Investigators from Harvard University and Murdoch University in Australia have published new study results in the Journal of Proteome Research indicating the presence of significant metabolic disruptions in children with varying conditions of COVID-19 infection, with the development of multisystem inflammatory syndrome in children (MIS-C) associated with particularly major shifts in blood metabolic patterns, including those associated with cardiovascular disease risk factors.1,2
With little research on long-term cardiovascular complications following childhood SARS-CoV-2 infection, insights into possible metabolic shifts post-infection are sorely needed. | Image Credit: © Chinnapong – stock.adobe.com
Some Children Face Serious Long-Term Risks Following COVID-19
Although children are thought to be mostly less susceptible to the potentially serious lung impacts associated with COVID-19 compared with adults, they are at unique risk of developing MIS-C, a rare, hyperinflammatory syndrome that often appears a month or more following SARS-CoV-2 infection. Despite being associated with difficult short-term complications, MIS-C can also lead to long-term difficulties, including severe gastrointestinal (GI) symptoms and cardiovascular injury. MIS-C is closely related to long COVID, which is a more indolent but increasingly chronic syndrome that results in long-lasting illness and neurological complications.1,3
What researchers find especially concerning about the disease is the involvement of cardiovascular processes. Because of the age of the children impacted by MIS-C or long COVID, the long-term cardiovascular complications possible with these chronic conditions are not fully recognized and could remain so without adequate research. Metabolic profiling is a novel tool that enables the profiling of specific disease states analyzed against a reference framework of population data and can offer key insights into biochemical shifts and patterns that arise in children following SARS-CoV-2 infection.1,4
It is known that, compared with uninfected individuals, adults infected with SARS-CoV-2 demonstrate sustained, perturbed metabolic patterns. These can include altered glutamine/glutamate ratios—indicating ongoing liver or muscle injury—and an increase in systemic inflammatory biomarkers. Investigators have also observed altered lipoproteins in individuals post-SARS-CoV-2 infection, with increases in apolipoprotein (apo-) B100/Apo-A1 ratio (ABA1) and low-density lipoprotein-bound triglyceride (LDTG), known markers for cardiovascular risk. However, as previously mentioned, possible metabolic changes in children with COVID-19 remain unexplored.1,4
Metabolic Profiling Reveals Shifts in Cardiovascular Risk in Children With SARS-CoV-2
Therefore, the current authors performed extensive, multivariate metabolic profiling on 147 children following infection with SARS-CoV-2 to elucidate the lasting impact of SARS-CoV-2 infection in children and children with MIS-C. Using novel analytic techniques and mathematical models, they sought to identify metabolic shifts through the postinfectious period and key metabolic biomarkers associated with acute COVID-19 infection in children with MIS-C. Blood samples were produced from the Massachusetts General Hospital Pediatric COVID-19 Biorepository in Boston, Massachusetts, ultimately constituting the largest cohort of metabolic profiling in children following SARS-CoV-2 infection as of publication.1
Samples included children in various stages of infection, including 55 children with acute COVID-19, 26 children with MIS-C, and 66 healthy children who were never infected with SARS-CoV-2. The authors performed deep metabolic phenotyping on 1101 quantitated metabolites, which demonstrated that both pediatric COVID-19 and MIS-C displayed distinct metabolic profiles compared with healthy children. There were marked shifts in lipid classes in children with COVID-19 and MIS-C; major shifts were observed in high-density lipoprotein (HDL)-2 and HDL-3-related parameters, LDL-related parameters, Apo-A1, and Apo-A2 between infected and healthy individuals.1
Since children often experience milder respiratory symptoms than adults with COVID-19, the authors compared the prevalence of key perturbed inflammatory markers in adults with children with acute COVID-19 and MIS-C. They found a strong intersection in metabolic perturbations between adults and children over multiple aspects despite clinical differences in severity. Critically, they found consistent elevations in the Apo-B100/Apo-A1 ratio, triglycerides, and LDL parameters, demonstrating that the acute inflammatory markers observed in adults with COVID-19 appear to be similar in children, despite their experiencing lesser symptoms.1
With Clear Long-Term Cardiovascular Risk, Further Research is Necessary
The investigators constructed a univariate analysis of the top discriminatory inflammatory and cardiovascular markers often found in the metabolic profiles of acute pediatric COVID-19 and MIS-C to determine the metabolites associated with cardiovascular risk in this population. Apo-A1 was observed to decrease in both acute COVID-19 and MIS-C, while Apo-B100 was predominantly increased in MIS-C. Notably, both pediatric cohorts indicated an increased Apo-B100/Apo-A1 ratio, which is an established predictive marker of atherosclerosis and future cardiovascular disease. Furthermore, HDL and LDL cholesterol were found to be decreased in both acute COVID-19 and MIS-C.1
Overall, the results of this study indicate similarities between the molecular signatures of not just pediatric MIS-C and COVID-19, but between pediatric and adult infection in general. In this study, patients with MIS-C were more severely affected and had more severe alterations to metabolic parameters. However, the authors observed that children may be better able to sustain metabolic homeostasis when infected with SARS-CoV-2, as only minor metabolic changes were demonstrated with acute infection. Despite this, the persistence of inflammatory and cardiovascular markers following SARS-CoV-2 infection raises prominent concerns regarding long-term health impacts and necessitates further research.1,2
“This research challenges the widespread assumption that children are largely unaffected by COVID-19 based on the relatively mild respiratory effects,” Jeremy Nicholson, professor and lead researcher of the study, said in a news release. “However, a minority of children experience a more severe immunologically driven form of [MIS-C] that is associated with longer-term GI effects and cardiovascular disease.”2