Abstract
Background and Objective:
Prior studies examining associations between Epstein Barr Virus (EBV)-positive infectious mononucleosis (IM) and risk of multiple sclerosis (MS) frequently lacked laboratory confirmation of EBV-positive IM or relied on billing codes to identify MS. We assessed whether laboratory-confirmed EBV-positive IM was associated with an increased risk of developing verified cases of MS.
Methods:
We conducted a population-based retrospective cohort study using medical records from the Rochester Epidemiology Project. We identified individuals with serologic evidence of EBV infection and an associated IM diagnosis (EBV-positive IM; exposed cohort) between 1998 and 2022. Age- (± 1 year) and sex-matched individuals without evidence of IM (3:1 match) comprised the unexposed cohort. Incident MS cases were verified through blinded expert chart review. Multivariate Cox proportional hazard models were used to assess associations between EBV-positive IM and risk of MS.
Results:
4,721 persons had EBV-positive IM (exposed cohort: 55% female, 70% <20 years). The referent cohort included 14,163 persons without EBV-positive IM (55% female, 70% <20 years). During follow-up (median, 6 years for exposed; 8 years for referents), MS developed in 8 individuals with EBV-positive IM (0.17%) and 10 referents (0.07%). EBV-positive IM was associated with a >3-fold increased risk of MS (adjusted Hazard Ratio: 3.14, 95% Confidence Interval: 1.18–8.34).
Discussion:
EBV-positive IM was associated with a substantially higher risk of MS. Findings are consistent with prior studies and underscore the importance of preventive strategies targeting EBV to reduce the long-term burden of MS.
Search Terms: [ 41 ] Multiple sclerosis, [ 59 ] Risk factors in epidemiology, [ 142 ] Viral infections, [ 54 ] Cohort studies
Introduction
Epstein Barr Virus (EBV) infection has been associated with an increased risk of developing multiple sclerosis (MS).1–3 In particular, a landmark study by Bjornevik and colleagues demonstrated that the risk of MS increased dramatically after infection with EBV. Risk of MS did not increase following infection with other viruses, including cytomegalovirus which is transmitted similarly through infected bodily fluids.4 These data suggest that EBV infection plays a causal role in the development of MS. However, seroprevalence studies indicate that EBV infection is nearly universal worldwide, and most individuals are infected by early adulthood (>80% seroprevalence by ages 18–19 in the United States, and even earlier in many low- and middle-income countries).5–7 Despite the high rates of EBV seroprevalence, MS remains relatively rare in the general population (2021 incidence rate of 6.5/100,000 persons in high income regions of North America).8 Thus, EBV infection appears to be a necessary, but not sufficient trigger for MS, with additional genetic and environmental health factors likely determining which individuals are at highest risk of developing disease.9, 10
Infection with EBV can also cause infectious mononucleosis (IM), a relatively uncommon respiratory illness (42 to 104 cases per 100,000 persons11–15) primarily diagnosed in adolescents and young adults.16 Several previous studies suggest that persons who develop IM are at a 2 to 3-fold increased risk of later developing MS.17–21 However, limitations of previous studies include reliance on self-reported history of IM, inability to verify that the IM case was associated with a serologically confirmed acute EBV infection, or reliance on billing codes for ascertainment of MS cases. These limitations raise concerns about misclassification of both the exposure (EBV-positive IM) and outcome (MS), potentially biasing estimates of the association.
To address this issue, we conducted a population-based retrospective cohort study in an upper midwest region of the USA. We identified individuals with an IM diagnosis who also had laboratory confirmation that EBV was the causative agent. We compared the development of new (incident) MS cases in this group to an age- and sex-matched referent population, and all potential cases of MS were verified via expert review of medical records.
