Abstract
Objective:
To investigate the optimal timing of initial intravenous immunoglobulin (IVIG) treatment in Kawasaki disease (KD) patients.
Methods:
KD patients were classified as the early group (day 1-4), conventional group (day 5-7), conventional group (day 8-10), and late group (after day 10). Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analyses and receiver operating characteristic (ROC) curve analysis.
Results:
There were no significant differences in IVIG resistance among the 4 groups (p = 0.335). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness (p = 0.761). In addition, patients who received IVIG administration more than 7 days from the onset had a higher proportion of coronary artery abnormalities (p = 0.034) and longer length of hospitalization (p = 0.033) than those who started IVIG administration less than 7 days. The optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41%.
Conclusions:
IVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required.
KEYWORDS
Kawasaki disease; KD; Intravenous immunoglobulin; IVIG; IVIG resistance
Introduction
Kawasaki disease (KD) is an acute, self-limited disease leading to systemic vasculitis that predominantly affects children younger than five.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4. KD surpasses acute rheumatic fever as a leading cause of acquired heart disease in developed countries.22 Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J Epidemiol. 2012;22:79–85. The most common complication of KD is coronary artery abnormalities (CAA), and its prevention is important to improve outcomes in patients with KD.33 Sánchez-Manubens J, Bou R, Anton J. Diagnosis and classification of Kawasaki disease. J Autoimmun. 2014;48-49: 113–7. Intravenous immunoglobulin (IVIG) is the mainstay of treatment in KD and has been known to be effective in abolishing vascular inflammations leading to coronary artery lesions (CALs).44 Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315:341–7. The fatality rates of KD have markedly decreased since the IVIG therapy was introduced in 1983.55 Takahashi K, Oharaseki T, Yokouchi Y, Yamada H, Shibuya K, Naoe S. A half-century of autopsy results–incidence of pediatric vasculitis syndromes, especially Kawasaki disease. Circ J. 2012;76:964–70.
However, the association between the earlier timing of IVIG administration of disease onset and risk for IVIG unresponsiveness remains debatable.66 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. Moreover, the literature comparing the early and routine IVIG therapy regarding the efficacy in preventing cardiac sequelae is limited and controversial.77 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9.,88 Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the efficacy of treatment of Kawasaki disease before day 5 of illness. Pediatr Cardiol. 2004;25:31–4.,99 Muta H, Ishii M, Furui J, Nakamura Y, Matsuishi T. Risk factors associated with the need for additional intravenous gammaglobulin therapy for Kawasaki disease. Acta Paediatr. 2006; 95:189–93.,1010 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.,1111 Zhang T, Yanagawa H, Oki I, Nakamura Y Factors relating to the cardiac sequelae of Kawasaki disease one month after initial onset. Acta Paediatr. 2002;91:517–20.,1212 Tse SM, Silverman ED, McCrindle BW, Yeung RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr. 2002;140:450–5. Furthermore, several latest guidelines on the optimal timing of IVIG administration and if IVIG can be given earlier remain inconclusive.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4.,1313 Marchesi A, Tarissi de Jacobis I, Rigante D, Rimini A, Malorni W, Corsello G, et al. Kawasaki disease: guidelines of the Italian Society of Pediatrics, part I - definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase. Ital J Pediatr. 2018;44:102.,1414 Fukazawa R, Kobayashi J, Ayusawa M, Hamada H, Miura M, Mitani Y, et al. JCS/JSCS 2020 guideline on diagnosis and management of cardiovascular sequelae in Kawasaki disease. Circ J. 2020;84:1348–407.
Given this background, the authors hypothesize that there is maybe a narrow therapeutic window of IVIG administration. Earlier or later IVIG treatment may affect the IVIG responsiveness and outcomes in KD patients. Thus, the authors performed a retrospective study to investigate the optimal timing of initial IVIG administration by comparing the outcomes of early and conventional IVIG treatment in KD patients.
Methods
The Chengdu Women’s and Children’s Central Hospital Ethics Committee approved the study protocol (Approval No.B202123) and waived informed consent requirements. All methods were carried out following the Declaration of Helsinki.
