Two new studies report specific mechanisms of impaired type I interferon (IFN) signaling in some hospitalized patients suffering from severe cases of COVID-19, suggesting that screens for these defects could help identify patients at the highest risk of life-threatening complications from SARS-CoV-2 infection. The results of the paired studies - which report that mutations in type I IFN-associated genes and high titers of neutralizing autoantibodies against type I IFNs may both be associated with severe COVID-19 respiratory symptoms - also suggest that administering specific type I IFNs to select high-risk patients could offer therapeutic benefits, especially early in the course of the disease. To test whether severe COVID-19 respiratory symptoms may be associated with the genetics of type I IFN signaling, Qian Zhang and colleagues performed whole-genome or whole-exome sequencing of 659 patients hospitalized with life-threatening COVID-19 pneumonia and 534 patients with asymptomatic or mild infection. Focusing on 13 gene loci known to govern TLR3- and IRF7-dependent type I IFN immunity to influenza virus, the researchers found rare loss-of-function gene variants in 3.5% of the patients with severe COVID-19 symptoms, but not in the asymptomatic/mild cohort. This subgroup of patients (23 in total) ranged in age from 17 to 77, with representation of both sexes and various ancestries. Based on their findings, the researchers suggest that mutations in other type I IFN-related genes may exist in other patients with life-threatening COVID-19 symptoms. In a related study, Paul Bastard and colleagues investigated whether neutralizing autoantibodies (which aberrantly recognize, bind to, and neutralize a patient's own proteins) against type I IFNs might also underlie severe COVID-19 pneumonia. In a screen of 987 patients with dire cases of COVID-19, the researchers found that 101 patients had autoantibodies against IFN-ω, IFN-a, or both. In contrast, 663 patients with asymptomatic or mild cases of COVID-19 had none of the autoantibodies, and only 4 of 1,227 healthy individuals, sampled before the pandemic, had one or more of the autoantibody types. Based on their findings, Bastard et al. conclude that "the neutralizing [autoantibodies] against type I IFNs, like inborn errors of type I IFN production, tip the balance in favor of the virus, resulting in devastating disease, with insufficient, and even perhaps deleterious, innate and adaptive immune responses."