, Jane W.; Burns, Jane C.; Bolger, Anne F.; Gewitz, Michael; Baker, Annette L.; Jackson, Mary Anne; Takahashi, Masato; Shah, Pinak B.; Kobayashi, Tohru; Wu, Mei-Hwan; Saji, Tsutomu T.; Pahl, Elfriede (2017). "Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association". Circulation. 135 (17): e927–e999. doi:10.1161/CIR.0000000000000484. ISSN 0009-7322.
  2. Khor, C. C.; Davila, S.; Shimizu, C.; Sheng, S.; Matsubara, T.; Suzuki, Y.; Newburger, J. W.; Baker, A.; Burgner, D.; Breunis, W.; Kuijpers, T.; Wright, V. J.; Levin, M.; Hibberd, M. L.; Burns, J. C. (2011). "Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease". Journal of Medical Genetics. 48 (7): 467–472. doi:10.1136/jmg.2010.086611. ISSN 0022-2593.
  3. Onouchi, Yoshihiro; Ozaki, Kouichi; Buns, Jane C.; Shimizu, Chisato; Hamada, Hiromichi; Honda, Takafumi; Terai, Masaru; Honda, Akihito; Takeuchi, Takashi; Shibuta, Shoichi; Suenaga, Tomohiro; Suzuki, Hiroyuki; Higashi, Kouji; Yasukawa, Kumi; Suzuki, Yoichi; Sasago, Kumiko; Kemmotsu, Yasushi; Takatsuki, Shinichi; Saji, Tsutomu; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Kishi, Fumio; Ouchi, Kazunobu; Sato, Yoshitake; Newburger, Jane W.; Baker, Annette L.; Shulman, Stanford T.; Rowley, Anne H.; Yashiro, Mayumi; Nakamura, Yoshikazu; Wakui, Keiko; Fukushima, Yoshimitsu; Fujino, Akihiro; Tsunoda, Tatsuhiko; Kawasaki, Tomisaku; Hata, Akira; Nakamura, Yusuke; Tanaka, Toshihiro (2010). "Common variants in CASP3 confer susceptibility to Kawasaki disease". Human Molecular Genetics. 19 (14): 2898–2906. doi:10.1093/hmg/ddq176. ISSN 1460-2083.
  4. Onouchi, Yoshihiro; Ozaki, Kouichi; Burns, Jane C; Shimizu, Chisato; Terai, Masaru; Hamada, Hiromichi; Honda, Takafumi; Suzuki, Hiroyuki; Suenaga, Tomohiro; Takeuchi, Takashi; Yoshikawa, Norishige; Suzuki, Yoichi; Yasukawa, Kumi; Ebata, Ryota; Higashi, Kouji; Saji, Tsutomu; Kemmotsu, Yasushi; Takatsuki, Shinichi; Ouchi, Kazunobu; Kishi, Fumio; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Sato, Yoshitake; Honda, Akihito; Kobayashi, Hironobu; Sato, Junichi; Shibuta, Shoichi; Miyawaki, Masakazu; Oishi, Ko; Yamaga, Hironobu; Aoyagi, Noriyuki; Iwahashi, Seiji; Miyashita, Ritsuko; Murata, Yuji; Sasago, Kumiko; Takahashi, Atsushi; Kamatani, Naoyuki; Kubo, Michiaki; Tsunoda, Tatsuhiko; Hata, Akira; Nakamura, Yusuke; Tanaka, Toshihiro (2012). "A genome-wide association study identifies three new risk loci for Kawasaki disease". Nature Genetics. 44 (5): 517–521. doi:10.1038/ng.2220. ISSN 1061-4036.
  5. Onouchi, Yoshihiro; Ozaki, Kouichi; Burns, Jane C; Shimizu, Chisato; Terai, Masaru; Hamada, Hiromichi; Honda, Takafumi; Suzuki, Hiroyuki; Suenaga, Tomohiro; Takeuchi, Takashi; Yoshikawa, Norishige; Suzuki, Yoichi; Yasukawa, Kumi; Ebata, Ryota; Higashi, Kouji; Saji, Tsutomu; Kemmotsu, Yasushi; Takatsuki, Shinichi; Ouchi, Kazunobu; Kishi, Fumio; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Sato, Yoshitake; Honda, Akihito; Kobayashi, Hironobu; Sato, Junichi; Shibuta, Shoichi; Miyawaki, Masakazu; Oishi, Ko; Yamaga, Hironobu; Aoyagi, Noriyuki; Iwahashi, Seiji; Miyashita, Ritsuko; Murata, Yuji; Sasago, Kumiko; Takahashi, Atsushi; Kamatani, Naoyuki; Kubo, Michiaki; Tsunoda, Tatsuhiko; Hata, Akira; Nakamura, Yusuke; Tanaka, Toshihiro (2012). "A genome-wide association study identifies three new risk loci for Kawasaki disease". Nature Genetics. 44 (5): 517–521. doi:10.1038/ng.2220. ISSN 1061-4036.
