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Welcome to Common Ground, a podcast series discussing new research and interesting projects in the field of complementary medicine. Hello, my name is Wendy McLean, Senior Writer & Presenter at vital.ly.
vital.ly is a digital platform, a health professional resource, and a distribution service all in one.
Firstly, I'd like to begin by acknowledging the Gadigal people of the Eora Nation as the traditional custodians of the land on which we gather here. I would also like to pay my respect to their elders, past, present, and emerging.
Today on Common Ground I am going to be discussing long COVID in children and adolescents. While children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are generally considered to have a lower risk of hospitalisation and lower mortality rates than adults, there are now concerns regarding the long-term health effects of SARS-CoV-2 infection in the younger population.
Children have generally been thought to be less vulnerable to the longer-term effects of COVID-19, with the risk decreasing the younger they are. It was thought this might be because younger children have fewer angiotensin-converting enzyme-2 (ACE2) receptors, the entry point for the SARS-CoV-2 virus. However, the emergence of the Omicron variant and its subvariants, which are far more infectious than previous forms, has led to a higher proportion of children becoming infected. Furthermore, emerging evidence from case studies, patient support groups and clinicians highlight that children with asymptomatic and symptomatic coronavirus disease-19 (COVID-19) are experiencing long-term effects weeks to months after the initial infection.
There are two long-term consequences of SARS-CoV-2 infection in children that raise concern. The first is multisystem inflammatory syndrome in children (MIS-C), a severe but rare hyperinflammatory disease that occurs 2-6 weeks after SARS-CoV-2 infection. It has similarities to other known inflammatory disorders, including Kawasaki disease and toxic shock syndrome. In children who develop it, organs and tissues, including the heart, blood vessels, kidneys, lungs, nervous system, digestive system, skin, and eyes, can become severely inflamed. The latest figures from the USA indicate that as of 2nd May, there had been 8,210 MIS-C cases related to COVID-19 and 68 deaths.
The second long term consequence is post-acute sequelae of COVID-19 (PASC), or what we know as long COVID. Clinicians worldwide have reported increasing numbers of children and adolescents diagnosed with long COVID in the past six months. However, the actual true number and how many children are affected remains a hotly debated topic.
Looking at the studies that have been published to date the prevalence of long COVID in children and adolescents varies widely anywhere from 4% to 66%. And this variability arises largely from a lack of a paediatric definition of long COVID. And also because of the heterogeneity in these studies; this includes differences in the sample size, the age of the population included, the duration, follow up, and how the symptoms are actually measured.
But there are other complicating factors, many children haven't, and won't be tested for SARS-CoV-2, either because they are asymptomatic, or they've had mild symptoms. In addition, not all children with long COVID seek medical attention, making tracking its incidence challenging. And then furthermore symptoms that present in adults don't always present the same in children. For example, fatigue can manifest in young children as hyperactivity rather than sluggishness, and this can make it difficult for parents to detect the problem. As a result, many studies likely only identify the occurrence of long COVID in adolescents who can self-report their symptoms.
There has been one Australian study following long-term clinical outcomes in children, three to six months after acute SARS-CoV-2 infection. This study followed 171 children at a dedicated COVID-19 follow up clinic at the Royal Children's Hospital (RCH) in Melbourne, Australia, between March 21, 2020, and March 17, 2021. So just keep in mind, this is before Omicron. Eight per cent reported post-COVID symptoms up to eight weeks after infection in this study. All of these patients had been symptomatic. The most common post-acute COVID-19 symptoms were mild post-viral cough, which lasted 3 to 8 weeks, and post-viral fatigue, which lasted 6 to 8 weeks from symptom onset.