Study design and participants
All the patients with KD who were hospitalized at the Chengdu Women’s and Children’s Central Hospital between January 2018 and December 2020 were identified as participants in this retrospective study. The Chengdu Women’s and Children’s Central Hospital is a tertiary referral center that serves a catchment area of approximately 2 million people per year who live in the southwest region of China. Patients were diagnosed with KD according to the American Heart Association (AHA) guideline in 2017.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4. The inclusion criteria for study subjects were as follows: (1) patients were <18 years old; (2) patients of initial onset of KD; (3) patients received standard treatment with 2 g/kg of IVIG of single infusion during the acute phase of illness. Exclusion criteria were as follows: (1 ) recurrent KD; (2) patients had a severe infection, allergy, autoimmune diseases, or collagen disease; (3) patients who had received IVIG in the first three months of admission; (4) patients who did not receive IVIG or initial IVIG dose was <2 g/kg; (5) patients with missing clinical or laboratory information. The AHA guideline for KD recommends starting IVIG treatment within 10 days from the onset of symptoms and, if possible, within 7 days to prevent CAA because this is when vasculitis worsens. Several retrospective studies, however, reported that IVIG use at ≤ 4 days of illness had no benefit in preventing CAA, but was instead associated with increased IVIG resistance.77 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9.,88 Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the efficacy of treatment of Kawasaki disease before day 5 of illness. Pediatr Cardiol. 2004;25:31–4. Therefore, the present study hypothesizes that the clinical outcomes differed among four categories (start of IVIG therapy up to 4 days, 5-7 days, 8-10 days, and more than 10 days). Thus, the remaining patients who meet the inclusion criteria were classified into four groups: those who received the initial IVIG ≤ day 4 of illness (the early treatment group), those who received IVIG on days 5-7 (the conventional treatment group), those who received IVIG on days 8-10 (the conventional treatment group), and those who were treated after day 10 (the late treatment group). The first day of fever was defined as day 1.
Data collection
The demographic, clinical outcomes, and laboratory data were extracted from the medical records. Blood samples were collected within 24 h pre-IVIG treatment. IVIG resistance was defined as recrudescent or persistent fever ≥36 h but not longer than 7 days after initial IVIG infusion.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4.
Treatment protocol for KD patients
In the present study’s hospital, all KD patients received the standard therapy with IVIG (2 g/kg) and aspirin (30-50 mg/ kg/d during the acute phase of illness) immediately after the diagnosis. The aspirin was lowered to 3-5 mg/kg/d 2-3 days after the patients were afebrile. Other therapies, including prednisolone, were not used in the initial treatment. Combined antiplatelet and anticoagulation therapy were recommended for patients with giant aneurysms. For IVIG-resistant patients, the 2nd IVIG of the same dosage was administrated. If fever persists 36 h after the 2nd IVIG infusion, intravenous methylprednisolone (30 mg/kg/dose) was performed for 3 consecutive days. No patients received additional treatment such as infliximab, plasma exchange, and cytotoxic agents.
Complete KD was diagnosed in any children with a fever and had four or more of the following five major symptoms: (I) erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa, (II) polymorphous exanthema, (III) bilateral conjunctival congestion, (IV) changes of the peripheral extremities, and (V) unilateral cervical lymphadenopathy. Incomplete KD was defined as a child with a fever with fewer than four major symptoms and compatible laboratory or echocardiographic findings.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4.
Echocardiography
Echocardiography was used to detect CAA during hospitalization. Echocardiography was performed and supervised by an experienced echocardiographer and with appropriate transducers. The coronary artery abnormalities were defined as follows: (1) normal: Z score < 2; (2) only dilation: Z score 2 to < 2.5; or initial Z score < 2, Z score decline during follow-up (usually 6-12 months) ≥ 1; (3) small coronary aneurysm: Z score ≥ 2.5 to < 5; (4) medium coronary aneurysm: Z score ≥ 5 to <10, and absolute dimension < 8 mm; (5) large or giant coronary aneurysm: Z score ≥ 10, or absolute dimension ≥ 8 mm.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4. Patients with a Z score ≥ 2.0 were considered to be CAA. Coronary artery aneurysms were classified into small aneurysms, medium aneurysms, and large (or giant) aneurysms.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4. The Z-score was measured before IVIG administration using the formula by Dallaire and Dahdah.1515 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. The authors chose the maximum Z-scores of the left main coronary artery, left anterior descending coronary artery, left circumflex artery, and right coronary artery.
