Antibody-based assay discriminates Zika virus infection from other flaviviruses.

Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged recently as a global health threat, causing a pandemic in the Americas. ZIKV infection mostly causes mild disease, but is linked to devastating congenital birth defects and Guillain-Barré syndrome in adults. The high level of cross-reactivity among flaviviruses and their cocirculation has complicated serological approaches to differentially detect ZIKV and dengue virus (DENV) infections, accentuating the urgent need for a specific and sensitive serological test. We previously generated a ZIKV nonstructural protein 1 (NS1)-specific human monoclonal antibody, which we used to develop an NS1-based competition ELISA. Well-characterized samples from RT-PCR-confirmed patients with Zika and individuals exposed to other flavivirus infections or vaccination were used in a comprehensive analysis to determine the sensitivity and specificity of the NS1 blockade-of-binding (BOB) assay, which was established in laboratories in five countries (Nicaragua, Brazil, Italy, United Kingdom, and Switzerland). Of 158 sera/plasma from RT-PCR-confirmed ZIKV infections, 145 (91.8%) yielded greater than 50% inhibition. Of 171 patients with primary or secondary DENV infections, 152 (88.9%) scored negative. When the control group was extended to patients infected by other flaviviruses, other viruses, or healthy donors (n = 540), the specificity was 95.9%. We also analyzed longitudinal samples from DENV-immune and DENV-naive ZIKV infections and found inhibition was achieved within 10 d postonset of illness and maintained over time. Thus, the Zika NS1 BOB assay is sensitive, specific, robust, simple, low-cost, and accessible, and can detect recent and past ZIKV infections for surveillance, seroprevalence studies, and intervention trials.

Protective effect of natural rotavirus infection in an Indian birth cohort.

BACKGROUND: More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected). METHODS: We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3. RESULTS: Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P[8], the most common viral strain, there was no evidence of homotypic protection. CONCLUSIONS: Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.).

Acute seizure risk in patients with encephalitis: development and validation of clinical prediction models from two independent prospective multicentre cohorts.

Objective: In patients with encephalitis, the development of acute symptomatic seizures is highly variable, but when present is associated with a worse outcome. We aimed to determine the factors associated with seizures in encephalitis and develop a clinical prediction model. Methods: We analysed 203 patients from 24 English hospitals (2005-2008) (Cohort 1). Outcome measures were seizures prior to and during admission, inpatient seizures and status epilepticus. A binary logistic regression risk model was converted to a clinical score and independently validated on an additional 233 patients from 31 UK hospitals (2013-2016) (Cohort 2). Results: In Cohort 1, 121 (60%) patients had a seizure including 103 (51%) with inpatient seizures. Admission Glasgow Coma Scale (GCS) ≤8/15 was predictive of subsequent inpatient seizures (OR (95% CI) 5.55 (2.10 to 14.64), p<0.001), including in those without a history of prior seizures at presentation (OR 6.57 (95% CI 1.37 to 31.5), p=0.025).A clinical model of overall seizure risk identified admission GCS along with aetiology (autoantibody-associated OR 11.99 (95% CI 2.09 to 68.86) and Herpes simplex virus 3.58 (95% CI 1.06 to 12.12)) (area under receiver operating characteristics curve (AUROC) =0.75 (95% CI 0.701 to 0.848), p<0.001). The same model was externally validated in Cohort 2 (AUROC=0.744 (95% CI 0.677 to 0.811), p<0.001). A clinical scoring system for stratifying inpatient seizure risk by decile demonstrated good discrimination using variables available on admission; age, GCS and fever (AUROC=0.716 (95% CI 0.634 to 0.798), p<0.001) and once probable aetiology established (AUROC=0.761 (95% CI 0.6840.839), p<0.001). Conclusion: Age, GCS, fever and aetiology can effectively stratify acute seizure risk in patients with encephalitis. These findings can support the development of targeted interventions and aid clinical trial design for antiseizure medication prophylaxis.

