# Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

Paul Bastard, Adrian Gervais, Maki Taniguchi, Liisa Saare, Karita Särekannu, Tom Le Voyer, Quentin Philippot, Jérémie Rosain, Lucy Bizien, Takaki Asano, et al.

► To cite this version:

Paul Bastard, Adrian Gervais, Maki Taniguchi, Liisa Saare, Karita Särekannu, et al. Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children. Journal of Experimental Medicine, 2024, 221 (2), 10.1084/jem.20231353. hal-04815875

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Distributed under a Creative Commons Attribution 4.0 International License
Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

Paul Bastard¹,²,³,⁴ Ⓓ, Adrian Gervais¹,²*, Ⓔ, Maki Taniguchi⁵* Ⓔ, Liisa Saare⁶* Ⓔ, Karita Särekannu⁷* Ⓔ, Tom Le Voyer¹,²* Ⓔ, Quentin Philippot¹,²* Ⓔ, Jérémie Rosain¹,²* Ⓔ, Lucy Bizien¹,²* Ⓔ, Takaki Asano⁵** Ⓔ, Marina Garcia-Prat⁸** Ⓔ, Alba Parra-Martínez⁸** Ⓔ, Mélanie Migaud¹,²** Ⓔ, Miyuki Tsumura⁵ Ⓔ, Francesca Conti⁹,¹⁰ Ⓔ, Alexandre Belot¹¹,¹²,¹³,¹⁴ Ⓔ, Jacques G. Rivière⁸ Ⓔ, Tomohiro Morio¹⁵ Ⓔ, Junko Tanaka¹⁶ Ⓔ, Etienne Javouhey¹⁷ Ⓔ, Filomeen Haerynck¹⁸ Ⓔ, Sotirija Duvlis¹⁹,²⁰ Ⓔ, Tayfun Ozcelik²¹ Ⓔ, Sevgi Keles²² Ⓔ, Yacine Tandjaoui-Lambiotte²³,²⁴,²⁵ Ⓔ, Simon Escoda²⁶ Ⓔ, Maya Husain²⁶ Ⓔ, Qiang Pan-Hammarström²⁷ Ⓔ, Lennart Hammarström²⁷ Ⓔ, Gloria Ahlijah¹ Ⓔ, Anthony Abi Haidar¹ Ⓔ, Camille Soudee¹ Ⓔ, Vincent Arseguel¹, Hassan Abolhassani²⁷,²⁸ Ⓔ, Sabina Sahanic²⁹ Ⓔ, Ivan Tancevski²⁹ Ⓔ, Yoko Nukui³⁰ Ⓔ, Seiichi Hayakawa⁵ Ⓔ, George P. Chrousos³¹ Ⓔ, Athanasios Michos³¹,³² Ⓔ, Elizabeth-Barbara Tatsi³¹,³² Ⓔ, Filippos Filippatos³¹,³² Ⓔ, Agusti Rodriguez-Palmero³³,³⁴,³⁵ Ⓔ, Jesus Troya³⁶ Ⓔ, Imran Tipu³⁷ Ⓔ, Isabelle Meyts³⁸,³⁹ Ⓔ, Lucie Rousseł⁴⁰,⁴¹ Ⓔ, Sisse Rye Ostrowski⁴² Ⓔ, Laire Schidlowski⁴³ Ⓔ, Carolina Prando⁴³ Ⓔ, Antonio Condino-Neto⁴⁴ Ⓔ, Nathalie Cheikh⁴⁵ Ⓔ, Ahmed A. Bousfiha⁴⁶ Ⓔ, Jalila El Bakkouri⁴⁷ Ⓔ, COVID Clinicians, GEN-COVID Study Group, COVID Human Genetic Effort, Pärt Peterson⁷ Ⓔ, Aurora Pujol⁴⁸ Ⓔ, Romain Lévy¹,²,⁴ Ⓔ, Pierre Quartier²,⁴ Ⓔ, Donald C. Vinh⁴⁰,⁴¹ Ⓔ, Bertrand Boisson¹,²,³ Ⓔ, Vivien Béziat¹,²,³ Ⓔ, Shen-Ying Zhang¹,²,³ Ⓔ, Alessandro Borghesi⁴⁹ Ⓔ, Andrea Pession⁹ Ⓔ, Evangelos Andreatos⁵⁰ Ⓔ, Nico Marr⁵¹ Ⓔ, Alexios-Fotios A. Mentis³¹ Ⓔ, Trine H. Mogensen⁵²,⁵³ Ⓔ, Carlos Rodríguez-Gallego⁵⁴,⁵⁵,⁵⁶ Ⓔ, Pere Soler-Palacin⁸ Ⓔ, Roger Colobran⁵⁷ Ⓔ, Vallo Tillmann⁶ Ⓔ, Bénédicte Neven²,⁴ Ⓔ, Sophie Trouillet-Assant¹³,¹⁴,⁵⁸,⁵⁹ Ⓔ, Petter Brodin⁶⁰,⁶¹ Ⓔ, Laurent Abel¹,²,³*** Ⓔ, Emmanuelle Jouanguy¹,²,³*** Ⓔ, Qian Zhang¹,²,³**** Ⓔ, Federico Martinón-Torres⁶²,⁶³,⁶⁴**** Ⓔ, Antonio Salas⁶⁴,⁶⁵**** Ⓔ, Alberto Gómez-Carballa⁶³,⁶⁴,⁶⁵**** Ⓔ, Luis I. Gonzalez-Granado⁶⁶**** Ⓔ, Kai Kisand⁷**** Ⓔ, Satoshi Okada⁵**** Ⓔ, Anne Puel¹,²,³**** Ⓔ, Aurélie Cobat¹,²,³***** Ⓔ, and Jean-Laurent Casanova¹,²,³,⁶⁷,⁶⁸***** Ⓔ

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7–9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2–5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6–35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1–9.6]) of IFN-ω and/or IFN-α2.

Introduction

Since the start of the pandemic of coronavirus disease 19 (COVID-19) (Zhou et al., 2020), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), close to 7 million people have died from COVID-19 pneumonia (Worldometers, 2023). Age is the major epidemiological risk factor for death from pneumonia in unvaccinated individuals, with the risk doubling every 5 years of age from childhood onward (Bogunovic and Merad, 2021; Levin et al., 2020; O'Driscoll et al., 2021). Unvaccinated adults with inborn errors of immunity (IEI) affecting the

production of, or response to, type I IFNs, or both, are prone to
critical COVID-19 pneumonia (Asano et al., 2021; Khanmohammadi
et al., 2021; Zhang et al., 2020b). These findings established the
crucial role of type I IFNs in fending off SARS-CoV-2 and explained
about 1–5% of cases (Zhang et al., 2022a). Autoantibodies (auto-Abs)
neutralizing high concentrations (10 ng/ml in plasma diluted 1/10)
of IFN-α2 and/or IFN-ω were found in at least another 10% of
unvaccinated adults with critical COVID-19 pneumonia (Bastard
et al., 2020). This observation was later replicated in various

COVID Clinicians, GEN-COVID Study Group, and COVID Human Genetic Effort members and affiliations are listed at the end of the PDF.

© 2024 Bastard et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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<footnote>*A. Gervais, M. Taniguchi, L. Saare, K. Särekannu, T. Le Voyer, Q. Philippot, J. Rosain, and L. Bizien contributed equally to this paper; **T. Asano, M. Garcia-Prat, A. Parra-Martínez, and M. Migaud contributed equally to this paper; ***L. Abel, E. Jouanguy, Q. Zhang, F. Martinón-Torres, A. Salas, A. Gómez-Carballa, L.I. Gonzalez-Granado, K. Kisand, S. Okada, and A. Puel contributed equally to this paper; ****A. Cobat and J.-L. Casanova contributed equally to this paper. Correspondence to Jean-Laurent Casanova: jean-laurent.casanova@rockefeller.edu; Paul Bastard: paul.bastard@institut reimagine.org</footnote>
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¹Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; ²University Paris Cité, Imagine Institute, Paris, France; ³St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; ⁴Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; ⁵Dept. of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; ⁶Dept. of Pediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; ⁷Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; ⁸Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; ⁹Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; ¹⁰Dept. of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy; ¹¹National Reference Center for Rheumatic, and Autoimmune and Systemic Diseases in Children, Lyon, France; ¹²Immunopathology Federation LIFE, Hospices Civils de Lyon, Lyon, France; ¹³Hospices Civils de Lyon, Lyon, France; ¹⁴International Center of Research in Infectiology, Lyon University, International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France; ¹⁵Dept. of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; ¹⁶Dept. of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; ¹⁷Pediatric Intensive Care Unit, Hospices Civils de Lyon, Hopital Fémée Mère Enfant, Lyon, France; ¹⁸Dept. of Paediatric Immunology and Pulmonology, Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, Ghent University Hospital, Ghent, Belgium; ¹⁹Faculty of Medical Sciences, University "Goce Delchev", Stip, Republic of Northern Macedonia; ²⁰Institute of Public Health of the Republic of North Macedonia, Skopje, North Macedonia; ²¹Dept. of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; ²²Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey; ²³Pulmonology and Infectious Disease Department, Saint Denis Hospital, Saint Denis, France; ²⁴INSERM UMR 1137 IAME, Paris, France; ²⁵INSERM UMR 1272 Hypoxia and Lung, Bobigny, France; ²⁶Pediatric Dept., Saint-Denis Hospital, Saint-Denis, France; ²⁷Division of Immunology, Dept. of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; ²⁸Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran; ²⁹Dept. of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria; ³⁰Dept. of Infection Control and Prevention, Medical Hospital, TMDU, Tokyo, Japan; ³¹University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens, Athens, Greece; ³²First Dept. of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece; ³³Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; ³⁴Dept. of Pediatrics, Germans Trias i Pujol University Hospital, UAB, Barcelona, Spain; ³⁵Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; ³⁶Dept. of Internal Medicine, Infanta Leonor University Hospital, Madrid, Spain; ³⁷University of Management and Technology, Lahore, Pakistan; ³⁸Dept. of Immunology, Laboratory of Inborn Errors of Immunity, Microbiology and Transplantation, KU Leuven, Leuven, Belgium; ³⁹Dept. of Pediatrics, Jeffrey Modell Diagnostic and Research Network Center, University Hospitals Leuven, Leuven, Belgium; ⁴⁰Dept. of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Canada; ⁴¹Infectious Disease Susceptibility Program, Research Institute-McGill University Health Centre, Montréal, Canada; ⁴²Dept. of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; ⁴³Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil; ⁴⁴Dept. of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; ⁴⁵Pediatric Hematology Unit, University Hospital of Besançon, Besançon, France; ⁴⁶Dept. of Pediatric Infectious Disease and Clinical Immunology, CHU Ibn Rushd and LICIA, Laboratoire d'Immunologie Clinique, Inflammation et Allergie, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco; ⁴⁷Laboratory of Immunology, CHU Ibn Rushd and LICIA, Laboratoire d'Immunologie Clinique, Inflammation et Allergie, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco; ⁴⁸Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies, Barcelona, Spain; ⁴⁹Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; ⁵⁰Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; ⁵¹Research Branch, Sidra Medicine, Doha, Qatar; ⁵²Dept. of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark; ⁵³Dept. of Biomedicine, Aarhus University, Aarhus, Denmark; ⁵⁴Hospital Universitario de Gran Canaria Dr Negrín, Canarian Health System, Las Palmas, Spain; ⁵⁵Dept. of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain; ⁵⁶Dept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; ⁵⁷Immunology Division, Genetics Dept., Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, UAB, Barcelona, Spain; ⁵⁸Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; ⁵⁹International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France; ⁶⁰Unit for Clinical Pediatrics, Dept. of Women's and Children's Health, Karolinska Institutet, Solna, Sweden; ⁶¹Department of Immunology and Inflammation, Imperial College London, London, UK; ⁶²Translational Pediatrics and Infectious Diseases, Pediatrics Dept., Hospital Clínico Universitario de Santiago, Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain; ⁶³GENVIP Research Group, Instituto de Investigación Sanitaria de Santiago (IDIS), Universidad de Santiago de Compostela, Galicia, Spain; ⁶⁴Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; ⁶⁵Facultade de Medicina, Unidade de Xenética, Instituto de Ciencias Forenses, Universidade de Santiago de Compostela, and GenPoB Research Group, IDIS, SERGAS, Galicia, Spain; ⁶⁶Immunodeficiencies Unit, Hospital 12 de octubre, Research Institute Hospital 12 octubre, Madrid, Spain; ⁶⁷Howard Hughes Medical Institute, New York, NY, USA; ⁶⁸Dept. of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.

regions of the world (Abers et al., 2021; Acosta-Ampudia et al., 2021; Akbil et al., 2022; Arrestier et al., 2022; Bastard et al., 2021c; Busnadiego et al., 2022; Carapito et al., 2022; Chang et al., 2021; Chauvineau-Grenier et al., 2022a; Chauvineau-Grenier et al., 2022b; Credle et al., 2022; Eto et al., 2022; Frasca et al., 2022; Goncalves et al., 2021; Grimm et al., 2023; Hansen et al., 2023; Koning et al., 2021; Lamacchia et al., 2022; Lemarquis et al., 2021; Mathian et al., 2022; Meisel et al., 2021; Petrikov et al., 2022; Philippot et al., 2023; Pons et al., 2023; Raadsen et al., 2022; Savvateeva et al., 2021; Schidlowski et al., 2022; Simula et al., 2022; Solanich et al., 2021; Soltani-Zangbar et al., 2022; Su et al., 2022; Troya et al., 2021; van der Wijst et al., 2021; Vanker et al., 2023; Vazquez et al., 2021; Wang et al., 2021; Ziegler et al., 2021). Moreover, at least 13% of unvaccinated adults with critical COVID-19 pneumonia were found to have auto-Abs neutralizing lower, more physiological concentrations (100 pg/ml in plasma diluted 1/10) of IFN-α2 and/or IFN-ω, whereas auto-Abs neutralizing IFN-β (10 ng/ml in plasma diluted 1/10) were found in another 1% of patients (Bastard et al., 2021a).

