Abstract
Objective:
Infectious mononucleosis (IM) or mono is typically caused by primary infection with Epstein-Barr virus (EBV) and may have a months-long, complicated course. We utilized population-based data to add to the limited literature on healthcare utilization following EBV infection.
Methods:
The Rochester Epidemiology Project includes medical records for ~60% of residents living in 27 counties of MN and WI. Persons meeting a case definition of recent EBV infection from January 1, 1998 to December 31, 2021 were compared to 3 persons not meeting the definition, matched on case’s sex, age, and index date. Emergency department (ED) visits and hospitalizations in the two groups were compared during 5-years’ follow-up divided into 3 periods (short-term =<3 mos, mid-term >3 mos-1 yr, long-term >1–5 yrs). Adjusted hazard ratios (AHR) were estimated to account for the potential influence of confounding variables.
Results:
6,423 persons had a recent EBV infection and were matched to 19,269 comparators. The risk of an ED visit was significantly higher among cases in the short-term period (24.3% vs referents: 7.6%, p<0.001; AHR=3.71, 95% CI: 3.41–4.03). Cases also had an increased risk of hospitalization in the short-term (5.2% vs 1.6%: referents, p<0.001; AHR=3.53, 95% CI: 2.94–4.24). For ED visits but not hospitalization, the excess risk persisted into the mid-term follow-up period. Persons without a concurrent clinical diagnosis of IM continued to have an increased risk of hospitalizations up to 1 year after index date (AHR=1.45, 95% CI: 1.09, 1.91) and an increased risk of ED visits up to 5 years after the index date (AHR=1.29, 95% CI: 1.14, 1.46).
Conclusion:
There is a substantial short- and mid-term increased risk of serious healthcare encounters associated with recent EBV infection. Mid- and long-term risks are increased in patients who do not have a concomitant diagnosis of IM.
MeSH index keywords: Epstein-Barr Virus Infections; Infectious Mononucleosis; Hospitalization; Emergency Service, Hospital; Follow-Up Studies; Confounding Factors, Epidemiologic
Introduction:
Epstein-Barr virus (EBV) is a gamma herpesvirus that infects most individuals by early adulthood (globally, ~95% seropositivity by age 24) and subsequently persists as a life-long infection.(1) Infectious mononucleosis (IM) is most frequently caused by primary infection with EBV, and is typically a relatively benign, self-limited disease.1 However, some infected patients develop symptoms which persist for months after the initial infection.1, 2 Other patients may have serious short-term complications, including skin rashes, splenic rupture, hepatitis, hemophagocytic syndrome, Guillain-Barre syndrome, myocarditis, and meningoencephalitis.3–8 In addition, while rare, EBV primary infection may pose risks to the developing fetus in pregnant women.9, 10 Despite the well-known epidemiology and clinical outcomes of acute EBV infections such as IM, data are limited regarding the health care utilization burden associated with primary EBV infection, regardless of symptomatology.
Risk of hospitalization has been estimated from 3.6% to 18% of those affected by IM.11, 12 Aside from one population-based study in Denmark (3), the remaining were in special populations: a small study in seronegative US college students (6) and persons in the US armed forces.(5) Additionally, a few studies have estimated length of hospitalization in persons with IM. For example, Liu and colleagues found that children hospitalized with IM in China had a median hospital stay of 8 days.13 Hocqueloux and colleagues found that French adults hospitalized due to primary EBV infection had a longer length of stay compared to children hospitalized with primary EBV infection (median 7 days vs 3 days, with higher associated costs).14 Risk of emergency department (ED) use in the months and years following IM is not described in the literature.
Additional population-based data are necessary to better understand the health care burden of EBV-associated disease in the US. Therefore, to address this gap, we studied health care resource utilization, including ED visits and hospitalizations, during the 5-year period after infection, in persons with a positive test for recent EBV infection compared to similar persons without a new or recent EBV infection.
Methods:
Data source.
