We tested the hypothesis that human inborn errors of the alternative NF-κB pathway—including autosomal-dominant NF-κB2 disorders, and autosomal-recessive RELB, IKKα and NIK deficiencies—can underlie the production of AAN-I-IFNs, thereby predisposing patients to severe viral diseases, including COVID-19 pneumonia. Here, RELB is linked to viral infectious disease.