Methods
Data source
We used data from the Rochester Epidemiology Project (REP) research infrastructure, which includes linked medical records from local health care providers in southeastern Minnesota and west central Wisconsin.22, 23 Briefly, the REP captures health care data from all visits to each health care provider for residents of this region. Data are coded and indexed electronically, and laboratory test result data have been available electronically since 1998. The population captured by this infrastructure is broadly similar to persons residing in the upper Midwest and the U.S. population in age (median age 39 years vs 38 years), proportion of persons with a college degree (34% vs 30%), and proportion of persons living below the poverty level (11% vs. 15%).22 However, the REP population is more homogenous than the U.S. Overall, 88% identify as White, and 5% are Hispanic compared to 77% and 17% nationally.
Standard Protocol Approvals, Registrations, and Patient Consents.
This study was approved by the Mayo Clinic Institutional Review Board (#22–007342), with a waiver of informed consent.
Persons with an EBV-positive case of IM (exposed cohort)
The exposed cohort was comprised of persons with both a laboratory confirmed EBV test result and a diagnosis code for IM (EBV-positive IM). To identify these individuals, we searched the REP electronic indices to identify all persons <100 years of age who underwent laboratory testing for EBV infection while a resident of this region at any time between January 1, 1998 and December 31, 2022. Overall, 20,319 persons were tested for EBV antibodies by serology, and 48,564 persons were tested by monospot during this period. Because testing methods and result reporting varied over time, EBV infection was defined as a positive or weakly positive monospot test, or as evidence of recent infection based on EBV antibody testing. For individuals with antibody results but no accompanying interpretation, we classified infection using standard serologic patterns: (1) positive viral capsid antigen (VCA) IgG, positive VCA IgM, and negative EBV nuclear antigen (EBNA); or (2) negative VCA IgG, positive VCA IgM, and negative EBNA, to capture early-stage infection prior to IgG seroconversion. The earliest qualifying test result was designated as the index date. To define IM, we required a corresponding International Classification of Diseases (ICD) code (ICD-9 code 075; ICD-10 codes B27.0–B27.9). Individuals with both a positive EBV test result and an IM diagnosis code comprised the exposed cohort. Individuals who did not meet these criteria were eligible for selection in the unexposed cohort (i.e., persons with EBV-positive results, but no associated IM diagnosis).
Unexposed cohort (referent population)
For each person in the exposed cohort, we selected three referent individuals who did not have evidence of EBV-positive IM during the study period. Referents were randomly sampled from all residents of the REP region between 1998 and 2022 who did not have a positive EBV test or an IM diagnosis code. Referents were matched to exposed individuals on sex, age (±1 year), and residency in the REP region on the index date. Each referent was assigned the same index date as their corresponding EBV-positive IM case.
Outcomes.
Our primary outcome was MS. However, to identify all possible cases of MS, we also evaluated persons who were initially identified with a broader set of ICD-9/10 codes (eTable 1). The goal of using a broader diagnosis code set was to identify persons who may have initially been diagnosed with a different condition, but who were found to have MS after further clinical examination. These included conditions such as neuromyelitis optica, optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. We searched for ICD codes in the 3 years preceding the index date to exclude prevalent cases, defined as individuals with ≥1 relevant code on or before the index date. Overall, 81 persons had at least one code for MS, neuromyelitis optica spectrum disorder, or demyelinating disease within 3 years prior to the index date through date of follow-up. All potential cases were reviewed by an expert in demyelinating diseases (B.M.K.) who adjudicated diagnoses and determined onset dates while blinded to exposure status. In addition to MS, 5 additional cases of central nervous system inflammatory disorders were identified during chart review; 3 in the exposed cohort and 2 among referents. These included myelin oligodendrocyte glycoprotein optic neuritis (n=2), aquaporin 4 neuromyelitis optica (n=1), recurrent optic neuritis (n=1), and clinically isolated demyelinating syndrome (n=1). Due to small sample sizes, these conditions were not considered as outcomes in analyses.
All persons were followed from the index date through date of last medical contact, development of MS, death, or September 30, 2023, whichever came first. Thus, if a person’s index date was in 1998 and the person did not die, develop MS, or move out of the region, that person was followed for 25 years. By contrast, persons with an index date in 2022 had the opportunity to be followed for 1 year.