We used the resources of the Rochester Epidemiology Project (REP) to identify persons tested for a recent EBV infection in persons residing in an upper midwest region between January 1, 1998 and December 31, 2021. The REP has been previously described.15, 16 Briefly, the REP includes linked medical records from local health care providers for persons who have lived in Olmsted County, Minnesota since 1966 or in a 27-county region of southeastern Minnesota and west central Wisconsin since 2010. The health care providers in the REP include primary and specialty care as well as emergency departments and hospitals. Health care data from all visits to any of the participating health care providers are coded and indexed electronically, and laboratory test result data are available electronically since 1998, regardless of where the care was delivered. Approximately 60% of persons living in the 27-county region are included in the REP, and characteristics of the population are similar to all persons residing in these counties and to persons residing in the upper midwest.15
This study used information obtained from medical records and was classified as secondary research for which consent is not required. It was approved by the Mayo Clinic Institutional Review Board as an exempt human subjects research project (#22–007342). Briefly, this study made use of existing data from electronic health records, and no patient contact was involved. Therefore, the Mayo Clinic Institutional Review Board waived the requirement for informed consent. However, Minnesota law requires patient authorization for use of medical record information for research (Minnesota State Privacy Law – statute 144.335, 1997). Patients are either asked for this authorization at the time of first health care visit or by letter following first visit. Parents provide authorization for children. Children receive letters requesting authorization at age 18. The system is “opt-out”, and if patients do not respond to 2 attempts at contact, their records are available for research studies. Minnesota is the only state that requires this type of authorization; however, the health care providers in the REP that are located in Wisconsin also collect this authorization for their patients. We did not include data for any persons who declined authorization (approximately 5% of the population).
Persons with a recent EBV infection (exposed cohort).
Our case definition for recent EBV infection included those with a positive EBV serology result indicating recent infection or early infection, as follows. We searched the REP electronic database to identify all persons who resided in the REP region and who had a laboratory test for EBV infection at any time between January 1, 1998 and December 31, 2021. Most EBV tests in this region are ordered as part of a primary care visit for patients with sore throats, fever, or lethargy that persist beyond 10 days, or in the context of symptoms that persist beyond antibiotic treatment (personal communication RMJ). EBV tests may also be ordered in the context of an emergency department visit or hospitalization. Therefore, EBV test results were included regardless of location of visit or the specialty of the health care practitioner. Overall, 19,372 persons were tested for EBV antibodies by serology, and 46,532 persons were tested by monospot between 1998 and 2021. The type of tests and reporting of test results changed over the time period. Therefore, among this population, we identified everyone who had received a positive or weakly positive result on a monospot test. We also identified all persons whose EBV antibody test results were interpreted as indicating “recent infection”. For persons who had antibody tests, but no associated interpretation, we included all persons with a positive viral capsid antigen immunoglobulin G (VCA IgG) result, a positive VCA IgM result, and a negative EBV nuclear antigen (EBNA) result as indicating recent infection.17 Finally, we included persons who had a negative IgG, positive IgM, and negative EBNA to capture persons with early stage infection, prior to appearance of IgG antibodies, as having a recent infection. If persons had more than one test result, the earliest positive test result was chosen as the index date. We also identified all persons who had a diagnosis of IM within 30 days of the EBV test result using International Classification of Diseases (ICD) billing codes (ICD-9 code: 075 and ICD-10 chapter B27; B27.0-B27.99).
Unexposed cohort (referent population).
Three persons who did not have a recent EBV infection in the study time frame were matched to each person with a positive EBV test to serve as the referent population. Persons in the unexposed cohort were randomly selected from all persons living in the REP region on the index date, and were matched on sex and within 1 year of age. All referents were then assigned the same index date as their EBV infected match.
Outcomes.
All persons in the study were followed passively via their linked medical records to identify health care utilization for up to 5 years after the index date, last known clinical contact, or death, whichever came first. Health care utilization consisted of all ED visits and inpatient hospitalizations that occurred during follow-up for the exposed and unexposed cohorts.
Other participant characteristics (potential confounders).
Race (White, Black, Asian, Other/mixed race) and ethnicity (Hispanic, non-Hispanic) were extracted from the REP databases. We used the area deprivation index (ADI) as a composite measure of neighborhood socioeconomic disadvantage. Briefly, the ADI uses 17 census measures capturing education, employment, income, poverty, and housing characteristics.18, 19 ADI values were calculated by linking US Census data to the patient addresses closest to the index date and were divided into quartiles for analysis. Higher quartiles indicated higher deprivation.
