Bali Pulendran, a professor of microbiology, immunology, and pathology at Stanford University, has researched a mystery unique to COVID-19 for two years.
“For almost every infectious disease, the most vulnerable populations are at the extremes of age—the very young and the very old,” he once said. “But with COVID-19, the young are spared.”
The picture surrounding this enigma is still incomplete, but answers are forthcoming.
Children Are Different
Children are not mini-adults. Depending on their age, they can have similar or very different responses to infectious diseases.
In the case of COVID-19, children generally experience a milder form of the disease.
“It’s an interesting question that no one has fully answered,” said Dr. Cody Meissner, a professor of paediatrics at Dartmouth College’s Geisel School of Medicine, in an interview with sources. “Several theories have been put forward to try and explain this.”
The primary reason is that children have a faster innate immune system, often referred to as the first line of defence, compared to adults. This enables them to mount a robust defence against respiratory infections more quickly.
Another explanation is that children are more susceptible to respiratory infections, and some of these prior infections may provide them with a degree of immune protection against COVID-19.
Anatomically speaking, children who are not fully grown are at a disadvantage when exposed to respiratory diseases. They have smaller airway diameters, meaning more severe symptoms when the airways get inflamed or have mucus buildup.
They also have a smaller lung capacity, making them more susceptible to hypoxia and respiratory infections, professor of immunology Kenneth Rosenthal, PhD, told sources.
However, compared to adults, children have been found to have higher levels of innate immune cells in the nose, which can help eliminate viruses early on.
“SARS-CoV-2 targets ACE-2 and TMPRSS, and these are expressed more in older adults,” Dr. Lael Yonker, paediatric pulmonologist and the co-director of Massachusetts General Hospital’s pulmonary genetics clinic, told sources. Children, in comparison, have fewer of both receptors, which may reduce the number of viral invasions.
Strong Innate Immunity
While children tend to have a fast and robust innate immune response, studies have found that most adults who experience severe COVID-19 tend to have an impaired innate immune response.
The innate immune response is the immune system we inherit when we are born.
“[The immune response is] always there and ready to respond to microbes and triggers on the fly,” Mr. Rosenthal explained. In contrast, the adaptive immune system, which is more developed in adults, can generate more memorised, targeted immunity. However, it is slower to respond and can take days to activate.
This is not to say that children do not have an adaptive immune response. But since this type of immunity is built up by experiences with viruses and other pathogens, children tend to have accumulated less immunological memory than adults.
Vaccination is primarily used to bolster adaptive immunity while children are young.
The most common innate protection impairment researchers saw in adults with severe COVID-19 was a deficit in types 1 and 3 interferons. Studies have shown that children mount the strongest types 1 and 3 interferon responses to COVID-19, and this response diminishes as people age.
“A large proportion of adult men prone to more serious COVID have antibodies to interferon,” Mr. Rosenthal said. Consequently, they cannot mount the initial innate response, though scientists do not know why some adults form these antibodies.
The infection progresses unhindered while the immune system attempts to restrain the extensive infection, which could “lead to problematic outcomes,” he added.
This can cause full-blown inflammatory responses.
Natural killer cells, innate immune cells responsible for killing cancer and infected cells, are also more active in children, particularly pre-pubescent children. The cell “dissipates in teen years,” Mr. Rosenthal said.
Less Prone to Inflammatory Storm
A significant risk factor for severe COVID-19 is the inflammatory cytokine storm caused by excessive levels of cytokines in the body.
During an infection, immune cells release cytokines to help activate and coordinate other immune cells. There is always some presence of them in the body.
When the immune system fails to control the infection and viruses replicate, immune cells dispatch more cytokines as a warning. These cytokines then activate more immune cells, causing intense inflammation, which can lead to tissue damage, organ failure, and eventually death.
Adults are more prone to cytokine storms because they tend to have more cytokines in the blood, meant to protect their bodies against daily assaults. These include smoke, toxic particles, toxic foods, and certain bacteria that live in our gut, on our skin, or elsewhere, Mr. Rosenthal said. The necessary protective responses produce inflammatory cytokines “on an everyday, routine basis.”
Children, however, have lower baseline cytokine levels due to fewer exposures to environmental and pathogenic assaults. Plus, they generally have healthier constitutions with fewer chronic diseases and unhealthy habits.
Even in the rare case of children developing severe COVID-19, which often presents as multisystem inflammatory syndrome in children (MIS-C), most children quickly recover without any persistent symptoms.
“[Children] were easier to treat than adults. I did not lose a single [paediatric] case, whereas adults, we were losing quite a bit of them,” critical care pulmonologist Dr. Joseph Varon, professor of clinical medicine at the University of Houston, told sources.
While mild COVID-19 in children and adolescents can be explained away by their fast innate immune systems and generally healthier constitutions, this explanation fails concerning infants and toddlers.
“It’s one of the great mysteries of human immunology,” Mr. Pulendran told sources.
Infants are typically born with immature innate and adaptive immune systems and weaker constitutions, making them more susceptible to infections. Premature infants are even more vulnerable.
Children under the age of 2 have a much higher chance of dying from respiratory diseases like respiratory syncytial virus (RSV) and influenza than older children and adults under the age of 50.
In general, infants “do not have any prior immune history and, therefore, no antibodies or T-cell memory to rapidly respond to the challenge,” Mr. Rosenthal said. They also have very few innate immune cells at birth. By the second month of life, they should accumulate enough innate immune cells to overcome this vulnerability.
Full maturation of the immune system occurs in the first seven to eight years of life.
Dehydration is also a deadly factor in infected children and infants due to their higher metabolic rates and reduced water reserves compared to adults.
Yet, to researchers’ amazement, infants were largely left unscathed during the COVID pandemic.