Comparison of Different Types and Regimens of Intravenous Immune Globulin (IVIG) in Patients with Kawasaki Disease

Original Article Acta Cardiol Sin 2004;20:15 20 Pediatric Cardiology Comparison of Different Types and Regimens of Intravenous Immune Globulin (IVIG) in Patients with Kawasaki Disease Chi-Ming Liang, 1 Pi-Chang Lee, 1 Betau Hwang, 1,2 Jen-Her Lu, 1 Ping-Yao Wang, 1 Chen-Hsiang Lien 1 and C.C. Laura Meng 1 Object: To evaluate the effect of different types and regimens of high-dose intravenous immune globulin (IVIG) on patients with Kawasaki Disease. Patients: From June 1994 to May 2002, 120 patients who met the diagnostic criteria of Kawasaki Disease (KD) at our institution were reviewed. Of them, 99 who had complete data were enrolled in this study. Before IVIG therapy, 25 (25.3%) of 99 patients had coronary artery involvement. Methods: Patients with KD were given a different brand and dosage of IVIG when available in the hospital in random order. They were divided randomly into 4 groups with different types and regimens of high-dose IVIG. Group I (33 cases)- G regimen, 400 mg/kg/day 5 days; Group II (47 cases)- G regimen, 2 gm/kg 1 dose; Group III (10 cases)- I regimen, 400 mg/kg/day 5 days; Group IV (9 cases)- I regimen, 2 gm/kg 1 dose. Patients data were collected including: 1. age and sex; 2. symptoms and signs; 3. fever lasting days after IVIG; 4. echocardiographic findings (before IVIG, at acute stage, at convalescent stage, and long term follow-up); 5. retreatment with IVIG. Results: 1. There were some differences in the clinical features, including sex, age, duration of fever before administration of IVIG, and diagnostic criteria of Kawasaki Disease among the 4 groups; 2. The durations of fever lasting after administration of IVIG were 3.9 2.2, 2.8 1.4, 4.3 2.5, and 2.0 1.3 days in Groups I, II, III and IV, respectively; 3. Two-dimensional echocardiographic evidence of coronary arterial dilatation/aneurysm detected before IVIG in Groups I, II, III and IV were, respectively, 36.4%, 40.4%, 30.0%, and 11.1%, at acute stage were 60.6%, 44.7%, 20%, and 22.2%, at convalescent stage were 12.1%, 17.0%, 0%, and 0%, and at long-term follow-up were 12.1%, 12.8%, 0%, and 0%. 4. The rates of retreatment with IVIG were 9.1%, 8.5%, 10%, 11.1% in Group I, II, III and IV, respectively. Conclusions: 1. Treatment of Kawasaki Disease with the regimen of 2 gm/kg one dose of IVIG had a better effect to shorten the duration of fever than that with 400 mg/kg/day 5 days. 2. G and I regimens seemed to make a difference in prevention of coronary dilation/aneurysm at acute stage, although the difference was without statistical significance; and there were no statistical differences in convalescent stage, long-term follow-up and retreatment, even for different dosages and brands. 3. If the patients with coronary abnormalities before IVIG were excluded, coronary abnormality prevention rates were 50.0%, 49.2%, 100%, and 100%, respectively, by the four different regimens of IVIG. Key Words: Intravenous immune globulin (IVIG) Kawasaki Disease Coronary artery Received: April 29, 2003 Accepted: June 16, 2003 1 Division of Pediatric Cardiology, Taipei Veterans General Hospital; 2 National Yang-Ming University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Pi-Chang Lee, Department of Pediatrics, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan. Tel: 886-2-2875-7576 ext. 102; Fax: 886-2-2873-9019; E-mail: liangcm5953@yahoo.com.tw INTRODUCTION Kawasaki Disease, or mucocutaneous lymph node syndrome, is an acute pediatric disorder characterized by fever, truncal rash, conjunctival injection, inflammation 15 Acta Cardiol Sin 2004;20:15 20