Body mass index (BMI) was calculated using height and weight information obtained during clinical care and documented in the medical records. 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.20 BMI percentiles were categorized as follows: underweight: <5%; normal: 5% to <85%; overweight: 85% to <95%; obese: ≥95%.21
Smoking status is routinely collected via patient questionnaires during health care visits and documented in the medical records. We extracted these data for the study population and categorized smoking status as never, past or current, or missing. 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.22
Frequency of previous health care use was defined as the number of days in the previous 31 days to one year prior to the index date with at least one Current Procedural Terminology (CPT) code. A one-month window prior to the index date was chosen to exclude any visits that occurred prior to the index date that were actually attributable to EBV infection.
Statistical analysis.
Patient characteristics were summarized as number and percent for categorical variables and median (interquartile range [IQR]) for continuous variables. Differences between persons with a recent EBV infection and the referent population were assessed with chi-square or Kruskal-Wallis tests, as appropriate. Associations between recent EBV infection and outcomes (ED visits and hospitalizations) were assessed using Andersen-Gill models, which allow for repeated events. Models were adjusted for age and sex, with further adjustment for race, ethnicity, ADI (categorized into quartiles with a category for missingness), smoking status, Elixhauser comorbidity scores (0, 1, ≥2), and natural logarithm of health care use in the previous 31 days to one year prior to the index date. For persons with no health care use, we used log(0.1). Follow-up was stratified into three separate time periods: 1) 30 days prior to 90 days after index date (short-term follow-up), 2) 91 days to 1 year after index date (mid-term follow-up), and 3) >1 year to 5 years after index date (long-term follow-up). In period 1, the window of 30 days prior to index date was included as follow-up time, as we assumed care during this short interval among a young population may have been attributable to EBV infection. In a sensitivity analysis, stratified Andersen-Gill models were run with the matched case/referent sets forming the strata. All analyses were conducted using SAS v. 9.4.
Results:
Overall, 6,423 persons had lab test results indicating recent EBV infection, and these persons were matched to 19,269 persons with no evidence of recent infection (referent population). Characteristics of the two populations are shown in Table 1. Persons with a recent EBV infection were more likely to be White and less likely to be Hispanic than persons with recent EBV infection. Similarly, they lived in more deprived regions, had more Elixhauser comorbidities, and had less missing smoking status information than persons with a recent EBV infection (Table 1). However, the two populations had similar frequencies of previous health care use in the 31 days to one year prior to the index date.
Table 1.
Baseline characteristics of the study populations
| Characteristic | Recent EBV infection | Referent cohort | P value |
|---|---|---|---|
| Total number of people | 6,423 | 19,269 | ---- |
| Sex | 1.00 | ||
| Male | 2,772 (43.2%) | 8,316 (43.2%) | |
| Female | 3,651 (56.8%) | 10,953 (56.8%) | |
| Age group (years) | 0.58 | ||
| 0-<10 | 510 (7.9%) | 1,527 (7.9%) | |
| 10-<15 | 676 (10.5%) | 2,184 (11.3%) | |
| 15-<20 | 3,230 (50.3%) | 9,459 (49.1%) | |
| 20-<25 | 1,107 (17.2%) | 3,390 (17.6%) | |
| 25-<30 | 367 (5.7%) | 1,122 (5.8%) | |
| 30-<40 | 311 (4.8%) | 925 (4.8%) | |
| 40+ | 222 (3.5%) | 662 (3.4%) | |
| Race | <0.0001 | ||
| White | 6,026 (93.8%) | 14,837 (77.0%) | |
