Children with inborn errors of immunity experience higher COVID-19 mortality rates
Click Here to Manage Email Alerts
Key takeaways:
- Gene defects and autoantibodies frequently affected 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 multisystem inflammatory syndrome in children have distinct inflammatory profiles compared with those children with IEI who do not have this complication.
- Children with IEI may experience more severe cases of COVID-19 and higher rates of mortality than children who do not have IEI.
Children with pre-existing inborn errors of immunity may have higher mortality rates due to COVID-19 than children who do not have these errors, according to a study published in The Journal of Allergy and Clinical Immunology.
These findings indicate a need to change the paradigm for treating children infected with SARS-CoV-2 by testing those with severe cases for primary immunodeficiencies, the researchers wrote.
“Our results indicate that basic immunological examination and genetic analysis should be conducted in children with severe COVID-19 or multi-inflammatory syndrome,” Qiang Pan-Hammarström, MD, PhD, professor in the department of biosciences and nutrition, Karolinska Institutet, Huddinge, Sweden, said in a press release.
“The clinicians will then be able to help these children with more precise therapies based on their genetic changes,” Pan-Hammarström said.
The researchers examined 31 patients with inborn errors of immunity (IEI), including six females and 25 males with a median age of 12 years (range, 5 months-19 years) who had severe or critical cases of COVID-19 in August and September 2020.
These patients all were infected with the wild type of the SARS-CoV-2 virus, and none of them had been vaccinated. Also, 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 among otherwise healthy children is approximately 0.01%, the researchers noted.
Using genomic DNA and whole-exome sequencing, the researchers identified potential 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, regulatory T-cell function, B-cell development, lymphocyte apoptosis pathway, motility of phagocytes pathway, inflammasome pathway, anti-inflammatory pathway and regulators of complement activation pathway.
Potential modifying gene defects in antiviral immunity-related pathways included the IFN pathway, 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.
Also, five patients (16.1%) presented with multisystem inflammatory syndrome in children (MIS-C), but none of them tested positive for antibodies against IFNs.
“This suggests that many children with this type of immune disease cannot produce antiviral antibodies and therefore would not have the full benefit of vaccination,” Hassan Abolhassani, MD, MPH, PhD, assistant professor of clinical immunology in the department of biosciences and nutrition, said in the press release.
Analyses of the patients’ immune responses found differences between the immunological profiles of the children with and without MIS-C, the researchers continued.
Additionally, the researchers reviewed other studies including 381 children with IEI and COVID-19 reported worldwide. Mainly, these children had Bruton tyrosine kinase or immunoglobulin G subclass deficiency, with a 23.6% severe COVID-19 rate and an 8.7% mortality rate.
Considering the high mortality rates among children with both IEI and COVID-19, the researchers recommended basic immunologic investigations and genetic evaluations for IEI among children who develop severe forms of COVID-19 or MIS-C.
The researchers also called for further studies to evaluate the importance of different virus variants and vaccines in this group of patients.
Reference:
- Higher risk of serious COVID-19 complications in children with primary immunodeficiency. https://news.ki.se/higher-risk-of-serious-covid-19-complications-in-children-with-immunodeficiency. Published Sept. 16, 2022. Accessed Sept. 19, 2022.
Perspective
Back to Top
This study confirmed that a large proportion of immunocompromised children who developed severe or critical COVID-19 had defects in innate immune pathways or in genes impacting lymphocyte development, autoinflammatory disorders and complement activity. These investigators previously demonstrated that many older adults with critical COVID-19 have autoantibodies targeting type I IFNs, but in this pediatric population, those autoantibodies were rare, and instead genetic defects in these pathways were seen.
Pediatric patients, including those who are immunocompromised, were far less likely to have severe COVID-19 than adults, but severe cases were still seen across the country, including children with MIS-C. This study indicates that these severe cases in pediatrics deserve in-depth investigation to uncover possible underlying causes.
Also, this study supports the proposal that children who develop severe or critical COVID-19 infection, particularly those with genetically undefined immunodeficiency disorders, should undergo advanced genetic evaluation for underlying diagnoses.
Providers, then, need to utilize genetic sequencing to improve diagnostics for patients with IEI and to strongly consider adjunctive therapies including antivirals and any effective monoclonal antibody therapies for patients with IEI and COVID-19 disease.
It is also notable that the patients studied, who had a dramatically elevated mortality rate, were all unvaccinated. This is strong evidence that vaccination does benefit most patients with IEI and is safe in this population. Accordingly, the importance of vaccination must be emphasized for this population as well as their caregivers and family.
Further prospective studies of severe viral illnesses in pediatric patients will be critical for determining the true prevalence of IEI in this setting.
Collapse
Read more about
Click Here to Manage Email Alerts