Chi-Ming Liang et al. of the oral mucosa, cervical adenopathy, edema, erythema and desquamation of hands and feet. 1 Originally recognized in Japan, cases of Kawasaki Disease have now been reported throughout the world. Taubert et al. 2 estimated the minimal incidence of Kawasaki Disease in the United States to be 2000 cases per year. Kawasaki Disease is self-limited in the majority of afflicted patients and cause unknown. 3 Between 20% and 25% of patients, however, develop coronary abnormalities, including ectasia, aneurysm, stenosis and thrombosis, that may lead to myocardial ischemia, infarction and sudden death. 4 Because of its anti-inflammatory and antithrombotic action, aspirin has generally been used in the treatment of Kawasaki Disease. 5,6 The data presented indicate that intravenous administration of immune globulin (IVIG) also has an important role in the management of this disorder. 7 Intravenous administration of high-dose immune globulin (IVIG) early in the course of Kawasaki Disease (KD) is well-known to reduce the incidence of coronary arterial lesion from 40% to 20% at acute stage and from 20% to less than 10% at convalescent dosage. 8-10 The Japanese Ministry of Health suggested that current treatment is more than 95% effective in preventing coronary artery changes. Echocardiographic measurements adjusted for body size imply a far higher incidence of coronary artery dilation despite prompt therapy. 11 Considering chronic alterations in endothelial function after KD, more effective management of acute and recurrent KD are needed. But the effects of different compositions and dosage of immune globulin to prevent the occurrence of coronary arterial lesion in patients with Kawasaki Disease need to be studied; such study was the purpose of this investigation. METHODS Patients The study participants were 120 patients who met the diagnostic criteria of Kawasaki Disease (KD), reviewed at our institution from June 1994 to May 2002. Ninety-nine of them who had complete data were enrolled for study. Twenty-five (25.3%) cases with coronary artery involvement were noted before IVIG therapy. Patients with KD were given a different brand and dosage of IVIG available in the hospital in random order. They were divided randomly into 4 groups with different types and regimen, which included: Group I (33 cases)- G regimen, 400 mg/kg/day 5 days; Group II (47 cases)- G regimen, 2 gm/kg 1 dose; Group III (10 cases)- I regimen, 400 mg/kg/day 5 days; and Group IV (9 cases)- I regimen, 2 gm/kg 1 dose. G regimen (Gamimune N, Cutter Biological, Berkeley, CA, USA, a division of Miles Laboratories, Inc.): The G regimen is a kind of human immunoglobulin containing a broad spectrum of opsonic and neutralizing IgG antibodies. It is produced by using cold ethanol fractionation of large pools of human plasma, isolated by diafiltration and ultrafiltration, and manufactured from pools of at least 1000 donors. Each milliliter (ml) contains 50 mg of protein, of which at least 98% is gamma globulin. Not less than 90% of which gamma gobulin is monomer, present trace of IgA and IgM. The distribution of subclasses is similar to that found in normal plasma (Table 3). Mean half-life was found to be 35 17 days and range 19 days to 52 days. I regimen (Intraglobin F, Biotest Pharma, GmbH, Dreieich, Germany): The I regimen works through its neutralizing effect that increases the opsonisation of toxins and microorganisms. It is manufactured by pooling of plasma from more than 1000 healthy donors. 1 ml solution contains human plasma protein 50 mg, of which immunoglobulin is at least 95%. The patients data included: age and sex; symptoms and signs; fever lasting days after IVIG; echocardiographic abnormalities before IVIG, at acute stage, convalescent stage, and long-term follow-up; and retreatment with IVIG. The coronary abnormalities criteria were 1) internal diameter greater than 3 mm in children younger than 5 years of age, 2) internal diameter greater than 4 mm in children older than 5 years of age, 3) internal diameter of a segment 1.5 times greater than that of an adjacent segment, and 4) irregular coronary artery lumen. 10 Two-dimensional echocardiography (2DE) was performed periodically before and after the administration of IVIG. Cardiac catheterization and coronary angiography was performed in patients with abnormal 2DE following or with symptoms and signs of myocardial ischemia. Statistical analysis The descriptions of basic data, such as age and sex, were presented as mean value ( SD) and percentage. Acta Cardiol Sin 2004;20:15 20 16

