Prospective Characterization of the Risk Factors for Transmission and Symptoms of Primary Human Herpesvirus Infections Among Ugandan Infants

Abstract

Background: Human herpesvirus (HHV) infections are common during infancy. Primary infections are frequently asymptomatic and best studied prospectively by using direct viral detection.

Methods: Oropharyngeal swab specimens were collected weekly from Ugandan newborn infants, their mothers, and other children in the household. Blood specimens were collected every 4 months. Samples were tested for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6A, HHV-6B, and HHV-8, using quantitative polymerase chain reaction.

Results: Thirty-two infants, 32 mothers, and 49 other household children were followed for a median of 57 weeks. Seventeen mothers had human immunodeficiency virus type 1 (HIV) infection; no infants acquired HIV-1. The 12-month incidence of postnatal infection was 76% for HHV-6B, 59% for CMV, 47% for EBV, 8% for HSV-1, and 0% for HHV-8. The quantity of oropharyngeal shedding by contacts was associated with HHV-6A or HHV-6B transmission. Maternal HIV-1 infection was associated with EBV transmission, while breastfeeding and younger child contacts were associated with CMV transmission. Except for HSV-1, primary HHV infections were subclinical.

Conclusions: By capturing exposures and acquisition events, we found that the incidence and risk factors of infection vary by HHV type. HSV-1 infection, unlike other HHV infections, caused acute clinical illness in these infants.

Keywords: Epstein-Barr virus; HHV-6A; HHV-6B; HHV-8; HIV-exposed uninfected; cytomegalovirus; herpes simplex virus; infant; primary infection.

Figure 1.

Cumulative incidence of primary infection with different human herpesviruses (HHVs). A, Postnatal infections occurring in the first 18 months of life for primary children are shown. The cumulative incidence of postnatal infection at 6 months was 55.7% (95% confidence interval [CI], 39.2%–73.6%) for HHV-6B, 48.2% (95% CI, 32.0%–67.4%) for cytomegalovirus (CMV), 12.9% (95% CI, 5.1%–30.9%) for Epstein-Barr virus (EBV), 0% for herpes simplex virus 1 (HSV-1), and 0% for HHV-8. The cumulative incidence of postnatal infection at 12 months was 76.2% (95% CI, 60.0%–89.4%) for HHV-6B, 59.3% (95% CI, 42.2%–77.1%) for CMV, 47.4% (95% CI, 31.3%–66.6%) for EBV, 8.0% (95% CI, 2.1%–28.5%) for HSV-1, and 0% for HHV-8. B and C, Stratified data showing infants born to human immunodeficiency virus type 1 (HIV-1)–uninfected women (B) and HIV-1–infected women (C).

Figure 2.

Temporal frequency and quantity of oropharyngeal shedding with different human herpesviruses (HHVs) by primary children. All infants with documented primary infection during the study who had at least 1 sample collected after infection are shown. The median log₁₀ number of copies per milliliter was computed only among samples in which that virus was detected. The number of infants providing data at each week varied and is shown just above the x-axes; data are not shown for weeks when only a single infant provided data. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV-1, herpes simplex virus 1.

Figure 3.

Oropharyngeal human herpesvirus (HHV) shedding by household contacts, stratified by acquisition of infection in primary children. A, HHV detected in oropharyngeal swab specimens from mothers. B, HHV detected in oropharyngeal swab specimens from secondary children. Only samples collected while the primary infants were at risk for acquisition of each virus were included. Bars represent the percentage of samples that were positive, and diamonds represent the median log₁₀ number of copies per milliliter detected among positive samples. Open bars/diamonds correspond to household contacts of infants who did not become infected with the specified HHV, and shaded bars/triangles correspond to household contacts of infants who became infected with the specified HHV. Typing was unable to distinguish HHV-6A from HHV-6B and herpes simplex virus type 1 (HSV-1) from HSV-2 in all contact samples. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus.