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1.
The effects of glucocorticoid plus intravenous immunoglobulin (IVIG) vs IVIG alone on platelet activation in children with Kawasaki disease
Wang, Q. Q., Zheng, L. Y., Zhao, S.
The Turkish journal of pediatrics. 2023;65(4):640-649
Abstract
BACKGROUND Even though intravenous immunoglobulin (IVIG) is a current treatment for Kawasaki disease (KD), 10-20% of patients require additional therapy. This study seeks to investigate the therapeutic effects of glucocorticoids plus IVIG on KD and to ascertain the subsequent effect on platelet activation during the acute phase. METHODS A total of 32 children with KD were randomly classified into two groups: the experimental group (16 cases) and the control group (16 cases). The control group was exposed to IVIG (2 g/kg), whereas children in the experimental group were treated with IVIG (2 g/kg) + glucocorticoid. Peripheral venous blood samples were obtained from all participants before treatment as well as three days post-treatment to test platelet activation levels with procaspase activating compound-1 (PAC-1) antibody, Toll-like receptor 4 (TLR4), interleukin-6 (IL- 6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and C-reactive protein (CRP). Fever duration posttreatment was documented for both groups. Additionally, the coronary arteries in both groups were evaluated during three months of treatment. RESULTS After treatment, the experimental group had remarkably lower levels of TNF-α, CRP, PCT, IL-6, PAC- 1, and TLR4 relative to the control group. The fever persistence rate was considerably elevated in the control group compared to the experimental group (log-rank, P=0.024). In addition, the z-score of coronary artery size dropped after IVIG + glucocorticoids treatment compared to the control group, although this difference was not significant. CONCLUSIONS The IVIG + glucocorticoids can quickly mitigate the inflammatory response and platelet activation. Moreover, it can also improve clinical symptoms in children with KD.
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2.
Intravenous Methylprednisolone Pulse Therapy Versus Intravenous Immunoglobulin in the Prevention of Coronary Artery Disease in Children with Kawasaki Disease: A Randomized Controlled Trial
Aslani N, Raeeskarami SR, Aghaei-Moghadam E, Tahghighi F, Assari R, Sadeghi P, Ziaee V
Cureus. 2022;14(6):e26252
Abstract
BACKGROUND Kawasaki disease (KD) is often complicated by coronary artery lesion (CAL), including dilatation or aneurysms. Intravenous immunoglobulin (IVIG) is used with aspirin to prevent CAL in KD. OBJECTIVE Given that the primary treatment for other vasculitis is the use of corticosteroids, this study has been performed to evaluate the effect of intravenous methylprednisolone pulse (IVMP) therapy in preventing CAL in KD. METHOD A randomized, single-blind clinical trial was conducted on 40 KD patients aged six months to five years. Patients were randomized into two groups according to the main treatment plan in addition to aspirin: case group (IVMP for three consecutive days and then oral prednisolone for three days) and control group (intravenous immunoglobulin 2 g/kg). Echocardiography was performed for all children at least three times, during the acute phase, two weeks, and two months later. RESULTS Data analysis at the end of the study was done on 40 patients (20 patients in each group). There were no significant differences in age and sex distribution, mean fever, and acute phase duration, as well as baseline echocardiography in the two groups. The frequency of CAL was 20% in the case group and 45% in the control group, after two weeks (p<0.05), but there was no significant difference between two groups in types of coronary artery lesion after two weeks and the frequency and severity of CAL after two months. CONCLUSION IVMP as initial line therapy effectively control systemic and vascular inflammation and decrease coronary artery damage in KD.
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3.
Etanercept with IVIg for acute Kawasaki disease: a long-term follow-up on the EATAK trial
Sagiv E, Slee A, Buffone A, Choueiter NF, Dahdah NS, Portman MA
Cardiology in the young. 2022;:1-6
Abstract
BACKGROUND The Etanercept as Adjunctive Treatment for Acute Kawasaki Disease, a phase-3 clinical trial, showed that etanercept reduced the prevalence of IVIg resistance in acute Kawasaki disease. In patients who presented with coronary artery involvement, it reduced the maximal size and short-term progression of coronary artery dilation. Following up with this patient group, we evaluated the potential long-term benefit of etanercept for coronary disease. METHODS Patients were followed for at least 1 year after the trial. The size of dilated arteries (z-score ≥ 2.5) was measured at each follow-up visit. The z-score and size change from baseline were evaluated at each visit and compared between patients who received etanercept versus placebo at the initial trial. RESULTS Forty patients who received etanercept (22) or placebo (18) in the Etanercept as Adjunctive Treatment for Acute Kawasaki Disease trial were included. All patients showed a persistent decrease in coronary artery size measurement: 23.3 versus 5.9% at the 6-month visit, 24 versus 13.1% at the 1-year visit, and 20.8 versus 19.3% at the ≥ 2-year visit for etanercept or placebo, respectively, with similar results for decrease in coronary artery z-scores. In a multivariate analysis, correcting for patients' growth, a greater size reduction for patients on the etanercept arm versus placebo was proved significant for the 6-month (p = 0.005) and the 1-year visits (p = 0.019) with a similar end outcome at the ≥ 2-year visit. DISCUSSION Primary adjunctive therapy with etanercept for children with acute Kawasaki disease does not change the end outcome of coronary artery disease but may promote earlier resolution of artery dilation.