These auto-Abs collectively account for about 20% of COVID-19 deaths across age groups in adults (Bastard et al., 2021a; Manry et al., 2022). They are present before infection and are causal for critical disease, being second only to age in importance as a risk factor (Manry et al., 2022). Remarkably, the prevalence of these auto-Abs in the adult general population remains stable until the age of 70 years (about 0.3% for auto-Abs neutralizing high concentrations of IFN and 1% for auto-Abs neutralizing low concentrations of IFNs), after which it increases sharply (reaching up to 4% and 7%, respectively, in individuals aged 80-85 years), consistent with the higher risk of life-threatening COVID-19 in the elderly population (Bastard et al., 2021a; Manry et al., 2022). Finally, the presence of these auto-Abs has been reported in about 20% of adults suffering from “breakthrough” hypoxemic COVID-19 pneumonia despite an appropriate Ab response to two injections of RNA vaccine (Bastard et al., 2022; Sokal et al., 2023). They also underlie 5% and 20% of cases of critical influenza and Middle East respiratory syndrome (MERS) pneumonia (Alotaibi et al., 2023; Zhang
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et al., 2022c), respectively, a third of the rare life-threatening adverse reactions to yellow fever vaccination (Bastard et al., 2021b), and about 40% of cases of West Nile virus encephalitis (Gervais et al., 2023), while contributing to herpetic viral infections in various contexts (Pozzetto et al., 1984; Nagafuchi et al., 2007; Hetemäki et al., 2021b; Mathian et al., 2022). Overall, auto-Abs against type I IFNs can underlie a significant number of cases of severe viral diseases in adults (Bucciol et al., 2023; Casanova and Anderson, 2023; Cobat et al., 2023; Hale, 2023; Quiros-Roldan et al., 2023; Samuel, 2023; Su et al., 2023; Tangye et al., 2023).

These genetic and immunological deficits account for about 20% of cases of critical COVID-19 pneumonia in adults. They provide a general mechanism for pathogenesis of the disease in adults, with insufficient type I IFN immunity during the first days of infection being the key driver of the disease (Campbell et al., 2022; Casanova and Abel, 2021, 2022; Casanova and Anderson, 2023; Cobat et al., 2023; Garcia-Garcia et al., 2023; Samuel, 2023; Su et al., 2023; Zhang et al., 2020a; Zhang et al., 2022a). However, much less is known about life-threatening COVID-19 pneumonia in children. Children are very rarely hospitalized for COVID-19 pneumonia, with the risk of hospitalization being only about 0.1% (O'Driscoll et al., 2021). Resilient inborn errors underlying complete deficiencies of a small set of genes governing type I IFN immunity have been found in ~10% of an international cohort of children hospitalized for COVID-19 pneumonia (COVID Human Genetic Effort [CHGE]; https://www.covidhge.com), suggesting that the same mechanisms of disease are at work in adults and children (Zhang et al., 2022b). Most children with X-linked recessive TLR7 deficiency, or autosomal recessive IFNAR1, TBK1, STAT2, or TYK2 deficiency infected with SARS-CoV-2 suffered life-threatening COVID-19 pneumonia (Asano et al., 2021; Schmidt et al., 2021; Zhang et al., 2022b). However, the human genetic and immunological determinants of COVID-19 pneumonia in the other 90% of children in this cohort remain unknown. With the CHGE, we recruited children hospitalized for COVID-19 pneumonia, including children with recessive inborn errors affecting type I IFNs (Zhang et al., 2022b). The rare children with autoimmune polyendocrine syndrome type I (APS-1), who harbor high titers of auto-Abs neutralizing type I IFNs from infancy onwards, are also known to be at high risk of life-threatening COVID-19 (Bastard et al., 2020, 2021c; Meisel et al., 2021; Valenzise et al., 2023). Furthermore, two Brazilian children hospitalized for severe COVID-19 were subsequently diagnosed with APS-1, following the identification of such auto-Abs (Schidlowski et al., 2022). We, therefore, tested the hypothesis that some of the unvaccinated children without APS-1 who suffered from COVID-19 pneumonia may also have harbored auto-Abs against type I IFNs before infection with SARS-CoV-2. We also assessed the prevalence of auto-Abs against type I IFNs in an uninfected pediatric population. We thus tested whether the main conclusions drawn with samples from adults, including both uninfected individuals and patients with various SARS-CoV-2 infections of various degrees of severity, also apply to children.

# Results

## Auto-Abs against type I IFNs in 19 of 183 children with COVID-19 pneumonia

We studied 183 previously healthy unvaccinated children hospitalized for COVID-19 pneumonia, including eight patients with one of the 15 known recessive IEI affecting type I IFNs (Zhang et al., 2022b) (see study flowchart). The patients were recruited via the CHGE and originated from nine countries (Brazil, France, Italy, Morocco, Saudi Arabia, Spain, Peru, Turkey, and Ukraine). The patients had a median age of 11 years and a mean age of 9 years (range: 0-17 years), and 50% were girls. As previously reported (Bastard et al., 2021a; Gervais et al., 2023), we used plasma or serum samples (diluted 1:10) from the patients for the assessment of anti-IFN-α2 IgG levels by Gyros (Fig. S1 A), and for assessments of neutralization activity against non-glycosylated IFN-α2 and IFN-ω at concentrations of 10 ng/ml and 100 pg/ml, and against glycosylated IFN-β at a concentration of 10 ng/ml (Fig. 1, A and B; and Table 1). The samples were obtained while the patients were hospitalized for COVID-19. The cohort studied here includes 53 of the 112 children previously reported in a study focusing on recessive IEI affecting type I IFNs (Zhang et al., 2022b). Only one of the eight children from our previously published cohort of 12 children with IEI affecting type I IFN immunity (Zhang et al., 2022b) tested had auto-Abs against type I IFNs. This patient had TLR7 deficiency and carried auto-Abs neutralizing 100 pg/ml IFN-ω. No plasma samples were available for the remaining four children from this cohort who were therefore not included in the cohort of 183 children studied here. Conversely, 130 of the children studied here were not included in the cohort investigated in the previous study (Zhang et al., 2022b). Our global cohort of 183 children consisted of 136 cases of critical disease requiring intensive care unit (ICU) hospitalization with high-flow oxygen (>6 L/min) supplementation or mechanical ventilation, 35 cases of severe COVID-19 pneumonia requiring <6 L/min of oxygen supplementation, and 12 with moderate infections that did not require oxygen supplementation. In this context, we identified 10 (5.5%) children with auto-Abs neutralizing IFN-α2: three (1.6%) with auto-Abs against IFN-α2 only, five (2.7%) with auto-Abs against IFN-α2 and IFN-ω, and two (1.1%) with auto-Abs against IFN-α2, IFN-ω, and IFN-β. In addition, nine children (4.9%) had auto-Abs neutralizing IFN-ω only. In total, 19 children (10.4%) had neutralizing auto-Abs against type I IFNs: 14 with critical, 4 with severe, and 1 with moderate COVID-19 pneumonia (Fig. 1, A and B; and Table 2). Moreover, plasma from 7 (3.8%) children contained auto-Abs that neutralized at least one IFN at a concentration of 10 ng/ml, whereas 12 (6.6%) children had auto-Abs neutralizing IFN only at a concentration of 100 pg/ml (Fig. 1, A and B). All patients with Gyros values over 200 had neutralizing auto-Abs (Fig. S1 B). Auto-Abs neutralizing IFN-α2, IFN-β, and/or IFN-ω were, thus, detected at the onset of COVID-19 pneumonia in 19 of the 183 unvaccinated children studied (10.4%): 10 (5.5%) with auto-Abs neutralizing IFN-α2 (three [1.6%] IFN-α2 only, five [2.7%] IFN-α2 and IFN-ω, and two [1.1%] IFN-α2, IFN-ω, and IFN-β), and nine (4.9%) with auto-Abs neutralizing IFN-ω only.
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A

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B

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C

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D

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E

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F

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**Figure 1.** **Neutralizing auto-Abs against IFN-α2 and/or IFN-ω in children with life-threatening COVID-19. (A)** Results for the neutralization of 10 ng/ml IFN-α2, IFN-ω, or IFN-β in the presence of plasma (1/10 dilution) from pediatric patients with critical (n = 136), severe (n = 35), or moderate (n = 12) COVID-19 pneumonia. Relative luciferase activity is shown (IFN-stimulated response element [ISRE] dual luciferase activity, with normalization against *Renilla* luciferase activity) after stimulation with 10 ng/ml IFN-α2, IFN-ω, or IFN-β in the presence of plasma (1/10 dilution). RLA: relative luciferase activity. All samples were tested twice independently. **(B)** Neutralization of 100 pg/ml IFN-α2 or IFN-ω in the presence of plasma (1/10 dilution) from pediatric patients with critical (n = 136), severe (n = 35), or moderate (n = 12) COVID-19 pneumonia. All samples were tested twice independently. **(C–F)** The proportion by age of pediatric and adult patients with life-threatening COVID-19 pneumonia positive for neutralizing auto-Abs (in plasma 1/10) against **(C)** IFN-α2 and/or IFN-ω at 10 ng/ml for both sexes, **(D)** IFN-α2 and/or IFN-ω at 10 ng/ml for men or women, **(E)** IFN-α2 and/or IFN-ω at 100 pg/ml for both sexes, and **(F)** IFN-α2 and/or IFN-ω at 100 pg/ml for men or women.
<figure><img src="image_12.png" /><figcaption>Table 1. Auto-Abs neutralized by the serum from the 19 patients</figcaption></figure>

<table><thead><tr><th>Patient</th><th>Anti-IFN-α2 auto-Abs (10 ng/ml)</th><th>Anti-IFN-β auto-Abs (10 ng/ml)</th><th>Anti-IFN-ω auto-Abs (10 ng/ml)</th><th>Anti-IFN-α2 auto-Abs (100 pg/ml)</th><th>Anti-IFN-ω auto-Abs (100 pg/ml)</th></tr></thead><tbody><tr><td>P1</td><td>1</td><td>0</td><td>0</td><td>1</td><td>0</td></tr><tr><td>P2</td><td>1</td><td>1</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P3</td><td>0</td><td>0</td><td>0</td><td>1</td><td>0</td></tr><tr><td>P4</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P5</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P6</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P7</td><td>0</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td>P8</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P9</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P10</td><td>0</td><td>0</td><td>0</td><td>1</td><td>0</td></tr><tr><td>P11</td><td>0</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td>P12</td><td>1</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td>P13</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P14</td><td>1</td><td>1</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P15</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P16</td><td>0</td><td>0</td><td>1</td><td>0</td><td>1</td></tr><tr><td>P17</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P18</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P19</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr></tbody></table>

1: neutralizing. 0: non-neutralizing.

<figure><img src="image_13.png" /></figure>

## Demographic and clinical features of the 19 patients with auto-Abs against type I IFNs

The 19 children with COVID-19 pneumonia and auto-Abs neutralizing type I IFNs comprised 10 girls and 9 boys, aged 3 mo to 18 years (mean: 11 years) (Fig. 1, C-F, Fig. S1, C-J, Fig. S2, A-J; and Table 3). They originated from four different countries (France,

Pakistan but living in Italy, Spain, and Turkey), with a particularly large proportion of patients from Turkey (79%). Turkish children did not account for a disproportionate number of the individuals with auto-Abs against type I IFNs (79% of Turkish children with antibodies (Abs) versus 66% without; P = 0.31; Fisher's exact test). None of these individuals had previously suffered from other severe viral infections known to be associated with these auto-Abs, such as live attenuated yellow fever viral vaccine disease (Bastard et al., 2021b), West Nile virus encephalitis (Gervais et al., 2023), critical influenza pneumonia (Zhang et al., 2022c), critical MERS pneumonia (Alotaibi et al., 2023), or severe zoster infection (Busnadiego et al., 2022; Mathian et al., 2022; Mogensen et al., 1981; Pozzetto et al., 1984; Walter et al., 2015). The two children under the age of 6 mo may have received the auto-Abs via materno-fetal transmission. APS-1 was excluded clinically (no other clinical features of autoimmunity) in all 19 patients and genetically in all 12 for whom DNA samples were available. Only 1 of the 12 children for whom DNA was available carried any of the known IEI-affecting type I IFNs. This patient produced auto-Abs neutralizing the lower concentration of IFN-ω and had X-linked TLR7 deficiency (Asano et al., 2021). All the children were hospitalized for pneumonia following SARS-CoV-2 infection. Among the 19 children with auto-Abs neutralizing type I IFNs, 1 (5%) with auto-Abs neutralizing IFN-ω only (at a concentration of 100 pg/ml) had moderate COVID-19 pneumonia, 4 children (21%) were hospitalized for severe COVID-19 pneumonia, and 14 children (74%) had critical
<figure><img src="image_14.png" /><figcaption>Table 2. Clinical and demographic information for the 19 pediatric patients with COVID-19 disease and auto-Abs neutralizing type I IFNs</figcaption></figure>

