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Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

Qian Zhang1,2,3, Daniela Matuozzo2,3, Jérémie Le Pen4

  • 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.

The Journal of Experimental Medicine
|June 16, 2022
PubMed

Insights

Inborn errors of type I interferon immunity explain critical COVID-19 pneumonia in children. These genetic conditions, particularly TLR7 deficiency, were found in 10.7% of pediatric cases, highlighting a key factor in severe SARS-CoV-2 infection.

Area of Science:

  • Immunology
  • Genetics
  • Infectious Diseases

Background:

  • Critical COVID-19 pneumonia in unvaccinated adults is linked to inborn errors of type I interferon (IFN) immunity.
  • The lower risk of severe COVID-19 in children compared to adults is not well understood.
  • Type I interferons are crucial for antiviral defense against SARS-CoV-2.

Purpose of the Study:

  • To investigate the genetic basis of severe COVID-19 pneumonia in unvaccinated children.
  • To determine if inborn errors of type I IFN immunity contribute to critical illness in pediatric COVID-19 patients.

Main Methods:

  • Analysis of an international cohort of 112 children (<16 years) hospitalized with COVID-19 pneumonia.
  • Genetic and biochemical characterization of patients with severe disease.
  • Comparison with a control group of 1,224 individuals with mild SARS-CoV-2 infection.

Main Results:

  • Twelve children (10.7%) with critical, severe, or moderate COVID-19 pneumonia had inborn errors of type I IFN immunity.
  • Identified deficiencies included X-linked TLR7 (7 children) and autosomal recessive IFNAR1, STAT2, or TYK2 (4 children).
  • These specific genetic deficiencies were absent in individuals with mild SARS-CoV-2 infection (P = 1.2 × 10-11).

Conclusions:

  • Recessive inborn errors of type I IFN immunity are a significant cause of critical COVID-19 pneumonia in children, accounting for approximately 10% of hospitalizations.
  • These genetic defects, particularly TLR7 deficiency, impair the innate immune response to SARS-CoV-2.
  • Understanding these genetic underpinnings is vital for managing severe COVID-19 in pediatric populations.

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