Less is known about the impact of Covid-19 infection among children compared to adults. Why do children experience milder symptoms on average compared to adults? Do children experience Long Covid, and what makes them different? What is MIS-C and what is its prevalence? A recent perspective published by Science explores current research and provides answers to these questions.

Why can Covid-19 be milder in children?

There are several theories as to why Covid-19 can be milder in children. One explanation is that a child’s innate immune system mounts a more vigorous attack at the onset of infection. A child’s acquired immunity changes throughout life and is found to be initially less extensive compared to adults. In particular, some studies have found that children have weaker memory T-cells and lower neutralizing and Fcγ-receptor activating responses compared to adults. Fcγ-receptors play a critical role in triggering the adapted immune system, and a lower activation provides a less robust cell immunity response. Additionally, cytokine interferon levels, which are heavily involved with inflammation, have been found to be age-dependent.

A study on mucosal responses at the time of Covid-19 diagnosis found that RNA sequencing data and measurement of cytokines had a much more brisk response in the nasal mucosa of children compared to adults. This finding can possibly be attributed to the “trained” immunity resulting from more frequent respiratory infections in children, which increases the baseline or standard innate activity in children.

The developing nature of a child’s acquired immune system is also hypothesized to contribute to mild cases. Studies have found that children have an increased frequency of naive T-cells, less natural killer cells, and lower frequency of cytotoxic T cells compared to adults. Additionally, the T-cell receptor declined clonal expansion among children who were previously infected by Covid-19 compared to adults.

Why do some children develop MIS-C?

Multisystem Inflammatory Syndrome in children (MIS-C), is a post-Covid infection condition where different systems of the body become inflamed. It can be seen in children 6 to 12 years old and occur within 3 to 6 weeks following Covid-19 infection. MIS-C symptoms include fever, atypical fatigue, red eyes, strong abdominal pain, severe or worsening vomiting or diarrhea, and rashes.

If a child is suspected of having MIS-C, they should immediately seek medical care. In the United States, roughly 3 in 10,000 people under the age of 21 were reported to have been diagnosed with a case of MIS-C infection, and there is an approximately 0.8% chance of mortality. MIS-C is a treatable condition with a high recovery rate. Healthcare providers may administer anti-inflammatory drugs to reduce inflammation in the body and protect vital organs from permanent damage. Studies have also found that Covid-19 vaccination as an effective means to reduce the risk of MIS-C, in part by reducing the risk of Covid-19 infection. Becoming vaccinated also reduces the incidence rate of MIS-C.

Long Covid in Children and Young People

Most children and adults fully recover from Covid-19. However, some individuals may experience symptoms beyond the average recovery period (3 to 4 weeks). This condition is known as Long Covid.

At least 200 different symptoms of Long Covid have been reported, and it has affected every organ system within the body. Depending on the methodology, cohort, and definition, global prevalence estimates of Long Covid among children are between 1:4 and 1:100. In the UK alone, 120,000 children experienced long Covid in 2021, with 26,000 having symptoms persisting for more than 1 year.

Children with Long Covid can be grouped based on their ability to return to “normal” life and the presence of additional post-infectious complications. Children may experience debilitating symptoms, such as unexplained fever, fatigue, pain, cognitive difficulties, and post-exertional symptom exacerbation, that interfere with daily life activities. Some post-infectious complications include MIS-C, acute neurological disease, and myocarditis, and can last a few weeks to many months past Covid-19 infection.

There are currently no established biomarkers that can identify Long Covid, making it challenging to diagnose. The first research definition of Long Covid was published this past July; in alignment with the clinical case definition released by the World Health Organization, it defined Long Covid as a “post-Covid infection condition with at least one physical symptom persisting 12 weeks past infection and cannot be explained by an alternative diagnosis.” A global agreement for a pediatric Long Covid definition is expected in 2023.

On a global front, we must work together and invest resources to understand the full implications of Covid-19 among children. In doing so, we can optimize treatments and create more effective therapies, enhancing recovery and reducing the prevalence of Long Covid.