NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2–related complications - 05/04/23

Doi : 10.1016/j.jaci.2022.11.020

Aaron Bodansky, MD ^a,^{^{∗
The first 2 authors contributed equally to this article, and both should be considered first author.}}, Sara E. Vazquez, PhD ^b,^c,^{^{∗
The first 2 authors contributed equally to this article, and both should be considered first author.}}, Janet Chou, MD ^d,^e,^⁎ , Tanya Novak, PhD ^f,^g, Amer Al-Musa, MD ^d, Cameron Young, BS ^f, Margaret Newhams, MPH ^f, Suden Kucukak, MD ^f, Laura D. Zambrano, PhD ^h, Anthea Mitchell, BS ^b,ⁱ, Chung-Yu Wang, BA ⁱ, Kristin Moffitt, MD ^e,^j, Natasha B. Halasa, MD, MPH ^k, Laura L. Loftis, MD ^l, Stephanie P. Schwartz, MD ^m, Tracie C. Walker, MD ^m, Elizabeth H. Mack, MD, MS ⁿ, Julie C. Fitzgerald, MD, PhD ^o, Shira J. Gertz, MD ^p, Courtney M. Rowan, MD, MScr ^q, Katherine Irby, MD ^r, Ronald C. Sanders, MD, MS ^r, Michele Kong, MD ^s, Jennifer E. Schuster, MD ^t, Mary A. Staat, MD, MPH ^u, Matt S. Zinter, MD ^v, Natalie Z. Cvijanovich, MD ^w, Keiko M. Tarquinio, MD ^x, Bria M. Coates, MD ^y, Heidi R. Flori, MD, FAAP ^z, Mary K. Dahmer, PhD ^z, Hillary Crandall, MD, PhD ^aa, Melissa L. Cullimore, MD, PhD ^bb, Emily R. Levy, MD, FAAP ^cc, Brandon Chatani, MD ^dd, Ryan Nofziger, MD, MBA ^ee,
Overcoming COVID-19 Network Study Group Investigators,^{^‡}
The Overcoming COVID-19 Network Study Group Investigators are listed in the Acknowledgments.
Michele Kong, MD, Ronald C. Sanders, MD, MS, Masson Yates, Chelsea Smith, Natalie Z. Cvijanovich, MD, MattS. Zinter, MD, Gwenn McLaughlin, MD, MSPH, Keiko M. Tarquinio, MD, Bria M. Coates, MD, Courtney M. Rowan, MD, MScr, Adrienne G. Randolph, MD, Margaret M. Newhams, MPH, Suden Kucukak, MD, Tanya Novak, PhD, Hye Kyung Moon, MA, Takuma Kobayashi, BS, Jeni Melo, BS, Cameron Young, BS, Sabrina R. Chen, BS, Janet Chou, MD, Heidi R. Flori, MD, FAAP, Mary K. Dahmer, PhD, Emily R. Levy, MD, FAAP, Supriya Behl, MSc, Noelle M. Drapeau, BA, Jennifer E. Schuster, MD, Melissa L. Cullimore, MD, PhD, Russell J. McCulloh, MD, Shira J. Gertz, MD, Stephanie P. Schwartz, MD, Tracie C. Walker, MD, Ryan A. Nofziger, MD, Mary Allen Staat, MD, MPH, Chelsea C. Rohlfs, BS, MBA, Julie C. Fitzgerald, MD, PhD, MSCE, Elizabeth H. Mack, MD, MS, Nelson Reed, MD, Natasha B. Halasa, MD, MPH, Laura L. Loftis, MD, Hillary Crandall, MD, PhD

