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The varicella-zoster virus (VZV) genome, as with all other human herpesviruses, comprises both unique and repeated regions. In addition, the genome includes six sequences of tandemly repeating short elements termed reiteration regions, designated R1 to R5. The R4 element is duplicated, with one copy each in the terminal repeat short (TRs) and the internal repeat short (IRs) regions. The reiteration regions (R) are an understudied feature of the VZV genome even though three of them (R1, R2 and R3) reside inside the coding regions of important viral genes. R1 is located in ORF11, a tegument protein and the homoolog to herpes simplex virus UL47. R2 is located in ORF 14, which encodes glycoprotein C. R3 is located in ORF22, a component of the viral tegument and the largest gene product encoded by the virus. It is the homolog to herpes simplex virus UL36. R4A is located in the IRs and is duplicated, usually in inverted orientation, as R4B in the TRs. R5 is located in a non-coding region between ORF60 and 61. We developed primers to amplify and Sanger sequence all six reiteration regions, including primers that independently amplify the two copies of R4. We sequenced the reiteration regions from more than 80 genomes for viruses selected from the Kaiser Permanente Herpes Zoster Study, each of which was sampled from patients with well-characterized cases of herpes zoster. Samples were selected to provide a broad representation of VZV clades. The remainder of these genomes were sequenced using the Illumina MiSeq platform.

It has been hoped that rapid SARS-CoV-2 antigen testing could reduce the tragic toll of COVID-19 in nursing homes. The performance of the BinaxNOW antigen test in a nursing home during an ongoing SARS-CoV-2 outbreak was evaluated., Visual Abstract. Serial SARS-CoV-2 Rapid Antigen Testing During a Nursing Home Outbreak. It has been hoped that rapid SARS-CoV-2 antigen testing could reduce the tragic toll of COVID-19 in nursing homes. The performance of the BinaxNOW antigen test in a nursing home during an ongoing SARS-CoV-2 outbreak was evaluated., Background: To address high COVID-19 burden in U.S. nursing homes, rapid SARS-CoV-2 antigen tests have been widely distributed in those facilities. However, performance data are lacking, especially in asymptomatic people. Objective: To evaluate the performance of SARS-CoV-2 antigen testing when used for facility-wide testing during a nursing home outbreak. Design: A prospective evaluation involving 3 facility-wide rounds of testing where paired respiratory specimens were collected to evaluate the performance of the BinaxNOW antigen test compared with virus culture and real-time reverse transcription polymerase chain reaction (RT-PCR). Early and late infection were defined using changes in RT-PCR cycle threshold values and prior test results. Setting: A nursing home with an ongoing SARS-CoV-2 outbreak. Participants: 532 paired specimens collected from 234 available residents and staff. Measurements: Percentage of positive agreement (PPA) and percentage of negative agreement (PNA) for BinaxNOW compared with RT-PCR and virus culture. Results: BinaxNOW PPA with virus culture, used for detection of replication-competent virus, was 95%. However, the overall PPA of antigen testing with RT-PCR was 69%, and PNA was 98%. When only the first positive test result was analyzed for each participant, PPA of antigen testing with RT-PCR was 82% among 45 symptomatic people and 52% among 343 asymptomatic people. Compared with RT-PCR and virus culture, the BinaxNOW test performed well in early infection (86% and 95%, respectively) and poorly in late infection (51% and no recovered virus, respectively). Limitation: Accurate symptom ascertainment was challenging in nursing home residents; test performance may not be representative of testing done by nonlaboratory staff. Conclusion: Despite lower positive agreement compared with RT-PCR, antigen test positivity had higher agreement with shedding of replication-competent virus. These results suggest that antigen testing could be a useful tool to rapidly identify contagious people at risk for transmitting SARS-CoV-2 during nascent outbreaks and help reduce COVID-19 burden in nursing homes. Primary Funding Source: None.

