Genetic and immunological evaluation of children with inborn errors of immunity and severe or critical COVID-19

J Allergy Clin Immunol. 2022 Sep 13;S0091-6749(22)01185-X. doi: 10.1016/j.jaci.2022.09.005. Online ahead of print.


Background: Most SARS-CoV-2 infected individuals are asymptomatic or only show a mild disease. In about 10% of cases, the infection leads to hypoxemic pneumonia, although it is much more rare in children.

Objective: We evaluated 31 young patients (0.5-19 years) who had pre-existing inborn errors of immunity (IEI) but lacked a molecular diagnosis and were later diagnosed with COVID-19 complications.

Methods: Genetic evaluation by whole-exome sequencing was performed in all patients. SARS-CoV-2 specific antibodies, autoantibodies against type I interferons (IFNs) and inflammatory factors in plasma were measured. We also reviewed COVID-19 disease severity/outcome in reported IEI patients.

Results: A potential genetic cause of the IEI was identified in 28 patients (90.3%), including mutations that may affect IFN signaling, T and B cell function, the inflammasome, and the complement system. Fourteen of the patients tested (66%) had detectable virus-specific antibodies and two patients (6.8%) had autoantibodies neutralizing type-I IFNs. Five patients (16.1%) fulfilled the diagnostic criteria of multisystem inflammatory syndrome in children (MIS-C). Eleven patients (35.4%) died due to COVID-19 complications. Altogether at least 381 IEI children with COVID-19 have been reported in the literature till date. Although many asymptomatic or mild patients may not have been reported, severe presentation of COVID-19 was observed in 23.6% of the published cases and the mortality rate was 8.7%.

Conclusion: Young patients with pre-existing IEI may have a higher mortality as compared to children without IEI when infected with SARS-CoV-2. Elucidating the genetic basis of IEI patients with severe/critical COVID-19 may help to develop better strategies for prevention and treatment of severe COVID-19 disease and complications in pediatric patients.

Keywords: COVID-19; Inborn errors of immunity; SARS-CoV-2; genetic diagnosis; immune response; multisystem inflammatory syndrome in children (MIS-C); primary immunodeficiency.