Enhanced Detection of DNA Viruses in the Cerebrospinal Fluid of Encephalitis Patients Using Metagenomic Next-Generation Sequencing.

The long and expanding list of viral pathogens associated with causing encephalitis confounds current diagnostic procedures, and in up to 50% of cases, the etiology remains undetermined. Sequence-agnostic metagenomic next-generation sequencing (mNGS) obviates the need to specify targets in advance and thus has great potential in encephalitis diagnostics. However, the low relative abundance of viral nucleic acids in clinical specimens poses a significant challenge. Our protocol employs two novel techniques to selectively remove human material at two stages, significantly increasing the representation of viral material. Our bioinformatic workflow using open source protein- and nucleotide sequence-matching software balances sensitivity and specificity in diagnosing and characterizing any DNA viruses present. A panel of 12 cerebrospinal fluid (CSFs) from encephalitis cases was retrospectively interrogated by mNGS, with concordant results in seven of nine samples with a definitive DNA virus diagnosis, and a different herpesvirus was identified in the other two. In two samples with an inconclusive diagnosis, DNA viruses were detected and in a virus-negative sample, no viruses were detected. This assay has the potential to detect DNA virus infections in cases of encephalitis of unknown etiology and to improve the current screening tests by identifying new and emerging agents.

Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study.

BACKGROUND: Since 2015, the arthropod-borne viruses (arboviruses) Zika and chikungunya have spread across the Americas causing outbreaks, accompanied by increases in immune-mediated and infectious neurological disease. The spectrum of neurological manifestations linked to these viruses, and the importance of dual infection, are not known fully. We aimed to investigate whether neurological presentations differed according to the infecting arbovirus, and whether patients with dual infection had a different disease spectrum or severity. METHODS: We report a prospective observational study done during epidemics of Zika and chikungunya viruses in Recife, Pernambuco, a dengue-endemic area of Brazil. We recruited adults aged 18 years or older referred to Hospital da Restauração, a secondary-level and tertiary-level hospital, with suspected acute neurological disease and a history of suspected arboviral infection. We looked for evidence of Zika, chikungunya, or dengue infection by viral RNA or specific IgM antibodies in serum or CSF. We grouped patients according to their arbovirus laboratory diagnosis and then compared demographic and clinical characteristics. FINDINGS: Between Dec 4, 2014, and Dec 4, 2016, 1410 patients were admitted to the hospital neurology service; 201 (14%) had symptoms consistent with arbovirus infection and sufficient samples for diagnostic testing and were included in the study. The median age was 48 years (IQR 34-60), and 106 (53%) were women. 148 (74%) of 201 patients had laboratory evidence of arboviral infection. 98 (49%) of them had a single viral infection (41 [20%] had Zika, 55 [27%] had chikungunya, and two [1%] had dengue infection), whereas 50 (25%) had evidence of dual infection, mostly with Zika and chikungunya viruses (46 [23%] patients). Patients positive for arbovirus infection presented with a broad range of CNS and peripheral nervous system (PNS) disease. Chikungunya infection was more often associated with CNS disease (26 [47%] of 55 patients with chikungunya infection vs six [15%] of 41 with Zika infection; p=0·0008), especially myelitis (12 [22%] patients). Zika infection was more often associated with PNS disease (26 [63%] of 41 patients with Zika infection vs nine [16%] of 55 with chikungunya infection; p≤0·0001), particularly Guillain-Barré syndrome (25 [61%] patients). Patients with Guillain-Barré syndrome who had Zika and chikungunya dual infection had more aggressive disease, requiring intensive care support and longer hospital stays, than those with mono-infection (median 24 days [IQR 20-30] vs 17 days [10-20]; p=0·0028). Eight (17%) of 46 patients with Zika and chikungunya dual infection had a stroke or transient ischaemic attack, compared with five (6%) of 96 patients with Zika or chikungunya mono-infection (p=0·047). INTERPRETATION: There is a wide and overlapping spectrum of neurological manifestations caused by Zika or chikungunya mono-infection and by dual infections. The possible increased risk of acute cerebrovascular disease in patients with dual infection merits further investigation. FUNDING: Fundação do Amparo a Ciência e Tecnologia de Pernambuco (FACEPE), EU's Horizon 2020 research and innovation programme, National Institute for Health Research. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Comparison of fifteen commercial assays for detecting Varicella Zoster virus IgG with reference to a time resolved fluorescence immunoassay (TRFIA) and the performance of two commercial assays for screening sera from immunocompromised individuals.

