Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.