Did multisystem inflammatory syndrome in children exist before the SARS-CoV2 pandemic?

MIS-C, characterized by myocardial/gut involvement, is not solely triggered by SARS-CoV2 and needs aggressive immunotherapy. Dear Editor, The SARS-CoV2 pandemic highlighted the ability of this virus to trigger multisystemic inflammatory syndrome in children (MIS-C), 3–6 weeks after exposure [1]. The first MIS-C cases were reported by intensive care unit (ICU) paediatricians, who initially found it overlapping with Kawasaki disease (KD). However, several discrepancies were highlighted by KD specialists [2], such as higher age of onset in MIS-C than KD (8.8 ± 3.7 vs 2.8 ± 2.4 years old) and more frequent digestive involvement. In addition, shock and myocardial failure were much more usual than coronary aneurysms. For these reasons, MIS-C phenotype appears more reminiscent of that of KD shock syndrome (KDSS), which typically requires management in ICU (KD-ICU), and was described prior to SARS-CoV2 pandemic [3, 4]. KD-ICU/SS pathophysiology is related to a cytokine storm [5], similarly described during the MIS-C, as a potential result of abnormal T cell expansion and responses [6]. A recent publication reinforced the hypothesis of clinical and pathophysiological similarities between MIS-C and KD-ICU/SS [7]. We thus aimed to compare clinical and paraclinical features of MIS-C-like syndromes occurred before COVID-19 to SARS-CoV2-induced MIS-C, with a focus on myocardial involvement. For that purpose, we reanalysed the French national cohort of pre-COVID-19 KD-ICU patients [2], in order to define whether these cases could fulfil MIS-C criteria and describe eventual distinguishing characteristics. Briefly, this multicentric cohort of KD-ICU children was constituted by a retrospective chart review of patients <18 years-old with KD (American Heart Association criteria) requiring admission to an ICU for the treatment of KD complications, between 2001 and 2018, in France and in one centre in Germany. The physicians members of the French Society of Paediatric Rheumatology and the French group of Paediatric Emergency and Intensive Care were contacted by e-mail. Family consent was obtained prior to the original publication, in accordance with local ethic committee (CPP no. CO-10-002) and was approved by the Comite Consultatif sur le Traitement de l’Information en matiere de Recherche dans le domaine de la Sante (no. 10.155bis) and the Commission Nationale de l’Informatique et des Libertes (no. DR-2010–032). We collected data on demographic characteristics, clinical manifestations, biological parameters, cardiac complications, electrocardiography and echocardiography data, and treatments. As myocardial involvement is a hallmark of MIS-C, we further studied herein the particularities of KD-ICU patients with myocardial involvement (MyoKD). Myocardial involvement was defined as: hypotension/shock plus myocardial echocardiography abnormalities, including a decrease in ejection fraction ± elevated troponin, which were not secondary to an obstructive or thrombotic acute coronary syndrome. This definition allowed us to distinguish KD-ICU patients with MyoKD from those with KDSS, in whom vasoplegic failure lead to a multisystemic failure responsible for the need of intensive care [3]. All the 48 KD-ICU included patients responded to the criteria of MIS-C defined by the American Academy of Paediatrics (https://www.aap.org) or the World Health Organization and (https://www.who.int) with the exception of exposure to SARS-CoV2 criteria. We compared the 9 MyoKD patients to the 39 other KD-ICU patients (Table 1). The latter were admitted to the ICU for: vasoplegic shock without myocardial failure —i.e. KDSS— [25/39 (64%)], neurologic involvement including coma, seizure, intense pain [7/39 (18%)], severe coronary aneurysms and/or cardiac-respiratory arrest that was not due to myocardial infarction secondary to giant coronary aneurysm thrombosis or obstruction [7/39 (18%)]. MyoKD patients tended to be older (4.1 ± 2.5 vs 2.6 ± 1.9 years old, P = 0.05) and presented systematically gastrointestinal system involvement [9/9 (100%) vs 26/39 (67%), P = 0.04], such as intense abdominal pain, vomiting, diarrhoea and digestive bleeding. MyoKD patients had longer duration of hospitalization (14.9 ± 22.4 vs 6.3 ± 7.1d, P = 0.04), more frequent haemodynamic compromise [5/9 (56%) vs 8/39 (21%), P = 0.03] and inotropic drugs requirement [7/9 (78%) vs 15/39 (39%), P = 0.03]. They presented higher level of initial and maximal C-reactive protein (respectively 286 ± 105 vs 157 ± 97, P < 0.001; and 344 ± 106 vs 247 ± 127 mg/l, P = 0.04), lower level of initial natremia (131.3 ± 4.3 vs 134.7 ± 