There have been a handful of controlled studies, which compare SARS-CoV-2 positive patients to uninfected control groups and these may provide a more accurate estimate of long COVID prevalence in children and adolescents. One of these recent controlled studies is the Children & Young People with Long COVID (CLoCk) study, a controlled study conducted by researchers at the University College London. Now this study included 3,065 11- to 17-year-olds in the UK who had a positive PCR test between January and March 2021 and a matched control group of 3,739 11- to 17- year olds who tested negative over that period. Three months after being tested, both groups completed a questionnaire regarding the symptoms they were experiencing. Both groups reported symptoms, but children who had tested positive (66.5%) were more likely to have long-COVID symptoms than those with a negative test result (53.3%). Furthermore, those who had tested positive were nearly twice as likely to report three or more symptoms at three months. Some of the main symptoms were fatigue, shortness of breath and persistent headache.
Now, as I mentioned, there's only been a handful of these controlled studies to date, and they have produced conflicting results. Some have shown no difference in symptom occurrence in SARS-CoV-2 positive and negative groups and others have shown differences. But I think what is interesting is that all of these studies are showing symptoms in SARS-CoV-2 negative control groups. And what this does highlight is that some of these symptoms may be due to the biological mechanisms of SARS-CoV-2, but some of these symptoms, particularly these mental health symptoms may just be due to the pandemic itself and the stress from isolation and lockdowns. And there may be other causes as well, such as paediatric viruses or illnesses. It really does highlight the importance of doing controlled studies with these two comparison groups.
Looking now at the clinical presentation…part of what makes defining long COVID difficult is that it appears to take many forms and more than 100 symptoms have been identified in children and adolescents involving many different organs and body systems: cardiovascular, respiratory, gastrointestinal, musculoskeletal, skin, nervous system, and general somatic symptoms.
A recent review of 14 studies, including nearly 20,000 children, identified the most common symptoms to be headache, fatigue, concentration, difficulties, sleep disturbance, abdominal pain, myalgia, and arthralgia. However, there was a wide variability in the occurrence of these symptoms. For example, fatigue ranged from 3% to 87% in these studies. What these studies did show was that most symptoms did not persist longer than 12 weeks.
Long COVID symptoms can occur in isolation or combination. They can remain constant over time. They can be transient or have an intermittent-relapsing pattern. Furthermore, symptoms may not appear until weeks after the initial infection and they can vary in their intensity. Now all of these factors complicate diagnosing long COVID.
Furthermore, experts suggest that long COVID may actually encompass several different conditions, including myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Chronic fatigue syndrome (ME) is a severe multisystemic disease characterised by profound fatigue, following exertion. This is known as post-exertional malaise, and this is not relieved by sleep or rest. It also is characterized by unrefreshing sleep and cognitive impairment or brain fog.
POTS is a form of orthostatic intolerance and involves dysfunction of the autonomic nervous system, which impairs blood circulation on standing and reduces blood flow to the brain. Now this can cause dizziness, lightheadedness, heart palpitations, and brain fog.
So what is the cause of COVID in children?
Children have several protective factors which leads to a mild severity and duration of the initial infection. And these factors include things like the ACE-2 receptors that I mentioned earlier. They have fewer comorbidities and age-related endothelial damage. They have a stronger innate immune response and active thymic function, which means that they have an increased presence of T cells, which can recognise viral proteins. And they have other protective factors including environmental or non-inheritable factors including past infections, vaccines, nutrition, and the gut microbiome. These protective factors we know can reduce the severity of acute infection, but whether they're protective against long COVID in children and adolescents, we don't know. And more research is required.
The underlying mechanisms causing the various clinical spectrum of long COVID are still unidentified, but they can be divided into two groups. So the first is related to organ damage during acute illness. And the second includes other less well characterised mechanisms. Now in adults, these mechanisms are theorised to include excessive immune response, reactivation of Epstein-Barr virus, viral-induced autoimmunity and sustained inflammatory response caused by the persistence of the virus or viral fragments in tissue and organs.
