The following is the summary of “Human genetics of SARS-CoV-2 infection and critical COVID-19” published in the November 2022 issue of Clinical Microbiology and Infection by Mogensen, et al.

Research conducted over the past 2 years has linked critical COVID-19 pneumonia to rare inborn errors of immunity (IEIs) in type interferon (IFN) pathways. As a result, investigators now better understand the pathophysiological mechanisms and immunological signaling circuits that determine human susceptibility to and outcome of SARS-CoV-2 infection. This article summarizes our current understanding of the IEIs underlying severe COVID-19, and discusses the significance of these results for personalized prevention and treatment. The review is based on a comprehensive search of the relevant literature, including retrospective descriptive investigations of the SARS-CoV-2 clinical course in persons with known IEIs and studies on whole-exome sequencing of patients with critical COVID-19.

The review discusses the unexpected discovery of phenocopies of these, represented by neutralizing autoantibodies to type IFN, in a substantial proportion of patients with critical pneumonia, especially in elderly men, and further enriched in patients with a lethal disease course. These phenocopies were first identified in patients with critical COVID-19 pneumonia. In addition, data on the infection, progression, and outcome of SARS-CoV-2 in patients with established IEI are given. Finally, various speculations on the potential genetic basis of autoimmune, inflammatory, and chronic sequelae of SARS-CoV-2 infection are provided and explored.

Insights into the fundamental principles of antiviral immune responses and the pathophysiology connected to SARS-CoV-2 infection can be gained by identifying the IEIs underlying significant COVID-19 or other severe SARS-CoV-2 clinical presentations. This information can be used to better prepare for future viral pandemics with both known and new viruses, as well as to minimize the disease burden through the identification of susceptible individuals and the diagnosis, prevention, and treatment of patients.