Epstein-Barr Virus Infection Triggers Hyperinflammation and Cytokine Storm in Healthy Children

Kailey Brodeur¹, Meng Liu², Rachel Weng², Evan Hsu², Lauren Henderson³, Fatma Dedeoglu², Jane Newburger³, Peter Nigrovic⁴, Mary Beth Son⁴ and Pui Lee⁵, ¹Boston Children's Hospital, Cumberland, RI, ²Boston Children's Hospital, Boston, MA, ³Boston Children's Hospital, Watertown, MA, ⁴Boston Children's Hospital, Brookline, MA, ⁵Boston Children's Hospital, Newton, MA

Meeting: ACR Convergence 2024

Keywords: cytokines, Infection, Inflammation, macrophage activation syndrome, Pediatric rheumatology

Session Information

Date: Saturday, November 16, 2024

Title: Abstracts: Pediatric Rheumatology – Basic Science

Session Type: Abstract Session

Session Time: 3:00PM-4:30PM

Background/Purpose: Epstein-Barr virus (EBV) is common pathogen responsible for infectious mononucleosis but also triggers hemophagocytic lymphohistiocytosis (HLH). This variation in the immune response to EBV is unexplained.

Methods: We recruited 352 children who presented to the emergency room with fever for ≥ 3 days. We performed immune profiling on 110 cases with confirmed viral infections using Olink proximity extension assay and flow cytometry. We compared the findings with cases of HLH (n=8), macrophage activation syndrome (MAS; n=18), Kawasaki disease (KD; n=20), and multisystem inflammatory syndrome in children (MIS-C; n=17).

Results: We studied 110 otherwise healthy children with confirmed viral infections, including EBV, adenovirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza virus, parainfluenza virus, and respiratory syncytial virus (RSV; Figure 1A). Using Olink proximity assay to profile 45 proinflammatory mediators, we found that acute EBV infection uniquely triggered high levels of multiple cytokines (IL-18, IL-27, tumor necrosis factor, and lymphotoxin alpha) and IFN-γ-induced chemokines (CXCL9 and CXCL11; Figure 1B). The pattern of cytokine and chemokine production are similar to the cytokine storm associated with HLH / MAS, but less consistent with the findings in KD and MIS-C (Figure 1C-D). Flow cytometry analysis revealed that CD38+HLA-DR+ T lymphocytes, which are pathogenic cells responsible for IFN-γ production in HLH / MAS, are vastly expanded in patients with acute EBV infection (Figure 2A), but not other viral infections. Cell sorting and morphology analysis identified CD38+HLA-DR+ T cells as atypical lymphocytes that are classically associated with EBV infection (Figure 2B).

Conclusion: These findings place acute EBV infection in the cytokine storm spectrum and inform both the unique clinical presentation of this disease and its connection to HLH.

Figure 1. Immune profiling of common viral infections in children. A) Schematic illustrating the study groups and identification of viral pathogens among patients with confirmed viral infection. B) Cytokine and chemokine levels quantified by Olink proximity extension assay. Comparison groups included healthy controls (n=15), and patients with adenovirus (n=28), EBV (n=19), RSV (n=18), SARS-CoV_2 (n=13), influenza virus (n=12), or parainfluenza virus (n=7) infection. Dotted line indicates upper limit of detection. P-value from Kruskal-Wallis test is indicated. # indicates p < 0.05 compared to all other groups after adjustment for multiple comparisons by Dunn’s test. C-D) Radar plots illustrating the median expression percentile of key cytokines (panel C) and chemokines (panel D) in healthy controls and patients with EBV, MAS, HLH, non-EBV viral infections, MIS-C or KD. The expression level of each analyte was normalized based on the percentile relative to the entire dataset and the median value of each group is plotted. The EBV group (green dotted line) is displayed in each plot to allow comparison to other groups.

Figure 2. Expansion of CD38+HLA-DR+ T cells in acute EBV infection. A) Representative flow cytometry plot of CD38+HLA-DR+ T cells (as percentage of CD4+ and CD8+ T lymphocytes) in healthy controls, and patients with EBV infection, HLH or MAS. B) Representative images and cell size quantification of sorted CD38+HLA-DR+ T cells and CD38-HLA-DR- T cells within the CD4+ and CD8+ T lymphocyte populations from a patient with EBV infection. Mann Whitney U test was used for comparison. * p<0.0001.

Disclosures: K. Brodeur: None; M. Liu: None; R. Weng: None; E. Hsu: None; L. Henderson: Adaptive Biotechnologies, 5, Bristol-Myers Squibb(BMS), 5, Pfizer, 1, Sobi, 2; F. Dedeoglu: UpToDate, 9; J. Newburger: None; P. Nigrovic: American Academy of Pediatrics, 9, Bristol-Myers Squibb(BMS), 5, Century Therapeutics, 2, Edelweiss Immuno, 8, Fresh Tracks Therapeutics, 2, Merck/MSD, 2, Monte Rosa Therapeutics, 2, Novartis, 2, Pfizer, 2, 5, Qiagen, 2, Sobi, 2, UpToDate, 9; M. Son: None; P. Lee: None.

To cite this abstract in AMA style:

Brodeur K, Liu M, Weng R, Hsu E, Henderson L, Dedeoglu F, Newburger J, Nigrovic P, Son M, Lee P. Epstein-Barr Virus Infection Triggers Hyperinflammation and Cytokine Storm in Healthy Children [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/epstein-barr-virus-infection-triggers-hyperinflammation-and-cytokine-storm-in-healthy-children/. Accessed .

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