SARS-CoV-2, Children, and Multi-Inflammatory Syndrome

October 1, 2021

With the advent of the school year and children returning to in-person classes, there comes a concern over consequences with respect to the spread of the highly contagious Delta variant. It has been accepted that children are not as susceptible to viral infection and severe illness as adults. However, the current prevalence of the Delta variant is producing different outcomes. Furthermore, vaccines are not yet approved for children under 12. How much do we know about the effect of the Delta variant on disease outcomes with children?

Rising Infections in Children

For the week of 8/26/21 to 9/2/21, about 250,000 children in the USA were infected with SARS-CoV-2. This is the highest rate since the start of the pandemic, although most infected children had only mild symptoms. Hospitalization rates rose five-fold among children and adolescents during late June to mid-August 2021. It appears that children may be at a somewhat greater risk than was previously thought. A possible reason could be, of course, that they are not vaccinated yet. Importantly, it has been suggested that infection with the Delta variant is causing enhanced disease severity and hospitalization rates, but this point has not yet been fully established. Besides the usual risk factors (obesity, diabetes, etc.), an age <3 months has been predictive for requiring respiratory support(1).

Child vs. Adult Immune Response

Overall, deaths among children and young people remain extremely rare(2-4). A recent study showed that infants through teenagers could have high viral loads, especially soon after being infected. The basis for greater protection is unclear, but may have to do with differences in innate immunity between children and adults. Children respond to infection with greater expression of IL-17A and INFγ(5). It has been postulated that the children mounted a less robust adaptive immune response because their innate response was more efficient at eliminating the threat. In fact, adults have higher levels of neutralizing antibodies, but these antibodies appear to differ between adults and children(6). Specifically, adults have more class-switched antibodies while children have higher Fc responses. This suggests that children have less pre-exposure to other coronaviruses, allowing them to make antibodies that are more narrowly tailored to SARS-CoV-2. However, it has been reported that perhaps as many as 10% of infected children experience “long covid”, persistent symptom lasting at least months, although again, children’s cases are lower than those of adults.

For the week of 8/26/21 to 9/2/21, about 250,000 children in the USA were infected with SARS-CoV-2. This is the highest rate since the start of the pandemic, although most infected children had only mild symptoms.

It has been postulated that the children mounted a less robust adaptive immune response because their innate response was more efficient at eliminating the threat. In fact, adults have higher levels of neutralizing antibodies, but these antibodies appear to differ between adults and children(6).

There is a potential life-threatening consequence of viral infection in children, called multisystem inflammatory syndrome (MIS-C)(7). MIS-C often occurs 4-6 weeks after developing mild or symptomatic Covid-19.

Multisystem Inflammatory Syndrome (MIS-C)

There is a potential life-threatening consequence of viral infection in children, called multisystem inflammatory syndrome (MIS-C)(7). MIS-C often occurs 4-6 weeks after developing mild or symptomatic Covid-19, and is marked by shock, cardiac dysfunction (including aneurisms), elevated inflammatory markers, and abdominal pain(8, 9). MIS-C often requires care in an ICU and can result in death. It is marked by immune activation similar to what is seen in severe Covid-19 in adults, including production of high levels of antibodies to the S protein. However, this can be transient, and the clinical course improves as immune activation decreases(10). MIS-C is clinically heterogeneous, which is characterized by high levels of IFN-γ and severe cases (11).

Recently, interest has focused on an elevated expression of S100A-family alarmins in MIS-C, and expression levels correlated with disease severity(12). There was also a correlation with elevated expression of cytotoxicity-related genes in NK and CD8+ T cells. Alarmins are peptides released by degranulation following cell injury or death(13). They function as intracellular mediators by acting as ligands for pattern recognition receptors, which leads to activation of host immune activities. However, overexpression can lead to detrimental effects, including cytokine storms. The S100 group of alarmins are cytosolic calcium-binding proteins that, when released by cell stress or damage, serve as danger signals(14). It is tempting to speculate that excess expression of extracellular alarmins contribute to the inflammatory nature of MIS-C.

Conclusion

It is clear that children are less susceptible to severe cases of COVID-19. However, children are readily exposed to the circulating Delta variant. Data from clinical trials of mRNA vaccines are showing convincing results for vaccination of children under 12, but this has not yet been approved by FDA. Also, one must consider the need to vaccinate low-income countries. In fact, other interventional strategies, such as masking, physical distancing, and regular testing, can effectively protect children against currently circulating variants and can further mitigate the community transmission of variants.

References

1. K. Graff et al., Risk Factors for Severe COVID-19 in Children. Pediatr Infect Dis J 40, e137-e145 (2021).
2. R. Harwood et al., Which children and young people are at higher risk of severe disease and death after SARS-CoV-2 infection: a systematic review and individual patient meta-analysis. medRxiv, 2021.2006.2030.21259763 (2021).
3. C. Smith et al., Deaths in Children and Young People in England following SARS-CoV-2 infection during the first pandemic year: a national study using linked mandatory child death reporting data. medRxiv, 2021.2007.2007.21259779 (2021).
4. J. L. Ward et al., Risk factors for intensive care admission and death amongst children and young people admitted to hospital with COVID-19 and PIMS-TS in England during the first pandemic year. medRxiv, 2021.2007.2001.21259785 (2021).
5. C. A. Pierce et al., Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Sci Transl Med 12, (2020).
6. K. J. Selva et al., Systems serology detects functionally distinct coronavirus antibody features in children and elderly. Nat Commun 12, 2037 (2021).
7. L. R. Feldstein et al., Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med 383, 334-346 (2020).
8. S. Godfred-Cato et al., COVID-19-Associated Multisystem Inflammatory Syndrome in Children – United States, March-July 2020. MMWR Morb Mortal Wkly Rep 69, 1074-1080 (2020).
9. E. Whittaker et al., Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA 324, 259-269 (2020).
10. L. A. Vella et al., Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci Immunol 6, (2021).
11. C. Diorio et al., Proteomic Profiling of MIS-C Patients Reveals Heterogeneity Relating to Interferon Gamma Dysregulation and Vascular Endothelial Dysfunction. medRxiv, (2021).
12. A. Ramaswamy et al., Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children. Immunity 54, 1083-1095 e1087 (2021).
13. Yang, Z. Han, J. J. Oppenheim, Alarmins and immunity. Immunol Rev 280, 41-56 (2017).
14. C. Xia, Z. Braunstein, A. C. Toomey, J. Zhong, X. Rao, S100 Proteins As an Important Regulator of Macrophage Inflammation. Frontiers in Immunology 8, (2018).