| Black | 92 (1.4%) | 1,757 (9.1%) | |
| Asian | 48 (0.8%) | 1,186 (6.2%) | |
| Other/mixed | 168 (2.6%) | 1,260 (6.5%) | |
| Unknown | 89 (1.4%) | 229 (1.2%) | |
| Ethnicity | <0.0001 | ||
| Hispanic | 240 (3.7%) | 1,500 (7.8%) | |
| Non-Hispanic | 6,183 (96.3%) | 17,769 (92.2%) | |
| Closest to index date | |||
| Area deprivation quintile | <0.0001 | ||
| Quartile 1 (least deprived) | 465 (7.2%) | 3,120 (16.2%) | |
| Quartile 2 | 2,414 (37.6%) | 7,548 (39.2%) | |
| Quartile 3 | 2,147 (33.4%) | 4,531 (23.5%) | |
| Quartile 4 (most deprived) | 753 (11.7%) | 946 (4.9%) | |
| Missing | 644 (10.0%) | 3,124 (16.2%) | |
| Body mass index (kg/m2), median (IQR) | 23.0 (20.4,26.7) | 23.0 (20.1,27.2) | 0.89 |
| Underweight (<18.5) | 620 (9.7%) | 2,123 (11.0%) | |
| Normal (18.5-<25) | 2,561 (39.9%) | 7,473 (38.8%) | |
| Overweight (25-<30) | 1,031 (16.1%) | 2,994 (15.5%) | |
| Obese (≥30) | 671 (10.5%) | 2,395 (12.4%) | |
| Missing | 1,540 (24.0%) | 4,284 (22.2%) | |
| Smoking status | <0.0001 | ||
| Never | 3,216 (50.1%) | 9,097 (47.2%) | |
| Past/current | 1,404 (21.9%) | 3,542 (18.4%) | |
| Unknown/missing | 1,803 (28.1%) | 6,630 (34.4%) | |
| Elixhauser co-morbidity index (median, IQR) | 0 (0,1) | 0 (0,1) | <0.0001 |
| 0 Elixhauser co-morbidity | 3614 (56.3%) | 11893 (61.7%) | |
| 1 Elixhauser co-morbidity | 1665 (25.9%) | 4388 (22.8%) | |
| ≥2 Elixhauser co-morbidity | 1144 (17.8%) | 2988 (15.5%) | |
| Health care use in the previous 31 days through 1 year | |||
| Number of days with a CPT code in 31 days through 1 year prior, median (IQR) | 2 (1,5) | 2 (1,5) | 0.20 |
Results are reported as N (%) unless otherwise noted.
CPT, current procedural terminology; EBV, Epstein-Barr virus; IQR, interquartile range
Persons with a recent EBV infection were more likely to have at least one ED visit compared to the referent population in the short-term follow-up period (EBV infected: 24.3% vs referent: 7.6%; p<0.001) and in the mid-term follow-up period (EBV infected: 16.1% vs referent: 14.5%; p<0.001; Table 2).
Table 2.
Outcomes among recent EBV infection cases and referents
| Outcomes | Recent EBV infection | Referents | P value |
|---|---|---|---|
| Follow-up time (years), median (IQR) | 7 (3,12) | 8 (4,12) | <0.0011 |
| Thirty days prior to 90 days after index date | |||
| Hospitalizations | |||
| 0 hospitalizations, N (%) | 6,092 (94.9%) | 18,961 (98.4%) | <0.0012 |
| 1 hospitalization, N (%) | 268 (4.2%) | 272 (1.4%) | |
| ≥2 hospitalization, N (%) | 63 (1.0%) | 36 (0.2%) | |
| Emergency department visits | |||
| 0 emergency department visits, N (%) | 4,861 (75.7%) | 17,810 (92.4%) | <0.0012 |
| 1 emergency department visit, N (%) | 1,104 (17.2%) | 1,213 (6.3%) | |
| ≥2 emergency department visits, N (%) | 458 (7.1%) | 246 (1.3%) | |
| >Ninety days after to 1 year after index date | |||
| Hospitalizations | |||
| 0 hospitalizations, N (%) | 6,225 (96.9%) | 18,609 (96.6%) | 0.092 |
| 1 hospitalization, N (%) | 155 (2.4%) | 553 (2.9%) | |
| ≥2 hospitalization, N (%) | 43 (0.7%) | 107 (0.6%) | |
| Emergency department visits | |||
| 0 emergency department visits, N (%) | 5,387 (83.9%) | 16,520 (85.7%) | <0.0012 |
| 1 emergency department visit, N (%) | 713 (11.1%) | 2,040 (10.6%) | |
| ≥2 emergency department visits, N (%) | 323 (5.0%) | 709 (3.9%) | |
| >One year after to 5 years after index date | |||
| Hospitalizations | |||
| 0 hospitalizations, N (%) | 5,712 (88.9%) | 16,797 (87.2%) | <0.0012 |
| 1 hospitalization, N (%) | 480 (7.5%) | 16,35 (8.5%) | |
| ≥2 hospitalization, N (%) | 231 (3.6%) | 837 (4.3%) | |
| Emergency department visits | |||
| 0 emergency department visits, N (%) | 4,176 (65.0%) | 12,385 (64.3%) | <0.0012 |
| 1 emergency department visit, N (%) | 1,016 (15.8%) | 3,438 (17.8%) | |
| ≥2 emergency department visits, N (%) | 1,231 (19.2%) | 3,446 (17.9%) |
Results are reported as N (%) unless otherwise noted.
