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You may have heard the buzz surrounding a new severe inflammatory condition observed in children that seems to be connected with COVID-19 infection. The emerging condition is called pediatric multi-system inflammatory syndrome (MIS-C).

Key Highlights

A new, Kawasaki-like inflammatory condition linked to COVID-19 was recently reported in a number of previously healthy children. Learn how this condition is helping researchers unlock more information about how COVID-19 impacts children.

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Jayne Helfrick
Jayne Helfrick

A group of clinicians in the UK first reported pediatric MIS-C on April 26, 2020, after noticing increased reports of previously healthy children presenting with symptoms that closely resembled that of Kawasaki disease, a rare inflammatory condition that primarily affects children. When left untreated, Kawasaki disease can lead to heart complications, including inflammation of the coronary arteries and heart muscle and heart valve problems. In very rare occurrences, the disease can lead to death.

Fortunately, effective treatment exists. When children are treated within ten days of when the condition first begins, the risk of lasting damage is greatly reduced.

Although MIS-C is similar in presentation to Kawasaki disease, the two are not related and prominent clinical signs are largely different. Of the 37 initial patients examined in the UK, most presented with some symptoms also seen in Kawasaki disease—prolonged fever, sore throat, headache, abdominal pain, and vomiting—while only some experienced a rash and conjunctivitis. The patients progressed rapidly to shock and organ disfunction.

Interestingly, most of the children observed for MIS-C were asymptomatic or exhibiting only mild COVID-19 symptoms. Only a third of the patients tested positive for the virus; however, a high number did test positive for coronavirus antibodies. Although many of the patients did not test positive for COVID-19 immediately, many received a positive result after repeated testing.

Once reported, concerns about pediatric MIS-C spread rapidly, with similar cases appearing in New York City and throughout the United States shortly after. Fortunately, after further observation, researchers determined that the condition appears to be very rare. When MIS-C was diagnosed early and treated with classical therapies commonly used to treat Kawasaki disease, patients rapidly recovered within a few days.

While these developments appear to be a positive discovery for pediatric patients with MIS-C, this syndrome highlights an important fact: there is still much we do not know about COVID-19, especially when it comes to emerging conditions and long-term effects of the virus in children. As we continue to search for treatments and vaccines to curb the spread of the novel coronavirus, we must begin incorporating children into the research and development process.

There is still much we do not know about COVID-19, especially when it comes to emerging conditions and long-term effects of the virus in children.

Why aren’t children included in most COVID-19 trials?

There are several reasons why children are widely excluded from current COVID-19 studies. In general, pediatric studies present more challenges than traditional adult studies. For starters, there are simply fewer patients to recruit. The pediatric population makes up only about 17% of the world population, and pediatric studies must segment age ranges within studies to ensure the safety of the participants. Typically, these studies separate participants into four age groups: <2, 2-5, 6-11, and 12-17 years old. Additionally, some conditions do not occur as frequently in children as they do in adults, which further reduces the population size for recruitment. On top of that, some conditions that occur in both children and adults present differently in each, often making it more difficult to identify and diagnose certain conditions in children.

Logistically, pediatric studies require the buy-in and participation of entire families. Studies must get both permission (informed consent) from the patient’s parent or legal guardian, as well as assent from the patient herself. Of course, consent is only part of the challenge. Retaining pediatric patients is difficult, especially when a study requires multiple site visits that children must be driven to or miss school for. Inevitably, the responsibility often falls on the parent to ensure their child is following study and treatment protocols. This combined with other common family elements—siblings with their own schedules and needs, single-parent households, and demanding work schedules, for example—can make participating in a pediatric trial a logistical challenge for both the patient and the rest of the family.

On top of the already existing hurdles to pediatric research, COVID-19 trials are being conducted during a global pandemic where social distancing is greatly encouraged. This raises even more questions and concerns. Many parents may wonder if it’s safe for their child to participate—could they be putting themselves or more vulnerable family members at greater risk by participating? Site visits that once allowed parents to attend with children may need to be rethought, and the use of mobile technology will likely be necessary.