Other participant characteristics (potential confounders)
We considered demographic, socioeconomic, and clinical factors that may confound the relationship between EBV-positive IM and MS. Sex, race, and ethnicity were self-reported (or reported by parents or guardians) during health care visits. Race/ethnicity and neighborhood deprivation were included to account for social determinants of health that may influence infection risk and health-care access. Race (White, Black, Asian, Other/mixed race) and ethnicity (Hispanic and non-Hispanic) were extracted from the REP indices. The Area Deprivation Index (ADI) was used as a composite measure of neighborhood socioeconomic disadvantage. Briefly, the ADI uses 17 census measures capturing education, employment, income, poverty, and housing characteristics at the census block group (neighborhood) level.24, 25 National ADI ranking values were obtained from the University of Wisconsin Neighborhood Atlas and linked to the geocoded patient address closest to January 1, 2020.26 ADI values were categorized into quartiles of the national percentile ranking with higher quartiles indicate greater deprivation.
Body mass index (BMI) and smoking status were also included because they have been associated with MS risk in prior studies.27, 28 For persons ≥20 years of age, BMI was calculated by dividing height in kilograms by weight in meters squared using height/weight pairs measured on the same day within ±3 years of the index date. BMI was categorized as follows: underweight: <18.5 kg/m2; normal: 18.5 to <25 kg/m2; overweight: 25 to <30 kg/m2; obese >30 kg/m2. For persons <20 years of age, BMI was calculated based on percentiles and z-scores for the child’s or adolescent’s sex and age using the Centers for Disease Control and Prevention growth charts and categorized using BMI percentile cutoffs.29 BMI percentiles were categorized as follows: underweight: <5%; normal: 5% to <85%; overweight: 85% to <95%; obese: ≥95%.30
Smoking status was obtained from medical record information closest to the index date and classified as never, past/current, or missing.
The Elixhauser comorbidity index was used to capture overall health status across a wide age range. This index assigns ICD codes to 38 comorbidity categories (see eTable 2), and a weighted index of conditions offers a simple way to adjust for number of comorbidities (disease burden) in patient populations. We selected the Elixhauser index, rather than the Charlson index, because it includes conditions relevant to younger populations (e.g., uncomplicated diabetes, depression, substance use disorders).31 ICD-9 and ICD-10 scores were extracted for 5 years prior to the index date and Elixhauser comorbidity scores were calculated using methods from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project.32
Statistical analysis
Patient characteristics were summarized as number and percent for categorical variables and median (interquartile range [IQR]) for continuous variables. Categorical variables were compared using chi-square tests and continuous variables using Kruskal–Wallis tests. Associations between EBV-positive IM and MS or death were assessed using Cox proportional hazard models among persons at risk for the outcome. Persons were censored on date of development of MS, death, date of last clinic visit, or September 30, 2023, whichever came first. Persons who had previously had MS prior to the index date (prevalent disease) were excluded from the analyses (eTable 3). Models were adjusted for variables that differed between the groups: race, ethnicity, ADI (quartiles plus missing), Elixhauser comorbidity scores (0, 1, ≥2), and smoking status (never, former, current, missing). All analyses were performed using SAS v. 9.4, and p values <0.05 were considered statistically significant.
Results
A total of 4,721 persons had a laboratory confirmed EBV infection and an IM diagnosis code (EBV-positive IM; exposed population). These persons were matched to 14,163 individuals with no evidence of recent infection (referent population). The referent population was statistically less likely to be white (77% vs 94%; p<0.0001), and more likely to be Hispanic (8% vs 4%; p<0.0001) and reside in less deprived regions than persons with a recent EBV infection (11% vs 4% living in the least deprived neighborhoods; p<0.0001; Table 1). Referents were also statistically less likely to be a past or current smoker, had fewer comorbidities, and had a slightly longer follow-up time (median of 8 vs 6 years; Table 2).
Table 1.