Kruskal-Wallis test for the median (IQR)
Chi square test for categorical p values
CPT, current procedural terminology; EBV, Epstein-Barr virus; IQR, interquartile range.
Persons with a recent EBV infection were also more likely to have at least one hospitalization in the short-term follow-up period (up to 3 months following infection) compared to the referent population (5.2% vs 1.6%; p<0.001; Table 2). However, there was no difference in the percent of persons with at least one hospitalization in the mid-term follow-up period (between 3 months and 1 year; EBV infected: 3.1% vs referent: 3.5%; p=0.09). Persons with a recent EBV infection were less likely to be hospitalized during the long-term follow-up period (between 1 and 5 years after the index date; EBV infected: 11.1% vs referent: 12.8%; p<0.001; Table 2).
After adjusting for potential confounding variables, persons with EBV infection had a 3.7-fold higher risk of ED use during short-term follow-up (HR: 3.71; 95% CI: 3.41, 4.03), and a slightly higher risk of ED use that persisted up to 1 year after infection (HR: 1.19; 95% CI: 1.09, 1.30; Table 3). Results from the stratified models were similar to the unstratified models (Supplemental Table 1).
Table 3.
Risk of outcomes in all patients with a recent EBV infection, overall and in persons with and without a diagnosis of IM, compared to referents.
| Recent EBV infection | Referent | |||||
|---|---|---|---|---|---|---|
|
Outcome |
N at risk | Number of outcomes | N at risk | Number of outcomes | Model 1* HR (95% CI) |
Model 2** HR (95% CI) |
| Thirty days prior to 90 days after index date | ||||||
| Hospitalizations | 6,423 | 331 | 19,269 | 308 | 3.78 (3.20,4.48) | 3.53 (2.94,4.24) |
| Emergency department visits | 6,423 | 1,562 | 19,269 | 1,459 | 3.88 (3.57,4.22) | 3.71 (3.41,4.03) |
| >90 days after to 1 year after index date | ||||||
| Hospitalizations | 6,423 | 198 | 19,269 | 660 | 1.04 (0.86,1.25) | 0.96 (0.79,1.17) |
| Emergency department visits | 6,423 | 1,036 | 19,269 | 2,749 | 1.27 (1.16,1.38) | 1.19 (1.09,1.30) |
| >1 year after to 5 years after index date | ||||||
| Hospitalizations | 6,423 | 711 | 19,269 | 2,472 | 0.93 (0.84,1.04) | 0.89 (0.80,0.99) |
| Emergency department visits | 6,423 | 2,247 | 19,269 | 6,884 | 1.16 (1.08,1.25) | 1.07 (0.99,1.15) |
| Recent EBV infection plus an IM diagnosis | Referent | |||||
| Thirty days prior to 90 days after index date | N at risk | Number of outcomes | N at risk | Number of outcomes | Model 1* HR (95% CI) |
Model 2** HR (95% CI) |
| Hospitalizations | 4534 | 247 | 13,602 | 211 | 3.93 (3.22,4.78) | 3.58 (2.87,4.45) |
| Emergency department visits | 4534 | 1,230 | 13,602 | 1015 | 4.41 (4.00,4.87) | 4.17 (3.79,4.60) |
| >90 days after to 1 year after index date | ||||||
| Hospitalizations | 4534 | 113 | 13,602 | 446 | 0.83 (0.65,1.06) | 0.74 (0.57,0.97) |
| Emergency department visits | 4534 | 725 | 13,602 | 1961 | 1.26 (1.13,1.40) | 1.14 (1.02,1.27) |
| >1 year after to 5 years after index date | ||||||
| Hospitalizations | 4534 | 476 | 13,602 | 1,705 | 0.82 (0.73,0.93) | 0.76 (0.67,0.87) |
| Emergency department visits | 4534 | 1,590 | 13,602 | 4,803 | 1.10 (1.01,1.19) | 0.98 (0.90,1.07) |
| Recent EBV infection without an IM diagnosis | Referent | |||||
| Thirty days prior to 90 days after index date | N at risk | Number of outcomes | N at risk | Number of outcomes | Model 1* HR (95% CI) |
Model 2** HR (95% CI) |
| Hospitalizations | 1,889 | 84 | 5,667 | 97 | 3.48 (2.52,4.81) | 3.42 (2.44,4.79) |
| Emergency department visits | 1,889 | 332 | 5,667 | 444 | 2.61 (2.23,3.05) | 2.55 (2.18,2.99) |
| >90 days after to 1 year after index date | ||||||
| Hospitalizations | 1,889 | 85 | 5,667 | 214 | 1.49 (1.12,1.98) | 1.45 (1.09,1.91) |
| Emergency department visits | 1,889 | 311 | 5,667 | 788 | 1.30 (1.12,1.52) | 1.30 (1.13,1.51) |
| >1 year after to 5 years after index date | ||||||
| Hospitalizations | 1,889 | 235 | 5,667 | 767 | 1.18 (0.96,1.44) | 1.19 (0.98,1.43) |
| Emergency department visits | 1,889 | 657 | 5,667 | 2,081 | 1.31 (1.15,1.50) | 1.29 (1.14,1.46) |
Model 1: Adjusted for age and sex.