<table><thead><tr><td>Patient</td><td>Age</td><td>Sex</td><td>Country of origin</td><td>Country of residence</td><td>Classification</td></tr></thead><tbody><tr><td>P1</td><td>10</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P2</td><td>14</td><td>F</td><td>France</td><td>France</td><td>Severe</td></tr><tr><td>P3</td><td>12</td><td>F</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P4</td><td>17</td><td>F</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P5</td><td>17</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Moderate</td></tr><tr><td>P6</td><td>3</td><td>M</td><td>Turkey</td><td>Turkey</td><td>MIS-C + critical</td></tr><tr><td>P7</td><td>15</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P8</td><td>18</td><td>M</td><td>France</td><td>France</td><td>Critical</td></tr><tr><td>P9</td><td>18</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P10</td><td>0.25</td><td>F</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P11</td><td>0.5</td><td>F</td><td>France</td><td>France</td><td>Critical</td></tr><tr><td>P12</td><td>14</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Severe</td></tr><tr><td>P13</td><td>7.3</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Severe</td></tr><tr><td>P14</td><td>11</td><td>F</td><td>Pakistan</td><td>Italy</td><td>Severe</td></tr><tr><td>P15</td><td>4</td><td>F</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P16</td><td>13</td><td>M</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P17</td><td>15</td><td>F</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P18</td><td>16</td><td>F</td><td>Turkey</td><td>Turkey</td><td>Critical</td></tr><tr><td>P19</td><td>2</td><td>F</td><td>Spain</td><td>Spain</td><td>Critical</td></tr></tbody></table>

F: female; M: male.

disease (Fig 1, A and B; and Table 3). One of the children with critical disease had cardiological, neurological, cutaneous, and gastrointestinal manifestations of the multisystem inflammatory syndrome in children (MIS-C) (Lee et al., 2023; Sancho-Shimizu et al., 2021). All the patients survived, and all except the patients with additional manifestations had positive SARS-CoV-2 RT-PCR results on samples from the respiratory tract. The patient with additional manifestations had critical pneumonia and a subsequent positive serological test demonstrated infection. Overall, these findings suggest that auto-Abs against type I IFNs can underlie life-threatening COVID-19 pneumonia in a significant proportion of previously healthy unvaccinated children.

### Auto-Abs neutralize all 12 IFN-α subtypes

We assessed the neutralization of the 12 individual IFN-α subtypes at the intermediate concentration of 1 ng/ml. There are 13 IFNA loci, but only 12 IFN-α proteins, as the products of IFNA1 and IFNA13 are identical (Moreau et al., 2023). Interestingly, for all patients with auto-Abs neutralizing 10 ng/ml IFN-α2, all 12 IFN-α subtypes were neutralized (Fig. 2 A). None of the patients with auto-Abs against IFN-ω but without detectable auto-Abs against IFN-α2 displayed neutralization of any of the 12 IFN-α subtypes. However, the patient tested for whom IFN-α2 neutralization was observed at 100 pg/ml, but not 10 ng/ml, also displayed neutralization at a concentration of 1 ng/ml, and neutralization of most of the other IFN-α subtypes (no

neutralization of IFN-α4/5/10). We did not assess the neutralization of these IFNs at 100 pg/ml. These findings are consistent with the high degree of similarity between the 12 IFN-α subtypes (Manry et al., 2011) and the presence of a B cell epitope recognized by the auto-Abs in a conserved region of these IFNs (Meyer et al., 2016). It also suggests that patients with auto-Abs neutralizing all IFN-α subtypes might be at higher risk of severe viral disease.

### Auto-Abs neutralize glycosylated IFNs

In our previous studies, we tested only unglycosylated IFN-α2a, IFN-α14, and IFN-ω produced in cells of the bacterium *Escherichia coli* and glycosylated IFN-β produced by mammalian CHO cells (Adolf et al., 1991; Nyman et al., 1998; Runkel et al., 1998). Here, we considered four human type I IFNs (IFN-α2a/b, IFN-α14, IFN-ω, and IFN-β) normally produced and secreted as glycosylated proteins. IFN-α2b is produced as an O-glycosylated form, whereas IFN-α2a is present in two forms, one fully and the other partially O-glycosylated. By contrast, IFN-α14, IFN-ω, and IFN-β are produced as N-glycosylated forms. We, therefore, investigated the effects of glycosylation on the recognition of these proteins by auto-Abs by determining whether auto-Abs recognized glycosylated but not unglycosylated IFNs or vice versa. We, therefore, tested the neutralization of glycosylated forms of IFN-α2b and IFN-ω produced in mammalian cells. We first determined the optimal experimental set-up. We found that the optimal concentration for testing was 1 ng/ml for
<figure><img src="image_15.png" /><figcaption>Table 3. Numbers of cases, proportion, and OR for COVID-19 pneumonia in pediatric patients</figcaption></figure>

<table><thead><tr><td>Auto-Abs (dose)</td><td>Number of patients positive</td><td>Proportion of patients testing positive (%)</td><td>OR [95% CI] for COVID-19 pneumonia</td><td>P value</td></tr></thead><tbody><tr><td>Anti-IFN-α2 (10 ng/ml)</td><td>6</td><td>3.4</td><td>57 [12–560]</td><td>3 × 10<sup>-07</sup></td></tr><tr><td>Anti-IFN-β (10 ng/ml)</td><td>2</td><td>1.1</td><td>23 [3–255]</td><td>4 × 10<sup>-03</sup></td></tr><tr><td>Anti-IFN-ω (10 ng/ml)</td><td>5</td><td>2.8</td><td>9 [3–29]</td><td>5 × 10<sup>-04</sup></td></tr><tr><td>Anti-IFN-α2 (100 pg/ml)</td><td>10</td><td>5.5</td><td>30 [10–103]</td><td>1 × 10<sup>-9</sup></td></tr><tr><td>Anti-IFN-ω (100 pg/ml)</td><td>16</td><td>8.8</td><td>5 [2–8]</td><td>7 × 10<sup>-06</sup></td></tr><tr><td>Anti-IFN-α2 and/or anti-IFN-ω (10 ng/ml)</td><td>7</td><td>3.9</td><td>11 [4–32]</td><td>2 × 10<sup>-05</sup></td></tr><tr><td>Anti-IFN-α2 and/or anti-IFN-β, and/or anti-IFN-ω (10 ng/ml)</td><td>7</td><td>3.8</td><td>11 [4–29]</td><td>3 × 10<sup>-05</sup></td></tr><tr><td>Anti-IFN-α2 and anti-IFN-ω (10 ng/ml)</td><td>4</td><td>2.4</td><td>112 [12–14,991]</td><td>9 × 10<sup>-04</sup></td></tr><tr><td>Anti-IFN-α2, anti-IFN-ω, and anti-IFN-β (10 ng/ml)</td><td>2</td><td>1.1</td><td>75 [6–10,328]</td><td>9 × 10<sup>-04</sup></td></tr><tr><td>Anti-IFN-α2 only (10 ng/ml)</td><td>2</td><td>1.1</td><td>23 [3–263]</td><td>4 × 10<sup>-03</sup></td></tr><tr><td>Anti-IFN-ω only (10 ng/ml)</td><td>1</td><td>0.6</td><td>3 [0.3–12]</td><td>3 × 10<sup>-01</sup></td></tr><tr><td>Anti-IFN-β only (10 ng/ml)</td><td>0</td><td>0.00</td><td>4 [0.03–57]</td><td>5 × 10<sup>-01</sup></td></tr><tr><td>Anti-IFN-α2 and/or anti-IFN-ω (100 pg/ml)</td><td>19</td><td>10.4</td><td>5 [3–9]</td><td>1 × 10<sup>-07</sup></td></tr><tr><td>Anti-IFN-α2 and anti-IFN-ω (100 pg/ml)</td><td>7</td><td>3.9</td><td>26 [7–106]</td><td>7 × 10<sup>-07</sup></td></tr></tbody></table>

glycosylated type I IFN (Fig. S3 A). We tested 183 children, including 19 with auto-Abs against type I IFNs. Most of the 19 patients with auto-Abs neutralizing unglycosylated IFN-α2 or IFN-ω also displayed neutralization of the glycosylated forms. However, three patients had auto-Abs that neutralized the unglycosylated but not the glycosylated form of IFN-ω, and three had auto-Abs neutralizing the unglycosylated but not the glycosylated form of IFN-α2, at a concentration of 1 ng/ml (Fig. 2, B-E). Interestingly, we also found two patients with auto-Abs neutralizing the glycosylated forms of both IFN-ω and IFN-α2b but not the unglycosylated form of either cytokine, and one patient with auto-Abs neutralizing the glycosylated form of IFN-α2b but not the unglycosylated form. Another two patients had auto-Abs neutralizing the glycosylated form of IFN-ω but not the unglycosylated form. We did not test the unglycosylated form of IFN-β. Serum from the six patients with auto-Abs neutralizing 10 ng/ml unglycosylated IFN-α2 also neutralized all 12 IFN-α subtypes and glycosylated IFN-α2 at a concentration of 1 ng/ml. Interestingly, 2 of the 183 patients tested had auto-Abs neutralizing the glycosylated but not the unglycosylated form of IFN-α2b or IFN-ω, whereas 3 had auto-Abs neutralizing the unglycosylated forms of both cytokines but not the glycosylated forms. These findings suggest that it may be useful to assess the neutralization of glycosylated forms of IFN-α2a and IFN-ω as a means of identifying previously unrecognized patients.

Auto-Abs neutralizing type I IFNs are rare in children from the general population

We previously tested large adult cohorts, comprising a total of 39,198 individuals, to assess the prevalence of auto-Abs against type I IFNs in the uninfected general population (Bastard et al., 2020, 2021a; van der Wijst et al., 2021). The prevalence of auto-Abs neutralizing 10 ng/ml (or 100 pg/ml) IFN-α2 or IFN-ω was

found to increase significantly with age, with the detection of such Abs in 0.17% (1.1%) of individuals under and >1.4% (4.4%) of those over the age of 70 years, making a major contribution to the higher risk of life-threatening COVID-19 in the elderly population (Manry et al., 2022). The prevalence of auto-Abs against IFN-β was lower and remained stable across age groups (0.26%) (Bastard et al., 2020). Interestingly, auto-Abs neutralizing IFN-α2 (at the lower concentration of 100 pg/ml), regardless of the presence or absence of auto-Abs neutralizing IFN-ω, were found in 0.3% of individuals under the age of 70 years, whereas those neutralizing 100 pg/ml IFN-ω were found in 0.9% of this population (Table 4). Strikingly, the prevalence of auto-Abs neutralizing IFN-α2 increased eightfold after the age of 65 years, whereas the prevalence of auto-Abs neutralizing IFN-ω increases only 2.5-fold (Fig. 3 C, Fig. 4, A-H; Fig. S3, B-H; Fig. S4, A-H; and Table 4). In men, the increase in the prevalence of auto-Abs against IFN-α2 was even greater, >10-fold after the age of 65 years. We therefore assessed the prevalence of these auto-Abs in 2,267 children from the general population with samples collected before the pandemic and, therefore, before any possibility of infection with SARS-CoV-2. Samples were collected in Belgium (n = 126), Canada (n = 161), Estonia (n = 288), Spain (n = 1,685), and Pakistan (n = 7). The children studied were aged 0–18 years (median and mean ages: 10 and 9 years, respectively), with an equal distribution between the sexes (56% were girls). Interestingly, in children, auto-Abs neutralizing IFN-α2 were exceedingly rare. Indeed, only one child (0.04%) had auto-Abs neutralizing IFN-α2 at 10 ng/ml and only three children (0.1%) had auto-Abs neutralizing this cytokine at a concentration of 100 pg/ml. The auto-Abs of these three children also neutralized IFN-ω. By contrast, auto-Abs neutralizing IFN-ω alone were found in a much higher proportion of uninfected children. Indeed, eight children (0.35%) had auto-Abs
<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 2.** **Auto-Abs neutralize all 12 IFN-α subtypes and the glycosylated IFNs. (A)** Results for the neutralization of 12 individual IFN-α subtypes, IFN-ω or IFN-β, from children with auto-Abs (n = 8), healthy controls (n = 2), or auto-Ab positive patients (n = 2). Relative luciferase activity is shown (ISRE dual luciferase activity, with normalization against *Renilla* luciferase activity, and to the non-stimulated [NS] condition) after stimulation with the various type I IFNs at a concentration of 1 ng/ml in the presence of plasma (1/10 dilution). All samples were tested once. RLA: relative luciferase activity. **(B–E)** Plots representing the</figcaption></figure>
<figure><img src="image_18.png" /></figure>

neutralization results for glycosylated (at 1 ng/ml) or unglycosylated (at 10 ng/ml or 100 pg/ml) forms of IFN-α2 and IFN-ω. The dots in the lower right part of the plot indicate neutralization of the glycosylated form of the IFN but not of the unglycosylated form, whereas the dots in the upper right part of the plot indicate neutralization of the unglycosylated form of the IFN but not of the glycosylated form. The dots in the lower left part of the plot indicate the neutralization of either form of the IFNs, whereas those in the upper right part of the plot indicate an absence of neutralization for both forms; (B) unglycosylated form of IFN-α2 at 10 ng/ml; (C) unglycosylated form of IFN-α2 at 100 pg/ml; (D) unglycosylated form of IFN-ω at 10 ng/ml; and (E) unglycosylated form of IFN-ω at 100 pg/ml.

neutralizing IFN-ω at 10 ng/ml, whereas an additional 38 (1.7%) had auto-Abs neutralizing IFN-ω at 100 pg/ml (Fig. 3, A and B). We also identified one girl, aged 1.5 years, with auto-Abs neutralizing only glycosylated IFN-β at a concentration of 10 ng/ml (0.04%) (Fig. 3 A). Finally, we tested two additional independent cohorts of healthy children. None of the individuals of a cohort of 249 healthy children aged 0–18 years (median: 9 years) from Japan tested positive (Fig. S5 A). These pediatric controls included 34 individuals who had had mild COVID infection and did not harbor auto-Abs against type I IFNs. A cohort of 200 healthy children from Estonia (all aged 8–9 years) included only three individuals with auto-Abs neutralizing IFN-ω at a concentration of 100 pg/ml (1.5%) (Fig. S5 B). Overall, 0.17% of uninfected children from our cohort had auto-Abs neutralizing IFN-α2 (4 of 2,267, including 3 at low and 1 at high concentration), whereas 0.04% had auto-Abs neutralizing glycosylated IFN-β (1 of 2,267, at 10 ng/ml) and 2% had auto-Abs neutralizing IFN-ω only (46 of 2,267, including 38 at low and 8 at high concentration). The neutralization of two IFNs simultaneously was exceedingly rare and restricted to IFN-α2 and IFN-ω at the lower concentration in three patients (0.1%).

### Characteristics of children from the general population with auto-Abs against type I IFNs

We found that 2,267 children from the general population tested included 4 with auto-Abs neutralizing IFN-α2 (0.2%) and 45 with auto-Abs neutralizing IFN-ω (2%). Three (6%) of these children had auto-Abs neutralizing both IFN-α2 and IFN-ω.

<table><caption>Table 4. Prevalence of auto-Abs against type I IFNs in the general population</caption><thead><tr><th>Type I IFN auto-Abs (in plasma 1/10)</th><th>Age</th><th>Proportion of individuals from the general population with neutralizing auto-Abs (%)</th></tr></thead><tbody><tr><td rowspan="3">Anti-IFN-α2 (100 pg/ml)</td><td>Children &lt;18 years</td><td>0.2%</td></tr><tr><td>Adults &lt;65 years</td><td>0.3%</td></tr><tr><td>Adults ≥65 years</td><td>2.6%</td></tr><tr><td rowspan="3">Anti-IFN-ω (100 pg/ml)</td><td>Children &lt;18 years</td><td>2%</td></tr><tr><td>Adults &lt;65 years</td><td>0.9%</td></tr><tr><td>Adults ≥65 years</td><td>2.2%</td></tr></tbody></table>

These three children were aged 8, 11, and 13 years, and all three were boys. The individual with auto-Abs neutralizing IFN-α2 only was a 9-year-old girl. Finally, the median age of the 42 children with auto-Abs neutralizing IFN-ω only was 8 years, and 31 (67%) of these children were boys. We also tested a cohort of 145 samples from children hospitalized for bacterial infections. Only one of these patients (0.7%) harbored auto-Abs against type I IFNs (against IFN-ω only) with neutralizing activity against a concentration of 100 pg/ml. None of these children had auto-Abs neutralizing IFN-α2 or IFN-β. None of the children with auto-Abs tested had any remarkable medical antecedents, despite having been infected with many viruses, as shown by Virscan analyses on nine of the positive children (Fig. 3 D). However, it should be noted that infections with influenza viruses or common coronaviruses were not investigated with Virscan. These findings probably attest to the higher tonic type I IFN activity in children than in adults (Loske et al., 2021; Pierangeli et al., 2022; Pierce et al., 2021). Overall, we found that auto-Abs neutralizing IFN-α2 were very rare in children from the general population. By contrast, auto-Abs neutralizing IFN-ω only, at the lower concentration, were less rare (2%) and mostly found in boys, at a rate slightly higher than that for young adults under the age of 40 years (45/2,267 [2%] in children versus 17/1,251 [1.4%] in adults between 18 and 40 years old, P = 0.28).

### Risk of life-threatening COVID-19 in children with auto-Abs against type I IFNs

We then assessed the risk of COVID-19 pneumonia (hospitalization for hypoxemic pneumonia, including severe or critical pneumonia) in children carrying auto-Abs capable of neutralizing different concentrations and combinations of type I IFNs, relative to uninfected children from the general population, as previously reported for COVID-19 and influenza in adults (Bastard et al., 2021a; Manry et al., 2022). All types of auto-Abs combinations were highly significant risk factors when patients with severe or critical COVID-19 pneumonia were compared with the general population (Fig. 5 and Table 2). The strongest association with severe or critical pneumonia was that for children with auto-Abs neutralizing both IFN-α2 and IFN-ω at a concentration of 10 ng/ml (OR [95% CI] = 122.8 [12.8–16,364.8], P = 6 × 10⁻⁶; OR, odds ratio; CI, confidence interval). Auto-Abs neutralizing IFN-α2 and IFN-ω at a lower concentration of 100 pg/ml were also highly significant risk factors (OR [95% CI] = 27.9 [8.2–116.5], P = 4 × 10⁻⁷), whereas auto-Abs neutralizing IFN-α2 or IFN-ω were weaker risk factors (OR [95% CI] = 5.5 [3.1–9.6] at 100 pg/ml and OR [95% CI] = 12.9 [4.6–35.9] at 10 ng/ml), with the OR for auto-Abs neutralizing high concentrations of IFN-α2 or IFN-ω significantly higher than that for auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω (P = 0.006).
<figure><img src="image_19.png" /><figcaption>A</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>B</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>C</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>D</figcaption></figure>

<figure><img src="image_23.png" /></figure>

**Figure 3.** Neutralizing auto-Abs against IFN-α2 and/or IFN-ω in children from the general population and their serological evaluation. (A) Results for the neutralization of 10 ng/ml IFN-α2, IFN-ω, or IFN-β in the presence of plasma (1/10 dilution) from children from the general population (n = 2,267). Relative luciferase activity is shown (ISRE dual luciferase activity, with normalization against *Renilla* luciferase activity). All samples were tested once. RLA: relative luciferase activity. (B) Neutralization of 100 pg/ml IFN-α2 or IFN-ω in the presence of plasma (1/10 dilution) from children from the general population (n = 2,267). (C) Prevalence of auto-Abs neutralizing type I IFNs, distributed by age, in individuals from the general population. (D) Serological evaluation of auto-Ab-positive children: Virscan results for children (n = 9) with auto-Abs against type I IFNs.
<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

<figure><img src="image_26.png" /></figure>

<figure><img src="image_27.png" /></figure>

<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /></figure>

<figure><img src="image_31.png" /></figure>

<figure><img src="image_32.png" /><figcaption>**Figure 4.** Neutralizing auto-Abs against IFN-α2 and/or IFN-ω in the pediatric and adult general population. (A–H) Proportion by age of pediatric and adult individuals from the general population positive for neutralizing auto-Abs (in plasma 1/10) against (A) IFN-α2 and/or IFN-ω, at 10 ng/ml, for both sexes; (B) IFN-α2 and/or IFN-ω, at 10 ng/ml, for men or women; (C) IFN-α2 and/or IFN-ω, at 100 pg/ml, for both sexes; (D) IFN-α2 and/or IFN-ω, at 100 pg/ml, for men or women; (E) IFN-α2, at 100 pg/ml, for both sexes; (F) IFN-α2, at 100 pg/ml, for men or women; (G) IFN-ω, at 100 pg/ml, for both sexes; and (H) IFN-ω, at 100 pg/ml, for men or women.</figcaption></figure>
<figure><img src="image_33.png" /></figure>

A

Risk of COVID-19 pneumonia
in children with neutralizing auto-Abs against type I IFNs

<figure><img src="image_34.png" /></figure>

B

Risk of life-threatening COVID-19 pneumonia
in children with neutralizing auto-Abs against type I IFNs

<figure><img src="image_35.png" /></figure>

Figure 5. **OR for COVID-19 pneumonia.** (A) Bar plot of the calculated OR for COVID-19 pneumonia in children with auto-Abs against type I IFNs. Adjusted ORs and 95% CI were computed by penalized profile likelihood. ORs and P values were estimated by means of Firth's bias-corrected logistic regression. (B) Bar plot of the calculated OR for life-threatening pneumonia in children with auto-Abs against type I IFNs. Adjusted ORs and 95% CI were computed by penalized profile likelihood. ORs and P values were estimated by means of Firth's bias-corrected logistic regression.

The risk of life-threatening COVID-19 pneumonia did not differ significantly between children with auto-Abs neutralizing only IFN-α2 at 100 pg/ml (OR [95% CI] = 67.6 [5.7–9196.6]) and those with auto-Abs neutralizing IFN-α2 and IFN-ω (OR [95% CI] = 27.9 [8.2–116.5], P = 0.5), but the risk for children with auto-Abs neutralizing only IFN-ω at a concentration of 100 pg/ml was significantly lower (OR [95% CI] = 2.6 [1.2–5.3], P = 0.006). Overall, auto-Abs neutralizing IFN-α2 were significantly stronger risk factors than auto-Abs neutralizing only IFN-ω, both at 10 ng/ml (OR [95% CI] = 62.9 [12.9–610.3] for auto-Abs neutralizing IFN-α2 versus 2.8 [0.3–13.2] for IFN-ω only, P = 0.0003) and 100 pg/ml (OR [95% CI] = 32.5 [11.2–111.2] for auto-

Abs neutralizing IFN-α2 versus 2.6 [1.2–5.3] for IFN-ω only, P = 0.03), consistent with the higher prevalence of auto-Abs neutralizing IFN-ω in the general population (Table 2). Overall, these findings indicate that auto-Abs against type I IFNs can be found in previously healthy children in whom they are a major risk factor for hypoxemic COVID-19 pneumonia, particularly if they neutralize IFN-α2. Indeed, auto-Abs against IFN-α confer the highest risk of life-threatening COVID-19. Interestingly, the ORs for critical COVID-19 were also higher for adults with auto-Abs neutralizing IFN-α than for those neutralizing IFN-ω, in comparison to adults with critical COVID-19 and asymptomatic infected adult controls (P = 0.008; Table 5). Moreover, the risk
<figure><img src="image_36.png" /><figcaption>Table 5. Increase in the risk of critical COVID-19 in adult patients with auto-Abs against IFN-α (neutralizing 10 ng/ml) versus IFN-ω (neutralizing at 10 ng/ml) (from Bastard et al., 2021a)</figcaption></figure>

<table><thead><tr><th>Type I IFN auto-Abs in adults (and amount of type I IFN neutralized in plasma diluted 1/10)</th><th>OR [95% CI]</th><th>P value</th></tr></thead><tbody><tr><td>Anti-IFN-α2 and anti-IFN-ω auto-Abs (10 ng/ml)</td><td>67.6<br>[4.1–1,108.6]</td><td>7.8 ×<br>10<sup>-13</sup></td></tr><tr><td>Anti-IFN-α2 and anti-IFN-ω auto-Abs (100 pg/ml)</td><td>54.0<br>[10.6–275.4]</td><td>&lt;10<sup>-13</sup></td></tr><tr><td>anti-IFN-α2 auto-Abs (10 ng/ml)</td><td>44.5<br>[8.82–225.0]</td><td>&lt;10<sup>-13</sup></td></tr><tr><td>anti-IFN-α2 auto-Abs (100 pg/ml)</td><td>23.3 [9.8–55.5]</td><td>&lt;10<sup>-13</sup></td></tr><tr><td>anti-IFN-ω auto-Abs (10 ng/ml)</td><td>12.9 [4.4–38.1]</td><td>1.4 ×<br>10<sup>-12</sup></td></tr><tr><td>anti-IFN-ω auto-Abs (100 pg/ml)</td><td>12.7 [7.1–22.9]</td><td>&lt;10<sup>-13</sup></td></tr><tr><td>anti-IFN-α2 auto-Abs only (10 ng/ml)</td><td>20.5<br>[3.9–107.0]</td><td>1.8 ×<br>10<sup>-9</sup></td></tr><tr><td>anti-IFN-α2 auto-Abs only (100 pg/ml)</td><td>9.5 [3.5–25.9]</td><td>2.8 ×<br>10<sup>-9</sup></td></tr><tr><td>anti-IFN-β auto-Abs only (10 ng/ml)</td><td>4.66<br>[0.88–24.6]</td><td>0.04</td></tr><tr><td>anti-IFN-ω auto-Abs only (10 ng/ml)</td><td>2.9 [0.9–9.8]</td><td>0.06</td></tr><tr><td>anti-IFN-ω auto-Abs only (100 pg/ml)</td><td>6 [3.1–11.7]</td><td>3.9 ×<br>10<sup>-10</sup></td></tr></tbody></table>

In comparisons of adult patients with critical COVID-19 and asymptomatic infected adult controls, ORs are higher in individuals with auto-Abs against IFN-α than in those with auto-Abs against IFN-ω only, particularly for Abs neutralizing IFN-α at a concentration of 10 ng/ml. This increase in risk for patients with auto-Abs against IFN-α is highly significant.

of hypoxemic pneumonia increases with the concentration of type I IFN neutralized in children and adults (Table 2 for children, Table 5 for adults).