The primary outcomes were IVIG resistance and the development of CAA in the acute phase. The secondary outcome was the length of hospitalization.
Statistical analysis
The normality of the distribution of variables was checked using the Kolmogorov-Smirnov test. Continuous variables were expressed as mean ± standard deviations or median and IQR (25th, 75th percentile) if non-normally distributed. Categorical variables were expressed by presenting the frequency and proportion in each category. To compare the difference of variables according to the timing of initial IVIG administration of disease onset (≤ day 4, days 5-7, days 8-10, and >day 10), analysis of variance (ANOVA) or Kruskal-Wallis H test was applied for continuous variables, and Chi-square analysis was applied for categorical variables. For significance found by ANOVA, Kruskal-Wallis H test, or Chi-square test, the further pairwise comparison was conducted through the Dunnett-t-test or the least-significant difference (LSD) test based on the homogeneity of data variance, or Bonferroni method for cross-table.
The multivariate regression analysis was conducted to explore the factors associated with the prevalence of IVIG resistance and coronary artery abnormalities, which were dependent variables. The independent variables for multivariate regression analysis contained both categorical and continuous variables. The continuous variables were first screened by univariate analysis, namely t-test or Mann-Whitney U test, based on the distribution normality of variables. The variables associated with dependent variables were included in the regression model. The area under the receiver operating characteristic (ROC) curve was analyzed to assess the predictive accuracy of initial IVIG administration time for IVIG-resistant and to identify the optimal cutoff point according to the Youden index. A subgroup analysis was performed by dividing CAA into dilation, small aneurysm, and medium to large (or giant) aneurysm according to the AHA guideline in 2017.11 McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4. The authors also performed a sensitivity analysis to compare the primary and secondary outcomes between the patients who received the initial IVIG ≤day 7 of illness and >day 7 of illness. A P value less than 0.05 was considered statistically significant. All statistical analyses were performed with the IBM SPSS Statistics 25.0 (SPSS, Chicago, IL, USA).
Results
Characteristics of included KD Patient
A total of 965 KD patients who meet the inclusion criteria were included (Fig. 1), with a median age of 28.10 ± 19.79 months, ranging from 1 to 132 months. The ratio of males to females was 1.53:1. All patients received initial IVIG treatment once the KD diagnosis was made. There were 883 patients diagnosed as complete KD, accounting for 91.50% of the total KD patients. Forty patients were classified into the early group (≤ 4 days), 726 into the conventional (5-7 days) group, 160 into the conventional (8-10 days) group, and 39 into the late group (> 10 days). There were no significant differences in age. A slight difference (p = 0.039) was observed in gender among the four groups. The proportions of complete KD in early and conventional (5-7 days) groups were significantly higher than patients in conventional (8-10 days) and late groups (p = 0.000). The detailed information on the characteristics of included KD patients can be seen in Table 1.
Laboratory findings
The neutrophils%, C-reactive protein (CRP), White Blood Cell (WBC) count, and Hemoglobin (HB) in early and conventional (5-7 days) groups were significantly higher than those in conventional (8-10 days) and late groups (p ☐ 0.05), suggesting inflammatory reaction is severe in early and conventional (5-7 days) groups. Platelet in early and conventional (5-7 days) groups were significantly lower than in conventional (8-10 days) and late groups (p ☐ 0.05). AST and ALT in the conventional (5-7 days) group were higher than in the conventional (8-10 days) group. The four groups showed no significant difference in albumin and erythrocyte sedimentation rate (ESR) (Appendix S1 Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.07.003. ).
