Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016

Respiratory syncytial virus (RSV) is considered the major pathogen causing severe lower respiratory tract infections among infants and young children [1]. RSV is the most common cause of hospitalisation for acute lower respiratory tract infection in children younger than 5 years and is estimated to cause between 66,000 and 199,000 deaths worldwide every year [2]. Its significance in causing substantial morbidity and hospitalisation in the first year of life has been affirmed in a recent study and a meta-analysis [3,4]. In England, average annual hospital admission rates are 35.1 per 1,000 children younger than 1 year and 5.31 per 1,000 children aged 1–4 years [5]. In addition to children, RSV causes a substantial disease burden in elderly people and patients with chronic obstructive pulmonary disease [6,7]. RSV causes seasonal epidemics worldwide [8], with one to two epidemics each year [9] following latitudinal gradients in timing, duration, seasonal amplitude and between-year variability [8,9]. In some studies, the seasonal periodicity has been connected to climatic factors [9-11], but a common factor that explains all observed periodicity has not been established. Meteorological conditions such as temperature and high relative humidity have been reported as important predictors of RSV epidemics [9,12]. In the United States (US) and Japan, annual national and regional variation of RSV season onset and end has been reported [13-15]. In the Nordic countries, a major outbreak often alternates with a minor one, with the minor peak in the spring and a major one the following winter [16-19], a phenomenon reported also in Croatia [20], Denmark [21] and Germany [22]. RSV antigenic groups A and B alternate in two-year cycles in Finland, with dominance of the group A viruses in years 1981–82, 1985–86 and 1989–90 and the group B viruses 1983–84 and 1987–88 [17,19], and different genotypes dominate the circulation in consecutive epidemics in Korea [23]. In Spain, no biennial rhythm has been detected but rather a stable annual epidemic with a peak between week 52 and week 1 and circulation 2–8 weeks earlier than influenza viruses [24]. Similarly, in the United Kingdom (UK), one stable epidemic per year is observed [5]. Immunoprophylaxis to prevent RSV infection with a neutralising monoclonal antibody, palivizumab, has been developed for administration to target groups on a monthly basis during the RSV season [25]. However, this drug is limited to high-risk infants, the cost prohibits its use in low- and middle-income countries and the data on effectiveness of the drug in children at high risk other than infants born at gestational age < 33 weeks and in children with chronic lung and heart diseases are limited [26]. The demonstrated high disease burden of RSV infection has created a longstanding interest in RSV vaccines. Approximately 60 RSV vaccine candidates are in preclinical to phase III clinical trials [27,28], with potential target groups including elderly people, pregnant women and infants. A vaccine is expected to enter the market within 5–10 years, presumably by 2025 [29]. As natural infection provides only limited protective immunity owing to evolution of the surface protein G and alternating dominance of antigenic groups A and B [30], most of the vaccine candidates target the fusion protein F, which is cross-reactive across RSV subtypes [27]. To circumvent issues with alternating strains, it has been also suggested to consider inclusion of both RSV A and B in a future RSV vaccine [30]. To plan optimal future vaccination strategies, it is critically important to understand who is affected by RSV and to identify which groups are at risk of more severe RSV infection requiring hospitalisation or intensive care. RSV infection is not notifiable in the European Union (EU) and European Economic Area (EEA), except in Ireland, but many countries have a long tradition of reporting laboratory-confirmed RSV infections at national and international level. The European Influenza Surveillance Network (EISN) collects RSV data for the purpose of interpreting the reports of influenza-like-illness (ILI); these data can also be used to analyse seasonality of RSV [31]. Inter-country comparative analysis of seasonal circulation of RSV across Europe is lacking as most of the published literature focuses on individual countries. Our study describes the seasonality of RSV in 15 countries in the EU/EEA, specifically the start and peak of the season, length of the season and geographical spread, as a baseline description of RSV circulation in Europe. We further aimed to test if the data reported through influenza surveillance systems in use in EU/EEA countries are appropriate to analyse RSV seasonality, including more countries and a more detailed analysis than previous studies.Peer Reviewe

