04-02 조성필

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1 Original Article 대한소아응급의학회지 2015 제 2 권제 2 호 Pediatric Emergency Medicine Journal Volume 2, Number 2, December, 2015 응급실에내원한불완전가와사키병환아에서심혈관합병증을예측하기위한인자로서 Pro-BNP 의유용성 조성필 강민경 문형준 이정원 김종호 순천향대학교의과대학응급의학교실 Pro-brain natriuretic peptide as predictive factor for cardiovascular abnormalities in children with incomplete Kawasaki disease in emergency department Sungpill Jo, M.D., Minkyoung Kang, M.D., Hyungjun Moon, M.D., Jungwon Lee, M.D., Jong Ho Kim, M.D. Department of Emergency Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea Purpose: The prevalence of incomplete Kawasaki disease (KD) is progressively increasing. The purpose of our study is to investigate the usefulness of pro-brain natriuretic peptide (pro-bnp) assay as a predictive biochemical marker of cardiovascular abnormality in children with incomplete KD. Methods: We retrospectively reviewed medical records of patients under 15 years of age with incomplete KD in the pediatric emergency department (PED) of Soonchunhyang University Cheonan Hospital from January 2010 to December Incomplete KD was diagnosed in 132 children, including 67 boys and 65 girls, aged 2 to 83 months (mean, 24.9 months). We assessed the risk of cardiovascular abnormality in relation to age, gender, duration of fever, symptoms, and laboratory data. Results: The distribution of epidemiologic characters, laboratory findings except platelet counts, and pro-bnp in the patient group without cardiovascular abnormality absent group did not significantly differ from those of the patient group with cardiovascular abnormality group. However, in the latter group with cardiovascular abnormality, serum platelet counts were significantly lower and concentration of pro-bnp levels were significantly higher. Conclusion: Pro-BNP might be a useful and important value for predicting cardiovascular abnormality in incomplete KD at PED. Therefore, incomplete KD patients with high concentraton of pro-bnp need further evaluation for cardiovascular abnormality. Key Words: Kawasaki Disease; Pro-brain natriuretic peptide; Cardiovascular Abnormalities; Complications; Risk Factors Corresponding Author Jong Ho Kim Department of Emergency Medicine, Soonchunhyang University College of Medicine, 44 Suncheonhyang 4-gil, Dongnam-gu, Cheonan 31151, Korea Tel: Fax: peddrjhkim@gmail.com 서론 가와사키병은영 유아에서발생하는급성전신성혈관염으로후천적인심장질환의원인이된다. 여아보다는남아에서더호발하며 ( 남아 : 여아 = :1), 약 80% 는 6 75

