Multisystem inflammatory syndrome in children (MIS-C) is a new illness that evolved during the COVID-19 pandemic with initial reports of severe disease including use of extracorporeal membrane ...oxygenation and death. Institutions rapidly assembled task forces to develop treatment algorithms. At the national/international levels, collaboratives and associations assembled consensus writing groups to draft guidelines. These guidelines and algorithms were initially on the basis of expert opinion and small case series. Some groups used the Delphi approach, and the resultant guidelines often mimicked those for other conditions that resembled MIS-C, like Kawasaki disease (KD). For instance, intravenous immunoglobulin (IVIG), a known effective treatment for KD, was recommended for MIS-C. Early in the pandemic many favoured IVIG over steroids as first-line therapy. As evidence evolved so did some guidelines, which now endorse the dual use of IVIG with steroids as first-line therapy. In contrast, withholding immunotherapy became an option for some MIS-C patients with mild symptoms. Herein, we review guidelines and discuss the evidence informing early recommendations, how this has evolved, the role and limitations of expert opinion and observational data, and the importance of leveraging existing research infrastructures, such as the intensive care unit collaborative (Overcoming COVID-19 surveillance registry), and the International Kawasaki Disease Registry. Finally, we discuss strategies to rapidly develop, deploy, and adapt clinical trials evaluating the treatment of such rare conditions in children, which might include alternatives to conventional clinical trial design. The emergence of MIS-C during the COVID-19 pandemic has highlighted unmet needs regarding research of a new condition.
Le syndrome inflammatoire multisystémique chez les enfants (SIME) est une nouvelle maladie qui s’est manifestée pendant la pandémie de COVID-19. Les premiers rapports faisaient état d’une maladie grave nécessitant parfois l’utilisation de l’oxygénation par membrane extracorporelle, et provoquant parfois la mort. Les établissements ont rapidement mis sur pied des groupes de travail ayant pour but de créer des algorithmes de traitement. À l’échelle nationale et internationale, des collectifs et des associations ont formé des groupes pour rédiger des lignes directrices préliminaires. Ces lignes directrices et ces algorithmes reposaient au départ sur l’avis d’experts et sur de petites séries de cas. Certains groupes ont adopté l’approche Delphi, et les lignes directrices qui en ont résulté étaient souvent très semblables à celles d’autres maladies ressemblant au SIME, comme la maladie de Kawasaki (MK). Par exemple, l’administration d’immunoglobulines par voie intraveineuse (IgIV), un traitement efficace pour la MK, a été recommandée dans les cas de SIME. Au début de la pandémie, nombre de personnes ont favorisé les IgIV plutôt que les stéroïdes comme traitement de première intention. De nouvelles données ont amené les instances à réviser certaines lignes directrices et à préconiser l’utilisation en première intention d’IgIV en association avec des stéroïdes. En contrepartie, l’absence d’immunothérapie est devenue une option pour certains patients atteints du SIME qui présentaient des symptômes légers. Dans la présente publication, nous passons en revue les lignes directrices et discutons des données qui ont servi de base aux premières recommandations; nous examinons leur évolution, les rôles et les limites des avis d’experts et des données observationnelles, et l’importance d’utiliser les infrastructures de recherche existantes, comme la collaboration entre les services de soins intensifs (registre de surveillance Overcoming COVID-19), et l’International Kawasaki Disease Registry (registre international de la maladie de Kawasaki). Enfin, nous discutons des stratégies à utiliser pour élaborer, déployer et adapter rapidement des essais cliniques sur le traitement de ce type de pathologie rare chez les enfants, y compris les solutions de rechange aux protocoles d’essais cliniques conventionnels. L’émergence du SIME pendant la pandémie de COVID-19 a mis en lumière des besoins non satisfaits quant à la recherche sur une nouvelle maladie.
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Purpose of Review
We provide the readers with a review of cardiac complications in children with multi-system inflammatory syndrome in children (MIS-C) and its short-term outcomes.
Recent Findings
...Recent reports described the acute cardiac manifestations of MIS-C in children and provided a glimpse of the short-term outcomes.