The performance of fifteen, commercially available, VZV IgG assays and an "in house" indirect immunofluorescence (IF) assay has been compared to a reference VZV IgG time resolved immunofluorescence assay (VZV TRFIA). A panel of 273 VZV TRFIA IgG positive serum samples and 136 VZV TRFIA IgG susceptible sera, collected from a number of UK hospitals was used. Irrespective of the interpretation of equivocal results the most sensitive assays were Dade Behring EIA (97.4%), "in house" IF (95.2%), Human EIA (92.3%) and Becton Dickinson latex agglutination (94.1%). The least sensitive assays were Virion EIA (69.6%), Diesse EIA (68.9%) and Diasys EIA (68.5%). The least sensitive (<70%) assays all had >99.0% specificity whereas the most sensitive assays had lower specificities; for example, Dade Behring EIA had a specificity of 69.9% when equivocals were treated as VZV IgG negative. For some assays e.g. Dade Behring EIA there were major discrepancies between our findings and those reported by the manufacturer which may reflect the constitution of the panel(s) of sera used for evaluation or the reference method adopted or the choice of cut-off criteria (particularly relevant to our findings for the Behring EIA). Care must be taken to choose an assay with high specificity in order to accurately assess the need for vaccination or immunoprophylaxis; however, high sensitivity is preferable to prevent inappropriate and expensive treatment.

Modulated Zika virus NS1 conjugate offers advantages for accurate detection of Zika virus specific antibody in double antigen binding and Ig capture enzyme immunoassays.

The accurate diagnosis and seroprevalence investigations of Zika virus (ZKV) infections remain complex due to cross reactivity with other flaviviruses. Two assay formats, both using labelled Zika virus NS1 antigen as a revealing agent (a double antigen binding assay, DABA, and an immunoglobulin Ig capture assay, G capture) were initially developed and compared with the indirect EuroimmunZ assay for the detection of anti-Zika antibody. Of 147 pre-Zika period serum samples, 39 (27%) were reactive in the EuroimmunZ or the DABA assays, 28 sera concordantly so. Such false reactivity was influenced by the serotype of Dengue virus (DV) to which individuals had been exposed to. Thus, of sera from patients undergoing secondary Dengue virus infection of known serotype, 91%, 45% and 28% of Dengue virus serotype 2, 3 and 4 respectively were reactive in one or more of the three assays. A novel method of quenching false sero-reactivity was therefore developed for the DABA and G capture assays. Initial addition of a single homologous Dengue virus serotype 3 NS1Ag quench significantly ablated false reactivities in the pre-Zika period sera. An equipotent quadrivalent quench comprising homologous Dengue virus serotypes 1 to 4 NS1Ag was shown to be optimum yet retained sensitivity for the detection of specific anti-Zika antibody. Comparing DABA and G capture assays using quenched and unquenched conjugates in comparison with EuroimmunZ early in the course of PCR-confirmed infection indicated that a significant component of the apparent early anti-ZIKA antibody response is likely to be due to a Zika virus-driven anamnestic anti-Dengue virus response. The increased specificity provided by homologous antigen quenching is likely to provide a significant improvement in sero-diagnostics and to be of clinical value.

Prevalence of eye signs in congenital rubella syndrome in South India: a role for population screening.