Baseline demographic characteristics of persons with EBV-positive IM (exposed cohort) and persons matched on age (+/− 1 year) and sex (referent cohort).
| Characteristic | EBV-positive IM N=4721, N (%) |
Referent cohort N=14,163, N (%) |
P value |
|---|---|---|---|
| Sex | 1.00 | ||
| Male | 2104 (44.6%) | 6312 (44.6%) | |
| Female | 2617 (55.4%) | 7851 (55.4%) | |
| Age group, years | 0.78 | ||
| 0-<10 | 321 (6.8%) | 946 (6.7%) | |
| 10-<15 | 493 (10.4%) | 1602 (11.3%) | |
| 15-<20 | 2501 (53.0%) | 7369 (52.0%) | |
| 20-<25 | 840 (17.8%) | 2552 (18.0%) | |
| 25-<30 | 272 (5.8%) | 809 (5.7%) | |
| 30-<40 | 193 (4.1%) | 587 (4.1%) | |
| 40+ | 101 (2.1%) | 298 (2.1%) | |
| Race | <0.0001 | ||
| White | 4437 (94.0%) | 10873 (76.8%) | |
| Black | 73 (1.6%) | 1315 (9.3%) | |
| Asian | 30 (0.6%) | 908 (6.4%) | |
| Other/mixed | 126 (2.7%) | 901 (6.4%) | |
| Unknown | 55 (1.2%) | 166 (1.2%) | |
| Ethnicity | <0.0001 | ||
| Hispanic | 171 (3.6%) | 1146 (8.1%) | |
| Non-Hispanic | 4550 (96.4%) | 13017 (91.9%) | |
| Area deprivation index quartile | <0.0001 | ||
| Q1 (least deprived) | 209 (4.4%) | 1606 (11.3%) | |
| Q2 | 1581 (33.5%) | 6137 (43.3%) | |
| Q3 | 1827 (38.7%) | 3190 (22.5%) | |
| Q4 (most deprived) | 498 (10.6%) | 502 (3.5%) | |
| Missing | 606 (12.8%) | 2728 (19.3%) |
Abbreviations: EBV=Epstein Barr Virus
Table 2.
Baseline clinical characteristics and follow-up time for persons with EBV-positive IM (exposed cohort) and persons matched on age (+/− 1 year) and sex (referent cohort).
| Characteristic | EBV-positive IM N=4721, N (%) |
Referent cohort N=14,163, N (%) |
P value |
|---|---|---|---|
| Body mass index, kg/m2 (median, IQR) | 23.1 (20.5,26.6) | 23.1 (20.2,27.4) | 0.99 |
| Underweight (<18.5) | 410 (8.7%) | 1443 (10.2%) | |
| Normal (18.5-<25) | 1945 (41.2%) | 5571 (39.3%) | |
| Overweight (25-<30) | 751 (15.9%) | 2252 (15.9%) | |
| Obese (>=30) | 490 (10.4%) | 1806 (12.8%) | |
| Missing | 1125 (23.8%) | 3091 (21.8%) | |
| Smoking status | <0.0001 | ||
| Never | 6469 (45.7%) | 2228 (47.2%) | |
| Past/current | 1013 (21.5%) | 2455 (17.3%) | |
| Unknown/missing | 1480 (31.4%) | 5239 (37.0%) | |
|
Elixhauser co-morbidity index
(median, IQR) |
0 (0,1) | 0 (0,1) | <0.0001 |
| 0 Elixhauser co-morbidity | 2618 (55.5%) | 8834 (62.4%) | |
| 1 Elixhauser co-morbidity | 1248 (26.4%) | 3123 (22.1%) | |
| ≥2 Elixhauser co-morbidities | 855 (18.1%) | 2206 (15.6%) | |
| Follow-up time, years (median, IQR) | 6 (3,11) | 8 (4,13) | <0.0001 |
Abbreviations: EBV=Epstein Barr Virus; IQR=interquartile range; Q= quartile.
Results are presented as N (%) unless otherwise noted.
