가와사끼병에서 정맥용 면역글로불린 치료 반응 예측의 한계

Limitation of Prediction on Intravenous Immunoglobulin Responsiveness in Kawasaki Disease

  • 김성구 (가톨릭대학교 의과대학 소아과학교실) ;
  • 한지윤 (가톨릭대학교 의과대학 소아과학교실) ;
  • 임정우 (가톨릭대학교 의과대학 소아과학교실) ;
  • 오진희 (가톨릭대학교 의과대학 소아과학교실) ;
  • 한지환 (가톨릭대학교 의과대학 소아과학교실) ;
  • 이경일 (가톨릭대학교 의과대학 소아과학교실) ;
  • 강진한 (가톨릭대학교 의과대학 소아과학교실) ;
  • 이준성 (가톨릭대학교 의과대학 소아과학교실)
  • Kim, Seong-Koo (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Han, Ji-Yoon (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Rhim, Jung Woo (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Oh, Jin Hee (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Han, Ji-Whan (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Lee, Kyung Yil (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Kang, Jin-Han (Department of Pediatrics, College of Medicine, The Catholic University of Korea) ;
  • Lee, Joon-Sung (Department of Pediatrics, College of Medicine, The Catholic University of Korea)
  • 투고 : 2010.07.10
  • 심사 : 2010.09.15
  • 발행 : 2010.12.25

초록

목적 : 가와사끼병 환자들에서 정맥용 면역글로불린(intravenous immunoglobulin, IVIG) 불응군의 예측 지표를 두 대조군을 사용하여 연구하였다. 방 법 : 가톨릭대학교 대전성모병원에서 IVIG 2 g/kg로 치료한 229명의 가와사끼병 환자들을 대상으로 하였다. 23명 IVIG 불응군(IVIG 투여 후에도 24시간 이상 발열이 지속)과, 첫번째 206명의 IVIG 반응군 및 두번째 연령과 치료 전 발열일을 일치시킨 46명의 대조군에 대해 임상적, 검사실 소견을 비교하였다. 결과 : 인구학적, 임상적 소견은 IVIG 불응군과 반응군이 유사하였다. 검사실 소견에서, 두 가지 연구 모두에서 IVIG 불응군은 반응군에 비해서 중성구 분획, CRP, AST, ALT 그리고, LDH는 유의하게 상승되었고, 림프구 분획, 총 단백질, 알부민, 혈소판 수, 그리고 총 콜레스테롤은 유의하게 저하되어 있었다(단변수분석). 그러나, 다변수분석에서 첫번째 연구에서 높은 중성구 분획(cutoff value, >77%, 민감도 68.4%, 특이도 79.5%)과 낮은 총 콜레스테롤(<124 mg/dL, 민감도 79%, 특이도 70.5%)이, 두번째 연구에서는 알부민(<3.6 g/dL, 민감도 73.7%, 특이도 60%)만이 불응군의 예측 지표로 나타났다. 결론 : 가와사끼병에서 염증의 중증도는 발병 시에 상승되거나 저하된 검사실 소견에 반영된다. 이러한 검사실 지표에 대한 다변수분석은 환아수, 연령 및 발열 기간 등의 인자에 의해서 영향을 받으므로, 관상동맥병변의 위험이 큰 가와사끼병 환자들을 찾기 위한 다른 접근 방법이 필요하다.

