Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia
Por:
García-García AP, Pérez de Diego R, Flores C, Rinchai D, Solé-Violán J, Deyà-Martinez A, García-Solis B, Lorenzo-Salazar JM, Hernández-Brito E, Lanz AL, Moens L, Bucciol G, Almuqamam M, Domachowske JB, Colino E, Santos-Perez JL, Marco FM, Pignata C, Bousfiha A, Turvey SE, Bauer S, Haerynck F, Ocejo-Vinyals JG, Lendinez F, Prader S, Naumann-Bartsch N, Pachlopnik Schmid J, Biggs CM, Hildebrand K, Dreesman A, Cárdenes MÁ, Ailal F, Benhsaien I, Giardino G, Molina-Fuentes A, Fortuny-Guasch C, Madhavarapu S, Conway DH, Prando C, Schidlowski L, Martínez de Saavedra Álvarez MT, Alfaro R, Rodríguez de Castro F, Meyts I, Hauck F, Puel A, Bastard P, Boisson B, Jouanguy E, Abel L, Cobat A, Zhang Q, Casanova JL, Alsina L and Rodríguez-Gallego C
Publicada:
3 mar 2023
Ahead of Print:
3 mar 2023
Resumen:
X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.
MyD88- and IRAK-4-deficient patients have a higher risk of hypoxemic COVID-19 pneumonia than individuals of similar age in the general population, due to impaired TLR7-dependent type I IFN production.
Filiaciones:
García-García AP:
Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona , Barcelona, Spain. ROR: https://ror.org/001jx2139
Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona , Barcelona, Spain
Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona , Barcelona, Spain
Pérez de Diego R:
Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital , Madrid, Spain
Flores C:
Genomics Division, Instituto Tecnológico y de Energías Renovables , Santa Cruz de Tenerife, Spain
Research Unit, Hospital Universitario N.S. de Candelaria , Santa Cruz de Tenerife, Spain. ROR: https://ror.org/005a3p084
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III , Madrid, Spain
Dept. of Clinical Sciences, University Fernando Pessoa Canarias , Las Palmas de Gran Canaria, Spain
Rinchai D:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Solé-Violán J:
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III , Madrid, Spain
Dept. of Clinical Sciences, University Fernando Pessoa Canarias , Las Palmas de Gran Canaria, Spain
Dept. of Intensive Care Medicine, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Deyà-Martinez A:
Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona , Barcelona, Spain. ROR: https://ror.org/001jx2139
Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona , Barcelona, Spain
Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona , Barcelona, Spain
García-Solis B:
Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital , Madrid, Spain
Lorenzo-Salazar JM:
Genomics Division, Instituto Tecnológico y de Energías Renovables , Santa Cruz de Tenerife, Spain
Hernández-Brito E:
Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Lanz AL:
Dept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München , Munich, Germany. ROR: https://ror.org/05591te55
Moens L:
Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven , Leuven, Belgium. ROR: https://ror.org/05f950310
Bucciol G:
Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven , Leuven, Belgium. ROR: https://ror.org/05f950310
Dept. of Pediatrics, Childhood Immunology, UZ Leuven , Leuven, Belgium
Almuqamam M:
Dept. of Pediatrics, Drexel University College of Medicine, St Christopher's Hospital for Children , Philadelphia, PA, USA. ROR: https://ror.org/05t3ett24
Domachowske JB:
Dept. of Pediatrics, SUNY Upstate Medical University , Syracuse, NY, USA. ROR: https://ror.org/040kfrw16
Colino E:
Unidad de Enfermedades Infecciosas, Complejo Hospitalario Universitario Insular-Materno Infantil , Las Palmas de Gran Canaria, Spain
Santos-Perez JL:
Unidad de Gestión Clínica de Pediatría y Cirugía Pediátrica, Hospital Virgen de las Nieves-IBS , Granada, Spain
Marco FM:
Dept. of Immunology, Alicante University General Hospital Doctor Balmis , Alicante, Spain
Alicante Institute for Health and Biomedical Research , Alicante, Spain
Pignata C:
Dept. of Translational Medical Sciences, Section of Pediatrics, Federico II University , Naples, Italy
Bousfiha A:
Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital , Casablanca, Morocco
Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca, Morocco
Turvey SE:
Dept. of Paediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada. ROR: https://ror.org/03rmrcq20
Bauer S:
Clinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen , Erlangen, Germany
Haerynck F:
Dept. of Pediatric Immunology and Pulmonology, Centre for Primary Immune Deficiency Ghent, Ghent University Hospital , Ghent, Belgium
Dept. of Internal Medicine and Pediatrics, PID Research Laboratory, Ghent University , Ghent, Belgium
Ocejo-Vinyals JG:
Dept. of Immunology, University Hospital Marqués de Valdecilla, IDIVAL , Santander, Spain
Lendinez F:
Dept. of Pediatric Oncohematology, Hospital Materno Infantil Torrecárdenas , Almería, Spain
Prader S:
Division of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