Model 2: Adjusted for age, sex, race, ethnicity, ADI (categorical, including missing category), smoking status, Elixhauser comorbidity index groups (0, 1, ≥2), and ln(health care use as measured by the number of days with a CPT code in the previous year).
CI, confidence interval; EBV, Epstein-Barr virus; HR, hazard ratio.
Similarly, persons with EBV infection were 3.5 times more likely to be hospitalized compared to those without an EBV infection in the short-term follow-up period (HR: 3.53; 95% CI: 2.94, 4.24; Table 3). However, these persons were not at an increased risk of hospitalization greater than 3 months following the index date (mid- to long-term follow-up; Table 3).
To understand the influence of IM on ED visits and hospitalizations, we stratified our analyses by presence of IM. Overall, 4,354 (71%) persons in the EBV positive cohort also had a diagnosis of IM within 30 days of the positive EBV test result. These persons still had an elevated risk of ED visits during both short- and mid-term follow-up and an elevated risk of hospitalizations during short-term follow-up. However, risk of hospitalizations and ED visits was not significantly different from that of referents 1 year after index date (Table 3). By contrast, persons with a positive EBV test result but without a diagnosis of IM continued to have an increased risk of hospitalizations during mid-term follow-up, and an elevated risk of ED visits during both mid- and long-term follow-up (Table 3).
Discussion:
We found that persons with a recent EBV infection had a 3.5-fold increased risk of both ED visits and hospitalizations in the initial short-term follow-up period (up to 3 months after infection) compared to persons without a recent EBV infection. A slightly higher risk of ED visits persisted in persons who had a recent EBV infection with an IM diagnosis during mid-term follow-up (up to one year after infection). However, there was not an increased risk of either ED visits or hospitalizations during long-term follow-up (one to five years after infection). By contrast, persons with a positive EBV test result but no diagnosis of IM had a higher risk of hospitalizations up to one year after infection, and a higher risk of ED visits up to 5 years after the index date. Together these data indicate that there is a substantial short-term increased risk of serious health care encounters associated with recent EBV infection, but this risk does not persist after 1 year in patients with an IM diagnosis. However, the risk does persist in persons with positive EBV test results, but no IM diagnosis. These patients may have more serious health conditions compared to the classic cases of IM.
These results are consistent with previous reports that primary EBV infections are largely self-limited, with a median duration of 18 days.1, 23 Our data are consistent with these findings, since hospitalizations in EBV patients more than 3 months following infection were similar to that of comparators of similar age and sex. However, persons with a recent EBV infection continued to have a slightly higher risk of ED use compared to persons of similar age and sex. Rea and colleagues have reported that about 10% of patients with IM will continue to experience symptoms after 6 months.1 This higher ED utilization rate may be driven by those persons who experience long-term EBV related symptoms.
