Delayed presentation of MIS-C following COVID-19 2/16/23, 18:44

Delayed presentation of MIS-C

following COVID-19
By Pooja Toshniwal PahariaFeb 15 2023Reviewed by Benedette Cuffari,
M.Sc.

In a recent Science journal paper, researchers elucidate the pathophysiology

of the multisystem inflammatory syndrome in children (MIS-C), wherein they
describe the probable reasons for the delayed presentation of the condition
following coronavirus disease 2019 (COVID-19).

Study: Exaggerated responses to a virus long gone. Image Credit: Jester-

Film / Shutterstock.com

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Delayed presentation of MIS-C following COVID-19 2/16/23, 18:44

What is MIS-C?
COVID-19, which is caused by infection with the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), has caused unprecedented
morbidity and mortality across the globe.

Several studies have reported greater COVID-19 severity outcomes such as

hospitalizations and deaths among the elderly; however, the opposite has
been observed in MIS-C, which is a rare and fatal disease that affects the
pediatric population. An improved understanding of MIS-C pathophysiology
could aid in the development of targeted therapies and improve the standard
of care for MIS-C patients.

MIS-C pathophysiology
MIS-C symptoms partially overlap with those associated with Kawasaki
disease, postinfectious vasculitis, and toxic shock syndrome due to
nonspecific superantigen-mediated T-lymphocyte activation. Superantigens
are viral or bacterial protein molecules that bind non-specifically to T-cell
receptors (TCRs), thus contrasting to peptides complexed with major
histocompatibility complex (MHC) molecules that activate T-lymphocyte
subsets recognizing complexes through TCR.

Mutation of the 2’-5’-oligoadenylate synthetase (OAS)-ribonuclease L

(RNase L) genes that sense SARS-CoV-2 ribonucleic acid (RNA) causes
exuberant inflammatory responses in myeloid cells among MIS-C patients,
thus indicating SARS-CoV-2 superantigen-regulated T-lymphocyte
activation in MIS-C. Notably, SARS-CoV-2 variants causing exuberant
inflammatory responses are reportedly overrepresented in MIS-C children.

MIS-C children with mutated OAS-RNase L pathway genes have shown

disproportionate variable-b21.3 chain-expressing T-lymphocyte expansion,
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Delayed presentation of MIS-C following COVID-19 2/16/23, 18:44

thus indicating a combined or synergistic impact of the phenomenon

underlying MIS-C. Serological cytokine profiling studies have reported broad
T-lymphocyte activation among MIS-C patients with autoantibody
lymphocyte repertoires, which suggests that T-lymphocytes could also
activate B-lymphocytes and cause tolerance loss. These findings could
justify other aspects of MIS-C pathophysiology and immunomodulatory
treatment responses.

COVID-19 vaccinations or previous SARS-CoV-2 infection reduce the risk of

developing MIS-C; however, some studies have reported MIS-C cases
triggered by vaccination (MIS-V). Future studies are needed to identify
genomic variants in suspected cases of MIS-V, as messenger RNA (mRNA)
coding for the SARS-CoV-2 spike protein in vaccines could trigger exuberant
immunological responses among OAS-ribonuclease L-deficient individuals.

Notably, the evolution of novel SARS-CoV-2 variants and an increase in

hybrid immunity from vaccinations and SARS-CoV-2 infections has led to a
reduced incidence of MIS-C in 2022.

Post-acute COVID-19, which is otherwise known as long COVID, also

presents with multisystem signs and symptoms that overlap partially and
clinically with MIS-C. These symptoms include coagulopathy, the activation
of immunological cells, and vasculopathy. OAS-RNase L pathway mutations
need to be studied further to develop targeted health interventions for
improved care of pediatric long COVID patients.

Possible causes of delayed MIS-C presentation

Despite the availability of studies on MIS-C pathogenesis, the reason for its
delayed presentation one month after acute infection is not clear and
requires further investigation. Diseases with similar clinical presentations

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Delayed presentation of MIS-C following COVID-19 2/16/23, 18:44

such as Kawasaki disease and toxic shock syndrome present with

comparable and exuberant activation of myeloid cells among individuals with
OAS-RNase L pathway deficiencies. The reason for superantigen-mediated
illnesses presenting one to two months following the initial SARS-CoV-2
infection has not been well characterized and requires further investigation.

COVID-19 severity depends on the robustness of early type I interferon (IFN-

I) activation at the initial sites of SARS-CoV-2 contact, such as the oral cavity
and airways. Individuals with low IFN-I levels are at an increased risk of
SARS-CoV-2 infection severity outcomes.

The pediatric population appears to express IFN-1 in the respiratory tract

more efficiently than adults. As a result, children often present with
asymptomatic or mild COVID-19 symptoms. Nevertheless, MIS-C could
develop among SARS-CoV-2-positive children, as they usually present with
mild/no symptoms that remain unnoticed, even as the disease progresses.

Most MIS-C patients present with SARS-CoV-2-negative results when

respiratory specimens are tested through the reverse transcription-
polymerase chain reaction (RT-PCR) assay, thus indicating that SARS-CoV-2
may be persistent at non-respiratory sites.

In fact, SARS-CoV-2 has been shown to persist in the gut of pediatric

patients. Furthermore, most MIS-C patients clinically present with
gastrointestinal symptoms, including nausea, loose stools, and pain.

Thus, delayed MIS-C presentation could be due to SARS-CoV-2 intestinal

persistence and repetitive stimulation requirements for pathogenic
lymphocytes and myeloid cells. Additionally, the late presentation of MIS-C
can be due to different aspects of intestinal tissue-resident cells. For
example, the cells may require repetitive stimulation to induce MIS-C, in
spite of OAS-RNase L variant expression.
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Previous studies have reported the persistence of SARS-CoV-2 in fecal

samples obtained from MIS-C children. The enhanced gut permeability and
inflammation during this condition have also led to detectable circulatory
SARS-CoV-2 spike protein levels.

Conclusions
MIS-C is characterized by dysregulation and probable self-propagation of
pathogenically activated T-lymphocytes and myeloid cells. Nevertheless,
research is needed to determine the precise mechanisms responsible for the
delayed clinical presentation of MIS-C following acute SARS-CoV-2
infections.

Journal reference:

Brodin, P. (2023). Exaggerated responses to a virus long gone. Science.

doi:10.1126/science.adg2776

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