These mechanisms may also be at play in children and adolescents. Although some researchers argue that there may be some other processes involved that are not necessarily the same as adults. And they argue that there is some slight difference in the symptom profiles of adults and children. So for example, many adults experience brain fog and neurological symptoms, which many believe are driven by presence of autoantibodies. Whereas in children, they're tending to see more fatigue, headaches, dizziness, and pain in the muscle and joints. And it's argued that if autoantibodies are the main driving cause of long COVID, then these should be produced irrespective of age and produce a similar symptom profile.
Another theory involves gut dysbiosis and intestinal permeability. The gastrointestinal tract is the frequent target of SARS-CoV-2, given the elevated expression of ACE-2 receptors along the mucosa. Several studies have found a strong association between gut dysbiosis and persistent symptoms in patients with COVID-19 up to six months after virus clearance. This gut dysbiosis is characterised by reduced microbiota diversity, increased abundance of opportunistic pathogens, and fewer gut commensals with immunomodulatory effects.
A recent study of children with post-COVID inflammation found that a prolonged presence of SARS-CoV-2 in the gastrointestinal tract led to the release of zonulin. That's a biomarker of intestinal permeability. This enhanced intestinal permeability allows the viral particles that are still residing in the gut to enter the bloodstream and to circulate around the body and produce an excessive or hyperinflammatory response.
However, as with adults, there are likely to be multiple mechanisms at play, and specific populations are at higher risk. Several studies have investigated risk factors for long COVID in children. One study reported that older age was significantly associated with persistent symptoms, with children above six years of age being at higher risk. Several other studies showed a positive correlation between increasing age and long COVID symptoms. Other risk factors include female gender, severe COVID-19, overweight or obesity, and other long-term co-morbidities.
In children, allergic diseases are also associated with a higher risk of long COVID. One of the main theories behind allergies has been an imbalance in the body's white blood cells, namely Th1 and Th2 cells. Th1 cells act as the first line of defence against external invaders and generate inflammation in response to viruses and bacteria. Th2 cells are the second line response and produce antibodies.
In a well-functioning immune system, both groups work in balance. However, there is an imbalance in some individuals, which can result in allergic or autoimmune diseases. Therefore, the association between allergy and risk of long COVID in children has led some researchers to propose that mast cell activation syndrome and a T helper 2 (Th2) dominant immunological response could cause long-COVID symptoms.
So how can we support children with long COVID?
There's no recognised formal medical? treatment, there's no universal or recognised standardised clinical management guideline. However, considering the multi-organ involvement that we are seeing in long COVID, we need a multidisciplinary approach. So after an initial assessment referral to other specialists may be required, and this could include a team of cardiologists, rheumatologists, neurologists, or psychologists and pulmonologists. And given that symptoms can emerge weeks to months after acute infection, we really do need some regular follow up.
And also, we are facing this epidemic of mental health issues in our youth and adolescents. Now, whether these are related to long COVID and the actual viral infection, or whether it's just from the stress caused by restrictions and social isolation and the pandemic itself, we need to address this. And there was a recent meta-analysis of 29 studies, which included 80,000 youth and it reported that one in four children and adolescents globally were experiencing elevated depressive symptoms. And one in five had elevated anxiety and these rates were double the pre-pandemic levels. And in addition, doctors and pediatricians have reported seeing an increase in the number of cases of children with things like tics and eating disorders. Supporting mental health is critical. And again, a multidisciplinary approach is needed, and therapies such as biofeedback, cognitive behavioral therapy, psychology psychotherapy, and mindfulness techniques can be beneficial for mental health. And these can also be beneficial for things like psychosomatic symptoms and chronic pain.
Furthermore, nutrition is going to play a key role as well. What we have seen during the acute stage of SARS-CoV-2 infection is that there are poorer outcomes with specific nutrient deficiencies. So deficiencies in vitamin D, zinc, selenium and magnesium, have all been associated with more severe forms of COVID-19 and/or higher mortality rates.
These nutrients we need to reduce inflammation, oxidative stress, and support immune function. So it would make sense that we would need adequate levels of such nutrients for our children and adolescents. And there aren't any specific studies yet looking at these nutrients in long COVID. But when you look at their key actions, you can understand why we would need these to prevent or manage long COVID.