2 대한소아응급의학회지제 2 권제 2 호 2015 개월에서 4세까지발생하는것으로알려져있다 1). 가와사키병의진단은 2004년미국심장협회가이드라인 (American Heart Association Guideline) 에서발표한임상기준에따르며 2), 5일이상의발열을동반하면서다음 5가지임상증상중 4가지이상발현되었을때진단된다. 5가지임상증상에는양안의결막충혈, 경부림프절비대, 다형피부발진, 입술과구개내점막의변화, 말초사지의변화등이있다. 하지만이러한조건을모두충족시키지못하여임상증상으로가와사키병을의심하는경우를불완전가와사키병이라하며이는전체가와사키병환자중 15%-20% 에달한다 1). 이러한경우심혈관의동맥류나협착과같은합병증이발생할수있으며심할경우심인성급사의원인이될수도있다. Pro-brain natriuretic peptide (pro-bnp) 는성인에서심부전및심근경색과관련된심실기능부전을반영하는중요한진단적지표이면서예후를예측하는인자로사용되고있으며, 소아에서도선천성심장병이나심근증의진단에이용되고있다. 따라서본연구는가와사키병의심환자에서심혈관합병증의발생과관련된인자들을살펴보고 pro-bnp가이를예측하는지표로사용될수있는지의여부를알아보고자하였다. 대상과방법 2010년 1월부터 2014년 12월까지응급실에내원하여가와사키병으로진단되고심초음파를시행한 214명의환자들에대한자료를수집하였다. 이중 20명은의무기록이충실히작성되지않아서, 이후 49명은완전가와사키병으로진단되어서, 13명은혈액검사가불충분하여배제되었다. 이에총 132명의불완전가와사키병의심환자에대한분석을시행하였다. 자료는환자의나이 ( 개월 ), 성별, 심초음파의시행여부, 심혈관합병증유무, 발열일수, 가와사키병의증상유무및혈액검사결과에대해수집하였다. 심혈관합병증은울혈성심부전, 심근염, 심막염, 판막질환, 심혈관의동맥류및확장으로정의하였다. 통계분석은 SPSS ver (SPSS Inc., Chicago, IL, USA) 을사용하였다. 불완전가와사키병환자군에서심혈관합병증이있는군과없는군의비교는 Student t-test와 chi-square test를이용하였으며, 불완전가와사키병에서의심혈관합병증발생의감별진단을위한 pro-bnp의진단적유용성분석을위해 receiver operating characteristic (ROC) curve를이용하였다. 통계적유의수준은 P < 0.05로하였다. 결과 연구에는 67명의남아 (50.3%) 와 65명의여아 (49.7%) 가포함되었고그비율은 1.03:1이었다. 진단당시의환아들의나이는 2-83개월 ( 평균값, 24.9개월 ) 이었다. 심혈관합병증이발생한군은 14명이었고해당군의평균연령은 21.2±14.2개월이었으며남아가 9례 (64.3%), 여아는 5례 (35.7%) 이었다. 심혈관합병증이발생하지않은군은 118명이었고해당군의평균연령은 25.6±17.4개월이었으며남아가 58례 (49.2%), 여아는 60례 (50.8%) 이었다. 하지만이두간의연령과성별은심혈관합병증의발생유무와관련이없었다 (Table 1). 혈액검사상심혈관합병증이발생한군과발생하지않은군사이에통계학적차이를보인값은혈소판수치와 pro-bnp였으며, 심혈관합병증이발생하지않은군과발생한군에서각각평균혈소판수치는 358.4± /μl 과 286.9± /μl 였으며 P = 0.022로유의한값을보였다. 또한 pro-bnp의경우두군에서값이각각 770.0±848.1 pg/ml과 1,782.1±1,849.5 pg/ml 이었다 (P < 0.001) (Table 1). 심혈관합병증이발생한군에서 pro-bnp의평균값이더높았고 (Fig. 1), 불완전가와사키병에서의심혈관합병증발생의감별진단을위한 pro-bnp의 ROC curve 아래의면적은 (95% 신뢰구간, ; P = 0.014) 이었다. 또한 cut-off 값을 로정했을때민감도는 85.7%, 특이도는 42.4% 이었다 (Fig. 2). Pro-BNP 수치에따른분포는심혈관합병증이없는군은 pg/ml에서가장많이나타났고심혈관합병증이발생한군에서는 500-1,000 pg/ml에서가장호발하였지만수치가높아질수록그빈도가증가하였으며 P = 0.003으로유의하였다 (Fig. 3). 하지만, 가와사키병의특정임상증상의유무나개수에따른 pro-bnp 값의차이는없었다 (Table 2). 혈액검사상 pro-bnp 값과유의성을보인검사로는, 전체혈구계산중혈색소와적혈구용적률이있었고, 화학검사상에서알칼리성인산염분해효소 (alkaline phosphatase) 와감마 -글루타밀전이효소(gamma-glutamyl transferase) 값이있었다 (Table 3). 76 Pediatric Emergency Medicine Journal

3 응급실에내원한불완전가와사키병환아에서심혈관합병증을예측하기위한인자로서 Pro-BNP 의유용성 Table 1. Clinical and biochemical characteristics of patients with normal coronary artery and cardiovascular abnormality (n=132) Variable Cardiovascular abnormality absent group Cardiovascular abnormality group P value Number Age (mo) 25.6± ± > 4 yr 013 (11.0) Male 058 (49.2) 09 (64.3) Symptom count (49.2) 06 (42.9) Fever 5 d 