LAUSR

Since December 2019, over 150 million individuals have been infected with SARS-CoV-2 globally. While most cases (>95%) are asymptomatic or mild, a small proportion develop moderate, severe, or critical COVID-19 pneumonia requiring hospitalization, at times in the intensive care unit [1]. At least 2 million patients have already died [2]. The main epidemiological risk factor associated with critical pneumonia or death is age > 65 years; however, life-threatening COVID-19 has also affected younger people, albeit sporadically. Studies have suggested that type I interferon (IFN) immunity contributes to the control of SARS-CoV-2 infection [3–8]. Notably, inborn errors of TLR3and IRF7-dependent type I IFN production or amplification underlie severe disease in ~3% of a cohort of relatively young adult patients analyzed by the COVID Human Genetic Effort (COVIDhge.com) [3]. In at least an additional 10% of cases, high levels of pre-existing auto-antibodies (auto-Abs) neutralizing most type I IFNs, but rarely IFN-β, abrogate type I IFN–dependent control of SARSCoV-2 replication in vitro, thereby underlying critical disease in vivo [3, 4, 9, 10]. This observation was replicated in other cohorts [11–15]. The mean age of patients with inborn errors was 48 years, while that of patients with auto-Abs was 65 years. These findings support a two-step model of COVID19 pathogenesis: defective type I IFN immunity in the first