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Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

2023; Rockefeller University Press; Volume: 220; Issue: 5 Linguagem: Inglês

10.1084/jem.20220170

1540-9538

Ana García‐García, Rebeca Pérez de Diego, Carlos Flores, Darawan Rinchai, Jordi Solé‐Violán, Àngela Deyà‐Martínez, Blanca García‐Solis, José M. Lorenzo-Salazar, Elisa Hernández-Brito, Anna-Lisa Lanz, Leen Moens, Giorgia Bucciol, Mohamed Almuqamam, Joseph B. Domachowske, Elena Colino, Juan Luis Santos, Francisco Manuel Marco de la Calle, Claudio Pignata, Aziz Bousfiha, Stuart E. Turvey, Stefanie Bauer, Filomeen Haerynck, J. Gonzalo Ocejo‐Vinyals, Francisco Lendínez, Seraina Prader, Nora Naumann‐Bartsch, Jana Pachlopnik Schmid, Catherine M. Biggs, Kyla J. Hildebrand, Alexandra Dreesman, Miguel Ángel Cárdenes, Fatima Ailal, Ibtihal Benhsaien, Giuliana Giardino, Agueda Molina-Fuentes, Clàudia Fortuny, Swetha Madhavarapu, Daniel Conway, Carolina Prando, Laire Schidlowski, María T. Martínez-Saavedra, Rafael Alfaro, Felipe Rodrı́guez de Castro, Gerhard Kindle, Nizar Mahlaoui, Markus G. Seidel, Lougaris Vassilios, Mikko Seppänen, Laurent Abel, Alessandro Aiuti, Saleh Al‐Muhsen, Fahd Al‐Mulla, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Hagit Baris Feldman, Alexandre Bélot, Catherine M. Biggs, Dusan Bogunovic, Alexandre Bolze, Анастасія Бондаренко, Ahmed Aziz Bousfiha, Petter Brodin, Yenan T. Bryceson, Carlos D. Bustamante, Manish J. Butte, Giorgio Casari, John Christodoulou, Antônio Condino‐Neto, Stefan N. Constantinescu, Megan A. Cooper, Clifton L. Dalgard, Murkesh Desai, Beth A. Drolet, Jamila El Baghdadi, Sara Elva Espinosa‐Padilla, Jacques Fellay, Carlos Flores, José Luis Franco, Antoine Froidure, Peter K. Gregersen, Bodo Grimbacher, Filomeen Haerynck, David Hagin, Rabih Halwani, Lennart Hammarström, James R. Heath, Sarah E. Henrickson, Elena W.Y. Hsieh, Eystein S. Husebye, Kohsuke Imai, Yuval Itan, Erich D. Jarvis, Timokratis Karamitros, Kai Kisand, Cheng‐Lung Ku, YL Lau, Yun Ling, C. Lucas, Tom Maniatis, Davood Mansouri, László Maródi, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Trine H. Mogensen, Tomohiro Morio, Lisa F. P. Ng, Luigi D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona OʼFarrelly, Satoshi Okada, Keisuke Okamoto, Tayfun Özçelık, Qiang Pan‐Hammarström, Jean W. Pape, Rebecca Perez de Diego, David S. Perlin, Graziano Pesole, Anna M. Planas, Carolina Prando, Aurora Pujol, Lluís Quintana‐Murci, Sathishkumar Ramaswamy, Laurent Rénia, Igor Resnick, Carlos Rodríguez‐Gallego, Vanessa Sancho‐Shimizu, Anna Šedivá, Mikko R.J. Seppänan, Mohammed Shahrooei, Anna Shcherbina, Ondřej Slabý, Andrew L. Snow, Pere Soler‐Palacín, András N. Spaan, Ivan Tancevski, Stuart G. Tangye, Ahmad Abou Tayoun, Stuart E. Turvey, K. M. Furkan Uddin, Mohammed Uddin, Diederik van de Beek, Donald C. Vinh, Horst von Bernuth, Joost Wauters, Mayana Zatz, Paweł Zawadzki, Helen C. Su, Jean‐Laurent Casanova, Isabelle Meyts, Fabian Hauck, Anne Puel, Paul Bastard, Bertrand Boisson, Emmanuelle Jouanguy, Laurent Abel, Aurélie Cobat, Qian Zhang, Jean‐Laurent Casanova, Laia Alsina, Carlos Rodríguez‐Gallego,

Pneumonia and Respiratory Infections

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.