Evidence from the first months of the pandemic suggests that, although children and adults likely are just as susceptible to infection, the risk of severe disease appears to be lower in children. However, serious cases of COVID-19 have been reported in children, including in neonates, young infants, and those with underlying medical conditions. It’s also important to note that testing has been much more limited in children, which could be responsible for the relatively low number of confirmed pediatric cases. As testing increases across the globe, so does the rate of positive cases in children.

Initially, priority was placed on providing care for those most severely impacted by the disease, including elderly and immuno-compromised patients. While emphasizing these at-risk populations is merited, we must also start identifying and filling the key knowledge gaps regarding COVID-19 infection in pediatric populations so that we can better address the needs of children. Including children in COVID-19 research will improve our understanding of the virology, innate, and acquired immune responses in children, helping us to develop therapies that improve outcomes in infected kids. Perhaps most importantly, including children in research may enable us to significantly reduce the spread of infection moving forward.

As testing increases across the globe, so does the rate of positive cases in children.

How do we get children involved in COVID-19 research—and when?

At the time of publishing, there were already more than 400 studies in place to identify treatments and vaccines for COVID-19. Both types of studies present unique challenges.

Treatments

These studies are designed to identify safe and effective treatment options for patients who already contracted COVID-19. Traditionally, adult trials that include pediatric patients are possible because of similarities in how the given disease or condition presents in both. That’s something we don’t typically see with COVID-19. While fever and respiratory symptoms are hallmarks of this disease, fewer than half of kids with the virus have both of these symptoms concurrently. Similarly, MIS-C seems to occur only in children, not in adults who are infected—another incidence where COVID-19 presents differently in children versus adults.

Most COVID-19 studies are not including pediatric populations at this time. A big reason for this is likely because children simply haven’t been as sick. This also makes them less easily identifiable, even if they were being recruited for these studies.

The accelerated timelines of these studies are also a concern for pediatric populations and their families. No one—not parents, drug developers, or healthcare professionals—wants to put kids into a trial where the treatment hasn’t been fully sorted out in adults. Knowing this, it is unlikely we’ll see many treatment studies start enrolling children before a drug has been thoroughly vetted and approved in adult patients first.

Vaccines

Vaccine trials research drugs that may prevent patients from contracting the virus in the first place. In contrast to treatment studies, clinical trials for vaccines are relatively common in pediatric populations, and pediatricians have significant expertise in evaluating the safety and efficacy of these types of drugs. These studies are historically lengthy, often taking five to ten years to complete. During that time, vaccine candidates must go through many steps to ensure their viability and safety, including an exploratory stage, pre-clinical stage, manufacturing and quality control, clinical development, and regulatory review and approval. Each of these stages is complex, time-consuming, and necessary to ensure that a vaccine candidate is not only safe but also effective in protecting patients from infection.

For COVID-19, the expected timeline is just 12 to 24 months. Part of this is due to the global effort and resources directed towards producing a vaccine. Typically, fewer than five companies work on any one vaccine at a time. There are currently more than 70 working on a COVID-19 vaccine. Traditional vaccine development processes have also been altered to speed up the development process, including overlapping stages, reducing the number of study participants, and shortening the timeline for monitoring results. While these changes mean we will likely have a vaccine for COVID-19 faster, a significantly shortened timeline also means that any approved vaccine’s safety and efficacy will not be fully understood when it is first given to the public.

Most children receive a combination of vaccines at an early age, many of which protect from life-threatening diseases that, for the most part, have been eradicated from society. Immunization schedules are developed based on years of scientific and epidemiologic research. These schedules are constantly reviewed by a panel of experts and approved by a large number of reputable organizations, including the American Academy of Pediatrics (AAP), the Centers for Disease Control and Prevention (CDC), and the American Academy of Family Physicians (AAFP). Encouraging parents to give their child a vaccine for a disease that does not at this point in time seem to severely impact large numbers of children will be a harder sell—but one of the utmost importance.

