The effectiveness of infliximab for Kawasaki disease in children: systematic review and meta-analysis
Translational pediatrics. 2021;10(5):1294-1306
BACKGROUND Kawasaki disease (KD) is a self-limited illness that results in coronary artery aneurysms (CAAs) and threatens children's health and lives. The therapeutic effects of single intravenous immunoglobulin gamma (IVIG) vs. infliximab (IFX) (with or without IVIG) in young children with KD remain unclear. Thus, we made a meta-analysis and systematic review, including all of the studies which have evaluated the effectiveness and safety of IFX and IVIG KD patients. METHODS The databases of the Cochrane Library, PubMed and Embase websites were searched for articles appearing from inception until December 31, 2020. Clinical studies that compared IFX either as initial therapy plus IVIG or rescue therapy after IVIG (IFX group) failure compared with IVIG treatment alone (IVIG group) in treating KD patients were included. RESULTS The meta-analysis included nine studies characterizing 712 patients. The treatment response was significantly higher in the adjunctive IFX therapy group than in the IVIG therapy group [odds ratio (OR) 2.64; 95% CI: 1.52-4.59; P=0.0005]. Subgroup analysis, the effect of IFX therapy on treatment response is more effectiveness in the group of the high-risk KD patients than IVIG therapy (OR 6.07; 95% CI: 2.30-16.04; P=0.0003; random-effects model). Further analysis showed no difference in the improvement of CAAs in short-term follow-up between the two groups. However, adding IFX either as initial therapy or as additional therapy all showed an advantageous effect regarding the ∆Z score of the left anterior descending (LAD) (MD =0.29; 95% CI: 0.27-0.31; P<0.00001) and right coronary artery (RCA) (MD =0.24; 95% CI: 0.22-0.26; P<0.00001). Further, IFX exhibited significant effect on the treatment response compared with IVIG therapy in the Asian group (OR, 2.84; 95% CI: 1.51-5.36; P=0.001; random-effects model), and the beneficial effects of IFX were given without increasing the risk of AEs. CONCLUSIONS This meta-analysis emphasizes the importance of IFX on the treatment response in the high-risk KD patients. IFX may play a role in the Asian KD patients and prevention of progressive CAA, and does not increase the risk of AEs in KD patients.
Evaluation of high-dose aspirin elimination in the treatment of Kawasaki disease in the incidence of coronary artery aneurysm
Annals of pediatric cardiology. 2021;14(2):146-151
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.
Monoclonal antibody and anti-cytokine biologics for Kawasaki disease: A systematic review and meta-analysis
Seminars in arthritis and rheumatism. 2021;51(5):1045-1056
BACKGROUND Kawasaki disease (KD) is a form of self-limiting vasculitis that causes coronary artery abnormalities in children. Although clinical trials of monoclonal antibodies and anti-cytokine biologics that block cytokine cascades have been conducted, the studies have revealed contradictory results. To examine the effectiveness of treatment with monoclonal antibodies and anti-cytokine biologics for KD patients, we conducted this systematic review and meta-analysis. METHODS Relevant randomized controlled trials (RCTs) and observational studies (e.g., cohort studies, case-control studies, case-series, and case-reports) were included to summarize available evidence, both qualitatively and quantitatively. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and ICUSHI were used for systematic research. Meta-analysis of the included studies was conducted using fixed-effect or random-effects models, depending on the degree of between-study heterogeneity. We assessed coronary artery and treatment outcomes of the interventions. The certainty of evidence and risk of bias were assessed using the GRADE and Cochrane risk of bias tool. The protocol of this review is registered with PROSPERO (CRD42016033079). RESULTS Results: Of all searched studies, 183 studies were qualitatively analyzed. We finally included four randomized controlled trials with 456 patients in quantitative syntheses. Monoclonal antibodies and anti-cytokine biologics did not reduce the frequency of CAA (risk ratio [RR], 0.93; 95% confidence interval [95%CI], 0.65 to 1.32, low certainty of evidence), compared with the conventional treatment with IVIG. However, the frequency of treatment resistance (RR, 0.60; 95%CI, 0.38 to 0.95, moderate certainty of evidence) was reduced by the antibodies. We found no statistical differences in either "any adverse event" (RR, 0.92; 95%CI, 0.80 to 1.06, low certainty of evidence) or "adverse events attributable to the administration of the medication" (RR, 1.10; 95%CI, 0.72 to 1.69, low certainty of evidence) between the two groups. CONCLUSION Conclusions: Although monoclonal antibodies and anti-cytokine biologics were not effective in reducing the frequency of CAA in KD patients, the frequency of treatment resistance might be reduced by those agents compared with conventional IVIG therapy alone.
