Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis.

The prevalence and concentration of human herpesvirus 6 (HHV-6) DNA in the cerebrospinal fluid (CSF) of the immunocompetent in primary infection was compared with that in viral chromosomal integration. Samples from 510 individuals with suspected encephalitis, 200 young children and 310 older children and/or adults, and 12 other patients were tested. HHV-6 DNA concentration (log(10) copies/ml) was measured in CSF, serum, and whole blood using PCR. Serum HHV-6 immunoglobulin G antibody was measured by indirect immunofluorescence. Primary infection was defined by antibody seroconversion and/or a low concentration of HHV-6 DNA (<3.0 log(10) copies/ml) in a seronegative serum. Chromosomal integration was defined by a high concentration of viral DNA in serum (>/=3.5 log(10) copies/ml) or whole blood (>/=6.0 log(10) copies/ml). The prevalences of CSF HHV-6 DNA in primary infection and chromosomal integration were 2.5% and 2.0%, respectively, in the young children (<2 years) and 0% and 1.3%, respectively, in the older children and/or adults. The mean concentration of CSF HHV-6 DNA in 9 children with primary infection (2.4 log(10) copies/ml) was significantly lower than that of 21 patients with viral chromosomal integration (4.0 log(10) copies/ml). Only HHV-6B DNA was found in primary infection, whereas in viral integration, 4 patients had HHV-6A and 17 patients HHV-6B. Apart from primary infection, chromosomal integration is the most likely cause of HHV-6 DNA in the CSF of the immunocompetent. Our results show that any diagnosis of HHV-6 encephalitis or other type of active central nervous system infection should not be made without first excluding chromosomal HHV-6 integration by measuring DNA load in CSF, serum, and/or whole blood.

Unexpected occasional persistence of high levels of HHV-6 DNA in sera: detection of variants A and B.

Previously it was thought that in the immunocompetent human herpesvirus-6 [HHV-6] DNA was present transiently in serum during early primary infection but not thereafter. In this study, HHV-6 serum IgG avidity was detected by immunofluorescence and HHV-6 variants A/B [HHV-6A/B] serum DNA by semi-quantitative PCR [titre-log(10) copies/ml] in: (a) young children <3 years old from an encephalitis Survey, and a control Anonymised Serum Bank and (b) children/adults referred for diagnosis. The results showed that 11 out of 15 children [all <2 years] with primary infection proven by seroconversion had transient low levels of serum HHV-6B DNA [mean titre 2.6]. However, 3.3% (6/184) of Survey Children had significantly higher levels [mean titre 5.3; 2 HHV-6A; 4 HHV-6B; P < 0.001]. Similarly high level serum DNA [mean titre 4.0; 4 HHV-6A; 6 HHV-6B] was found in 1.5% (10/653) of the Serum Bank Children. Moreover, seven young children <3 years old [four Survey Children and three referred for diagnosis] had high titre serum HHV-6 DNA [mean 4.8] persisting i.e., in all available samples [median 186 days]. Three older children >3 years old and 4 adults [3 of whom were the mothers of 3 of the young children with persisting HHV-6] also had persisting high titre viral DNA [mean 4.2; median 108 days]. Thus in contrast to acute primary infection, where only HHV-6B DNA is found transiently, both HHV-6A and B DNA persist in serum at high titre in occasional individuals of all ages. The significance of this newly described phenomenon in relation to diagnosis, clinical consequences and congenital infection are discussed.