Prospective studies of infectious mononucleosis in university students

Abstract

We performed an intensive prospective study designed to obtain as much data as possible on the incubation and early illness periods of primary Epstein-Barr virus (EBV) infection. Undergraduate students who lacked EBV antibody and oral EBV DNA (EBV-naive) were seen every 2 weeks during their freshman year. Clinical and behavioral data, oral washes and venous blood were obtained. EBV antibodies were quantified by enzyme immunoassay and viral loads by PCR. During a median 8 months of observation, 14/85 subjects experienced primary EBV infections (24 cases/100 person-years). The only significant risk factor for acquisition of EBV infection was deep kissing (P=0.02). Eleven subjects had infectious mononucleosis with a median duration of 21 days. Two subjects were hospitalized. Infections were initially identified in 12 subjects by finding EBV DNA in oral cells before onset of symptoms and in 2 subjects by symptom reporting. EBV DNA and viral capsid antigen (VCA) IgM and gp350 IgG antibodies were present in the blood before onset of illness. To provide a more robust evaluation of primary EBV infection in undergraduate university students, we combined data on risk factors and antibody responses from this and an earlier study that used the exact same clinical and laboratory methods. The observation that the only significant risk factor for acquisition of EBV infection was deep kissing was confirmed. Most importantly, higher amounts of gp350 antibody correlated significantly with a lower severity of infectious mononucleosis (P<0.0001), which strengthens the rationale for a gp350-based prophylactic EBV vaccine.

Figure 1

Median severity of illness scores during the month after onset of infectious mononucleosis among 11 subjects followed prospectively.

Figure 2

Social history data and acquisition of primary EBV infection during freshman year for the classes of 2010, 2011 and 2016. Information was provided by 203 (89%) of 228 subjects. The difference in the rate of acquisition of primary EBV infection between the ‘No Kissing or Sexual Activity' group (N=30) was significantly different than the ‘Kissing Only' (N=60) or ‘Sexually Active' (N=113) groups. P=0.0003, log-rank test.

Figure 3

EBV-specific antibody responses among 80 subjects with primary EBV infections followed prospectively. Values above the cutoff are considered positive. Curve smoothing was performed using Prism software, averaging the closest four neighbors of a single point. IgG antibody against gp350 and IgM antibody against VCA were first to appear and then waned. The gp350 response was biphasic with the highest peak occurring 40 weeks after onset of illness. IgG antibody against EBNA-1 was the slowest to appear but remained elevated as did IgG antibody against VCA.

Figure 4

gp350 IgG antibody levels in 27 subjects who had infectious mononucleosis with at least four samples collected during the first year after onset of illness. Values above the cutoff are considered positive. The area under the AUC was significantly greater among 12 subjects whose maximum SOI was milder (maximum SOI score 1–3) as compared with 15 subjects whose illness was more severe (maximum SOI score 4–6). AUC, 1641 versus 661; P<0.0001, unpaired, two-tailed t-test.