024 (20.3) 02 (14.3) Conjunctival injection 110 (93.2) 12 (85.7) Changes in lips and oral cavity 091 (77.1) 13 (92.9) Changes in extremities 064 (54.2) 07 (50.0) Polymorphous exanthema 098 (83.1) 12 (85.7) Cervical lymphadenopathy 043 (36.4) 05 (35.7) White blood cell ( 10 3 /μl, n=132) 14.3± ± Hemoglobin (g/dl, n=132) 11.5± ± Hematocrit (%, n=132) 33.9± ± Platelet ( 10 3 /μl, n=132) 358.4± ± Erythrocyte sedimentation rate (mm/hr, n=130) 66.9± ± C-reactive protein (mg/l, n=129) 62.5± ± Aspartate aminotransferase (IU/L, n=131) 093.8± ± Alanine aminotransferase (IU/L, n=131) 102.6± ± Alkaline phosphatase (IU/L, n=131) 254.5± ± Gamma-glutamyltransferase (IU/L, n=106) 077.7± ± Blood urea nitrogen (mg/dl, n=131) 8.03± ± Creatinine (mg/dl, n=131) 0.27± ± Pro-brain natriuretic peptide (pg/ml, n=132) 770.0± ,782.1±1,849.5 < Values are presented as mean±standard deviation or number (%). Fig. 1. Comparison of pro-bnp concentration levels between patients with and without cardiovascular abnormality. pro-bnp: pro-brain natriuretic peptide. Fig. 2. Receiver operating characteristic curve for pro-brain natriuretic peptide in patients with cardiovascular abnormality due to incomplete Kawasaki disease. Pediatric Emergency Medicine Journal 77

4 대한소아응급의학회지제 2 권제 2 호 2015 Fig. 3. Patient distribution with respect to concentration of pro-brain natriuretic peptide. Table 2. Comparison of pro-brain natriuretic peptide concentration between patients with and without specific manifestations Variable Absent Present P value Age > 4 yr (n=13) ±1, ± Fever 5 d (n=26) ±1, ± Symptom count 4 (n=64) ±1, ± Conjunctival injection (n=122) ±1, ± Changes in lips and oral cavity (n=104) 765.6± ±1, Changes in extremities (n=71) ±1, ±1, Polymorphous exanthema (n=110) ±1, ± Cervical lymphadenopathy (n=48) 1,008.5±1, ± Values are presented as mean±standard deviation. Table 3. Correlations between biochemical markers and pro-brain natriuretic peptide Variable Pearson correlation coefficient P value White blood cell (n=132) Hemoglobin (n=132) Hematocrit (n=132) Platelet (n=132) Erythrocyte sedimentation rate (n=130) C-reactive protein (n=129) < Aspartate aminotransferase (n=131) Alanine aminotransferase (n=131) Alkaline phosphatase (n=131) Gamma-glutamyl transferase (n=106) Blood urea nitrogen (n=131) Creatinine (n=131) Pediatric Emergency Medicine Journal

