Section 5: Potential explanation for the difference between children and adults in COVID-19 (from DOI: 10.1016/j.clim.2020.108427)

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Article	COVID-19 pathophysiology: A review (DOI: 10.1016/j.clim.2020.108427)
Sections in this Publication
Section	Section 1: Introduction (from DOI: 10.1016/j.clim.2020.108427)
Section	Section 2: Epidemiological data of COVID-19 (from DOI: 10.1016/j.clim.2020.108427)
Section	Section 3: Mechanism of SARS-CoV-2 invasion into host cells (from DOI: 10.1016/j.clim.2020.108427)
Section	Section 4: Host response to SARS-CoV-2 (from DOI: 10.1016/j.clim.2020.108427)
Section	Section 5: Potential explanation for the difference between children and adults in COVID-19 (from DOI: 10.1016/j.clim.2020.108427)
Section	Section 6: Conclusions (from DOI: 10.1016/j.clim.2020.108427)
Section	Financial support (from DOI: 10.1016/j.clim.2020.108427)
Section	Declaration of Competing Interest (from DOI: 10.1016/j.clim.2020.108427)
Section	References (from DOI: 10.1016/j.clim.2020.108427)
Named Entities in this Section
Entity	Severe acute respiratory syndrome-related coronavirus (species)
Entity	Memory Disorders (disease - MeSH descriptor)
Entity	Multiple Organ Failure (disease - MeSH descriptor)
Entity	Respiratory syncytial virus (species)
Entity	Orthomyxoviridae (species)
Entity	angiotensin I converting enzyme 2 (gene)
Entity	angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (gene)
Entity	CD8a molecule (gene)
Entity	CD28 molecule (gene)
Entity	CD27 molecule (gene)
Entity	Human (species)
Entity	2019 novel coronavirus (species)
Entity	Respiratory Infection (disease - MeSH descriptor)
Entity	Infections (disease - MeSH descriptor)
Entity	Cardiac Death (disease - MeSH descriptor)
Entity	Acute Respiratory Distress Syndrome (disease - MeSH descriptor)
Dataset	Pubtator Central BioC-JSON formatted article files

From publication: "COVID-19 pathophysiology: A review" published as Clin. Immunol.; 2020 Apr 20 108427. DOI: https://doi.org/10.1016/j.clim.2020.108427

Section 5: Potential explanation for the difference between children and adults in COVID-19

Infants and young children are typically at high risk for admission to hospitals due to respiratory tract infection with viruses as respiratory syncytial virus and influenza virus. In contrast, pediatric COVID-19 patients have relatively milder symptoms in general compared to elder patients. The reason for this difference between children and adults remains elusive. Because the recent report suggested the correlation between the severity of COVID-19 and the amount of viral loads (or the duration of virus-shedding period), children may have less virus loads even if they get COVID-19. In this line, a couple of hypotheses can be considered.

The first possibility is that the expression level of ACE2 may differ between adults and children. A previous study showed that ACE2 was more abundantly expressed on well-differentiated ciliated epithelial cells. Human lung and epithelial cells continue to develop following the birth. ACE2 expression may be lower in pediatric population. From the lung gene expression analysis portal (https://research.cchmc.org/pbge/lunggens/mainportal.html), ACE2 expression in mice increased around at birth (Fig. 2 ). Its expression reduced till around P10, then increased. Because infants were susceptible to severe disease among children, this pattern may be in line with patients' clinical picture. In addition, gender may also affect ACE2 expression. ACE2 gene is located on the X-chromosome. Circulating ACE2 levels are higher in men than in women. This may be in part responsible for the difference in severity and mortality between men and women both in the adult and the pediatric population.

The second possibility is that children have a qualitatively different response to the SARS-CoV-2 virus to adults. With ageing, continuous antigen stimulation and thymic involution lead to a shift in T cell subset distribution from naive T cells to central memory T cells, effector T cells and effector memory T cells. This process is accompanied by the loss of expression of co-stimulatory molecules such as CD27 and CD28, with increased susceptibility to infections. Whether the appearance of pathological T cells in adult patients with severe COVID-19 diseases is due to the compensation for this fundamental ageing process or not is unclear. At the early stage after birth, CD4+ T cells are impaired in production of Th1 associated proinflammatory cytokines and skewed toward Th2. CD8+ T cells reduced expression of cytotoxic and inflammatory mediators. Less killing ability by T cells at early stage after birth may explain susceptibility to SARS-CoV-2 in infants. The study comparing aged and young macaques infected with SARS-CoV showed that aged macaques had more robust proinflammatory responses with worse lung pathology. A similar result was reported using aged and young mice infected with SARS-CoV. Severe COVID-19 infection is characterized by a massive proinflammatory response or cytokine storm that results in ARDS and multi-organ dysfunction (MODS). It has been also suggested that inflammatory responses in adults and children are much different. Ageing is associated with increasing proinflammatory cytokines that govern neutrophil functions and have been correlated with the severity of ARDS. So far there is no animal model for SARS-CoV-2, but we expect to see a preclinical model in the future.

The third possibility is that the simultaneous presence of other viruses in the mucosa lungs and airways, common in young children, can let SARS-CoV-2 virus compete with them and limit its growth. At this point, we do not have study testing various viruses along with SARS-CoV-2 to determine this possibility.

Rather a combination of these possibilities may explain pediatric and adult COVID-19 phenotypes. Understanding why children in general are less susceptible to severe COVID-19 would help to design immunotherapy to eradicate this virus.