ABSTRACT
Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-ß. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2-specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-ß and compensatory adaptive immunity.
Subject(s)
COVID-19 , Influenza, Human , Virus Diseases , Viruses , Adult , COVID-19/genetics , Humans , Influenza, Human/genetics , SARS-CoV-2Subject(s)
COVID-19/immunology , Immunoglobulins, Intravenous/therapeutic use , Interleukins/immunology , Plasmapheresis/methods , Polyendocrinopathies, Autoimmune/immunology , SARS-CoV-2/immunology , Transcription Factors/genetics , Adaptive Immunity , Adrenal Cortex Hormones/therapeutic use , Antibodies, Viral/blood , Autoantibodies/blood , COVID-19/therapy , Cells, Cultured , Child , Female , Humans , Interferon Type I/immunology , Lymphocyte Activation , Polyendocrinopathies, Autoimmune/therapy , Severity of Illness IndexABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.