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Erschienen in: Heart and Vessels 10/2020

24.05.2020 | Original Article

The combination of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as a novel predictor of intravenous immunoglobulin resistance in patients with Kawasaki disease: a multicenter study

verfasst von: Takashi Kanai, Seiichiro Takeshita, Yoichi Kawamura, Keiji Kinoshita, Keigo Nakatani, Satoru Iwashima, Yuji Takizawa, Keiichi Hirono, Kazuetsu Mori, Yusuke Yoshida, Shigeaki Nonoyama

Erschienen in: Heart and Vessels | Ausgabe 10/2020

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Abstract

Introduction

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to be a predictor for intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD) recently. The objective of the present study was to elucidate the predictive validity of this new marker in a multicenter study.

Materials and methods

We retrospectively reviewed the clinical records of 520 consecutive KD patients (development data set) and 332 subsequent patients (validation data set) at 7 hospitals in Japan.

Results

Both NLR and PLR were significantly higher in the IVIG-resistant group than in the IVIG-responsive group. When we set the cut-off point as NLR ≥ 4.11 and PLR ≥ 119, multiple logistic regression analyses showed that a high NLR and PLR before initial IVIG were independent predictors of IVIG resistance, and their combination was a stronger predictor than either alone. The sensitivity and specificity of the combination of NLR ≥ 4.11 and PLR ≥ 119 were 0.58 and 0.73 in the development data set. Validated using an independent data set, they were 0.54 and 0.72 in the validation data set. On comparing the AUC of this predictor with those of the Gunma and Kurume scores, the AUC was highest for this predictor, followed by the Gunma score and Kurume score (0.70, 0.68, and 0.64, respectively).

