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

Journal

Book Volume: 220

Pages Range: e20220170

Journal Issue: 5

DOI: 10.1084/jem.20220170

Abstract

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

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

How to cite

APA:

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. https://doi.org/10.1084/jem.20220170

MLA:

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.

BibTeX: Download