Type I IFN autoantibodies in three of seven Europeans with life-threatening Usutu virus infection

We previously reported that two of three patients with severe Usutu virus (USUV) disease carried circulating autoantibodies (auto-Abs) neutralizing type I IFNs (AAN-I-IFN). Here, we studied four additional patients, bringing the total number of European patients with life-threatening USUV infection to seven (Austria, n = 1; France, n = 1; Hungary, n = 4; Italy, n = 1). Three of these patients (all male, aged 43, 77, and 78 years, one French and two Hungarian) had blood auto-Abs neutralizing at least 10 ng/ml IFN-α2 and IFN-ω and at least 1 ng/ml IFN-β. They suffered from meningitis (n = 1), meningoencephalitis (n = 1), or myocarditis (n = 1). The other four patients were similar demographically and clinically but had no detectable AAN-I-IFN. No AAN-I-IFN were found in the 63 individuals with silent USUV infection tested (P = 6.4 × 10-4, Fisher's exact test). These AAN-I-IFN increased the risk of life-threatening USUV disease by 98.8-fold (95% CI: 4.12-2,369; P = 0.0046, Firth's bias-corrected logistic regression) and, thus, account for almost half the cases of life-threatening USUV infection in Europe.