PURPOSE: Congenital rubella syndrome (CRS) resulting from maternal rubella infection, especially in the first trimester, affects an estimated 100 000 infants each year worldwide. Immunisation has reduced its occurrence in the developed world, though it remains a problem in countries with poor immunisation coverage. This population-based study was aimed at screening children below 5 years of age for ocular signs suspicious of CRS. METHODS: Suspected CRS cases were recruited from hospital and outreach services of the Aravind Eye Care System over a 24-month period. Clinical confirmation was based on the fulfilment of the World Health Organization (WHO) definition, and laboratory confirmation was based on a positive test for IgM antibody. RESULTS: Children under 5 years of age (n = 51 548) with ocular complaints were screened for eye signs suspicious of CRS; CRS compatible signs were detected in 1.92% (1090) children. Of these suspects (299), 27.42% were subsequently confirmed clinically according to WHO definition, and (46) 4.2% were serologically (Laboratory) confirmed. Of all the eye signs evaluated for screening, cataracts were the most sensitive (80.43%). CONCLUSIONS: Cataracts among children have a high sensitivity for detecting CRS in India. It is the only clinical eye finding that has a high enough sensitivity and specificity to be useful as a screening tool for CRS.

Increased rates of sequelae post-encephalitis in individuals attending primary care practices in the United Kingdom: a population-based retrospective cohort study.

The true extent of sequelae in encephalitis survivors relative to rates within the general population is not known. This study aimed to quantify increased risks of epilepsy, depressive disorders, anxiety disorders, psychotic disorders, bipolar disorder, cognitive problems, dementia, headache, and alcohol abuse among encephalitis cases. 2460 exposed individuals diagnosed with incident encephalitis in the Clinical Practice Research Datalink and 47,914 unexposed individuals without a history of encephalitis were included. Multivariable Poisson regression was used to estimate adjusted rate ratios in individuals with encephalitis compared to the general population and to estimate whether the effect of these outcomes varied over time. Individuals with encephalitis had an increased risk of all investigated outcomes. The highest RR was seen for epilepsy (adjusted RR 31.9; 95 % confidence interval 25.38-40.08), whereas the lowest was seen for anxiety disorders (1.46, 1.27-1.68). The second highest RRs were for particular psychiatric illnesses, including bipolar disorder (6.34, 3.34-12.04) and psychotic disorders (3.48, 2.18-5.57). The RR was highest in the first year of follow-up for all outcomes except headache; this was particularly true for epilepsy (adjusted RR in first year of follow-up 139.6, 90.62-215.03). This study shows that sequelae are common in survivors of encephalitis. We confirm the presence of outcomes more commonly linked to encephalitis and describe those less commonly identified as being associated with encephalitis. The results of this study have important implications for the management of encephalitis patients and for the design of tertiary prevention strategies, as many of these sequelae are treatable.

Association of genital shedding of herpes simplex virus type 2 and HIV-1 among sex workers in rural Zimbabwe.

INTRODUCTION: Herpes simplex virus type 2 (HSV-2) facilitates sexual acquisition of HIV-1 but data on transmission are less clear. In this study the interaction between genital shedding of HIV-1 and HSV-2 was explored among Zimbabwean sex workers. METHODS: Women (n = 214) were interviewed about genital symptoms. Blood samples were analysed for HIV-1 and HSV-2 antibodies, HIV-1 plasma viral load (PVL) and CD4 lymphocyte count and genital swabs for detection of HIV-1 and HSV-2 genital shedding, Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis, and a cervico-vaginal lavage (CVL) for quantitative measurement of HIV-1 shedding. Shedding analyses were undertaken on women co-infected with HSV-2 and HIV-1. RESULTS: A total of 124 women were co-infected with HIV-1 and HSV-2; 58 were infected with HSV-2 alone. Most HIV-1-infected women were co-infected with HSV-2 (95.4%). Genital HIV-1 shedding was detected in 84.3% of co-infected women and was associated with low CD4 cell count and high PVL but not with reported symptoms of genital herpes or genital shedding of HSV-2. There was no difference in HIV-1 shedding among women shedding HSV-2 (79.3%) and women not shedding HSV-2 (83.2%) (P = 0.64). The adjusted odds ratio for HIV-1 shedding between HSV-2 shedders and non-shedders was 0.8 [95% confidence interval (CI), 0.2-3.3]. HIV-1 PVL(log10) and CVL viral load(log10) were correlated (r = 0.38; 95%CI, 0.2-0.5). After adjusting for PVL, genital symptoms and age, HSV-2 shedding had no effect on CVL viral load (P = 0.13). CONCLUSION: Rate and quantity of HIV-1 genital shedding do not appear to be altered by presence of HSV-2 genital shedding.