Intravenous Immune Globulin in Kawasaki Disease Analysis of variance (ANOVA) test (2-sided test) was used to compare the basic data with continuous clinical features as independent variables. Additionally, the categorical clinical feature variables were compared using Chi-Square test (2-sided test). To investigate the difference for the incidence of coronary arterial lesion in the 4 groups, Chi-Square test (2-sided test) and Fisher s exact test (2-sided test) were undertaken with the five categorical variables, Before IVIG, Acute stage, Convalescent stage, Long-term follow-up and Re-treatment rate. The advantage of Fisher s exact test (2-sided test) was applicable to the rare data set. Finally, to understand the varieties of IVIG effect in each group, the three categorical variables, acute stage, convalescent stage and long-term follow-up, were analyzed by McNemar s test (2-sided test). It was suitable to analyze matched-pair data structures by utilizing McNemar s test (2-sided test). We set the significance level in all tests as > 0.05. RESULTS The clinical features including sex, age, duration of fever before administration of IVIG, and diagnostic criteria of Kawasaki disease were somewhat different among these 4 groups (Table 1). The durations of fever lasting after administration of IVIG were 3.9 2.2, 2.8 1.4, 4.3 2.5, and 2.0 1.3 days in Group I, II, III, and IV, respectively (Table 1). We compared these 4 groups; for shorter lasting fever days, IVIG with 2 gm/kg/day 1 dose was better than 400 mg/kg/day 5daysinbothG and I regimen (I vs. II, p < 0.05, III vs. IV, p < 0.05) and there were no statistical differences among G and I regimens (I vs. III, p > 0.05, II vs. IV, p > 0.05) (Table 1). Two-dimensional echocardiographic evidence of coronary arterial dilatation/aneurysm was detected in 36.4%, 40.4%, 30.0%, and 11.1% before IVIG, 60.6%, 44.7%, 20.0%, and 22.2% at acute stage, and 12.1%, 17.0%, 0%, and 0% at convalescent stage in Groups I, II, III and IV, respectively (Table 2). And the rates of retreatment with IVIG were 9.1%, 8.5%, 10%, 11.1% in Groups I, II, III and IV, respectively (Table 2). We also compared at acute stage: I vs. II, II vs. III, II vs. IV, III vs. IV were all p > 0.05, but I vs. III and I vs. IV were both p < 0.05; this means I regimen was better than G regimen in 400 mg/kg/day 5daysor2gm/kg 1 doses (Table 2). Then we compared at convalescent, long-term follow-up, retreatment with IVIG rate: I vs. II, I vs. III, I vs. IV, II vs. IV, II vs. IV, and III vs. IV all were p > Table 2. Echocardiographic coronary abnormalities in different groups and comparisons Groups I (n = 33) II (n = 47) III (n = 10) IV (n = 9) Before IVIG 12 (36.4) 19 (40.4) 3 (30.3) 1 (11.1) Acute stage 20 (60.6)* 21 (44.7) 3(20)* 2(22.2) Convalescent stage 4 (12.1) 8(17) 0(0)** 0(0)** Long term follow up 4 (12.1) 6(12.8) 0(0)** 0(0)** Re-treatment 3 (9.1) 4 (8.5) 1 (10) 0 (0) Data are presented as the mean SD or number (%); *I vs. III, Fisher s exact test: p = 0.034;** unable to estimate the statistics; group I and II: acute stage vs. convalescent stage, acute stage vs. long-term follow-up, all p < 0.05 (by McNemar s test); group I and II: convalescent stage vs. long-term follow-up, p > 0.05 (by McNemar s test); unable to estimate the statistics. Table 1. General data of different groups, duration of fever