Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that primarily affects small- and mediumsized

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1 N-Terminal Pro-Brain Natriuretic Peptide and Risk of Coronary Artery Lesions and Resistance to Intravenous Immunoglobulin in Kawasaki Disease Ken Yoshimura, MD, Takahisa Kimata, MD, Kenji Mine, MD, Takamichi Uchiyama, MD, Shoji Tsuji, MD, and Kazunari Kaneko, MD Objective To determine whether the serum N-terminal pro-brain natriuretic peptide () can be a useful marker not only to identify the patients with Kawasaki disease (KD) who are at a higher risk of developing coronary artery lesions (CAL), and predict resistance to intravenous immunoglobulin (IVIG). Study design We enrolled 80 patients with the acute phase of KD at a single center. The demographic, clinical, and laboratory data were prospectively collected. Results Nineteen of the 80 patients developed CAL, despite IVIG administration. They had a significantly higher serum level in comparison with the patients without CAL. The cut-off value of 1300 pg/ml yielded a sensitivity of 95% and a specificity of 85% for predicting CAL. However, 17 of the 80 patients were IVIG non-responders. They also had a significantly higher serum level in comparison with the IVIG responders. The cut-off value of 800 pg/ml yielded a sensitivity of 71% and a specificity of 62% for predicting IVIG non-responders. Conclusions The serum level is increased in children with KD with CAL and IVIG resistance. It may be useful to predict CAL and IVIG resistance in KD. (J Pediatr 2013;162:1205-9). Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that primarily affects small- and mediumsized arteries in infants and children, with the development of coronary artery lesions (CAL) occurring in as many as 3% to 5% of children treated with intravenous immunoglobulin (IVIG). 1 Approximately 10%-15% of patients with KD do not respond to IVIG therapy 1 and resistance to IVIG is a greater risk for developing CAL. 2 It is important to identify these patients because they might benefit from more aggressive initial treatment. Currently, several studies have reported new stratified strategies that are effective for the treatment of patients predicted to have severe KD, based on various scoring systems. 3,4 However, no useful single marker has so far been discovered. Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide () are released from ventricular cardiomyocytes in response to an increase in ventricular wall stress and to myocardial ischemia. 5,6 Both BNP and have been proven to be reliable diagnostic and prognostic biomarkers in patients with heart failure and coronary artery disease in adults. 7 Several studies reported increased plasma BNP or levels in patients with the acute phase of KD without cardiac involvement, thus providing useful markers for diagnosing KD The purpose of this study was to determine whether the serum levels can be a useful marker for patients with KD who are at higher risk of developing CAL and resistance to IVIG. Methods The study subjects consisted of patients diagnosed with KD at the Department of Pediatrics of Kansai Medical University Hospital, Japan, between November 2008 and May All of the subjects fulfilled the Criteria for Diagnostic Guideline established by the Kawasaki Disease Research Committee in Japan. 12 The exclusion criteria included the presence of another disease known to mimic KD, previous diagnosis of KD, and incomplete KD. All patients received 30 mg/kg/d aspirin until they were afebrile and 2 g/kg of IVIG for 24 hours. The first illness day was defined BNP Brain natriuretic peptide as the day of fever onset. CAL CRP IVIG KD LMT plad prca WBC Coronary artery lesions C-reactive protein Intravenous immunoglobulin Kawasaki disease Left main trunk N-terminal pro-brain natriuretic peptide Proximal left anterior descending Proximal right coronary artery White blood cell From the Department of Pediatrics, Kansai Medical University, Osaka, Japan Funded by the Mami Mizutani Foundation. The authors declare no conflicts of interest /$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved

2 THE JOURNAL OF PEDIATRICS Vol. 162, No. 6 No response to the initial treatment with IVIG was defined as a fever lasting more than 24 hours after the end of the IVIG infusion. 13 Echocardiograms were performed on all subjects before the initial treatment, at 36 hours after the end of the IVIG infusion, and at 2 weeks and 1 month after the day of illness. The presence of CAL was diagnosed based on the Z scores of the left main trunk (LMT) coronary artery, proximal left anterior descending (plad) coronary artery, and proximal right coronary artery (prca) using echocardiograms, and was defined as the Z scores of 2.5 or more. The value of Z scores from a standardized coronary artery dimension were calculated from the body surface area 14 based on Haycock s formula. 15 Blood samples were obtained from the enrolled subjects. Laboratory tests, including white blood cell (WBC) counts, serum sodium levels, serum C-reactive protein (CRP) levels, serum albumin concentration, and serum levels were performed on all subjects before the initial IVIG treatment. WBC were analyzed using an XE-2100 instrument (Sysmex Co, Kobe, Japan). The serum levels of sodium, CRP, and albumin were measured by an auto-analyzer (AU5400 and AU2700; Beckman-Coulter Japan, Tokyo, Japan). Serum was measured using an electrochemiluminescence immunoassay on the ECLusys 2010 analyzer (Roche Diagnostics, Indianapolis, Indiana). Parental informed consent was obtained for each child enrolled in this study. The Research Ethics Committee of Kansai Medical University approved the study (no. H110401). The patients were categorized into 2 groups according to whether they were complicated with CAL: those who developed a significant CAL (CAL + ), and those who did not develop CAL (CAL ), and also whether they responded to the initial IVIG treatment: those who respond to the initial IVIG treatment (IVIG + ), and those who resisted the initial IVIG treatment (IVIG ). Demographic data, such as the age or sex, and clinical data, such as the day of illness and response to treatment, were compared between the CAL + and CAL groups, and between the IVIG + and IVIG groups. In addition to the serum levels of, routine laboratory data, such as the WBC, the serum levels of sodium, CRP, and albumin were compared between the CAL + and CAL groups, and also the IVIG + and IVIG groups. A receiver operating characteristic curves analysis was performed on, WBC, sodium, albumin, and CRP to predict CAL and IVIG resistance. Statistical Analyses The data are presented as the medians with the 25th and 75th percentiles in square brackets. The statistical analysis for comparisons of the CAL + versus the CAL group and the IVIG + and IVIG groups were performed by the Mann Whitney U test for numerical data and 2-sided c 2 test for categorical data. All P values were 2-tailed. A value of P <.05 was considered to be statistically significant for all tests. All of the statistical analyses were performed using the statistical package for social sciences (add-in software for Microsoft Excel: Excel Statistics 2010; SSRI, Tokyo, Japan) for the Windows software package. Results Eighty children (54 males and 26 females) with the acute phase of KD, age range years (median age: 1.7 years), were enrolled in this study. Nineteen of the 80 eligible patients developed CAL despite receiving IVIG. The distribution of CAL was LMT in 6 patients, plad artery in 13 patients, and prca in 10 patients. Although a maximum Z score $2.5 was noted in 24% (19/80) of patients during the first month of illness, all patients demonstrated a Z score <2.5 thereafter. There were no significant differences in the age or the ratio of males to females between the CAL and CAL + groups (age: 2.0 [ ] and 1.1 [ ] years; male/female: 43/18 and 11/8, respectively) (Table I). No significant difference was found for the day of the illness before IVIG (4.0 [ ] and 5.0 [ ] day) and the sampling day of illness (4.0 [ ] and 4.0 [ ] day). The number of initial IVIG-resistant patients was significantly higher in the CAL + group (42% in CAL + vs 15% in CAL, P =.0213). In the laboratory data that have been previously reported as possible predictors for risk of CAL, the patients in the CAL + group had higher WBC counts (CAL + vs CAL group, 16.9 [ ] vs 12.8 [ ] 10 3 /ml; P =.0041), a lower serum albumin level (3.4 [ ] vs 3.7 [ ] g/dl; P =.0231), and a higher serum level (2592 [ ] vs 453 [ ] pg/ml; P <.0001) in comparison with the patients in the CAL group. There were no significant differences in any other examined variables, such as the serum sodium and CRP levels, between the 2 groups. The serum levels to predict CAL in patients with KD was assessed by a receiver operating characteristic curves analysis (Figure). The area under the curve for predicting CAL with various variables were as follows: serum NTproBNP 0.932, WBC 0.719, CRP 0.646, serum sodium 0.539, serum albumin Thus, the serum level of was considered to be the best single predictor for CAL among these biochemical markers in patients with KD. A NTproBNP cut-off value of 1300 pg/ml yielded a sensitivity of 95%, a specificity of 85%, a positive predictive value of 67%, and a negative predictive value of 98% for predicting CAL in the acute phase of KD (Table II). McCrindle et al reported that the normal anatomic variations in the size of LMT render the interpretation of CAL less reliable. 