Clinical Features in Children With Kawasaki Disease Shock Syndrome: A Systematic Review and Meta-Analysis
Frontiers in cardiovascular medicine. 2021;8:736352
Objective: This study aimed to identify the clinical features of Kawasaki disease shock syndrome (KDSS) in children. Methods: The case-control studies of KDSS and KD children up until April 30, 2021 were searched in multiple databases. The qualified research were retrieved by manually reviewing the references. Review Manager 5.3 software was used for statistical analysis. Results: The results showed that there was no significant difference in the incidence of male and female in children with KDSS. Children with KDSS compared with non-shocked KD, there were significant difference in age, duration of fever, white blood cell (WBC) count, percentage of neutrophils (NEUT%), platelet count (PLT), c-reactive protein level (CRP), alanine transaminase concentration (ALT), aspartate transaminase concentration (AST), albumin concentration (ALB), sodium concentration (Na), ejection fraction, and length of hospitalization as well as the incidence of coronary artery dilation, coronary artery aneurysm, left ventricular dysfunction, mitral regurgitation, pericardial effusion, initial diagnosis of KD, intravenous immunoglobulin (IVIG) resistance and receiving second dose of IVIG, vasoactive drugs, hormones, and albumin. In contrast, there was no difference in the hemoglobin concentration, erythrocyte sedimentation rate, and the incidence of conjunctival injection, oropharyngeal change, polymorphous rash, extremity change, and incomplete KD. Conclusion: Current evidence suggested that the children with KDSS had more severe indicators of inflammation and more cardiac abnormalities. These patients were resistant to immunoglobulin treatment and required extra anti-inflammatory treatment. Systematic Review Registration: PROSPERO registration number CRD42021241207.
Efficacy of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis
Experimental and therapeutic medicine. 2021;21(1):15
The present study aimed to review the relevant studies in order to determine the efficacy of infliximab (IFX) in the treatment of Kawasaki disease (KD). The relevant studies were retrieved using the PubMed, Cochrane and Embase databases. Key sources in the literature were reviewed; all articles published by July 2019 were considered for inclusion. For each study, odds ratios, mean difference and 95% confidence interval (95% CI) were assessed to evaluate study outcomes. A total of 16 studies involving 429 patients were relevant to the questions of interest of the current meta-analysis. Compared with intravenous immunoglobulin (IVIG), IFX or IFX plus IVIG significantly reduced the incidence of adverse events, including the number of patients with fever, changes in lip and oral cavity and/or cervical lymphadenopathy. The white blood cell (WBC), neutrophil and C-reactive protein (CRP) levels were also reduced in the IFX or IFX plus IVIG group compared with those in the IVIG or polyethylene glycol-treated human immunoglobulin (VGIH) groups. The platelet counts, alanine aminotransferase (ALT) levels and Z-scores were increased in the IFX or IFX plus IVIG groups compared with those in the IVIG or VGIH groups. In the single-arm studies, the incidence of coronary artery aneurysm was 0.150 (95% CI: 0.024, 0.277), the non-response rate was 0.097 (95% CI: 0.056, 0.138), and the incidence of adverse events was 0.156 (95% CI: 0.122, 0.190). IFX not only effectively reduced the incidence of fever, conjunctival injection, changes in lip and oral cavity and cervical lymphadenopathy polymorphous exanthema, but also the WBC, neutrophil, ALT and CRP levels. The platelet levels were increased in patients after the IFX therapy compared with patients in the IVIG or VGIH groups. IFX or IFX plus IVIG exhibited improved clinical efficacy in the treatment of KD compared with that of IVIG or VGIH. However, as a limited number of studies was included in the current study, the findings should be verified further.
