Rare Primary Immunodeficiency Diseases and COVID-19: Evolving Insights and Implications for Clinical and Public Health Practice

Posted on by Emily Drzymalla, Muin J. Khoury, and Marta Gwinn, Office of Genomics and Precision Public Health, Centers for Disease Control and Prevention, Atlanta, Georgia

shadows of three children with a COVID-19 virus and DNAIn this post, we explore how new research on rare genetic diseases is contributing to our understanding of COVID-19 occurrence and outcomes and discuss potential clinical and public health implications. Understanding the mechanisms involved in these inherited disorders may shed light on biological mechanisms and natural history of COVID-19.

Primary Immunodeficiency and COVID-19

Primary immunodeficiency (PI)—often used interchangeably with inborn error of immunity (IEI)—refers to a set of rare, single-gene disorders that affect the functioning of the immune system. As of 2022, 485 different types of PI had been described, affecting different components of the immune system and resulting in a variety of disorders, including increased susceptibility to severe infections and autoimmunity.

Studies of severe COVID-19 outcomes in PI patients have had inconsistent results, possibly due to small sample sizes and the heterogeneity of underlying genetic causes. For example, a study in the United Kingdom with 67 PI patients found a case fatality ratio of 28.5%, while another study in Israel with 20 PI patients reported a case fatality ratio of 0%. Reviews that compiled results of multiple, smaller studies have found some types of PI to be a potential risk factor for severe COVID-19 outcomes. In our recent systematic review of 68 studies, we calculated an overall 9% case fatality rate, 49% hospitalization rate, and 29% oxygen supplementation rate in the 459 people with PI and COVID-19.

Inborn Errors of Interferon type 1 Immunity and COVID-19

A recent review by Casanova and Anderson concluded that inherited and autoimmune deficiencies of type I interferon (IFN) immunity together account for 15%–20% of critical COVID-19 pneumonia in unvaccinated individuals. The type I IFN signaling pathway includes toll-like receptor 3 (TLR3) and interferon regulator factor 7 (IRF7). TLR3 acts earlier in the pathway and recognizes double stranded viral RNA, while IRF7 is a transcription factor to initiate IFN production. Inborn errors of type I IFN immunity due to mutations in TLR3 and IRF7 have been previously associated with life-threatening influenza pneumonia.

One study included in the review found that mutations in TLR3 and IRF7 and genes in related pathways were more common in patients with severe COVID-19, compared to patients with mild or asymptomatic COVID-19. Mutations in toll-like receptor 7 (TLR7), which are responsible for X-linked recessive toll-like receptor 7 deficiency (XR TLR7 deficiency), were also associated with severe COVID-19. This PI was not previously known and was discovered during the pandemic. XR TLR7 deficiency was estimated to be present in 1% of critical COVID-19 cases in men under 60 years old. Studies of COVID-19-related multisystem inflammatory disease in children (MIS-C) have suggested that deficiencies in type I IFN immunity also have a role in MIS-C susceptibility.

Autoantibodies to type I IFN have also been associated with severe COVID-19. These autoantibodies have been estimated to account for 10% of severe COVID-19 cases and 20% of COVID-19 related deaths.

Clinical and Public Health Implications

Research on PI and severe COVID-19 outcomes illustrates how studying rare genetic causes of common diseases can offer insight into disease mechanisms. Most human diseases are caused by the interplay between numerous genetic and environmental factors, and infectious diseases are no exception. Although only a small proportion of patients are ill due to rare, single gene disorders, studying them may improve understanding of underlying biological pathways, eventually leading to new therapies that are relevant across the disease spectrum.

Posted on by Emily Drzymalla, Muin J. Khoury, and Marta Gwinn, Office of Genomics and Precision Public Health, Centers for Disease Control and Prevention, Atlanta, GeorgiaTags ,
Page last reviewed: March 27, 2023
Page last updated: March 27, 2023