14 Therefore, we reanalyzed our data, excluding the two patients with enlargement of the LMT without accompanying dilation of plad artery or prca. Re-analysis confirmed the serum level of to be the best single predictor for CALs. Its cut-off value of 1300 pg/ml yielded a sensitivity of 94%, a specificity of 83%, a positive predictive value of 59%, and a negative predictive value of 98%. Seventeen of the 80 eligible patients were IVIG nonresponders (IVIG )(Table III). There was no significant 1206 Yoshimura et al

3 June 2013 ORIGINAL ARTICLES Table I. Demographic, laboratory characteristics of patients at the diagnosis in the group without CAL and with CAL CAL (n = 61) CAL + (n = 19) P value Age (y) 2.0 [ ] 1.1 [ ].1974 ( ) ( ) Male sex (%)* Body surface 0.51 [ ] 0.43 [ ].0512 area (m 2 ) ( ) ( ) Day of illness of 4.0 [ ] 5.0 [ ].6640 IVIG (d) ( ) ( ) IVIG non-responder (%)* 15 (9/61) 42 (8/19).0213 Sampling day of 4.0 [ ] 4.0 [ ].2012 illness (d) ( ) ( ) WBC count (10 3 /ml) 12.8 [ ] ( ) 16.9 [ ] ( ).0041 Sodium (meq/l) [ ] [ ].6036 ( ) ( ) CRP (mg/dl) 6.5 [ ] 8.4 [ ].0553 ( ) ( ) Albumin (g/dl) 3.7 [ ] 3.5 [ ].0231 ( ) ( ) (10 2 pg/ml) 4.5 [ ] ( ) 25.9 [ ] ( ) <.0001 Presented as the median with the 25th and 75th percentiles in square brackets; the mean SD in round brackets. Mann-Whitney U test. *2-sided c 2 test. difference in sex between the IVIG + and IVIG groups (male/ female: 46/17 and 8/9, respectively). No significant difference was found for the day of the illness before IVIG (5.0 [ ] and 4.0 [ ] day) and the sampling day of illness (4.0 [ ] and 4.0 [ ] day). The number of patients who developed CAL was significantly higher in the IVIG group (47% in IVIG vs 17% in IVIG + group, P =.0213). In the laboratory data that have been previously reported as possible predictors for risk of CAL, the patients in the IVIG group had a lower serum sodium level (IVIG vs IVIG + group, [ ] vs [ ] meq/l; P =.0326), a higher CRP level (10.4 [ ] vs 6.5 [ ] mg/dl; P =.0029), and a higher serum NTproBNP level (1790 [570-3,115] vs 536 [ ] pg/ml; P =.0049) in comparison with the patients in the IVIG + group. In addition, no significant differences were observed in any other variables examined, including the WBC counts and serum albumin levels, between the 2 groups. The area under the curve for predicting resistance to IVIG (Figure) with various variables were: serum 0.724, CRP 0.737, WBC 0.499, serum albumin 0.610, serum sodium Therefore, the serum level of and serum CRP were considered to be better single predictor for IVIG non-responders. A cut-off value of 800 pg/ml yielded a sensitivity of 71%, a specificity of 62%, a positive predictive value of 89%, and a negative predictive value of 33% for predicting IVIG non-responders in the acute phase of KD (Table II). Discussion Kurotobi and Takeuchi suggested that left ventricle diastolic dysfunction may occur in children with acute phase KD, and 1 : 1364 pg/ml A 1 : 886 pg/ml B Sensitivity Sensitivity Specificity 1 - Specificity AUC White blood cell count C-reactive protein Sodium Albumin A B Figure. Receiver operating characteristic curves comparing the sensitivity and specificity of various variables and A, echocardiographic diagnosis of CAL; B, the response to initial IVIG treatment. AUC, area under the curve., filled circles; WBC count, open squares; CRP, open triangles; sodium, open circles; albumin, filled squares. N-Terminal Pro-Brain Natriuretic Peptide and Risk of Coronary Artery Lesions and Resistance to Intravenous Immunoglobulin in Kawasaki Disease 1207

