Drug development for long Covid-19 in children warrants unique focus
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Drug development for long Covid-19 in children warrants unique focus on how mechanisms, prevalence differ from adults

By Manasi Vaidya and  By William Newton 24 Jun 2021

Treating long Covid-19 in children will require a specific focus on that population’s symptom profile and underlying disease mechanisms, despite apparent similarities between paediatric and adult long-haulers, experts and advocacy group leaders said.

Drug development for long Covid-19 in children warrants unique focus on how mechanisms, prevalence differ from adults
In children, the lack of well-documented acute Covid-19 cases, the lagging awareness of long Covid-19’s prevalence, and the safety concerns associated with younger individuals present unique research barriers. Credits: aslysun/Shutterstock.com.

Treating long Covid-19 in children will require a specific focus on that population’s symptom profile and underlying disease mechanisms, despite apparent similarities between paediatric and adult long-haulers, experts and advocacy group leaders said. In children, the lack of well-documented acute Covid-19 cases, the lagging awareness of long Covid-19’s prevalence, and the safety concerns associated with younger individuals present unique research barriers, they added.

While many long Covid-19 cases in adults can be traced back to documented—and often severe—acute infections, most children with long Covid-19 did not have a laboratory-confirmed diagnosis, experts explained. As a result, it will be very difficult to establish control groups for research studies or recruit patients with confirmed cases for clinical trials, they said. Instead, finding biomarkers that correlate with known long Covid-19 cases in children will provide a more reliable framework for testing treatments and understanding the disease, they said.

In addition, inadequate research in this population means researchers are unaware how long Covid-19 symptoms and underlying mechanisms compare between children and adults, experts said. Nevertheless, they agreed, symptoms between the two populations appear similar enough that many clinical and pharmacological strategies for mitigating the condition in adults could be adapted to children, provided there is adequate research.

But—as is the case with adults—it is important that clinicians and researchers take a holistic treatment approach recognising that psychological and inflammatory-related symptoms are often interrelated, they added. Increased acknowledgement and awareness of long Covid-19 in children represent crucial next steps in addressing the syndrome, experts agreed.

Greater understanding of symptoms and mechanism differences necessary

Despite garnering less public recognition and awareness among clinicians, children with long Covid-19 appear to experience symptoms at comparable rates to adults with the condition, said Long Covid Kids co-founder Frances Simpson. Also, Long Covid Kids, a UK-based research and advocacy group with a database of over 1,200 children with long Covid-19, has documented similar symptoms in children to those seen in adults, Simpson explained. These include fatigue, headache, muscle and joint pain and mental health issues.

But despite these parallels, there appear to be some subtle differences, including one where children uniquely experience symptoms like those seen in multisystem inflammatory syndrome in children (MISC-C), Simpson added. But a study in MISC-C linked to Covid-19 found no evidence that recovery time differed between children treated with intravenous immune globulin (IVIG), IVIG plus glucocorticoids, or glucocorticoids alone (McArdle A, et al. New England Journal of Medicine, 16 June 2021).

In addition, though lung sequalae, joint muscle pain, tachycardia, and joint pain symptoms stemming from long Covid-19 in children are like those in adults, there is little evidence of cardiac sequelae in children, said Dr Danilo Buonsenso, medical director, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario, Rome, Italy. It is possible that adults with long Covid-19 have more frequent organ damage, while children are more likely to experience fatigue due to chronic inflammatory triggers rather than lung damage, Buonsenso explained.

Still, while much more research into the slightly different symptoms and mechanisms of long Covid-19 in children is necessary, Buonsenso and Simpson agreed that clinical strategies and therapeutics for long Covid-19 in adults could, in theory, be repurposed for children with sufficient research.

But repurposing drugs can be challenging because any drug that is safe for adults is not necessarily safe in children, said Daniel Altmann, PhD, professor, Immunology and Inflammation, Imperial College, England. Even the routine examinations often required for diagnoses and research, such as MRIs and CT scans, are more difficult to conduct in children because most of these tests require cooperation from the patient, which can be challenging with younger children, Buonsenso said. In addition, there are ethical concerns with radiation exposure in younger individuals, so they need to be selected carefully, he added.

For a clinical study in Covid-19 in children, it is difficult to find a perfect control group that has ruled out any Covid-19 infections, or a control group with respiratory disease but not Covid-19, since children were tested less frequently for the disease, Altmann noted. Going forward, clinicians should focus on objective immune and organ biomarkers to detect history of Covid-19 in the absence of a well-documented infection history, he added.

Research into precise diagnostic tests to determine mechanisms that drive long Covid-19 in children that look at autoimmunity, viral reservoirs in the gut or tissue damage based on MRIs are necessary before testing potential drugs in this population, Altmann explained. Collecting blood samples and lung function measurements (FEV1) in larger studies could also help develop a step-by-step approach to personalised treatment for children, Buonsenso added.

These voids in research could be addressed, in part, by an upcoming UK-based 1,200-patient observational long Covid-19 study including paediatric populations, this publication previously reported on 26 May. The trial is meant to identify immunological patterns seen after a Covid-19 infection by comparing participants with long Covid-19 symptoms and a control group. The EU Executive announced it was funding a study of ten undisclosed drugs for Covid-19, which could also help with symptoms of long Covid-19, according to a 6 May Reuters report.

Furthermore, additional academic and clinical research into the possible connection between Mast Cell Activation Syndrome (MCAS) and long Covid-19 in both children and adults could provide insight into its underlying causes, said Dr Tina Peers, consultant, The Menopause Consultancy, London, UK. Inflammation from mast cell activation, which goes largely undiagnosed in the real world, is like Covid-19-driven hyperinflammation, Peers explained. As a result, it is possible that acute Covid-19 inflammation exacerbates MCAS, leading patients to experience long Covid-19 symptoms, she said. Though children with MCAS often have less pronounced symptoms, research into this link is still important to see if mast cell activation could influence long Covid-19 in a similar manner to adults, she added.

Lack of documented infection history adds to challenges

Because acute Covid-19 in children often goes undetected or unconfirmed, it can be difficult to link long Covid-19 symptoms to prior disease, Simpson explained. Even most adults who contracted Covid-19 during the first wave lack laboratory confirmation of the disease, and children have generally been tested at a much lower rate, Altmann added. As a result, clinicians can be unaware that children they see could have symptoms linked to an acute case months ago, they said.

In addition, children, like many adults, often have trouble getting referred even when they describe their symptoms and their likely previous Covid-19 infection, Altmann said. Adults presenting long Covid-19 symptoms, and in particular psychological symptoms, have faced scepticism in clinics, and so children with similar symptoms are often met with even more doubt, Simpson added.

The fact that children tend to have less severe acute cases only adds to the difficulty in detecting long Covid-19, Simpson added. Though hospitalised Covid-19 patients can experience long-term symptoms like those of any patient who spends extensive time in the ICU, mild acute cases leading to long Covid—19 which represent a substantial portion of total cases—have been more difficult to pinpoint, explained James Jackson, PsyD, assistant director, ICU Recovery Center, Vanderbilt University, Nashville, Tennessee.

But overall, initial data suggests a significant percentage of children with an acute Covid-19 case develop long Covid-19 symptoms, Simpson said. After more than 120 days from diagnosis, 35 out of 68 children had at least one long Covid-19 symptom and 29 out of 68—or 42.6%—were considered distressed by these symptoms (Buonsenso D, et al. Acta Paediactra, 18 April 2021).

Manasi Vaidya is a Associate Editor and William Newton is a Healthcare Reporter for Pharmaceutical Technology parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.