Discussion

The predictive validity of the combination of a high NLR and PLR, which is a simple and convenient indicator, was equal to or better than that of the existing scoring systems. The new predictive marker may be a suitable indicator for predicting IVIG resistance in KD patients.
Literatur
1.
Zurück zum Zitat Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H (1974) A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 54:271–276PubMed Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H (1974) A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 54:271–276PubMed
2.
Zurück zum Zitat Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, Colan SD, Duffy CE, Fulton DR, Glode MP et al (1991) A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 324:1633–1639CrossRefPubMed Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, Colan SD, Duffy CE, Fulton DR, Glode MP et al (1991) A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 324:1633–1639CrossRefPubMed
3.
Zurück zum Zitat Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y, Kotani K, Tsogzolbaatar EO, Yanagawa H (2012) Epidemiologic features of Kawasaki disease in Japan: results of the 2009–2010 nationwide survey. J Epidemiol 22:216–221CrossRefPubMedPubMedCentral Nakamura Y, Yashiro M, Uehara R, Sadakane A, Tsuboi S, Aoyama Y, Kotani K, Tsogzolbaatar EO, Yanagawa H (2012) Epidemiologic features of Kawasaki disease in Japan: results of the 2009–2010 nationwide survey. J Epidemiol 22:216–221CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, Matsuishi T (2006) Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 149:237–240CrossRefPubMed Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, Matsuishi T (2006) Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr 149:237–240CrossRefPubMed
5.
Zurück zum Zitat Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, Kobayashi T, Morikawa A (2006) Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 113:2606–2612CrossRefPubMed Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, Kobayashi T, Morikawa A (2006) Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 113:2606–2612CrossRefPubMed
6.
Zurück zum Zitat Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, Kogaki S, Hara J (2007) Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr 166:131–137CrossRefPubMed Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, Kogaki S, Hara J (2007) Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr 166:131–137CrossRefPubMed
7.
Zurück zum Zitat Sato S, Kawashima H, Kashiwagi Y, Hoshika A (2013) Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients. Int J Rheum Dis 16:168–172CrossRefPubMed Sato S, Kawashima H, Kashiwagi Y, Hoshika A (2013) Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients. Int J Rheum Dis 16:168–172CrossRefPubMed
8.
Zurück zum Zitat Wakiguchi H, Hasegawa S, Suzuki Y, Kudo K, Ichiyama T (2015) Relationship between T-cell HLA-DR expression and intravenous immunoglobulin treatment response in Kawasaki disease. Pediatr Res 77:536–540CrossRefPubMed Wakiguchi H, Hasegawa S, Suzuki Y, Kudo K, Ichiyama T (2015) Relationship between T-cell HLA-DR expression and intravenous immunoglobulin treatment response in Kawasaki disease. Pediatr Res 77:536–540CrossRefPubMed
9.
Zurück zum Zitat Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, Atz AM, Printz BF, Baker A, Vetter VL, Newburger JW, Pediatric Heart Network I (2011) Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr 158:831 e3–835 e3CrossRef Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, Atz AM, Printz BF, Baker A, Vetter VL, Newburger JW, Pediatric Heart Network I (2011) Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr 158:831 e3–835 e3CrossRef
10.
Zurück zum Zitat Acet H, Ertas F, Akil MA, Ozyurtlu F, Polat N, Bilik MZ, Aydin M, Oylumlu M, Yuksel M, Yildiz A, Kaya H, Akyuz A, Ozbek M (2016) Relationship between hematologic indices and global registry of acute coronary events risk score in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost 22:60–68CrossRefPubMed Acet H, Ertas F, Akil MA, Ozyurtlu F, Polat N, Bilik MZ, Aydin M, Oylumlu M, Yuksel M, Yildiz A, Kaya H, Akyuz A, Ozbek M (2016) Relationship between hematologic indices and global registry of acute coronary events risk score in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost 22:60–68CrossRefPubMed
11.
Zurück zum Zitat Lian L, Xia YY, Zhou C, Shen XM, Li XL, Han SG, Zheng Y, Mao ZQ, Gong FR, Wu MY, Chen K, Tao M, Li W (2015) Application of platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and prognostic prediction in patients with resectable gastric cancer. Cancer Biomark 15:899–907CrossRefPubMed Lian L, Xia YY, Zhou C, Shen XM, Li XL, Han SG, Zheng Y, Mao ZQ, Gong FR, Wu MY, Chen K, Tao M, Li W (2015) Application of platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and prognostic prediction in patients with resectable gastric cancer. Cancer Biomark 15:899–907CrossRefPubMed
13.
Zurück zum Zitat Kawamura Y, Takeshita S, Kanai T, Yoshida Y, Nonoyama S (2016) The combined usefulness of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in predicting intravenous immunoglobulin resistance with Kawasaki disease. J Pediatr 178(281–284):e1 Kawamura Y, Takeshita S, Kanai T, Yoshida Y, Nonoyama S (2016) The combined usefulness of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in predicting intravenous immunoglobulin resistance with Kawasaki disease. J Pediatr 178(281–284):e1