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4.
Evaluation of high-dose aspirin elimination in the treatment of Kawasaki disease in the incidence of coronary artery aneurysm
Sanati F, Bagheri M, Eslami S, Khalooei A
Annals of pediatric cardiology. 2021;14(2):146-151
Abstract
BACKGROUND Standard first-step therapy for Kawasaki disease consists of Intravenous immunoglobulin and high dose Aspirin (80-100 mg/kg/day). The standard dose of Intravenous immunoglobulin (2gr/kg) is strongly effective in reducing the risk of coronary arteries abnormalities. So, the proper dose and efficacy of Aspirin to decrease the risk of coronary arteries abnormalities is a controversial issue. In this study, it is tried to assess the result of eliminating high-dose Aspirin in the treatment of the acute phase of Kawasaki and observe the incidence rate of coronary arteries abnormalities when only Intravenous immunoglobulin was administered. METHODS This study is a prospective randomized, open-label, blinded end-points clinical trial performed in Afzalipour hospital in Kerman University of Medical Sciences from September 2017 to September 2018 in 62 patients with typical and atypical Kawasaki disease. The study group received Intravenous immunoglobulin (2 g/kg) and the control group get the same dose of Intravenous immunoglobulin plus Aspirin with the dose of 80-100 mg/Kg/day until they were afebrile for 48 hours. Afterward, both groups received a daily single dose (3-5 mg/kg) of Aspirin for six weeks. Echocardiography was done after two weeks, six weeks, and six months. Internal diameter of the left and right main coronary arteries was measured and then the corresponding Z-score was calculated. RESULTS In the study group, coronary arteries abnormalities decreased from 38.7% in the 2nd week to 16.1% in the 6th month. In the control group, it declined from 54.8% to 22.6%. There was no statistically significant difference between the groups in term of frequency of abnormal coronary arteries at the study period (P=0.151). CONCLUSIONS We concluded that high dose Aspirin does not have a significant role in preventing coronary arteries abnormalities in Kawasaki disease and giving standard 2 gr/kg/day Intravenous immunoglobulin without high-dose Aspirin in acute-phases therapy does not increase the risk of coronary arteries abnormality.
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5.
Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency
Smits BM, Kleine Budde I, de Vries E, Ten Berge IJM, Bredius RGM, van Deuren M, van Dissel JT, Ellerbroek PM, van der Flier M, van Hagen PM, et al
Journal of clinical immunology. 2020
Abstract
BACKGROUND Patients with an IgG subclass deficiency (IgSD) ± specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study. OBJECTIVE To compare the efficacy of PA and IRT in a randomized crossover trial. METHODS A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared. RESULTS The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01). CONCLUSION We found comparable efficacy of IRT and PA in patients with IgSD ± SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT. CLINICAL IMPLICATION Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA.
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6.
Etanercept With IVIg for Acute Kawasaki Disease: A Randomized Controlled Trial
Portman MA, Dahdah NS, Slee A, Olson AK, Choueiter NF, Soriano BD, Buddhe S, Altman CA
Pediatrics. 2019
Abstract
OBJECTIVES Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor alpha receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression. METHODS In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg; n = 100) or placebo (n = 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation (z score >2.5) at baseline. We used generalized estimating equations to analyze z score change and a prespecified algorithm for change in absolute diameters. RESULTS IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (P = .10). Etanercept reduced IVIg resistance in patients >1 year of age (P = .03). In the entire population, 46 (23%) had a coronary z score >2.5 at baseline. Etanercept reduced coronary z score change in those with and without baseline dilation (P = .04 and P = .001); no improvement occurred in the analogous placebo groups. Etanercept (n = 22) reduced dilation progression compared with placebo (n = 24) by algorithm in those with baseline dilation (P = .03). No difference in the safety profile occurred between etanercept and placebo. CONCLUSIONS Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities.
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7.
Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial
Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, Okajima Y, Kurotobi S, Hirai K, Soga T, et al
Lancet (London, England). 2019
Abstract
BACKGROUND Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0.46; 95% CI 0.25-0.86; p=0.010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0.78). INTERPRETATION Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING Japan Agency for Medical Research and Development (grant CCT-B-2503).
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8.