We also found that persons who had a positive EBV test result, but did not have a diagnosis of IM, had an increased risk of hospitalizations and ED utilization that persisted up to 1 and 5 years after the index date (respectively). Unfortunately, diagnoses other than IM were not available in this dataset, but our results suggest that persons with a positive EBV test result, but no IM diagnosis, may have more serious conditions than a classic case of IM. For example, such test results may represent reactivation of an existing EBV infection in the context of immunosuppression.17
The overall hospitalization rate in persons with recent EBV infection in our cohort, 5.2%, was in the range of what has been reported in previous studies (3.6% to 18%).2, 11, 12 including from another population-based study where the proportion hospitalized was 7.4%.2 Strengths of our study were the ability to identify recent EBV infections and associated hospitalizations and ED visits in a large, geographically defined population, over a short-, mid-, and long-term period of follow-up. In addition, we were able to control for comorbidity status at baseline, health care use in the previous year, and other variables (smoking and socioeconomic environment) that may have confounded the association between EBV infection and hospitalization or ED use.
Potential limitations of our study were the inclusion of all persons positive for either a monospot test or EBV antibody results suggesting a recent infection. As such, we may have included some persons in the exposed cohort who had a recent EBV reactivation (i.e., EBV-related cancer patients or transplant patients), and such patients might be expected to have higher hospitalizations and ED visits. However, we conducted a sensitivity analysis including only those persons and their matched referents who also had a concurrent diagnosis of IM. Results were of approximately the same magnitude and in the same direction as the analyses that included all persons with a positive EBV test, suggesting that inclusion of persons with a reactivation of EBV due to cancer or transplant in the cohort was not responsible for the increase in ED visits and hospitalizations. Additionally, as this study focused on a population residing in the upper Midwest region of the United States, additional studies are necessary to determine whether populations in other regions have similar ED and hospitalization visit patterns.
Conclusions
In summary, we found a strong association between recent EBV infection and increased risk of both ED visits and hospitalizations in the 30 days prior to 90 days after infection. A slightly increased risk of ED visits persisted for up to one year after EBV infection. These data provide comprehensive information on the short-, medium-, and long-term risks of ED visits and hospitalizations associated with recent EBV infection.
Supplementary Material
Acknowledgements:
We acknowledge Moderna employees Kevork Ourfalian, for assistance with submission of this manuscript, and Enejda Senko, for assistance with project management.
This study used the resources of the Rochester Epidemiology Project (REP) medical records-linkage system, which is supported by the National Institute on Aging (NIA; AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or the Mayo Clinic.
Footnotes
Transparency section
Declaration of funding: This study was funded by Moderna. Moderna authors made contributions to this manuscript as described below.
Declaration of financial/other relationships: JLS has grant funding from Moderna for studies of infectious mononucleosis and congenital cytomegalovirus, and grant funding from Exact Sciences for studies of colorectal cancer. 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, Zimvie Inc. SAW has grant funding from Moderna for studies of infectious mononucleosis and congenital cytomegalovirus. CF has grant funding from Moderna for studies of infectious mononucleosis. Authors RAM and POB are employees of Moderna and have equity interest in Moderna; SAH was an employee of Moderna at the time this study was conducted. Authors JLS, RMJ, and CF are employees of Mayo Clinic; SAW was an employee of Mayo Clinic at the time this study was conducted.
References
- 1.Rea TD, Russo JE, Katon W, et al. Prospective study of the natural history of infectious mononucleosis caused by Epstein-Barr virus. J Am Board Fam Pract 2001;14(4):234–42. [PubMed] [Google Scholar]
- 2.Rostgaard K, Balfour HH Jr., Jarrett R, et al. Primary Epstein-Barr virus infection with and without infectious mononucleosis. PLoS One. 2019;14(12):e0226436. doi: 10.1371/journal.pone.0226436. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jenson HB. Acute complications of Epstein-Barr virus infectious mononucleosis. Curr Opin Pediatr 2000;12(3):263–8. doi: 10.1097/00008480-200006000-00016. [DOI] [PubMed] [Google Scholar]