5 응급실에내원한불완전가와사키병환아에서심혈관합병증을예측하기위한인자로서 Pro-BNP 의유용성 고찰 가와사키병은 20% 에서심혈관의동맥류를형성하며 5% 에서심근경색을일으키고 1% 에서심인성급사를유발한다 3,4). 최근세계적으로발생률이증가하고있기때문에그임상적중요성은더욱높아지고있다 5-7). 가와사키병에서남아와여아의발생비율은 1.5-2:1 정도로알려져있으나, 본연구에서는거의동일하였다. 또한본연구에서불완전가와사키병환자에서심혈관합병증의발생률은 132례중 14례로 10.6% 정도로나타났다. Pro-BNP는심혈관합병증을보인군에서상승된소견을보였고, 심혈관합병증의예측인자로서도의미있는값을보였다. 따라서불완전가와사키병을진단받은환자에서 pro-bnp의상승을통해심혈관합병증을예측할수있을것으로기대할수있다. 가와사키병에있어심혈관합병증이발생한환자의경우약 20% 에서심혈관협착이발생하거나침습적인심혈관시술이필요한데, 조기에아스피린및정맥주사용면역글로불린으로치료하였을때가와사키병의심혈관합병증의발생률이 20-25% 에서 3-5% 로감소하는것으로알려져있다 1,8-11). 한편 pro-bnp는심실근의장력이나심실충만압이증가할때좌심실에서분비되는호르몬으로서, 심부전이나심근경색등심실의기능부전이심할수록혈중농도가증가한다 12). 따라서가와사키병에서심혈관계를침범하는경우 pro-bnp 농도가증가한다면, 심혈관계합병증발생을예측하는데진단적가치가있다고가정할수있다. Pro-BNP와그 N-terminal pro-bnp는심근이늘어나거나심부전, 신부전, 또는일차성고알도스테론증의경우와같이체액이증가할때, 그리고심실비대나허혈이있을때좌심실에서생성되고분비되는호르몬으로, 정상인에서는매우낮은농도를보인다 13,14). 한편가와사키병의급성기에는 pro-bnp가증가하게되는데, 그이유로는 Kawamura 등 15) 이언급한바와같이국소적인심근의염증또는허혈에의한것으로생각할수있다. BNP는심근경색에서크게증가한다고알려져있고, BNP의합성과분비는심근의괴사혹은심실에대한주변의자극에의해증가된다고 Morita 등 16) 이언급하 였다. 이를통해심근의괴사또는허혈이국소적일때에도 BNP가증가된다고추정할수있다. 또한급성기가와사키병에서 pro-bnp가증가하는또다른기전으로사이토카인의역할을들수있다. Tumor necrosis factor (TNF)-α또는 interleukin (IL)-1β는심근세포로부터 BNP의분비를유도한다고보고되고있다. 그리고 TNF-α, IL-1α, IL-1β와 interferon-β등의사이토카인은가와사키병급성기에증가하는것으로알려져있다 16-20). 특히 IL-1β는 BNP 전사를자극하는사이토카인으로쥐의심근세포를배양한실험에서 BNP 생성에관여한다고보고되고있다. 이러한사이토카인이가와사키병급성기에심근염을일으키고 BNP의분비를유도한다고추정할수있다. Dahdah 등 21) 은가와사키병과비가와사키병군에서 pro-bnp를비교하여가와사키병을진단하기위한검사로서유용성을보여주었고, Cho 등 22) 은가와사키병을진단하기위한검사로 pro-bnp와 C-reactive protein을비교하여 pro-bnp가가와사키병을진단하는데진단적가치가있으며불완전가와사키병을진단하고치료를시작하는데도움이됨을보여주었다. 하지만심혈관합병증발생의예측인자로서의 pro-bnp의유용성에대한보고는없었다. 따라서본연구에서는불완전가와사키병에서심혈관합병증에대한예측인자로서 pro-bnp의유용성을최초로보여주었다는의미가있다. 또한이러한시도는향후가와사키병의합병증을예측하는데유용할것으로생각한다. 하지만본연구는단일기관에서수집된자료를바탕으로시행된연구이기때문에포함된환자군이제한적이라는점과의무기록검토를통해후향적으로진행되었다는점에서, 자료를선택함에있어서오차가있을수있다. 따라서추후더많은환자군을대상으로하는연구가필요할것으로생각한다. 하지만이러한시도는향후가와사키병의합병증을예측하는데유용한정보를제공할것으로생각한다. 결론적으로, 불완전가와사키병의신속한진단과심혈관합병증발생의예측은환자의예후에도움이될수있으며, pro-bnp는심혈관합병증발생의예측인자로이용될수있을것이다. REFERENCES 01. Yim D, Curtis N, Cheung M, Burgner D. An update on Kawasaki disease II: clinical features, diagnosis, treatment and outcomes. J Paediatr Child Health 2013;49: 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 Pediatric Emergency Medicine Journal 79

6 대한소아응급의학회지제 2 권제 2 호 2015 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: Freeman AF, Shulman ST. Kawasaki disease: summary of the American Heart Association guidelines. Am Fam Physician 2006;74: Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 1996;94: Luca NJ, Yeung RS. Epidemiology and management of Kawasaki disease. Drugs 2012;72: Lin YT, Manlhiot C, Ching JC, Han RK, Nield LE, Dillenburg R, et al. Repeated systematic surveillance of Kawasaki disease in Ontario from 1995 to Pediatr Int 