Background Monkeypox is a poorly described emerging zoonosis endemic to Central and Western Africa. Methods Using surveillance data from Tshuapa Province, Democratic Republic of the Congo during 2011–2015, we evaluated differences in incidence, exposures, and clinical presentation of polymerase chain reaction–confirmed cases by sex and age. Results We report 1057 confirmed cases. The average annual incidence was 14.1 per 100 000 (95% confidence interval, 13.3–15.0). The incidence was higher in male patients (incidence rate ratio comparing males to females, 1.21; 95% confidence interval, 1.07–1.37), except among those 20–29 years old (0.70; .51–.95). Females aged 20–29 years also reported a high frequency of exposures (26.2%) to people with monkeypox-like symptoms.The highest incidence was among 10–19-year-old males, the cohort reporting the highest proportion of animal exposures (37.5%). The incidence was lower among those presumed to have received smallpox vaccination than among those presumed unvaccinated. No differences were observed by age group in lesion count or lesion severity score. Conclusions Monkeypox incidence was twice that reported during 1980–1985, an increase possibly linked to declining immunity provided by smallpox vaccination. The high proportion of cases attributed to human exposures suggests changing exposure patterns. Cases were distributed across age and sex, suggesting frequent exposures that follow sociocultural norms.

Recent enhanced monkeypox (MPX) surveillance in the Democratic Republic of Congo, where MPX is endemic, has uncovered multiple cases of MPX and varicella zoster virus (VZV) coinfections. The purpose of this study was to verify if coinfections occur and to characterize the clinical nature of these cases. Clinical, epidemiological, and laboratory results were used to investigate MPX/VZV coinfections. A coinfection was defined as a patient with at least one Orthopoxvirus/MPX-positive sample and at least one VZV-positive sample within the same disease event. Between September 2009 and April 2014, 134 of the 1,107 (12.1%) suspected MPX cases were confirmed as MPX/VZV coinfections. Coinfections were more likely to report symptoms than VZV-alone cases and less likely than MPX-alone cases. Significantly higher lesion counts were observed for coinfection cases than for VZV-alone but less than MPX-alone cases. Discernible differences in symptom and rash severity were detected for coinfection cases compared with those with MPX or VZV alone. Findings indicate infection with both MPX and VZV could modulate infection severity. Collection of multiple lesion samples allows for the opportunity to detect coinfections. As this program continues, it will be important to continue these procedures to assess variations in the proportion of coinfected cases over time.

Background During the 2014-2015 US influenza season, 320 cases of non-mumps parotitis (NMP) among residents of 21 states were reported to the Centers for Disease Control and Prevention (CDC). We conducted an epidemiologic and laboratory investigation to determine viral etiologies and clinical features of NMP during this unusually large occurrence. Methods NMP was defined as acute parotitis or other salivary gland swelling of >2 days duration in a person with a mumps- negative laboratory result. Using a standardized questionnaire, we collected demographic and clinical information. Buccal samples were tested at the CDC for selected viruses, including mumps, influenza, human parainfluenza viruses (HPIVs) 1-4, adenoviruses, cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex viruses (HSVs) 1 and 2, and human herpes viruses (HHVs) 6A and 6B. Results Among the 320 patients, 65% were male, median age was 14.5 years (range, 0-90), and 67% reported unilateral parotitis. Commonly reported symptoms included sore throat (55%) and fever (48%). Viruses were detected in 210 (71%) of 294 NMP patients with adequate samples for testing, ≥2 viruses were detected in 37 samples, and 248 total virus detections were made among all samples. These included 156 influenza A(H3N2), 42 HHV6B, 32 EBV, 8 HPIV2, 2 HPIV3, 3 adenovirus, 4 HSV-1, and 1 HSV-2. Influenza A(H3N2), HHV6B, and EBV were the most frequently codetected viruses. Conclusions Our findings suggest that, in addition to mumps, clinicians should consider respiratory viral (influenza) and herpes viral etiologies for parotitis, particularly among patients without epidemiologic links to mumps cases or outbreaks.