Raif S. Geha, MD ^d, Joseph DeRisi, PhD ^b,ⁱ, Angela P. Campbell, MD, MPH ^h, Mark Anderson, MD, PhD ^c,^{^{§
The last 2 authors contributed equally to this article, and both should be considered senior author.}}, Adrienne G. Randolph, MD, MSc ^e,^f,^g,^{^{§
The last 2 authors contributed equally to this article, and both should be considered senior author.}}
^a Department of Pediatric Critical Care Medicine, University of California, San Francisco, Calif
^b Department of Biochemistry and Biophysics, University of California, San Francisco, Calif
^c Diabetes Center, School of Medicine, University of California, San Francisco, Calif
^d Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^e Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, Mass
^f Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, Mass
^g Department of Anesthesia, Harvard Medical School, Boston, Mass
^h COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, Ga
ⁱ Chan Zuckerberg Biohub, San Francisco, Calif
^j Division of Infectious Diseases, Boston Children’s Hospital, Boston, Mass
^k Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tenn
^l Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Tex
^m Department of Pediatrics, University of North Carolina at Chapel Hill Children’s Hospital, Chapel Hill, NC
ⁿ Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston, SC
^o Department of Anesthesiology and Critical Care, Division of Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa
^p Department of Pediatrics, Division of Pediatric Critical Care, Cooperman Barnabas Medical Center, Livingston, NJ
^q Department of Pediatrics, Division of Pediatric Critical Care Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, Ind
^r Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, Ark
^s Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Ala
^t Department of Pediatrics, Division of Pediatric Infectious Diseases, Children’s Mercy Kansas City, Kansas City, Mo
^u Department of Pediatrics, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
^v Department of Pediatrics, Divisions of Critical Care and Bone Marrow Transplantation, University of California, San Francisco, Calif
^w Division of Critical Care Medicine, UCSF Benioff Children’s Hospital, Oakland, Calif
^x Department of Pediatrics, Division of Critical Care Medicine, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Ga
^y Department of Pediatrics, Division of Critical Care Medicine, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Ill
^z Department of Pediatrics, Division of Pediatric Critical Care Medicine, Mott Children’s Hospital and University of Michigan, Ann Arbor, Mich
^aa Department of Pediatrics, Division of Pediatric Critical Care, Primary Children’s Hospital and University of Utah, Salt Lake City, Utah
^bb Department of Pediatrics, University of Nebraska Medical Center, College of Medicine, Children’s Hospital and Medical Center, Omaha, Neb
^cc Department of Pediatric and Adolescent Medicine, Division of Pediatric Infectious Diseases, Division of Pediatric Critical Care Medicine, Mayo Clinic, Rochester, Minn
^dd Department of Pediatrics, Division of Pediatric Critical Care Medicine, Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, Fla
^ee Department of Pediatrics, Division of Critical Care Medicine, Akron Children’s Hospital, Akron, Ohio

^∗∗Corresponding author: Janet Chou, MD, 1 Blackfan Circle, Karp Building #10007D, Boston, MA 02115.1 Blackfan CircleKarp Building #10007DBostonMA02115

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Abstract

Background

Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown.

Objective

We quantified anti–type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections.

Methods

Circulating anti–IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti–IFN-α2 autoantibodies exceeding the assay’s positive control.

Results

Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti–IFN-α2 antibodies. Anti–IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa–light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient’s peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity.

Conclusions

High levels of anti–IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.

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Key words : Anti-interferon autoantibody, COVID-19, MIS-C, NFKB2, inborn errors of immunity

Abbreviations used : APS-1, COVID-19, IVIG, MIS-C, PBMC, SARS-CoV-2

Plan

Introduction

Results and discussion

Supported by contracts 75D30120C07725 and 75D30121C10297 from the Centers for Disease Control and Prevention. Additional support was from the US National Institute of Allergy and Infectious Diseases (R01AI154470 to A.G.R., 5P01AI118688 for M. Anderson, and R01AI139633-04S1 to R.S.G. and J.C.), National Institute of Diabetes and Digestive and Kidney Diseases (1F30DK123915 to S. Vazquez; R01DK130465 to J.C.), Pediatric Scientist Development Program and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD000850 to A. Bodansky), Chan Zuckerberg Biohub for J. DeRisi. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 151 - N° 4

P. 926 - avril 2023 Retour au numéro

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NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2–related complications - 05/04/23

Abstract

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Methods

Results

Conclusions

Plan

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