Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond

Abstract

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

Case report: Presentations and cytokine profiles of inflammatory non-pulmonary COVID-19 and related diseases in children

“…ANE associated with COVID-19 is not a novel disease entity; in fact, ANE usually occurs to children after an infection with influenza, rotavirus, enterovirus, or herpes virus ( 17 , 18 ). In Asia, ANE is prominently related to an influenza infection associated with a sudden onset of high fever and intractable seizure, and progresses to necrosis of deep brain neurons with a high fatality within a few days ( 17 , 18 ).…”

“…ANE associated with COVID-19 is not a novel disease entity; in fact, ANE usually occurs to children after an infection with influenza, rotavirus, enterovirus, or herpes virus ( 17 , 18 ). In Asia, ANE is prominently related to an influenza infection associated with a sudden onset of high fever and intractable seizure, and progresses to necrosis of deep brain neurons with a high fatality within a few days ( 17 , 18 ). Although the prevalence of ANE is much lower in Caucasians, it could occur to subjects with mutations in the RAN binding protein 2 ( RANBP2 ) gene, named as ANE type 1 ( ANE1 ), which can be familial and recurrent ( 18 ).…”

“…In Asia, ANE is prominently related to an influenza infection associated with a sudden onset of high fever and intractable seizure, and progresses to necrosis of deep brain neurons with a high fatality within a few days ( 17 , 18 ). Although the prevalence of ANE is much lower in Caucasians, it could occur to subjects with mutations in the RAN binding protein 2 ( RANBP2 ) gene, named as ANE type 1 ( ANE1 ), which can be familial and recurrent ( 18 ). Many other genes involved in the metabolism or immunity have been linked to ANE, including neuronal sodium voltage-gated channel alpha subunit 1 ( SCN1A ), carnitine palmitoyltransferase II ( CPT2 ), and human thiamine transporter 2 (h THTR2 ) ( 18 ).…”

“…Although the prevalence of ANE is much lower in Caucasians, it could occur to subjects with mutations in the RAN binding protein 2 ( RANBP2 ) gene, named as ANE type 1 ( ANE1 ), which can be familial and recurrent ( 18 ). Many other genes involved in the metabolism or immunity have been linked to ANE, including neuronal sodium voltage-gated channel alpha subunit 1 ( SCN1A ), carnitine palmitoyltransferase II ( CPT2 ), and human thiamine transporter 2 (h THTR2 ) ( 18 ). Both CPT2 and h THTR2 mutations are very sensitive to febrile infections in which mitochondrial dysfunction is linked to hyperinflammation ( 17 , 18 ).…”

“…Many other genes involved in the metabolism or immunity have been linked to ANE, including neuronal sodium voltage-gated channel alpha subunit 1 ( SCN1A ), carnitine palmitoyltransferase II ( CPT2 ), and human thiamine transporter 2 (h THTR2 ) ( 18 ). Both CPT2 and h THTR2 mutations are very sensitive to febrile infections in which mitochondrial dysfunction is linked to hyperinflammation ( 17 , 18 ). We treated this patient with a combination of IVIG, pulse methylprednisolone, and hypothermia (33.5 °C) therapies in 24 h. This treatment resulted in a decrease in the lactate and CRP levels, but it did not rescue the severe neurological sequela.…”