IVIG resistance, development of Coronary artery abnormalities, and the length of hospitalization
A total of 101 patients had IVIG resistance, accounting for 10.47% of the included KD patients. The early group had a higher IVIG-resistance rate (17.5%) than the other three groups. The conventional (5-7 days) group had the lowest IVIG-resistance rate (9.92%) among the 4 groups. However, there were no significant differences in IVIG resistance rate among the 4 groups (p = 0.335) (Table 2). The length of hospitalization of the late group was significantly longer than the two conventional groups (p = 0.000). There were 213 patients involved in CAA, accounting for 22.07%. The late group had the highest rate of CAA (38.46%). The rate of CAA in the late group was significantly higher than in the conventional (5-7 days) group (p < 0.05) (Table 2).
In the subgroup analysis, there was no significance in the proportion of dilation between each group. The conventional (5-7 days) group had the lowest proportion of small aneurysms (11.71%) and medium to large aneurysms (1.93%). Moreover, the early group has a proportion of small aneurysms significantly higher than the conventional (5-7 days) group (p < 0.01), while the late group has a proportion of medium to large aneurysms significantly higher than conventional (5-7 days) group (p < 0.01) (Table 3). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤day 7 of illness and those who received IVIG >day 7 of illness. There was a significant difference in the higher proportion of CAA (OR = 0.680; 95%CI = 0.476-0.972, p = 0.034) and longer length of hospitalization (p = 0.033) for those who started IVIG administration more than 7 days from the onset (Appendix S2 Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.07.003. ).
ROC curve regarding IVIG resistance and multivariate regression analysis
According to the ROC analysis, the optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41% (area under the curve was 0.785, 95% confidence interval was 0.758-0.811; p < 0.001) (Appendix S3 Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.07.003. ).
According to the multivariable logistic regression analysis, age and albumin were independent predictors of IVIG resistance in patients with KD (Appendix S4 Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.07.003. ). Incomplete KD, Gender, CRP, and albumin were independent risk factors of CALs in KD patients (Appendix S5 Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.07.003. ).
Discussion
This study aimed to investigate the optimal time option for initial IVIG treatment in KD patients. There were no significant differences in IVIG resistance among the 4 groups in the present study, although the early group had the highest IVIG resistance rate. The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness. However, patients who received IVIG administration more than 7 days from the onset had a higher proportion of CAA and longer length of hospitalization than those who started IVIG administration less than 7 days. Thus, IVIG therapy within 7 days of illness is more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness.
The late and conventional (8-10 days) groups had higher proportions of incomplete KD than the early and conventional (5-7 days) groups in the present study. A higher proportion of incomplete KD may experience significant delays in diagnosis,1616 Minich LL, Sleeper LA, Atz AM, McCrindle BW, Lu M, Colan SD, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics. 2007;120:e1434–40. which leads to the late IVIG therapy. Furthermore, it is not surprising that patients treated earlier had a higher level of CRP, neutrophils%, WBC, and lower platelet counts. It was suggested that the patients in the early and conventional (5-7 days) groups might likely have more typical symptoms and more severe cases than conventional (8-10 days) and late groups, leading to an early initial administration of IVIG.1717 Zhang T, Yanagawa H, Oki I, Nakamura Y, Yashiro M, Ojima T, et al. Factors related to cardiac sequelae of Kawasaki disease. Eur J Pediatr. 1999;158:694–7.
