Kawasaki disease

Japanese: 川崎病

Definition/Concept Kawasaki disease is an acute febrile inflammatory disease affecting blood vessel walls that occurs suddenly and resolves after a course of approximately two weeks. During this course, various symptoms arise and subside in association with vasculitis of medium-sized muscular arteries throughout the body, but the presence or absence and severity of coronary artery disease in particular have a significant impact on the prognosis of the patient. Kawasaki disease is ranked number one among acquired childhood heart diseases, surpassing the number of cases of rheumatic valvular heart disease.
In recent years, 10,000-12,000 cases have been reported annually. Kawasaki disease shows unique age characteristics with a peak at 1 year of age, with more than 85% of cases occurring in children aged 0-5 years. It is more common in boys, with peak incidence in early spring. The incidence of coronary artery lesions was initially 25-30% of diseased children, but with the introduction of high-dose gamma globulin therapy this has decreased to 5-8% (500-800 cases/year). Mortality has now decreased to less than 0.04%.
No specific infectious agent has been identified as the cause or etiology , but the epidemiological pattern of prevalence and spread suggests the involvement of an infectious agent. The pathology is characterized by activation of the immune system and excessive production of inflammatory cytokines, followed by destruction of the tunica media, activation and rupture of endothelial cells, and coronary artery damage. Although it is an acute inflammatory disease, there is concern that coronary artery damage may progress to atherosclerosis after middle age.
Clinical symptoms, course, and pathology Kawasaki disease is a syndrome characterized by acute inflammation that begins with a sudden fever. Symptoms in the acute phase appear and disappear over time, overlapping and rapidly changing. By the third to seventh day of illness, the patient will have a characteristic facial appearance, and symptoms such as swollen cervical lymph nodes, conjunctival congestion (engorgement of subconjunctival blood vessels), strawberry tongue, mucosal symptoms such as redness, cracking, and bleeding of the lips, redness and ulceration of the BCG vaccination site, hard edema of the hands and feet, and redness of the tips of the fingers and toes will be complete. In cases with coronary artery lesions, echocardiography shows increased brightness of the coronary arteries from around the seventh day of illness, and dilation and aneurysm formation are detected on the 10th to 12th day of illness. Histologically, lesions begin with medial lesions and endothelial cell destruction in the blood vessels, and then progress to the intima and adventitia, resulting in panarteritis. These pathological changes were consistent with vascular wall edema and degeneration of the smooth muscle in the media on days 7-10 of hospitalization, and with coronary artery dilatation and aneurysm formation due to destruction of the muscularis media on days 10-14 of hospitalization.
Pathogenesis and test resultsThe pathogenesis of Kawasaki disease can be summarized into two points: 1) excessive production of inflammatory cytokines and 2) panvasculitis. As vasculitis progresses, destruction of the tunica media and release of tissue factors from around endothelial cells and exposure of intimal collagen activate the coagulation-fibrinolysis system, which can progress to disseminated intravascular coagulation (DIC), especially in cases where steroids have been used. Test values include a marked increase in white blood cell count (mature neutrophil count), high levels of inflammatory markers such as CRP, high levels of FDP-E/D-dimer along with destruction of endothelial cells, decreased albumin, and sometimes liver dysfunction and high levels of bilirubin.
DiagnosisThe diagnostic guideline (5th edition, 2002) from the Ministry of Health, Labor and Welfare research group is shown in Table 10-19-3. The most important differential diagnosis is polyarteritis nodosa. It is often impossible to differentiate between these two conditions during the acute phase of Kawasaki disease.
TreatmentThe principle of treatment is early suppression of inflammation, and it is generally essential to end inflammation within 10 days of illness. ① High-dose gamma globulin therapy, ② antiplatelet therapy with aspirin, and ③ measures to treat non-cardiovascular complications (gallbladder enlargement, ileus, DIC, etc.) should be promptly implemented. In cases where the following overlapping findings are observed despite high-dose gamma globulin therapy: ① no reduction in fever, ② no decrease in CRP, ③ no decrease in white blood cell count, especially neutrophil percentage, ④ decrease in albumin (especially below 3 g/dL), ⑤ decrease in platelet count, ⑥ no decrease in FDP-E/D-dimer or urinary _β2 -microglobulin, ⑦ increase in coronary artery brightness, a single dose of a TNF inhibitor (infliximab) should be administered. Furthermore, plasma exchange therapy should be performed in cases that are unresponsive to TNF inhibitors. A meta-analysis has revealed that steroids have no effect on reducing coronary artery damage. In cases where coronary artery changes have occurred, thrombolytic therapy for aneurysm formation and measures to prevent myocardial infarction and peripheral arterial disease are added, and the patient is placed under long-term observation. [Shunpei Yokota]
■ References
Kahn P: Juvenile idiopathic arthritis: an update on pharmacotherapy. Bull NYU Hosp Joint Dis, 69: 264-276, 2011.
Yokota S, Imagawa T, et al: Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet, 371: 998-1006, 2008.
Engel ME, Stander R, et al: Genetic susceptibility to acute rheumatic fever: a systemic review and meta-analysis of twin studies. PLoS ONE, 6: 1-6, 2011.

Table 10-19-3
Kawasaki Disease Diagnosis Guide (5th Revised Edition) ">

Table 10-19-3

Kawasaki disease (vasculitis syndrome)

(4) Kawasaki disease [⇨10-19-3)] [Shoichi Ozaki]
■ References
Falk RJ, et al: Granulomatosis with polyangiitis (Wegener's): An alternative name for Wegener's granulomatosis. Ann Rheum Dis, 70: 704, 2011.
Jennette JC, Falk RJ, et al: 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum, 65: 1-11, 2013.
Mukhtyar CL, et al: EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis, 68: 310-317, 2009.

