Ivig Resistent In Kawasaki Disease By Ho Chang Kuo (郭和昌)川崎症

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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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  • KS is the most common cause of acquired heart disease now. The clinical picture of patient with KD is Conjuctivitis, strawberry tongue, skin rash, induration and desquamation KD was first described in 1967 by Dr. Kawasaki in japan
  • From previous reports: Increased prevalence of Atopic Dermatitis has been noted in KD And also, peripheral blood eosinophilia and eosinophil accumulation in coronary microvessels have been found in KD
  • We then analyzed the levels of eosinophil related Th2 cytokines and mediators , and found that the levels of IL-4, IL-5, eotaxin, ECP and CRP were significantly higher in KD patients before IVIG treatment when compared to the controls.
  • Further, we analyzed the relationship between the changes of eosinophil, Th2 cytokines and ECP We found that the change of eosinophil is positively correlated with the changes of IL-5 levels but not the ECP levels. This result suggests therefore that the increase of eosinophil may be related to the upregulated IL-5 levels.
  • We next examined the levels of eosinophil and IL-5 in patients with or without CAL after IVIG treatment, and interestingly, we found that both the eosinpphil percentage abd the levels of plasma IL-5 were significantly higher in KD patients without CAL than those found in patients with CAL.  These results suggest, therefore, that eosinophil and related cytokines may be associated with protection of CAL formation
  • Ivig Resistent In Kawasaki Disease By Ho Chang Kuo (郭和昌)川崎症

    1. 1. 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
    2. 2. 9th IKDS, April 10-12, 2008 Taipei, Taiwan.
    3. 3. <ul><li>Introduction </li></ul><ul><li>Diagnosis </li></ul><ul><li>Treatment </li></ul><ul><li>Prognosis </li></ul><ul><ul><li>CAL formation </li></ul></ul><ul><ul><li>IVIG resistance </li></ul></ul><ul><ul><ul><li>(non-responsiveness) </li></ul></ul></ul>Content
    4. 4. 何謂川崎病 (Kawasaki disease) ? <ul><li>是一種多系統血管發炎症候群 </li></ul><ul><li>目前造成的原因仍不清楚 </li></ul><ul><li>主要發生在嬰兒以及小於五歲的幼童 </li></ul><ul><li>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 </li></ul><ul><li>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。 </li></ul>
    5. 5. 臨床表現特點 ( 診斷要件 ) Kuo et al. Acta Pediatr Twiwan . 2006;47(suppl):7-17.
    6. 6. Kawasaki Disease- 後天性心臟病之主因 Involved small and medial size vessel Coronary artery aneurysm
    7. 7. <ul><li>Japan: 120~150 個案例 / 每十萬名小於五歲的幼童 </li></ul><ul><li>Korea:100-120 </li></ul><ul><li>Taiwan: 66 </li></ul><ul><ul><li>1976 年首先有川崎氏症的案例報告 </li></ul></ul><ul><li>Hong Kong: 25 </li></ul><ul><li>USA: 10 </li></ul><ul><li>Australian: 4 </li></ul><ul><li>European: 3 </li></ul><ul><li>Male/female ratio: 1.4 </li></ul><ul><li>85% < 5y/o </li></ul><ul><li>50% <1 y/o </li></ul>Epidemiology Lancet 2004;364:533–44.
    8. 8. Pediatrics International (2008) 50 , 287–290. Increased incidence in the past 10 years in Japan
    9. 9. Pediatrics International (2008) 50 , 287–290. Age distribution of KD in Japan and CGMH-KS CGMH-KS (1999-2007)
    10. 10. Pediatrics International (2008) 50 , 287–290. CAL formation in KD in Japan 2003-2004
    11. 11. <ul><li>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 </li></ul><ul><li>BCG 接種部位反應 </li></ul>Kuo et al. Acta Pediatr Twiwan . 2006;47(suppl):7-17. 非特異性臨床特徵
    12. 12. 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).
    13. 13. Poor response to repeat IVIG dosage and response to MP pulse Non-LCH in KD IVIG IVIG MP
    14. 14. Oct 2007, Tokyo, Japan.