There are still many questions about the role children play in COVID-19 transmission. While the evidence shows that the majority of children are less severely affected, there is little evidence that suggests they are less likely to contract and spread the virus. Kids who are asymptomatic or only experience minor symptoms potentially risk exposing not just elderly and immunocompromised individuals to the virus, but also young children who are vulnerable and unable to get vaccines. That means that, until a vast majority of children are vaccinated and some level of herd immunity is developed, COVID-19 will likely continue to circulate and disproportionately affect those most at risk.

While the evidence shows that the majority of children are less severely affected, there is little evidence that suggests they are less likely to contract and spread the virus.

So, when and how do we get kids into a vaccine trial?

There are still many questions regarding the appropriate time and strategy to add a pediatric arm to these studies. The pediatric research community will need to work closely with vaccine researchers to determine at what phase it is safe to enroll children, as well as what age groups to initially include. When the time comes, they’ll also have to confront the barriers to pediatric enrollment that still exist.

One of the greatest challenges researchers working to advance vaccines face is public opinion. There are many misconceptions surrounding the safety of clinical trials that our industry must continue to educate the public on. Any new treatment or vaccine candidate must pass many tests before they are ever studied in humans. Traditionally, candidates are then studied and proven safe in adults before tested in children. Transparent and continued communication, education, and community engagement about the clinical development process as well as the risks and benefits of participation will be key moving forward.

COVID-19 is a global challenge that people around the world have been forced to confront on an almost daily basis. Not only are individuals being asked to socially distance or stay home, they regularly hear about new drugs that may help treat or prevent exposure to the novel coronavirus. For many, this is the first time they’re learning about the clinical trial process. With so much attention currently placed on clinical trials, now is a good time for our industry to prioritize addressing common misconceptions. It will be up to drug developers, researchers, and healthcare professionals to communicate and educate the general public about the important role of clinical trials in finding life-saving drugs. By engaging with children and their parents and explaining the extreme measures taken to ensure the safety of participants, we can open up a dialogue and start to assuage apprehension in pediatric participation.

The good news is that many kids want to help. This is an unprecedented time for all of us—and children are acutely aware of that. It’s not uncommon to feel stuck or a lack of control in situations like the one we’re in. The desire to help is an innately human response, one that many kids share. The International Children’s Advisory Network (iCAN) is a global consortium of children’s advisory groups known as Kids Impacting Disease Through Science (KIDS) and Young Persons Advisory Groups (YPAGS). iCAN’s youth members are committed to providing a voice for children and families in medicine, research, and innovation. Throughout the COVID-19 pandemic, iCAN has shared the efforts of children helping throughout their communities.

Scott from Houston took in foster puppies when an area shelter overflowed and had to reduce staff. In Michigan, Abby started a non-profit to provide activity kits and supplies to inpatients at C.S. Mott Children’s Hospital while Reece checked in on her neighbors. “Many of my neighbors are elderly and can’t go out during the pandemic,” she said. “By baking them special treats and making front porch, no-contact deliveries, I’m able to check in on them and remind them how special they are to me.”

The KIDS Albania chapter shifted to virtual meetings to ensure they could continue their important work. One member explained, “Even with social distancing in place, our chapter wanted to continue to meet to help others. We know we can help support pediatric clinical research and continue to make a difference for all kids around the world.”

Community volunteers will help move COVID-19 vaccine development forward.

Moving forward, it’s important to remember that we’ll never have an approved drug or vaccine without clinical research volunteers. We’ve seen many communities come together over the last few months to tackle the pandemic head-on. Many people practice social distancing and wear masks when out in public. Others shop for their at-risk family members and neighbors who cannot risk exposure. Healthcare workers continue to work tirelessly to care for those who fall sick. And many children are stepping up to help.

Every individual’s contributions to fighting COVID-19 will look different. For families and children who are able and willing, participating in a pediatric vaccine trial is one option that could end up saving tens of thousands of lives.

For families and children who are able and willing, participating in a pediatric vaccine trial is one option that could end up saving tens of thousands of lives.

Learn more about how PRA is navigating the COVID-19 pandemic.

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