14.
Zurück zum Zitat Takeshita S, Kanai T, Kawamura Y, Yoshida Y, Nonoyama S (2017) A comparison of the predictive validity of the combination of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and other risk scoring systems for intravenous immunoglobulin (ivig)-resistance in Kawasaki disease. PLoS ONE 12:e0176957CrossRefPubMedPubMedCentral Takeshita S, Kanai T, Kawamura Y, Yoshida Y, Nonoyama S (2017) A comparison of the predictive validity of the combination of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and other risk scoring systems for intravenous immunoglobulin (ivig)-resistance in Kawasaki disease. PLoS ONE 12:e0176957CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Kanai T, Ishiwata T, Kobayashi T, Sato H, Takizawa M, Kawamura Y, Tsujimoto H, Nakatani K, Ishibashi N, Nishiyama M, Hatai Y, Asano Y, Kobayashi T, Takeshita S, Nonoyama S (2011) Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study. Circulation 124:2822–2828CrossRefPubMed Kanai T, Ishiwata T, Kobayashi T, Sato H, Takizawa M, Kawamura Y, Tsujimoto H, Nakatani K, Ishibashi N, Nishiyama M, Hatai Y, Asano Y, Kobayashi T, Takeshita S, Nonoyama S (2011) Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study. Circulation 124:2822–2828CrossRefPubMed
16.
Zurück zum Zitat Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, Ishii M, Harada K, Kawasaki Disease Research C (2005) Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 47:232–234CrossRefPubMed Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, Ishii M, Harada K, Kawasaki Disease Research C (2005) Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int 47:232–234CrossRefPubMed
17.
Zurück zum Zitat DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845CrossRefPubMed DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845CrossRefPubMed
18.
Zurück zum Zitat Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458CrossRefPubMed Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458CrossRefPubMed
19.
Zurück zum Zitat Tang Y, Yan W, Sun L, Huang J, Qian W, Ding Y, Lv H (2016) Prediction of intravenous immunoglobulin resistance in Kawasaki disease in an East China population. Clin Rheumatol 35:2771–2776CrossRefPubMed Tang Y, Yan W, Sun L, Huang J, Qian W, Ding Y, Lv H (2016) Prediction of intravenous immunoglobulin resistance in Kawasaki disease in an East China population. Clin Rheumatol 35:2771–2776CrossRefPubMed
20.
Zurück zum Zitat Ha KS, Lee J, Jang GY, Lee J, Lee KC, Son CS, Lee JW (2015) Value of neutrophil-lymphocyte ratio in predicting outcomes in Kawasaki disease. Am J Cardiol 116:301–306CrossRefPubMed Ha KS, Lee J, Jang GY, Lee J, Lee KC, Son CS, Lee JW (2015) Value of neutrophil-lymphocyte ratio in predicting outcomes in Kawasaki disease. Am J Cardiol 116:301–306CrossRefPubMed
21.
Zurück zum Zitat Yuan YD, Sun J, Li PF, Wei CL, Yu YH (2017) Values of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in predicting sensitivity to intravenous immunoglobulin in Kawasaki disease. Chin J Contemp Pediatr 19:410–413 Yuan YD, Sun J, Li PF, Wei CL, Yu YH (2017) Values of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in predicting sensitivity to intravenous immunoglobulin in Kawasaki disease. Chin J Contemp Pediatr 19:410–413
22.
Zurück zum Zitat Cho HJ, Bak SY, Kim SY, Yoo R, Baek HS, Yang S, Hwang IT, Ban JE (2017) High neutrophil: lymphocyte ratio is associated with refractory Kawasaki disease. Pediatr Int 59:669–674CrossRefPubMed Cho HJ, Bak SY, Kim SY, Yoo R, Baek HS, Yang S, Hwang IT, Ban JE (2017) High neutrophil: lymphocyte ratio is associated with refractory Kawasaki disease. Pediatr Int 59:669–674CrossRefPubMed
23.
Zurück zum Zitat Niwa Y, Sohmiya K (1984) Enhanced neutrophilic functions in mucocutaneous lymph node syndrome, with special reference to the possible role of increased oxygen intermediate generation in the pathogenesis of coronary thromboarteritis. J Pediatr 104:56–60CrossRefPubMed Niwa Y, Sohmiya K (1984) Enhanced neutrophilic functions in mucocutaneous lymph node syndrome, with special reference to the possible role of increased oxygen intermediate generation in the pathogenesis of coronary thromboarteritis. J Pediatr 104:56–60CrossRefPubMed
24.
Zurück zum Zitat Takeshita S, Nakatani K, Kawase H, Seki S, Yamamoto M, Sekine I, Yoshioka S (1999) The role of bacterial lipopolysaccharide-bound neutrophils in the pathogenesis of Kawasaki disease. J Infect Dis 179:508–512CrossRefPubMed Takeshita S, Nakatani K, Kawase H, Seki S, Yamamoto M, Sekine I, Yoshioka S (1999) The role of bacterial lipopolysaccharide-bound neutrophils in the pathogenesis of Kawasaki disease. J Infect Dis 179:508–512CrossRefPubMed
25.
Zurück zum Zitat Azab B, Zaher M, Weiserbs KF, Torbey E, Lacossiere K, Gaddam S, Gobunsuy R, Jadonath S, Baldari D, McCord D, Lafferty J (2010) Usefulness of neutrophil to lymphocyte ratio in predicting short- and long-term mortality after non-ST-elevation myocardial infarction. Am J Cardiol 106:470–476CrossRefPubMed Azab B, Zaher M, Weiserbs KF, Torbey E, Lacossiere K, Gaddam S, Gobunsuy R, Jadonath S, Baldari D, McCord D, Lafferty J (2010) Usefulness of neutrophil to lymphocyte ratio in predicting short- and long-term mortality after non-ST-elevation myocardial infarction. Am J Cardiol 106:470–476CrossRefPubMed
26.
