Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia
Authors: García-García Ana , Pérez de Diego Rebeca , Flores Carlos , Rinchai Darawan , Solé-Violán Jordi , Deyà-Martínez Àngela , García-Solis Blanca , Lorenzo-Salazar José M. , Hernández-Brito Elisa , Lanz Anna-Lisa , Moens Leen , Bucciol Giorgia , Almuqamam Mohamed , Domachowske Joseph B. , Colino Elena , Santos-Perez Juan Luis , Marco Francisco M. , Pignata Claudio , Bousfiha Aziz , Turvey Stuart E. , Bauer Stefanie , Haerynck Filomeen , Ocejo-Vinyals Javier Gonzalo , Lendinez Francisco , Prader Seraina , Naumann-Bartsch Nora , Pachlopnik Schmid Jana , Biggs Catherine M. , Hildebrand Kyla , Dreesman Alexandra , Cárdenes Miguel Ángel , Ailal Fatima , Benhsaien Ibtihal , Giardino Giuliana , Molina-Fuentes Agueda , Fortuny Claudia , Madhavarapu Swetha , Conway Daniel H. , Prando Carolina , Schidlowski Laire , Martínez de Saavedra Álvarez María Teresa , Alfaro Rafael , Rodríguez de Castro Felipe ,   ESID Registry Working Party, Kindle Gerhard , Mahlaoui Nizar , Seidel Markus G. , Vassilios Lougaris , Seppänen Mikko R.J. ,   COVID Human Genetic Effort, Abel Laurent , Aiuti Alessandro , Al-Muhsen Saleh , Al-Mulla Fahd , Anderson Mark S. , Andreakos Evangelos , Arias Andrés A. , Baris Feldman Hagit , Belot Alexandre , Biggs Catherine M. , Bogunovic Dusan , Bolze Alexandre , Bondarenko Anastasiia , Bousfiha Ahmed A. , Brodin Petter , Bryceson Yenan , Bustamante Carlos D. , Butte Manish J. , Casari Giorgio , Christodoulou John , Condino-Neto Antonio , Constantinescu Stefan N. , Cooper Megan A. , Dalgard Clifton L. , Desai Murkesh , Drolet Beth A. , El Baghdadi Jamila , Espinosa-Padilla Sara , Fellay Jacques , Flores Carlos , Franco José Luis , Froidure Antoine , Gregersen Peter K. , Grimbacher Bodo , Haerynck Filomeen , Hagin David , Halwani Rabih , Hammarström Lennart , Heath James R. , Henrickson Sarah E. , Hsieh Elena W.Y. , Husebye Eystein , Imai Kohsuke , Itan Yuval , Jarvis Erich D. , Karamitros Timokratis , Kisand Kai , Ku Cheng-Lung , Lau Yu-Lung , Ling Yun , Lucas Carrie L. , Maniatis Tom , Mansouri Davood , Maródi László , Meyts Isabelle , Milner Joshua D. , Mironska Kristina , Mogensen Trine H. , Morio Tomohiro , Ng Lisa F.P. , Notarangelo Luigi D. , Novelli Antonio , Novelli Giuseppe , O’Farrelly Cliona , Okada Satoshi , Okamoto Keisuke , Ozcelik Tayfun , Pan-Hammarström Qiang , Pape Jean W. , Perez de Diego Rebecca , Perlin David S. , Pesole Graziano , Planas Anna M. , Prando Carolina , Pujol Aurora , Quintana-Murci Lluis , Ramaswamy Sathishkumar , Renia Laurent , Resnick Igor , Rodríguez-Gallego Carlos , Sancho-Shimizu Vanessa , Sediva Anna , Seppänan Mikko R.J. , Shahrooei Mohammed , Shcherbina Anna , Slaby Ondrej , Snow Andrew L. , Soler-Palacín Pere , Spaan András N. , Tancevski Ivan , Tangye Stuart G. , Tayoun Ahmad Abou , Turvey Stuart E. , Uddin K M Furkan , Uddin Mohammed J. , van de Beek Diederik , Vinh Donald C. , von Bernuth Horst , Wauters Joost , Zatz Mayana , Zawadzki Pawel , Su Helen C. , Casanova Jean-Laurent , Meyts Isabelle , Hauck Fabian , Puel Anne , Bastard Paul , Boisson Bertrand , Jouanguy Emmanuelle , Abel Laurent , Cobat Aurélie , Zhang Qian , Casanova Jean-Laurent , Alsina Laia , Rodríguez-Gallego Carlos 
Published: March 2023

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 &lt; 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.