[Clinical effect of double filtration plasmapheresis combined with glucocorticoid and immunosuppressant in treatment of children with severe Henoch-Schonlein purpura nephritis]
Liu N, Ma ZZ, Yan HF, Li Q, Lyu XQ, Kang WL, Yin ZR
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2019;21(10):955-959
Abstract
OBJECTIVE To study the clinical effect and safety of double filtration plasmapheresis (DFPP) combined with double pulse therapy with methylprednisolone (MP) and cyclophosphamide (CTX) in the treatment of children with severe Henoch-Schonlein purpura nephritis (HSPN). METHODS A total of 60 children with severe HSPN who were admitted to the hospital from January 2014 to March 2018 were enrolled and were randomly divided into an observation group and a control group (n=30 each). In addition to routine treatment, the children in the control group were given MP+CTX pulse therapy. Those in the observation group were given DFPP treatment in addition to the treatment in the control group, with three courses of treatment in total. After three courses of treatment, the two groups were compared in terms of 24-hour urinary protein, urinary microproteins, renal function parameters, adverse reactions, and clinical outcome. RESULTS After three courses of treatment, the observation group had significantly greater reductions in 24-hour urinary protein, urinary albumin, urinary immunoglobulin G, urinary beta2-microglobulin, serum creatinine, and blood urea nitrogen than the control group (P<0.05). After the treatment ended, the observation group had a significantly shorter time to achieve remission than the control group (P<0.05). No serious adverse reactions, such as hemorrhagic cystitis, thrombocytopenia, and hemolysis, were observed, and there was no significant difference in the overall incidence rate of adverse reactions between the two groups (P>0.05). CONCLUSIONS Compared with MP+CTX pulse therapy alone in the treatment of severe HSPN in children, DFPP combined with MP+CTX pulse therapy can further alleviate renal injury and improve clinical outcome and does not increase the incidence rate of adverse reactions.
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9.
Intravenous Immunoglobulin Gamma (IVIG) versus IVIG Plus Infliximab in Young Children with Kawasaki Disease
Han CL, Zhao SL
Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2018;24:7264-7270.
Abstract
BACKGROUND Kawasaki disease (KD) is a serious disease characterized by systemic lesions of the skin and mucous membranes, as well as lymphomas and vascular inflammation. KD threatens the health and lives of children, especially young ones. Here, we compared the therapeutic effects of single intravenous immunoglobulin gamma (IVIG) vs. a combination of IVIG and infliximab in young children with Kawasaki disease (KD). MATERIAL AND METHODS A total of 154 children with KD, younger than 5 years old, were enrolled in the study from January 2013 to January 2017. The patients were randomly divided into an IVIG group and a combination of IVIG and infliximab treatment group. After systematic treatments, the therapeutic indicators of the 2 groups were compared. During the treatment process, body temperature and other important inflammatory indicators, including C-reactive protein (CRP), white blood cell count (WBC), and tumor necrosis factor alpha (TNF-alpha), were monitored in the first 4 days. RESULTS There were fewer refractory KD patients in the combined treatment group than in the IVIG group (4 vs. 14, p<0.001). KD patients in the combined treatment group had better outcomes with shorter fever durations and hospital stays, as well as less coronary artery dilation. However, there was no obvious differences in the incidence rate of coronary artery aneurysms between the 2 groups (p>0.05). Costs of administration were similar between groups (p>0.05). Body temperature, CRP, WBC, and TNF-alpha in the combined therapy group all showed an earlier drop than in the IVIG group, indicating a more effective anti-inflammation effect. CONCLUSIONS The introduction of IVIG combined with infliximab in the treatment of young children with KD has more advantages than single IVIG therapy and can be considered as a preferred treatment for KD. However, it would be necessary to further investigate whether there is a significant difference in aneurysm frequency and long-term outcome between these 2 strategies among a larger number of patients.
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10.
Clarithromycin plus intravenous immunoglobulin therapy can reduce the relapse rate of Kawasaki disease: a phase 2, open-label, randomized control study
Nanishi E, Nishio H, Takada H, Yamamura K, Fukazawa M, Furuno K, Mizuno Y, Saigo K, Kadoya R, Ohbuchi N, et al
Journal of the American Heart Association. 2017;6((7))
Abstract
BACKGROUND We previously reported that biofilms and innate immunity contribute to the pathogenesis of Kawasaki disease. Therefore, we aimed to assess the efficacy of clarithromycin, an antibiofilm agent, in patients with Kawasaki disease. METHODS AND RESULTS We conducted an open-label, multicenter, randomized, phase 2 trial at 8 hospitals in Japan. Eligible patients included children aged between 4 months and 5 years who were enrolled between days 4 and 8 of illness. Participants were randomly allocated to receive either intravenous immunoglobulin (IVIG) or IVIG plus clarithromycin. The primary end point was the duration of fever after the initiation of IVIG treatment. Eighty-one eligible patients were randomized. The duration of the fever did not differ between the 2 groups (mean+/-SD, 34.3+/-32.4 and 31.1+/-31.1 hours in the IVIG plus clarithromycin group and the IVIG group, respectively [P=0.66]). The relapse rate of patients in the IVIG plus clarithromycin group was significantly lower than that in the IVIG group (12.5% versus 30.8%, P=0.046). No serious adverse events occurred during the study period. In a post hoc analysis, the patients in the IVIG plus clarithromycin group required significantly shorter mean lengths of hospital stays than those in the IVIG group (8.9 days versus 10.3 days, P=0.049). CONCLUSIONS Although IVIG plus clarithromycin therapy failed to shorten the duration of fever, it reduced the relapse rate and shortened the duration of hospitalization in patients with Kawasaki disease. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000015437.