Keywords
coronavirus - COVID-19 - neonates - SARS-CoV-2
The novel coronavirus disease 2019 (COVID-19) pandemic, first noted in Wuhan, China,
during late 2019, has spread across the globe. Strikingly, initial reports suggest
that neonates, infants, and young children are less affected by the disease ([Fig. 1]).
Fig. 1 (A) A pie chart showing distribution of population in United states based on age as
adults (>19-year olds), pediatrics (1–18 years) and infants (<1-year olds). (B) The reported COVID-19 cases in adults, pediatrics and infant population in United
States. Blue represents adults over 19-year olds, orange represents pediatric cases
age 0–18-year olds, and gray represents infants <1-year olds. COVID-19, novel coronavirus
disease 2019.[1]
As of April 18, 2020, the COVID-19 pandemic has resulted in approximately 2.3 million
cases and over 157,000 deaths worldwide. In the United States, there have been 374,329
confirmed cases and 12,064 deaths. Twenty-two percent of United States population
is less than 18 years of age. Among the 149,082 reported cases, only 2,572 (1.7%)
were children out of which 398 (0.2%) were infants with <1-year age and a total of
three deaths have been reported.[1]
This paralleled the trend that was seen in China, where out of over 80,000 cases,
approximately 2,000 (2.5%) were under 18 years of age and 379 were infants (0.4%).
Over 90% of all patients were asymptomatic, mild, or moderate cases.[2]
Human coronaviruses were discovered in the 1960s by researchers studying the etiology
of upper respiratory infections (URIs) in children and young adults. The human coronaviruses
cause 15 to 35% of URIs depending on the specific year.[3] Mostly respiratory tract infections affect pediatric and geriatric population more
severely than the younger adults. Centers for Disease Control and Prevention (CDC)
estimated the overall cumulative hospitalization rate from influenza was 68 per 100,000
population across all age groups in the United States and 94 per 100,000 in 0 to 4
year age group. A total of 162 influenza-associated deaths in children have been reported
so far this season.[4] The flu vaccine reduced children's risk of flu-related pediatric intensive care
unit (PICU) admission by 74% during flu seasons.[5]
Lessons Learnt from other Coronavirus-Associated Diseases: SARS and MERS
Lessons Learnt from other Coronavirus-Associated Diseases: SARS and MERS
Prior to the past two decades, the four circulating species of coronaviruses associated
with human disease were known to be a significant cause of the common cold and other
mild URIs. More severe lower respiratory infections (LRIs) were associated with the
recent zoonotic crossovers of the severe acute respiratory syndrome (SARS)-associated
coronavirus (SARS-CoV) identified in 2002 and Middle East respiratory syndrome coronavirus
(MERS-CoV) identified in 2012.
A notable feature of the 2003 global SARS outbreak was the relative paucity of infections
among children. In a published review of case series, the authors noted the absence
of mortality in children and adolescents. In particular, children under 13 years of
age had milder disease, no mortality, and only mild residual changes in exercise tolerance
and pulmonary function at 6 months after resolution of illness.[6] It was suggested that prior exposure to other respiratory viruses, making their
immune systems more resilient, and inability to mount a mature immune response during
the immune dysregulation phase of SARS and thus less organ damage was associated with
low morbidity and mortality in children.[7]
As of November 2019, World Health Organization (WHO) reported a total of 2,494 laboratory-confirmed
cases of MERS including 858 associated deaths (case–fatality rate: 34.4%) globally.
A review of pediatric cases through April 2016 revealed only 31 pediatric cases representing
roughly 1% of cases known at the time. Only 18 were symptomatic and there was one
death reported in a child with cystic fibrosis. The authors postulated a variety of
explanations for lower case numbers in children including lower exposure rates, less
symptomatic cases, and the presence of yet to be identified factors.[8]
COVID-19: Why Are Young Children and Infants Not Severely Affected?
COVID-19: Why Are Young Children and Infants Not Severely Affected?
Many theories have been postulated to explain this remarkable difference in the pediatric
and adult population with COVID-19. Besides the various lifestyle factors (less overall
and lifetime exposure to smoke or pollution, better nutrition, and more daily exercise),
children have other specific advantages that might limit disease progression following
SARS-CoV-2 infection ([Fig. 2]).
Fig. 2 A schematic showing possible factors resulting in low incidence and less severity
of coronavirus disease (COVID-19) in pediatric age group. Children in generally have
healthier lungs and are less exposed to smoke and pollution. The maturity, binding
ability and function of Angiotensin converting enzyme (ACE2) receptors required by
severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2) to enter the cells, is
lower in children resulting in minimal lung injury. More extensive exposure to other
viruses may provide cross immunity to SARS-COV2. A cytokine storm or systemic inflammatory
response syndrome that results in inflammation and fluid buildup leading to respiratory
distress is not well developed in children. More efficient T-cells response in children
may be another reason for superior outcomes. SARS-CoV-2 proteins appear to attack
β hemoglobin chains and “capture” porphyrins inactivating gas exchange capabilities
of hemoglobin (Hb) and interfering with heme anabolic cycle. Young infants, with fetal
Hb (α2γ2) without β chains, may potentially be less susceptible to SARS-CoV-2 mediated
effects on Hb. Image courtesy: Satyan Lakshminrusimha.
Role of Angiotensin-Converting Enzyme 2
Like SARS-CoV and coronavirus NL63, recent evidence indicates that entry of SARS-CoV-2
into cells requires the presence of angiotensin-converting enzyme 2 (ACE2) protein.[9] ACE2 receptors are expressed in human airway epithelia, as well as lung parenchyma.
