Circulating cell-free mitochondrial DNA as a candidate marker of hyperinflammation and immune activation in pre-adolescents, adolescents and young adults with COVID-19 and comorbidities

Youth encompasses pre-adolescence (10-14 years), adolescence (15-17 years), and young adulthood (18-24 years). Adolescents in general, particularly those with comorbidities, appear more susceptible to severe COVID-19, a vulnerability also observed in newborns and young infants. The mechanisms underlying this increased risk remain unclear, highlighting the need for early disease biomarkers. Circulating cell-free mitochondrial DNA (ccf-mtDNA), a damage-associated molecular pattern (DAMP), has been linked to systemic inflammation and immune activation during viral infections. This study evaluated plasma ccf-mtDNA levels in pre-adolescents, adolescents, and young adults with and without COVID-19, all presenting respiratory symptoms and predominantly harboring comorbidities, some with coinfections by other respiratory viruses. In this prospective study of 88 participants aged 12-21 years, half tested positive and half negative for SARS-CoV-2 by Reverse-Transcribed Polymerase Chain Reaction (RT-PCR). Comorbidities were present in 75% of COVID-19-positive and 54.5% of COVID-19-negative participants. Coinfections were detected in 52.3% and 25% of tested participants, respectively. Plasma ccf-mtDNA was quantified by a quantitative Real Time PCR (qPCR) targeting the mitochondrial NADH dehydrogenase 2 (ND2) gene or MT-ND2. COVID-19-positive participants exhibited significantly higher ccf-mtDNA levels than both symptomatic COVID-19-negative individuals and healthy controls (p