Zurück zum Zitat Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T, Simoons ML, Hamm CW, Investigators C (2003) Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 108:1440–1445CrossRefPubMed Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T, Simoons ML, Hamm CW, Investigators C (2003) Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 108:1440–1445CrossRefPubMed
27.
Zurück zum Zitat Hansen PR (1995) Role of neutrophils in myocardial ischemia and reperfusion. Circulation 91:1872–1885CrossRefPubMed Hansen PR (1995) Role of neutrophils in myocardial ischemia and reperfusion. Circulation 91:1872–1885CrossRefPubMed
28.
Zurück zum Zitat Mehta J, Dinerman J, Mehta P, Saldeen TG, Lawson D, Donnelly WH, Wallin R (1989) Neutrophil function in ischemic heart disease. Circulation 79:549–556CrossRefPubMed Mehta J, Dinerman J, Mehta P, Saldeen TG, Lawson D, Donnelly WH, Wallin R (1989) Neutrophil function in ischemic heart disease. Circulation 79:549–556CrossRefPubMed
29.
Zurück zum Zitat Ommen SR, Gibbons RJ, Hodge DO, Thomson SP (1997) Usefulness of the lymphocyte concentration as a prognostic marker in coronary artery disease. Am J Cardiolo 79:812–814CrossRef Ommen SR, Gibbons RJ, Hodge DO, Thomson SP (1997) Usefulness of the lymphocyte concentration as a prognostic marker in coronary artery disease. Am J Cardiolo 79:812–814CrossRef
30.
Zurück zum Zitat Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ (1998) Predictive power of the relative lymphocyte concentration in patients with advanced heart failure. Circulation 97:19–22CrossRefPubMed Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ (1998) Predictive power of the relative lymphocyte concentration in patients with advanced heart failure. Circulation 97:19–22CrossRefPubMed
31.
Zurück zum Zitat Zahorec R (2001) Ratio of neutrophil to lymphocyte counts–rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 102:5–14PubMed Zahorec R (2001) Ratio of neutrophil to lymphocyte counts–rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 102:5–14PubMed
32.
Zurück zum Zitat Beiser AS, Takahashi M, Baker AL, Sundel RP, Newburger JW (1998) A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group. Am J Cardiol 81:1116–1120CrossRefPubMed Beiser AS, Takahashi M, Baker AL, Sundel RP, Newburger JW (1998) A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group. Am J Cardiol 81:1116–1120CrossRefPubMed
33.
Zurück zum Zitat Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, Martin DD, Newburger JW, Burns JC (2008) Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 153:117–121CrossRefPubMedPubMedCentral Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, Martin DD, Newburger JW, Burns JC (2008) Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 153:117–121CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Levin M, Holland PC, Nokes TJ, Novelli V, Mola M, Levinsky RJ, Dillon MJ, Barratt TM, Marshall WC (1985) Platelet immune complex interaction in pathogenesis of Kawasaki disease and childhood polyarteritis. Br Med J (Clin Res Ed) 290:1456–1460CrossRef Levin M, Holland PC, Nokes TJ, Novelli V, Mola M, Levinsky RJ, Dillon MJ, Barratt TM, Marshall WC (1985) Platelet immune complex interaction in pathogenesis of Kawasaki disease and childhood polyarteritis. Br Med J (Clin Res Ed) 290:1456–1460CrossRef
35.
Zurück zum Zitat Ueno K, Nomura Y, Hashiguchi T, Masuda K, Morita Y, Hazeki D, Eguchi T, Maruyama I, Kawano Y (2010) Platelet vascular endothelial growth factor is a useful predictor for prognosis in Kawasaki syndrome. Br J Haematol 148:285–292CrossRefPubMed Ueno K, Nomura Y, Hashiguchi T, Masuda K, Morita Y, Hazeki D, Eguchi T, Maruyama I, Kawano Y (2010) Platelet vascular endothelial growth factor is a useful predictor for prognosis in Kawasaki syndrome. Br J Haematol 148:285–292CrossRefPubMed
36.
Zurück zum Zitat Yahata T, Suzuki C, Yoshioka A, Hamaoka A, Ikeda K (2014) Platelet activation dynamics evaluated using platelet-derived microparticles in Kawasaki disease. Circ J 78:188–193CrossRefPubMed Yahata T, Suzuki C, Yoshioka A, Hamaoka A, Ikeda K (2014) Platelet activation dynamics evaluated using platelet-derived microparticles in Kawasaki disease. Circ J 78:188–193CrossRefPubMed
37.
Zurück zum Zitat Tuttle HA, Davis-Gorman G, Goldman S, Copeland JG, McDonagh PF (2003) Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease. Cardiovasc Diabetol 2:12CrossRefPubMedPubMedCentral Tuttle HA, Davis-Gorman G, Goldman S, Copeland JG, McDonagh PF (2003) Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease. Cardiovasc Diabetol 2:12CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Furie B, Furie BC (1997) Leukocyte crosstalk at the vascular wall. Thromb Haemost 78:306–309CrossRefPubMed Furie B, Furie BC (1997) Leukocyte crosstalk at the vascular wall. Thromb Haemost 78:306–309CrossRefPubMed
Metadaten
Titel
The combination of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as a novel predictor of intravenous immunoglobulin resistance in patients with Kawasaki disease: a multicenter study
verfasst von
Takashi Kanai
Seiichiro Takeshita
Yoichi Kawamura
Keiji Kinoshita
Keigo Nakatani
Satoru Iwashima
Yuji Takizawa
Keiichi Hirono
Kazuetsu Mori
Yusuke Yoshida
Shigeaki Nonoyama
Publikationsdatum
24.05.2020
Verlag
Springer Japan
Erschienen in
Heart and Vessels / Ausgabe 10/2020
Print ISSN: 0910-8327
Elektronische ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-020-01622-z

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