Impact of SARS-CoV-2 infection and COVID-19 on patients with inborn errors of immunity

Since the arrival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, its characterization as a novel human pathogen, and the resulting coronavirus disease 2019 (COVID-19) pandemic, over 6.5 million people have died worldwide-a stark and sobering reminder of the fundamental and nonredundant roles of the innate and adaptive immune systems in host defense against emerging pathogens. Inborn errors of immunity (IEI) are caused by germline variants, typically in single genes. IEI are characterized by defects in development and/or function of cells involved in immunity and host defense, rendering individuals highly susceptible to severe, recurrent, and sometimes fatal infections, as well as immune dysregulatory conditions such as autoinflammation, autoimmunity, and allergy. The study of IEI has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. Indeed, this has been exemplified by assessing the impact of SARS-CoV-2 infection in individuals with previously diagnosed IEI, as well as analyzing rare cases of severe COVID-19 in otherwise healthy individuals. This approach has defined fundamental aspects of mechanisms of disease pathogenesis, immunopathology in the context of infection with a novel pathogen, and therapeutic options to mitigate severe disease. This review summarizes these findings and illustrates how the study of these rare experiments of nature can inform key features of human immunology, which can then be leveraged to improve therapies for treating emerging and established infectious diseases. (J Allergy Clin Immunol 2023;151:818-31.)

Automated summary

Since the emergence of SARS-CoV-2 in December 2019, the COVID-19 pandemic has resulted in over 6.5 million deaths worldwide, highlighting the crucial role of the immune system in defending against emerging pathogens. Inborn errors of immunity (IEI), characterized by defects in immune cell development and function, make individuals highly susceptible to severe infections and immune dysregulation. The study of IEI has provided valuable insights into the mechanisms of disease pathogenesis and immunopathology, which can inform the development of therapies for both emerging and established infectious diseases.