Retrospective In Silico Analysis of Routine Laboratory Data Supports a Specific Association of Epstein–Barr Virus and Multiple Sclerosis

FIGURE 1. EBV seroprevalences in patients with MS and patients with 10 different control diseases. The number of patients with a given diagnosis is indicated in parentheses. Statistical significance of differences of the EBV seroprevalences between patients with MS and patients with other diseases was assessed by Chi‐square tests, demonstrating significant differences in all pairwise comparisons (p < 0.05). AE = autoimmune encephalitides, MG = myasthenia gravis, MS = multiple sclerosis, NMO = neuromyelitis optica, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, SS = Sjogren's syndrome.

FIGURE 2. Correlation of EBV seroprevalence rates with the mean age of patients in the 10 different control disease groups. The significance of the association of EBV seroprevalences with age was assessed by Spearman rank correlation. AE = autoimmune encephalitides, BL = Burkitt's lymphoma, HL = Hodgkin's lymphoma, LD = Lyme disease, MG = myasthenia gravis, NMO = neuromyelitis optica, r = Spearman's r, RA = rheumatoid arthritis, SA = sarcoidosis, SLE = systemic lupus erythematosus, SS = Sjogren's syndrome.

FIGURE 3. Levels of EBNA‐1 IgG (A) and VCA IgG (B) in sera of patients with MS and patients with 10 other diseases. The number of patients with a given diagnosis is indicated in parentheses. Statistical significance of differences between patients with MS and patient with other diseases was assessed by Mann Whitney tests. Thick horizontal lines indicate the median. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. AE = autoimmune encephalitides, EBNA‐1 = Epstein–Barr nuclear antigen‐1, IgG = immunoglobulin G, MG = myasthenia gravis, MS = multiple sclerosis, NMO = neuromyelitis optica, RA = rheumatoid arthritis, SS = Sjogren's syndrome, VCA = viral capsid antigen.

FIGURE 4. (A) Seroprevalences of EBV and six other common viruses in patients with MS. The number of patients with results of antiviral antibody tests available is indicated in parentheses. (B) Frequencies of elevated AIs (AI > 1.5) to EBV and six other common viruses among patients with MS in whom AIs to the respective viruses were determined. The number of patients with results of AI determinations available is indicated in parentheses. (C) Index indicating the frequencies of an elevated antiviral AI among patients with MS with available results of AI determinations divided through the seroprevalence of the respective virus in patients with MS. The number of patients included in the analyses is indicated in parentheses. (D) Absolute AI values for EBV and 6 further microbes in patients with MS. The number of patients with available data is indicated in parentheses. Thick horizontal lines indicate the mean. The dashed line indicates the cut‐off of 1.5, AI levels above which were considered elevated. AI = antibody index, CMV = cytomegalovirus, EBV = Epstein–Barr virus, HSV = herpes simplex virus, VZV = varicella zoster virus.