EAACI statement on the pathogenesis, immunology, and immune-targeted management of the Multisystem Inflammatory Syndrome in Children (MIS-C) or Pediatric Inflammatory Multisystem Syndrome (PIMS). (preprint)

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately four weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Epithelial RIG-I inflammasome activation suppresses antiviral immunity and promotes inflammatory responses in virus-induced asthma exacerbations and COVID-19 (preprint)

Rhinoviruses (RV) and inhaled allergens, such as house dust mite (HDM) are the major agents responsible for asthma onset, its life-threatening exacerbations and progression to severe disease. The role of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in exacerbations of asthma or the influence of preexisting viral or allergic airway inflammation on the development of coronavirus disease 2019 (COVID-19) is largely unknown. To address this, we compared molecular mechanisms of HDM, RV and SARS-CoV-2 interactions in experimental RV infection in patients with asthma and healthy individuals. RV infection was sensed via retinoic acid-inducible gene I (RIG-I) helicase, but not via NLR family pyrin domain containing 3 (NLRP3), which led to subsequent apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) recruitment, oligomerization and RIG-I inflammasome activation. This phenomenon was augmented in bronchial epithelium in patients with asthma, especially upon pre-exposure to HDM, which itself induced a priming step, pro-IL-1{beta} release and early inhibition of RIG-I/TANK binding kinase 1/I{kappa}B kinase {epsilon}/type I/III interferons (RIG-I/TBK1/IKK{epsilon}/IFN-I/III) responses. Excessive activation of RIG-I inflammasomes was partially responsible for the alteration and persistence of type I/III IFN responses, prolonged viral clearance and unresolved inflammation in asthma. RV/HDM-induced sustained IFN I/III responses initially restricted SARS-CoV-2 replication in epithelium of patients with asthma, but even this limited infection with SARS-CoV-2 augmented RIG-I inflammasome activation. Timely inhibition of the epithelial RIG-I inflammasome and reduction of IL-1{beta} signaling may lead to more efficient viral clearance and lower the burden of RV and SARS-CoV-2 infection.