Summary
Children with MIS-C have been reported to acutely have variable degrees of cardiac findings including abnormal cardiac enzymes, abnormal electrocardiographs, decreased systolic function, coronary artery abnormalities from coronary dilation to giant aneurysms, mitral valve regurgitation, tricuspid valve regurgitation, aortic valve insufficiency, pericardial effusion, diastolic dysfunction, abnormal cardiac strain, and abnormal cardiac MRI. The majority of these abnormalities resolved during short-term follow-up. Further studies are needed to assess if transient or persistent cardiac complications are associated with long-term adverse cardiac events in children with MIS-C.
Multisystem inflammatory syndrome in children is a newly defined complication of severe acute respiratory syndrome coronavirus 2 infection that can result in cardiogenic shock in the pediatric ...population. Early detection of cardiac dysfunction is imperative in directing therapy and identifying patients at highest risk for deterioration. This study compares the strengths of conventional and strain echocardiography in identifying cardiac dysfunction in critically ill children with multisystem inflammatory syndrome in children and their association with ICU therapeutic needs and clinical outcomes.
Retrospective, observational cohort study.
A large, quaternary care PICU.
Sixty-five pediatric patients admitted to the PICU with the diagnosis of multisystem inflammatory syndrome in children from March 2020 to March 2021.
Global longitudinal strain four chamber was measured retrospectively by strain echocardiography and compared with conventional echocardiography. Cardiac dysfunction was defined by left ventricular ejection fraction less than 55% and global longitudinal strain four chamber greater than or equal to -17.2%. Clinical variables examined included cardiac biomarkers, immune therapies, and ICU interventions and outcomes.
Twenty-four patients (37%) had abnormal left ventricular ejection fraction and 56 (86%) had abnormal global longitudinal strain four chamber. Between patients with normal and abnormal left ventricular ejection fraction, we failed to identify a difference in cardiac biomarker levels, vasoactive use, respiratory support needs, or ICU length of stay. Global longitudinal strain four chamber was associated with maximum cardiac biomarker levels. Abnormal global longitudinal strain four chamber was associated with greater odds of any vasoactive use (odds ratio, 5.8; 95% CI, 1.3-25.3; z-statistic, 2.3; p = 0.021). The number of days of vasoactive infusion was correlated with global longitudinal strain four chamber (r = 0.400; 95% CI, 2.4-3.9; p < 0.001). Children with abnormal strain had longer ICU length of stay (4.5 d vs 2 d; p = 0.014).
Our findings suggest strain echocardiography can detect abnormalities in cardiac function in multisystem inflammatory syndrome in children patients unrecognized by conventional echocardiography. These abnormalities are associated with increased use of intensive care therapies. Evaluation of these patients with strain echocardiography may better identify those with myocardial dysfunction and need for more intensive therapy.
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.
Abstract
Background
Our goal was to improve pediatric residents' advanced communication skills in the setting of referral to address the entrustable professional activity of subspecialty referral ...identified by the American Board of Pediatrics. To accomplish this aim, we created a referral and consultation curriculum to teach and assess core communication skills in subspecialty referral involving an adolescent with syncope, an anxiety-provoking symptom that is rarely associated with serious pathology.
Methods
We utilized blended multimodal educational interventions to improve resident communication skills in referral of patients. Trainees participated in 1) an interactive online module on syncope focusing on “red-flag” symptoms that would warrant a subspecialty cardiology referral and 2) a 4-h intervention with Standardized Parents (SPs), focusing on the case-based application of communication skills. Communication skills were assessed by two pre- and post- Objective Structured Clinical Examination encounters of patients with syncope, with an SP evaluation using a 20-item checklist. Analysis was performed with Sign test and McNemar’s test. Trainees provided feedback on a Critical Incident Questionnaire, which was analyzed qualitatively.
Results
Sixty-four residents participated. There was an overall improvement in communication skills based on SP scores (82.7 ± 10.9% to 91.7 ± 5.0%,
p
< 0.001), and 13/20 items demonstrated significant improvement post-intervention. Residents’ improved performance enabled them to address patient/family emotions, explain referral logistics, and clarify concerns to agree on a plan.