    15. 15. <ul><li>Fever >= 5 days </li></ul><ul><li>< 4 diagnostic criteria, with CAL </li></ul><ul><li>About 15% </li></ul><ul><ul><li>Nippon Rinsho. 2008 ;66:321-5. </li></ul></ul><ul><li><3m/o or > 6y/o </li></ul><ul><li><6m/o vs. > 6m/o </li></ul><ul><ul><li>(35% vs.12%, p=0.025) </li></ul></ul><ul><ul><ul><li>Pediatr Infect Dis J 2006; 25:241-4. </li></ul></ul></ul>Incomplete or atypical KD
    16. 16. <ul><li>ESR>40 or CRP >30 </li></ul><ul><li>輔助性的診斷 指標 ( ≧3) : </li></ul><ul><li>白蛋白指數 (< 3) </li></ul><ul><li>尿液檢查 (WBC>10/HPF) </li></ul><ul><li>肝功能指數異常 </li></ul><ul><li>白血球數量 (>15000) </li></ul><ul><li>血色素 (anemia by age) </li></ul><ul><li>血小板數目 (45 萬 ,7 days) </li></ul><ul><li>排除其他類似之臨床疾患 。 </li></ul>Circulation 2004;110;2747-2771. Incomplete or atypical KD
    17. 17. 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)
    18. 18. Pediatrics 2007;120;e1434-e1440. Delayed Diagnosis of Kawasaki Disease: What Are the Risk Factors?
    19. 19. Feb 2008, Seoul, Korea
    20. 20. History of IVIG in KD <ul><li>1981: Imback: IVIG in ITP ( Lancet ) </li></ul><ul><li>1983: Furusho: IVIG in 40 Japanese patients with KD ( Lancet ) </li></ul><ul><li>1986: US Multicenter KD Study Group: 168 KD patients, 400mg/kg x 4 d reduces CAA from 20% to 3-5 % ( NEJM ) </li></ul><ul><li>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 ) </li></ul>
    21. 21. <ul><li>High dose IVIG (2gm/kg) </li></ul><ul><li>Aspirin (80-100 mg/kg) in acute stage </li></ul><ul><li>Aspirin (3-5 mg/kg) after fever subside </li></ul><ul><ul><li>Normal ESR, Plt and 2D echo </li></ul></ul><ul><li>Aspirin: (should receive an annual influenza vaccine) </li></ul><ul><ul><li>北美地區 (80~100mg/kg/day)  Nelson textbook </li></ul></ul><ul><ul><ul><li>Circulation 1993; 87:1776-80. </li></ul></ul></ul><ul><ul><li>日本地區中等劑量 (30~50mg/kg/day) </li></ul></ul><ul><ul><ul><li>Prog Clin Biol Res 1987; 250:401-13. </li></ul></ul></ul><ul><ul><li>Hsieh KS et al. 於 1993~2003 統計 162 位 KD </li></ul></ul><ul><ul><ul><li>Pediatrics 2004; 114;689-93. </li></ul></ul></ul>Treatment Q2: standard Tx for KD
    22. 22. <ul><li>Day 4 </li></ul><ul><ul><li>Early IVIG treatment for KD: the nationwide surveys in Japan. </li></ul></ul><ul><ul><ul><li>J Pediatr 2005;146:149-50. </li></ul></ul></ul><ul><li>Day 5 </li></ul><ul><ul><li>15,940 KD patients in Japan </li></ul></ul><ul><ul><ul><li>Pediatr Infect Dis J. 2008;27:155-160. </li></ul></ul></ul>Treatment- IVIG timing
    23. 23. Infection vs. KD Pediatrics 2005;116;e760-e766. Diagnosis of KD  start IVIG Tx  stop antibiotics ?
