Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma

Abstract

Background: Infection with Epstein-Barr virus (EBV) early in life and repeated malaria exposure have been proposed as risk factors for endemic Burkitt lymphoma (eBL).

Methods: Infants were enrolled from 2 rural sites in Kenya: the Kisumu District, where malaria transmission is holoendemic and risk for eBL is high, and the Nandi District, where malaria transmission is limited and the risk for eBL is low. Blood samples were taken from infants through 2 years of age to measure EBV viral load, EBV antibodies, and malaria parasitemia.

Results: We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age. To analyze how different predictors affected EBV viral load over time, we performed multilevel mixed modeling. This modeling revealed that residence in Kisumu and younger age at first EBV infection were significant predictors for having a higher EBV viral load throughout the period of observation.

Conclusions: Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

Figure 1.

Representative figures of primary infection detected by first appearance of Epstein–Barr virus (EBV) DNA or by first appearance of EBV-specific antibodies. Data are shown for infants with primary infection with appearance of DNA before and at the same time as antibodies in Kisumu (A) and Nandi (B), as well as infants who have antibodies appear before EBV DNA in Kisumu (C) and Nandi (D). The left y-axis shows the median fluorescence intensity (MFI) of at least 75 beads for the response against each EBV antigen studied. The right y-axis plots EBV viral load. EBV DNA levels, solid black circle and solid black line; viral capsid antigen (VCA) IgG, solid black triangle and dotted line; and EBNA1 IgG, light gray open square and dotted line.

Figure 2.

A, Younger age at time of primary Epstein–Barr virus (EBV) infection in children from Kisumu compared with children in Nandi. Shown is the mean age at time of EBV in infants from Kisumu and Nandi (7.28 vs 8.39 months, respectively); each dot represents individual ages at time of infection. B, Comparable age at time of waning of maternal antibodies to EBV antigens in infants from Kisumu and Nandi. Shown is the mean age at which EBV-specific IgG (to viral capsid antigen or EBV nuclear antigen 1, depending on which was last detected) became undetectable in infants from Kisumu and Nandi (3.7 and 4.1 months, respectively; P = .33); each dot represents individual ages at time of waning. C, Correlation between age at time of last detection of maternal antibodies and age at time of infection by EBV for children from Kisumu and Nandi (R = 0.3240, P = .0001). Of note, there were group differences in age at time of EBV infection even after factoring out the effect of the age at time of last observed maternal antibody (P = .043), as shown by the parallel lines for the correlation between age at time of infection and age at time of last detection of maternal antibodies for both sites separately.