Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Børre Fevang, Vegard Bruun Bratholm Wyller, Tom Eirik Mollnes, Maria Pedersen, Tarjei Tørre Asprusten, Annika Michelsen, Thor Ueland, Kari Otterdal, Børre Fevang, Vegard Bruun Bratholm Wyller, Tom Eirik Mollnes, Maria Pedersen, Tarjei Tørre Asprusten, Annika Michelsen, Thor Ueland, Kari Otterdal

Abstract

Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics.

Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively.

Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group.

Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT02335437" title="See in ClinicalTrials.gov">NCT02335437.

Keywords: CFS; CRP; EBV; Epstein-Barr virus; RANTES; chronic fatigue syndrome; fatigue; infectious mononucleosis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Fevang, Wyller, Mollnes, Pedersen, Asprusten, Michelsen, Ueland and Otterdal.

Figures

Figure 1
Figure 1
Supernatant levels of IL-1β, IL-1Ra, IL-2, IL-6, IL-8, IL-10, MIP-1α, MIP-1β, VEGF and mGSF in cell cultures of PBMC from healthy controls (CTR) and EBV-patients with and without chronic fatigue (CF+ and CF-, respectively) at baseline and after 6 months. *p†p<0.05, CF+ vs CF-.
Figure 2
Figure 2
Supernatant levels of TNF, IFN- γ, RANTES, MCP-1 and IP-10 in cell cultures of PBMC from healthy controls (CTR) and EBV-patients with and without chronic fatigue (CF+ and CF-, respectively) at baseline and after 6 months. *p†p<0.05, ††p<0.01 CF+ vs CF-.
Figure 3
Figure 3
Plasma levels of cytokines and inflammatory markers in healthy controls (HC) and EBV patients with and without fatigue (CF+ and CF-, respectively) at baseline and after 6 months. Black p-value group effect, CF+ vs CF- irrespective of time. Red p-value time effect irrespective of group. Green p-value interaction of time vs group. Levels of controls with 95% CI marked in light green.

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