Autoantibodies against IL-1-receptor-antagonist in multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C or PIMS) is a rare but serious complication after an infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently neutralizing autoantibodies against anti-inflammatory receptor antagonists progranulin (PGRN) and IL-1-receptor antagonist (IL-1-Ra) were discovered in adult patients with critical COVID-19. Plasma of an index case with severe PIMS/MIS-C was analyzed for autoantibodies against IL-1-Ra and PGRN. The study was extended by a case series of 12 additional patients. In addition to ELISA for of antibodies, IL-1-Ra plasma levels were determined and IL-1-Ra was analyzed by Western-blot and isoelectric focusing. Functional activity of the autoantibodies was examined in vitro with IL-1{beta} reporter assays. Antibodies against IL-1-Ra could be detected in 10 of 13 (76.9%) patients with PIMS/MIS-C, but not in controls. In contrast to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS/MIS-C. IL-1-Ra-antibodies exclusively belonged to IgG1. No antibodies directed against PGRN were detected. Western blots and ELISA showed a concomitant reduction of free IL-1-Ra plasma levels in the presence of IL-1-Ra-antibodies. The antibodies inhibited IL-1-Ra function in IL-1{beta} reporter cell assays. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1-Ra was observed in all IL-1-Ra autoantibody-positive patients. To conclude, IL-1-Ra autoantibodies were observed in high frequency in children with PIMS/MIS-C. They may represent a diagnostic and pathophysiologically relevant marker for PIMS/MIS-C. Their generation is likely to be triggered by an atypical, hyperphosphorylated isoform of IL-1-Ra.

Surface Acoustic Wave-Based Microfluidic Coagulation Device for Monitoring Anticoagulant Therapy.

An universal coagulation test that reliably detects prolonged coagulation times in patients, regardless of which anticoagulant is administered, is not yet available. The authors developed a novel, miniaturized device utilizing surface acoustic waves (SAW) to detect clotting, and used it to develop a novel universal microfluidic coagulation test. Results from this assay were compared with results from standard coagulation assays to detect classical anticoagulants (unfractionated heparin, argatroban) and direct oral anticoagulants (dabigatran, rivaroxaban). The SAW-clotting time (SAW-CT) of this novel device was prolonged in a dose-dependent manner for heparin, argatroban, dabigatran, and rivaroxaban, comparable to standard assays. The authors confirmed the clinical utility of this device in a small patient population admitted to a stroke unit. Preliminary clinical data prove the suitability of the SAW-CT in patients receiving warfarin, rivaroxaban, or dabigatran. The device could be particularly useful as a point-of-care test to assess whole blood coagulation (e.g., in stroke units or in other emergency settings).