after IVIG Group I (n = 33) II (n = 47) III (n = 10) IV (n = 9) Male/Female 13/20 19/28 8/2 8/1 Mean age SD (year old) 2.1 2.2 2.1 2.0 2.1 1.5 2.3 1.3 Clinical manifestations Fever 5 days 32 (97) 43 (91.5) 8 (80) 9 (100) Limbs indurations 22 (66.7) 26 (55.3) 7 (70) 2 (22.2) Tips desquamation 15 (44.5) 19 (40.4) 5 (50) 3 (33.3) Rashes 28 (84.9) 41 (87.2) 8 (80) 9 (100) Conjunctival congestion 29 (87.9) 41 (87.2) 9 (90) 9 (100) Oral redness 32 (97) 46 (97.9) 10 (100) 9 (100) Cervical lymphoadenopathy 21 (63.6) 22 (46.8) 8 (80) 4 (44.4) Duration of fever after IVIG (Mean SD) days 3.9 2.2* 2.8 1.4* 4.3 2.5** 2.0 1.3** *I vs. II, p < 0.05; ** III vs. IV, p < 0.05; Data are presented as the mean SD or number (%). 17 Acta Cardiol Sin 2004;20:15 20

Chi-Ming Liang et al. Figure 1. Echocardiographic evaluations of coronary abnormalities in different groups of patients. 0.05; which means there were no statistical differences among G regimen and I regimens even in 400 mg/kg/day 5daysorin2gm/kg 1 dose (Table 2). We also compared at acute stage, at convalescent, and long-term follow-up s coronary abnormality rates by McNemar s test in different groups, which showed that IVIG use could improve coronary abnormality in subsequent echocardiographic studies (Table 2, Figure 1). DISCUSSION The coronary abnormality rates before the IVIG therapy were higher than in previous reports, possibly because our hospital is a tertiary medical center which usually accepts referral patients in more serious condition. 12 To shorten the fever days, 2 gm/kg 1 dose had better effect than 400 mg/kg/day 5 days, a finding similar to Barron et al. s report in 1990 in which 1 gm/kg single dose was more effective than 400 mg/kg/day 4 days to shorten the duration of fever after IVIG. 13 Hwang et al. have reported no difference in the prevalence of coronary aneurysm between the groups of a single high dose and multiple doses, although the single high dose of IVIG could improve the clinical symptoms more quickly and shorten the duration of hospitalization. 14 Sato N, et al. reported that the incidence of coronary artery complications in the 2 g group was significantly lower than in the 400 mg group. 15 The duration of high fever, positive duration of C-reactive protein and the hospital days in the 2 g group were all significantly shorter than in the 400 mg group. 15 Tsai et Table 3. IgG subclass in plasma and IVIG analysis IgG subclass G regimen I regimen Plasma IgG 1 58.7% 62% 60% IgG 2 29.3% 34% 29.4% IgG 3 6.3% 0.5% 6.5% IgG 4 5.1% 3.5% 4.1% al. reported that G regimen was better than the other brands in preventing coronary dilation and lowering retreatment rate. 16 In our data, G regimen appeared to make lower retreatment rate than I regimen, but the difference was not significant (because numbers of I regimen were too small). According to the instructions of product, preparation, methods and compositions of G and I regimens were nearly alike, except that IgG 3 and IgG 4 in G regimen were slightly higher than in I regimen (Table 3). The number of patients in Group III and Group IV was small, and the coronary artery abnormality rate in Group I was higher in our study than other groups; all the above may lead to some bias appearance, especially the coronary artery abnormality rates in convalescent and long-term follow-up of Group III and Group VI being zero, which made our comparison doubtful. So, in the future, we should collect more cases of Group III and Group IV, in order to reduce bias in different groups. Results in Table 2 and Figure 1 confirm that IVIG used can improve coronary abnormality rate over time. The 4 groups compositions, including sex and age, were different, which may produce some bias in later comparison between groups; but for before IVIG echocardiographic coronary abnormalities, we compared Acta Cardiol Sin 2004;20:15 20 18