Purpose : We aimed to evaluate predictive parameters for non-response to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD) before IVIG use using two controls. Methods : We evaluated 229 consecutive KD patients who were treated with 2 g/kg of IVIG at a single center. Those who had persistent fever >24 hours after IVIG infusion made up the 23 IVIG non-responders; the first control included a total 206 defervesced cases and the second control included 46 cases that were matched for age and pre-treatment fever duration to non-responders. Results : Demographic and clinical characteristics were similar in IVIG non-responders and responders at presentation. As for laboratory findings, the neutrophil differential, CRP, AST, ALT, and LDH were higher, and lymphocyte differential, total protein, albumin, platelet count, and total cholesterol were significantly lower in IVIG non-responders compared to responders by univariate analysis in both study designs. However in multivariate analysis, non-responders showed a significantly higher neutrophil differential (cutoff value, >77%, sensitivity 68.4% and specificity 79.5%) and lower cholesterol (<124 mg/dL, sensitivity 79% and specificity 70.5%). Whereas plasma albumin (<3.6 g/dL, sensitivity 73.7% and specificity 60%) was the sole laboratory parameter of non-responders in the second study design. Conclusion : Severity of inflammation in KD was reflected by higher or lower laboratory values at presentation. Because the multivariate analysis for these indices may be influenced by some confounding factors, including the numbers of patients of different ages and fever duration, other assessment modalities are needed for KD patients with the greatest risk of coronary artery lesions.

