Review Multisystem inflammatory syndrome in children (MIS-C): Implications for long COVID, 2023, Constantin et al

[Wyva]

Abstract

The COVID-19 pandemic caused by the coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2) has significantly affected people around the world, leading to substantial morbidity and mortality. Although the pandemic has affected people of all ages, there is increasing evidence that children are less susceptible to SARS-CoV-2 infection and are more likely to experience milder symptoms than adults. However, children with COVID-19 can still develop serious complications, such as multisystem inflammatory syndrome in children (MIS-C).

This narrative review of the literature provides an overview of the epidemiology and immune pathology of SARS-CoV-2 infection and MIS-C in children. The review also examines the genetics of COVID-19 and MIS-C in children, including the genetic factors that can influence the susceptibility and severity of the diseases and their implications for personalized medicine and vaccination strategies. By examining current evidence and insights from the literature, this review aims to contribute to the development of effective prevention and treatment strategies for COVID-19, MIS-C, and long COVID syndromes in children.

Open access: https://link.springer.com/article/10.1007/s10787-023-01272-3

 

[Wyva]

The part about long covid:

Implications for Long COVID
Long COVID refers to the persistence of symptoms related to infection with the SARS-CoV-2 virus (Soriano et al. 2022). Specific symptoms and their duration can vary widely between individuals, but common symptoms of long COVID include fatigue, shortness of breath, chest pain, coughing, joint pain, headache, difficulty sleeping, brain fog, and loss of taste or smell sense. Other less common symptoms can also occur, such as gastrointestinal symptoms, heart palpitations, and skin rashes.

Long COVID can affect people of all ages, including children (Berg et al. 2022). Among children, the most frequently reported symptoms were fatigue, headache, arthromyalgia, chest tightness or pain, and dyspnea (Borch et al. 2022a; Pellegrino et al. 2022).

Research has shown that these long-term COVID symptoms cannot be attributed to any psychological effects of recent social restrictions in place (Borch et al. 2022b). Fortunately, long COVID symptoms are often temporary and improve in 1–5 months; however, they can still greatly reduce someone's quality of life.

Scientific evidence on the immunopathology behind the long COVID syndrome in children is still limited. However, some studies suggest that long COVID in children may be associated with an immune-mediated inflammatory response similar to what has been observed in adults with long COVID (Son et al. 2022). One hypothesis is that long COVID in children may be triggered by an autoimmune response. Unlike short-lived systemic problems caused by cytokine storms, autoantibodies are believed to trigger more specific and long-term damage and therefore may play a role in the pathogenesis of long COVID (Wang et al. 2021; Su et al. 2022; Zhang et al. 2023). The SARS-CoV-2 superantigen motif, which we have previously discussed in detail, could potentially contribute to the development of COVID-19 hyperinflammatory syndromes, such as MIS-C, and autoimmune reactions related to long COVID (Rivas et al. 2022).

In addition, there have been reports of neurological symptoms, such as brain fog and memory problems, that may be related to an autoimmune response. Women who have recovered from toxic shock syndrome regularly report persistent neurological symptoms such as headaches, impaired cognition, and memory loss (Rosene et al. 1982). These signs are strikingly similar to the neuropsychiatric problems described by those with long-term COVID. This provides further evidence that superantigens may be involved in the induction of long COVID. Furthermore, the recognition of neurotoxin patterns in SARS-CoV-2 opens up the possibility that inflammation caused by its spike protein could directly contribute to neurological symptoms associated with MIS-C and prolonged COVID (Rivas et al. 2022).In summary, gaining a clear and deeper understanding of the early and late immune response to SARS-CoV-2 infection could be a key factor in understanding the prolonged effects of long COVID.

Interesting that out of all things the authors think it is the aftereffects of toxic shock syndrome that neuro long covid is strikingly similar to.

 

[EndME]

Both Polybio https://polybio.org/projects/sars-c...-spike-protein-in-pediatric-long-covid-mis-c/ and RECOVER https://classic.clinicaltrials.gov/ct2/show/NCT04588363 seem to be studying MIS-C as well, so there should be more studies on this coming out soon.

 

[livinglighter]

There is also multisystem inflammatory syndrome in adults (MIS-A). Which appeared to be acknowledged sometime after the announcement of MIS-C.