IVIG has been the mainstay of treatment in KD to reduce the prevalence of CAA. However, about 10–20% of patients show resistance to IVIG treatment and present a higher risk of coronary vasculitis.1818 Bar-Meir M, Kalisky I, Schwartz A, Somekh E, Tasher D. Israeli Kawasaki Group. Prediction of resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatric Infect Dis Soc. 2018;7:25–9. Initial IVIG resistance is also associated with an increased risk of coronary artery aneurysms.1919 Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr. 2011;158:831–5. e3.,2020 Moffett BS, Syblik D, Denfield S, Altman C, Tejtel-Sexson K. Epidemiology of immunoglobulin resistant Kawasaki disease: results from a large, national database. Pediatr Cardiol. 2015;36:374–8. The criteria for when to provide IVIG are unclear and differ from previous studies.77 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9.,1212 Tse SM, Silverman ED, McCrindle BW, Yeung RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr. 2002;140:450–5.,2121 Han RK, Silverman ED, Newman A, McCrindle BW. Management and outcome of persistent or recurrent fever after initial intravenous gamma globulin therapy in acute Kawasaki disease. Arch Pediatr Adolesc Med. 2000;154:694–9.,2222 Shiozawa Y, Inuzuka R, Shindo T, Mafune R, Hayashi T, Hirata Y, et al. Effect of i.v. immunoglobulin in the first 4 days of illness in Kawasaki disease. Pediatr Int. 2018;60:334–41.,2323 Li W, He X, Zhang L, Wang Z, Wang Y, Lin H, et al. A retrospective cohort study of intravenous immunoglobulin therapy in the acute phase of Kawasaki disease: the earlier, the better? Cardi-ovasc Ther. 2021;2021:6660407. The 2004 AHA and 2018 Italian Society of Pediatrics guidelines stated that IVIG should be used within 10 days after the onset of disease and, if possible, within 7 days. In the latest 2017 AHA guideline, it is suggested that IVIG should be instituted as early as possible within the 10 days of illness onset of fever; However, there is no suggestion on the optimal timing of IVIG and if it can be given earlier. Several studies reported that IVIG use at ≤ 4 days of illness is associated with increased IVIG resistance.77 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9.,2121 Han RK, Silverman ED, Newman A, McCrindle BW. Management and outcome of persistent or recurrent fever after initial intravenous gamma globulin therapy in acute Kawasaki disease. Arch Pediatr Adolesc Med. 2000;154:694–9.,2222 Shiozawa Y, Inuzuka R, Shindo T, Mafune R, Hayashi T, Hirata Y, et al. Effect of i.v. immunoglobulin in the first 4 days of illness in Kawasaki disease. Pediatr Int. 2018;60:334–41.,2424 Yan F, Zhang H, Xiong R, Cheng X, Chen Y, Zhang F. Effect of early intravenous immunoglobulin therapy in Kawasaki disease: a systematic review and meta-analysis. Front Pediatr. 2020;8:593435. These results must be interpreted with caution. Muta et al.77 Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9. reported early treatment is likely to result in a greater requirement for additional IVIG. Still, they did not perform multivariate analysis because of limited data associated with the need for IVIG retreatment. The present results are similar to previous studies that showed earlier IVIG treatment within 4 days may not increase the higher incidence of IVIG resistance.1212 Tse SM, Silverman ED, McCrindle BW, Yeung RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr. 2002;140:450–5.,2323 Li W, He X, Zhang L, Wang Z, Wang Y, Lin H, et al. A retrospective cohort study of intravenous immunoglobulin therapy in the acute phase of Kawasaki disease: the earlier, the better? Cardi-ovasc Ther. 2021;2021:6660407. The early group showed a high rate of IVIG resistance because there might be more patients with severe inflammation or atypical clinical course, respectively.
The IVIG resistance may be associated with the dynamic activation status of macrophages and the level of serum cytokines during the acute phase of KD.2525 Matsubara T, Ichiyama T, Furukawa S. Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease. Clin Exp Immunol. 2005;141:381–7. Inappropriate time options for IVIG treatment may affect the balance of pro-inflammatory and counter-inflammatory cytokines and subsequently the patient’s clinical outcome, including additional treatment and development of CAA. Future studies should focus on the pharmacokinetics of IVIG and the influence of immunological changes during the acute phase of KD on treatment response. The ROC analysis showed the optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days. Multivariable logistic regression analysis revealed that age and albumin were independent predictors of IVIG resistance, which is compatible with the previous studies.1010 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.,2626 Kuo HC, Liang CD, Wang CL, HRYu, Hwang KP, Yang KD. Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease. Acta Paediatr. 2010; 99:1578–83.
