郭和昌 于鴻仁 王 玲 吳自強 醫師

楊崑德 教授

高雄長庚醫院 兒童過敏免疫風濕科長庚大學臨研所

Feb 14, 2008

999 朵玫瑰花束特價 39999 元， 365 朵玫瑰特價 8999 元

Happy Valentine’s Day !!!

• Introduction

• Diagnosis (typical KD and atypical or incomplete KD)

• Infection and genetics

• Treatment

• Prognosis – CAL– IVIG resistant

Content

何謂川崎氏症 (Kawasaki disease) ？

• 是一種多系統血管發炎症候群• 目前造成的原因仍不清楚• 主要發生在嬰兒以及小於五歲的幼童• 於 1974 年川崎富作 (Tomisaku Kawasaki) 醫師首先用英文發表五十位川崎氏症病患

• 迄今已有超過 3718 篇文章發表探討此疾病 (PubMed,2008 Feb 13)

• 到目前為止，川崎氏症的標準診斷仍完全依靠臨床症狀，還沒有任何一個具體的實驗室檢驗數據可用於確認及診斷川崎氏症。

Q1: diagnosis criteria for KD

臨床表現特點 ( 診斷要件 )

Kuo et al. Acta Pediatr Twiwan. 2006;47(suppl):7-17.

Kawasaki Disease- 後天性心臟病之主因Kawasaki Disease- 後天性心臟病之主因

Involved small and medial size vessel Coronary artery aneurysm

• Japan: 120~150 個案例 / 每十萬名小於五歲的幼童• Korea:100-120• Taiwan: 66

– 1976 年首先有川崎氏症的案例報告• Hong Kong: 25• USA: 10• Australian: 4• European: 3• Male/female ratio: 1.4• 85% < 5y/o• 50% <1 y/o

Epidemiology

Lancet 2004;364:533–44

• 躁動、虹彩炎、無菌性腦膜炎、咳嗽、嘔吐、腹瀉、腹部疼痛、膽囊水腫、尿道炎、關節痛、關節炎、白蛋白指數低下、肝功能上升以及心臟衰竭

• BCG 接種部位反應

Kuo et al. Acta Pediatr Twiwan. 2006;47(suppl):7-17.

N=172

非特異性臨床特徵

• Fever >= 5 days

• < 4 diagnostic criteria, with CAL

• About 15%– Nippon Rinsho. 2008 ;66:321-5.

• <3m/o or > 6y/o

• <6m/o vs. > 6m/o – (35% vs.12%, p=0.025)

• Pediatr Infect Dis J 2006; 25:241-4.

Incomplete or atypical KD

• ESR>40 or CRP >30• 輔助性的診斷指標 ( 3)≧ :• 白蛋白指數 (< 3)• 尿液檢查 (WBC>10/HPF)• 肝功能指數異常• 白血球數量 (>15000)• 血色素 (anemia by age)• 血小板數目 (45 萬 ,7 day

s)

• 排除其他類似之臨床疾患。

Circulation 2004;110;2747-2771

Incomplete or atypical KD

Delay diagnosis of KD

Pediatrics 2005;115;428-433

>10 days

High risk of CAL

J Chin Med Assoc. 2007;70:374-9.

( 北榮 , N=14/78)

清溪川 = 李明博 總統

Snowing

CMVbocavirus

川崎氏症是否為感染性疾病？

Kuo et al. Acta Pediatr Twiwan. 2006;47(suppl):7-17.

Wang and Kuo et al. Pediatr Infect Dis J 2005;24:998–1004.

曾被報告過與川崎氏症有關的基因多型性

• (MMP-2-735C>T, MMP-3-1612 5A/6A, MMP-9-1562C>T, MMP-12-82A>G, and MMP-13-77A>G) – Pediatr Res. 2008 ;63:182-185.

• VEGF C-634 G Polymorphism in Taiwanese Children With KD, no association with CAL formation– Pediatr Cardiol. 2007. (中國 )

• Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease. – Clin Exp Immunol. 2007;150:83-90.

• The IL-10 (-627 A/C) promoter polymorphism may be associated with coronary aneurysms and low serum albumin in Korean children with KD.– Pediatr Res. 2007;61:584-7.

• Genetic variations of HLA-DRB1 and susceptibility to Kawasaki disease in Taiwanese children. – Hum Immunol. 2007;68:69-74. (馬偕 )

曾被報告過與川崎氏症有關的基因多型性

Nat Genet. 2008;40:35-42.