Conclusions
By participating in this curriculum, residents’ communication skills improved immediately post-intervention. Further research is needed to assess if this intervention improves patient care by providing residents with enduring skills to judiciously manage the referral process.
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.
Overweight/obesity, prevalent cardiovascular risk factors in children, can be associated with increased risk of adverse outcomes in children with heart disease. The American College of Cardiology ...(ACC) developed quality metrics including a BMI metric related to identifying and counseling overweight and obese children presenting to cardiology clinics. This metric was used for a multicenter collaborative learning Quality improvement (QI) Project through the ACC Quality Network (QNet). Our aim was to increase the percentage of children between ages 3 and 18 years presenting to cardiology clinics at participating centers with BMI > 85th percentile who received appropriate counseling. Participating centers submitted data quarterly to QNet for a sample of patients who received counseling. A Key Driver Diagram was created to help teams drive improvement. Individual centers customized interventions and participated in network-wide educational learning sessions about QI and shared experience. Statistical process control charts were used. From 04/01/2017 to 09/30/2019, 27,511 patient visits were included. Among 32 participating centers, overall counseling rate was 54%. The BMI counseling rate increased from 25% in 2017Q2 to 54% in 2019Q3. There was a wide variation from 10 to 100% in the performance of individual centers. The overall rate of identification and counseling of overweight and obese children presenting to ambulatory cardiology clinics in participating centers is low. There is wide variation in the performance of centers, providing an opportunity for improvement. Using this multicenter learning approach, individual centers have demonstrated improvement. This demonstrates that collaborative learning approaches in QI can increase implementation of the metric.
Recommendations for management of patients with Kawasaki disease (KD) and coronary artery aneurysms (CAA) include physical activity (PA) promotion. This study aimed to characterize self-reported ...practices of KD providers to evaluate practice variation in use of cardiopulmonary exercise testing (CPET) and PA recommendations. We developed a REDCap survey with different clinical scenarios of KD patients. It was completed by members of the International Kawasaki Disease Registry (IKDR) and community pediatric cardiologists. Twenty-eight physicians responded; 63% practiced in the US, 63% practiced in an academic setting, 48% were general pediatric cardiologists, and 55% were IKDR members. Most respondents (69%) followed < 50 KD patients. The great majority (93%) agreed that patients with no CAA do not require CPET and could be cleared for all PA. For patients with small CAA, 43% of respondents recommended CPET and 75% cleared for all PA if CAAs regressed completely, but only 32% cleared if CAA persisted. For patients with medium CAA, 66% respondents cleared for PA if CAA regressed, and only 7% if CAA persisted; with 66% and 75% recommending CPET, respectively. For patients with large/giant CAA, 81% of respondents recommended CPET. No respondents felt comfortable clearing their patients with persistent large/giant CAA for PA and 19% would restrict from the entire physical education program. There is practice variation in use of CPET in KD patients with CAAs. Providers are hesitant to promote PA in KD patients with CAA despite known benefits and current guidelines.
Objective
To decrease referrals to cardiology of patients ages 7 to 21 years with low-probability cardiac pathology who presented to primary care with chest pain by 50% within 24 months.
Study Design
...A multidisciplinary team designed and implemented an initiative consisting of 1) a decision support tool (DST), 2) educational sessions, 3) routine feedback to improve use of referral criteria, and 4) patient family education. Four pediatric practices, comprising 34 pediatricians and 7 nurse practitioners, were included in this study. We tracked progress via statistical process control charts.
Results
A total of 421 patients ages 7 to 21 years presented with chest pain to their pediatrician. The utilization of the DST increased from baseline of 16% to 68%. Concurrently, the percentage of low-probability cardiology referrals in pediatric patients ages 7 to 21 years who presented with chest pain decreased from 17% to 5% after our interventions. At a median follow-up time of 0.9 years (interquartile range, 0.3–1.6 years), no patient had a life-threatening cardiac event.
Conclusion
Our health care improvement initiative to reduce low-probability cardiology referrals for children presenting to primary care practices with chest pain was feasible, effective, and safe.
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