A new proteomics study reveals that even short-term COVID-19 in children can leave behind blood markers of cardiovascular risk, particularly in those with MIS-C, challenging the notion that children recover unscathed.
Study: Children with Post COVID-19 Multisystem Inflammatory Syndrome Display Unique Pathophysiological Metabolic Phenotypes. Image Credit: Chatchai.wa / Shutterstock
Observational accounts have led many clinicians to believe that, unlike their adult counterparts, children generally experience milder outcomes from SARS-CoV-2 infection. However, the underlying metabolic effects have not been fully characterized. In a recent study in the Journal of Proteome Research, a collaborative research team from the Australian National Phenome Centre and Harvard analysed blood plasma samples (n = 147) from pediatric patients to investigate these effects.
Advanced blood characterization tools identified acute disruptions in lipid and lipoprotein metabolism, known markers of long-term cardiovascular risk. During acute COVID-19 infections, children exhibit plasma signatures similar to those observed in adults with severe COVID-19, which contain markers associated with long-term cardiovascular risk. This study challenges the assumptions of a universally mild pediatric COVID-19 and calls for further investigation and monitoring in children to mitigate future cardiovascular disease (CVD) risk.
Background
Children have long been considered largely untouched by COVID-19’s long-term consequences, especially concerning heart health. However, the emergence of multisystem inflammatory syndrome in children (MIS-C), alongside broader reports of persistent symptoms in pediatric long COVID cases, has shattered these perceptions, demonstrating that SARS-CoV-2 can spark life-threatening systemic inflammation weeks after recovery from mild COVID-associated respiratory illnesses.
MIS-C is a rare but severe condition characterized by potentially life-threatening multi-organ inflammation across cardiovascular, gastrointestinal, and mucocutaneous systems. A growing body of evidence suggests shared metabolic pathways between some post-COVID illnesses and the severe inflammatory response seen in MIS-C.
Unfortunately, given the relative novelty of COVID-19 and the prevailing scientific views on child-associated SARS-CoV-2 outcomes, only a handful of studies have explored the lingering metabolic effects of pediatric COVID-19. Data from blood-based biomarker analyses, particularly those that identify previously undetected, long-term cardiovascular risks, are lacking.
About the study
The present study aims to address existing scientific knowledge gaps by conducting a comprehensive suite of advanced biochemical and proteomic assays on children during acute COVID-19 and MIS-C.
Study data were obtained from the Massachusetts General Hospital Pediatric COVID-19 Biorepository, Boston, US, and included sociodemographic information and medical health records. Biometric measures and plasma samples were collected once from each participant during their acute illness.
US Centers for Disease Control and Prevention (CDC) definitions were used to classify the study participants into three categories: 1. Healthy children who had never been infected by SARS-CoV-2 (healthy), 2. Acute COVID-19 (COVID-19), and 3. Confirmed MIS-C cases (MIS-C). All participant plasma samples were subjected to high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) to facilitate the identification of a broad spectrum of metabolites.
To obtain a detailed metabolic fingerprint, researchers used nuclear magnetic resonance (NMR) data to identify and quantify cholesterol and its derivatives, triglycerides, and inflammatory markers. They then compared these metabolic profiles to those from a previously studied cohort of adults with COVID-19.
Statistical analyses included principal component analyses (PCAs) to identify the primary sources of data variation, random forest data imputation (for missing data), and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) for elucidating infection-associated data variance. The data were subsequently analyzed and visualized using multivariate analyses, adjusted for demographics and other confounding factors.
Study findings
The final study sample cohort comprised 147 children. CDC guidelines classified these participants into three groups: 1. 66 healthy children (no SARS-CoV-2 infections), 2. 55 with acute COVID-19 infections (25% severe), and 3. 26 with MIS-C. MIS-C patients exhibited symptoms involving the cardiovascular, mucocutaneous, and gastrointestinal systems.
Study findings revealed several alarming outcomes:
Children with COVID-19 (particularly those with MIS-C) demonstrated marked alterations in lipid metabolism during their acute illness. These include elevated triglyceride levels indicative of pediatric hypertriglyceridemia, marked reductions in high-density lipoprotein (HDL) concentrations, and increased inflammatory lipoproteins, as well as certain low-density lipoprotein (LDL) particles.
Elevated triglycerides and specific LDL particles are hallmarks of early cardiovascular disease, while HDL cholesterol is a known protective factor against cardiovascular disease (CVD) risk. These findings hence suggest that children with acute COVID-19 (especially MIS-C patients) exhibit a profile that may place them at increased risk of chronic CVD outcomes.
Lipoprotein analyses revealed that the inflammatory lipoproteins in children with COVID-19 and MIS-C showed a strong similarity to those seen in adults with severe COVID-19.
The authors also noted a high prevalence of overweight and obesity in the patient cohorts, which they suggest could be a contributing factor that exacerbates the observed lipid abnormalities and future cardiovascular risk.
Notably, individuals in the healthy control group did not mirror any of these findings, suggesting a COVID-19-specific metabolic shift in childhood patients.
Conclusions
The present study debunks the comforting assumption that children experience mild COVID-19 infections without lasting consequences. It highlights that children with acute COVID-19 and MIS-C develop metabolic profiles closely resembling those containing markers of future cardiovascular risk. MIS-C patients, in particular, showed significant metabolic disruption, foreshadowing potential long-term cardiovascular risk.
These insights underscore the need for further investigation into the lasting effects of SARS-CoV-2 infection on pediatric health. Clinicians and public health officials must now consider that follow-up beyond respiratory recovery may be warranted to facilitate timely treatment and mitigate potential long-term health implications.
Journal reference:
- Lawler, N. G., Yonker, L. M., Lodge, S., Nitschke, P., Leonard, M. M., Gray, N., Whiley, L., Masuda, R., Holmes, E., Wist, J., Fasano, A., & Nicholson, J. K. (2025). Children with Post COVID-19 Multisystem Inflammatory Syndrome Display Unique Pathophysiological Metabolic Phenotypes. Journal of Proteome Research. DOI: 10.1021/acs.jproteome.5c00062, https://pubs.acs.org/doi/10.1021/acs.jproteome.5c00062