Infections of the central nervous system (CNS) are often acute, with significant morbidity and mortality. Routine diagnosis of such infections is limited in developing countries and requires modern equipment in advanced laboratories that may be unavailable to a number of patients in sub-Saharan Africa. We developed a TaqMan array card (TAC) that detects multiple pathogens simultaneously from cerebrospinal fluid. The 21-pathogen CNS multiple-pathogen TAC (CNS-TAC) assay includes two parasites ( Balamuthia mandrillaris and Acanthamoeba ), six bacterial pathogens ( Streptococcus pneumonia e, Haemophilus influenzae , Neisseria meningitidis , Mycoplasma pneumoniae , Mycobacterium tuberculosis , and Bartonella ), and 13 viruses (parechovirus, dengue virus, Nipah virus, varicella-zoster virus, mumps virus, measles virus, lyssavirus, herpes simplex viruses 1 and 2, Epstein-Barr virus, enterovirus, cytomegalovirus, and chikungunya virus). The card also includes human RNase P as a nucleic acid extraction control and an internal manufacturer control, GAPDH (glyceraldehyde-3-phosphate dehydrogenase). This CNS-TAC assay can test up to eight samples for all 21 agents within 2.5 h following nucleic acid extraction. The assay was validated for linearity, limit of detection, sensitivity, and specificity by using either live viruses (dengue, mumps, and measles viruses) or nucleic acid material (Nipah and chikungunya viruses). Of 120 samples tested by individual real-time PCR, 35 were positive for eight different targets, whereas the CNS-TAC assay detected 37 positive samples across nine different targets. The CNS-TAC assays showed 85.6% sensitivity and 96.7% specificity. Therefore, the CNS-TAC assay may be useful for outbreak investigation and surveillance of suspected neurological disease.

To describe varicella cases in Tshuapa Province of the Democratic Republic of the Congo identified during monkeypox surveillance.Demographic, clinical and epidemiological data were collected from each suspected monkeypox case 2009-2014. Samples were tested by PCR for both Orthopoxviruses and varicella-zoster virus (VZV); a subset of VZV-positive samples was genotyped. We defined a varicella case as a rash illness with laboratory-confirmed VZV.There were 366 varicella cases were identified; 66% were ≤19 years old. Most patients had non-typical varicella rash with lesions reported as the same size and stage of evolution (86%), deep and profound (91%), on palms of hands and/or soles of feet (86%) and not itchy (49%). Many had non-typical signs and symptoms, such as lymphadenopathy (70%) and sensitivity to light (23%). A higher proportion of persons aged ≥20 years than persons aged ≤19 years had ≥50 lesions (79% vs. 65%, P = 0.007) and were bedridden (15% vs. 9%, P = 0.056). All VZV isolates genotyped from 79 varicella cases were clade 5. During the surveillance period, one possible VZV-related death occurred in a 7-year-old child.A large proportion of patients presented with non-typical varicella rash and clinical signs and symptoms, highlighting challenges identifying varicella in an area with endemic monkeypox. Continued surveillance and laboratory diagnosis will help in rapid identification and control of both monkeypox and varicella and improve our understanding of varicella epidemiology in Africa.Décrire les cas de varicelle identifiés dans la province de Tshuapa en République Démocratique du Congo (RDC) au cours de la surveillance de la variole du singe (monkeypox). MÉTHODES: Des données démographiques, cliniques et épidémiologiques ont été recueillies pour chaque cas présumé de monkeypox entre 2009 et 2014. Les échantillons ont été testés par PCR pour les orthopoxvirus et le virus varicelle-zona (VZV); un sous-ensemble d’échantillons positifs au VZV a été génotypé. Nous avons défini un cas de varicelle comme une éruption cutanée avec confirmation du VZV en laboratoire. RÉSULTATS: 366 cas de varicelle ont été identifiés; 66% avaient 19 ans ou moins. La plupart des patients présentaient une éruption non typique de varicelle avec des lésions rapportées de la même taille et le même stade d’évolution (86%), profonds (91%), sur la paume des mains et/ou la plante des pieds (86%), sans démangeaisons (49%). Nombre d'entre eux présentaient des signes et des symptômes inhabituels, tels qu'une adénopathie lymphatique (70%) et une sensibilité à la lumière (23%). Une proportion plus élevée de personnes âgées de 20 ans et plus que de personnes âgées de 19 ans et moins avaient 50 lésions ou plus (79% contre 65%, p = 0,007) et étaient alitées (15% contre 9%; p = 0,056). Tous les isolats de VZV génotypés chez 79 cas de varicelle appartenaient au clade 5. Au cours de la période de surveillance, un décès possible lié au VZV est survenu chez un enfant de 7 ans.Une forte proportion de patients ont présenté une éruption de varicelle ainsi que des signes et symptômes cliniques non typiques, soulignant les difficultés rencontrées pour identifier la varicelle dans une zone endémique pour le monkeypox. Une surveillance continue et des diagnostics de laboratoire aideront à identifier et à contrôler rapidement le monkeypox et la varicelle et à améliorer notre compréhension sur l’épidémiologie de la varicelle en Afrique.

