Long COVID, also known as long-haul COVID, is thought to be a set of long-term post-viral syndromes or complications that can affect individuals across all demographics following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent that causes coronavirus disease 2019 (COVID-19). Also called post-acute sequelae of COVID-19 (or PASC), this category of illness comprises symptoms such as prolonged fatigue, shortness of breath, chest pain and an overall reduction in the quality of life.
Many reports are beginning to emerge on the ‘long COVID’ phenomenon. But a new study, released as a preprint on the medRxiv* server, describes, for the first time, immunologic changes observed in children with PASC.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Features of PASC
Most children with SARS-CoV-2 infection are asymptomatic or have only mild and transient disease. However, in a small percentage, thought to be under 10% by some scientists, symptoms continue to present and evolve over weeks after the child is clinically free of the virus.
Severe COVID-19 is thought to be related to dysregulated inflammatory pathways, triggered by abnormal immune activation in response to the viral infection. This systemic inflammation leads to damage in affected organs, causing multiorgan failure and even death in a significant minority of patients.
Features of long COVID in children include mainly fatigue, insomnia, joint pains and trouble with breathing. The underlying reasons have to do with the persisting dysregulation of the immune system, with hyperactive inflammation, direct toxic effects of viral replication on human tissues, damage to the endothelium, and microvascular injury.
Study details
The current study examined children identified to have PASC based on an international survey form.
All children had persistent symptoms for over five weeks, involving two or more body systems. Children with a history of COVID-19 but with no residual symptoms were enrolled as a control group.
In both groups, the investigators examined T regulatory cells (Tregs), which modulate T lymphocyte activation, and B cells, which produce specific antibodies. They also assessed the levels of key pro-inflammatory cell signaling molecules, or cytokines – IL (interleukin) 6, IL1β and TNF (tumor necrosis factor) α.
The PASC cohort had higher numbers of plasmablasts, as well as IgD-CD27+ memory and switched IgM-IgD- B cells, compared to the fully recovered children. IL6 and IL1β levels were also raised.
The recovered cohort had higher numbers of naïve and unswitched IgM+IgD+ and IgM+CD27-CD38dim B cell subsets.
There were no significant changes in Treg numbers in either group.
The implications
The study findings underline the existence of PASC in children as an organic entity rather than one that is ‘all in the mind,’ owing its origin rather to pandemic- and infection-induced isolation. These are the first objective signs that PASC is the result of specific immunologic changes in affected children.
Whereas fully recovered children showed complete B cell restoration to normalcy, as shown by the B cell subset analysis mentioned above, this is not observed in children with PASC. Instead, these patients continue to suffer abnormal activation of plasmablasts, switched B cells and memory B cells, which leads to chronic symptoms.
The high levels of two pivotal inflammatory cytokines also indicate that innate immunity is a key underlying process in pediatric PASC. These findings could explain why symptoms like tiredness, inability to exert oneself, headache, joint and muscle pain, and tachycardia, are characteristic of this state.
Some scientists have suggested that low levels of the virus persist following acute infection in a few children, causing PASC symptoms or Multisystem Inflammatory Syndrome in Children (MIS-C). Some reports claim to have detected the viral particles in the endothelium of skin blood vessels, using specialized microscopic imaging tools.
This is supported by the finding of echinocytes, spinous-like cells, found in the blood of MIS-C patients, which are found in inflammatory conditions. The current study may add to the evidence that chronic inflammation and aberrant immune activation result in the appearance of PASC. More research will be required to understand the origin of this condition.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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