| dc.description.abstract | Long COVID may be defined as a “post-COVID-19 condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis” (World Health Organization). To date, little is known about the pathophysiological background of Long COVID, especially in adolescents and young adults. One of the hallmark symptoms of Long COVID is fatigue, affecting the daily life of these individuals. The aim of the present study was thus to examine the presence and etiology of long-lasting symptoms in Norwegian adolescents with and without COVID-19 infection during the COVID-19 pandemic. Hence, non-hospitalized SARS-CoV-2 positive (n = 404) and SARS-CoV-2 negative (n = 105) adolescents aged 12-25 years were followed prospectively for twelve months after SARS-CoV-2 testing. During this period, all participants underwent regular assessments including clinical examination, questionnaires and blood sampling. Immunological assays, including RNA-sequencing of whole blood and deep immune profiling of peripheral blood mononuclear cells (PBMC) by cytometry by time-of-flight, were performed and showed that participants with Long COVID had an altered gene expression in whole blood 6 months post-COVID. Gene alterations were mostly related to pathways involving the immune system, in addition to cell cycle, homeostatic stress and organization of the extracellular matrix. Additionally, when investigating in vitro immune responses in PBMC from the study participants, changes in the immune cell frequencies/phenotypes associated with both Long COVID after earlier COVID-19 infection and fatigue symptoms in non-COVID-19 participants, were observed. This might indicate that there are two types of Long COVID: one “true” Long COVID following COVID-19 infection with a pathophysiological background, and another type of Long COVID that could be a consequence of pandemic-associated stress. Moreover our data showed that “true” Long COVID participants had increased lipopolysaccharide (LPS) induced B cell frequency and cytokine expression, and also decreased LPS induced monocyte cytokine expression compared to COVID recovered and healthy controls. Hence, the present study adds to the understanding of how the “true" Long COVID symptoms are associated with long-term immune changes in adolescents. In addition, Long COVID may be related to increased LPS responsiveness of the immune system, including upregulation of transitional B cells, increased cytokine production in HLA-DR+ and CD45RA+ B cells and decreased cytokine expression from patrolling monocytes after LPS exposure. We conclude that COVID-19 infection leaves an imprint on the immune system in patients that develop Long COVID symptoms in a different way than in those who recover. | eng |