Genetic variability of measles virus in acute and persistent infections.

RNA viruses have high nucleotide substitution rates, and therefore the potential to mutate rapidly. In the case of vaccine preventable RNA viruses, this may potentially lead to emergence of vaccine escape mutants. The WHO has targeted measles virus (MV) for elimination in many regions, and its genetic variability is monitored to estimate appearance of such mutants. Phylogenetic analysis of partial N or H genes of 230 MV strains circulating in the UK over a 10-year period was performed. Substitution rates in three outbreaks were determined to be 3.9 x 10(-3) to 6.7 x 10(-3) per nucleotide per annum. This is an order of magnitude higher than previously reported for circulating MV. Analysis of virus detected sporadically in the UK between 1992 and 2000 lead to a slightly higher substitution rate of 7.8 x 10(-3) per site per year. Additionally, genetic variability of persistent MV, isolated from subacute sclerosing panencephalitis (SSPE) patients, was investigated and appeared more stable than circulating viruses. Profiles of nucleotide changes in acute and persistent virus were compared. In acute virus, 33% of all mutation events occurred from A-to-G, which contrasts the predominant U-to-C mutations found in persistent infections. Mutations do not seem to be driven by positive selection and no association with known biological functions could be found. We conclude that substitution rates in circulating virus may be higher than in persistent, hypermutated virus and that the high substitution rate of MV may allow evolution of escape. Diversity of circulating strains should be closely monitored in the future.

School based HIV prevention in Zimbabwe: feasibility and acceptability of evaluation trials using biological outcomes.

OBJECTIVE: To determine the feasibility and acceptability of conducting a community randomized trial (CRT) of an adolescent reproductive health intervention (ARHI) using biological measures of effectiveness. SETTING: Four secondary schools and surrounding communities in rural Zimbabwe. METHODS: Discussions were held with pupils, parents, teachers and community leaders to determine acceptability. A questionnaire and urine sampling survey was undertaken among Form 1 and 2 pupils. Studies were undertaken to inform likely participation and follow up in a future CRT. A community survey of 16-19-year-olds was conducted to determine levels of secondary school attendance and likely HIV prevalence at final follow up in the event of a trial. RESULTS: Form 1 and 2 pupils aged 12-18 years (n = 723; median age, 15 years) participated in the research. Prevalences of HIV, Chlamydia and gonorrhoea were 3.6% [95% confidence interval (CI), 2.3-5.3%], 0.4% (95% CI, 0.1-1.3%) and 1.9% (95% CI, 1.0-3.3%) respectively. There was poor correlation between biological evidence of sexual experience and questionnaire responses, due to concerns about confidentiality. Only 13% (95% CI, 4-27%) of those infected with HIV and/or a sexually transmitted disease admitted to having had sex. In the community survey of 573 adolescents aged 16-19 years, 6.6% (95% CI, 3.9-10.3%) of females and 5.1% (95% CI, 2.9-8.2%) of males were HIV positive. High participation and retention rates are achievable within a trial in this setting. CONCLUSIONS: It is acceptable and feasible to conduct randomized trials to establish the effectiveness of ARHIs. However, self-reported behavioural outcomes will probably be biased, emphasizing the importance of using externally validated biological outcome measures to determine effectiveness.

Clinical manifestation of norovirus gastroenteritis in health care settings.