Of note, undifferentiated cells expressing little ACE2 were found to be poorly infected
with SARS-CoV, while well-differentiated cells expressing more ACE2 were readily infected.[10] ACE2 is less mature in young children and thus may not function properly as a receptor
for SARS-CoV-2.[11] In addition, the intracellular response induced by ACE2 in the alveolar epithelial
cells of children may be lower than that of adults. ACE2 are more abundant on cells
of the lower respiratory tract,[12] which is typically the site of severe COVID-19 disease. Consistent with this observation,
recent data indicate that children experience more SARS-CoV-2 infections in the upper
respiratory tract than the lower respiratory tract.[13]
Fetal Hemoglobin
SARS-CoV-2 virus proteins (orf1ab, ORF10, and ORF3a) have been shown to attack the
heme on the 1-β chain of hemoglobin to dissociate the iron to form porphyrin.[14] This attack not only reduces hemoglobin leading to hypoxia but also inhibits the
normal metabolic pathway of heme. Liu and Li suggest that this mechanism moreover
interferes with the normal heme anabolic pathway in the human body causing disease.
Newborn infants have up to 80% fetal hemoglobin, made of alpha and gamma chain, which
may be protective against the coronavirus.[15] However, this explanation does not explain the low incidence of severe disease in
older children.
Cross-Immunity with Other Viral Agents
Acquired immunity with other viruses, including other coronaviruses, may be protective
to the pediatric population. A study investigating the presence of short-lived relative
cross-protection conferred by specific prior viral infections against subsequent febrile
respiratory illness showed that adenovirus-positive participants tended to be protected
against subsequent infection with adenovirus, coronavirus, enterovirus, rhinovirus,
and influenza virus.[16] On an average, children up to 6 years old can have 8 to 12 URIs per year in comparison
to adolescents and adults who average 2 to 4 URIs per year.[17] Severity of SARS-CoV-2 infection in infants with more likelihood of hospitalization
as compared with toddlers and young children[2] may be explained by the fact that infant's humoral immunity is initially dependent
on maternal immunoglobulins.
Obtunded Systemic Inflammatory Response Syndrome
A cytokine storm or systemic inflammatory response syndrome is an overproduction of
immune cells and their activating compounds associated with a surge of activated immune
cells into the lungs resulting in inflammation and fluid buildup that can lead to
respiratory distress and can be contaminated by a secondary bacterial pneumonia. This
increases the risk of mortality in patients.[18] This response is underdeveloped in children[19] and could explain the recently published CDC data where only 54% pediatric cases
had cough as compared with 80% in adults.[20] Shortness of breath was also much lower in children compared with adults (13 vs.
43%).[1] Clinical observations in Wuhan, China, have confirmed that the absolute number of
peripheral blood lymphocytes in adult patients progressively declines during the inflammatory
response to SARS-CoV-2, which could help the virus to proliferate and spread. The
white blood cell count and the absolute number of lymphocytes in pediatric cases were
found to be generally normal, which may be related to the incomplete development of
natural immunity.[2]
Differences in Humoral Immunity
The use of convalescent serum containing neutralizing antibodies has been used previously
in SARS-CoV and MERS and was recently reported in a small cohort for SARS-CoV-2.[21] However, several studies imply certain antibody responses may contributed to pathology.[22] In a SARS-CoV macaque model, antibodies against the Spike protein were shown to
contribute to lung injury. In the feline infectious peritonitis virus, antibodies
against the spike protein contributed to enhancement of infection.[23] Higher neutralizing antibody titers against even SARS-CoV-2 have been correlated
with lymphopenia and elevated C-reactive protein; however, this may simply represent
increased immune stimulation from more severe illness.[24] Because of differences in infectious history, children may use more favorable immunoglobulin
isotypes or have improved antibody focused targeting to SARS-CoV-2.
More Efficient T-cells
Day et al. showed that T-cells are especially important in clearing viruses from mice
infected with SARS-CoV.[25] Another study in mice also stressed the importance of CD4+ helper T-cells, which
stimulate B-cells to make antibodies against pathogens, in controlling SARS-CoV infection.[26] In children, the young immune system and its efficient T-cells may potentially perform
a superior job of responding to SARS-CoV-2. T-cell subsets also undergo dynamic changes
between younger children and adolescents, particularly with declining T regulatory
cells and increasing memory cells.[27]
Asymptomatic but Effective Carriers
Asymptomatic but Effective Carriers
The incubation period of COVID-19 has been reported in the range of 0 to 24 days.[28] Studies have shown asymptomatic and presymptomatic carrier transmission of the disease.[29]
[30] In the United States, 27% of the pediatric cases that tested positive were asymptomatic,
while only 7% of adults were asymptomatic as stated by CDC. An observational cohort
study in Zhejiang, China, reported 28% asymptomatic carriers among exposed children
as well.[31] Another study in Shenzhen, China, validated that children are at similar risk of
infection as the general population, and less likely to have severe symptoms.[32] These asymptomatic and mildly symptomatic children may play a major role in the
spread of SARS-CoV-2 in the community and hence social distancing may be crucial to
reduce the rate at which the pandemic spreads across the world. CDC recommends limiting
a child's contact with older adults and people with chronic medical conditions.
Conclusion
Coronavirus leaves young children and neonates with minimal or no symptoms (a silver
lining). This continued mystery may point to vital clues regarding both viral function
and optimal immune system targeting. The milder and more often asymptomatic childhood
presentations of SARS-CoV-2 may contribute to increased transmission of the virus
to vulnerable adults (a black cloud). Studies in this area can help the researchers
to develop prophylactic and therapeutic strategies to combat this deadly disease.
