Figure 3 A pie chart illustrating the distribution of COVID-19 disease severity categories.
We have approached the review of clinical data regarding ”COVID-19 in the pediatric population” with meticulous care. In our study, we have adhered to the same categorization and harmonized the pooled data accordingly. Following this categorization, it appears that the disease severity in children tends to be mild or moderate. Mild cases often manifest with subtle and transient clinical features, resulting in varying proportions of asymptomatic patients across different studies. Some of these results may reflect the early stages of the COVID-19 outbreak, where more symptomatic or severe cases were reported, similar to what was observed in adults. This variation contributes to a moderate level of heterogeneity in the pooled data regarding clinical features.
Despite the generally benign nature of pediatric COVID-19 cases, there are exceptions. For instance, in one report by Chen F et al. (2020), a 1-year-old boy was classified as critical. He initially presented with vomiting and diarrhea over a period of 6 days, without apparent cough or respiratory symptoms. However, his condition rapidly deteriorated after admission, leading to shock and subsequently progressing to acute respiratory distress syndrome (ARDS), necessitating mechanical ventilation. Additionally, acute kidney injury requiring hemodialysis occurred during his hospitalization. Diagnosing such unusual presentations promptly can pose greater challenges in pediatric cases.
When compared to other viral illnesses that have caused pandemics or epidemics, the relatively small number of cases and low mortality rate in pediatric COVID-19 cases stand out as highly intriguing. In comparison to a closely related virus, SARS-CoV, it’s evident that SARS-CoV-2 leads to milder disease. While the precise factors contributing to this phenomenon are still being investigated, some of these parameters are widely acknowledged. Several factors could potentially explain this:
Absence of pre-existing baseline inflammation
In comparison to adults, children exhibit a more robust immune response and are less likely to have pre-existing medical conditions ( Singh T et al., 2020). Unlike adults, children have rarely been observed to progress to severe respiratory issues requiring intensive care (Rodriguez-Morales AJ et al., 2020). It’s worth noting that children with pneumonia often experience coinfections involving both viruses and bacteria, which may contribute to their immune memory against a broader range of pathogens. However, it remains uncertain whether this holds true for pneumonia related to SARS-CoV-2.
Furthermore, children are less prone to underlying diseases such as diabetes mellitus, chronic obstructive pulmonary disease, or cardiovascular conditions, which are more common among adults. These underlying conditions in adults may predispose them to severe COVID-19 outcomes. Nonetheless, the exact pathogenesis remains unknown. Consequently, further investigation is necessary to understand the differences in disease severity between adults and children in the context of COVID-19.
2. Multisystem inflammatory syndrome (MIS-C)
Multisystem inflammatory syndrome in children (MIS-C), which is temporally linked to COVID-19, is a newly identified, uncommon, and potentially life-threatening hyperinflammatory condition. It exhibits overlapping features with typical or incomplete Kawasaki disease and toxic shock syndrome (Riphagen S et al., 2020; Viner RM et al. 2020 ; Jones VG et al., 2020).
Furthermore, understanding the various risks associated with children can be challenging. Children in whom Coronaviruses are detected in the respiratory tract may experience viral coinfections in up to two-thirds of cases ( Heimdal I et al., 2019).
3. ACE-2 Receptors
Another highly notable hypothesis that warrants consideration regarding the lower severity risk of COVID-19 in children compared to adults is the reduced expression of cell surface enzyme angiotensin-converting enzyme 2 (ACE2) receptors in the nasal epithelia of children (Bunyavanich S et al., 2020). Since ACE2 serves as a functional receptor for SARS-CoV-2 (Li W et al., 2003), it is plausible that the limited expression of ACE2 receptors in children’s nasal epithelia contributes to a diminished viral entry, resulting in milder infections. The binding affinity of SARS-CoV-2 to ACE2 partially explains why it causes less severe disease than SARS-CoV but remains highly infectious. However, it’s important to note that this explanation doesn’t comprehensively address why children are less susceptible to severe COVID-19. Previous studies have shown that SARS-CoV induced higher ACE2 shedding than human coronavirus NL63.
The varying regulation of ACE2 receptors is closely associated with lung injury (Glowacka I et al., 2010). A study has shown that aging results in an alteration of the pulmonary renin-angiotensin system, which corresponds to increased inflammation and more pronounced lung injury in a rat model ( Schouten LR et al.,2016). It’s undeniable that smoking is a prevalent factor among adults rather than children. One hypothesis suggests that smoking elevates ACE2 expression, potentially leading to an increased entry of coronaviruses into pulmonary epithelial cells ( YH et al., 2016).