    24. 24. <ul><li>約 7.8%~38% </li></ul><ul><ul><li>Pediatr Cardiol. 2003; Pediatr Infect Dis J. 1998 </li></ul></ul><ul><ul><li>Pediatr . 2008 Jul;153(1):117-21. </li></ul></ul><ul><li>Our hospital: 10.8% (30/278) </li></ul><ul><li>3-4% non-response to 2nd dose IVIG </li></ul><ul><ul><li>4/278 (1.4 % in our hospital) </li></ul></ul><ul><li>20% in Japan </li></ul><ul><ul><li>Nippon Rinsho . 2008;66:332-7. </li></ul></ul><ul><li>Recurrent KD: 6.89 per 1000/years </li></ul><ul><ul><li>Acta Paediatr. 2001;90:40-4 . </li></ul></ul><ul><li>2/278 (0.72% in our hospital) </li></ul>Initial IVIG treatment failure
    25. 25. Sep 2008, KL, Malaysia
    26. 26. 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%
    27. 27. J Pediatr 2008;153:117-21. IVIG responsive and resistant KD patients in San Diego County (1998-2006)
    28. 28. J Pediatr 2008;153:117-21 Comparison between IVIG responsive and resistant KD patients
    29. 29. Eur J Pediatr (2007) 166:131–137 Risk factors to predict IVIG resistance in KD
    30. 30. Sep 2008, Xiamen, China
    31. 31. Taiwan 1996-2002 Pediatrics. 2004 Dec;114(6):e678-82. <ul><li>Recurrence: 1.3% (94/7305) of these children </li></ul><ul><ul><li>The median (range) of the interval between the first attack of KD and the second attack was 145 (9-1891) days. </li></ul></ul><ul><ul><li>85% (80/94) of the second attack occurred within 2 years following the first episode </li></ul></ul><ul><li>coronary artery aneurysm in 7.3% (536/7305) </li></ul>
    32. 32. Kawasaki Disease in a Pediatric Intensive Care Unit: A Case-Control Study Pediatrics published online Sep 22, 2008;
    33. 33. J Pediatr 2008;153:365-8. Risk Factors for Nonresponse to Therapy in Kawasaki Disease
    34. 34. <ul><li>Methylpredinsolone pulse </li></ul><ul><li>Cyclosporin </li></ul><ul><li>Cyclophosphamide </li></ul><ul><li>Methotrexate </li></ul><ul><ul><li>Scand J Rheumatol 2005;34:136-9. </li></ul></ul><ul><li>Plasma exchange </li></ul><ul><ul><li>Eur J Pediatr. 2004;163:263–264. </li></ul></ul><ul><li>Pentoxifylline (inhibit TNF mRNA) </li></ul><ul><ul><li>Eur J Pediatr. 1994;153:663–667. </li></ul></ul><ul><li>Abciximab </li></ul><ul><li>Enbrel </li></ul><ul><li>Ulinastatin </li></ul><ul><ul><li>trypsin inhibitor </li></ul></ul>Other Treatment
    35. 35. N Engl J Med 2007;356:663-75. MP pulse in KD
    36. 36. MP pulse in KD Wang CL et al. J Microbiol Immunol Infect. 2005. J Pediatr 2003;143:363-7
    37. 37. Sep 2008, Xiamen, China
    38. 38. May 2008, Honolulu, Hawaii
    39. 39. 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
    40. 40. Kuo and Yang et al. Pediatr Allergy Immunol 2007;18:354–359.
    41. 41. In press: Pediatr Allergy Immunol 2008
    42. 42. Eosinophil increase in acute KD and inverse correlation with IVIG resistant Kuo and Yang et al. Pediatr Allergy Immunol 2007;18:354–359.
    43. 43. In press: Pediatr Allergy Immunol 2008
    44. 44. Prognosis - role of eosinophil Kuo et al. Pediatr Allergy Immunol 2007 In press: Pediatr Allergy Immunol 2008
    45. 45. May different brands of IVIG affect the eosinophil counts in KD ? Kuo et al. Pediatr Allergy Immunol 2008;19:184-5.
    46. 46. <ul><li>Male gender </li></ul><ul><li>Recurrent KD </li></ul><ul><li>IVIG before day 4 </li></ul><ul><li>IVIG after day 10 </li></ul><ul><li>IVIG dose <1000 mg/kg </li></ul><ul><li>Hb<10 gm/dL </li></ul><ul><li>Neutrophil >75% </li></ul><ul><li>band form </li></ul><ul><li>Eosinophil </li></ul><ul><li>Albumin < 3 gm/dL </li></ul>Predict of IVIG resistance
    47. 47. Immune Activation Genetic Susceptibility Vasculitis Coronary artery lesions (CD40L, Skewed Th1/Th2) ( CTLA4 polymorphism ) ( NO vs NOS ) Infections, Super-Ag Kawasaki Disease vs. IVIG
    48. 48. Gender limited cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphism with intravenous Immunoglobulin resistant in Kawasaki Disease 2008 FIMSA
    49. 49. CTLA4 +49 A allele was significantly associated with the IVIG resistance in females, but not males 2008 FIMSA P=0.01 P=0.7
    50. 50. 2008 FIMSA
    51. 51. Thanks a lot for your attention and comment !!!