What we know about MIS-A
Multisystem inflammatory syndrome (MIS) is a rare but severe condition initially recognized in children and adolescents (MIS-C) infected with SARS-CoV-2, the virus that causes COVID-19. Like in children, adults who have been infected with SARS-CoV-2 can develop MIS (MIS-A) days to weeks after getting sick with COVID-19. MIS-A is a condition where inflammation occurs in different internal and external body parts like the heart, gastrointestinal tract, skin, or brain.

MIS-A is less common than MIS-C. Compared with MIS-C, MIS-A can also be more difficult to distinguish from acute COVID-19. However, like children with MIS-C, adults with MIS-A appear to recover quickly from the most dangerous heart-related complications.

https://www.cdc.gov/mis/mis-a.html


It would be interesting to know if the two named syndromes are a new phenomenon or if the same mechanism has happened alongside other post-infectious illnesses.

 

[SNT Gatchaman]

It would be interesting to know if the two named syndromes are a new phenomenon or if the same mechanism has happened alongside other post-infectious illnesses.

For the children, there are a lot of overlaps with Kawasaki disease. I think the coronary artery aneurysms that are a common late effect in KD are not seen as frequently in MIS-C however. [ETA: however may be similar, see next comment]

MIS-C: myths have been debunked, but mysteries remain (2023, Nature Reviews Rheumatology)
Kawasaki disease and MIS-C share a host immune response (2022, Nature Reviews Rheumatology)
A comparison of Kawasaki Disease and multisystem inflammatory syndrome in children (2022, Progress in Pediatric Cardiology)
Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis (2022, Frontiers in Immunology)

See also —

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children (2023, Science)

 

[SNT Gatchaman]

From Kawasaki disease and MIS-C share a host immune response (2022, Nature Reviews Rheumatology) —

whether MIS-C is a new syndrome consisting of SARS-CoV2-mediated fever with cytokine release or is SARS-CoV-2-triggered Kawasaki disease, or some combination thereof, remains unclear.

Kawasaki disease is a heterogeneous syndrome that is thought to be triggered by infectious agents, including coronaviruses.

In some cases, Kawasaki disease is complicated by coronary artery aneurysms, shock and/or macrophage activation syndrome (MAS), which occur in 5%, 6% and 2% of patients, respectively.

MIS-C has a more extreme phenotype than Kawasaki disease, with shock and MAS occurring in approximately 20% and 40% of affected children, respectively, but the incidence of coronary artery abnormalities is similar.

The overlapping immunophenotype based on viral signatures supports the hypothesis that Kawasaki disease and MIS-C are not in fact separate entities but are names describing the different ends of the spectrum of the host immune response.

The subsequent bias that affects the spectrum of disease captured has continued to skew our understanding of MIS-C. An alternative approach is to stratify post-infection hyperinflammation syndrome into subgroups on the basis of the clinical phenotype recognized at the beside, in a manner agnostic to the infectious trigger. Such an approach would recognize the full spectrum of phenotypes and complications, including cardiogenic shock (such as MIS-C shock and Kawasaki disease shock syndrome), MAS [Macrophage Activation Syndrome] (cytokine storm-associated cytopenias and coagulopathies triggered by infection), Kawasaki disease (the typical, complete Kawasaki disease phenotype, triggered by SARS-CoV-2 or another infectious agent), and fever and hyperinflammation (mild or incomplete features of Kawasaki disease).

This is summary commentary on An Artificial Intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease (2022, Nature Communications)

 

[Wyva]

Btw, interesting tidbit about the corresponding author, Tamás Constantin, who is a well-known pediatrician here (a rheumatologist):

He streamed a Facebook video very early into long covid, which was a discussion of pediatric long covid with three other pediatricians. I watched it back then and I remember that among other things he talked about how we cannot dismiss the potential psychological effects of the lockdowns, the isolation etc on children and how these very likely contribute to the symptoms. He also mentioned how it is known in medicine that people sometimes feel amplified pain due to some stressful trigger or at least that's how they perceive it. I actually wrote about the video here if anyone is interested.

I criticized this discussion a bit on my Facebook page (I didn't have a website back then) but I also criticized this in a comment below the video (I have no idea if Constantin ever saw it, there were a lot of comments).

So it was nice to read this paper coming from him as the lead author and with even a sentence like this in it: "Research has shown that these long-term COVID symptoms cannot be attributed to any psychological effects of recent social restrictions in place (Borch et al. 2022b)."