Undergraduate students acquired primary EBV infections at the rate of 14.4 cases per 100 person-years, and 89% of these infections (59 of 66) were symptomatic. Freshmen had a significantly higher incidence of infection as compared with sophomores, juniors, and seniors. Deep kissing with or without coitus was the only significant risk factor we identified for acquisition of infection. Crawford et al [18
] suggested that spread of EBV is enhanced by penetrative sexual intercourse, but we found that subjects who reported deep kissing with or without penetrative sexual intercourse had the same higher risk of primary infection as those who reported no kissing. The persistence of large quantities of virus in the oral cells and supernatant after primary EBV infection supports our view that oral secretions are the major source of transmission. EBV has been recovered from the male and female genital tracts [19
], but neither the quantity nor the duration of genital viral shedding has been described.
We observed that the quantity of EBV in whole blood, CD8+
lymphocytosis, and increased NK cells all correlated positively with disease severity. Since CD8+
T cells produce IFN-γ, which has an elevated level in the serum during infectious mononucleosis, and because IFN-γ treatment can result in mononucleosis-like symptoms, it could be argued that CD8+
T-cell production of high levels of IFN-γ might cause some of the symptoms classically associated with infectious mononucleosis. However, we did not observe a positive correlation between IFN-γ levels and disease severity. Furthermore, unlike a previous study by Silins et al [7
], we found that blood viral load also correlated positively with severity of illness, as it did with CD8+
and NK cell numbers. This is consistent with our earlier study, which reported that the rate of viral elimination from whole blood was similar to the rate of improvement in severity of illness [8
]. Thus, it is possible that high viral load may induce multiple immune, inflammatory, and cytopathic effects, making it difficult to conclude that infectious mononucleosis is simply a CD8+
T cell–mediated immunopathologic disease.
A study of NK cell numbers and severity of pharyngitis during primary EBV infection correlated NK cell expansion with less severe symptoms [21
]. There was also an inverse correlation between NK cells and blood viral load, suggesting that NK cell elimination of EBV-infected B cells contributed to milder illness. In contrast, we describe a positive correlation between NK cell expansion, blood viral load, and disease severity. It should be noted that interpretation of the data presented by Williams et al [21
] is confounded by the fact that NK cell numbers were examined in association with disease severity, but NK cell frequency (ie, percentages) was examined in association with viral load in the blood. Because of the substantial increase in CD8+
T cells during acute infectious mononucleosis, use of NK cell percentages may underestimate the changes in NK cell expansion. Second, Williams et al [21
] examined viral load per 106
PBMCs, whereas we represented viral load as the log-transformed value of the EBV load per milliliter of whole blood. Importantly, our conclusions are based on a larger set of subjects with internal controls for NK cell numbers and frequency before, during, and after EBV infection. Nonetheless, NK cells are a heterogeneous population, and it is possible that expansion of a particular subset of NK cells would be associated with better viral control and reduced symptoms. Further work on this important question is required.
A positive correlation between the blood viral load and host response factors such as increased CD8+
and NK cell numbers may not seem surprising. However, our finding is inconsistent with a paradigm often discussed in the context of EBV infection, which asserts that preexisting aspects of the CD8+
T-cell repertoire, such as memory T cell reactivity to other viruses, would result in a more severe primary EBV infection, independent of the viral load [22
]. Rather, it seems that host response factors that allow higher blood viral loads in the 4–6 weeks following initial infection result in more severe symptoms. Unfortunately, very little is understood about the virus-host dynamics during the long incubation period of this virus, which has compelled computer-based modeling of infection dynamics [23
]. A prospective study with more frequent observations during the incubation period may shed light on this important period of host-virus interaction.
In summary, acquisition of primary EBV infection in undergraduate students was associated with kissing, the vast majority (89%) of infections were symptomatic, and disease severity was related to high numbers of NK and CD8+ T cells and elevated blood viral loads. Our data suggest that preventing or reducing viremia by immunization or antiviral therapy could lessen the morbidity of primary EBV infection.