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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Our take —

A subset (3.5%) of 659 patients with severe COVID-19 pneumonia had uncommon genetic variants that suppress the type I interferon response to SARS-CoV-2 infection; none had previous severe viral illness. Some of these mutations are known to increase susceptibility to influenza, while others were not previously identified. This study, along with an accompanying study in the same journal, suggests that some people may have inborn deficiencies in their immune response that render them more susceptible to severe disease should they become infected with SARS-CoV-2. More research is necessary to determine if provision of type I interferons could improve outcomes in these patients.

Study design

Case series, Case control

Study population and setting

This study included 659 patients with severe COVID-19 pneumonia who were admitted to the ICU from four cohorts in France, Italy, and the United States (mean age 51.8 years, range 0.1 to 99 years, 74.5% male). Patients with Kawasaki-like disease were excluded. A control group of 534 individuals with mild laboratory-confirmed or suspected SARS-CoV-2 infection was also enrolled. The authors sequenced the genomes of participants from whole blood, with the aim of identifying monogenic inborn errors (primary immunodeficiency) of SARS-CoV-2 immunity that were associated with severe COVID-19. In particular, the authors tested the hypothesis that errors of TLR3- and IRF7-dependent type I interferon (INF) immunity were associated with severe COVID-19, by comparing the frequency of variants at 13 loci known to be mutated in patients with severe influenza pneumonia (or connected to three core genes dictating susceptibility to pneumonia) between cases and controls. Cells from patients with the identified variants were then tested in vitro for their effects on type I INF production after stimulation with SARS-CoV-2. Finally, blood concentrations of the 13 types of IFN-ɑ were measured in 10 patients with the identified mutations.

Summary of Main Findings

Four patients had biallelic variants of IRF7 or IFNAR1, while 113 patients had an additional 113 monoallelic variants at 12 loci; 9 of these variants were predicted to be loss-of-function (pLOF). Compared to controls, patients with severe COVID-19 were enriched in the pLOF variants at the 13 loci associated with influenza susceptibility. Of the 118 total variants, the authors tested 113 in overexpression systems, and 24 (carried by 23 patients) were found to be deleterious. In all, 23 of the 659 patients (3.5%) carried a deficiency at one of eight loci among the 13 loci tested. In vitro stimulation with SARS-CoV-2 of cells from patients with selected genotypes found those with autosomal recessive IRF7 deficiency had impaired production of type I INF by plasmacytoid dendritic cells, and deficiencies of TLR3 or IFNAR1 impaired fibroblast-intrinsic type I INF immunity to SARS-CoV-2. Ten of the 23 patients with the identified mutations had blood samples available, and among them, IFN-ɑ levels were all below 1 pg/mL, much lower than previously published measures in other patients with severe COVID-19.

Study Strengths

This was a multi-level study; variants that were enriched in the patient population were tested for responses to SARS-CoV-2 in vitro, and concentrations of IFN-ɑ were measured in blood samples from a subset of patients. Patients were from multiple countries and were of multiple ethnicities.


Although it is biologically plausible, this study cannot establish that impaired INF type I production is responsible for severe COVID-19 among the subset of patients with the identified mutations. Patient demographic and clinical characteristics were not well described. Concentrations of IFN-ɑ were only measured in blood samples from 10 patients, all of whom had variants at the loci investigated; this limits possible inference.

Value added

This carefully conducted study suggests a mechanism for inborn susceptibility to severe COVID-19 among a subset of the population.

This review was posted on: 29 October 2020