Discussion

We report that auto-Abs neutralizing unglycosylated and glycosylated type I IFN-α2 or IFN-β are exceedingly rare (0.17% and 0.04%) in children from the general population, whereas about 0.35% of these children harbor auto-Abs neutralizing IFN-ω at a concentration of 10 ng/ml, and up to 2% of them harbor auto-Abs neutralizing this cytokine at 100 pg/ml. This relatively high proportion of individuals with auto-Abs neutralizing IFN-ω is similar to that found in young adults under the age of 40 years (Bastard et al., 2021a; Manry et al., 2022; van der Wijst et al., 2021). Nevertheless, all these proportions are significantly different from those for adults under the age of 70 years, in whom auto-Abs neutralizing IFN-α2 were found in only 0.3%, auto-Abs neutralizing IFN-ω were found in about 0.9%, and auto-Abs neutralizing IFN-β were found in about 0.3% (Bastard et al., 2020, 2021a; Manry et al., 2022; van der Wijst et al., 2021). Auto-Abs against glycosylated IFN-α2 and IFN-ω were not investigated in the studies on adults (Bastard et al., 2020, 2021a; Manry et al., 2022; van der Wijst et al., 2021), but the similar

frequencies of auto-Abs against glycosylated and unglycosylated forms suggest that this is not a major bias. The prevalence of auto-Abs against the three type I IFNs therefore appears to remain stable over time, with two exceptions of different magnitudes. First, the levels of auto-Abs against IFN-ω decrease slightly during middle age. Second, the levels of auto-Abs against IFN-α2, and to a lesser extent IFN-ω (but not IFN-β), suddenly begin to increase after the age of 65 years (Bastard et al., 2020, 2021a; Manry et al., 2022; van der Wijst et al., 2021). The prevalence of auto-Abs neutralizing IFN-α2 increased eightfold after the age of 65 years (the increase was even as great as 10-fold in men), a much greater increase than was observed for the prevalence of auto-Abs neutralizing IFN-ω only (which increased only 2.5-fold). Overall, auto-Abs neutralizing 1 ng/ml glycosylated IFN-β are exceedingly rare in children (0.04%), rare in adults below 65 years of age (0.3%), and not more common in the elderly (0.18%). Auto-Abs neutralizing at least 100 pg/ml glycosylated IFN-α2 are very rare in children (0.17%), rare in adults (0.3%), and much more common in the elderly (2.6%). Finally, auto-Abs neutralizing at least 100 pg/ml IFN-ω are less rare in children (2%) than in adults (0.9%) and display a lesser increase in prevalence in the elderly (2%).

The levels of auto-Ab against type I IFNs do not appear to be markedly lower in the youngest children (those under the age of 5 years). This suggests that the production of these pathogenic auto-Abs, especially those against IFN-α2 or IFN-β, in children and young adults may have a germline genetic etiology. In support of this hypothesis, several inborn errors are known to underlie the occurrence of these auto-Abs. Indeed, (i) most, if not all patients with APS-1 and biallelic deleterious variants of AIRE produce such auto-Abs from early childhood onward, as do some patients with dominant-negative variants of AIRE (Ahonen et al., 1990; Bastard et al., 2021c; Meyer et al., 2016; Oftedal et al., 2015, 2023; Ossart et al., 2018); (ii) about a third of women suffering from incontinentia pigmenti due to heterozygosity for loss-of-function mutations of IKBKG harbor these auto-Abs (Bastard et al., 2020; Rosain, 2023); (iii) most patients heterozygous for NFKB2 variants that are gain-of-function for IκBδ activity and loss-of-function for p52 activity, and patients with recessive deficiencies of NIK or RELB have such auto-Abs (Le Voyer, 2023); and (iv) patients with autosomal dominant IKZF2 (Helios) deficiency (Hetemäki et al., 2021a), biallelic RAG1 or RAG2 hypomorphic variants (Chen et al., 2014; Walter et al., 2015) or FOXP3 deficiency (Rosenberg et al., 2018) also carry these auto-Abs. New inborn errors underlying the production of these auto-Abs are expected to be discovered in the future. Other germline genetic etiologies may underlie the production of auto-Abs against IFN-α or IFN-ω, particularly in children and young adults. It is also surprising that the prevalence of anti-IFN-ω auto-Abs seems to decrease slightly with age, before increasing again, together with the prevalence of anti-IFN-α auto-Abs, after the age of 65 years. Auto-Abs arising after the age of 65 years are less likely to be caused by germline variants; their production may be due to somatic variants, epigenetic changes in hematopoietic or non-hematopoietic cell lineages, or thymic lesions, such as thymomas (Cheng et al., 2010; Meager et al., 2003; Rapnouil et al., 2023, Preprint; Shiono et al., 2003). The
<figure><img src="image_37.png" /></figure>

differences in prevalence with age also suggest that the patho-
genesis of auto-Abs against type I IFNs may differ, in each age
group, between auto-Abs neutralizing IFN-α2, IFN-β, and IFN-ω.

We also report that at least 10% of the children hospitalized for COVID-19 pneumonia studied had neutralizing auto-Abs against type I IFNs, as reported by other groups in smaller cohorts (Abolhassani et al., 2022). We also show that these auto-Abs neutralized normally glycosylated IFN-α2a/b, IFN-α14, IFN-ω, and IFN-β. Only glycosylated IFN-β was tested in our previous studies (Bastard et al., 2020, 2021a, 2021b, 2021c, 2022). The risk of life-threatening COVID-19 pneumonia in children with auto-Abs neutralizing type I IFNs is very high, as previously reported for adults (Barcenas-Morales et al., 2016; Bastard et al., 2021a; Puel et al., 2022). The very high risk of life-threatening COVID-19 pneumonia in children harboring auto-Abs against type I IFNs is consistent with that in children with recessive IEI affecting the type I IFN pathway (Zhang et al., 2022b). In the light of our screening of uninfected children, for the combinations tested, auto-Abs against IFN-α conferred a significantly higher risk of life-threatening COVID-19 than auto-Abs against IFN-ω, regardless of the concentration of cytokine neutralized. A similar pattern has also been observed in adults. The risk of critical COVID-19 in adults with auto-Abs neutralizing IFN-α (regardless of their ability to neutralize IFN-ω) is much higher than that in adults with auto-Abs neutralizing IFN-ω only (P = 0.008 at 100 pg/ml and P = 0.0006 at 10 ng/ml; Table 5). Furthermore, in adults with critical COVID-19 pneumonia, the prevalence of auto-Abs neutralizing IFN-α2 at 10 ng/ml doubles after the age of 60 years (5.6% before 60 years versus 11.2% after 60 years).

As previously observed in adults (Manry et al., 2022), the risk of life-threatening COVID-19 is also higher for children carrying auto-Abs neutralizing high concentrations of IFN-α2 and/or IFN-ω than for children carrying only auto-Abs neutralizing low concentrations, further suggesting that auto-Abs neutralizing high concentrations of IFN-α2 and/or IFN-ω have a more deleterious impact on COVID-19 outcomes. The risk of life-threatening COVID-19 is even higher in patients with auto-Abs neutralizing both IFN-αs and IFN-ω, further suggesting that the IFN-α subtypes and IFN-ω may not be completely redundant in the context of COVID-19. In addition, the risk of hypoxemic pneumonia increased with the concentration of type I IFNs neutralized. The risk of other viral diseases is unclear, although severe influenza has been reported in several children with auto-Abs against type I IFNs (Walter et al., 2015; Zhang et al., 2022c). Children may have higher tonic or virus-induced type I IFN levels than adults in the tissues in which these molecules are most needed as an initial barrier, such as the naso-epithelial barrier for COVID-19 (Alfi et al., 2021; Beer et al., 2022; Hatton et al., 2021; Lopez et al., 2021; Ziegler et al., 2021).

Despite our discovery of recessive IEI of type I IFN immunity in about 10% of the children studied and of auto-Abs against type I IFNs in another 10%, the cause of severe COVID-19 pneumonia remains unexplained in most children. Other auto-Abs (against type III IFNs, for example) (Vanker et al., 2023), or other IEI, possibly, but not necessarily affecting type I IFNs, might explain these remaining cases. However, our findings already have broad clinical implications. Children hospitalized for COVID-19

pneumonia should be tested for auto-Abs against type I IFNs as targeted therapies can be proposed. When effective against the circulating strains, mAbs neutralizing the virus can be effective if administered promptly (Gupta et al., 2021), as recently shown for an IRF9-deficient child during the first wave of the epidemic (Levy et al., 2021) and other patients with IEI (Johnson et al., 2023). Antiviral compounds, such as remdesivir (Beigel et al., 2020; Gottlieb et al., 2021), molnupiravir (Jayk Bernal et al., 2021), or nirmatrelvir plus ritonavir (Hammond et al., 2022), may also be of benefit in these patients, provided that they are administered sufficiently early in the course of infection. Likewise, early recombinant IFN-β therapy may be considered to prevent the development of hypoxemic pneumonia in patients whose auto-Abs do not neutralize IFN-β (Monk et al., 2021; Vinh et al., 2021). Nasal IFN-α2b could also be considered in patients without auto-Abs or IEI affecting the response to type I IFNs (Zhou et al., 2023). Treatment with type III IFNs is another possibility (Sokal et al., 2023). In the most severe cases, a combination of these therapies with plasmapheresis may be proposed (Bastard et al., 2021c).

Children with auto-Abs against type I IFNs should be fol-
lowed prospectively. In the general population, it is not entirely
clear which group of children should be screened because of the
high risk of such auto-Abs. Children with IEI should certainly
be screened, particularly those with known genetic etiologies
of auto-Abs against type I IFNs (Ahonen et al., 1990; Chen
et al., 2014; Oftedal et al., 2015, 2023; Walter et al., 2015;
Meyer et al., 2016; OSSart et al., 2018; Bastard et al., 2021c;
Hetemäki et al., 2021a; Le Voyer, 2023; Rosain, 2023). Children
with a history of unusually severe viral infection should also be
tested, as the clinical phenotype of anti-type I IFN auto-Ab
production is expanding to include other severe viral diseases
(Bastard et al., 2021b, 2022; Gervais et al., 2023; Zhang et al.,
2022c). Children with auto-Abs neutralizing type I IFNs should
be vaccinated against SARS-CoV-2 and influenza, but not with
live-attenuated vaccines (Bastard et al., 2021b). Finally, it would
be of interest to conduct pilot studies of the screening of selected
populations, such as children with autoimmune conditions (e.g.,
lupus erythematosus, which is associated with these auto-Abs in
adults) (Gupta et al., 2016; Kisand et al., 2010; Londe et al., 2023;
Mathian et al., 2022; Panem et al., 1982). Many questions remain
unanswered. Severe viral infections might occur at higher fre-
quency in individuals with these auto-Abs. By inference from
the known risk of severe adverse reaction to the live-attenuated
virus vaccine against yellow fever in adults with auto-Abs
against type I IFNs (Bastard et al., 2021b), children with these
auto-Abs should not receive this vaccine. Surprisingly, MMR
vaccination seems to be well tolerated in APS-1 patients despite
the presence of high levels of auto-Abs against type I IFNs. Other
live attenuated vaccines (against varicella-zoster virus or mon-
key pox, for example) should probably be avoided due to the
unknown risk of adverse reaction. By contrast, children with
these auto-Abs would benefit from RNA vaccination against
SARS-CoV-2 and boosters as they are able to mount an Ab re-
sponse capable of neutralizing the virus (Bastard et al., 2022;
Sokal et al., 2023; Wolff et al., 2023). Finally, the follow-up of
these children will also be of interest as the changes in the levels
<figure><img src="image_38.png" /></figure>

of these auto-Abs over time and their association with other
viral, tumoral, and autoimmune diseases remain unclear. Life-
long follow-up of this cohort should provide answers to these
questions and help to improve the clinical management of these
children.

**Materials and methods**

Study design

We enrolled 183 patients with proven COVID-19 pneumonia
from nine countries (Brazil, France, Italy, Morocco, Saudi Ara-
bia, Spain, Peru, Turkey, and Ukraine) in this study. We col-
lected plasma or serum samples for all these individuals for
immunoassay testing for the presence of auto-Abs against type I
IFNs. 2,267 children from the general population were recruited
in Belgium (n = 126), Canada (n = 161), Estonia (n = 288), Spain
(n = 1,685), and Pakistan (n = 7). Two additional cohorts were
established independently in Estonia and Japan, and the cohorts
of patients with bacterial infections were established indepen-
dently in Spain. All individuals were recruited according to
protocols approved by local institutional review boards (IRBs).
Written informed consent was obtained in the country of resi-
dence of each patient. Experiments were conducted in France
and the United States in accordance with local regulations and
with the approval of the IRB of the Institut National de la Santé
et de la Recherche Médicale and the Rockefeller University,
respectively. Approval was obtained from the French Ethics
Committee (Comité de Protection des Personnes), the French
National Agency for Medicine and Health Product Safety, the
Institut National de la Santé et de la Recherche Médicale in Paris,
France (protocol no. C10-13), and the Rockefeller University
Institutional Review Board in New York, USA (protocol no. JCA-
0700).

COVID-19 classification

The severity of COVID-19 was assessed for each patient, as fol-
lows (Bastard et al., 2020; Zhang et al., 2020b): “critical COVID-
19 pneumonia” was defined as pneumonia developing in patients
with critical disease, whether pulmonary, with high-flow oxy-
gen, mechanical ventilation (continuous positive airway pres-
sure, bilevel positive airway pressure, intubation), septic shock,
or with damage to any other organ requiring admission to the
ICU. “Severe COVID-19” was defined as pneumonia developing in
patients requiring low-flow oxygen (<6 L/min) supplementation.

