Journal
JOURNAL OF CLINICAL IMMUNOLOGY
Volume 42, Issue 3, Pages 471-483Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-022-01215-7
Keywords
COVID-19; critical pneumonia; multisystem inflammatory syndrome in children (MIS-C); inborn errors of immunity (IEI); primary immunodeficiency (PID); IFNAR1
Categories
Funding
- Karolinska Institute
- European Union's Horizon 2020 research and innovation program (ATAC) [101003650]
- Center for Innovative Medicine at Karolinska Institutet
- Swedish Research Council
- Knut and Alice Wallenberg Foundation (KAW)
- Howard Hughes Medical Institute
- Rockefeller University
- St. Giles Foundation
- National Institutes of Health (NIH) [R01AI088364, R01AI163029]
- National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program [UL1TR001866]
- Emergent Ventures, Mercatus Center at George Mason University
- Fisher Center for Alzheimer's Research Foundation
- Meyer Foundation
- JPB Foundation
- French National Research Agency (ANR) [ANR-10-IAHU-01]
- ANR [ANR-14-CE14-0008-01, ANR-18-CE15-0020-02, ANR20-CE93-003, ANR-20-CO11-000,1, ANR-21-COVR-0039]
- Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]
- French Foundation for Medical Research (FRM) [EQU201903007798, EA20170638020]
- FRM
- ANR GENCOVID project [ANR-20-COVI-0003]
- ANRS Nord-Sud [ANRSCOV05]
- European Union [824110]
- Square Foundation
- Grandir-Fonds de solidarite pour l'enfance
- SCOR Corporate Foundation for Science
- Fondation du Souffle
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- REACTing-INSERM
- University of Paris
- Imagine Institute (Fondation Bettencourt-Schueller)
- Sidra Medicine [SDR400048]
- Qatar National Research Fund [NPRP9-251-3-045]
- Agence Nationale de la Recherche (ANR) [ANR-18-CE15-0020, ANR-20-COVI-0003, ANR-21-COVR-0039] Funding Source: Agence Nationale de la Recherche (ANR)
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This study identified a rare case with concomitant critical COVID-19 pneumonia and MIS-C, and found a genetic variant associated with IFNAR1 deficiency through whole exome sequencing. It highlights the importance of type I interferon immunity and suggests that inherited or acquired dysregulation of this immune response may contribute to MIS-C.
Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.
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