Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection typically affects children only mildly, multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS) is a serious but rare complication occurring after infection.
PIMS or MIS-C symptoms in affected children
PIMS or MIS-C usually occurs 2 to 6 weeks after SARS-CoV-2 infection, and the most common symptom in all affected children is persistent fever, while other clinical features such as acute abdominal pain, muscle pain, diarrhea or vomiting, headache, and fatigue vary across affected children.
Hyperemia and exanthema, a “strawberry tongue,” and swollen hands and feet resembling Kawasaki´s disease have been seen in a high proportion of PIMS/MIS-C patients.
Cardiovascular issues such as myocardial dysfunction, arterial hypotension, or systemic shock have also been regularly seen, while myocarditis, pericarditis, and valve and coronary artery involvement may also develop.
Lab analyses show intensive inflammation with elevated levels of serum C-reactive protein, ferritin, procalcitonin, troponin, and markers of coagulopathy and hematologic abnormalities. Most children affected by PIMS will need ICU care due to multiorgan failure and shock.
Studies have discussed a possible involvement of pathogenetically relevant autoantibodies in MIS-C. Scientists recently discovered neutralizing autoantibodies against the IL-1-receptor antagonist (IL-1-Ra) and anti-inflammatory receptor antagonists progranulin (PGRN) in adult patients with severe COVID-19.
Studying plasma of children with severe PIMS/MIS-C to detect the presence of PGRN and IL-1-Ra autoantibodies
In a recent study, researchers analyzed the plasma of an index case with severe PIMS/MIS-C for autoantibodies against PGRN and IL-1-Ra. They then extended the study by a series of 12 additional patients. They used ELISA to detect antibodies and Western blot and isoelectric focusing for analyzing IL-1-Ra. Functional activity of the autoantibodies was investigated in vitro using IL-1ß reporter assays. The study is published on the medRxiv* preprint server.
The results show that IL-1-Ra antibodies were detected in 10 out of 13 or 76.9% patients with PIMS/MIS-C, but not detected in controls. Compared to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS/MIS-C. The IL-1-Ra-antibodies detected belonged exclusively to the IgG1 class.
None of the antibodies detected were directed against PGRN. Western blots and ELISA revealed a concomitant reduction in free IL-1-Ra plasma levels in the presence of IL-1-Ra antibodies. The antibodies inhibited IL-1-Ra function in IL-1ß reporter cell assays.
Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1-Ra was observed in all patients positive for IL-1-Ra autoantibodies.
“To summarize, autoantibodies against IL-1-Ra together with an immunogenic isoform of IL1-Ra were observed in a PIMS/MIS-C case and subsequently in a high percentage of a case series.”
Detected antibodies are pathogenetically relevant and need to be further investigated in PIMS/MIS-C cases
This study reported on the high prevalence of neutralizing autoantibodies against the anti-inflammatory molecule IL-1-Ra in a case series of pediatric patients with PIMS/MIS-C. In adults with severe COVID-19, IL-1-Ra antibodies were detected in about 50% of patients and autoantibodies against PGRN in about 40% of patients.
In conclusion, IL-1-Ra autoantibodies were detected in high frequency in children having PIMS/MIS-C. These antibodies may be relevant diagnostic and pathophysiological markers for MIS-C. A hyperphosphorylated isoform of IL-1-Ra possibly triggers the generation of these antibodies.
“The relatively small number of cases included in the present study, due to the rarity of the disease, is a limitation. Nonetheless, these antibodies suggest to be pathogenetically relevant and should be further investigated in PIMS/MIS-C and other hyperinflammatory diseases.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Autoantibodies against IL-1-receptor-antagonist in multisystem inflammatory syndrome in children Jochen Pfeifer, Bernhard Thurner, Christoph Kessel, Natalie Fadle, Evi Regitz, Marie-Christin Hoffmann, Igor Kos, Klaus-Dieter Preuss, Yvan Fischer, Klaus Roemer, Stefan Lohse, Kristina Heyne, Marie-Claire Detemple, Michael Fedlmeier, Hendrik Juenger, Harald Sauer, Sascha Meyer, Tilman Rohrer, Helmut Wittkowski, Katja Masjosthusmann, Sören L. Becker, Sigrun Smola, Moritz Bewarder, Michael Boehm, Jordi Anton, Rosa Maria Pino-Ramirez, Hashim Abdul-Khaliq, Dirk Foell, Lorenz Thurner, medRxiv, 2021.09.08.21263027; doi: https://doi.org/10.1101/2021.09.08.21263027, https://www.medrxiv.org/content/10.1101/2021.09.08.21263027v1
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