ITPKC and NFAT in KD

• Cause of KD (40 years): ?• High incidence in Asia (10-20 folds)• High incidence in family (10 folds)• unidentified infectious agents appear to play some role • siblings and offspring of KD patients are at higher risk of th

e disease – Fujita et al. 1989; Uehara et al. 2003

• male predominance of its occurrence (male:female ratio 1.4) and cardiac complications – Yanagawa et al. 1998

• Double hit: certain genetic defect with infection– Med Hypotheses. 2007;69:642-51.

Infectious vs. genetics factors

Circulation 2004;110;2747-2771

Differential Diagnosis of KD

• High dose IVIG (2gm/kg)• Aspirin (80-100 mg/kg) in acute stage• Aspirin (3-5 mg/kg) after fever subside

– Normal ESR, Plt and 2D echo • Aspirin: (should receive an annual influenza vaccine)

– 北美地區 (80~100mg/kg/day) Nelson textbook• Circulation 1993; 87:1776-80.

– 日本地區中等劑量 (30~50mg/kg/day)• Prog Clin Biol Res 1987; 250:401-13.

– Hsieh KS et al. 於 1993~2003 統計 162 位 KD• Pediatrics 2004; 114;689-93.

TreatmentQ2: standard Tx for KD

• Day 4– Early IVIG treatment for KD: the nationwide

surveys in Japan. – J Pediatr 2005;146:149-50.

• Day 5– 15,940 KD patients in Japan– Pediatr Infect Dis J. 2008;27:155-160.

Treatment- IVIG timing

Infection and KD

Pediatrics 2005;116;e760-e766

Diagnosis of KD start IVIG Tx stop antibiotics ?

• 約 7.8%~23%– Pediatr Cardiol. 2003;24:145–148– Pediatr Infect Dis J. 1998;17:1144–1148

• Our hospital: 15.1% (26/172)

• 3-4% still non-response to 2nd dose IVIG

• 20% in Japan– Nippon Rinsho. 2008;66:332-7.

• Recurrent KD: 6.89 per 1000/years– Acta Paediatr. 2001;90:40-4.

Initial IVIG treatment failure

• Methylpredinsolone pulse• Cyclosporin• Cyclophosphamide• Methotrexate

– Scand J Rheumatol 2005;34:136-9.• Plasma exchange

– Eur J Pediatr. 2004;163:263–264.• Pentoxifylline (inhibit TNF mRNA)

– Eur J Pediatr. 1994;153:663–667.• Abciximab• Enbrel • Ulinastatin

– trypsin inhibitor

Other Treatment

N Engl J Med 2007;356:663-75.

MP pulse in KD

MP pulse in KD

Wang CL et al. J Microbiol Immunol Infect. 2005.

J Pediatr 2003;143:363-7

百萬夜景

• Untreated: 20-25% aneurysm formation• IVIG Tx: 3-10% • Predict factors

– Delay Tx– Persistent fever – Low IgG– High IgA– Low Hb– Resistant to initial IVIG Tx– Hct<32.5, neutrophil >68%

• Acta Paediatr 2002; 91:517-20.– Albumin<3– Persistent monocytosis

• Kuo et al. J Microbiol Immunol Infect. 2007;40:395-400. – Eosinophil and IL-5.

Prognosis - CALPrognosis - CAL

• 2D echo f/u schedule

• CAL formation on an average of 9-13 days

• 2D echo – Initial before IVIG – 2-3 wks– 6-8 wks

Prognosis - CALPrognosis - CAL

1. Decreased nitric oxide production after intravenous immunoglobulin treatment in patients with KD.Wang CL et al. J Pediatr. 2002;141:560-5.

2. Expression of CD40 ligand on CD4+ T-cells and platelets correlated to the coronary artery lesion and disease progress in Kawasaki disease.Wang CL et al. Pediatrics. 2003;111:E140-7.

Prognosis - CALPrognosis - CAL

Anti-CD40L, anti-iNOS maybe benefit in KD

CD40L

NO, iNOS

CAL- timing CAL- timing

Arch Pediatr Adolesc Med. 2006;160:686-90.