Noroviruses are generally believed to cause relatively mild gastroenteritis of short duration in otherwise healthy adults. However, outbreaks in health care settings are common and affect vulnerable populations. During 2002-2003, a total of 4 major hospitals, 11 community hospitals, and 135 nursing homes in the county of Avon, England, were prospectively monitored for outbreaks of gastroenteritis. For 482 hospital staff, 166 nursing home staff, and 266 nursing home residents, the median duration of norovirus gastroenteritis was 2 days, with 75% achieving complete recovery within 3 days. The median duration of norovirus gastroenteritis for 730 hospital patients was 3 days (75% of the patients achieved complete recovery within 5 days), which was significantly longer than that for all other groups (P<.001). Therefore, infection in hospitalized persons may be more severe than that in other groups in the community at large. This increased duration of acute illness should be considered when implementing measures to prevent transmission in hospital settings.

Multiplexed immunoassays by flow cytometry for diagnosis and surveillance of infectious diseases in resource-poor settings.

An accurate, rapid and cost-effective diagnosis is the cornerstone of efficient clinical and epidemiological management of infections. Here we discuss the relevance of an emerging technology, multiplexed immunoassays read by flow cytometry, for the diagnosis of infectious diseases. In these assays, multiple fluorescent microspheres, conjugated to different antigens or antibodies, constitute the solid phase for detecting antibodies or antigens in biological samples. These assays seem to be more sensitive than traditional immunoassays, have a high throughput capacity, and provide a wide analytical dynamic range. Additionally, they have multiplexing ability-ie, they are capable of measuring multiple antibodies or antigens simultaneously. We discuss four different areas where this technology could make an impact in resource-poor settings: (i) infections causing rash and fever in children; (ii) sero-epidemiological studies on vaccine-preventable diseases; (iii) management of genital ulcers and vaginal discharge; and (iv) screening of infections in blood banking. We predict a widespread use for a new breed of small, affordable, practical flow cytometers as field instruments for replacing ELISA and RIA tests, which will also be capable of doing cellular immunological tests such as CD4+ T-cell enumeration and Plasmodium falciparum detection in whole blood.

Application of the heteroduplex mobility assay (HMA) for the investigation of the genomic diversity among noroviruses in environmental samples.

Recent studies have demonstrated the widespread contamination of river and seawater with noroviruses (NV), often with more than one strain. The heteroduplex mobility assay (HMA) in which amplicons from study samples are hybridised (by denaturing and reannealing) to amplicons from reference strains and resolved by electrophoresis, has the potential to provide a simple and rapid means to identify samples containing multiple NV strains and to establish the diversity of strains within that sample. PCR amplicons from environmental samples that were tested directly in the HMA assay were shown to contain more than one strain. In order to evaluate HMA for investigations of NV diversity in environmental samples, amplicons from three representative samples were cloned and, for each, 20 amplicons derived from individual clones were analysed by HMA. Between two and six different HMA profiles were demonstrated among clones from a single sample indicating the extent of NV diversity in the sample. Sequence analysis confirmed the relationship of HMA profile and NV 'genotype'. Far greater diversity was seen among Genogroup (G) II (Ni/E3) amplicons than Genogroup (G) I (Ando/E3) amplicons (generated from the RNA dependent RNA polymerase region of the ORF1 of noroviruses), which often contained only a single strain, which is reflective of the greater prevalence of GII NVs over GI NVs. Overall, four GII and four GI strains were identified in these environmental water/sewage samples.

Expression and antigenic characterization of the major capsid proteins of human polyomaviruses BK and JC in Saccharomyces cerevisiae.

BK and JC viruses are ubiquitous human polyomaviruses that are associated with post-transplant interstitial nephritis (BK virus) and progressive multifocal leucoencephalopathy (JC virus). The use of a yeast system to express the major capsid protein (VP1) of two antigenic variants of BKV (strains SB and AS) and JCV is described. VP1s of AS and JCV expressed in Saccharomyces cerevisiae produced proteins of expected molecular weight as determined by gel electrophoresis whereas that of SB appeared to be lower than anticipated. However, all VP1s self-assembled into virus-like particles (VLP) retaining sialic acid-binding and antigenic properties of native virions. This method is highly efficient for producing recombinant proteins and therefore provides an alternative to the baculovirus system.

