Human inherited complete STAT2 deficiency underlies inflammatory viral diseases

The study reports on 23 patients with autosomal recessive complete STAT2 deficiency from 10 families across 7 countries. The research included functional studies on patient cells and transfected cells, showing impaired expression of interferon-stimulated genes and impaired viral control in vitro. Clinical review revealed severe adverse reactions to live attenuated viral vaccines (LAV) and severe viral infections, including critical influenza and COVID-19 pneumonia. Hyperinflammation, often triggered by viral infection or LAV, was common. Transcriptomic analysis identified circulating monocytes, neutrophils, and CD8+ memory T cells as contributors to inflammation. Eight patients died in early childhood, with mortality linked to viral infection or heart failure during febrile illness. The findings establish STAT2 deficiency as a cause of severe viral disease and hyperinflammation, with implications for early diagnosis and prophylactic strategies.