Summary Background In September, 2017, human monkeypox re-emerged in Nigeria, 39 years after the last reported case. We aimed to describe the clinical and epidemiological features of the 2017–18 human monkeypox outbreak in Nigeria. Methods We reviewed the epidemiological and clinical characteristics of cases of human monkeypox that occurred between Sept 22, 2017, and Sept 16, 2018. Data were collected with a standardised case investigation form, with a case definition of human monkeypox that was based on previously established guidelines. Diagnosis was confirmed by viral identification with real-time PCR and by detection of positive anti-orthopoxvirus IgM antibodies. Whole-genome sequencing was done for seven cases. Haplotype analysis results, genetic distance data, and epidemiological data were used to infer a likely series of events for potential human-to-human transmission of the west African clade of monkeypox virus. Findings 122 confirmed or probable cases of human monkeypox were recorded in 17 states, including seven deaths (case fatality rate 6%). People infected with monkeypox virus were aged between 2 days and 50 years (median 29 years [IQR 14]), and 84 (69%) were male. All 122 patients had vesiculopustular rash, and fever, pruritus, headache, and lymphadenopathy were also common. The rash affected all parts of the body, with the face being most affected. The distribution of cases and contacts suggested both primary zoonotic and secondary human-to-human transmission. Two cases of health-care-associated infection were recorded. Genomic analysis suggested multiple introductions of the virus and a single introduction along with human-to-human transmission in a prison facility. Interpretation This study describes the largest documented human outbreak of the west African clade of the monkeypox virus. Our results suggest endemicity of monkeypox virus in Nigeria, with some evidence of human-to-human transmission. Further studies are necessary to explore animal reservoirs and risk factors for transmission of the virus in Nigeria. Funding None.

We report whole-genome sequences (WGSs) for four varicella-zoster virus (VZV) samples from a shingles study conducted by Kaiser Permanente of Southern California. Comparative genomics and phylogenetic analysis of all published VZV WGSs revealed that strain KY037798 is in clade IX, which shall henceforth be designated clade 9. Previously published single nucleotide polymorphisms (SNP)-based genotyping schemes fail to discriminate between clades 6 and VIII and employ positions that are not clade-specific. We provide an updated list of clade-specific positions that supersedes the list determined at the 2008 VZV nomenclature meeting. Finally, we propose a new targeted genotyping scheme that will discriminate the circulating VZV clades with at least a twofold redundancy. Genotyping strategies using a limited set of targeted SNPs will continue to provide an efficient ‘first pass’ method for VZV strain surveillance as vaccination programmes for varicella and zoster influence the dynamics of VZV transmission.

Congenital cytomegalovirus (CMV) transmission can occur when women acquire CMV while pregnant. Infection control guidelines may reduce risk for transmission. We studied the duration of CMV survival after application of bacteria to the hands and after transfer from the hands to surfaces and the effectiveness of cleansing with water, regular and antibacterial soaps, sanitizer, and diaper wipes. Experiments used CMV AD169 in saliva at initial titers of 1 × 10 5 infectious particles/ml. Samples from hands or surfaces (points between 0 and 15 min) were placed in culture and observed for at least 2 weeks. Samples were also tested using CMV real-time PCR. After application of bacteria to the hands, viable CMV was recovered from 17/20 swabs at 0 min, 18/20 swabs at 1 min, 5/20 swabs at 5 min, and 4/20 swabs at 15 min. After transfer, duration of survival was at least 15 min on plastic (1/2 swabs), 5 min on crackers and glass (3/4 swabs), and 1 min or less on metal and cloth (3/4 swabs); no viable virus was collected from wood, rubber, or hands. After cleansing, no viable virus was recovered using water (0/22), plain soap (0/20), antibacterial soap (0/20), or sanitizer (0/22). Viable CMV was recovered from 4/20 hands 10 min after diaper wipe cleansing. CMV remains viable on hands for sufficient times to allow transmission. CMV may be transferred to surfaces with reduced viability. Hand-cleansing methods were effective at eliminating viable CMV from hands.

