郭和昌 醫師 高雄長庚醫院 兒童過敏免疫風濕科 長庚大學臨研所 Oct 15, 2008 Update of IVIG resistance in Kawasaki disease

9th IKDS, April 10-12, 2008 Taipei, Taiwan.

Introduction Diagnosis Treatment Prognosis CAL formation IVIG resistance (non-responsiveness) Content

Introduction

Diagnosis

Treatment

Prognosis

CAL formation

IVIG resistance

(non-responsiveness)

何謂川崎病 (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 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。

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

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。

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 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.

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

Pediatrics International (2008) 50 , 287–290. Increased incidence in the past 10 years in Japan

Pediatrics International (2008) 50 , 287–290. Age distribution of KD in Japan and CGMH-KS CGMH-KS (1999-2007)

Pediatrics International (2008) 50 , 287–290. CAL formation in KD in Japan 2003-2004

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. 非特異性臨床特徵

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

Non-Langerhans cell histiocytosis in KD Figure 3:The dermis reveals infiltration of histiocytes and multinucleate giant cells mixed with some lymphocytes (hematoxylin and eosin stain, 100X). Touton giant cells are also present (upper right corner, 400X). Figure 4: On immunohistochemical study, the histiocytes are diffuse positive for CD68 (A), but negative for S100 (B) and CD1a (C).

Poor response to repeat IVIG dosage and response to MP pulse Non-LCH in KD IVIG IVIG MP

Oct 2007, Tokyo, Japan.

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

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.

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 days) 排除其他類似之臨床疾患 。 Circulation 2004;110;2747-2771. 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 days)

排除其他類似之臨床疾患 。

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)

Pediatrics 2007;120;e1434-e1440. Delayed Diagnosis of Kawasaki Disease: What Are the Risk Factors?

Feb 2008, Seoul, Korea

History of IVIG in KD 1981: Imback: IVIG in ITP ( Lancet ) 1983: Furusho: IVIG in 40 Japanese patients with KD ( Lancet ) 1986: US Multicenter KD Study Group: 168 KD patients, 400mg/kg x 4 d reduces CAA from 20% to 3-5 % ( NEJM ) 1991: US Multicenter KD Study Group: 549 US patients, single infusion of 2 g/kg superiors to 400mg/kg x 4d in reducing fever and inflammatory markers ( NEJM )

1981: Imback: IVIG in ITP ( Lancet )

1983: Furusho: IVIG in 40 Japanese patients with KD ( Lancet )

1986: US Multicenter KD Study Group: 168 KD patients, 400mg/kg x 4 d reduces CAA from 20% to 3-5 % ( NEJM )

1991: US Multicenter KD Study Group: 549 US patients, single infusion of 2 g/kg superiors to 400mg/kg x 4d in reducing fever and inflammatory markers ( NEJM )

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. Treatment Q2: standard Tx for 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.

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

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.

Infection vs. KD Pediatrics 2005;116;e760-e766. Diagnosis of KD  start IVIG Tx  stop antibiotics ?

約 7.8%~38% Pediatr Cardiol. 2003; Pediatr Infect Dis J. 1998 Pediatr . 2008 Jul;153(1):117-21. Our hospital: 10.8% (30/278) 3-4% non-response to 2nd dose IVIG 4/278 (1.4 % in our hospital) 20% in Japan Nippon Rinsho . 2008;66:332-7. Recurrent KD: 6.89 per 1000/years Acta Paediatr. 2001;90:40-4 . 2/278 (0.72% in our hospital) Initial IVIG treatment failure

約 7.8%~38%

Pediatr Cardiol. 2003; Pediatr Infect Dis J. 1998

Pediatr . 2008 Jul;153(1):117-21.

Our hospital: 10.8% (30/278)

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

4/278 (1.4 % in our hospital)

20% in Japan

Nippon Rinsho . 2008;66:332-7.

Recurrent KD: 6.89 per 1000/years

Acta Paediatr. 2001;90:40-4 .