Statistics

OR and P values for the effect of auto-Abs neutralizing each
type I IFN on critical or severe COVID-19 using patients with
asymptomatic/mild disease or the general population as con-
trols, adjusted for age in three classes (≤5 years old, (5–10 years
old], and (10–18 years old]) and sex, were estimated by means of
Firth’s bias-corrected logistic regression (Firth, 1993; Heinze
and Schemper, 2002) as implemented in the “logistf” R pack-
age (https://rdrr.io/cran/logistf/). The risks of critical or severe
COVID-19 for carriers of different combinations of neutralizing
auto-Abs were compared by Firth’s logistic regression adjusted
for age in three classes and sex, as described above, in the

subsample of individuals (cases and individuals from the gen-
eral population) carrying the auto-Ab combinations compared.
The standard error of the mean for the prevalence of neutral-
izing auto-Abs against each type I IFN by age group and sex was
estimated with the Agresti-Coull approximation (Agresti and
Coull, 1998).

Detection of anti-cytokine auto-Abs

Gyros

Cytokines, recombinant human (rh)IFN-α2 (ref. number 130-108-984; Miltenyi Biotec) or rhIFN-ω (ref. number SRP3061; Merck), were first biotinylated with EZ-Link Sulfo-NHS-LC-Biotin (cat. number A39257; Thermo Fisher Scientific), according to the manufacturer's instructions, with a biotin-to-protein molar ratio of 1:12. The detection reagent contained an Alexa Fluor 647 goat anti-human IgG Ab (ref. number A21445; Thermo Fisher Scientific) diluted in Rexip F (ref. number P0004825; 1/500 dilution of the 2 mg/ml stock to yield a final concentration of 4 µg/ml; Gyros Protein Technologies). PBS-Tween (PBS-T) 0.01% buffer and Gyros Wash buffer (ref. number P0020087; Gyros Protein Technologies) were prepared according to the manufacturer's instructions. Plasma or serum samples were then diluted 1/100 in PBS-T 0.01% and tested with Bioaffy 1000 CD (ref. number P0004253; Gyros Protein Technologies) and Gyrolab X-Pand (ref. number P0020520; Gyros Protein Technologies). Cleaning cycles were performed in 20% ethanol.

Functional evaluation of anti-cytokine auto-Abs

Luciferase reporter assays

The blocking activity of anti-IFN-α2 and anti-IFN-ω auto-Abs
was assessed by measuring luciferase reporter activity. Briefly,
HEK293T cells were transfected with a plasmid containing the
firefly luciferase gene under the control of the human ISRE
promoter in the pGL4.45 backbone and a plasmid constitutively
expressing Renilla luciferase for normalization (pRL-SV40).
Cells were transfected in the presence of the X-tremeGene9
transfection reagent (ref. number 6365779001; Sigma-Aldrich)
for 24 h. Cells in DMEM (Thermo Fisher Scientific) supple-
mented with 2% FCS and 10% healthy control or patient serum/
plasma (after inactivation at 56°C, for 20 min) were either left
unstimulated or were stimulated with IFN-α2 (ref. number 130-
108-984; Miltenyi Biotec) or IFN-ω (ref. number SRP3061;
Merck) at 10 ng/ml or 100 pg/ml, or with IFN-β (ref. number:
130-107-888; Miltenyi Biotec) at 10 ng/ml for 16 h at 37°C. Each
sample was tested once for each cytokine and dose. Finally, cells
were lysed for 20 min at room temperature and luciferase levels
were measured with the Dual-Luciferase Reporter 1000 assay
system (ref. number E1980; Promega) according to the manu-
facturer's protocol. Luminescence intensity was measured with a
VICTOR-X Multilabel Plate Reader (PerkinElmer Life Sci-
ences). Firefly luciferase activity values were normalized against
Renilla luciferase activity values. These values were then nor-
malized against the median level of induction for non-neutralizing
samples and expressed as a percentage. Samples were considered
neutralizing if luciferase induction after normalization against
Renilla luciferase activity was below 15% the median value for
controls tested the same day.
<figure><img src="image_39.png" /></figure>

## Phage immunoprecipitation sequencing (PhIP-Seq)

The reactivity of circulating Abs against common pathogens in plasma samples from patients and healthy controls was analyzed by PhIP-Seq, as previously described (Hasan et al., 2021). Pooled human plasma for IVIg (Privigen CSL Behring AG), human IgG-depleted serum (supplier no. HPLASERGFA5ML; Molecular Innovations, Inc.), and plasma samples from unrelated healthy children were included as controls. PhIP-Seq was carried out as previously described but with the following modifications. Total IgG levels were determined with the Human IgG total ELISA Ready-SET-Go kit (Thermo Fisher Scientific) and diluted samples containing 4 mg total IgG were incubated at 4°C overnight with 2 × 10¹⁰ plaque-forming units of a modified version of the original VirScan phage library. Specifically, the T7 phage library used here for peptide display contained the same viral peptides as the original VirScan phage library plus additional peptides derived from protein sequences of various microbial B cell antigens available from the Immune Epitope Database (https://www.iedb.org). For the computational analysis and background correction, the phage library was sequenced before (input library sample) and after immunoprecipitation with beads alone (mock IP). Single-end sequencing was performed with the NextSeq500 system (Illumina) to generate ~2 million reads per sample and ~20 million reads for the input library samples. Reads were mapped onto the original library sequences with Bowtie 2 and read counts were adjusted according to library size. A zero-inflated generalized Poisson model was used to estimate the P values to reflect enrichment for each of the peptides. We considered peptides to be significantly enriched only if the -log₁₀ P value was at least 2.3 in all replicates. Species-specific score values were computed for each serum or plasma sample by counting the significantly enriched peptides for a given species with a continuous sequence of no more than seven residues, the estimated size of a linear epitope, in common. We corrected for the nonspecific binding of peptides to the capture matrix by also calculating species-specific background score values by counting the peptides displaying enrichment to the 90th percentile for the mock IP samples. These peptides were used for background subtraction.

## Online supplemental material

Fig. S1 describes neutralizing auto-Abs against type I IFNs in children with life-threatening COVID-19. Fig. S2 describes neutralizing auto-Abs against IFN-α2 and/or IFN-ω in children and adults with life-threatening COVID-19. Fig. S3 describes neutralizing auto-Abs against glycosylated type I IFNs, and proportion of children and adults from the general population with neutralizing auto-Abs against type I IFNs. Fig. S4 describes neutralizing auto-Abs against IFN-α2 or IFN-ω in children from the general population. Fig. S5 describes neutralizing auto-Abs against IFN-α2 and/or IFN-ω in children from the general population in Estonia and Japan.

## Data availability

The data are available from the corresponding author upon reasonable request. All the data needed to evaluate the

conclusions of the paper are present in the paper or the online supplemental material.

## Acknowledgments

We thank the patients and their families for placing their trust in us. We warmly thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases. We warmly thank Y. Nemirovskaya, M. Woollett, D. Liu, S. Boucherit, M. Chrabieh, and L. Lorenzo for administrative assistance. We thank Helen C. Su and Jonathan Bohlen for their helpful discussions.

The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364, R01AI163029, and R21AI160576), the National Center for Advancing Translational Sciences, the NIH Clinical and Translational Science Award program (ULITR001866), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the Stavros Niarchos Foundation Institute for Global Infectious Disease Research, the program "Investissement d'Avenir" launched by the French Government and implemented by the Agence Nationale de la Recherche (ANR) (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), ANR AI2D (ANR-22-CE15-0046), and ANR AAILC (ANR-21-LIBA-0002) projects, the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU COVIFERON Program (ANR-21-RHUS-08), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, the University of Paris Cité and Imagine Institute, Battersea & Bowery Advisory Group, and William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director and Head of Business in EMEA, and the General Atlantic Foundation. I. Meyts is a senior clinical researcher at FWO Vlaanderen; I. Meyts is funded by the European Research Council under HORIZON-HLTL-2021-ID: 101057100 "Undine," KU Leuven CI6/18/007, and FWO grant G0B5120N (DADA2). L.D. Notarangelo and H.C. Su (members of the COVID Human Genetic Effort) were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. P. Bastard was supported by the French Foundation for Medical Research (FRM, EA20170638020). P. Bastard and T. Le Voyer were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). P. Bastard was supported by the "Poste CCA-INSERM-Bettencourt" (with the support of the Fondation Bettencourt-Schueller). S. Okada was supported by MEXT/JSPS
<figure><img src="image_40.png" /></figure>

KAKENHI (grant numbers 22H03041 and 22KK0113) and AMED (grant numbers JP21fk0108436 and JP22fk0108514). L.I. Gonzalez-Granado is supported by the Instituto de Salud Carlos III (ISCIII) through the project FIS-PI21/01642 and cofunded by the European Union. D.C. Vinh is supported by a Fonds de Recherche du Québec - Santé, Senior Clinician-Scientist scholar award. Q. Pan-Hammarström was funded by the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. K. Kisand's laboratory was funded by the Estonian Research Council grants PRG1117 and PRG1428. This study also received support from ISCIII (TRINEO: PI22/00162; DIAVIR: DTS19/00049; ResVomics: PI19/01039 [A. Salas]; ReSVinext: PI16/01569 [F. Martinón-Torres]; EnteroGen: PI19/01090 [F. Martinón-Torres]); OMI-COVI-VAC (PI22/00406 [F. Martinón-Torres] jointly financed by FEDER), GAIN: Grupos con Potencial de Crecimiento (IN607B 2020/08 [A. Salas]); ACIS: BI-BACVIR (PRIS-3 [A. Salas]), and CovidPhy (SA 304 C [A. Salas]); and consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CB21/06/00103; F. Martinón-Torres); GEN-COVID (IN845D 2020/23, F. Martinón-Torres) and Grupos de Referencia Competitiva (IIN607A2021/05, F. Martinón-Torres). The study was funded by ISCIII (COV20_01333, COV20_01334, PI16/00759, PI18/00223, PI19/00208, PI20/00876, and PI21/00211), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, EU), the Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC19/43, PIFIISC22/27), Grupo DISA (OA18/017), Fundación MAPFRE Guanarteme (OA21/131), Cabildo Insular de Tenerife (CGIEU0000219140 and "Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19"). A. Pujol is supported by ACCI20-759 CIBERER, H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. This research is supported by the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases. Open Access funding provided by Rockefeller University.

Author contributions: P. Bastard, A. Cobat, and J.-L. Casanova wrote the manuscript, with the assistance of L. Abel, Q. Zhang, E. Jouanguy, K. Kisand, S. Okada, and A. Puel who edited the manuscript, tables, and figures. P. Bastard, A. Gervais, M. Taniguchi, L. Saare, K. Särekannu, T. Le Voyer, Q. Philippot, J. Rosain, L. Bizien, T. Asano, M. Garcia-Prat, A. Parra-Martínez, M. Migaud, M. Tsumura, F. Conti, A. Belot, J.G. Rivière, T. Morio, J. Tanaka, E. Javouhey, F. Haerynck, S. Duvlis, T. Ozcelik, S. Keles, Y. Tandjaoui-Lambiotte, S. Escoda, M. Husain, Q. Pan-Hammarström, L. Hammarström, G. Ahlijah, A. Abi Haidar, C. Soudee, V. Arseguel, H. Abolhassani, S. Sahanic, I. Tancevski, Y. Nukui, S. Hayakawa, G.P. Chrousos, A. Michos, E.-B. Tatsi, F. Filippatos, A. Rodriguez-Palmero, J. Troya, I. Tipu, I. Meyts, L. Roussel, S.R. Ostrowski, L. Schidlowski, C. Prando, A. Condino-Neto, N. Cheikh, P. Peterson, A. Pujol, R. Lévy, P. Quartier, D.C. Vinh, B. Boisson, V. Béziat, S.-Y. Zhang, A. Borghesi, A. Pession, E. Andreakos, N. Marr, A.-F.A. Mentis, T.H. Mogensen, C. Rodríguez-Gallego, P. Soler-Palacin, R. Colobran, V. Tillmann, B. Neven, S. Trouillet-Assant, P. Brodin, L. Abel, E. Jouanguy, Q. Zhang, F.

Martinón-Torres, A. Salas, A. Gómez-Carballa, L.I. Gonzalez-Granado, K. Kisand, S. Okada, A. Puel, A. Cobat, and J.-L. Casanova performed the experiments, generated or analyzed data, and treated and recruited the patients. A. Cobat and J.-L. Casanova supervised the study.

Disclosures: Q. Philippot reported personal fees from Gilead outside the submitted work. E. Javouhey reported non-financial support from Biomerieux during the conduct of the study. Y. Tandjaoui-Lambiotte reported personal fees from STANE, QUANTIQ, and Digital Medical Hub outside the submitted work. I. Meyts reported grants from CSL-Behring, other from Boehringer-Ingelheim, and other from Takeda outside the submitted work. D.C. Vinh reported personal fees from Moderna, AsstraZeneca, Merck Canada, Novartis Canada, Qu Biologics, and Takeda outside the submitted work; in addition, D.C. Vinh had a patent number 40101099 licensed; and is supported by the Fonds de recherche du Québec—Santé clinician-scientist senior scholar award. A.-F. Mentis reported “other” from BGI Genetics, and grants from ELIDEK and the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate (project code: T2EDK-02222) outside the submitted work. S. Trouillet-Assant reported non-financial support and grants from bioMérieux outside the submitted work. No other disclosures were reported.