4 THE JOURNAL OF PEDIATRICS Vol. 162, No. 6 Table II. Differences in among the subgroups (pg/ml) CAL (n) CAL + (n) Total (n) > < Total (n) (pg/ml) IVIG + (n) IVIG (n) Total (n) > < Total (n) Sensitivity: 95%, specificity: 85%, positive predictive value: 67%, negative predictive value: 98%. Sensitivity: 71%, specificity: 62%, positive predictive value: 89%, negative predictive value: 33%. the serum BNP may therefore be useful as a clinical marker of the severity of KD. 21,22 On the other hand, inflammation itself might be associated with increased BNP. Several studies reported that inflammatory cytokines can directly promote BNP synthesis and secretion from cardiomyocytes. Ogawa et al reported that inflammation induced lipopolysaccharides increase the gene expression of cytokines and chemokines, which significantly correlates with the BNP gene expression in rats. 23 We previously reported that can be a useful biomarker to predict which patients with KD are at greater risk of CAL before initial IVIG. 24 In the present study, we further confirmed that the serum levels increased in KD children with CAL in a larger sample and also found that it was increased in IVIG non-responders. Regarding the comparative strengths and limitations of BNP and, a rapid rise and fall of circulating Table III. Demographic, laboratory characteristics of patients at the diagnosis in the IVIG responsive group, and the IVIG resistant group IVIG + (n = 63) IVIG (n = 17) P value Age (y) 2.0 [ ] 1.0 [ ].0202 ( ) ( ) Male sex (%)* Body surface area (m 2 ) 0.51 [ ] 0.42 [ ].0157 ( ) ( ) Day of illness of 5.0 [ ] 4.0 [ ].2650 IVIG (d) ( ) ( ) Complicated with 17 (11/63) 47 (8/17).0213 CAL (%)* Sampling day of 4.0 [ ] 4.0 [ ].4815 illness (d) ( ) ( ) WBC count (10 3 /ml) 13.4 [ ] 14.3 [ ].9906 ( ) ( ) Sodium (meq/l) [ ] [ ].0326 ( ) ( ) CRP (mg/dl) 6.5 [ ] 10.4 [ ].0029 ( ) ( ) Albumin (g/dl) 3.7 [ ] 3.5 [ ].1652 ( ) ( ) (10 2 pg/ml) 5.4 [ ] ( ) 17.9 [ ] ( ).0049 Presented as the median with the 25th and 75th percentiles in square brackets; the mean SD in round brackets. Mann-Whitney U test. *2-sided c 2 test. BNP may not be readily captured in a disease where myocardial dysfunction is not an overt feature, and increased NTproBNP appears to be sustained in the circulation. Thus, it may provide a more practical tool for following myocardial stress in acute KD than BNP. 8 BNP is cleared from the plasma by binding to the natriuretic peptide receptor and through proteolysis by the neutral endopeptidases, and is mainly cleared by renal excretion. Thus, they have distinct half-lives (BNP: 20 min; : 120 min). Consequently, serum levels are approximately 6 times higher than serum BNP levels, even though both molecules are released in equimolar proportions. 25 At our institution, CAL were previously assessed by performing serial echocardiography, primarily by quantifying the internal coronary artery dimension the Japanese Ministry of Health criteria, including a maximum absolute internal diameter >3 mm in children <5 years of age or >4 mm in children 5 years and older, or segment 1.5 times greater than an adjacent segment or the presence of luminal irregularity. 26 The Japanese Ministry criteria are not strictly based on the body size of the individual patients, but coronary artery dimensions in normal children increase linearly with indices of body size. Therefore, the Japanese Ministry criteria tend to underestimate the true incidence of coronary artery dilatation in patients with KD. 14,27 To avoid these errors in the present study, we diagnosed the presence of CAL based on the Z scores of coronary arteries calculated by regression equations based on body surface area of non-febrile normal children. 14 There is a limitation with respect to the variation of NTproBNP with age. Nir et al 28 described that the levels were very high soon after birth, and thereafter, decreased drastically in the first days and gradually with age throughout childhood. However, it seems unlikely that the age-dependent variation in the serum levels of NT-pro BNP strongly affect our conclusions. All subjects in the present study were over 1 month of age. Furthermore, age-specific incidence of KD is very low among children aged 0-2 months, who demonstrate the very high levels of, In addition, levels of all subjects in CAL + subgroup in our study were greater than the 97.5th percentile reported in the article by Nir et al. 28 Nonetheless, the inability to obtain age-specific correlation could be a limitation of our study. A larger scale prospective controlled study to test the diagnostic validity of considering its age-related variability would be helpful. The serum concentration of may be useful for predicting CAL and IVIG resistance in patients with the acute phase of KD. It is worthwhile to consider and evaluate risk stratified strategies for patients at higher risk of developing severe KD based on the serum concentration of NTproBNP. n Submitted for publication Jul 21, 2012; last revision received Oct 16, 2012; accepted Nov 9, Reprint requests: Ken Yoshimura, MD, Department of Pediatrics, Kansai Medical University, Shin-machi, Hirakata-shi, Osaka , Japan. yoshimuk@hirakata.kmu.ac.jp 1208 Yoshimura et al

