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What is the immunopathogenesis of pediatric COVID-19?

Symptoms and outcomes associated with pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections differ significantly from those in adult patients, with lower mortality and morbidity rates. Understanding the factors responsible for the lesser number of adverse effects of COVID-19 on pediatric populations could play an important role in assessing COVID-19 disease severity in adults and developing novel therapies against SARS-CoV-2.

Immunology of pediatric COVID-19

In the present study, researchers summarized reports that investigated cytokine profiles, pre-existing immunity, antibody, B-cell, and innate responses among children diagnosed with multisystem inflammation and acute COVID-19.

Studies have reported multiple phases of the human immune response against COVID-19 infection. Among adult patients, the first phase involves a protective immune response that aims to eliminate the virus. The second phase is characterized by a dysregulated or over-activated host response along with a more severe multi-system disorder. The third phase includes the post-acute COVID-19 sequelae and is called ‘long-COVID’. Most pediatric patients have been reported to display an effective first-phase response while a small proportion of patients develop a hyperinflammatory response leading to multisystem inflammatory syndrome in children (MIS-C).

Pre-existing immunity

Heterogeneous outcomes observed after SARS-CoV-2 infections are likely a result of pre-existing immunity derived from prior exposure to seasonal Coronaviruses like HCoV-229E and HCoV-NL63. While most primary Coronavirus infections are reported in childhood, high incidences of reinfection occur in adults. Moreover, adults residing with children in the same household have an increased risk of exposure to viruses and increased cross-reactive immunity, thus leading to a lower risk of COVID-19 infection proportional to the higher number of children sharing the household.

Furthermore, individuals with a history of previous seasonal Coronavirus infection had a lower chance of experiencing severe COVID-19 as well as better survival probability as opposed to those with no history. A study found that 62% of children and 5% of adults had cross-reactive antibodies, which displayed a neutralizing activity against SARS-CoV-2. In contrast, another study noted that the cross-reactive antibodies found were rarely neutralizing.     

Pathogenesis of MIS-C

Similarities of MIS-C with other disorders such as toxic shock syndrome, macrophage activation syndrome, and sepsis have triggered further research to understand MIS-C pathogenesis and treatment. These include the measurement of cytokine and the determination of adaptive or innate immune responses in MIS-C.

Cytokine response

Studies have demonstrated a remarkable inflammatory profile characterized by an anti-inflammatory response in all the patient groups with slight variations between COVID-19-pneumonia and MIS-C. Interferon-alpha (IFN⍺) was at a comparable or higher proportion in MIS-C as compared to adult COVID-19 infections, while interleukin-10 (IL-10), IL-17, and tumor necrosis factor alpha (TNF-α) were at higher levels in MIS-C than in adults. Chemokines are involved in the activation and recruitment of several immune cells such as T cells, natural killer (NK) cells, monocytes, and neutrophils.

Innate response

Various studies suggest that an early and significant innate response plays a key role in the determination of COVID-19 disease severity. This led to the possibility that an excessive innate response was important in the development of MIS-C. IFN release along with the induction of cytokines such as IL-1, IL-6, IL-18, and TNF-α resulted in the suppression of viral load and the stimulation of the adaptive immune response. A study highlighted the importance of adequate IFN response by detecting inborn mutations in IFN signaling in 3.5% of lethal COVID-19 cases. In contrast, another study showed that 13% of the patients experiencing severe COVID-19 had autoantibodies against type 1 IFN.                  

B-cell/antibody response

A study showed comparable anti-SARS-CoV-2 spike protein responses among MIS-C and acute COVID-19 patients and adult donors of convalescent plasma. However, adults diagnosed with COVID-pneumonia displayed the highest concentrations of anti-spike protein responses. While neutralizing antibodies were noted in children after diagnosing varying severities of COVID-19, adults had higher concentrations of neutralizing antibodies than children. At the same time, no such difference was observed among children with acute COVID-19 and MIS-C.

Another study observed broadly normal frequencies of B-cells among MIS-C patients. Furthermore, increased immunoglobulin G1 (IgG1) and IgG3 plasmablasts were also detected among children with MIS-C and acute COVID-19. Moreover, MIS-C patients had lower levels of plasmablasts displaying somatic hypermutation. At the same time, the same levels were higher in severe MIS-C cases than in non-severe MIS-C cases.         

Treatment of MIS-C

The international Best Available Treatment Study (BATS) has provided sufficient evidence to conclude that the commonly used immunomodulatory treatments such as corticosteroids, intravenous immunoglobulin (IVIG), or a combination of corticosteroids and IVIG are related to a faster resolution of inflammation as compared no immunomodulatory therapy. Some studies have displayed rapid resolution of cardiac dysfunction among patients who initially received IVIG and corticosteroid treatment as opposed to those treated with IVIG alone.

Overall, the study summarized the various immunopathogenic aspects of MISC-C and pediatric COVID-19.

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