2/278 (0.72% in our hospital)

Sep 2008, KL, Malaysia

30/278, 10.8% IVIG responsive and resistant KD patients from 1999-2007 in CGMH-KS 17.3% 7.3% 7.8% 17.5% 15% 9.1% 13.6% 6.9% 5.12%

J Pediatr 2008;153:117-21. IVIG responsive and resistant KD patients in San Diego County (1998-2006)

J Pediatr 2008;153:117-21 Comparison between IVIG responsive and resistant KD patients

Eur J Pediatr (2007) 166:131–137 Risk factors to predict IVIG resistance in KD

Sep 2008, Xiamen, China

Taiwan 1996-2002 Pediatrics. 2004 Dec;114(6):e678-82. Recurrence: 1.3% (94/7305) of these children The median (range) of the interval between the first attack of KD and the second attack was 145 (9-1891) days. 85% (80/94) of the second attack occurred within 2 years following the first episode coronary artery aneurysm in 7.3% (536/7305)

Recurrence: 1.3% (94/7305) of these children

The median (range) of the interval between the first attack of KD and the second attack was 145 (9-1891) days.

85% (80/94) of the second attack occurred within 2 years following the first episode

coronary artery aneurysm in 7.3% (536/7305)

Kawasaki Disease in a Pediatric Intensive Care Unit: A Case-Control Study Pediatrics published online Sep 22, 2008;

J Pediatr 2008;153:365-8. Risk Factors for Nonresponse to Therapy in Kawasaki Disease

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

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

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

Sep 2008, Xiamen, China

May 2008, Honolulu, Hawaii

Kuo and Yang et al. Pediatr Allergy Immunol 2007;18:354–359. Univariate and multivariate analysis of KD patients between IVIG responsive and IVIG-resistant groups

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

In press: Pediatr Allergy Immunol 2008

Eosinophil increase in acute KD and inverse correlation with IVIG resistant Kuo and Yang et al. Pediatr Allergy Immunol 2007;18:354–359.

In press: Pediatr Allergy Immunol 2008

Prognosis - role of eosinophil Kuo et al. Pediatr Allergy Immunol 2007 In press: Pediatr Allergy Immunol 2008

May different brands of IVIG affect the eosinophil counts in KD ? Kuo et al. Pediatr Allergy Immunol 2008;19:184-5.

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

Male gender

Recurrent KD

IVIG before day 4

IVIG after day 10

IVIG dose <1000 mg/kg

Hb<10 gm/dL

Neutrophil >75%

band form

Eosinophil

Albumin < 3 gm/dL

Immune Activation Genetic Susceptibility Vasculitis Coronary artery lesions (CD40L, Skewed Th1/Th2) ( CTLA4 polymorphism ) ( NO vs NOS ) Infections, Super-Ag Kawasaki Disease vs. IVIG

Gender limited cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphism with intravenous Immunoglobulin resistant in Kawasaki Disease 2008 FIMSA

CTLA4 +49 A allele was significantly associated with the IVIG resistance in females, but not males 2008 FIMSA P=0.01 P=0.7

2008 FIMSA

Thanks a lot for your attention and comment !!!

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. 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.

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 Control: upper respiratory track infection, student t test. <0.001 2.98±0.23 10.9±1.71 ECP (pg/ml) <0.001 2.65±0.55 5.17±0.56 IL-5 (pg/ml) 0.004 74.52±7.45 116.7±12.5 Eotaxin (pg/ml) <0.001 5.96±0.54 12.07±1.36 IL-4 (pg/ml) P value Control (N=30) KD (N=95)

Changes of eosinophil-related Th2 cytokine and ECP after IVIG treatment

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

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. Kuo et al. Pediatr Allergy Immunol 2008. Prognosis - CAL

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.

Kuo et al. Pediatr Allergy Immunol 2008.

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 - 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

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

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 incomplete KD the late diagnosis of KD is associated with phenotype. Eur J Clin Invest. 2000;30:379-82 .

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 incomplete KD

the late diagnosis of KD is associated with phenotype.

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 )

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.