5 June 2013 ORIGINAL ARTICLES References 1. Burns JC, Glode MP. Kawasaki syndrome. Lancet 2004;364: Durongpisitkul K, Soongswang J, Laohaprasitiporn D, Nana A, Prachuabmoh C, Kangkagate C. Immunoglobulin failure and retreatment in Kawasaki disease. Pediatr Cardiol 2003;24: Ogata S, Ogihara Y, Honda T, Kon S, Akiyama K, Ishii M. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial. Pediatrics 2012;129:e Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Arakawa H, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomized, open-label, blinded-endpoints trial. Lancet 2012;379: Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S, et al. Human brain natriuretic peptide, a novel cardiac hormone. Lancet 1990;335: Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90: 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: 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: Kawamura T, Wago M. Brain natriuretic peptide can be a useful biochemical marker for myocarditis in patients with Kawasaki disease. Cardiol Young 2002;12: McNeal-Davidson A, Fournier A, Spigelblatt L, Saint-Cyr C, Mir TS, Nir A, et al. Value of amino-terminal pro B-natriuretic peptide in diagnosing Kawasaki disease. Pediatr Int 2012;54: Kishimoto S, Suda K, Teramachi Y, Nishino H, Kudo Y, Ishii H, et al. Increased plasma type B natriuretic peptide in the acute phase of Kawasaki disease. Pediatr Int 2011;53: Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 2005;47: Saji T, Sonobe T, Uemura S, Akagi T, Ayusawa M, Kato H, et al. Guideline of acute phase therapy for Kawasaki disease. J Japan Pediatr Soc 2003;107: (in Japanese). 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: Haycock GB, Schwartz GJ, Wisotsky DH. Genometric method for measuring body surface area: a height-weight formula dated in infants, children, and adults. J Pediatr 1978;93: 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: Muta H, Ishii M, Furui J, Nakamura Y, Matsuishi T. Risk factors associated with the need for additional intravenous gamma-globulin therapy for Kawasaki disease. Acta Paediatr 2006;95: Nakamura Y, Yashiro M, Uehara R, Watanabe M, Tajimi M, Oki I, et al. Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease. Pediatr Int 2004;46: Song D, Yeo Y, Ha K, Jang G, Lee J, Lee K, et al. Risk factors for Kawasaki disease-associated coronary abnormalities differ depending on age. Eur J Pediatr 2009;168: Beiser AS, Takahashi M, Baker AL, Sundel RP, Newburger JW. A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group. Am J Cardiol 1998;81: Kurotobi S, Kawakami N, Shimizu K, Aoki H, Nasuno S, Takahashi K, et al. Brain natriuretic peptide as a hormonal marker of ventricular diastolic dysfunction in children with Kawasaki disease. Pediatr Cardiol 2005;26: Takeuchi D, Saji T, Takatsuki S, Fujiwara M. Abnormal tissue Doppler images are associated with elevated plasma brain natriuretic peptide and increased oxidative stress in acute Kawasaki disease. Circ J 2007; 71: Ogawa T, de Bold AJ. Uncoordinated regulation of atrial natriuretic factor and brain natriuretic peptide in lipopolysaccharide-treated rats. Biomarkers 2012;17: Kaneko K, Yoshimura K, Ohashi A, Kimata T, Shimo T, Tsuji S. Prediction of the risk of coronary arterial lesions in Kawasaki disease by brain natriuretic peptide. Pediatr Cardiol 2011;32: de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362: Research Committee on Kawasaki Disease. Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesion in Kawasaki Disease. Tokyo, Japan: Japanese Ministry of Health and Welfare; 1984 (in Japanese). 27. de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW. Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr 1998;133: Nir A, Lindinger A, Rauh M, Bar-Oz B, Laer S, Koch A, et al. NT-pro-Btype natriuretic peptide in infants and children: reference values based on combined date from four studies. Pediatr Cardiol 2009;30:3-8. N-Terminal Pro-Brain Natriuretic Peptide and Risk of Coronary Artery Lesions and Resistance to Intravenous Immunoglobulin in Kawasaki Disease 1209