- 4.Elazary AS, Wolf DG, Amir G, et al. Severe Epstein-Barr virus-associated hemophagocytic syndrome in six adult patients. J Clin Virol 2007;40(2):156–9. doi: 10.1016/j.jcv.2007.06.014. [DOI] [PubMed] [Google Scholar]
- 5.Schechter S, Lamps L. Epstein-Barr Virus Hepatitis: A Review of Clinicopathologic Features and Differential Diagnosis. Arch Pathol Lab Med 2018;142(10):1191–95. doi: 10.5858/arpa.2018-0208-RA. [DOI] [PubMed] [Google Scholar]
- 6.Tam CC, O’Brien SJ, Petersen I, et al. Guillain-Barre syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database. PLoS One. 2007;2(4):e344. doi: 10.1371/journal.pone.0000344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Ciccarese G, Trave I, Herzum A, et al. Dermatological manifestations of Epstein-Barr virus systemic infection: a case report and literature review. Int J Dermatol 2020;59(10):1202–09. doi: 10.1111/ijd.14887. [DOI] [PubMed] [Google Scholar]
- 8.Watanabe M, Panetta GL, Piccirillo F, et al. Acute Epstein-Barr related myocarditis: An unusual but life-threatening disease in an immunocompetent patient. J Cardiol Cases 2020;21(4):137–40. doi: 10.1016/j.jccase.2019.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Icart J, Didier J, Dalens M, et al. Prospective study of Epstein Barr virus (EBV) infection during pregnancy. Biomedicine. 1981;34(3):160–3. [PubMed] [Google Scholar]
- 10.Fleisher G, Bologonese R. Epstein-Barr virus infections in pregnancy: a prospective study. J Pediatr 1984;104(3):374–9. doi: 10.1016/s0022-3476(84)81098-7. [DOI] [PubMed] [Google Scholar]
- 11.Stahlman S, Williams VF, Ying S. Infectious mononucleosis, active component, U.S. Armed Forces, 2002–2018. MSMR. 2019;26(7):28–33. [PubMed] [Google Scholar]
- 12.Grimm JM, Schmeling DO, Dunmire SK, et al. Prospective studies of infectious mononucleosis in university students. Clin Transl Immunology 2016;5(8):e94. doi: 10.1038/cti.2016.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Liu M, Wang X, Zhang L, et al. Epidemiological characteristics and disease burden of infectious mononucleosis in hospitalized children in China: A nationwide retrospective study. Virol Sin 2022;37(5):637–45. doi: 10.1016/j.virs.2022.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hocqueloux L, Causse X, Valery A, et al. The high burden of hospitalizations for primary EBV infection: a 6-year prospective survey in a French hospital. Clin Microbiol Infect 2015;21(11):1041 e1–7. doi: 10.1016/j.cmi.2015.07.015. [DOI] [PubMed] [Google Scholar]
- 15.Rocca WA, Grossardt BR, Brue SM, et al. Data Resource Profile: Expansion of the Rochester Epidemiology Project medical records-linkage system (E-REP). Int J Epidemiol. 2018;47(2):368–68j. doi: 10.1093/ije/dyx268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.St Sauver JL, Grossardt BR, Finney Rutten LJ, et al. Rochester Epidemiology Project Data Exploration Portal. Prev Chronic Dis 2018;15:E42. doi: 10.5888/pcd15.170242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Hess RD. Routine Epstein-Barr virus diagnostics from the laboratory perspective: still challenging after 35 years. J Clin Microbiol 2004;42(8):3381–7. doi: 10.1128/JCM.42.8.3381-3387.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Hu J, Kind AJH, Nerenz D. Area Deprivation Index Predicts Readmission Risk at an Urban Teaching Hospital. Am J Med Qual 2018;33(5):493–501. doi: 10.1177/1062860617753063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zuelsdorff M, Larson JL, Hunt JFV, et al. The Area Deprivation Index: A novel tool for harmonizable risk assessment in Alzheimer’s disease research. Alzheimers Dement (N Y). 2020;6(1):e12039. doi: 10.1002/trc2.12039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Centers for Disease Control and Prevention. The SAS Program for CDC Growth Charts that Includes the Extended BMI Calculations. 2023. [cited 2023 04/11/2023]; Available from: https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm
- 21.Centers for Disease Control and Prevention. Defining Child BMI Categories. 2023. [cited 2023 04/11/2023]; Available from: https://www.cdc.gov/obesity/basics/childhood-defining.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fobesity%2Fchildhood%2Fdefining.html
- 22.Project HCaU. Elixhauser Comorbidity Software Refined for ICD-10-CM. Healthcare Cost and Utilization Project User Support 2022. [cited 2023 04/11/2023]; Available from: https://hcup-us.ahrq.gov/toolssoftware/comorbidityicd10/comorbidity_icd10.jsp [Google Scholar]
- 23.Dunmire SK, Verghese PS, Balfour HH Jr. Primary Epstein-Barr virus infection. J Clin Virol 2018;102:84–92. doi: 10.1016/j.jcv.2018.03.001. [DOI] [PubMed] [Google Scholar]
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