    52. 52. <ul><li>Increased prevalence of atopic dermatitis in KD. </li></ul><ul><ul><li>Pediatr Infect Dis J . 1988. </li></ul></ul><ul><li>Peripheral blood eosinophilia and eosinophil accumulation in coronary microvessels in acute KD. </li></ul><ul><ul><li>Pediatr Infect Dis J . 2002. </li></ul></ul>Eosinophil and allergy in KD
    53. 53. Eosinophil increase in acute KD and inverse correlation with IVIG resistant Kuo and Yang et al. Pediatr Allergy Immunol 2007;18:354–359.
    54. 54. 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)
    55. 55. Changes of eosinophil-related Th2 cytokine and ECP after IVIG treatment
    56. 56. Changes of eosinophils positively correlated with IL-5 but not ECP Eosinophil vs. IL-5 Eosinophil vs. ECP
    57. 57. Mann-Whitney U test Eosinophils and IL-5 after IVIG treatment were significantly higher in KD without CAL
    58. 58. <ul><li>Untreated: 20-25% aneurysm formation </li></ul><ul><li>IVIG Tx: 3-10% </li></ul><ul><li>Predict factors </li></ul><ul><ul><li>Delay Tx </li></ul></ul><ul><ul><li>Persistent fever </li></ul></ul><ul><ul><li>Low IgG </li></ul></ul><ul><ul><li>High IgA </li></ul></ul><ul><ul><li>Low Hb </li></ul></ul><ul><ul><li>Resistant to initial IVIG Tx </li></ul></ul><ul><ul><li>Hct<32.5, neutrophil >68% </li></ul></ul><ul><ul><ul><li>Acta Paediatr 2002; 91:517-20. </li></ul></ul></ul><ul><ul><li>Albumin<3 </li></ul></ul><ul><ul><li>Persistent monocytosis </li></ul></ul><ul><ul><ul><li>Kuo et al. J Microbiol Immunol Infect . 2007;40:395-400. </li></ul></ul></ul><ul><ul><li>Eosinophil and IL-5. </li></ul></ul><ul><ul><ul><li>Kuo et al. Pediatr Allergy Immunol 2008. </li></ul></ul></ul>Prognosis - CAL
    59. 59. <ul><li>2D echo f/u schedule </li></ul><ul><li>CAL formation on an average of 9-13 days </li></ul><ul><li>2D echo </li></ul><ul><ul><li>Initial before IVIG </li></ul></ul><ul><ul><li>2-3 wks </li></ul></ul><ul><ul><li>6-8 wks </li></ul></ul>Prognosis - CAL
    60. 60. CAL- timing Arch Pediatr Adolesc Med. 2006;160:686-90.
    61. 61. Late diagnosis of Kawasaki disease is associated with haptoglobin phenotype <ul><li>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). </li></ul><ul><ul><li>Hp 2-1 have patterns of delayed or incomplete KD </li></ul></ul><ul><ul><li>the late diagnosis of KD is associated with phenotype. </li></ul></ul><ul><ul><ul><li>Eur J Clin Invest. 2000;30:379-82 . </li></ul></ul></ul>
    62. 62. Renal scarring sequelae in childhood KD <ul><li>2002 - 2005, 50 KD </li></ul><ul><li>DMSA, renal SPECT </li></ul><ul><li>26 of the 50 patients (52%) had renal inflammatory foci. </li></ul><ul><li>renal involvement vs. CAL (P<0.01; OR: 5.18) </li></ul><ul><li>all patients were free of clinical symptoms, </li></ul><ul><li>6 month f/u: DMSA renal SPECT showed renal scarring in 11 of the 24 patients (46%). </li></ul><ul><li>initial abnormal renal ultrasound did predict a greatly increased risk of scarring (P<0.05; OR 16.2) </li></ul><ul><li>long-term clinical sequelae: CAL and renal scar formation. </li></ul><ul><ul><li>Pediatr Nephrol . 2007 ;22:684-9. ( 成大 ) </li></ul></ul>
    63. 63. Pediatr Res 2008;63: 207–210.

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