Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

Multiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS). We characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation. Together, these data argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 expressing T cell activation.

BackgroundChronic parenchymal lung disease (LD) is a new emerging severe life-threatening complication of sJIA. The number of sJIA patients with LD is apparently increasing and interestingly they are reported more frequently in North America. Data regarding frequency and features of sJIA-LD in Europe are not available.ObjectivesTo evaluate the burden of sJIA-LD in Europe.MethodsPatients with diagnosis of sJIA with LD, including pulmonary alveolar proteinosis (PAP), interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), followed in European paediatric rheumatology centres were identified through a survey sent to the members of the MAS/SJIA Working Party.ResultsData from 34 sJIA-LD patients, diagnosed in 15 European paediatric rheumatology centres between 2007 and 2022, were collected. 33 patients were Caucasian and 1 was African-American; 21 were female. The median age at sJIA onset was 6 years and LD occurred after a median time of 2 years. 19 patients had a chronic persistent sJIA course, 14 had a polycyclic course and only 1 patient had a monocyclic course; 29 (85%) had active sJIA at time of LD diagnosis. During the disease course, 28 (82%) patients developed MAS, 12 (35%) of whom had MAS at sJIA onset and 19 (56%) had full-blown MAS at time of LD diagnosis; 23 (68%) patients had >1 MAS episode. 28 (82 %) patients were treated with at least one IL-1 or IL-6 inhibitor before LD diagnosis: 15 with canakinumab, 24 with anakinra and 13 with tocilizumab; 13 (38%) patients experienced drug adverse reaction to a cytokine inhibitor: 9 to tocilizumab and 4 to anakinra. 24 (70%) patients developed ILD, 6 (18%) PAP and 4 (12%) PAH. 15 (44%) patients presented acute digital clubbing; 16 (47%) patients developed hypoxia and 9 (26%) developed pulmonary hypertension. A chest CT scan was performed in all patients with evidence of septal thickening, peri-bronchovascular thickening and ground glass opacities in the majority of patients (26, 18 and 18 respectively). In 17 patients a bronchoalveolar lavage was performed and 12 underwent a lung biopsy. The histopathological pattern was alveolar proteinosis in 5 patients, endogenous lipoid pneumonia in 3, vasculitis in 1 and fibrosis in 1. Half of the patients (17) required ICU admission and 6 (18%) died. All the patients were treated with glucocorticoids (GCs) at time of diagnosis, and 26 received IL-1 or IL-6 inhibitor after the diagnosis (13 canakinumab, 20 anakinra, 14 tocilizumab).ConclusionLung involvement is an emerging life-threatening complication of sJIA and patients are also diagnosed in Europe. Prompt recognition is crucial and new therapeutic strategies are needed to reduce the risk and improve the outcome of this complication.References[1]Saper VE et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis. 2019 Dec;78(12):1722-1731.[2]Schulert GS et al. Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: Characterization and Risk Factors. Arthritis Rheumatol. 2019 Nov;71(11):1943-1954.AcknowledgementsMAS/sJIA working party of Pediatric Rheumatology European Society.Disclosure of InterestsClaudia Bracaglia Speakers bureau: SOBI, Novartis, Consultant of: SOBI, Francesca Minoia Consultant of: SOBI, christoph kessel Speakers bureau: SOBI, Consultant of: Novartis, Grant/research support from: Novartis, Sebastian Vastert: None declared, Manuela Pardeo Consultant of: SOBI, Alessia Arduini: None declared, Özge Basaran: None declared, Nural Kiper: None declared, Mikhail Kostik: None declared, Mia Glerup: None declared, Sarka Fingerhutova: None declared, Roberta Caorsi Consultant of: SOBI, Novartis, AnnaCarin Horne: None declared, Giovanni Filocamo Consultant of: SOBI, Helmut Wittkowski: None declared, Marija Jelusic: None declared, Jordi Anton Speakers bureau: SOBI, Novimmune, Novartis, GSK, Pfizer., Consultant of: SOBI, Novimmune, Novartis, Pfizer, GSK, Grant/research support from: SOBI, Novimmune, Novartis, Abbvie, Pfizer, GSK, Roche, Amgen, Lilly, BMS, Sanofi, Samira Khaldi-Plassart: None declared, alexandre belot Consultant of: SOBI, Novartis, Roche, Pfizer., Gerd Horneff Speakers bureau: Abbvie, Chugai, Lilly, Sanofi, Novartis, Pfizer, Grant/research support from: MSD, Novartis, Roche, Seraina Palmer Sarott: None declared, Elvira Cannizzaro: None declared, Pavla Doležalová: None declared, Angelo Ravelli: None declared, Seza Ozen Speakers bureau: SOBI, Novartis, Consultant of: SOBI, Novartis, Fabrizio De Benedetti Consultant of: Abbvie, SOBI, Novimmune, Novartis, Roche, Pfizer.