The most common sequela of KD is CAA, which is speculated to be caused by acute systemic inflammation.2727 Chen S, Dong Y, Kiuchi MG, Wang J, Li R, Ling Z, et al. Coronary artery complication in Kawasaki disease and the importance of early intervention: a systematic review and meta-analysis. JAMA Pediatr. 2016;170:1156–63. In the present study, the late group had the highest rate of CAA. It was significantly higher than the conventional (5-7 days) group, indicating the IVIG should be administrated within 10 days after the disease onset to prevent the CAA. The results of the subgroup analysis were similar - the late group has a rate of medium to large aneurysms significantly higher than the conventional (5-7 days) group. Although the early group has a higher proportion of small aneurysms than the conventional (5-7 days) group, one possible reason is that this was due to a bias caused by including severe cases with full clinical symptoms as early as day 4 after onset. The sensitivity analysis also showed that patients who began IVIG treatment more than 7 days of illness onset might develop CAA more frequently than those treated on days ≤ 7. To minimize cardiac sequelae, it is crucial to avoid any delay in IVIG treatment because earlier inflammatory suppression may contribute to avoiding developing CAAs.2828 Abrams JY, Belay ED, Uehara R, Maddox RA, Schonberger LB, Nakamura Y Cardiac complications, earlier treatment, and initial disease severity in Kawasaki disease. J Pediatr. 2017;188:64–9. Multivariate regression revealed that the incomplete KD, male gender, higher level of CRP, and lower level of albumin were independent risk factors of CALs, in line with other reported studies.2626 Kuo HC, Liang CD, Wang CL, HRYu, Hwang KP, Yang KD. Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease. Acta Paediatr. 2010; 99:1578–83.,2929 Duan J, Jiang H, Lu M. Risk factors for coronary artery lesions in children with Kawasaki disease. Arch Argent Pediatr. 2020; 118:327–31. English, Spanish.,3030 Liu X, Shao S, Wang L, Zhang N, Wu M, Liu L, et al. Predictive value of the systemic immune-inflammation index for intravenous immunoglobulin resistance and cardiovascular complications in Kawasaki disease. Front Cardiovasc Med. 2021 ;8:711007.
Limitations
This study has several limitations. First, it was a retrospective observational study with potential selection and information bias. Second, all the KD patients came from Sichuan, southwest China, limiting the findings’ generalization. Third, the study results could have been limited by incomplete data caused by patients being lost in follow-up after discharge from the hospital. A rigorous prospective study with long-term follow-up patients from other districts is needed.
Conclusion
IVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. All patients meeting diagnostic criteria for KD should be treated as soon as the course of illness as the diagnosis can be established. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required.
Supplementary materials
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.07.003.
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FundingThis manuscript did not receive any funding.
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Ethical approvalThe Chengdu Women’s and Children’s Central Hospital Ethics Committee approved the study protocol (Approval No. B202123) and waived informed consent requirements.
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Data availabilityThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
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1McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135:e927–99. Erratum in: Circulation. 2019;140:e181–4.
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2Uehara R, Belay ED. Epidemiology of Kawasaki disease in Asia, Europe, and the United States. J Epidemiol. 2012;22:79–85.
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3Sánchez-Manubens J, Bou R, Anton J. Diagnosis and classification of Kawasaki disease. J Autoimmun. 2014;48-49: 113–7.
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4Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315:341–7.
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5Takahashi K, Oharaseki T, Yokouchi Y, Yamada H, Shibuya K, Naoe S. A half-century of autopsy results–incidence of pediatric vasculitis syndromes, especially Kawasaki disease. Circ J. 2012;76:964–70.
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6Kobayashi 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.
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7Muta H, Ishii M, Egami K, Furui J, Sugahara Y, Akagi T, et al. Early intravenous gamma-globulin treatment for Kawasaki disease: the nationwide surveys in Japan. J Pediatr. 2004;144:496–9.
-
8Fong NC, Hui YW, Li CK, Chiu MC. Evaluation of the efficacy of treatment of Kawasaki disease before day 5 of illness. Pediatr Cardiol. 2004;25:31–4.
-
9Muta H, Ishii M, Furui J, Nakamura Y, Matsuishi T. Risk factors associated with the need for additional intravenous gammaglobulin therapy for Kawasaki disease. Acta Paediatr. 2006; 95:189–93.
-
10Egami 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.
-
11Zhang T, Yanagawa H, Oki I, Nakamura Y Factors relating to the cardiac sequelae of Kawasaki disease one month after initial onset. Acta Paediatr. 2002;91:517–20.