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　川崎病は血管壁を場とする急性熱性炎症性疾患であり，突然に発症し約2週間の経過で終息する．この経過中全身の中型筋型動脈の血管炎に伴い種々の症状が生起し消退するが，特に冠動脈病変の有無・重症度が患児の予後に重大な結果をもたらす．小児期の後天性心疾患としてはリウマチ熱弁膜症の数を上回り川崎病が，第1位にランクされる．
　最近では年間10000～12000人の報告がなされている．川崎病の発症は1歳をピークとする独特の年齢的特徴を示し，0歳〜5歳までで85％以上を占める．男児に多く，早春に発生のピークがみられる．冠動脈病変の発生は当初病児の25〜30％であったが，大量ガンマグロブリン療法が導入されて5〜8％まで軽減した（500～800人/年）．また死亡例は現在では0.04％以下に減少した．
原因・病因
　特定の感染因子は同定されていないが，疫学的に流行・波及のパターンから感染因子の関与が推察される．病態は免疫系の活性化と炎症性サイトカインの過剰産生，それに引き続く中膜の破壊，内皮細胞活性化と破綻，冠動脈障害に特徴づけられる．急性炎症性疾患であるが，冠動脈障害は中年以降の粥状硬化症に進展することが危惧されている．
臨床症状・経過・病理
　川崎病は突然の発熱で始まる急性炎症を病態とする症候群である．急性期の症状は時間経過に伴い重複かつ速やかに変化しつつ出没する．第3〜7病日までには特有の顔貌を呈しつつ頸部リンパ節腫脹，眼球結膜の充血（眼球結膜下血管の怒張），いちご舌，口唇の発赤・亀裂・出血などの粘膜症状，BCG接種痕の発赤と潰瘍化，手足の硬性浮腫や指趾先端の発赤などが揃い病像は完成する．そして冠動脈病変をきたす例では第7病日前後から心エコー検査にて冠動脈の輝度上昇が認められ，第10〜12病日に拡張〜瘤形成が検出される．組織学的には血管の中膜病変と内皮細胞破綻に始まり，内膜と外膜にも至り汎動脈炎となる．この病理学的変化は，第7〜10病日の血管壁浮腫と中膜平滑筋変性と第10〜14病日の中膜筋板の破壊による冠動脈拡張〜瘤形成に一致する．
病態・検査成績
　川崎病の病態は，①炎症性サイトカインの過剰な産生，②汎血管炎の2点に集約できる．血管炎の進展に伴い，中膜の破壊と内皮細胞周囲からの組織因子の放出・内膜コラーゲンの露出を起点とする凝固線溶系の活性化により，特にステロイドを使用した例では播種性血管内凝固症候群（DIC）へ進展することがある．検査値では白血球数（成熟好中球数）の著増，CRPなど炎症マーカーの高値，内皮細胞の破壊とともにFDP-E/D-ダイマーの高値ダイマー，アルブミン低下，ときに肝機能障害やビリルビンの高値を認める．
診断
　厚生労働省研究班の診断の手引き（2002年第5版）を表10-19-3に示す．鑑別診断の中で最も重要なものは結節性多発動脈炎である．川崎病の急性期には鑑別できないことが多い．
治療
　治療の原則は早期炎症抑制にあり，一般に第10病日以内に炎症の収束をはかることが肝要である．①大量ガンマグロブリン療法，②アスピリンによる抗血小板療法，③心血管系以外の合併症の対策（胆囊腫大，イレウス，DICなど），などを速やかに実施する．大量ガンマグロブリン療法にもかかわらず①解熱しない，②CRPが低下しない，③白血球数，特に好中球％が低下しない，④アルブミンが低下する（特に3 g/dL以下），⑤血小板数が減少する，⑥FDP-E/D-ダイマーの低下や尿中β₂-ミクログロブリンの低下がみられない，⑦冠動脈輝度が上昇する，などの所見が重複して認められる例では，TNF阻害薬（インフリキシマブ）1回投与を行う．さらにTNF阻害薬不応例には血漿交換療法を実施する．なお，ステロイドは，メタ解析により冠動脈障害を減少させる効果はないことが明らかにされている．冠動脈変化をきたした例にはさらに動脈瘤形成に対する血栓溶解療法，心筋梗塞や末梢動脈障害の対策などを加え，長期経過観察に移行する．［横田俊平］
■文献
Kahn P: Juvenile idiopathic arthritis: an update on pharmacotherapy. Bull NYU Hosp Joint Dis, 69: 264-276, 2011.
Yokota S, Imagawa T, et al: Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet, 371: 998-1006, 2008.
Engel ME, Stander R, et al: Genetic susceptibility to acute rheumatic fever: a systemic review and meta-analysis of twin studies. PLoS ONE, 6: 1-6, 2011.

表10-19-3
川崎病診断の手引き（改訂5 版）">

表10-19-3

川崎病(血管炎症候群)

（4）川崎病
【⇨10-19-3）】［尾崎承一］
■文献
Falk RJ, et al: Granulomatosis with polyangiitis (Wegener's): An alternative name for Wegener's granulomatosis. Ann Rheum Dis, 70: 704, 2011.
Jennette JC, Falk RJ, et al: 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum, 65: 1-11, 2013.
Mukhtyar CL, et al: EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis, 68: 310-317, 2009.

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