Abstract
Background
During the past 2 years, studies on patients with SARS-CoV-2 infection have revealed rare inborn errors of immunity (IEIs) in type interferon (IFN) pathways underlying critical COVID-19 pneumonia. This has provided insights into pathophysiological mechanisms and immune signaling circuits regulating antiviral responses to SARS-CoV-2 and governing the susceptibility to and outcome of SARS-CoV-2 infection in humans.
Objectives
In this review, the current knowledge on IEIs underlying critical COVID-19 is presented, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined.
Sources
The review is based on a broad literature search, including primarily studies on whole-exome sequencing, and to a lesser extent genome-wide association studies, of patients with critical COVID-19, as well as retrospective descriptive studies of the SARS-CoV-2 disease course in individuals with known IEIs.
Content
The review describes the discovery of monogenic IEI in 9 genetic loci related to the production or responses to type I IFN in patients with critical COVID-19 pneumonia and the surprising finding of phenocopies of these, represented by neutralizing autoantibodies to type IFN in a significant proportion of patients with critical pneumonia, particularly in elderly men, and further enriched in patients with lethal disease course. Moreover insights gained from studies on SARS-CoV-2 infection, disease course, and outcome in patients with known IEI is presented. Finally, some hypotheses for a possible genetic basis of autoimmune, inflammatory, and long-term complications of SARS-CoV-2 infection are presented and discussed.
Implications
Uncovering IEIs underlying critical COVID-19 or other severe SARS-CoV-2 disease manifestations provides valuable insights into the basic principles of antiviral immune responses and pathophysiology related to SARS-CoV-2 infection. Such knowledge has important clinical implications for identification of susceptible individuals and for diagnosis, prophylaxis, and treatment of patients to reduce disease burden and improve preparedness against viral pandemics with known or emerging viruses in the future.
【저자키워드】 COVID-19, SARS-CoV-2, Innate immunity, interferon, MIS-C, Inborn error of immunity, 【초록키워드】 Treatment, Immunity, Pneumonia, knowledge, SARS-COV-2 infection, susceptibility, Genetic, whole-exome sequencing, Infection, Diagnosis, outcome, immune, Prophylaxis, pathophysiology, humans, response, Genome-wide association studies, Patient, pathway, Pandemics, Complication, IFN, Neutralizing, Autoimmune, disease, Critical, genetic loci, Signaling, antiviral response, retrospective, Inflammatory, Type I IFN, autoantibody, antiviral immune response, individual, disease course, pathophysiological mechanism, disease manifestation, content, lethal disease, men, objective, severe SARS-CoV-2, IMPROVE, Course, virus, proportion, provided, provide, reduce, Source, hypothese, clinical implication, outlined, patients with SARS-CoV-2, susceptible individual, the SARS-CoV-2, 【제목키워드】 SARS-COV-2 infection, Human, genetics, Critical,