Herpes Simplex Virus Type 1 Us3 Gene Deletion Influences Toll-like Receptor Responses in Cultured Monocytic Cells

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors have a key role in innate immune response to microbial infection. The toll-like receptor (TLR) family consists of ten identified human TLRs, of which TLR2 and TLR9 have been shown to initiate innate responses to herpes simplex virus type 1 (HSV-1) and TLR3 has been shown to be involved in defence against severe HSV-1 infections of the central nervous system. However, no significant activation of the TLR3 pathways has been observed in wild type HSV-1 infections. In this work, we have studied the TLR responses and effects on TLR gene expression by HSV-1 with Us3 and ICP4 gene deletions, which also subject infected cells to apoptosis in human monocytic (U937) cell cultures.</p> <p>Results</p> <p>U937 human monocytic cells were infected with the Us3 and ICP4 deletion herpes simplex virus (d120), its parental virus HSV-1 (KOS), the Us3 deletion virus (R7041), its rescue virus (R7306) or wild type HSV-1 (F). The mRNA expression of TLR2, TLR3, TLR4, TLR9 and type I interferons (IFN) were analyzed by quantitative real-time PCR. The intracellular expression of TLR3 and type I IFN inducible myxovirus resistance protein A (MxA) protein as well as the level of apoptosis were analyzed by flow cytometry. We observed that the mRNA expression of TLR3 and type I IFNs were significantly increased in d120, R7041 and HSV-1 (F)-infected U937 cells. Moreover, the intracellular expression of TLR3 and MxA were significantly increased in d120 and R7041-infected cells. We observed activation of IRF-3 in infections with d120 and R7041. The TLR4 mRNA expression level was significantly decreased in d120 and R7041-infected cells but increased in HSV-1 (KOS)-infected cells in comparison with uninfected cells. No significant difference in TLR2 or TLR9 mRNA expression levels was seen. Both the R7041 and d120 viruses were able to induce apoptosis in U937 cell cultures.</p> <p>Conclusion</p> <p>The levels of TLR3 and type I IFN mRNA were increased in d120, R7041 and HSV-1 (F)-infected cells when compared with uninfected cells. Also IRF-3 was activated in cells infected with the Us3 gene deletion viruses d120 and R7041. This is consistent with activation of TLR3 signaling in the cells. The intracellular TLR3 and type I IFN inducible MxA protein levels were increased in d120 and R7041-infected cells but not in cells infected with the corresponding parental or rescue viruses, suggesting that the HSV-1 Us3 gene is involved in control of TLR3 responses in U937 cells.</p

Current practices for respiratory syncytial virus surveillance across the EU/EEA Member States, 2017

Background: Respiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections worldwide and several vaccine candidates are currently in development. Following vaccine introduction, reliable RSV surveillance should enable monitoring of vaccination impact. Data on the RSV disease burden in the European Union and European Economic Area (EU/EEA) are sparse. Aim: The aim of this study was to gather knowledge on current practices of national RSV surveillance in the EU/EEA. Methods: National Coordinators and National Focal Points for Influenza (epidemiologists and virologists) from the EU/EEA countries (n = 31) were invited to participate in an online survey in August and September 2017. The questionnaire covered questions on epidemiological and laboratory aspects of RSV surveillance. Results: All EU/EEA countries except Liechtenstein replied to the survey. Eighteen countries reported to have a sentinel surveillance system, 26 countries a non-sentinel surveillance system and three countries to have neither. RSV data collection was mostly done within the context of influenza surveillance. A wide range of diagnostic and characterisation assays was used for the detection of RSV. Discussion: The majority of EU/EEA countries have some surveillance for RSV in place. The prevailing integration of RSV surveillance into the existing influenza sentinel surveillance system may lead to under-reporting of RSV. The documented variations in existing RSV surveillance systems and their outputs indicate that there is scope for developing guidelines on establishing comparable methods and outcomes for RSV surveillance across the EU/EEA, to ensure the availability of a consistent evidence base for assessing future vaccination programmes.S