2010;52: Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J Epidemiol 2012; 22: Bhatnagar SK, Paul G, Subramanian R, Al Hosni MS, Al Khusaiby SM. Kawasaki disease in Oman: a clinical study. J Trop Pediatr 2003;49: Singh S, Kawasaki T. Kawasaki disease: an Indian perspective. Indian Pediatr 2009;46: Kim SH, Kim KH, Kim DS. Clinical characteristics of Kawasaki disease according to age at diagnosis. Indian Pediatr 2009;46: Juan CC, Hwang B, Lee PC, Lin YJ, Chien JC, Lee HY, et al. The clinical manifestations and risk factors of a delayed diagnosis of Kawasaki disease. J Chin Med Assoc 2007;70: Hall C. Essential biochemistry and physiology of (NTpro) BNP. Eur J Heart Fail 2004;6: Cowie MR, Mendez GF. BNP and congestive heart failure. Curr Probl Cardiol 2003;28: Cowie MR, Jourdain P, Maisel A, Dahlstrom U, Follath F, Isnard R, et al. Clinical applications of B-type natriuretic peptide (BNP) testing. Eur Heart J 2003;24: Kawamura T, Wago M, Kawaguchi H, Tahara M, Yuge M. Plasma brain natriuretic peptide concentrations in patients with Kawasaki disease. Pediatr Int 2000;42: Morita E, Yasue H, Yoshimura M, Ogawa H, Jougasaki M, Matsumura T, et al. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation 1993;88: Suzuki H, Uemura S, Tone S, Iizuka T, Koike M, Hirayama K, et al. Effects of immunoglobulin and gamma-interferon on the production of tumour necrosis factor-alpha and interleukin-1 beta by peripheral blood monocytes in the acute phase of Kawasaki disease. Eur J Pediatr 1996;155: Sato N, Sagawa K, Sasaguri Y, Inoue O, Kato H. Immunopathology and cytokine detection in the skin lesions of patients with Kawasaki disease. J Pediatr 1993;122: Maury CP, Salo E, Pelkonen P. Circulating interleukin-1 beta in patients with Kawasaki disease. N Engl J Med 1988;319: Kawamura T, Wago M. Brain natriuretic peptide can be a useful biochemical marker for myocarditis in patients with Kawasaki disease. Cardiol Young 2002;12: Dahdah N, Siles A, Fournier A, Cousineau J, Delvin E, Saint-Cyr C, et al. Natriuretic peptide as an adjunctive diagnostic test in the acute phase of Kawasaki disease. Pediatr Cardiol 2009;30: Cho SY, Kim Y, Cha SH, Suh JT, Han MY, Lee HJ. Adjuvant laboratory marker of Kawasaki disease; NT-pro- BNP or hs-crp? Ann Clin Lab Sci 2011;41: Pediatric Emergency Medicine Journal

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경락경혈학회지 Vol.27, No.1, pp.87 106, 2010 Journal of Meridian & Acupoint Dept. of 1 Meridian & Acupoint, 3 Acupuncture & Moxibustion, College of Oriental Medicine, Daejeon University 2 Division of Clinical