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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.

SUBMITTER: Garcia-Garcia A

PROVIDER: S-EPMC9998661 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

García-García Ana A Pérez de Diego Rebeca R Flores Carlos C Rinchai Darawan D Solé-Violán Jordi J Deyà-Martínez Àngela À García-Solis Blanca B Lorenzo-Salazar José M JM Hernández-Brito Elisa E Lanz Anna-Lisa AL Moens Leen L Bucciol Giorgia G Almuqamam Mohamed M Domachowske Joseph B JB Colino Elena E Santos-Perez Juan Luis JL Marco Francisco M FM Pignata Claudio C Bousfiha Aziz A Turvey Stuart E SE Bauer Stefanie S Haerynck Filomeen F Ocejo-Vinyals Javier Gonzalo JG Lendinez Francisco F Prader Seraina S Naumann-Bartsch Nora N Pachlopnik Schmid Jana J Biggs Catherine M CM Hildebrand Kyla K Dreesman Alexandra A Cárdenes Miguel Ángel MÁ Ailal Fatima F Benhsaien Ibtihal I Giardino Giuliana G Molina-Fuentes Agueda A Fortuny Claudia C Madhavarapu Swetha S Conway Daniel H DH Prando Carolina C Schidlowski Laire L Martínez de Saavedra Álvarez María Teresa MT Alfaro Rafael R Rodríguez de Castro Felipe F Meyts Isabelle I Hauck Fabian F Puel Anne A Bastard Paul P Boisson Bertrand B Jouanguy Emmanuelle E Abel Laurent L Cobat Aurélie A Zhang Qian Q Casanova Jean-Laurent JL Alsina Laia L Rodríguez-Gallego Carlos C

The Journal of experimental medicine 20230303 5

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 hosp ...[more]

PMID: 36880831

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Project description:PurposeTo report a French experience in patients admitted to Intensive Care Unit (ICU) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requiring high fractional concentration of inspired oxygen supported by high flow nasal cannula (HFNC) as first-line therapy.MethodsRetrospective cohort study conducted in two ICUs of a French university hospital. All consecutive patients admitted during 28-days after the first admission for SARS-CoV-2 pneumonia were screened. Demographic, clinical, respiratory support, specific therapeutics, ICU length-of-stay and survival data were collected.ResultsData of 43 patients were analyzed: mainly men (72%), median age 61 (51-69) years, median body mass index of 28 (25-31) kg/m2, median simplified acute physiology score (SAPS II) of 29 (22-37) and median PaO2/fraction of inspired oxygen (FiO2) (P/F) ratio of 146 (100-189) mmHg. HFNC was initiated at ICU admission in 76% of patients. Median flow was 50 (45-50) L/min and median FiO2 was 0.6 (0.5-0.8). 79% of patients presented at least one comorbidity, mainly hypertension (58%). At day (D) 28, 32% of patients required invasive mechanical ventilation, 3 patients died in ICU. Risk factors for intubation were diabetes (10% vs. 43%, P=0.04) and extensive lesions on chest computed tomography (CT) (P=0.023). Patients with more than 25% of lesions on chest CT were more frequently intubated during ICU stay (P=0.012). At ICU admission (D1), patients with higher SAPS II and Sequential Organ Failure Assessment (SOFA) scores (respectively 39 (28-50) vs. 27 (22-31), P=0.0031 and 5 (2-8) vs. 2 (2-2.2), P=0.0019), and a lower P/F ratio (98 (63-109) vs. 178 (126-206), P=0.0005) were more frequently intubated. Among non-intubated patients, the median lowest P/F was 131 (85-180) mmHg. Four caregivers had to stop working following coronavirus 2 contamination, but did not require hospitalization.ConclusionOur clinical experience supports the use of HFNC as first line-therapy in patients with SARS-COV-2 pneumonia for whom face mask oxygen does not provide adequate respiratory support.

Dataset Information

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

Publications

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

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