Markers of Epstein-Barr virus and Human Herpesvirus-6 infection and multiple sclerosis clinical progression

Chunrong Tao; Steve Simpson-Yap; Bruce Taylor; Leigh Blizzard; Robyn Lucas; Anne-Louise Ponsonby; Simon Broadley; Ingrid van der Mei; AusLong/Ausimmune Investigators Group

doi:10.1016/j.msard.2022.103561

Markers of Epstein-Barr virus and Human Herpesvirus-6 infection and multiple sclerosis clinical progression

Mult Scler Relat Disord. 2022 Mar:59:103561. doi: 10.1016/j.msard.2022.103561. Epub 2022 Jan 25.

Authors

Chunrong Tao¹, Steve Simpson-Yap², Bruce Taylor³, Leigh Blizzard³, Robyn Lucas⁴, Anne-Louise Ponsonby⁵, Simon Broadley⁶, Ingrid van der Mei⁷; AusLong/Ausimmune Investigators Group⁸

Affiliations

¹ Multiple Sclerosis Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² Multiple Sclerosis Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, Australia. Electronic address: steve.simpsonyap@unimelb.edu.au.
³ Multiple Sclerosis Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
⁴ National Centre for Epidemiology and Population Health, Research School of Population Health, Australian National University, Canberra, Australia; Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia.
⁵ Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia; Murdoch Children's Research Institute, The University of Melbourne, Melbourne, Australia.
⁶ School of Medicine, Gold Coast Campus, Griffith University QLD, Australia.
⁷ Multiple Sclerosis Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. Electronic address: ingrid.vandermei@utas.edu.au.
⁸ A full list of members is provided in the Acknowledgments.

PMID: 35131728
DOI: 10.1016/j.msard.2022.103561

Abstract

Background: Infections with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) have been implicated in multiple sclerosis (MS) onset but little work has studied their relationships in early disease.

Objective: Evaluate associations between markers of EBV and HHV-6 infection/reactivation and MS conversion, relapse and EDSS/MSSS amongst 205 CIS participants with EBV/HHV-6 data followed over 5 years.

Method: Baseline serological and viral load measures of EBV and HHV-6 exposure/reactivation were measured and infectious mononucleosis (IM) history recorded. Conversion to MS and relapses were assessed annually, and EDSS/MSSS measured at 5-year review. Determinants of MS conversion and relapse assessed by Cox regression, and disability progression by linear regression.

Results: IM history showed a strong positive trend with higher relapse risk (aHR=1.45,95%CI=0.97-2.16) but was not associated with MS conversion (aHR=0.92,95%CI=0.57-1.48). Anti-HHV-6 IgG titre>40 also showed strong positive trends with higher relapse (aHR=1.61,95%CI=0.99-2.63) and MS conversion risks (aHR=1.48,95%CI=0.89-2.46). Anti-HHV-6 IgG titre≥640 was significantly associated with higher MSSS (0.15(95%CI=0.00,0.30) and also showed a strong positive trend with higher EDSS 0.10(95%CI=-0.02,0.21). HHV-6 DNA detection showed strong positive trends with 83%(95%CI=-6-357) and 77%(95%CI=-4-328) higher MS conversion and relapse risk. Anti-EBV-EA-D IgG titre was associated with a lower annualised disability progression by EDSS (p_trend=0.037) and also showed strong positive trend with higher MSSS (p_trend=0.053). No associations were seen for other serological or viral load markers.

Conclusion: Overall, our data provides evidence that higher HHV-6 IgG was associated with increased risk of MS conversion and relapse but of borderline significance, and greater annualised disability progression, while that for EBV was more limited.

Keywords: Conversion; Epstein-Barr virus; First demyelinating event; Human herpesvirus-6; Relapse; multiple sclerosis.

MeSH terms

Antibodies, Viral
Epstein-Barr Virus Infections* / complications
Epstein-Barr Virus Infections* / epidemiology
Herpesvirus 4, Human / genetics
Herpesvirus 6, Human* / physiology
Humans
Infectious Mononucleosis* / complications
Multiple Sclerosis* / diagnosis

Substances

Antibodies, Viral