• Male • Recurrent KD• IVIG before day 4• IVIG after day 9• IVIG dose <1000 mg/kg • Hb<10 gm/dL• Neutrophil >75%• band form• Albumin < 3 gm/dL• Eosinophil

Predict of IVIG Tx failure

Prognosis - role of eosinophil

Kuo et al. Pediatr Allergy Immunol 2007 In revision: Pediatr Allergy Immunol

May different brands of IVIG affect the eosinophil counts in KD ?

Kuo et al. Pediatr Allergy Immunol 2008;19:184-5.

Late diagnosis of Kawasaki disease is associated with haptoglobin phenotype

• 5 out of 20 patients with haptoglobin (Hp) 2-1 were recognized in subacute stage, and their incidence of CAA was 80.0% (4/5). – Hp 2-1 have patterns of delayed or incompl

ete KD– the late diagnosis of KD is associated with p

henotype. • Eur J Clin Invest. 2000;30:379-82.

Renal scarring sequelae in childhood KD

• 2002 - 2005, 50 KD

• DMSA, renal SPECT

• 26 of the 50 patients (52%) had renal inflammatory foci.

• renal involvement vs. CAL (P<0.01; OR: 5.18)

• all patients were free of clinical symptoms,

• 6 month f/u: DMSA renal SPECT showed renal scarring in 11 of the 24 patients (46%).

• initial abnormal renal ultrasound did predict a greatly increased risk of scarring (P<0.05; OR 16.2)

• long-term clinical sequelae: CAL and renal scar formation.

– Pediatr Nephrol. 2007 ;22:684-9. ( 成大 )

Pediatr Res 2008;63: 207–210.

In revision: Pediatr Allergy Immunol (SCI IF:2.849, rank 7/74)

Eosinophil and allergy in KD Eosinophil and allergy in KD

• Increased prevalence of atopic dermatitis in KD. – Pediatr Infect Dis J. 1988.

• Peripheral blood eosinophilia and eosinophil accumulation in coronary microvessels in acute KD.– Pediatr Infect Dis J. 2002.

  KD (N = 95)

Control (N = 30)

P values

Total leukocyte/mm3 13792 ± 733 9412 ± 551 < 0.01

Hemoglobin (g/dL) 10.8 ± 0.1 12.2 ± 0.1 < 0.01

Platelet (×104/mm3) 37.6 ± 1.4 26.4 ± 1.1 < 0.01

Neutrophil (%) 65.9 ± 1.4 62.4 ± 2.7 0.23

Lymphocyte (%) 24.6 ± 1.2 27.5 ± 2.5 0.31

Monocyte (%) 5.7 ± 0.3 6.8 ± 0.7 0.20

Eosinophil (%) 2.4 ± 0.2 0.4 ± 0.1 < 0.01

Basophil (%) 0.17 ± 0.03 0.21 ± 0.05 0.61

Analysis of CBC/DC in KD and ControlsAnalysis of CBC/DC in KD and Controls

Student’s t-test

Eosinophil increase in acute KD and inverse correlation with IVIG resistant

Eosinophil increase in acute KD and inverse correlation with IVIG resistant

Kuo and Yang et al. Pediatr Allergy Immunol 2007;18:354–359.

Levels of eosinophil-related Th2 cytokines and ECP were higher in KD

Levels of eosinophil-related Th2 cytokines and ECP were higher in KD

KD

(N=95)

Control

(N=30)P value

IL-4 (pg/ml) 12.07±1.36 5.96±0.54 <0.001

IL-5 (pg/ml) 5.17±0.56 2.65±0.55 <0.001

Eotaxin (pg/ml) 116.7±12.5 74.52±7.45 0.004

ECP (pg/ml) 10.9±1.71 2.98±0.23 <0.001

Control: upper respiratory track infection, student t test.

Changes of eosinophil-related Th2 cytokine and ECPafter IVIG treatment

Changes of eosinophil-related Th2 cytokine and ECPafter IVIG treatment

Changes of eosinophils positively correlated with IL-5 but not ECP

Changes of eosinophils positively correlated with IL-5 but not ECP

Eosinophil vs. IL-5 Eosinophil vs. ECP

Mann-Whitney U test

Eosinophils and IL-5 after IVIG treatment were significantly higher in KD without CAL

Eosinophils and IL-5 after IVIG treatment were significantly higher in KD without CAL

Deadline for Submission: Jan 15, 2007

Abstracts submitted to 9th KD symposium till Jan 15, 2008

如履薄冰

Thanks a lot for your

attention and comment !!!