Submitted: 2 August 2023

Revised: 22 October 2023

Accepted: 15 November 2023

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Zhang, Q., A. Pizzorno, L. Miorin, P. Bastard, A. Gervais, T. Le Voyer, L. Biazien, J. Manry, J. Rosain, Q. Philippot, et al. 2022c. Autoantibodies against type I IFNs in patients with critical influenza pneumonia. *J. Exp. Med.* 219:e20220514. https://doi.org/10.1084/jem.20220514

Zhou, J., X. Chen, Y. Lu, L. Wang, and H. Yu. 2023. Interferon-alpha-2b nasal spray for treating SARS-CoV-2 omicron variant-infected children. *J. Clin. Immunol.* 43:862-864. https://doi.org/10.1007/s10875-023-01452-4

Zhou, P., X.L. Yang, X.G. Wang, B. Hu, L. Zhang, W. Zhang, H.R. Si, Y. Zhu, B. Li, C.L. Huang, et al. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. *Nature.* 579:270-273. https://doi.org/10.1038/s41586-020-2012-7

Ziegler, C.G.K., V.N. Miao, A.H. Owings, A.W. Navia, Y. Tang, J.D. Bromley, P. Lotfy, M. Sloan, H. Laird, H.B. Williams, et al. 2021. Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. *Cell.* 184: 4713-4733.e22. https://doi.org/10.1016/j.cell.2021.07.023

Worldometers. 2023. COVID-19 Coronavirus Pandemic. https://www.worldometers.info/coronavirus/ (accessed November 22, 2023)
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**Supplemental material**
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A

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C

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E

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G

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I

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B

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D

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F

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H

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J

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Figure S1. Neutralizing auto-Abs against type I IFNs in children with life-threatening COVID-19. (A) Gyros (high-throughput automated ELISA) results for auto-Abs against IFN-α2 for positive controls (n = 4), pediatric patients (n = 188), and healthy controls (n = 16). (B) Plot of anti-IFN-α2 auto-Ab IgG levels, as determined by Gyros, against their neutralization capacity at 10 ng/ml in the luciferase assay. For plasma from each patient, luciferase activity was normalized against the mean induction of control plasma tested on the same day in the luciferase assay. The horizontal dotted line indicates the threshold of neutralization, defined as the level of induction below 15% of the mean value for controls tested on the same day. (C–J) Proportion by age of pediatric and adult patients from the general population positive for neutralizing auto-Abs (in plasma 1:10) against (C) IFN-α2 at 10 ng/ml, for both sexes; (D) IFN-α2, at 10 ng/ml, for men or women; (E) IFN-ω, at 10 ng/ml, for both sexes; (F) IFN-ω, at 10 ng/ml, for men or women; (G) IFN-β, at 10 ng/ml, for both sexes; (H) IFN-β, at 10 ng/ml, for men or women; (I) IFN-α2 and IFN-ω, at 10 ng/ml, for both sexes; and (J) IFN-α2 and IFN-ω, at 10 ng/ml, for men or women.
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Figure S2. Neutralizing auto-Abs against IFN-α2 and/or IFN-ω in children and adults with life-threatening COVID-19. (A–J) Proportion by age of pediatric and adult patients from the general population positive for neutralizing auto-Abs (in plasma 1:10) against (A) IFN-α2 and IFN-ω, at 100 pg/ml, for both sexes; (B) IFN-α2 and IFN-ω, at 100 pg/ml, for men or women; (C) IFN-α2, at 100 pg/ml, for both sexes; (D) IFN-α2, at 100 pg/ml, for men or women; (E) IFN-ω, at 100 pg/ml, for both sexes; (F) IFN-ω, at 100 pg/ml, for men or women; (G) IFN-α2 only, at 10 ng/ml, for both sexes; (H) IFN-α2 only, at 10 ng/ml, for men or women; (I) IFN-ω only, at 10 ng/ml, for both sexes; and (J) IFN-ω only, at 10 ng/ml, for men or women.
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Figure S3. Neutralizing auto-Abs against glycosylated type I IFNs, and proportion of children and adults from the general population with neutralizing auto-Abs against type I IFNs. (A) Results for the neutralization of various doses of the glycosylated form of IFN-α2 or IFN-ω in the presence of plasma (1/10 dilution) from children with (C−) and without (C+) auto-Abs neutralizing type I IFNs. Relative luciferase activity is shown (ISRE dual luciferase activity, with normalization against Renilla luciferase activity) after stimulation with 10 ng/ml IFN-α2 or IFN-ω in the presence of plasma (1/10 dilution). RLA: relative luciferase activity. (B–H) Proportion of children and adults from the general population with neutralizing auto-Abs against type I IFNs. (B) Prevalence of auto-Abs neutralizing type I IFNs, by type of IFN neutralized. (C–H) Proportion, by age, of pediatric and adult individuals from the general population positive for neutralizing auto-Abs (in plasma diluted 1:10) against (C) IFN-β, at 10 ng/ml, for both sexes; (D) IFN-β, at 10 ng/ml, for men or women; (E) IFN-α2 and IFN-ω, at 10 ng/ml, for both sexes; (F) IFN-α2 and IFN-ω, at 10 ng/ml, for men or women; (G) IFN-α2 and IFN-ω, at 100 pg/ml, for both sexes; and (H) IFN-α2 and IFN-ω, at 100 pg/ml, for men or women.
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<figure><img src="image_84.png" /></figure>

<figure><img src="image_85.png" /></figure>

Figure S4. Neutralizing auto-Abs against IFN-α2 or IFN-ω in children from the general population. (A–H) Proportion, by age, of pediatric and adult individuals from the general population positive for neutralizing auto-Abs (in plasma diluted 1:10) against (A) IFN-α2, at 10 ng/ml, for both sexes; (B) IFN-α2, at 10 ng/ml, for men or women; (C) IFN-ω, at 10 ng/ml, for both sexes; (D) IFN-ω, at 10 ng/ml, for men or women; (E) IFN-α2 only, at 10 ng/ml, for both sexes; (F) IFN-α2 only, at 10 ng/ml, for men or women; (G) IFN-ω only, at 10 ng/ml, for both sexes; and (H) IFN-ω only, at 10 ng/ml, for men or women.
<figure><img src="image_86.png" /></figure>

A

<figure><img src="image_87.png" /></figure>

B

<figure><img src="image_88.png" /><figcaption>**Figure S5.** Neutralizing auto-Abs against IFN-α2 and/or IFN-ω in children from the general population in Estonia and Japan. (A) Results for the neutralization of 10 ng/ml IFN-α2, IFN-ω, or IFN-β or 100 pg/ml IFN-α2 or IFN-ω in the presence of plasma (1/10 dilution) from children from Japan (n = 249). (B) Results for the neutralization of 10 ng/ml or 100 pg/ml IFN-α2, IFN-ω, or IFN-β in the presence of plasma (1/10 dilution) from children from Estonia (n = 200). (A and B) Relative luciferase activity is shown (ISRE dual luciferase activity, with normalization against *Renilla* luciferase activity) after stimulation with IFN-α2, IFN-ω, or IFN-β in the presence of plasma (1/10 dilution). RLA: relative luciferase activity.</figcaption></figure>
COVID Human Genetic Effort members

Laurent Abel¹, Alessandro Aiuti², Saleh Al-Muhsen³, Fahd Al-Mulla⁴, Ali Amara⁵,
Mark S. Anderson⁶, Evangelos Andreakos⁷, Andrés A. Arias⁸, Lisa M. Arkin⁹, Hagit Baris
Feldman¹⁰, Paul Bastard¹, Alexandre Belot¹¹, Catherine M. Biggs¹², Dusan Bogunovic¹³,
Alexandre Bolze¹⁴, Anastasiia Bondarenko¹⁵, Ahmed A. Bousfiha¹⁶, Petter Brodin¹⁷, Yenan
Bryceson¹⁸, Manish J. Butte¹⁹, Jean-Laurent Casanova²⁰, Giorgio Casari²¹, John
Christodoulou²², Aurélie Cobat¹, Roger Colobran²³, Antonio Condino-Neto²⁴, Stefan N.
Constantinescu²⁵, Megan A. Cooper²⁶, Clifton L. Dalgard²⁷, Murkesh Desai²⁸, Beth A.
Drolet²⁹, Xavier Duval³⁰, Jamila El Baghdadi³¹, Philippine Eloy³², Sara Espinosa-Padilla³³,
Jacques Fellay³⁴, Carlos Flores³⁵, José Luis Franco³⁶, Antoine Froidure³⁷, Guy Gorochov³⁸,
Peter K. Gregersen³⁹, Bodo Grimbacher⁴⁰, Filomeen Haerynck⁴¹, David Hagin⁴², Rabih
Halwani⁴³, Lennart Hammarström⁴⁴, James R. Heath⁴⁵, Elena W.Y. Hsieh⁴⁶, Eystein
Husebye⁴⁷, Kohsuke Imai⁴⁸, Yuval Itan⁴⁹, Erich D. Jarvis⁵⁰, Emmanuelle Jouanguy¹,
Elżbieta Kaja⁵¹, Timokratis Karamitros⁵², Kai Kisand⁵³, Cheng-Lung Ku⁵⁴, Yu-Lung Lau⁵⁵,
Yun Ling⁵⁶, Carrie L. Lucas⁵⁷, Davood Mansouri⁵⁹, László Maródi⁶⁰, France Mentré³²,
Isabelle Meyts⁶¹, Joshua D. Milner⁶², Kristina Mironska⁶³, Trine H. Mogensen⁶⁴, Tomohiro
Morio⁶⁵, Lisa F.P. Ng⁶⁶, Luigi D. Notarangelo⁶⁷, Antonio Novelli⁶⁸, Giuseppe Novelli⁶⁹,
Cliona O'Farrelly⁷⁰, Satoshi Okada⁷¹, Keisuke Okamoto⁷², Tayfun Ozcelik⁷³, Qiang Pan-
Hammarström⁴⁴, Jean W. Pape⁷⁴, Rebeca Perez de Diego⁷⁵, Jordi Perez-Tur⁷⁶, David S.
Perlin⁷⁷, Graziano Pesole⁷⁸, Anna M. Planas⁷⁹, Carolina Prando⁸⁰, Aurora Pujol⁸¹, Anne
Puel¹, Lluis Quintana-Murci⁸², Sathishkumar Ramaswamy⁸³, Laurent Renia⁶⁶, Igor
Resnick⁸⁴, Carlos Rodríguez-Gallego⁸⁵, Vanessa Sancho-Shimizu⁸⁶, Anna Sediva⁸⁷, Mikko
R.J. Seppänen⁸⁸, Mohammed Shahrooei⁸⁹, Anna Shcherbina⁹⁰, Ondrej Slaby⁹¹, Andrew L.
Snow<sup>92</sup>, Pere Soler-Palacín<sup>93</sup>, Vassili Soumelis<sup>94</sup>, András N. Spaan<sup>95</sup>, Helen C. Su<sup>67</sup>, Ivan Tancevski<sup>96</sup>, Stuart G. Tangye<sup>97</sup>, Ahmad Abou Tayoun<sup>83</sup>, Şehime Gülsün Temel<sup>98</sup>, Christian Thorball<sup>99</sup>, Pierre Tiberghien<sup>100</sup>, Sophie Trouillet-Assant<sup>101</sup>, Stuart E. Survey<sup>102</sup>, K M Furkan Uddin<sup>103</sup>, Mohammed J. Uddin<sup>104</sup>, Diederik van de Beek<sup>105</sup>, Donald C. Vinh<sup>106</sup>, Horst von Bernuth<sup>107</sup>, Joost Wauters<sup>108</sup>, Mayana Zatz<sup>109</sup>, Pawel Zawadzki<sup>110</sup>, Qian Zhang<sup>1</sup>, and Shen-Ying Zhang<sup>1</sup>

<sup>1</sup>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Cité University, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

<sup>2</sup>San Raffaele Telethon Institute for Gene Therapy, IRCCS Ospedale San Raffaele, and Vita Salute San Raffaele University, Milan, Italy.

<sup>3</sup>Immunology Research Lab, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

<sup>4</sup>Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Dasman, Kuwait.

<sup>5</sup>Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR 7212, Université de Paris, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France.

<sup>6</sup>Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
⁷Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

⁸St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia (UdeA), Medellín, Colombia; School of Microbiology, University of Antioquia UdeA, Medellín, Colombia.

⁹Department of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.

¹⁰The Genetics Institute, Tel Aviv Sourasky Medical Center and Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

¹¹Pediatric Nephrology, Rheumatology, Dermatology, HFME, Hospices Civils de Lyon, National Referee Centre RAISE, and INSERM U1111, Université de Lyon, Lyon, France.

¹²Department of Pediatrics, BC Children's and St. Paul's Hospitals, University of British Columbia, Vancouver, BC, Canada.

¹³Icahn School of Medicine at Mount Sinai, New York, NY, USA.

¹⁴Helix, San Mateo, CA, USA.

¹⁵International European University, Kiev, Ukraine.

¹⁶Department of Pediatric Infectious Disease and Clinical Immunology, CHU Ibn Rushd and LICIA, Laboratoire d'Immunologie Clinique, Inflammation et Allergie, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco.
¹⁷SciLifeLab, Department Of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

¹⁸Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.