Alternating patterns of seasonal influenza activity in the WHO European Region following the 2009 pandemic, 2010-2018

Background: Influenza virus infections are common and lead to substantial morbidity and mortality worldwide. We characterized the first eight influenza epidemics since the 2009 influenza pandemic by describing the distribution of viruses and epidemics temporally and geographically across the WHO European Region. Methods: We retrospectively analyzed laboratory-confirmed influenza detections in ambulatory patients from sentinel sites. Data were aggregated by reporting entity and season (weeks 40-20) for 2010-2011 to 2017-2018. We explored geographical spread using correlation coefficients. Results: There was variation in the regional influenza epidemics during the study period. Influenza A virus subtypes alternated in dominance, except for 2013-2014 during which both cocirculated, and only one season (2017-2018) was B virus dominant. The median start week for epidemics in the Region was week 50, the time to the peak ranged between four and 13 weeks, and the duration of the epidemic ranged between 19 and 25 weeks. There was evidence of a west-to-east spread across the Region during epidemics in 2010-2011 (r = .365; P = .019), 2012-2013 (r = .484; P = .001), 2014-2015 (r = .423; P = .006), and 2017-2018 (r = .566; P < .001) seasons. Variation in virus distribution and timing existed within reporting entities across seasons and across reporting entities for a given season. Conclusions: Aggregated influenza detection data from sentinel surveillance sites by season between 2010 and 2018 have been presented for the European Region for the first time. Substantial diversity exists between influenza epidemics. These data can inform prevention and control efforts at national, sub-national, and international levels. Aggregated, regional surveillance data from early affected reporting entities may provide an early warning function and be helpful for early season forecasting efforts.WHO Regional Office for Europe was supported for work on influenza by a cooperative agreement from the United States Centers for Disease Control and Prevention (NU511P000876); the funder had no role in the analysis or interpretation of the data.S

Recommendations for respiratory syncytial virus surveillance at national level

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes

New perspectives on respiratory syncytial virus surveillance at the national level:lessons from the COVID-19 pandemic

Learning from the COVID-19 pandemic and considering the effects of this pandemic, we provide recommendations that can guide towards sustainable RSV surveillance with the potential to be integrated into the broader perspective of respiratory surveillance. https://bit.ly/40TsO0

Molecular Epidemiology and Evolutionary Trajectory of Emerging Echovirus 30, Europe

In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains collected in 22 countries in Europe during 2016-2018. Most E30 cases affected persons 0-4 years of age (29%) and 25-34 years of age (27%). Sequences were divided into 6 genetic clades (G1-G6). Most (53%) sequences belonged to G1, followed by G6 (23%), G2 (17%), G4 (4%), G3 (0.3%), and G5 (0.2%). Each clade encompassed unique individual recombinant forms; G1 and G4 displayed >= 2 unique recombinant forms. Rapid turnover of new clades and recombinant forms occurred over time. Clades G1 and G6 dominated in 2018, suggesting the E30 upsurge was caused by emergence of 2 distinct clades circulating in Europe. Investigation into the mechanisms behind the rapid turnover of E30 is crucial for clarifying the epidemiology and evolution of these enterovirus infections.Peer reviewe

Recommendations for enterovirus diagnostics and characterisation within and beyond Europe.

Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for non-polio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5'noncoding regions (5'NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5'NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Upsurge in echovirus 30 detections in five EU/EEA countries, April to September, 2018

An upsurge in Echovirus 30 (E30) infections, associated with meningitis/meningoencephalitis, has been observed in Denmark, Germany, the Netherlands, Norway and Sweden in the period April to September 2018, compared with 2015-2017. In total, 658 E30 infections among 4,537 enterovirus infections were detected in 15 countries between January and September 2018 and affected mainly newborns and 26-45 year-olds. National public health institutes are reminded to remain vigilant and inform clinicians of the ongoing epidemic.status: publishe