4.6 mmol/l, P = 0.04), a tendency of increased cardiac troponin level [4/8 (50%) vs 6/31 (19%), P = 0.08] and had no coronary aneurysm. Regarding immunomodulatory treatments, MyoKD patients were more frequently resistant to IVIG [7/9 (78%) vs 16/39 (41%), P = 0.04], taking into account that they received an earlier treatment in disease course (3.0 ± 5.4 vs 5.0 ± 1.6 days, P = 0.04), and a comparable use of additional corticosteroids [4/9 (44%) vs 11/39 (28%), P = 0.3]. Among MyoKD patients, 1/6 was positive for respiratory syncytial virus, whereas 6/26 patients without myocarditis had positive viral screening, including non-SARS-CoV2-coronavirus, respiratory syncytial virus, enterovirus, rotavirus or picornavirus. Phenotypic comparison of pre-COVID-19 KD-ICU children depending on the presence/absence of myocardial involvement Significant results (P < 0.05) are highlighted in bold. World Health Organization criteria of multisystem inflammation syndrome in children (MIS-C), to the exception of SARS-CoV2 exposure (https://www.who.int). American Heart Association criteria of Kawasaki Disease (https://www.aap.org). Abnormal level of troponin, according to local laboratory, was notified in the medical files but not systematically the absolute level. Dilatation and aneurysm distinguished by echocardiography Z score. A second IVIG infusion was performed in case of resistance to the first one. Corticosteroids received whatever dose/administration modality. Anakinra in all patients. ALT: alanine amino-transferase; AST: aspartate aminotransferase; d: day; ICU: intensive care unit; IVIG: intravenous immunoglobulins; KD: Kawasaki disease; WBC: white blood cells; y: year. Phenotypic comparison of pre-COVID-19 KD-ICU children depending on the presence/absence of myocardial involvement Significant results (P < 0.05) are highlighted in bold. World Health Organization criteria of multisystem inflammation syndrome in children (MIS-C), to the exception of SARS-CoV2 exposure (https://www.who.int). American Heart Association criteria of Kawasaki Disease (https://www.aap.org). Abnormal level of troponin, according to local laboratory, was notified in the medical files but not systematically the absolute level. Dilatation and aneurysm distinguished by echocardiography Z score. A second IVIG infusion was performed in case of resistance to the first one. Corticosteroids received whatever dose/administration modality. Anakinra in all patients. ALT: alanine amino-transferase; AST: aspartate aminotransferase; d: day; ICU: intensive care unit; IVIG: intravenous immunoglobulins; KD: Kawasaki disease; WBC: white blood cells; y: year. To conclude, in our pre-COVID-19 cohort of KD-ICU patients, those with myocardial involvement, so-called MyoKD, had all features of MIS-C, both characterized by the combination of myocardial and gastrointestinal involvement, hyperinflammation and high resistance rate to IVIG in monotherapy. MyoKD and MIS-C might belong to a common spectrum; clinical and therapeutic research about MyoKD/MIS-C should thus be conducted regardless of the triggering agents. We believe that fundamental research about MyoKD/MIS-C should take into account risk factors related to both individual genetic/immune features and the ability of particular antigens to act as superantigens [7] and/or to induce an acute intestinal injury with microbiota dysbiosis [8], inducing a systemic and myocardial inflammation through a gut-myocardial axis. The data that support the findings of this study are available on reasonable request to the corresponding author. B.C., I.K.-P., M.P. contributed to the conception and design of the work, performed the acquisition, analysis and interpretation of data for the work; B.C., I.K.-P., M.P., N.D. drafted the work and reviewed it critically; B.C., I.K.-P., M.P., N.D. approved the final version to be published; B.C., I.K.-P., M.P., N.D. were accountable for all aspects of the work in ensuring that questions related to the accuracy/integrity of any part of the work are appropriately investigated. The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Disclosure statement: I.K.-P. has received consulting fees from SOBI, Novartis, LFB, Amgen, CHUGAI, Fresenius Kabi, Zydus, Pfizer. M.P. has received consulting fees from Sanofi, Pfizer, Boeringher Ingelhem, CSL Behring, Novartis, Sun Pharma, Pierre Fabre Dermatology. The remaining authors have declared no conflicts of interest. We thank families and patients. We also thank Drs Ballot, Dauphin, Javouhey, Lacroix, Mortramet, Patural, Saulnier, Schuetz and Terzic for providing cases. We thank the French Society of Paediatric Rheumatology.

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