University of Zurich , Zurich, Switzerland
Naumann-Bartsch N:
Clinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen , Erlangen, Germany
Pachlopnik Schmid J:
Division of Immunology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
University of Zurich , Zurich, Switzerland
Biggs CM:
Dept. of Paediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada. ROR: https://ror.org/03rmrcq20
Hildebrand K:
Dept. of Paediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada. ROR: https://ror.org/03rmrcq20
Dreesman A:
Dept. of Pediatrics, CHU St Pierre, ULB/VUB , Brussels, Belgium
Cárdenes MÁ:
Dept. of Internal Medicine, Unit of Infectious Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Ailal F:
Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital , Casablanca, Morocco
Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca, Morocco
Benhsaien I:
Dept. of Pediatric Infectious Diseases and Clinical Immunology, Ibn Rushd University Hospital , Casablanca, Morocco
Clinical Immunology, Autoimmunity and Inflammation Laboratory, Faculty of Medicine and Pharmacy, Hassan II University , Casablanca, Morocco
Giardino G:
Dept. of Translational Medical Sciences, Section of Pediatrics, Federico II University , Naples, Italy
Molina-Fuentes A:
Dept. of Immunology, UGC Laboratories, University Hospital of Jaén , Jaén, Spain
Fortuny-Guasch C:
Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona , Barcelona, Spain
Pediatric Infectious Diseases Unit, Hospital Sant Joan de Déu , Barcelona, Spain
CIBER of Epidemiology and Public Health, Madrid, Spain
Translational Research Network in Pediatric Infectious Diseases , Madrid, Spain
Dept. of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, University of Barcelona , Barcelona, Spain
Madhavarapu S:
Dept. of Pediatrics, Drexel University College of Medicine, St Christopher's Hospital for Children , Philadelphia, PA, USA. ROR: https://ror.org/05t3ett24
Conway DH:
Dept. of Pediatrics, Drexel University College of Medicine, St Christopher's Hospital for Children , Philadelphia, PA, USA. ROR: https://ror.org/05t3ett24
Prando C:
Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe , Curitiba, Brazil
Schidlowski L:
Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Hospital Pequeno Príncipe , Curitiba, Brazil
Martínez de Saavedra Álvarez MT:
Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Alfaro R:
Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Rodríguez de Castro F:
Dept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria , Las Palmas de Gran Canaria, Spain
Dept. of Respiratory Diseases, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Meyts I:
Laboratory for Inborn Errors of Immunity, Dept. of Microbiology, Immunology and Transplantation KU Leuven , Leuven, Belgium. ROR: https://ror.org/05f950310
Dept. of Pediatrics, Childhood Immunology, UZ Leuven , Leuven, Belgium
Hauck F:
Dept. of Pediatrics, Division of Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München , Munich, Germany. ROR: https://ror.org/05591te55
Puel A:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Bastard P:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Pediatric Hematology and Immunology Unit, Department of Pediatrics, Necker Hospital for Sick Children, AP-HP , Paris, France
Boisson B:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Jouanguy E:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Abel L:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Cobat A:
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Zhang Q:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Casanova JL:
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University , New York, NY, USA. ROR: https://ror.org/0420db125
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children , Paris, France. ROR: https://ror.org/02vjkv261
University Paris Cité, Imagine Institute , Paris, France
Department of Pediatrics, Necker Hospital for Sick Children , Paris, France
Howard Hughes Medical Institute , New York, NY, USA
Alsina L:
Pediatric Allergy and Clinical Immunology Dept., Clinical Immunology and Primary Immunodeficiencies Unit, Hospital Sant Joan de Déu, Barcelona , Barcelona, Spain. ROR: https://ror.org/001jx2139
Study Group for Immune Dysfunction Diseases in Children, Institut de Recerca Sant Joan de Déu, Barcelona , Barcelona, Spain
Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic Barcelona , Barcelona, Spain
Dept. of Surgery and Surgical Specializations, Facultat de Medicina i Ciències de la Salut, University of Barcelona , Barcelona, Spain
Rodríguez-Gallego C:
Dept. of Clinical Sciences, University Fernando Pessoa Canarias , Las Palmas de Gran Canaria, Spain
Dept. of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System , Las Palmas de Gran Canaria, Spain
Dept. of Medical and Surgical Sciences, School of Medicine, University of Las Palmas de Gran Canaria , Las Palmas de Gran Canaria, Spain
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