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Original research
Increased cytomegalovirus immune responses at disease onset are protective in the long-term prognosis of patients with multiple sclerosis
  1. Manuel Comabella1,
  2. Mar Tintore1,
  3. Augusto Sao Avilés1,
  4. Pere Carbonell-Mirabent1,
  5. Sunny Malhotra1,
  6. Alex Rovira2,
  7. Nicolás Fissolo1,
  8. Jan D Lünemann3,
  9. Xavier Montalban1
  1. 1 Neurology-Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron University Hospital, Barcelona, Spain
  2. 2 Servei de Neuroradiología, Vall d'Hebron University Hospital, Barcelona, Spain
  3. 3 Neurology, Faculty of Medicine, University of Münster, Munster, Germany
  1. Correspondence to Dr Manuel Comabella, Neurology-Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron University Hospital, Barcelona 08035, Spain; manuel.comabella{at}


Objective It remains unclear whether viral infections interfere with multiple sclerosis (MS) disease progression. We evaluated the prognostic role of antibody responses toward viruses determined at disease onset on long-term disease outcomes.

Methods Humoral immune responses against Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1, viral capsid antigen (VCA) and early antigen, and toward cytomegalovirus (HCMV), human herpesvirus 6 and measles were investigated in a cohort of 143 patients with MS for their association with long-term disability and inflammation disease outcomes.

Results Median (IQR) follow-up was 20 (17.2–22.8) years. In univariable analysis, increased HCMV levels were associated with a lower risk to Expanded Disability Status Scale 4.0 (HR 0.95; 95% CI 0.91 to 0.99; p=0.03), to develop a secondary progressive MS (HR 0.94; 95% CI 0.90 to 0.99; p=0.02) and to first-line treatment (HR 0.98; 95% CI 0.96 to 0.99; p=0.04). High HCMV IgG levels were associated with a longer time to first-line treatment (p=0.01). Increased immune responses against EBV-VCA were associated with higher risk for first-line (HR 1.45; 95% CI 1.12 to 1.88; p=0.005) and second-line treatments (HR 2.03; 95% CI 1.18 to 3.49; p=0.01), and high VCA IgG levels were associated with shorter time to first-line (p=0.004) and second-line (p=0.02) therapies. EBNA1-specific IgG levels correlated with disease severity (0.17; p=0.04) and with an increased relapse rate during follow-up (relapse rate 1.26; 95% CI 1.03 to 1.56; p=0.02) that remained stable in multivariable analysis.

Conclusions These results indicate that elevated immune responses against HCMV at disease onset have protective effects on long-term disability and inflammation disease outcomes. Our data also indicate that increased immune responses against EBV in early phases may influence long-term disease prognosis.

  • multiple sclerosis

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • Contributors MC conceptualised and designed the study. MT, AR, SM, NF and XM acquired the data. ASA and PC-M conducted the analysis. MC wrote the first draft of the manuscript. MC, MT, ASA, PC-M, SM, AR, NF, JDL and XM revised the work for valuable intellectual content and final approval of the version. MC accepts full responsibility for the work and conduct of the study and had access to the data. MC is also responsible for the overall content as guarantor for the article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.