Objective To determine the safety and pharmacokinetics of etanercept (Amgen, Thousand Oaks, California) a tumor necrosis factor-α receptor blocker, in children with acute Kawasaki disease (KD). ...Standard therapy of acute KD includes intravenous immunoglobulin (IVIG) and high-dose aspirin, but a substantial number of patients are refractory and require additional treatment. Tumor necrosis factor-α levels are elevated in children with KD, suggesting a role for etanercept in treatment. Study design We performed a prospective open-label trial of etanercept in patients with KD (age range, 6 months-5 years; n = 17) meeting clinical criteria and with fever ≤10 days. All received IVIG and high-dose aspirin. They received etanercept immediately after IVIG infusion and then weekly two times. For the initial safety evaluation, the first 5 patients received 0.4 mg/kg/dose. Subsequent subjects received 0.8 mg/kg/dose. Results Fifteen patients completed the study. The pharmacokinetics were similar to that in older children in published series. No serious adverse events related to etanercept occurred. No patient demonstrated prolonged or recrudescent fever requiring re-treatment with IVIG. No patient showed an increase in coronary artery diameter or new coronary artery dilation/cardiac dysfunction. Conclusion Etanercept appears to be safe and well tolerated in children with KD. The data support performance of a placebo-controlled trial.
To describe the similarities and differences in the evaluation and treatment of multisystem inflammatory syndrome in children (MIS-C) at hospitals in the US.
We conducted a cross-sectional survey ...from June 16 to July 16, 2020, of US children's hospitals regarding protocols for management of patients with MIS-C. Elements included characteristics of the hospital, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers in which >5 patients had been treated vs those in which ≤5 patients had been treated.
In all, 40 centers of varying size and experience with MIS-C participated in this protocol survey. Overall, 21 of 40 centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely recommended medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols primarily for moderate or severe cases. Aspirin was commonly recommended for mild cases, whereas heparin or low molecular weight heparin were to be used primarily in severe cases. In severe cases, anakinra and vasopressors frequently were recommended; 39 of 40 centers recommended follow-up with cardiology. There were similar findings between centers in which >5 patients vs ≤5 patients had been managed. Supplemental materials containing hospital protocols are provided.
There are many similarities yet key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C.
Ventricular strain and dyssynchrony can be measured in patients with repaired tetralogy of Fallot (TOF), but their effect on clinical outcomes is poorly understood. The purpose of this study was to ...investigate if ventricular strain and dyssynchrony measured by cardiac magnetic resonance feature tracking are associated with death and sustained ventricular tachycardia. Patients with TOF who died or had ventricular tachycardia (TOF case, n = 16) were compared with age-matched patients with TOF with no adverse outcome (TOF control, n = 32). For each patient, midventricular short-axis and 4-chamber cine steady-state free precession images were analyzed using cardiac magnetic resonance feature-tracking software. Peak left ventricular (LV) and right ventricular (RV) global circumferential and longitudinal strain and indexes of dyssynchrony were compared between groups. Compared with the TOF control group, median strain values were significantly lower for the TOF case group for both the LV (circumferential: 17% vs 23%, p = 0.003; longitudinal: 13% vs 18%, p <0.001) and the RV (circumferential: 10% vs 16%, p = 0.001; longitudinal: 11% vs 18%, p <0.001). In a multivariate model including strain and dyssynchrony parameters, RV and LV longitudinal strain were strongly associated with the adverse outcome (p = 0.003 and 0.04, respectively; area under the curve = 0.92). No differences in ventricular dyssynchrony were identified between the groups. In conclusion, patients with TOF in this cohort who experienced adverse outcomes had lower values of all strain parameters than those who did not, and impaired longitudinal strain of both ventricles was strongly associated with adverse clinical outcomes.
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 α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression.
In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg;
= 100) or placebo (
= 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 (
score >2.5) at baseline. We used generalized estimating equations to analyze
score change and a prespecified algorithm for change in absolute diameters.
IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (
= .10). Etanercept reduced IVIg resistance in patients >1 year of age (
= .03). In the entire population, 46 (23%) had a coronary
score >2.5 at baseline. Etanercept reduced coronary
score change in those with and without baseline dilation (
= .04 and
= .001); no improvement occurred in the analogous placebo groups. Etanercept (
= 22) reduced dilation progression compared with placebo (
= 24) by algorithm in those with baseline dilation (
= .03). No difference in the safety profile occurred between etanercept and placebo.
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.
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.
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.
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.
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.
The emergence of increasing reports worldwide of a severe inflammatory process and shock in pediatric patients resembling Kawasaki disease (KD)—and, more specifically, Kawasaki disease shock syndrome ...(KDSS)—prompted us to explore KDSS in a preamble of a systematic comparison between the 2 conditions.
We completed a systematic review of KDSS and performed a meta-analysis comparison between reported KDSS cases and KD controls.
A total of 10 case-control series were included in the meta-analysis. Patients with KDSS were older (38.4 ± 30.6 vs 21.9 ± 19.5 months; P < 0.001) compared with standard KD with equal sex distribution and completeness of clinical diagnostic criteria. KDSS present higher C-reactive protein (59.4 ± 29.2 mg/dL vs 20.8 ± 14.8 mg/dL; P < 0.001), lower albumin (2.7 ± 0.5 g/dL vs 3.3 ± 0.5 g/dL; P < 0.01), and lower platelets (255 ± 149 109/L vs 394 ± 132 109/L; P < 0.001) but only borderline higher white blood cells (P = 0.06). Differences in alanine transaminase, aspartate aminotransferase, and erythrocyte sedimentation rate were nonsignificant. The odds of intravenous immunoglobulin resistance (44.4% vs 9.6%; (P < 0.001) and the hospital length of stay (10.9 ± 5.8 vs 5.0 ± 3.0 days; P < 0.001) were higher in KDSS, as were the odds of coronary-artery abnormalities (33.9% vs 8.6%; P < 0.001).
This first meta-analysis on KDSS vs KD represents a basis for future works on KDSS and opens the opportunity for future multicentre studies in the search of causal relationships between presenting elements and the eventual complications of KDSS. The similarities between SARS-CoV-2 multisystem inflammatory syndrome in children and KDSS open new horizons to the understanding of the etiology and pathophysiology related to KDSS.
À l’échelle mondiale, de plus en plus d'enfants sont touchés par un processus inflammatoire grave avec état de choc mimant la maladie de Kawasaki – nommément le syndrome de choc de la maladie de Kawasaki (Kawasaki disease shock syndrome ou KDSS). Cette situation nous a incités à mieux caractériser le KDSS en préambule à une comparaison systématique des deux pathologies.
Nous avons passé systématiquement en revue les cas de KDSS et effectué une méta-analyse comparant les cas déclarés de KDSS à des témoins atteints de la maladie de Kawasaki.
La méta-analyse a porté sur 10 séries cas/témoins en tout. Les patients atteints de KDSS étaient plus âgés (38,4 ± 30,6 mois vs 21,9 ± 19,5 mois; p < 0,001) que les patients présentant la forme classique de la maladie de Kawasaki, il y avait répartition égale par sexe et sur le taux des critères de diagnostic clinique réunis. Le KDSS se caractérise par une concentration plus élevée de protéine C-réactive (59,4 ± 29,2 mg/dl vs 20,8 ± 14,8 mg/dl; p < 0,001), une concentration plus faible d'albumine (2,7 ± 0,5 g/dl vs 3,3 ± 0,5 g/dl; p < 0,01) et un nombre moins élevé de plaquettes (255 ± 149 109/L vs 394 ± 132 109/L; p < 0,001), mais les taux de globules blancs sont à peine plus élevés (p = 0,06). Les différences relatives à l'alanine transaminase, à l'aspartate aminotransférase et à la vitesse de sédimentation érythrocytaire n’étaient pas significatives. Le risque de résistance aux immunoglobulines intraveineuses (44,4 % vs 9,6 %; (p < 0,001) et la durée d'hospitalisation (10,9 ± 5,8 vs 5,0 ± 3,0 jours; p < 0,001) étaient plus grands chez les patients atteints de KDSS, tout comme le risque d'anomalies coronariennes (33,9 % vs 8,6 %; p < 0,001).