During follow-up, MS developed in 8 persons with EBV-positive IM (0.17%; 2.25 per 10,000 person-years) and in 10 referents (0.07%; 0.77 per 10,000 person-years; Table 3). Among the patients who developed MS, the median time to diagnosis in persons with EBV-positive IM was 9.7 years (interquartile range (IQR): 3.3, 11.9) compared to a median of 14.2 years (IQR: 6.6, 17.1) in the referent population. After adjusting for race, ethnicity, ADI, smoking status and Elixhauser comorbidity score, those with EBV-positive IM infection were at a significantly increased risk of MS (HR: 3.14, 95% CI: 1.18, 8.34) compared to referents (Table 3). Risk of death did not differ between groups.
Table 3.
Risk of incident (new) outcomes in EBV-positive IM cases compared to matched referents.
| Recent EBV infection + IM diagnosis | Referent | Adjusted resultsa | |||||
|---|---|---|---|---|---|---|---|
| Outcome | N at risk | Number of new cases (%) | Incidence rate/10,000 person years (95% CI) | N at risk | Number of new cases (%) | Incidence rate/10,000 person years (95% CI) | HR (95% CI) |
| Multiple sclerosis | 4720 | 8 (0.17) | 2.25 (0.97,4.44) | 14156 | 10 (0.07) | 0.77 (0.37,1.41) | 3.14 (1.18,8.34) |
| Death | 4721 | 31 (0.66) | 8.73 (5.93,12.39) | 14163 | 101 (0.71) | 7.72 (6.29,9.39) | 1.00 (0.65,1.50) |
Adjusted for race, ethnicity, categorical ADI, smoking status, and Elixhauser categories.
Abbreviations: ADI=Area Deprivation Index, CI=confidence interval; EBV=Epstein Barr Virus; HR=hazard ratio.
Statistically significant results are highlighted in bold type.
Discussion
We found that persons with EBV-positive IM had a greater than 3-fold increased risk of developing MS compared to persons without a documented EBV infection. Although MS is relatively rare at the population level, it carries risks of significant disability, high treatment costs, and early mortality.8 In addition, the number of incident cases of MS in the US increased 15% from 1990 through 2021.8 Our results add to the growing body of evidence linking EBV-positive IM infection to MS risk and highlight the need for further research into preventative strategies.
Our findings are broadly consistent with previous studies that have reported an increased risk of MS in patients with EBV infection or IM. Several large, population-based studies have also consistently reported associations between EBV infection1–4 or IM19–21 and an approximately 2-fold increased risk of multiple sclerosis. While our results indicate an over 3-fold increased risk of multiple sclerosis in EBV-positive IM patients, the wide confidence intervals overlap with prior estimates.
Strengths of our study were the ability to identify EBV-positive IM cases using both confirmed laboratory test results and diagnosis codes, which helped minimize exposure misclassification. We also leveraged a large, geographically defined population with long term follow-up which allowed us to study a relatively rare outcome in a representative population, minimizing referral bias. Another strength was the availability of extensive clinical and demographic data which allowed us to adjust our analyses for a range of potential confounding variables. Finally, we were able to verify the MS cases through rigorous review by a clinical expert in demyelinating disease, which reduced the potential for outcome misclassification.