  6. Onouchi, Yoshihiro; Gunji, Tomohiko; Burns, Jane C; Shimizu, Chisato; Newburger, Jane W; Yashiro, Mayumi; Nakamura, Yoshikazu; Yanagawa, Hiroshi; Wakui, Keiko; Fukushima, Yoshimitsu; Kishi, Fumio; Hamamoto, Kunihiro; Terai, Masaru; Sato, Yoshitake; Ouchi, Kazunobu; Saji, Tsutomu; Nariai, Akiyoshi; Kaburagi, Yoichi; Yoshikawa, Tetsushi; Suzuki, Kyoko; Tanaka, Takeo; Nagai, Toshiro; Cho, Hideo; Fujino, Akihiro; Sekine, Akihiro; Nakamichi, Reiichiro; Tsunoda, Tatsuhiko; Kawasaki, Tomisaku; Nakamura, Yusuke; Hata, Akira (2007). "ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms". Nature Genetics. 40 (1): 35–42. doi:10.1038/ng.2007.59. ISSN 1061-4036.
  7. Onouchi, Yoshihiro; Ozaki, Kouichi; Burns, Jane C; Shimizu, Chisato; Terai, Masaru; Hamada, Hiromichi; Honda, Takafumi; Suzuki, Hiroyuki; Suenaga, Tomohiro; Takeuchi, Takashi; Yoshikawa, Norishige; Suzuki, Yoichi; Yasukawa, Kumi; Ebata, Ryota; Higashi, Kouji; Saji, Tsutomu; Kemmotsu, Yasushi; Takatsuki, Shinichi; Ouchi, Kazunobu; Kishi, Fumio; Yoshikawa, Tetsushi; Nagai, Toshiro; Hamamoto, Kunihiro; Sato, Yoshitake; Honda, Akihito; Kobayashi, Hironobu; Sato, Junichi; Shibuta, Shoichi; Miyawaki, Masakazu; Oishi, Ko; Yamaga, Hironobu; Aoyagi, Noriyuki; Iwahashi, Seiji; Miyashita, Ritsuko; Murata, Yuji; Sasago, Kumiko; Takahashi, Atsushi; Kamatani, Naoyuki; Kubo, Michiaki; Tsunoda, Tatsuhiko; Hata, Akira; Nakamura, Yusuke; Tanaka, Toshihiro (2012). "A genome-wide association study identifies three new risk loci for Kawasaki disease". Nature Genetics. 44 (5): 517–521. doi:10.1038/ng.2220. ISSN 1061-4036.
  8. McCrindle, Brian W.; Rowley, Anne H.; Newburger, Jane W.; Burns, Jane C.; Bolger, Anne F.; Gewitz, Michael; Baker, Annette L.; Jackson, Mary Anne; Takahashi, Masato; Shah, Pinak B.; Kobayashi, Tohru; Wu, Mei-Hwan; Saji, Tsutomu T.; Pahl, Elfriede (2017). "Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association". Circulation. 135 (17): e927–e999. doi:10.1161/CIR.0000000000000484. ISSN 0009-7322.
  9. Amano S, Hazama F, Hamashima Y (July 1979). "Pathology of Kawasaki disease: I. Pathology and morphogenesis of the vascular changes". Jpn. Circ. J. 43 (7): 633–43. PMID 41111.
  10. Rowley AH, Baker SC, Shulman ST, Garcia FL, Fox LM, Kos IM, Crawford SE, Russo PA, Hammadeh R, Takahashi K, Orenstein JM (February 2008). "RNA-containing cytoplasmic inclusion bodies in ciliated bronchial epithelium months to years after acute Kawasaki disease". PLoS ONE. 3 (2): e1582. doi:10.1371/journal.pone.0001582. PMC 2216059. PMID 18270572.

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