Intravenous Immune Globulin in Kawasaki Disease all groups; all p values were greater than 0.05, so there were no echocardiographic coronary abnormality rate differences before IVIG, and then later comparisons were meaningful. In the future, we will design for different sexes and ages for IVIG therapy study, in order to rule out the influence of age and sex. CONCLUSIONS Treatment of Kawasaki disease with a regimen of 2 gm/kg one dose of IVIG has a better effect to shorten the duration of fever than that of 400 mg/kg/day 5 days. G and I regimens seemed to make a difference in the prevention of coronary dilation/aneurysm at acute stage; I regimen was better than G regimen, but there was no statistically significant difference in convalescent stage, long-term follow-up and retreatment with IVIG rate between G and I regimens. If the patients with coronary abnormalities before IVIG were excluded, the prevention rates of coronary abnormalities were 50.0%, 49.2%, 100%, 100%, respectively, in the different regimens of IVIG in this study. For the prevention of coronary dilation/aneurysm, at acute stage, I regimen was better than G regimen in 400 mg/kg/day 5daysor 2gm/kg 1 dose, but there were no statistical differences among convalescent stage, long-term follow-up and retreatment with IVIG rate between G regimen and I regimen, even in 400 mg/kg/day 5daysor2gm/kg 1 dose. ACKNOWLEDGMENT We are grateful for support from the Cardiac Children s Foundation, R.O.C. REFERENCES 1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi 1967;16:178-222. 2. Taubert KA, Rowley AH, Shulman ST. Seven-year national survey of Kawasaki disease and acute rheumatic fever. Pediatr Infect Dis J 1994;13:704-8. 3. Fischer P, Uttenreuther-Fischer MM, Naoe S, et al. Kawasaki disease: update on diagnosis, treatment, and a still controversial etiology. Pediatr Hematol Oncol 1996;13:487-501. 4. Sundel RP. Update on the treatment of Kawasaki disease in childhood. Curr Rheumatol Rep 2002;4:474-82. 5. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324:1633-9. 6. Barron KS. Kawasaki disease. Epidemiology, late prognosis, and therapy. Rheum Dis Clin North Am 1991;17:907-19. 7. Yanagawa H, Yashiro M, Nakamura Y, et al. IV gamma globulin treatment of Kawasaki disease in Japan: results of a nationwide survey. Acta Paediatr 1995;84:765-8. 8. Barron KS, Murphy DJ Jr, Silverman ED, et al. Treatment of Kawasaki syndrome: a comparison of two dosage regimens of intravenously administered immune globulin. J Pediatr 1990; 117:638-44. 9. Hwang B, Lin CY, Hsieh KS, et al. High-dose intravenous gamma globulin therapy in Kawasaki disease. Acta Peadiatr Sinica 1989;30:15-22. 10. Engle MA, Fatica NS, Bussel JB, et al. Clinical trial of single-dose intravenous gamma globulin in acute Kawasaki disease: Preliminary report. Am J Dis Child 1989;143:1300-4. 11. Sundel RP. Update on the treatment of Kawasaki disease in childhood. Curr Rheumatol Rep 2002;4:474-82. 12. Research Committee on Kawaski disease. Report of Subcommittee on standarization of diagnostic criteria and report of coronary artery lesions in Kawasaki disease. Tokyo: Ministry of Health and Welfare, 1984. 13. Jiao F, Yang L, Li Y, et al. Epidemiologic and clinical characteristics of Kawasaki disease in Shaanxi Province, China, 1993-1997. J Trop Pediatr 2001;47:54-6. 14. Hwang KP, Wu IR, Huang LY, et al. Clinical manifestations and effects of IVGG in patients with Kawasaki disease. Kaohsiung J Med Sci 1996;12:159-66. 15. Sato N, Sugimura T, Akagi T, et al. Selective high dose gammaglobulin treatment in Kawasaki disease: assessment of clinical aspects and cost effectiveness. Pediatr Int 1999;41:1-7. 16. Tsai MH, Yen MH, Huang YC, et al. Intravenous immunoglobulin treatment in Kawasaki disease: effective in all brands. The 171 st Scientific Meeting of Taiwan Pediatric Association, oral presention. 19 Acta Cardiol Sin 2004;20:15 20