Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia
Qian Zhang, Daniela Matuozzo, Jérémie Le Pen, Danyel Lee, Leen Moens, Takaki Asano, Jonathan Bohlen, Zhiyong Liu, Marcela Moncada‐Vélez, Yasemin Kendir Demirkol, Huie Jing, Lucy Bizien, Astrid Marchal, Hassan Abolhassani, Selket Delafontaine, Giorgia Bucciol, COVID Human Genetic Effort, Laurent Abel, Hassan Abolhassani, Alessandro Aiuti, Özge Metin Akcan, Saleh Al‐Muhsen, Fahd Al‐Mulla, Gülsüm Alkan, Mark S. Anderson, Evangelos Andreakos, Andrés A. Arias, Jalila El Bakkouri, Hagit Baris Feldman, Alexandre Bélot, Catherine M. Biggs, Dusan Bogunovic, Alexandre Bolze, Анастасія Бондаренко, Ahmed Aziz Bousfiha, Şefika Elmas Bozdemir, Petter Brodin, Yenan T. Bryceson, Carlos D. Bustamante, Manish J. Butte, Giorgio Casari, John Christodoulou, Roger Colobrán, Antônio Condino‐Neto, Stefan N. Constantinescu, Megan A. Cooper, Clifton L. Dalgard, Murkesh Desai, Beth A. Drolet, Jamila El Baghdadi, Melike Emiroğlu, Emine Hafize Erdeniz, Sara Elva Espinosa‐Padilla, Jacques Fellay, Carlos Flores, José Luis Franco, Antoine Froidure, Peter K. Gregersen, Bodo Grimbacher, Belgi̇n Gülhan, 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, Petr Jabandžiev, Erich D. Jarvis, Timokratis Karamitros, Adem Karbuz, Kai Kisand, Cheng‐Lung Ku, YL Lau, Yun Ling, C. Lucas, Tom Maniatis, Davood Mansouri, László Maródi, Ayşe Metìn, Isabelle Meyts, Joshua D. Milner, Kristina Mironska, Trine H. Mogensen, Tomohiro Morio, Lisa F. P. Ng, Luigi D. Notarangelo, Antonio Novelli, Giuseppe Novelli, Cliona O’Farrelly, Satoshi Okada, Keisuke Okamoto, Şadiye Kübra Tüter Öz, Tayfun Özçelık, Qiang Pan‐Hammarström, Maria Papadaki, Jean W. Pape
Abstract
Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.