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).