키워드

참고문헌

  1. Kawasaki T. Kawasaki disease. Historical background and current issues. Prog Clin Biol Res 1987;250:1-4.
  2. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and longterm management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004;114:1708-33. https://doi.org/10.1542/peds.2004-2182
  3. Burgner D, Harnden A. Kawasaki disease: what is the epidemiology telling us about the aetiology? Int J Infec Dis 2005;9:185-94. https://doi.org/10.1016/j.ijid.2005.03.002
  4. Lee KY, Han JW, Lee JS. Kawasaki disease may be a hyperimmune reaction of genetically-susceptible children to variants of normal environmental flora. Med Hypotheses 2007;69:642-51. https://doi.org/10.1016/j.mehy.2006.12.051
  5. Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, et al. High dose intravenous gamma globulin therapy for Kawasaki syndrome. Lancet 1984;2:1055-8.
  6. Newberger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of Kawasaki syndrome. N Engl J Med 1991; 324:1633-9. https://doi.org/10.1056/NEJM199106063242305
  7. Wright DA, Newburger JW, Baker A, Sundel RP. Treatment of immunoglobulin-resistant Kawasaki disease with pulsed doses of corticosteroids. J Pediatr 1996;128:146-9. https://doi.org/10.1016/S0022-3476(96)70447-X
  8. Burns JC, Capparelli EV, Brown JA, Newburger JW, Glode MP. Intravenous gamma-globulin treatment and retreatment in Kawasaki disease: US/Canadian Kawasaki Syndrome Study Group. Pediatr Infect Dis J 1998;17: 1144-8. https://doi.org/10.1097/00006454-199812000-00009
  9. Burns JC, Mason WH, Hauger SB, Janai H, Bastian JF, Wohrley JD, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005;146:662-7. https://doi.org/10.1016/j.jpeds.2004.12.022
  10. Nakano H, Ueda K, Saito A, Tsuchitani Y, Kawamori J, Miyake T, et al. Scoring method for identifying patients with Kawasaki disease at high risk coronary artery aneurysms. Am J Cardiol 1986;58:739-42. https://doi.org/10.1016/0002-9149(86)90348-6
  11. Koren G, Lavi S, Rose V, Rowe R. Kawasaki disease: review of risk factors for coronary aneurysms. J Pediatr 1986;108:388-92. https://doi.org/10.1016/S0022-3476(86)80878-2
  12. Beiser AS, Takahashi M, Baker AL, Sundel RP, Newburger JW. A predictive instrument for coronary artery aneuryms in Kawasaki disease. Am J Cardiol 1998;81: 1116-20. https://doi.org/10.1016/S0002-9149(98)00116-7
  13. Harada K. Intravenous gamma-globulin treatment in Kawasaki disease. Acta Pediatr Jpn 1991;33:805-10. https://doi.org/10.1111/j.1442-200X.1991.tb02612.x
  14. McCrindle BW, Li JS, Minich LL, Colan SD, Atz AM, Takahashi M, et al. Coronary artery involvement in children with Kawasaki disease; risk factors from analysis of serial normalized measurements. Circulation 2007;116:174-9. https://doi.org/10.1161/CIRCULATIONAHA.107.690875
  15. Mori M, Imagawa T, Yasui K, Kanaya A, Yokota S. Predictors of coronary artery lesions after intravenous $\gamma$-globulin treatment in Kawasaki disease. J Pediatr 2000;137:177-80. https://doi.org/10.1067/mpd.2000.107890
  16. Fukunishi M, Kikkawa M, Hamana K, Onodera T, Matsuzaki K, Matsumoto Y, et al. Prediction of nonresponsiveness to intravenous high-dose $\gamma$-globulin therapy in patients with Kawasaki disease at onset. J Pediatr 2000;137:172-6. https://doi.org/10.1067/mpd.2000.104815
  17. Durongpisitkul K, Soongswang J, Laohaprasitiporn D, Nana A, Prachuabmoh C, Kangkagate C. Immunoglobulin failure and retreatment in Kawasaki diseasae. Pediatr Cardiol 2003;24:145-8. https://doi.org/10.1007/s00246-002-0216-2
  18. Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 2006;149:237-40. https://doi.org/10.1016/j.jpeds.2006.03.050
  19. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006;113:2606-12. https://doi.org/10.1161/CIRCULATIONAHA.105.592865
  20. 20) Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr 2007;166:131-7.
  21. Uehara R, Belay ED, Maddox RA, Holman RC, Nakamura Y, Yashiro M, et al. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan. Pediatr Infect Dis J 2008;27:155-60.
  22. Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008;153:117-21. https://doi.org/10.1016/j.jpeds.2007.12.021
  23. Research Committee on Kawasaki disease. Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki disease. Tokyo, Japan: Ministry of Health and Welfare: 1984
  24. Lee KY, Hong JH, Han JW, Lee JS, Lee BC, Burgner D. Features of Kawasaki disease at the extreams of age. J Paediatr Child Health 2006;42:423-7. https://doi.org/10.1111/j.1440-1754.2006.00898.x
  25. Lee KY, Han JW, Hong JH, Lee HS, Lee JS, Whang KT. Inflammatory processes in Kawasaki disease reach their peak at the sixth day of fever onset: laboratory profiles according to duration of fever. J Korean Med Sci 2004;19:765-71.
  26. Checchia PA, Borensztajn J, Schulman ST. Circulating cardiac troponin I levels in Kawasaki disease. Pediatr Cardiol 2001;22:102-6. https://doi.org/10.1007/s002460010170
  27. Kelley-Hedgepeth A, Lloyd-Jones DM, Colvin A, Matthews KA, Johnston J, Sowers MR, et al. Ethnic differences in C-reactive protein concentration. Clin Chem 2008;54:1027-37. https://doi.org/10.1373/clinchem.2007.098996
  28. Sakata K, Hamaoka K, Ozawa S, Niboshi A, Yoshihara T, Nishiki T, et al. A randomized prospective study on the use of 2 g-IVIG or 1 g-IVIG as therapy for Kawasaki disease. Eur J Pediatr 2007;16:565-71.
  29. Lee KY, Lee HS, Hong JH, Han JW, Lee JS, Whang KT. High-dose intravenous immunoglobulin downregulates the activated levels of inflammatory indices except erythrocyte sedimentation rate in acute stage of Kawasaki disease. J Trop Pediatr 2005;51:98-101. https://doi.org/10.1093/tropej/fmh087
  30. Hwang JY, Lee KY, Rhim JW, Youn YS, Oh JH, Han JW, et al. Assessment of intravenous immunoglobulin non-responders in Kawasaki disease. Arch Dis Child 2010 Jun 15. [Epub ahead of print]
  31. Kushner HI, Macnee RP, Burns JC. Kawasaki disease in India: increasing awareness or increased incidence? Perspect Biol Med 2009;52:17-29.
  32. Du ZD, Zhao D, Du J, Zhang YL, Lin Y, Liu C, et al. Epidemiologic study on Kawasaki disease in Beijing from 2000 through 2004. Pediatr Infect Dis J 2007;26: 449-51. https://doi.org/10.1097/01.inf.0000261196.79223.18