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

Garcia-Garcia A, De Diego RP, Flores C, Rinchai D, Sole-Violan J, Deya-Martinez A, Garcia-Solis B, Lorenzo-Salazar JM, Hernandez-Brito E, Lanz AL, Moens L, Bucciol G, Almuqamam M, Domachowske J, Colino E, Santos-Perez JL, Marco F, Pignata C, Bousfiha A, Turvey S, Bauer S, Haerynck F, Ocejo-Vinyals JG, Lendinez F, Prader S, Naumann-Bartsch N, Pachlopnik Schmid J, Biggs C, Hildebrand K, Dreesman A, Cardenes MA, Ailal F, Benhsaien I, Giardino G, Molina-Fuentes A, Fortuny C, Madhavarapu S, Conway D, Prando C, Schidlowski L, Alvarez MTMDS, Alfaro R, De Castro FR, Meyts I, Hauck F, Puel A, Bastard P, Boisson B, Jouanguy E, Abel L, Cobat A, Zhang Q, Casanova JL, Alsina L, Rodriguez-Gallego C (2023)

Publication Language: English

Publication Type: Journal article

Publication year: 2023


Book Volume: 220

Pages Range: e20220170

Journal Issue: 5

DOI: 10.1084/jem.20220170


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.

Additional Organisation(s)

Involved external institutions

Università degli Studi di Napoli Federico II IT Italy (IT) Centre Hospitalier Universitaire Ibn Rochd / Ibn Rushd University Hospital MA Morocco (MA) University of British Columbia CA Canada (CA) University Hospital Ghent BE Belgium (BE) Complejo Hospitalario Torrecárdenas ES Spain (ES) Universitäts-Kinderspital Zürich CH Switzerland (CH) Saint-Pierre University Hospital BE Belgium (BE) Hospital Universitario de Gran Canaria Doctor Negrín ES Spain (ES) Complejo Hospitalario de Jaén ES Spain (ES) Institut de Recerca Sant Joan de Déu (IRSJD) ES Spain (ES) Drexel University US United States (USA) (US) Hospital Pequeno Príncipe BR Brazil (BR) Universidad de Las Palmas Gran Canaria ES Spain (ES) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Rockefeller University US United States (USA) (US) Hospital Sant Joan de Déu Barcelona ES Spain (ES) Universidad Fernando Pessoa Canarias ES Spain (ES) Hospital Universitario La Paz ES Spain (ES) Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) ES Spain (ES) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Hôpital Necker-Enfants malades FR France (FR) Instituto Tecnológico y de Energías Renovables (ITER) ES Spain (ES) State University of New York Upstate Medical University (SUNY) US United States (USA) (US) Hospital Universitario Insular de Gran Canaria ES Spain (ES) Hospital Universitario Virgen de las Nieves ES Spain (ES) Hospital General Universitario de Alicante ES Spain (ES) Marqués de Valdecilla University Hospital / Hospital Universitario de Marqués de Valdecilla (HUMV) ES Spain (ES)

How to cite


Garcia-Garcia, A., De Diego, R.P., Flores, C., Rinchai, D., Sole-Violan, J., Deya-Martinez, A.,... Rodriguez-Gallego, C. (2023). Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia. Journal of Experimental Medicine, 220(5), e20220170.


Garcia-Garcia, Ana, et al. "Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia." Journal of Experimental Medicine 220.5 (2023): e20220170.

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