Several limitations should be noted. First, our study population was relatively young, with a median follow-up time of 6–8 years, and additional cases of MS associated with EBV-IM may develop later in life. Therefore, while our younger population allowed us to capture early outcomes of EBV-IM, our results may underestimate the lifetime risk of MS associated with EBV-positive IM that would require extended follow-up. Second, our study focused on a predominantly white population residing in a single region of the U.S.22, 33, which may limit generalizability to other populations, although our results align with findings from other large cohorts. Third, due to changes in laboratory testing and in diagnostic coding systems over time, EBV test results and IM diagnoses are not readily available for this population prior to 1998, and EBV-positive IM cases in the referent population may have been missed, particularly among older individuals. In addition, heterophile antibody tests (e.g., monospot) are highly specific (≥98%), but less sensitive (81–95%).34 Therefore, it is possible that some cases of EBV-positive IM cases were missed in the referent population due to the lower sensitivity of the monospot test. Missing EBV-positive IM cases in the referent population would be most likely to bias our estimates toward the null. Fourth, excluding persons with an EBV-positive test but no associated IM diagnosis from our referent population may have resulted in a slightly healthier than normal referent population. Our results showed that the referent population was slightly less likely to smoke and had a lower overall burden of disease (as measured by the Elixhauser comorbidity index). We were able to adjust for these characteristics in analyses, and EBV-positive IM status was still significantly associated with increased risk of MS. However, as in all observational studies, residual confounding cannot be excluded. We also were unable to assess the impact of changes in potential confounding variables over time on the observed association. However, for these factors to explain the observed association, EBV-positive IM would need to influence subsequent changes in variables such as BMI. Future studies to examine the impact of EBV-positive IM on health changes over time prior to onset of MS could offer clues to the underlying pathogenic process accounting for the observed associations. Fifth, shorter follow-up among the EBV-positive IM group could mean that some outcomes were not yet observed in the exposed cohort, again biasing associations toward the null. Sixth, during the time frame of much of this study there was no option to report non-binary sex on the standardized intake forms for the health care providers who participated in the REP. Thus, results may not generalize to non-binary intersex individuals. Finally, we did not verify the cases of IM in the exposed cohort through expert clinical review, but relied on diagnosis codes. However, requiring that each case also had an EBV-positive test result likely minimized misclassification.
In summary, EBV-positive IM was associated with an approximately three-fold higher risk of MS in this population-based cohort. Together with prior studies, our findings highlight the importance of continued efforts to develop preventive strategies against EBV-positive IM.
Supplementary Material
Acknowledgment:
We thank Trisha Shulze for assistance with formatting and submitting this manuscript.
Study Funding:
This study was funded by ModernaTX, Inc. ModernaTX, Inc. authors made contributions to this manuscript as described in the Disclosure. Moderna provided a grant to Mayo Clinic for design and conduct of the study.
Disclosure:
JLS has grant funding from Moderna for studies of infectious mononucleosis and congenital cytomegalovirus; RMJ has grant funding from Moderna for studies of infectious mononucleosis and congenital cytomegalovirus, income from Optum for case reviews of vaccine safety; income from Merck for service on safety review committee; inherited stock in 3M Company, Abbott laboratories, AbbVie Company, Baxter, Becton Dickinson & Co., Eli Lilly & Company, Embecta, Johnson & Johnson, Medtronic PLC F, PRM International, Takeda Pharma Co., Zimmer Biomet Hldgs, and Zimvie Inc.; CF has grant funding from Moderna for studies of infectious mononucleosis; BMK is a consultant for Moderna, EMD Serono and Tr1X, Inc. payments to Mayo Clinic; royalties from Oxford University Press Mayo Clinic Cases in Neuroimmunology. RAM, POB, and JDD are employees of Moderna and have equity interest in Moderna; SAH was an employee of Moderna at the time this study was conducted. JLS, RMJ, BMK, and CF are employees of Mayo Clinic.
Abbreviations and Acronyms
- EBV
Epstein Bar Virus
- IM
Infectious Mononucleosis
- MS
Multiple Sclerosis
- REP
Rochester Epidemiology Project
- ICD
International Classification of Diseases
- VCA
Viral Capsid Antigen
- EBNA
Epstein Bar Virus Nuclear Antigen
- ADI
Area Deprivation Index
- IQR
Interquartile Range
- HR
Hazard Ratio
- BMI
Body Mass Index
- CI
Confidence Interval
Data availability statement
Data are available on reasonable request. REP data include identifiable patient information, but limited or deidentified datasets may be shared with appropriate IRB approvals and enactment of data use agreements with Mayo Clinic and Olmsted Medical Center.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available on reasonable request. REP data include identifiable patient information, but limited or deidentified datasets may be shared with appropriate IRB approvals and enactment of data use agreements with Mayo Clinic and Olmsted Medical Center.