Is there an association between intravenous immunoglobulin resistance and coronary artery lesion in Kawasaki disease?-Current evidence based on a meta-analysis
PloS one. 2021;16(3):e0248812
BACKGROUND Coronary artery lesion (CAL) caused by Kawasaki disease (KD) is a leading cause of acquired heart disease in children. Initial treatment of intravenous immunoglobulin (IVIG) can reduce the incidence of CAL. Although most of the current studies have shown a certain correlation between CAL and IVIG resistance, the conclusions are not completely consistent. Thus, we performed this meta-analysis to evaluate the association between IVIG resistance and CAL in KD. METHODS PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure through April 21, 2020 were searched to detect relevant studies. Data analysis was performed with STATA 15.1. RESULTS A total of 53 relevant studies were eligible to this analysis, including 30312 KD patients, of which 4750 were IVIG resistance and 25562 were responders. There was a significant difference found between IVIG resistance and IVIG response groups in the incidence of CAL (P < 0.001, odds ratio (OR), 3.89; 95% confidence interval (CI) (3.18, 4.75)). The heterogeneity test results showed that the I2 value was 74.8%. The meta-regression analysis showed that the study regions might be the sources of heterogeneity. The subgroup analysis suggested that the incidence of CAL in the IVIG resistance group was still higher than that in the IVIG response group under different regions, IVIG resistance diagnostic criteria, CAL diagnostic criteria, and study types. Meanwhile, the sensitivity analysis did not find any significant impact from every single study. CONCLUSIONS This is the first meta-analysis to reveal the incidence of CAL was associated with IVIG resistance in KD patients. Further well-designed studies with uniform criteria are needed to evaluate the incidence of CAL in IVIG resistant patients.
Immunoglobulin Replacement Therapy Versus Antibiotic Prophylaxis as Treatment for Incomplete Primary Antibody Deficiency
Journal of clinical immunology. 2020
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.
What dose of aspirin should be used in the initial treatment of Kawasaki disease? A meta-analysis
Rheumatology (Oxford). 2020
OBJECTIVE The use of IVIG plus high- or low-dose aspirin for the initial treatment of Kawasaki disease remains controversial. The aim of this study was to evaluate the efficacy of IVIG plus high-dose aspirin compared with IVIG plus low-dose aspirin in the treatment of Kawasaki disease. METHODS Studies related to aspirin therapy for Kawasaki disease were selected by searching the databases of Medline (PubMed), Embase and the Cochrane Library before March 2019. Statistical analyses were performed by using a Review Manager Software package and STATA v.15.1. RESULTS Eight retrospective cohort studies, characterizing 12 176 patients, were analysed. Overall, no significant difference was found in the incidence of coronary artery abnormalities between the high- and low-dose aspirin groups [relative risk (RR) 1.15; 95% CI: 0.93, 1.43; P = 0.19; random-effects model]. The patients treated with high-dose aspirin had slightly faster resolution of fever [mean difference (MD) -0.30; 95% CI: -0.58, -0.02; P = 0.04; random-effects model]. but the rates of IVIG resistance (RR, 1.26; 95% CI: 0.55, 2.92; P = 0.59; random-effects model) and days in hospital (MD, 0.22; 95% CI: -0.93, 1.37; P = 0.71; random-effects model) were similar between the two groups. CONCLUSION Low-dose aspirin plus IVIG might be as effective as high-dose aspirin plus IVIG for the initial treatment of Kawasaki disease. Considering that high-dose aspirin may cause more adverse reactions than low-dose aspirin, low-dose aspirin plus IVIG should be recommended as the first-line therapy in the initial treatment of Kawasaki disease.
Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenic purpura: meta-analysis
Immune thrombocytopenic purpura (ITP) is an autoimmune disorder presenting with low platelet count <100 x 10(9)/L. The condition affects both adults and children. Thrombopoietin receptor agonists (TPO-RAs) are second-line of therapy that includes Romiplostim and Eltrombopag, which stimulate the production of normally functioning platelets. Although the biological effect of these drugs is well established, there has not been a meta-analysis in children. To estimate the efficacy and safety of Romiplostim and Eltrombopag, we performed a systematic review and meta-analysis in children with chronic ITP. Systematic literature search was conducted in the following database: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Review Manager 5.3 for Windows was used to analyze the data. Five randomized controlled trials with total of 261 pediatric patients from 1-17 years of age were included. The efficacy and safety analysis showed TPO-RA groups were superior over placebo, and there was no difference in adverse event occurrence between TPO-RA (Romiplostim and Eltrombopag) and placebo groups. The efficacy and safety of Eltrombopag did not differ significantly from those of Romiplostim. Both drugs were effective in treatment of children with chronic ITP. Our findings extend the currently available data on ITP treatment and is helpful for pediatric health providers and for the design of future clinical trials.
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
Lancet (London, England). 2019
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).