Cette première méta-analyse comparative portant sur le KDSS et la maladie de Kawasaki jette les bases de travaux ultérieurs sur le KDSS et prépare la voie pour des études multicentriques axées sur la recherche des relations causales entre les signes cliniques et les complications possibles du KDSS. Les similitudes entre le syndrome inflammatoire multisystémique pédiatrique lié au SRAS-CoV-2 et le KDSS ouvrent de nouvelles perspectives en matière de compréhension des aspects étiologiques et physiopathologiques du KDSS.
Since April 2020, there have been numerous reports of children presenting with systemic inflammation, often in critical condition, and with evidence of recent infection of severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2). This condition, since defined as the multisystem inflammatory syndrome in children (MIS-C), is assumed to be a delayed immune response to coronavirus disease 2019 (COVID-19), and there are frequently cardiac manifestations of ventricular dysfunction and/or coronary artery dilation.
We surveyed the inpatient MIS-C management approaches of the members of the International Kawasaki Disease Registry across 38 institutions and 11 countries.
Among the respondents, 56% reported using immunomodulatory treatment for all MIS-C patients, regardless of presentation. Every respondent reported use of intravenous immunoglobulin (IVIG), including 53% administering IVIG in all patients. Steroids were most often used for patients with severe clinical presentation or lack of response to IVIG, and only a minority used steroids in all patients (14%). Acetylsalicylic acid was frequently used among respondents (91%), including anti-inflammatory and/or antiplatelet dosing. Respondents reported use of prophylactic anticoagulation, especially in patients at higher risk for venous thromboembolism, and therapeutic anticoagulation, particularly for patients with giant coronary artery aneurysms.
There is variation in management of MIS-C patients, with suboptimal evidence to assess superiority of the various treatments; evidence-based gaps in knowledge should be addressed through worldwide collaboration to optimize treatment strategies.
Depuis avril 2020, de nombreux cas d’enfants présentant une inflammation généralisée, se trouvant souvent dans un état critique et montrant des signes d’une infection récente au coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2), ont été signalés. On pense que cet état, désigné depuis sous le nom de syndrome inflammatoire multisystémique de l’enfant (SIME), pourrait être une réponse immunitaire tardive au virus de la maladie à coronavirus 2019 (COVID-19); les patients présentent souvent des manifestations cardiaques associées à une dysfonction ventriculaire ou à une dilatation des artères coronaires.
Nous avons mené un sondage sur les stratégies de prise en charge du SIME en milieu hospitalier auprès des membres du registre international de la maladie de Kawasaki, qui sont rattachés à 38 établissements répartis dans 11 pays.
Au total, 56 % des répondants ont déclaré opter pour un traitement immunomodulateur pour tous les patients présentant un SIME, quelles qu’en soient les manifestations. Tous les répondants ont déclaré avoir recours à l’administration d’immunoglobulines par voie intraveineuse, 53 % d’entre eux utilisant ce traitement chez tous les patients. Les stéroïdes étaient plus souvent utilisés chez les patients présentant des symptômes cliniques graves ou ne répondant pas aux immunoglobulines administrées par voie intraveineuse; seule une minorité de répondants ont déclaré utiliser des stéroïdes chez tous les patients (14 %). Les répondants utilisaient aussi fréquemment l’acide acétylsalicylique (91 %), à des doses anti-inflammatoires ou antiplaquettaires. Ils ont en outre déclaré avoir recours à des anticoagulants en prophylaxie, en particulier chez les patients présentant un risque élevé de thromboembolie veineuse, et à une anticoagulothérapie chez les patients présentant des anévrismes coronaires géants.
La prise en charge des patients présentant un SIME varie d’un médecin à l’autre, et les données permettant d’évaluer la supériorité des divers traitements employés sont insuffisantes; il conviendrait donc de mettre en place des initiatives de collaboration afin de combler les lacunes des connaissances et d’optimiser les stratégies thérapeutiques.
Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare delayed hyperinflammatory response to SARS-CoV-2 infection and causes severe morbidity in the pediatric age group. Although ...MIS-C shares many clinical similarities to Kawasaki disease (KD), important differences in epidemiologic, clinical, immunologic, and potentially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemiologic features include male predominance, peak age of 6 to12 years, and specific racial or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and neurologic complaints, and patients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnormalities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein—as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens—are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that underlie the pathogenesis of MIS-C vs both acute SARS-CoV-2 infection and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine-associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac complications, provide insights into the underlying immunologic pathophysiology, and define similarities and differences with KD.
Le syndrome inflammatoire multisystémique de l’enfant (SIME) qui s’est révélé une réponse hyperinflammatoire tardive rare à l’infection SRAS-CoV-2 cause une morbidité grave chez les enfants. Bien que le SIME ait en commun plusieurs similarités cliniques avec la maladie de Kawasaki (MK), d’importantes différences dans les facteurs épidémiologiques, cliniques, immunologiques et potentiellement génétiques existent et suggèrent des différences potentielles dans la physiopathologie, et des points à explorer et à expliciter. Les caractéristiques épidémiologiques sont les suivantes : la prédominance masculine, le groupe d’âge le plus touché (de 6 à 12 ans), et les prédispositions raciales et ethniques particulières. Le SIME est caractérisé par de la fièvre, des symptômes gastro-intestinaux marqués, des manifestations mucocutanées, des symptômes respiratoires et des plaintes neurologiques, et les patients sont souvent en état de choc. Les complications cardiaques fréquentes sont les suivantes : la dysfonction ventriculaire, la régurgitation valvulaire, l’épanchement péricardique, la dilatation coronaire et les anévrismes, les anomalies de conduction et les arythmies. De nouvelles données probantes en ce qui concerne les mécanismes immunologiques potentiels suggèrent que la réponse excessive des cellules T à un superantigène sur la glycoprotéine spiculaire du SRAS-CoV-2 ainsi que la formation des autoanticorps contre les antigènes cardiovasculaires, gastro-intestinaux et endothéliaux sont les principaux facteurs qui contribuent au milieu inflammatoire du SIME. D’autres études sont nécessaires pour déterminer la ou les voies immunologiques partagées et distinctes qui sous-tendent la pathogenèse du SIME vs l’infection SRAS-CoV-2 et la MK. Des données probantes suggèrent que le rare risque de myopéricardite plus bénigne associée au vaccin à ARNm l’emporte sur la réduction du risque d’un SIME plus grave. Dans la présente revue, nous faisons la synthèse de la littérature publiée afin de décrire les facteurs associés et les mécanismes potentiels en ce qui concerne le risque accru de SIME et de complications cardiaques, donnons un aperçu de la physiopathologie immunologique sous-jacente et définissions les similarités et les différences avec la MK.
The complexity of congenital heart disease has been primarily stratified on the basis of surgical technical difficulty, specific diagnoses, and associated outcomes. We report on the refinement and ...validation of a pediatric echocardiography complexity (PEC) score.
The American College of Cardiology Quality Network assembled a panel from 12 centers to refine a previously published PEC score developed in a single institution. The panel refined complexity categories and included study modifiers to account for complexity related to performance of the echocardiogram. Each center submitted data using the PEC scoring tool on 15 consecutive inpatient and outpatient echocardiograms. Univariate and multivariate analyses were performed to assess for independent predictors of longer study duration. Among the 174 echocardiograms analyzed, 68.9% had underlying congenital heart disease; 44.8% were outpatient; 34.5% were performed in an intensive care setting; 61.5% were follow-up; 46.6% were initial or preoperative; and 9.8% were sedated. All studies had an assigned PEC score. In univariate analysis, longer study duration was associated with several patient and study variables (age <2 years, PEC 4 or 5, initial study, preoperative study, junior or trainee scanner, and need for additional imaging). In multivariable analysis, a higher PEC score of 4 or 5 was independently associated with longer study duration after controlling for study variables and center variation.
The PEC scoring tool is feasible and applicable in a variety of clinical settings and can be used for correlation with diagnostic errors, allocation of resources, and assessment of physician and sonographer effort in performing, interpreting, and training in pediatric echocardiography.
PDF