-
12Tse SM, Silverman ED, McCrindle BW, Yeung RS. Early treatment with intravenous immunoglobulin in patients with Kawasaki disease. J Pediatr. 2002;140:450–5.
-
13Marchesi A, Tarissi de Jacobis I, Rigante D, Rimini A, Malorni W, Corsello G, et al. Kawasaki disease: guidelines of the Italian Society of Pediatrics, part I - definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase. Ital J Pediatr. 2018;44:102.
-
14Fukazawa R, Kobayashi J, Ayusawa M, Hamada H, Miura M, Mitani Y, et al. JCS/JSCS 2020 guideline on diagnosis and management of cardiovascular sequelae in Kawasaki disease. Circ J. 2020;84:1348–407.
-
15McCrindle 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.
-
16Minich LL, Sleeper LA, Atz AM, McCrindle BW, Lu M, Colan SD, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics. 2007;120:e1434–40.
-
17Zhang T, Yanagawa H, Oki I, Nakamura Y, Yashiro M, Ojima T, et al. Factors related to cardiac sequelae of Kawasaki disease. Eur J Pediatr. 1999;158:694–7.
-
18Bar-Meir M, Kalisky I, Schwartz A, Somekh E, Tasher D. Israeli Kawasaki Group. Prediction of resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatric Infect Dis Soc. 2018;7:25–9.
-
19Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr. 2011;158:831–5. e3.
-
20Moffett BS, Syblik D, Denfield S, Altman C, Tejtel-Sexson K. Epidemiology of immunoglobulin resistant Kawasaki disease: results from a large, national database. Pediatr Cardiol. 2015;36:374–8.
-
21Han RK, Silverman ED, Newman A, McCrindle BW. Management and outcome of persistent or recurrent fever after initial intravenous gamma globulin therapy in acute Kawasaki disease. Arch Pediatr Adolesc Med. 2000;154:694–9.
-
22Shiozawa Y, Inuzuka R, Shindo T, Mafune R, Hayashi T, Hirata Y, et al. Effect of i.v. immunoglobulin in the first 4 days of illness in Kawasaki disease. Pediatr Int. 2018;60:334–41.
-
23Li W, He X, Zhang L, Wang Z, Wang Y, Lin H, et al. A retrospective cohort study of intravenous immunoglobulin therapy in the acute phase of Kawasaki disease: the earlier, the better? Cardi-ovasc Ther. 2021;2021:6660407.
-
24Yan F, Zhang H, Xiong R, Cheng X, Chen Y, Zhang F. Effect of early intravenous immunoglobulin therapy in Kawasaki disease: a systematic review and meta-analysis. Front Pediatr. 2020;8:593435.
-
25Matsubara T, Ichiyama T, Furukawa S. Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease. Clin Exp Immunol. 2005;141:381–7.
-
26Kuo HC, Liang CD, Wang CL, HRYu, Hwang KP, Yang KD. Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease. Acta Paediatr. 2010; 99:1578–83.
-
27Chen S, Dong Y, Kiuchi MG, Wang J, Li R, Ling Z, et al. Coronary artery complication in Kawasaki disease and the importance of early intervention: a systematic review and meta-analysis. JAMA Pediatr. 2016;170:1156–63.
-
28Abrams JY, Belay ED, Uehara R, Maddox RA, Schonberger LB, Nakamura Y Cardiac complications, earlier treatment, and initial disease severity in Kawasaki disease. J Pediatr. 2017;188:64–9.
-
29Duan J, Jiang H, Lu M. Risk factors for coronary artery lesions in children with Kawasaki disease. Arch Argent Pediatr. 2020; 118:327–31. English, Spanish.
-
30Liu X, Shao S, Wang L, Zhang N, Wu M, Liu L, et al. Predictive value of the systemic immune-inflammation index for intravenous immunoglobulin resistance and cardiovascular complications in Kawasaki disease. Front Cardiovasc Med. 2021 ;8:711007.
Publication Dates
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Publication in this collection
17 Apr 2023 -
Date of issue
Mar-Apr 2023
History
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Received
26 May 2022 -
Accepted
26 July 2022 -
Published
20 Aug 2022