Enterovirus D68-Associated Acute Respiratory Illness - New Vaccine Surveillance Network, United States, July-October, 2017 and 2018.

In the fall of 2014, an outbreak of enterovirus D68 (EV-D68)-associated acute respiratory illness (ARI) occurred in the United States (1,2); before 2014, EV-D68 was rarely reported to CDC (2,3). In the United States, reported EV-D68 detections typically peak during late summer and early fall (3). EV-D68 epidemiology is not fully understood because testing in clinical settings seldom has been available and detections are not notifiable to CDC. To better understand EV-D68 epidemiology, CDC recently established active, prospective EV-D68 surveillance among pediatric patients at seven U.S. medical centers through the New Vaccine Surveillance Network (NVSN) (4). This report details a preliminary characterization of EV-D68 testing and detections among emergency department (ED) and hospitalized patients with ARI at all NVSN sites during July 1-October 31, 2017, and the same period in 2018. Among patients with ARI who were tested, EV-D68 was detected in two patients (0.8%) in 2017 and 358 (13.9%) in 2018. Continued active, prospective surveillance of EV-D68-associated ARI is needed to better understand EV-D68 epidemiology in the United States.

Early developmental outcomes of children with congenital HHV-6 infection.

OBJECTIVE: The goal of this study was to determine if congenital human herpesvirus-6 (HHV-6) infection influences early neurodevelopment. METHODS: We enrolled 57 newborns with HHV-6 congenital infection and 242 control newborns without congenital infection into a prospective, double-blind study with 4 visits between 4 and 30 months of age. Assessments included the Fagan Test of Infant Intelligence, the Visual Expectation Paradigm, and the Mental Development Index (MDI) of the Bayley Scales of Infant Development II. Newborn audiology screening and follow-up audiology examinations were completed at 12 to 24 months. RESULTS: No differences were noted in baseline characteristics between infants with HHV-6 congenital infection and control infants. No clinical syndrome due to congenital infection with HHV-6 was evident at birth. No differences were identified on the Fagan Test of Infant Intelligence or the Visual Expectation Paradigm between the two groups. In 39 infants with HHV-6 congenital infection, the mean ± SD Bayley Scale of Infant Development II MDI score was 103.4 ± 8.9 at 12 months of age. The matched control infants had a mean score of 105.4 ± 12.4. After controlling for covariates, HHV-6 congenital infection was associated with lower scores on the Bayley Scale of Infant Development II MDI at 12 months of age (mean difference: 4.3 [95% confidence interval: 0.4 to 8.1]; P = .03) compared with infants without HHV-6 congenital infection. CONCLUSIONS: Congenital HHV-6 infection may have a detrimental effect on neurodevelopment at 12 months of age and requires further study given that congenital infection with HHV-6 is present in ∼1 in every 101 births.

Field evaluation of TaqMan Array Card (TAC) for the simultaneous detection of multiple respiratory viruses in children with acute respiratory infection.

BACKGROUND: Multipathogen reverse transcription real-time PCR (RT-qPCR) platforms have proven useful in surveillance for acute respiratory illness (ARI) and study of respiratory outbreaks of unknown etiology. The TaqMan(®) Array Card (TAC, Life Technologies™), can simultaneously test 7 clinical specimens for up to 21 individual pathogens (depending on arrangement of controls and use of duplicate wells) by arrayed singleplex RT-qPCR on a single assay card, using minimal amounts of clinical specimens. A previous study described the development of TAC for the detection of respiratory viral and bacterial pathogens; the assay was evaluated against well-characterized analytical materials and a limited collection of human clinical specimens. OBJECTIVES: We wished to compare TAC assay performance against standard individual RT-qPCR assays for respiratory viral detection, focusing on 10 viruses (adenovirus, human metapneumovirus, human parainfluenza viruses 1-4, influenza viruses A and B, respiratory syncytial virus, and rhinovirus) from a larger collection of human specimens. STUDY DESIGN: We used specimens from 942 children with ARI enrolled systematically in a population-based, ARI surveillance study (New Vaccine Surveillance Network, NVSN). RESULTS: Compared with standard individual RT-qPCR assays, the sensitivity of TAC for the targeted viruses ranged from 54% to 95% (54%, 56%, and 75% for adenovirus, human parainfluenza viruses-1 and -2, respectively, and 82%-95% for the other viruses). Assay specificity was 99%, and coefficients of variation for virus controls ranged from 1.5% to 4.5%. CONCLUSION: The TAC assay should prove useful for multipathogen studies and rapid outbreak response.

Diagnostic assays for active infection with human herpesvirus 6 (HHV-6).