Background. Sporadic cases of parotitis are generally assumed to be mumps, which often requires a resourceintensive public health response. This project surveyed the frequency of viruses detected among such cases. Methods. During 2009–2011, 8 jurisdictions throughout the United States investigated sporadic cases of parotitis. Epidemiologic information, serum, and buccal and oropharyngeal swabs were collected. Polymerase chain reaction methods were used to detect a panel of viruses. Anti–mumps virus immunoglobulin M (IgM) antibodies were detected using a variety of methods. Results. Of 101 specimens, 38 were positive for a single virus: Epstein-Barr virus (23), human herpesvirus (HHV)-6B (10), human parainfluenza virus (HPIV)-2 (3), HPIV-3 (1), and human bocavirus (1). Mumps virus, enteroviruses (including human parechovirus), HHV-6A, HPIV-1, and adenoviruses were not detected. Early specimen collection did not improve viral detection rate. Mumps IgM was detected in 17% of available specimens. Patients in whom a virus was detected were younger, but no difference was seen by sex or vaccination profile. No seasonal patterns were identified. Conclusions. Considering the timing of specimen collection, serology results, patient vaccination status, and time of year may be helpful in assessing the likelihood that a sporadic case of parotitis without laboratory confirmation is mumps.

The live attenuated Oka varicella vaccine (vOka), derived from clade 2 wild-type (wt) virus pOka, is used for routine childhood immunization in several countries, including the United States, which has caused dramatic declines in the incidence of varicella. vOka can cause varicella, establish latency, and reactivate to cause herpes zoster (HZ). Three loci in varicella-zoster virus (VZV) open reading frame 62 (ORF62) (106262, 107252, and 108111) are used to distinguish vOka from wt VZV. A fourth position (105705) is also fixed for the vOka allele in nearly all vaccine batches. These 4 positions and two vOka mutations (106710 and 107599) reportedly absent from Varivax were analyzed on Varivax-derived ORF62 TOPO TA clones. The wt allele was detected at positions 105705 and 107252 on 3% and 2% of clones, respectively, but was absent at positions 106262 and 108111. Position 106710 was fixed for the wt allele, whereas the vOka allele was present on 18.4% of clones at position 107599. We also evaluated the 4 vOka markers in an isolate obtained from a case of vaccine-caused HZ. The isolate carried the vOka allele at positions 105705, 106262, and 108111. However, at position 107252, the wt allele was present. Thus, all of the ORF62 vOka markers previously regarded as fixed occur as the wt allele in a small percentage of vOka strains. Characterization of all four vOka markers in ORF62 and of the clade 2 subtype marker in ORF38 is now necessary to confirm vOka adverse events.

Congenital cytomegalovirus (CMV) affects ~1 of 150 births and is a leading cause of hearing loss and intellectual disability. It has been suggested that transmission may occur via contaminated surfaces. CMV AD169 in filtered human saliva, applied to environmental surfaces, was recovered at various time points. Samples were evaluated by culture and real-time polymerase chain reaction. CMV was found viable on metal and wood to 1 hour, glass and plastic to 3 hours, and rubber, cloth, and cracker to 6 hours. CMV was cultured from 83 of 90 wet and 5 of 40 dry surfaces. CMV was more likely to be isolated from wet, highly absorbent surfaces at earlier time points.

OBJECTIVE We present the largest longitudinal study to date that examines the association between Kaposi's Sarcoma (KS) disease progression and the presence and viral load of human herpesvirus 8 (HHV-8). METHODS Ninety-six men were enrolled at HIV clinics in Atlanta, Georgia, who had KS (n = 47) or were without KS but seropositive for HHV-8. Visits occurred at 6-month intervals for 2 years at which the patient's KS status was evaluated and oral fluid and blood were collected for quantification of HHV-8 DNA and antibodies. RESULTS The presence of HHV-8 DNA in blood was more common (P < 0.001) and the viral load higher (P < 0.001) in men with KS in comparison with men without KS. Mean HHV-8 viral loads in blood and oral fluids were associated with disease status, being highest among patients with progressing KS, intermediate among patients with stable KS, and lowest among patients with regressing KS. Consistent with our previous report high antibody titers to HHV-8 orf 65 were inversely associated with HHV-8 shedding in oral fluid. CONCLUSIONS We observed a significant association between changes in KS disease severity and the presence and viral load of HHV-8. HHV-8 viral load in blood may provide useful information to clinicians for assessment of the risk of further disease progression in patients with KS.