B vitamins, are needed for energy metabolism, immunomodulation, and they are cofactors in mitochondrial enzymes and protein enzymes, and they are antioxidants and regulate inflammatory pathways.
Vitamin C is one of the body's most important antioxidants and it is required for neurotransmitter synthesis, energy metabolism, and innate and adaptive immune function. Furthermore fatigue, pain, brain fog, and depression like symptoms are known symptoms of a vitamin C deficiency.
Vitamin D is another one. We know it has immunomodulatory effects in both the innate and adaptive immune responses, it is antiviral, anti-inflammatory and has a protective effect on endothelial dysfunction.
It also has a protective effect in the development of autoimmunity, which we are seeing in COVID-19 patients. And it is an important regulator of gastrointestinal microbiota. And interestingly supplementation has been shown to mitigate Epstein Barr viral reactivation, which we are seeing in our COVID 19 patients.
Magnesium is another key nutrient. Magnesium deficiency is associated with inflammation conditions like type two diabetes and hypertension. Deficiency is associated with mitochondrial dysfunction and is possibly causally related to fatigue and chronic fatigue syndrome, which we know is a common manifestation of long COVID.
And then other key nutrients, of course, selenium and zinc, which are anti-inflammatory, antioxidant and are key for innate and adaptive immune function.
We also need to enhance our intake of phytochemicals compounds, which are found in fruit and vegetables, so compounds like resveratrol, quercetin, sulforaphane and curcumin. These molecules have anti-inflammatory and antioxidant effects. Preclinical evidence shows that they are antiviral and anti-inflammatory; therefore, it is important to ensure that we have adequate intakes. They also have antiplatelet aggregation activity, so may reduce the risk of thrombosis.
And then of course we need to support the gut microbiome. The association between a persistently altered gut microbiome and long-term sequelae of COVID-19, together with emerging evidence from small clinical trials with probiotics in patients with long COVID, suggests that there is an opportunity to ameliorate these long-lasting symptoms by regulating the gut microbiome.
There was a small, recent experimental study supplemented with a lactobacillus probiotic blend and inulin for 30 days. In long COVID patients, they significantly improved, gastrointestinal symptoms, cough, fatigue, and wellbeing. Now in these patients, their average symptom length was 120 days.
And then there was a second RCT including 200 long COVID patients. They had oral supplementation with a probiotic and systemic enzyme complex for 14 days and this resulted in the resolution of fatigue in a greater percentage of subjects in the probiotic arm than in the control arm (91% vs. 15%). In addition, supplementation significantly reduced all physical fatigue symptoms, and brain fog.
So, in conclusion, there is increasing evidence that children can be affected by long-term sequelae after COVID- 19 infection. However, the relative scarcity of studies on long COVID and the limitations of those reported to date means the true incidence of this syndrome in children and adolescents remains uncertain.
Studies show that most children recover spontaneously within the first six months, but not all. In addition, studies indicate that the risk is higher in older children and those with allergic disease, co-morbidities and overweight or obesity.
The lack of a paediatric definition of long COVID has hindered research and diagnosis, appropriate clinical management and treatment of children suffering long-term symptoms after SAR-CoV-2 infection.
The first definition of long COVID in children was recently published, which states that symptoms must follow a confirmed case of COVID-19, impact the child’s life and physical, mental, or social well-being, and persist for at least 12 weeks. Adopting this definition would allow researchers to reliably compare and evaluate studies on prevalence, disease course and outcome of long COVID.
Long COVID is an emerging health crisis, and research is urgently needed to assess the impact of things like age disease, severity, and duration, virus, strain, and vaccination status on the risk of long COVID in this age group. Furthermore, we need research to understand the biological mechanisms and causes of long COVID. And we need interventional trials to inform treatment strategies and improve long term COVID patient outcomes.
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