Emerging Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome Associated With COVID-19 in Children.

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.

COVID-19 Positive Versus Negative Complete Kawasaki Disease: A Study from the International Kawasaki Disease Registry.

To determine clinical differences for children with complete Kawasaki disease (KD) with and without evidence of preceding SARS-CoV-2 infection. From January 2020, contemporaneous patients with complete KD criteria were classified as either SARS-CoV-2 positive (KDCOVID+; confirmed household exposure, positive PCR and/or serology) or SARS-CoV-2 negative (KDCOVID-; negative testing and no exposure) and compared. Of 744 patients in the International Kawasaki Disease Registry, 52 were KDCOVID- and 61 were KDCOVID+. KDCOVID+ patients were older (median 5.5 vs. 3.7 years; p < 0.001), and all additionally met diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C). They were more likely to have abdominal pain (60% vs. 35%; p = 0.008) and headache (38% vs. 10%; p < 0.001) and had significantly higher CRP, troponin, and BUN/creatinine, and lower hemoglobin, platelets, and lymphocytes. KDCOVID+ patients were more likely to have shock (41% vs. 6%; p < 0.001), ICU admission (62% vs. 10%; p < 0.001), lower left ventricular ejection fraction (mean lowest LVEF 53% vs. 60%; p < 0.001), and to have received inotropic support (60% vs. 10%; p < 0.001). Both groups received IVIG (2 doses in 22% vs. 18%; p = 0.63), but KDCOVID+ were more likely to have received steroids (85% vs. 35%; p < 0.001) and anakinra (60% vs. 10%; p = 0.002). KDCOVID- patients were more likely to have medium/large coronary artery aneurysms (CAA, 12% vs. 0%; p = 0.01). KDCOVID+ patients differ from KDCOVID-, have more severe disease, and greater evidence of myocardial involvement and cardiovascular dysfunction rather than CAA. These patients may be a distinct KD phenotype in the presence of a prevalent specific trigger.

Management of Multisystem Inflammatory Syndrome in Children Associated With COVID-19: A Survey From the International Kawasaki Disease Registry.

BACKGROUND: 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. METHODS: We surveyed the inpatient MIS-C management approaches of the members of the International Kawasaki Disease Registry across 38 institutions and 11 countries. RESULTS: 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. CONCLUSIONS: 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.

CONTEXTE: 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. MÉTHODOLOGIE: 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. RÉSULTATS: 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. CONCLUSIONS: 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.