¹⁹Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and the Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA.

²⁰The Rockefeller University & Howard Hughes Medical Institute, New York, NY, USA; Necker Hospital for Sick Children & INSERM, Paris, France.

²¹Clinical Genomics, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.

²²Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

²³Immunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain.

²⁴Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

²⁵de Duve Institute, UC Louvain and Ludwig Cancer Research, Brussels, Belgium.

²⁶Washington University School of Medicine, St. Louis, MO, USA.
<sup>27</sup>Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

<sup>28</sup>Bai Jerbai Wadia Hospital for Children, Mumbai, India.

<sup>29</sup>School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.

<sup>30</sup>Université de Paris, IAME UMR-S 1137, INSERM, Paris, France; Inserm CIC 1425, Paris, France.

<sup>31</sup>Genetics Unit, Military Hospital Mohamed V, Rabat, Morocco.

<sup>32</sup>Hôpital Bichat, Paris, France.

<sup>33</sup>Instituto Nacional de Pediatria (National Institute of Pediatrics), Mexico City, Mexico.

<sup>34</sup>School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

<sup>35</sup>Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid; Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain; Faculty of Health Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Canary Islands, Spain.

<sup>36</sup>Group of Primary Immunodeficiencies, University of Antioquia UDEA, Medellín, Colombia.

<sup>37</sup>Pulmonology Department, Cliniques Universitaires Saint-Luc ; Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
³⁸Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (CIMI PARIS), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Pitié-Salpêtrière, Paris, France.

³⁹Feinstein Institute for Medical Research, Northwell Health USA, Manhasset, NY, USA.

⁴⁰Center for Chronic Immunodeficiency & Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

⁴¹Department of Paediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Laboratory, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium.

⁴²The Genetics Institute Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

⁴³Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates; Immunology Research Lab, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

⁴⁴Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

⁴⁵Institute for Systems Biology, Seattle, WA, USA.

⁴⁶Departments of Pediatrics, Immunology and Microbiology, University of Colorado, School of Medicine, Aurora, CO, USA.

⁴⁷Department of Medicine, Haukeland University Hospital, Bergen, Norway.

⁴⁸Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
<sup>49</sup>Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

<sup>50</sup>Laboratory of Neurogenetics of Language and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.

<sup>51</sup>Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, Poznan, Poland.

<sup>52</sup>Bioinformatics and Applied Genomics Unit, Hellenic Pasteur Institute, Athens, Greece.

<sup>53</sup>Molecular Pathology, Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu Estonia.

<sup>54</sup>Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan County, Taiwan.

<sup>55</sup>Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong, China.

<sup>56</sup>Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

<sup>57</sup>Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

<sup>59</sup>Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases
(NRITLD), Masih Daneshvari Hospital, Shahid Beheshti, University of Medical Sciences,
Tehran, Iran.

⁶⁰Primary Immunodeficiency Clinical Unit and Laboratory, Department of
Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest,
Hungary.

⁶¹Department of Pediatrics, University Hospitals Leuven; KU Leuven, Department of
Microbiology, Immunology and Transplantation; Laboratory for Inborn Errors of
Immunity, KU Leuven, Leuven, Belgium.

⁶²Department of Pediatrics, Columbia University Irving Medical Center, New York,
NY, USA.

⁶³University Clinic for Children's Diseases, Department of Pediatric Immunology,
Medical Faculty, University “St.Cyril and Methodij” Skopje, North Macedonia.

⁶⁴Department of Biomedicine, Aarhus University, Aarhus, Denmark.

⁶⁵Tokyo Medical & Dental University Hospital, Tokyo, Japan.

⁶⁶A*STAR Infectious Disease Labs, Agency for Science, Technology and Research,
Singapore; Lee Kong Chian School of Medicine, Nanyang Technology University,
Singapore.

⁶⁷National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD, USA.

⁶⁸Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital, Rome,
Italy.
<sup>69</sup>Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.

<sup>70</sup>Comparative Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.

<sup>71</sup>Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

<sup>72</sup>Tokyo Medical and Dental University, Tokyo, Japan.

<sup>73</sup>Department of Molecular Biology and Genetics, Bilkent University, Bilkent - Ankara, Turkey.

<sup>74</sup>Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti.

<sup>75</sup>Institute of Biomedical Research of IdiPAZ, University Hospital “La Paz”, Madrid, Spain.

<sup>76</sup>Institut de Biomedicina de València-CSIC, CIBERNED, ISCIII, València, Spain

<sup>77</sup>Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.

<sup>78</sup>Department of Biosciences, Biotechnology and Environment, University of Bari A. Moro, Bari, Italy.

<sup>79</sup>IIBB-CSIC, IDIBAPS, Barcelona, Spain.

<sup>80</sup>Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil.
⁸¹Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.

⁸²Human Evolutionary Genetics Unit, CNRS U2000, Institut Pasteur, Paris, France; Human Genomics and Evolution, Collège de France, Paris, France.

⁸³Al Jalila Children's Hospital, Dubai, UAE.

⁸⁴University Hospital St. Marina, Varna, Bulgaria.

⁸⁵Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria; Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.

⁸⁶Department of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.

⁸⁷Department of Immunology, Second Faculty of Medicine Charles University, V Uvalu, University Hospital in Motol, Prague, Czech Republic.

⁸⁸Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

⁸⁹Clinical and Diagnostic Immunology, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium; Dr. Shahrooei Lab, Tehran, Iran
<sup>90</sup>Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

<sup>91</sup>Central European Institute of Technology & Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

<sup>92</sup>Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

<sup>93</sup>Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.

<sup>94</sup>Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, Paris, France; AP-HP, Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France.

<sup>95</sup>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.

<sup>96</sup>Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.

<sup>97</sup>Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia.

<sup>98</sup>Departments of Medical Genetics & Histology and Embryology, Faculty of Medicine; Department of Translational Medicine, Health Sciences Institute, Bursa Uludağ University, Bursa, Turkey.
⁹⁹Precision Medicine Unit, Lausanne University Hospital and University of Lausanne,
Lausanne, Switzerland.

¹⁰⁰Etablissement Francais Du Sang, La Plaine-Saint Denis, Saint-Denis, France.

¹⁰¹Hospices Civils de Lyon, Lyon, France; International Center of Research in
Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon,
France.

¹⁰²BC Children's Hospital, The University of British Columbia, Vancouver, Canada.

¹⁰³Centre for Precision Therapeutics, Genetics & Genomic Medicine Centre, NeuroGen
Children's Healthcare and Lecturer, Holy Family Red Crescent Medical College Dhaka,
Bangladesh.

¹⁰⁴College of Medicine, Mohammed Bin Rashid University of Medicine and Health
Sciences, Dubai, UAE; Cellular Intelligence (Ci) Lab, GenomeArc Inc., Toronto, ON,
Canada.

¹⁰⁵Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical
Center, University of Amsterdam, Amsterdam, The Netherlands.

¹⁰⁶Department of Medicine, Division of Infectious Diseases, McGill University Health
Centre, Montréal, Québec, Canada; Infectious Disease Susceptibility Program, Research
Institute, McGill University Health Centre, Montréal, Québec, Canada.

¹⁰⁷Department of Pediatric Pneumology, Immunology and Intensive Care, Charité
Universitätsmedizin, Berlin University Hospital Center, Berlin, Germany; Labor Berlin
GmbH, Department of Immunology, Berlin, Germany; Berlin Institutes of Health (BIH),
Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.
¹⁰⁸Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium.

¹⁰⁹Biosciences Institute, University of São Paulo, São Paulo, Brazil.

¹¹⁰Molecular Biophysics Division, Faculty of Physics, A. Mickiewicz University, Poznań, Poland.
GEN-COVID Study Group members (https://www.gencovid.eu)

Antonio Aguilera Guirao³, Julián Álvarez Escudero⁷, Antonio Antela López⁵, Gema Barbeito Castiñeiras³, Xabier Bello Paderne¹, Miriam Ben García¹, María Victoria Carral García¹², Miriam Cebey López¹, Amparo Coira Nieto³, Mónica Conde Pájaro⁹, José Javier Costa Alcalde³, María José Currás Tuala¹, Ana Isabel Dacosta Urbieta¹, Blanca Díaz Esteban¹, María Jesús Domínguez Santalla⁵, Cristina Fernández Pérez⁹, Juan Fernández Villaverde⁶, Cristóbal Galbán Rodríguez⁶, José Luis García Allut⁶, Luisa García Vicente¹, Elena Giráldez Vázquez⁶, Alberto Gómez Carballa¹, José Gómez Rial¹, Francisco Javier González Barcala⁴, Beatriz Guerra Liñares⁹, Pilar Leboráns Iglesias¹, Beatriz Lence Massa⁶, Marta Lendoiro Fuentes¹, Montserrat López Franco¹, Ana López Lago⁶, Federico Martinón-Torres¹, Antonio Salas¹,², Daniel Navarro De la Cruz³, Eloína Núñez Masid¹⁰, Juan Bautista Ortolá Devesa⁸, Jacobo Pardo Seco¹, María Pazo Núñez⁵, Marisa Pérez del Molino Bernal³, Hugo Pérez Freixo⁹, Lidia Piñeiro Rodríguez¹, Sara Pischedda¹, Manuel Portela Romero¹¹, Antonio Pose Reino,⁵ Gloria María Prada Hervella⁷, Teresa Queiro Verdes⁹, Lorenzo Redondo Collazo¹, Patricia Regueiro Casuso¹, Susana Rey García¹, Sara Rey Vázquez¹, Vanessa Riveiro Blanco⁴, Irene Rivero Calle¹, Carmen Rivero Velasco⁶, Nuria Rodríguez Núñez⁴, Carmen Rodríguez-Tenreiro Sánchez¹, Eva Saborido Paz⁶, José Miguel Sadiki Orayyou¹, Carla Saito Villanueva⁶, Sonia Serén Fernández¹, Pablo Souto Sanmartín⁹, Manuel Taboada Muñiz⁷, Rocío Trastoy Pena³, Mercedes Treviño Castellano³, Luis Valdés Cuadrado⁴, Pablo Varela García⁵, María Soledad Vilas Iglesias¹, Sandra Viz Laseras¹, Rocío Ferreiro-Iglesias¹³, Iria Bastón-Rey¹³, and Cristina Calviño-Suárez¹³
¹Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain, and GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Universidad de Santiago de Compostela, Galicia, Spain.

²Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPop Research Group, Instituto de Investigaciones Sanitarias (IDIS), Hospital Clínico Universitario de Santiago, Galicia, Spain.

³Microbiology Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

⁴Pneumology Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

⁵Internal Medicine Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

⁶Intensive Care Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

⁷Anesthesiology and Resuscitation Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

⁸Clinical Chemistry Laboratory, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

⁹Preventive Medicine Unit, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain
¹⁰Manager of the Health Care Area of Santiago de Compostela and Barbanza, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

¹¹Deputy Director of Pharmaceutical Delivery, Training, Teaching, Research and Innovation, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

¹²Director of Nursing Processes, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain

¹³Digestive Service, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain.
COVID Clinicians

Sergio Aguilera-Albesa<fnref n="1" />, Suzan A. AlKhater<fnref n="2" />, Gulsum Alkan<fnref n="3" />, Riccardo Castagnoli<fnref n="4" />,¹⁹, Cyril Cyrus<fnref n="5" />, Sefika Elmas Bozdemir<fnref n="6" />, Melike Emiroglu<fnref n="3" />, Belgin Gulhan<fnref n="7" />, Emine Hafize Erdeniz<fnref n="8" />, Nevin Hatipoglu<fnref n="9" />, Gülsün Iclal Bayhan¹⁰, Petr Jabandziev¹¹, Saliha Kanik Yuksek¹², Adem Karbuz¹³, Şadiye Kübra Tüter Öz<fnref n="3" />, Gian Luigi Marseglia<fnref n="4" />,¹⁹, Ozge Metin Akcan¹⁴, Ahmet Osman Kılıç¹⁴, Aslinur Ozkaya Parlakay<fnref n="7" />, Maria Papadaki¹⁷, Katerina Slaba¹¹, Esra Sevketoglu¹⁸, Juan Valencia-Ramos¹⁶, and Aysun Yahşi<fnref n="7" />

<footnote n="1">¹Navarra Health Service Hospital, Pamplona, Spain.</footnote>

<footnote n="2">²Department of Pediatrics, King Fahad Hospital of the University, Al Khobar, Saudi Arabia; College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.</footnote>

<footnote n="3">³Selcuk University, Faculty of Medicine, Konya, Turkey.</footnote>

<footnote n="4">⁴Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy.</footnote>

<footnote n="5">⁵Department of Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.</footnote>

<footnote n="6">⁶Bursa City Hospital, Bursa, Turkey.</footnote>

<footnote n="7">⁷Ankara City Hospital, Children's Hospital, Ankara, Turkey.</footnote>

<footnote n="8">⁸Ondokuz Mayıs University, Faculty of Medicine, Samsun, Turkey.</footnote>

<footnote n="9">⁹Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.</footnote>
¹⁰Yildirim Beyazit University, Faculty of Medicine, Ankara City Hospital, Children's Hospital, Ankara, Turkey.

¹¹Department of Pediatrics, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

¹²Health Science University Ankara City Hospital, Ankara, Turkey.

¹³Prof. Dr. Cemil Tascıoglu City Hospital, Istanbul, Turkey.

¹⁴Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey.

¹⁶University Hospital of Burgos, Burgos, Spain.

¹⁷Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.

¹⁸Pediatric Intensive Care Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.

¹⁹Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.