Background Young, healthy children shedding cytomegalovirus (CMV) in urine and saliva appear to be the leading source of CMV in primary infection of pregnant women. Findings We screened 48 children 6 months – 5 years old for CMV IgG and measured levels of CMV IgG, IgM and IgG avidity antibodies, frequency of CMV shedding, and viral loads in blood, urine, and saliva. Thirteen of the 48 children (27%) were CMV IgG positive, among whom 3 were also CMV IgM positive with evidence of recent primary infection. Nine of the 13 seropositive children (69%) were shedding 102-105 copies/ml of CMV DNA in one or more bodily fluid. Among seropositive children, low IgG antibody titer (1:20–1:80) was associated with the absence of shedding (p = 0.014), and enrollment in daycare was associated with the presence of CMV shedding (p = 0.037). Conclusions CMV antibody profiles correlated with CMV shedding. The presence of CMV IgM more often represents primary infection in children than in adults. Correlating antibodies with primary infection and viral shedding in healthy children adds to the understanding of CMV infection in children that can inform the prevention of CMV transmission to pregnant women.

We investigated a varicella outbreak in a residential facility for adults with intellectual disabilities. A case of varicella was defined as a generalized maculopapular rash that developed in a facility resident or employee. Immunoglobulin M testing was conducted on serologic samples, and polymerase chain reaction testing was performed on environmental and skin lesion samples. Eleven cases were identified among 70 residents and 2 among ∼145 staff. An unrecognized case of herpes zoster was the likely source. Case patients first entered any residential facility at a younger age than non-case residents (9.5 vs 15.0 years; P < .01). Varicella zoster virus DNA was detected 2 months after the outbreak in environmental samples obtained from case patients' residences. This outbreak exemplifies the potential for at-risk pockets of varicella-susceptible adults, especially among those who have lived in residential facilities from a young age. Evidence of immunity should be verified for all adults and healthcare staff in similar residential settings.

BACKGROUND Cytomegalovirus (CMV) is a leading cause of congenital illness and disability, including hearing loss and mental retardation. However, there are no nationwide estimates of CMV seroprevalence among pregnant women or the overall population of the United States. METHODS To determine CMV prevalence in a representative sample of the US population, we tested serum samples for CMV-specific immunoglobulin G from participants aged > or =6 years (n=21,639) in the third National Health and Nutrition Examination Survey (1988-1994). RESULTS The prevalence of CMV infection was 58.9% in individuals > or =6 years old. CMV seroprevalence increased gradually with age, from 36.3% in 6-11-year-olds to 90.8% in those aged > or =80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans. Racial and/or ethnic differences in CMV seroprevalence persisted when controlling for household income level, education, marital status, area of residence, census region, family size, country of birth, and type of medical insurance. Among women, racial and/or ethnic differences were especially significant; between ages 10-14 years and 20-24 years, seroprevalence increased 38% for non-Hispanic black persons, 7% for non-Hispanic white persons, and

TOC Summary: This virus should be considered endemic to the wetland areas of Bentiu, Unity State, Sudan., To determine the outbreak source of monkeypox virus (MPXV) infections in Unity State, Sudan, in November 2005, we conducted a retrospective investigation. MPXV was identified in a sub-Sahelian savannah environment. Three case notification categories were used: suspected, probable, and confirmed. Molecular, virologic, and serologic assays were used to test blood specimens, vesicular swabs, and crust specimens obtained from symptomatic and recovering persons. Ten laboratory-confirmed cases and 9 probable cases of MPXV were reported during September–December 2005; no deaths occurred. Human-to-human transmission up to 5 generations was described. Our investigation could not fully determine the source of the outbreak. Preliminary data indicate that the MPXV strain isolated during this outbreak was a novel virus belonging to the Congo Basin clade. Our results indicate that MPXV should be considered endemic to the wetland areas of Unity State. This finding will enhance understanding of the ecologic niche for this virus.