"Most children with COVID-19 have no or only mild symptoms, most commonly fever, cough, sore throat and changes in sense of smell or taste," said Nigel Curtis, PhD, leader of the Infectious Diseases Research Group at the Murdoch Children's Research Institute and professor at the University of Melbourne, in a statement. "Even children with the usual risk factors for severe infections, such as immunosuppression, were not at high risk of severe COVID-19 disease."

The infection pattern of SARS-CoV-2 is different from that of infection with most other respiratory viruses (respiratory syncytial virus [RSV], metapneumovirus, parainfluenza or influenza viruses to name a few) for which the prevalence and severity are both higher in children.

Some studies have indicated that children are just as likely as adults to become infected with SARS-CoV-2, while others indicated that children are less likely to become infected after contact with the virus. Additional researchers have even suggested that children carry similar viral loads as adults, while not being symptomatic, pointing to an increased risk of transmission among children.

Therefore, whether children are less often infected by SARS-CoV-2 is an ongoing debate. Also, if they are less often infected, why is this so?

Differences in endothelium

SARS-CoV-2 can infect endothelial cells (lining blood vessels) and with the impact of angiogenesis can lead to heart attacks and strokes. This can explain why individuals with diabetes and hypertension are at greater risk for severe COVID-19. The endothelium in children is less "predamaged" compared with adults and the coagulation system makes children less prone to abnormal clotting.

"We know pre-existing blood vessel damage plays an important role in COVID-19 severity and can lead to blood clots," Curtis said. "COVID-19 can infect these endothelial cells and cause blood vessel inflammation. The endothelium in children has experienced far less damage compared with adults and their clotting system is also different, which makes children less prone to abnormal blood clotting."

Differences in immunity

"Children have a stronger innate immune response, which is the first-line defense against COVID-19," said Dr. Petra Zimmermann, PhD from the University of Fribourg. "Another important factor is 'trained immunity' which primes innate immune cells after mild infections and vaccinations, leading to a type of 'innate immune memory'. Children infected with COVID-19 often have co-infections with other viruses. Recurrent viral infections could lead to improved trained immunity, making kids more effective at clearing COVID-19."

Children generally have a stronger innate immune response, including higher levels of natural killer cells. Children also have a higher proportion of lymphocytes and absolute numbers of T and B cells, compared to adults. The frequent state of infection in children could also enhance activation of the innate immune system, making it easier to clear SARS-CoV-2.

Children have higher levels of nonneutralizing cross-reactive human coronavirus antibodies and lower levels of neutralizing antibodies compared to adults. The high levels of neutralizing antibodies have been known to cause antibody-dependent enhancement, leading to higher viral loads and more severe COVID-19 in older adults.

The authors also pointed out that more recent immunization with live vaccines, such as with the measles, mumps, and rubella (MMR) vaccine, could boost the immune system and might play a role in protecting children.

Differences in microbiota

According to the authors, another potential explanation for less severe disease in children is differences in their respiratory and gastrointestinal microbiota.

"The microbiota plays an important role in the regulation of immunity, inflammation and in the defense against illnesses," Zimmermann said. "Children are more likely to have viruses and bacteria, especially in the nose, where these bugs might limit the growth of COVID-19."

Children are more heavily colonized with viruses and bacteria than adults, especially in the nasal cavity where microbial interactions and competition may prevent the growth of SARS-CoV-2. In terms of gastrointestinal microbiota, children usually have greater numbers of Bifidobacterium, which may reduce the presence of SARS-CoV-2 in the gastrointestinal tract. However, the authors cautioned that differences in microbiota can be influenced by many different factors and are difficult to pinpoint.

The researchers closed by stating that unraveling the mechanisms underlying age-related differences in the severity of COVID-19 will provide insights for the prevention and treatment of SARS-CoV-2.

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