Why Children Typically Experience Milder Symptoms of Covid-19 Than Adults
A pediatrician explains how kids can crush the novel coronavirus with the strength of their innate immune system.
Epidemiological data indicates the severity of Covid-19 is strongly correlated with age. However, the reason children typically exhibit milder symptoms than adults remains unclear. A study published earlier this year in Nature Communications by Dr. Melanie Neeland and colleagues shed light on this mystery by analyzing detailed features of the immune response to Covid-19 in a cohort of 48 children compared to 70 adults.
The study took place in Melbourne, Australia from April to August of 2020 and investigated non-hospitalized patients most of whom experienced mild symptoms of Covid-19 such as fever, cough, sore throat, muscle aches, and fatigue. Blood samples were collected in patients who had either tested positive for the novel coronavirus, SARS-CoV-2 or had a known household exposure but repeatedly tested negative. These blood samples were obtained at two distinct time points — during the acute phase (i.e. within a few days of diagnosis or exposure) and the convalescent phase (i.e. 4–7 weeks after diagnosis or exposure). Testing for SARS-CoV-2 was performed by a nasal swab and analyzed by polymerase chain reaction (PCR).
Innate versus adaptive immunity
Before discussing the study’s findings, it’s important to understand each branch of the army that comprises the body’s immune system. The first branch is called the innate immune system. To borrow a military analogy I’ve used in the past, the cells of the innate immune system are the frontline foot soldiers in the defense against pathogens. They are able to attack foreign invaders quickly but in a nonspecific fashion. The release of inflammatory particles by the innate immune system is akin to heaving grenades. While useful to respond to the initial assault, such a broad attempt to destroy the enemy virus cannot continue for long without risking collateral damage to the body’s own organs and tissues.
Conversely, cells of the adaptive immune system are like snipers. These cells receive classified information about their adversary in the form of an antigen, a viral protein segment recognized as foreign by the adaptive immune cells. After gathering this intelligence, the adaptive immune system is able to systematically dismantle the enemy with efficiency and precision. The adaptive immune system is slow to take action when the body experiences a particular infection (or a vaccine) for the first time, but upon subsequent exposures, adaptive immune cells are primed to produce a faster response.
In their study, Neeland and colleagues used a technique called flow cytometry to analyze a subset of infection-fighting cells in the blood called peripheral blood mononuclear cells (PBMCs). PBMCs are a type of white blood cell that has a round nucleus when observed under a microscope. Using flow cytometry, researchers are able to sort immune cells based on their cell surface proteins. This process allows investigators to understand fine details about the immune system that would be impossible to identify with a light microscope alone.
The Australian researchers found that certain cells of the innate immune system were present in fewer numbers in children acutely infected with SARS-CoV-2. For example, one type of innate immune cell, dendritic cells, made up 0.50% of PBMCs in the convalescent phase, but this population was nearly halved (0.26%) during the acute phase. Such a discrepancy was not observed among adults. Their dendritic cell populations were similar in both the convalescent and acute phases of infection.
A similar phenomenon was seen when comparing natural killer (NK) cells, another type of innate immune cell, in children versus adults. The researchers discovered that NK cells represented 4.8% of PBMCs in acutely infected children compared to 8.3% in acutely exposed (i.e. uninfected) kids. On the other hand, adults in the acute phase exhibited no such difference — a nearly identical 9.1% and 8.8% NK cells in the infected and exposed cohorts, respectively.
Flow cytometry was also used to evaluate a third type of innate immune cell, called neutrophils, which can be identified by their multi-lobed nuclei. The scientists searched for neutrophils with a particular protein, called CD63, on their surface. CD63 is a marker of neutrophil activation (i.e. increased activity). These activated neutrophils were found in 22% of infected children but only 1.7% of exposed children. Conversely, no significant difference in neutrophil activation was observed between infected and exposed adults.
Deciphering the results
So what is the implication of these findings? A press release from the Murdoch Childrens Research Institute in Melbourne summarized, “Children are protected from severe COVID-19 because their innate immune system is quick to attack the virus.” This makes sense looking at the neutrophil activation data above.
But what about the findings in dendritic and NK cells? Didn’t the investigators find a smaller portion of these cells in the blood of acutely infected kids? The authors clarify, “The observation that several innate cell populations were considerably reduced in the circulation during pediatric infection suggests that these cells may be recruited to sites of infection.” In other words, we see fewer innate immune cells in the blood of acutely infected children because these cells have exited the bloodstream and have traveled to locations like the nose, throat, and lungs to confront the virus where it is most actively replicating.
In addition to exhibiting a robust ability to fight infection, children in this study also displayed some degree of immune response to exposure alone. This fits with other research which indicates that children exposed to SARS-CoV-2 do mount a measurable immune response even when testing negative for the virus. The author's comment, “We also show that exposure to SARS-CoV-2 induces changes in the immune response in the absence of virological confirmation of infection.”
An evolving situation
Lastly, the study contrasts childrens’ immune response to SARS-CoV-2 with their response to other viruses. Covid-19 is unique in this aspect because other respiratory viruses generally infect children at a higher frequency and often produce more severe symptoms than what is seen in adults. “Children are less likely to become infected with the virus [SARS-CoV-2] and up to a third are asymptomatic, which is strikingly different to the higher prevalence and severity observed in children for most other respiratory viruses,” Dr. Neeland elaborates.
While this study doesn’t explicitly offer an explanation as to why SARS-CoV-2 seems to flip the age demographic compared to the majority of respiratory viruses, I suspect this paradox is mostly a matter of timing. Remember, Covid-19 is a disease that no one’s immune system had ever encountered until the fall of 2019. Assuming SARS-CoV-2 is on an eventual path towards becoming endemic, as the years go by, Covid-19 will evolve to become more and more like the common cold caused by the four other endemic coronaviruses.
Over the following months, the vast majority of children will have either been exposed to the novel coronavirus or will have been vaccinated against it. Moreover, their immune systems will continue to encounter SARS-CoV-2 from time to time as they grow into adults. By then, a generation or two from now, I would venture to guess Covid-19 will no longer assault aging adults with such severity. Perhaps future generations of children will continue to experience a generally mild infection or perhaps they will be routinely vaccinated. Regardless, this virus and its interaction with humanity remain subject to change — that’s something even a child can count on.