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

ESID Registry Working Party

doi:10.1084/jem.20220170

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

ESID Registry Working Party

Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain
IdiPAZ Institute for Health Research
Scottish Renal Registry, Meridian Court, Glasgow, UK; and Division of Population Health and Genomics, University of Dundee, Dundee, UK
Rockefeller University
Spain CIBER de Enfermedades Respiratorias, Universidad Europea, Madrid, Spain.
University Hospital of Gran Canaria Dr. Negrín
University and University Hospital Würzburg
Laboratory for Inborn Errors of Immunity
Drexel University College of Medicine
SUNY Upstate Medical University
Complejo Hospitalario Universitario Insular-Materno Infantil
Hospital Virgen de las Nieves-IBS
Alicante University General Hospital Doctor Balmis
Federico II University, Italy
Ibn Rushd University Hospital
Faculty of Medicine, University of British Columbia School of Medicine, Vancouver, British Columbia, Canada
Clinic for Children and Adolescents. Dept. of Hematology and Oncology. University Clinic Erlangen
Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium.
University Hospital and Research Institute of Marqués de Valdecilla (IDIVAL)
Hospital Materno Infantil Torrecárdenas
Department of Economics, University of Zurich, Zurich, Switzerland.
BC Children’s Hospital, University of British Columbia, Vancouver CA, dept pediatrics
University Hospital of Jaén
Study Group for Immune Dysfunction Diseases in Children
Hospital Pequeno Príncipe
Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Las Palmas, Spain
Necker Hospital for Sick Children
University Fernando Pessoa Canarias

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Journal	Journal of experimental medicine
Volume	220
Issue number	5
DOIs	https://doi.org/10.1084/jem.20220170
Publication status	Published - 1 May 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Child
Humans
Adaptor Proteins, Signal Transducing
COVID-19/complications
Myeloid Differentiation Factor 88/genetics
SARS-CoV-2
Toll-Like Receptor 7

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10.1084/jem.20220170

Humans-with-inherited-myd88-and-irak-4-deficiencies-are-predisposed-to-hypoxemic-covid-19-pneumonia.pdfFinal published version, 2.73 MBLicence: Taverne

Cite this

@article{7d98e6f72a0249139a8a07647d711616,

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

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.",

keywords = "Child, Humans, Adaptor Proteins, Signal Transducing, COVID-19/complications, Myeloid Differentiation Factor 88/genetics, SARS-CoV-2, Toll-Like Receptor 7",

author = "\{ESID Registry Working Party\} and Ana Garc{\'i}a-Garc{\'i}a and \{P{\'e}rez de Diego\}, Rebeca and Carlos Flores and Darawan Rinchai and Jordi Sol{\'e}-Viol{\'a}n and {\`A}ngela Dey{\`a}-Mart{\'i}nez and Blanca Garc{\'i}a-Solis and Lorenzo-Salazar, \{Jos{\'e} M\} and Elisa Hern{\'a}ndez-Brito and Anna-Lisa Lanz and Leen Moens and Giorgia Bucciol and Mohamed Almuqamam and Domachowske, \{Joseph B\} and Elena Colino and Santos-Perez, \{Juan Luis\} and Marco, \{Francisco M\} and Claudio Pignata and Aziz Bousfiha and Turvey, \{Stuart E\} and Stefanie Bauer and Filomeen Haerynck and Ocejo-Vinyals, \{Javier Gonzalo\} and Francisco Lendinez and Seraina Prader and Nora Naumann-Bartsch and \{Pachlopnik Schmid\}, Jana and Biggs, \{Catherine M\} and Kyla Hildebrand and Alexandra Dreesman and C{\'a}rdenes, \{Miguel {\'A}ngel\} and Fatima Ailal and Ibtihal Benhsaien and Giuliana Giardino and Agueda Molina-Fuentes and Claudia Fortuny and Swetha Madhavarapu and Conway, \{Daniel H\} and Carolina Prando and Laire Schidlowski and \{Mart{\'i}nez de Saavedra {\'A}lvarez\}, \{Mar{\'i}a Teresa\} and Rafael Alfaro and \{Rodr{\'i}guez de Castro\}, Felipe and Isabelle Meyts and Fabian Hauck and Anne Puel and Paul Bastard and Bertrand Boisson and Emmanuelle Jouanguy and Laurent Abel and Aur{\'e}lie Cobat and Qian Zhang and Jean-Laurent Casanova and Laia Alsina and Carlos Rodr{\'i}guez-Gallego and \{van de Beek\}, Diederik",

note = "{\textcopyright} 2023 Garc{\'i}a Garc{\'i}a et al.",

year = "2023",

month = may,

day = "1",

doi = "10.1084/jem.20220170",

language = "English",

volume = "220",

journal = "Journal of experimental medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "5",

}

TY - JOUR

T1 - Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

AU - ESID Registry Working Party

AU - García-García, Ana

AU - Pérez de Diego, Rebeca

AU - Flores, Carlos

AU - Rinchai, Darawan

AU - Solé-Violán, Jordi

AU - Deyà-Martínez, Àngela

AU - García-Solis, Blanca

AU - Lorenzo-Salazar, José M

AU - Hernández-Brito, Elisa

AU - Lanz, Anna-Lisa

AU - Moens, Leen

AU - Bucciol, Giorgia

AU - Almuqamam, Mohamed

AU - Domachowske, Joseph B

AU - Colino, Elena

AU - Santos-Perez, Juan Luis

AU - Marco, Francisco M

AU - Pignata, Claudio

AU - Bousfiha, Aziz

AU - Turvey, Stuart E

AU - Bauer, Stefanie

AU - Haerynck, Filomeen

AU - Ocejo-Vinyals, Javier Gonzalo

AU - Lendinez, Francisco

AU - Prader, Seraina

AU - Naumann-Bartsch, Nora

AU - Pachlopnik Schmid, Jana

AU - Biggs, Catherine M

AU - Hildebrand, Kyla

AU - Dreesman, Alexandra

AU - Cárdenes, Miguel Ángel

AU - Ailal, Fatima

AU - Benhsaien, Ibtihal

AU - Giardino, Giuliana

AU - Molina-Fuentes, Agueda

AU - Fortuny, Claudia

AU - Madhavarapu, Swetha

AU - Conway, Daniel H

AU - Prando, Carolina

AU - Schidlowski, Laire

AU - Martínez de Saavedra Álvarez, María Teresa

AU - Alfaro, Rafael

AU - Rodríguez de Castro, Felipe

AU - Meyts, Isabelle

AU - Hauck, Fabian

AU - Puel, Anne

AU - Bastard, Paul

AU - Boisson, Bertrand

AU - Jouanguy, Emmanuelle

AU - Abel, Laurent

AU - Cobat, Aurélie

AU - Zhang, Qian

AU - Casanova, Jean-Laurent

AU - Alsina, Laia

AU - Rodríguez-Gallego, Carlos

AU - van de Beek, Diederik

PY - 2023/5/1

Y1 - 2023/5/1

N2 - 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.

AB - 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.

KW - Child

KW - Humans

KW - Adaptor Proteins, Signal Transducing

KW - COVID-19/complications

KW - Myeloid Differentiation Factor 88/genetics

KW - SARS-CoV-2

KW - Toll-Like Receptor 7

U2 - 10.1084/jem.20220170

DO - 10.1084/jem.20220170

M3 - Article

C2 - 36880831

SN - 0022-1007

VL - 220

JO - Journal of experimental medicine

JF - Journal of experimental medicine

IS - 5

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

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