A summertime peak of "winter vomiting disease": surveillance of noroviruses in England and Wales, 1995 to 2002.

BACKGROUND: Noroviruses are the most common cause of gastroenteritis outbreaks in industrialised countries. Gastroenteritis caused by Norovirus infection has been described as a highly seasonal syndrome, often referred to as "winter vomiting disease". METHODS: The Public Health Laboratory Service Communicable Disease Surveillance Centre has systematically collected reports of laboratory confirmed cases of Norovirus-gastroenteritis since 1995. We analysed these data for annual and seasonal trends and age distribution. RESULTS: A mid-summer peak in reported cases of Norovirus was observed in 2002, unlike all six previous years when there was a marked summer decline. Total reports from 2002 have also been higher than all previous years. From the first 10 months of 2002, a total of 3029 Norovirus diagnoses were reported compared the previous peak in 1996 of 2437 diagnoses for the whole 12-month period. The increase in 2002 was most marked in the 65 and older age group. CONCLUSION: This surveillance data challenges the view that Noroviruses infections exclusively have wintertime seasonality.

Emergence of the GII-4 Norovirus Sydney2012 strain in England, winter 2012-2013.

Norovirus is the commonest cause of acute gastrointestinal disease and is the main aetiological agent of outbreaks of gastroenteritis, particularly in semi-closed environments. Norovirus infections in England typically peak between December and March each year. The most commonly detected norovirus strains belong to the genetically diverse genogroup-II genotype-4 (GII-4) genocluster and in the previous two norovirus winter seasons the majority of GII-4 strains in circulation worldwide have been genetically similar to the GII-4 strain New Orleans 1805/2009/USA. At the beginning of the 2012/13 season a genetically distinct GII-4 strain (Sydney 2012/NSW0514/2012/AU) was described which emerged worldwide during the winter of 2012/13. Here we describe the emergence of norovirus strains genetically related to Sydney2012 in England during the 2012/13 season to replace NewOrleans2009 strains as the most commonly detected variant of GII-4 norovirus in England. Furthermore, we demonstrate that whilst the emergence of Sydney2012 coincided with an early peak in the number of norovirus outbreaks, there was not an overall increase in norovirus activity compared to the previous season. Finally, we show that the Sydney2012 strain is associated with distinct genetic changes compared to the NewOrleans2009 strain, and these changes may have contributed to the emergence of the Sydney2012 strain.

Quality of life and associated socio-clinical factors after encephalitis in children and adults in England: a population-based, prospective cohort study.

OBJECTIVE: We sought to measure HRQoL in all-cause encephalitis survivors and assess the impact of various socio-clinical factors on outcome. METHODS: We used a prospective cohort study design, using the short-form 36 (SF-36) to measure the HRQoL in patients 15 years and older, and the short-form 10 (SF-10) for patients less than 15 years old. We posted questionnaires to individuals six months after discharge from hospital. All scores were normalised to the age- and sex-matched general population. We used multivariate statistical analysis to assess the relative association of clinical and socio-demographic variables on HRQoL in adults. RESULTS: Of 109 individuals followed-up, we received 61 SF-36 and twenty SF-10 questionnaires (response rate 74%). Patients scored consistently worse than the general population in all domains of the SF-36 and SF-10, although there was variation in individual scores. Infectious encephalitis was associated with the worst HRQoL in those aged 15 years and over, scoring on average 5.64 points less than immune-mediated encephalitis (95% CI -8.77- -2.89). In those aged less than 15 years the worst quality of life followed encephalitis of unknown cause. Immuno compromise, unemployment, and the 35-44 age group all had an independent negative association with HRQoL. A poor Glasgow Outcome Score was most strongly associated with a poor HRQoL. Less than half of those who had made a 'good' recovery on the score reported a HRQoL equivalent to the general population. CONCLUSIONS: Encephalitis has adverse effects on the majority of survivors' wellbeing and quality of life. Many of these adverse consequences could be minimised by prompt identification and treatment, and with better rehabilitation and support for survivors.