Children with inborn errors of immunity experience higher COVID-19 mortality rates

September 23, 2022

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The central theses:

  • Gene defects and autoantibodies commonly impair interferon signaling, T and B cell function, the inflammasome, and the complement system in children with inborn errors of immunity (IEI) and COVID-19.
  • Children with IEI and pediatric multisystem inflammatory syndrome have different inflammatory profiles compared to children with IEI who do not have this complication.
  • Children with IEI may experience more severe cases of COVID-19 and higher mortality rates than children without IEI.

Children with pre-existing congenital immunity defects may have higher mortality rates from COVID-19 than children who do not have the defects, according to a study published in The Journal of Allergy and Clinical Immunology.

These findings suggest a need to change the paradigm for treating children infected with SARS-CoV-2 by testing those with severe cases for primary immunodeficiency, the researchers wrote.

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child in a hospital bed
Courtesy: Adobe Stock

“Our results indicate that basic immunological testing and genetic analysis should be performed in children with severe COVID-19 or multiinflammatory syndrome.” Qiang Pan-HammarstrOm, MD, PhD, Professor in the Department of Life Sciences and Nutrition, Karolinska Institutet, Huddinge, Sweden, said in a press release.

“Clinicians will then be able to help these children with more precise therapies based on their genetic changes,” Pan-Hammarström said.

The researchers studied 31 patients with congenital immunodeficiencies (IEI), including six women and 25 men, with a mean age of 12 years (range 5 months to 19 years), who had severe or critical cases of COVID-19 in August and September 2020.

These patients were all infected with wild-type SARS-CoV-2 virus and none of them had been vaccinated. In addition, 26 (83.8%) had been admitted to the ICU with symptoms related to COVID-19 and 11 (35.4%) died due to COVID-19 complications. The mortality rate for COVID-19 in otherwise healthy children is about 0.01%, the researchers found.

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Using genomic DNA and whole exome sequencing, researchers identified possible genetic causes behind the IEI in 28 (90.3%) patients.

These causes included genetic defects in the interferon (IFN) pathway, T cell development/epigenetic regulation, T cell regulatory function, B cell development, lymphocyte apoptosis pathway, phagocyte pathway motility, inflammasome pathway, anti-inflammatory pathway and regulators of the complement activation pathway.

Potential modifying gene defects in signaling pathways associated with antiviral immunity included IFN signaling, lymphocyte development/epigenetic regulation, DNA repair, IL-1/inflammasome activation, nuclear factor kappa B activation, and autoinflammatory responses.

According to the researchers, 14 (66%) of the patients had detectable virus-specific antibodies and two (6.8%) had autoantibodies that neutralize type I IFNs.

In addition, five patients (16.1%) presented with multisystem inflammatory syndrome in children (MIS-C), but none of them tested positive for antibodies to IFNs.

“This suggests that many children with this type of immune disorder are unable to produce antiviral antibodies and therefore would not get the full benefit of vaccination,” HAssan AbolhassaniMD, km/h, PhD, Assistant Professor of Clinical Immunology in the Department of Life Sciences and Nutrition, said in the press release.

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Analysis of the patients’ immune responses revealed differences between the immunological profiles of the children with and without MIS-C, the researchers continued.

In addition, the researchers reviewed other studies including 381 children with IEI and COVID-19 that were reported around the world. Mainly, these children had Bruton’s tyrosine kinase or immunoglobulin G subclass deficiency with a severe COVID-19 rate of 23.6% and a mortality rate of 8.7%.

Given the high mortality rates in children with IEI and COVID-19, the researchers recommended basic immunological testing and genetic testing for IEI in children who develop severe forms of COVID-19 or MIS-C.

The researchers also called for further studies to assess the importance of different virus variants and vaccines in this patient population.


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