BACKGROUND: Human herpesvirus 6 (HHV-6) causes ubiquitous infection in early childhood with lifelong latency or persistence. Reactivation of HHV-6 has been associated with multiple diseases including encephalitis. Chromosomal integration of HHV-6 also occurs. Previous studies have suggested that the detection of HHV-6 DNA in plasma is an accurate marker of active viral replication. OBJECTIVE: We sought to determine whether PCR assays on plasma could correctly differentiate between primary HHV-6 infection, chromosomal integration of HHV-6 and latent HHV-6 infection. STUDY DESIGN: We performed qualitative PCR, real-time quantitative PCR (RQ-PCR), and reverse-transcriptase PCR (RT-PCR) assays on samples of peripheral and cord blood mononuclear cells, as well as plasma, from groups of subjects with well defined HHV-6 infection, including subjects with chromosomally integrated HHV-6. RESULTS AND CONCLUSIONS: The detection of HHV-6 DNA in plasma was 92% sensitive compared to viral isolation for the identification of primary infection with HHV-6. All plasma samples from infants with chromosomally integrated HHV-6 had HHV-6 DNA detectable in plasma while only 5.6% were positive by RT-PCR. The specificity of plasma PCR for active replication of HHV-6 was 84% compared to viral culture while the specificity of RT-PCR was 98%. Our results demonstrate that qualitative or quantitative PCR of plasma is insufficient to distinguish between active viral replication and chromosomal integration with HHV-6. We found a higher specificity of RT-PCR performed on PBMC samples compared to PCR or RQ-PCR performed on plasma when evaluating samples for active HHV-6 replication.

Transplacental congenital human herpesvirus 6 infection caused by maternal chromosomally integrated virus.

Congenital human herpesvirus 6 (HHV-6) infection results from germline passage of chromosomally integrated HHV-6 (CI-HHV-6) and from transplacental passage of maternal HHV-6 infection. We aimed to determine whether CI-HHV-6 could replicate and cause transplacentally acquired HHV-6 infection. HHV-6 DNA, variant type, and viral loads were determined with samples (cord blood, peripheral blood, saliva, urine, and hair) obtained from 6 infants with transplacentally acquired HHV-6 and with samples of their parents' hair. No fathers but all mothers of infants with transplacentally acquired HHV-6 had CI-HHV-6, and the mother's CI-HHV-6 variant was the same variant causing the transplacentally acquired congenital HHV-6 infection. This suggests the possibility that CI-HHV-6 replicates and may cause most, if not all, congenital HHV-6 infections.

Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection.

OBJECTIVE: We examined the frequency and characteristics of chromosomally integrated human herpesvirus 6 among congenitally infected children. METHODS: Infants with and without congenital human herpesvirus 6 infection were prospectively monitored. Cord blood mononuclear cell, peripheral blood mononuclear cell, saliva, urine, and hair follicle samples were examined for human herpesvirus 6 DNA. Human herpesvirus 6 RNA, serum antibody, and chromosomally integrated human herpesvirus 6 levels were also assessed. RESULTS: Among 85 infants, 43 had congenital infections and 42 had postnatal infections. Most congenital infections (86%) resulted from chromosomally integrated human herpesvirus 6; 6 infants (14%) had transplacental infections. Children with chromosomally integrated human herpesvirus 6 had high viral loads in all sites (mean: 5-6 log(10) genomic copies per mug of cellular DNA); among children with transplacental infection or postnatal infection, human herpesvirus 6 DNA was absent in hair samples and inconsistent in other samples, and viral loads were significantly lower. One parent of each child with chromosomally integrated human herpesvirus 6 who had parental hair samples tested had hair containing human herpesvirus 6 DNA. Variant A caused 32% of chromosomally integrated human herpesvirus 6 infections, compared with 2% of postnatal infections. Replicating human herpesvirus 6 was detected only among chromosomally integrated human herpesvirus 6 samples (8% of cord blood mononuclear cells and peripheral blood mononuclear cells). Cord blood human herpesvirus 6 antibody levels were similar among children with chromosomally integrated human herpesvirus 6, transplacental infection, and postnatal infection and between children with maternal and paternal chromosomally integrated human herpesvirus 6 transmission. CONCLUSIONS: Human herpesvirus 6 congenital infection results primarily from chromosomally integrated virus which is passed through the germ-line. Infants with chromosomally integrated human herpesvirus 6 had high viral loads in all specimens, produced human herpesvirus 6 antibody, and mRNA. The clinical relevance needs study as 1 of 116 newborns may have chromosomally integrated human herpesvirus 6 blood specimens.