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The resistance of IVIG treatment in Kawasaki disease, an review of literature by Dr. Ho-Chang Kuo from Taiwan.
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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
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。
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.
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
Age distribution of KD in CGMH-KS (1999-2007)
0
10
20
30
40
50
60
70
80
90
0.5 1 2 3 4 5 6 7 8 12
Age (year)
Cas
e nu
mbe
r
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
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
33
34
35
36
37
38
39
40
41
Days after admission
Bod
y te
mpe
ratu
re (
C)
IVIG IVIG MP
Non-LCH in KD
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
• 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)
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)
• 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 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
Sep 2008, KL, Malaysia
IVIG resistance in Kawasaki disease 1999-2007 in CGMH-KS
0
5
10
15
20
25
30
35
40
45
50
1999 2000 2001 2002 2003 2004 2005 2006 2007
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 1996-2002Pediatrics. 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)
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
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
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
Immune Activation Genetic Susceptibility
Vasculitis
Coronary artery lesions
(CD40L, Skewed Th1/Th2)
(CTLA4 polymorphism)
( NO vs NOS )
Infections, Super-Ag
Kawasaki Diseasevs.
IVIG
Gender limited cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphism with intravenous
Immunoglobulin resistant in Kawasaki Disease
2008 FIMSA
P=0.01 P=0.7
CTLA4 +49 A allele was significantly associated with the IVIG resistance in females, but not males
2008 FIMSA
2008 FIMSA
Thanks a lot for your
attention and comment !!!
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.
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
• 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 - 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
CAL- timing 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 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.