Human genetic and immunological determinants of critical COVID-19 pneumonia
Zhang Q., Bastard P., Karbuz A., Gervais A., Tayoun AA., Aiuti A., Belot A., Bolze A., Gaudet A., Bondarenko A., Spaan AN., Guennoun A., Arias AA., Planas AM., Sediva A., Shcherbina A., Neehus AL., Puel A., Froidure A., Novelli A., Parlakay AÖ., Pujol A., Yahşi A., Gülhan B., Bigio B., Boisson B., Drolet BA., Franco CAA., Flores C., Rodríguez-Gallego C., Prando C., Biggs CM., Luyt CE., Dalgard CL., O’Farrelly C., Matuozzo D., Dalmau D., Perlin DS., Mansouri D., van de Beek D., Vinh DC., Dominguez-Garrido E., Hsieh EWY., Erdeniz EH., Jouanguy E., Şevketoglu E., Talouarn E., Quiros-Roldan E., Andreakos E., Husebye E., Alsohime F., Haerynck F., Casari G., Novelli G., Aytekin G., Morelle G., Alkan G., Bayhan GI., Feldman HB., Su HC., von Bernuth H., Resnick I., Bustos I., Meyts I., Migeotte I., Tancevski I., Bustamantem J., Fellay J., El Baghdadi J., Martinez-Picado J., Casanova JL., Rosain J., Manry J., Chen J., Christodoulou J., Bohlen J., Franco JL., Li J., Anaya JM., Rojas J., Ye J., Uddin KMF., Yasar KK., Kisand K., Okamoto K., Chaïbi K., Mironska K., Maródi L., Abel L., Renia L., Lorenzo L., Hammarström L., Ng LFP., Quintana-Murci L., Erazo LV., Notarangelo LD., Reyes LF., Allende LM., Imberti L., Renkilaraj MRLM.
SARS-CoV-2 infection is benign in most individuals but, in ˜10% of cases, it triggers hypoxemic COVID-19 pneumonia, which becomes critical in ˜3% of cases. The ensuing risk of death (˜1%) doubles every five years from childhood onward and is ˜1.5 times greater in men than in women. What are the molecular and cellular determinants of critical COVID-19 pneumonia? Inborn errors of type I IFNs, including autosomal TLR3 and X-linked TLR7 deficiencies, are found in ˜1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing autoantibodies neutralizing IFN-α, –β, and/or –ω, which are more common in men than in women, are found in ˜15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can apparently be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defense against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation.