Human genetic and immunological determinants of critical COVID-19 pneumonia.
Qian ZhangPaul Bastardnull nullAurélie CobatJean Laurent CasanovaPublished in: Nature (2022)
SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 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 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 defence 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.
Keyphrases
- dendritic cells
- sars cov
- immune response
- coronavirus disease
- toll like receptor
- respiratory syndrome coronavirus
- inflammatory response
- respiratory failure
- regulatory t cells
- respiratory tract
- polycystic ovary syndrome
- end stage renal disease
- newly diagnosed
- community acquired pneumonia
- endothelial cells
- emergency department
- chronic kidney disease
- nuclear factor
- middle aged
- type diabetes
- pregnancy outcomes
- metabolic syndrome
- prognostic factors
- pregnant women
- young adults
- dna methylation
- acute respiratory distress syndrome
- skeletal muscle
- extracorporeal membrane oxygenation
- mechanical ventilation
- quality improvement