Search

Background: In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment.Objectives: Analyze plasma cytokines in COVID-19 patients and investigate their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Method: Hospitalized patients (n=34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2-5 and 7-10 days. RF was defined as PaO2/FiO2 ratio (P/F) Measurements and Results: COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79-0.80, pConclusion: Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.

Background Acute gastroenteritis (AGE) is a common illness in both adults and children worldwide and is caused by several microorganisms including viruses, bacteria and parasites. Rotavirus (RV), which is the main cause of AGE, can occur as a mixed infection with other viruses. The aim of this study is to assess the molecular epidemiology of viral enteric viruses and assess RV co-infections with other enteric viruses and their influence on disease severity before and after RV vaccine introduction in children under 5 years of age. Materials and methods A total of 600 samples collected from children hospitalized for AGE in five large hospitals in Norway, and were analyzed for viral GE agents by EIA and qRT-PCR. Positive results confirmed either by Sanger sequencing or genotyped by multiplex semi-nested RT-PCR. Results In total, 243 of the 300 (81%) samples, collected from the pre-vaccine cohort, were positive for at least one of the four viruses tested in this study. RV was most frequently identified in 82.6% of the samples. In the post-vaccine cohort, 114 of the 300 (38%) samples were positive for at least one of the viruses tested. RV found in 36.5% of the samples. Co-infections found less frequently in the post-vaccine cohort. Conclusion Among circulating enteric viruses in Norway, RV is the most important cause of viral gastrointestinal infection. As expected, there were fewer RV positive and fewer co-infections after RV vaccine implementation. The results provide valuable data that can aid in further evaluation of the vaccine impact. This article is protected by copyright. All rights reserved.

Polymerase chain reaction (PCR) detection has become the gold standard for diagnosis and typing of enterovirus (EV) and human parechovirus (HPeV) infections. Its effectiveness depends critically on using the appropriate sample types and high assay sensitivity as viral loads in cerebrospinal fluid samples from meningitis and sepsis clinical presentation can be extremely low. This study evaluated the sensitivity and specificity of currently used commercial and in‐house diagnostic and typing assays. Accurately quantified RNA transcript controls were distributed to 27 diagnostic and 12 reference laboratories in 17 European countries for blinded testing. Transcripts represented the four human EV species (EV‐A71, echovirus 30, coxsackie A virus 21, and EV‐D68), HPeV3, and specificity controls. Reported results from 48 in‐house and 15 commercial assays showed 98% detection frequencies of high copy (1000 RNA copies/5 µL) transcripts. In‐house assays showed significantly greater detection frequencies of the low copy (10 copies/5 µL) EV and HPeV transcripts (81% and 86%, respectively) compared with commercial assays (56%, 50%; P = 7 × 10−5). EV‐specific PCRs showed low cross‐reactivity with human rhinovirus C (3 of 42 tests) and infrequent positivity in the negative control (2 of 63 tests). Most or all high copy EV and HPeV controls were successfully typed (88%, 100%) by reference laboratories, but showed reduced effectiveness for low copy controls (41%, 67%). Stabilized RNA transcripts provide an effective, logistically simple and inexpensive reagent for evaluation of diagnostic assay performance. The study provides reassurance of the performance of the many in‐house assay formats used across Europe. However, it identified often substantially reduced sensitivities of commercial assays often used as point‐of‐care tests. © 2019 The Authors. Journal of Medical Virology published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa")., Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF)., Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).

Background:There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high dependency unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics.Methods:We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay.Results:Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors.Conclusions:Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly evolving situation.Funding:This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill & Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

BACKGROUND Globally, rotavirus (RV) is the leading cause of acute gastroenteritis (AGE) in young children under 5 years of age. Implementation of RV vaccination is expected to result in fewer cases of RV in the target population, but it is unknown if this also results in vaccine-induced virus strain replacement. Rotarix, a monovalent vaccine based on G1P[8] rotavirus, was introduced in Norway in the children's immunization programme in September 2014. The main aim of this study was to describe the diversity of rotavirus circulating pre and post introduction of RV vaccine in Norway and investigate changes in genotype distribution during the first four years after implementation. MATERIALS AND METHODS A total of 1108 samples were collected from children under 5 years enrolled with AGE from five large hospitals in Norway and were analyzed for RV by EIA. All positive results were genotyped by multiplex semi-nested RT-PCR for identification of G and P types. RESULTS In total, 487 of the 1108 (44%) samples, collected from the enrolled children, were positive for RV by EIA method which were further genotyped. G1P[8] was found to be the most common type of RV pre and post RV vaccine implementation followed by G9P[8]. There were neither geographical nor temporal differences in genotype dominance. Also, no apparent changes were shown in the genotype distribution in the post-vaccine era for years from 2015 to 2018. In 21.4% of the cases, vaccine strains were detected. CONCLUSION Continuous rotavirus genotype surveillance is vital for assessing the effect of a vaccine program and monitoring for any emergence of vaccine-escape strains. Genotyping is also necessary to detect vaccine strains to avoid reporting false positive cases of active rotavirus infection in newly vaccinated cases. This article is protected by copyright. All rights reserved.

Summary Background Enteroviruses can cause severe infections, especially in young children. Non-polio enterovirus infections are not notifiable in most countries in the EU and European Economic Area (EEA) region, and surveillance varies substantially between countries. We collected and analysed available enterovirus data across EU and EEA countries to assess the current epidemiological situation and need for standardising surveillance. Methods Aggregated data on any enterovirus detected between Jan 1, 2015, and Dec 31, 2017, through national enterovirus reference laboratories were requested from representatives in all 31 EU and EEA countries. Information collected included enterovirus types detected by month, patient age group, symptom, and specimen type. We also collected sequence data on viral capsid sequences for the three most clinically relevant enterovirus types, as identified from the data. Findings Aggregated data were provided by representatives from 24 (77%) of 31 countries. 9914 (66%) of 14 999 enterovirus infections with information about age were in children younger than 5 years, and 3197 (45%) of 7139 individuals for whom symptoms were reported had neurological symptoms. Other symptoms were non-specific fever (in 1607 [23%] patients), respiratory symptoms (in 1197 [17%] patients), hand, foot, and mouth disease (in 528 [7% patients), and myocarditis (in 39 [1%] patients). 68 deaths were temporally associated with enterovirus infection. Typing for 11 559 (67%) of 17 136 specimens revealed 66 enterovirus types. Coxsackievirus A6 was the most frequently detected enterovirus type (in 1556 [13%] of 11 559 typed enteroviruses), and 292 (65%) of 448 patients with coxsackievirus A6 infection with available clinical data presented with hand, foot, and mouth disease. Echovirus 30 was the second most frequently detected enterovirus type, representing 1412 (12%) of 11 559 typed enteroviruses, and 384 (82%) of 467 individuals with echovirus 30 infection with available clinical data had neurological symptoms. Sequences available from 18 countries showed circulation of newly emerging strains of enterovirus A71 and enterovirus D68. Interpretation To our knowledge, this study is the largest investigation of enterovirus circulation in EU and EEA countries and confirms the availability of non-polio enterovirus data in the region. Our study highlights the wide circulation of non-polio enteroviruses in Europe, mostly affecting young children and leading to neurological symptoms. Collecting data on morbidity and mortality related to enterovirus infections, as well as harmonising case definition for surveillance, should be encouraged. Funding None.

Background: There is an urgent need for new treatment modalities in COVID-19 patients. Recently, the WHO Solidarity trial showed no effects of remdesivir or hydroxychloroquine (HCQ) on mortality. However, the antiviral effects of these drugs and the possible relation to clinical characteristics at admission is not known. Methods: NOR-Solidarity is an independent add-on study to the WHO Solidarity trial, including biobanking, and a clinical three-month follow-up. Eligible patients were adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection. Patients were randomly assigned to receive remdesivir, HCQ or standard of care (SoC). In-hospital mortality, admission to intensive care unit and initiation of mechanical ventilation were primary and secondary clinical endpoints shared with WHO Solidarity. Secondary endpoints were impact of remdesivir or HCQ on SARS-CoV-2 clearance in the oropharynx, as well as their effects on systemic inflammation and the degree of respiratory failure (ClinicalTrials.gov: NCT04321616). Findings: Between March 28 and October 4, 185 patients from 23 hospitals in Norway were randomized and 181 included in the full analysis set: remdesivir (n=42), HCQ (n=52) and SoC (n=87). No significant differences in mortality during hospitalisation, ICU admission or occurrence of mechanical ventilation between the treatment groups and SoC were observed. There was a marked decrease in SARS-CoV-2 load in oropharynx during the first week with similar decrease and 10-day levels between remdesivir, HCQ and their respective SoC. Remdesivir and HCQ did not exert any effect on the degree of respiratory failure or on inflammatory parameters in peripheral blood. Notably, the lack of anti-viral effect was not associated with symptom duration, level of viral load or presence of antibodies against SARS-CoV-2 at hospital admittance. Interpretation: We found no effect on viral clearance by either remdesivir or HCQ in hospitalised COVID-19 patients. Trial Registration: (ClinicalTrials.gov: NCT04321616) Funding: National Clinical Therapy Research in the Specialist Health Services, Norway. Declaration of Interests: All authors declare no competing interest. Ethics Approval Statement: The trial protocol was approved by the Regional Ethic Committee (118684) and by the Norwegian Medicines Agency (20/04950-23) and was overseen by an independent data and safety monitoring board.

Background Erythema migrans (EM) is the most common manifestation of Lyme borreliosis. Here, we examined EM patients in Norwegian general practice to find the proportion exposed to tick-transmitted microorganisms other than Borrelia, and the impact of co-infection on the clinical manifestations and disease duration. Methods Skin biopsies from 139/188 EM patients were analyzed using PCR for Neoehrlichia mikurensis, Rickettsia spp., Anaplasma phagocytophilum and Babesia spp. Follow-up sera from 135/188 patients were analyzed for spotted fever group (SFG) Rickettsia, A. phagocytophilum and Babesia microti antibodies, and tested with PCR if positive. Day 0 sera from patients with fever (8/188) or EM duration of ≥ 21 days (69/188) were analyzed, using PCR, for A. phagocytophilum, Rickettsia spp., Babesia spp. and N. mikurensis. Day 14 sera were tested for TBEV IgG. Results We detected no microorganisms in the skin biopsies nor in the sera of patients with fever or prolonged EM duration. Serological signs of exposure against SFG Rickettsia and A. phagocytophilum were detected in 11/135 and 8/135, respectively. Three patients exhibited both SFG Rickettsia and A. phagocytophilum antibodies, albeit negative PCR. No antibodies were detected against B. microti. 2/187 had TBEV antibodies without prior immunization. There was no significant increase in clinical symptoms or disease duration in patients with possible co-infection. Conclusions Co-infection with N. mikurensis, A. phagocytophilum, SFG Rickettsia, Babesia spp. and TBEV is uncommon in Norwegian EM patients. Despite detecting antibodies against SFG Rickettsia and A. phagocytophilum in some patients, no clinical implications could be demonstrated.

Objective: The objectives of this study were to describe the incidence and genetic diversity of Rotavirus (RV) infection among children up to 3 years of age in a community in Nepal.Methods: We investigated community-acquired cases of asymptomatic and symptomatic RV infections in children from birth to 36 months of age in a community-based birth cohort in Bhaktapur, Nepal. Monthly surveillance and diarrheal stool samples were collected from 240 children enrolled at birth, of which 238 completed the 3 years of follow-up. Samples were screened for rotavirus by Enzyme Immuno Assay (EIA). All RV screened positives were further genotyped by reverse transcription-polymerase chain reaction for the capsid genes VP7 and VP4.Results: In total, 5,224 stool samples were collected from 238 children, followed from birth to 36 months of age. Diarrhea occurred in 92.4% (230/238) of all children in the cohort. During the 3 years study period, RV was more frequently seen in children with symptoms (7.6%) than in non-symptomatic children (0.8%). The highest RV detection rate was found in younger children between 3 and 21 months of age. Although rotavirus is known as winter diarrhea, it was detected throughout the year except in August. The highest positivity rate was observed in the months between December and March, with a peak in January. Four common G types were seen: G2 (30%), G1 (29%), G12 (19%), and G9 (16%). The most predominant genotypes seen were G2P[4] (30%), followed by G1P[8] (27.0%), G12P[6] (14.0%), G9P[8] (10%), and remaining were mixed, partial, and untyped.Conclusion: Our study confirms that rotavirus is a common cause of gastroenteritis in young children in the community. The prevalence and pathogenicity of rotavirus infection differed by age. There was substantial variability in circulating strains in the community samples compared to samples collected from hospitals. This shows the importance of including community-based surveillance systems to monitor the diversity of circulating rotavirus strains in Nepal.

Background and aims Respiratory tract infections (RTIs) cause considerable morbidity and mortality in all age groups, but the epidemiology and role of several of the viral RTIs in the adult and elderly patients are still unclear, as is the extent of prehospitalization antibacterial drug use in this population. Methods We conducted a three‐year (2015‐2018) observational study of viral RTIs in hospitalized patients in a 500‐bed hospital in Southeastern Norway, including all patients ≥18 years with RTI symptoms where one of the following viral agents was detected in a respiratory specimen (Seegene Allplex): Influenza A/B, RSV A/B, human metapneumovirus (hMPV), adenovirus and parainfluenza virus 1‐4. Viral findings, demographical data, and information on prehospital antibiotic prescriptions were recorded. Results In 1182 patients 1222 viral infection events occurred. The mean patient age was 69.6 years, and 53% were females. Influenza virus A/B (63%), RSV A/B (15%) and hMPV (13%) were the most common agents detected. The proportional burden of influenza A H1 was found to be relatively high (65%) in the age groups

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Background - A high proportion of COVID‐19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS‐CoV‐2 and the renin‐angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID‐19 patients. Methods - Plasma levels of a gut leakage marker (LPS‐binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL‐1β, IL‐18 and their regulatory proteins) were measured at three time points (day 1, 3–5 and 7–10) in 39 hospitalized COVID‐19 patients and related to cardiac involvement. Results - Compared to controls, COVID‐19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT‐pro‐BNP levels, whereas IL‐18, IL‐18BP and IL‐1Ra were associated with higher troponin levels. Conclusion - Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut‐heart axis in COVID‐19.

Background The pathogenesis of COVID-19 is still incompletely understood, but seems to involve immune activation and immune dysregulation. Objective We examined parameters of activation of different leukocyte subsets in COVID-19 infected patients in relation to disease severity. Methods We analyzed plasma levels of myeloperoxidase (MPO, neutrophil activation), soluble (s) CD25 and soluble T cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T cell activation and exhaustion) and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19 infected patients at hospital admission and two additional times during the first 10 days in relation to the need for ICU treatment. Results Our major findings were: (i) Severe clinical outcome (ICU) was associated with high plasma levels sTIM-3 and MPO suggesting activated and potentially exhausted T cells and activated neutrophils, respectively. (ii) In contrast, sCD14 and sCD163 showed no association with need for ICU treatment. (iii) sCD25, sTIM-3 and MPO were inversely correlated with the degree of respiratory failure as assessed by P/F ratio and positively correlated with the cardiac marker N-terminal pro-B-type natriuretic peptide. Conclusion Our findings suggest that neutrophil activation and in particular activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T cell targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder., Capsule summaryOur study evaluating plasma leukocyte activation markers during hospitalization for COVID-19 disease indicate neutrophil and T cell activation, with signs of T cell exhaustion, associated with severe outcome.

Summary Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

Significance The new SARS-CoV-2 pandemic leads to COVID-19 with respiratory failure, substantial morbidity, and significant mortality. Overactivation of the innate immune response is postulated to trigger this detrimental process. The complement system is a key player in innate immunity. Despite a few reports of local complement activation, there is a lack of evidence that the degree of systemic complement activation occurs early in COVID-19 patients, and whether this is associated with respiratory failure. This study shows that a number of complement activation products are systemically, consistently, and long-lastingly increased from admission and during the hospital stay. Notably, the terminal sC5b-9 complement complex was associated with respiratory failure. Thus, complement inhibition is an attractive therapeutic approach for treatment of COVD-19., Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

Introduction: Parvovirus B19 (B19V) is the infectious cause of exanthema infectiosum. In Europe around 40% of pregnant women are susceptible to infection. Having small children at home is the main risk factor for contracting an infection during pregnancy. The association between B19V‐infection and perinatal death is not yet settled. The aims of the study were to estimate the association between maternal parvovirus B19 infection in pregnancy and perinatal death, and to assess the significance of a positive B19V PCR in pregnancy. Material and methods: The study population consists of women included in the Norwegian Mother and Child Cohort Study, a prospective population‐based pregnancy cohort of nearly 100 000 women. Blood samples were obtained during weeks 17‐18 in pregnancy (M1), at birth, and in umbilical cord blood. Within participants in the pregnancy cohort, 138 cases of perinatal death and 1350 controls with live‐born children were included in a nested case‐control study. Samples were analyzed with B19V serology and B19V PCR according to a predefined test algorithm. For cases, medical records and laboratory results from hospitals were combined with the results of B19V serology and PCR. The reported causes of perinatal death were categorized using the classification system: Causes Of Death and Associated Conditions (CODAC). Results: The B19V seroconversion rates were 9.8% for cases and 6.8% for control mothers. The odds ratio for maternal B19V infection in cases compared with controls was 1.28 (95% CI 0.35‐4.70), adjusted for age, parity, body mass index and tobacco use. B19V‐PCR‐positive samples were detected at weeks 17‐18 of gestation in both cases and controls. The proportion of positive samples was similar in cases and controls, 24% and 28.2%, respectively. Mothers with PCR‐positive M1 samples transmitted B19V vertically in 9.1% of cases and in 11.9% of the controls. Of all perinatal deaths, 53% were attributed to placental pathology or unknown causes. Conclusions: B19V PCR positivity was high and similar in both cases and controls. In our study B19V DNAemia was not seen to be associated with fatal outcome of pregnancy. The clinical significance of B19V DNA detection during pregnancy is uncertain. Caution is needed when diagnosing a B19V infection based only on B19V DNAemia. publishedVersion

CMV is the most common cause of congenital infection. During the past few decades, there has been a change in behaviour that possibly has affected the CMV infection rate of mother and child. We investigated 1350 randomly selected pregnant women from the Norwegian Mother and Child Cohort Study using an algorithm for detection of maternal and congenital CMV (cCMV) infection including both serology and nucleic acid amplification assay. The CMV IgG seroprevalence was 54% and 23 (3.7%) mothers seroconverted. Three (0.22%) children had a positive CMV PCR in the umbilical cord blood. The transmission rate was lower than reported in previous studies, probably due to lower sensitivity in plasma compared to saliva and urine. The prevalence of cCMV in the present study was compared with the number registered with the ICD-10 code P.35.1-congenital CMV infection in the Norwegian Patient Register. The number registered was lower than the number of estimated infections. Factors like lower level of education and parity were associated with higher CMV IgG seroprevalence, but no significant difference could be linked to age. In conclusion, in this cohort of pregnant women, a high CMV IgG seroconversion rate was found, while the vertical transmission rate was low.

Background Around 40% of pregnant women in Norway are parvovirus B19 (B19 V) seronegative and thus at risk for B19 V infection. Studies on samples from women with symptomatic disease or known exposure have shown that nucleic acid amplification assays combined with serology increase the sensitivity and improves the diagnostic procedure. Objectives The aim was to investigate the seroprevalence of B19 V infection, the occurrence of new infections and vertical transmission in a population-based pregnancy cohort, with special emphasis on the diagnostic methods. Study design We randomly selected 1350 pregnant women from the Norwegian Mother and Child Cohort Study (MoBa), using an algorithm for the detection of B19 V infection, including both serology and PCR. Results Maternal infection was confirmed in 50 subjects (3.7% of 1349 women), of which 35(70%) were viremic. Of the initially seronegative 33(6.8%) seroconverted. The estimated average annual seroconversion rate was 15.5%, with the highest estimated annual seroconversion rate of 31.6%. The rates of yearly seroconversion followed the pattern found in reports from Norwegian microbiology laboratories. Among all women, 31 (2.3%) had an inconclusive serological profile and 17 (54.8%) had detectable virus. Of the 16 women with virus detectable at gestational week 17–18, seven were still seronegative with absent seroconversion in the second sample taken at birth. All together 10 children were vertically infected. Conclusions High incidence of viremic B19 V infections and high estimated annual seroconversion rates were found. Lack of seroconversion despite longstanding viremia emphasizes the importance of including PCR when testing for B19 V infection during pregnancy.

Members of the European Influenza Surveillance Network: Portugal (Figueiredo Augusto Gonçalo, Machado Jorge, Moreira Guiomar Raquel, Nogueira Paulo, Rebelo de Andrade Helena, Rodrigues Ana Paula) The yearly influenza epidemics during each winter season vary in burden and severity. During the 2016/17 and 2017/18 seasons, all-cause excess mortality was observed during periods of high influenza virus circulation. Our aim is to describe and compare the pattern of influenza virus circulation and related disease severity by number of patients and fatal cases in intensive care units (ICUs) across European Union/European Economic Area (EU/EEA) countries for the seasons 2016/17 and 2017/18. As influenza circulation progressed from a west to east direction across Europe in 2017/18, a better understanding of the current epidemiological situation might help to prepare countries in the eastern part of the World Health Organization (WHO) European Region for high influenza activity and severity. info:eu-repo/semantics/publishedVersion

Purpose of Review Hepatitis E (HEV) is a continuing public health problem in developing countries, causing high mortality in pregnant women. This article reviews the latest knowledge on HEV in pregnancy, the vaccine candidates that have reached clinical trials, and their potential use during pregnancy. Recent Findings New evidence suggests that a genotype-specific tropism to uteroplacental cells contributes to the multifactorial pathology leading to the increased severity of HEV during pregnancy. Data from pregnant women inadvertently vaccinated are limited but show similar rates of adverse events as non-pregnant women, and no evident harm to newborns. Protective anti-HEV IgG antibodies are estimated to last longer after vaccination than natural infection. Accelerated vaccination appears safe and provides protective antibodies similar to a normal dosing regimen. Summary HEV239 is the most extensively studied vaccine and has been shown to be safe and effective, but more data are needed to recommend use of this vaccine on a global basis. Further studies should focus on safety and efficacy in pregnant women, and evaluate a shorter two-dose regime, which is highly warranted in outbreak situations.

IntroductionInfection with varicella zoster virus (VZV) in pregnancy may lead to serious outcomes both for the mother and the newborn. Targeted screening and vaccination of non-immune women during reproductive age could prevent varicella infection in pregnancy. Currently, no universal varicella screening of pregnant women is implemented in Norway, but serological testing in pregnancy is recommended in particular situations. We examined seroprevalence of VZV in a national pregnancy cohort in order to help assess a need for VZV screening of women during reproductive age.MethodsWe determined the susceptibility to VZV and the reliability of self-reported history of VZV infection in the Norwegian obstetric population by using a random sample of 1,184 pregnant women from the Norwegian Mother and Child Cohort study (MoBa). The MoBa study included approximately 95,200 pregnant women in Norway between 1998 and 2009. Blood samples taken at gestational week 17-18 were analysed using a commercial enzyme immunoassay for specific IgG antibodies to Varicella-Zoster virus. Second sample taken at birth was tested if the first sample result was negative or equivocal.ResultsOf the 1,184 pregnant women, 98.6% (n = 1,167) were seropositive, 0.83% (n = 10) remained seronegative, and four women (0.34%) seroconverted during their pregnancy. No significant associations were found between serological status and women's age at birth, gestational age, women's country of birth and year of child's birth. One woman reported prior history of varicella, whereas 143 (12.1%) women reported a household exposure to childhood diseases with fever and rash, of which 25 reported exposure to varicella, of which all were seropositive.ConclusionsThe findings support antenatal screening recommendations in Norway advising testing for VZV in pregnant women with unknown immunity to VZV. Further studies are however needed to better identify target groups for screening and vaccination.

Picornaviruses (family Picornaviridae) are small, nonenveloped, positive-sense, single-stranded RNA viruses. The members of this family are currently classified into 47 genera and 110 species. Of picornaviruses, entero-and parechoviruses are associated with aseptic meningitis. They are transmitted via fecal-oral and respiratory routes, and occasionally, these viruses may cause a brief viremia and gain access to central nervous system (CNS). During the diagnostic screening of entero-and parechovirus types in Finland in year 2013-14, we detected a cluster of echovirus 4 (E4) infections in young adults and adolescents. As E4 is infrequently detected in Finland, we contacted several Northern and Central European laboratories that conduct routine surveillance for enteroviruses and, for those who have had E4 cases, we send a query for E4 sequences and data. Here we report CNS infections caused by E4 in Finland, Sweden, Norway, Denmark, Iceland and Germany in 2013 and 2014, and show that the E4 detected in these countries form a single lineage. In contrast, E4 strains circulating in these countries preceding the year 2013, and those circulating elsewhere in Europe during 2013-2014, formed several independent clusters.

Following its discovery in California in 1962, enterovirus D68 (EV-D68) was reported only sporadically around the world. In August 2014, a marked increase of EV-D68 cases in young children with severe respiratory infections was reported in the USA and Canada and later in Europe and Asia. Some of these cases were also found to be associated with acute flaccid paralysis, which exacerbated public health concern, and has since triggered international efforts to strengthen both EV-D68 and acute flaccid paralysis surveillance systems. This review summarizes the current knowledge on EV-D68, offering an overview of EV-D68 epidemiology, clinical presentations, diagnostic methodologies, and treatment strategies, as well as surveillance and outbreak management.

Infection by Toxoplasma gondii may lead to complications in the foetus if the mother suffers from primary infection during pregnancy. Previously infected women have produced toxoplasma-specific IgG antibodies. The most recent study on prevalence of toxoplasma IgG in the Norwegian pregnant population was conducted 20 years ago. The present study is part of a research programme initiated by the Norwegian Institute of Public Health. We aimed to update the knowledge regarding the prevalence of toxoplasma IgG among pregnant women in Norway. In this cross-sectional study, sera from 1922 pregnant women in Buskerud (992) and Sør-Trøndelag counties (930) in Norway were collected consecutively. The presence of toxoplasma IgG was identified by values ≥8 IU/mL using an ELISA test. The overall prevalence of toxoplasma IgG seropositivity was 9.3% (95% CI 8.1-10.7); Sør-Trøndelag 10.4% (95% CI 8.6-12.6) and Buskerud 8.3% (95% CI 6.7-10.2). There was no difference between the counties (p = 0.13), and the result did not differ from prevalences found in 1974 (12.1%) and 1994 (10.7%). We found a higher prevalence among women ≥40 years (OR 2.65, 95% CI 1.30-5.42). The prevalence of toxoplasma IgG among pregnant women in Norway is low and has been stable during the last decades.

Current influenza virus vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia virus Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA-based vaccines 4 weeks apart and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza virus HA and/or NP had high frequencies of virus-specific CD4 + and CD8 + T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC plays a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective. IMPORTANCE Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs typically are effective but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. Therefore, we evaluated a vaccine strategy designed to induce both antibody and T cell responses, which may provide more broadly cross-protective immunity against influenza. Here, we show in a translational primate model that vaccination with a modified vaccinia virus Ankara encoding hemagglutinin from a heterosubtypic H5N1 virus was associated with reduced shedding of a pandemic H1N1 virus challenge, while vaccination with MVA encoding nucleoprotein, an internal viral protein, was not. Unexpectedly, this reduced shedding was associated with nonneutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Therefore, antibody-dependent cellular cytotoxicity (ADCC) may play a role in cross-protective immunity to influenza virus. Vaccines that stimulate ADCC antibodies may enhance protection against pandemic influenza virus.

Hantaviruses pose a public health concern worldwide causing haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Puumala virus (PUUV) is the most prevalent hantavirus in Central and Northern Europe, and causes a mild form of HFRS, also known as nephropathia epidemica (NE). In nature, the main host of PUUV is the bank vole (Myodes glareolus), and transmission to humans occurs through inhalation of aerosols from rodent excreta. Nephropathia epidemica is particularly prevalent in Nordic countries, however, few studies of PUUV have been performed in Norway. The aim of this study was to analyse the dynamics of PUUV in Norway and compare with bank vole population dynamics, and also to complement the current diagnostic methodology of NE in Norway. Our results showed a significant seasonal and geographical variation of NE, and a general parallel peak trend between bank vole population densities and human NE incidence. A real-time and a nested PCR were successfully established as an invaluable diagnostic tool, with detection and sequencing of PUUV in a human serum sample for the first time in Norway. Phylogenetic analysis showed clustering of the obtained human sample with previous Norwegian bank vole isolates.

Background Bulk stool specimens are traditionally used for rotavirus detection but may be challenging to obtain from young children. Immediate and easy sampling may however be required in different situations, such as outbreak investigation. Objectives We assessed the diagnostic performance of rectal swabs compared to bulk stools for the detection of rotavirus by Enzyme Immunoassay (EIA) and multiplex semi-nested reverse transcription PCR (semi-nested RT-PCR) in children recruited through active hospital-based surveillance of acute gastroenteritis in Norway. Study design We obtained 265 paired bulk stool and rectal swab specimens from children under 5 years of age hospitalized with acute gastroenteritis (AGE). Both types of specimens were analyzed for rotavirus by EIA and semi-nested RT-PCR. In addition, VP6-spesific real-time PCR was used to evaluate the detection performance in the two specimen types. Results Concordant results were obtained in 257 (97%) paired specimens by EIA and in 248 (94%) pairs by semi-nested RT-PCR. Results of VP6-specific real-time PCR obtained from 100 pairs of specimens showed concordance in 91% of the pairs. Sensitivity and specificity for rectal swab specimens were 95% and 100% by EIA; 95% and 92% by semi-nested RT-PCR, respectively. Conclusion Both EIA and semi-nested RT-PCR showed a high accuracy, and rectal swab specimens are appropriate for rotavirus diagnosis and may be used as an alternate specimen type when collection of bulk stool is not feasible. © 2017. This is the authors’ accepted and refereed manuscript to the article. Locked until 1.11.2018 due to copyright restrictions. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

Free PMC Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685210/ Members of the ZIKV reference laboratory group: Portugal: Maria João Alves, National Institute of Health Dr. Ricardo Jorge, Lisbon With international travel, Zika virus (ZIKV) is introduced to Europe regularly. A country's ability to robustly detect ZIKV introduction and local transmission is important to minimise the risk for a ZIKV outbreak. Therefore, sufficient expertise and diagnostic capacity and capability are required in European laboratories. To assess the capacity, quality, operational specifics (guidelines and algorithms), technical and interpretation issues and other possible difficulties that were related to ZIKV diagnostics in European countries, a questionnaire was conducted among national reference laboratories in 30 countries in the European Union/European Economic Area (EU/EEA) in May 2016. While the coverage and capacity of ZIKV diagnostics in the EU/EEA national reference laboratories were found to be adequate, the assessment of the quality and needs indicated several crucial points of improvement that will need support at national and EU/EEA level to improve ZIKV preparedness, response and EU/EEA ZIKV surveillance activities. This study was conducted with ECDC-funding SRS-003-2016-RS. info:eu-repo/semantics/publishedVersion

The aim of this study was to assess the seroprevalence of antibodies to tick-borne encephalitis virus (TBEV) and Anaplasma phagocytophilum in a healthy adult population from Sogn and Fjordane county in western Norway. Sera from 1, 213 blood donors were analysed for IgG-antibodies to TBEV, and a random subgroup of 301 donors for IgG to A. phagocytophilum. In the TBEV ELISA, five (0.4%) sera were positive. These were all interpreted as “false” positives, as four had received vaccines against flaviviruses, and the remaining was negative for neutralizing antibodies to TBEV. Antibodies to A. phagocytophilum were detected by indirect immunofluorescence in 49 (16.2%) subjects (titer range 80-1280). The results indicate that TBE currently is not endemic in this part of western Norway. However, there is serological evidence of the existence of human granulocytic anaplasmosis in the population. acceptedVersion

Tick-borne encephalitis (TBE) is an emerging tick-borne disease in Europe. In Norway, the first TBE case occurred in 1997, and since then 1-14 cases have been detected annually along the southern coast. No TBE cases have yet been notified from the eastern coastal area. This study was conducted to assess the need for diagnostic tests and vaccine recommendation for this part of Norway.Four hundred and sixty-one blood donors living in the county of Østfold were enrolled. After informed consent was obtained, the participants submitted a blood sample and filled out a questionnaire regarding tick bites, outdoor activities, and Flavivirus vaccines and diseases. Ixodes ricinus ticks were collected from the immediate vicinity and were examined in pools of 10 for TBE virus.Eight human samples were TBE virus IgG-positive by ELISA and 5 of these samples were confirmed positive by neutralization test. Excluding the 2 samples from participants who had reported previous TBE vaccination, this shows a seroprevalence among blood donors of 0.65%. The existence of TBEV in the region was verified in nymphs of Ixodes ricinus by a prevalence of 0.14%.The seroprevalence of TBE virus IgG and the TBE virus detected in ticks, indicate that TBE cases could occasionally occur in the area. The results should be made available to health care personnel to raise awareness for preventative measures.

Infections caused by cytomegalovirus (CMV), parvovirus B19 (B19), and rubella can lead to serious complications in pregnant women. The aim of this study was to determine the susceptibility to CMV, B19, and rubella antibodies in pregnant women in Norway. Consecutive sera samples were collected from pregnant women in two different regions in Norway. Sera were collected from age groups; ≤19, 20-24, 25-29, 30-34, 35-39, and ≥40 years old. Of the 2,000 pregnant women tested, anti-CMV IgG was positive in 62.8% anti-parvovirus B19 IgG in 59.7% and anti-rubella IgG in 94.4%. CMV IgG susceptibility has decreased in pregnant women less than 30 years of age, from 60% in a study conducted in 1973-1974 to 37.2% in present study. There was a significant difference in CMV IgG seropositivity rate between the two regions (58.6% and 67.1%). Serum levels of rubella IgG was lowest in age group 25-29 years with a positivity rate of 91.0%. Women born before vaccination with two doses of MMR started, had both a higher positivity rate and significantly higher levels of rubella antibody titre, 96.1% and 82.2 IU/ml compared to those born after 92.9% and 41.7 IU/ml. Significantly lower anti-rubella IgG titre found in the youngest age groups highlights the need for continued antenatal screening. A considerable increase in anti-CMV-IgG seropositivity rate was observed and might be associated with higher rate of breastfeeding and a higher percentage attending day-care centres.

SUMMARYIn Norway, no published data on seroprevalence of hepatitis E virus (HEV) in humans and swine exists. Serum samples from blood donors, veterinarians, swine farm workers and swine were analysed by ELISA to estimate the seroprevalence of HEV in Norway and to investigate the association between direct contact with swine and HEV seroprevalence in humans. The seroprevalence of HEV IgG antibodies was 30% (24/79) in farm workers, 13% (21/163) in veterinarians, 14% (162/1200) in blood donors and 90% (137/153) in swine. Our results show a high seroprevalence of HEV in humans and swine in Norway. HEV seroprevalence in farm workers and blood donors increased with age, and veterinarians working with swine were twice as likely to be HEV seropositive compared to other veterinarians. High HEV seroprevalence in farm workers and veterinarians working with swine support previous reports suggesting swine as a reservoir for HEV infections in humans in Europe.

Rapid bedside inactivation of Ebola virus would be a solution for the safety of medical and technical staff, risk containment, sample transport, and high-throughput or rapid diagnostic testing during an outbreak. We show that the commercially available Magna Pure lysis/binding buffer used for nucleic acid extraction inactivates Ebola virus. A rapid bedside inactivation method for nucleic acid tests is obtained by simply adding Magna Pure lysis/binding buffer directly into vacuum blood collection EDTA tubes using a thin needle and syringe prior to sampling. The ready-to-use inactivation vacuum tubes are stable for more than 4 months, and Ebola virus RNA is preserved in the Magna Pure lysis/binding buffer for at least 5 weeks independent of the storage temperature. We also show that Ebola virus RNA can be manually extracted from Magna Pure lysis/binding buffer-inactivated samples using the QIAamp viral RNA minikit. We present an easy and convenient method for bedside inactivation using available blood collection vacuum tubes and reagents. We propose to use this simple method for fast, safe, and easy bedside inactivation of Ebola virus for safe transport and routine nucleic acid detection.

Members of the World Health Organization European Region and European Influenza Surveillance Network of the reporting countries - Portugal: Raquel Guiomar, Pedro Pechirra, Paula Cristovão, Inês Costa, Patrícia Conde, Baltazar Nunes, Ana Rodrigues Influenza A(H1N1)pdm09 viruses predominated in the European influenza 2015/16 season. Most analysed viruses clustered in a new genetic subclade 6B.1, antigenically similar to the northern hemisphere vaccine component A/California/7/2009. The predominant influenza B lineage was Victoria compared with Yamagata in the previous season. It remains to be evaluated at the end of the season if these changes affected the effectiveness of the vaccine for the 2015/16 season. info:eu-repo/semantics/publishedVersion

The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. An Asp-to-Gly change at position 222 of the receptor-binding protein hemagglutinin (HA) correlates with more-severe infections in humans. The amino acid at position 222 of HA contributes to receptor-binding specificity with Asp (typically found in human influenza viruses) and Gly (typically found in avian and classic H1N1 swine influenza viruses), conferring binding to human- and avian-type receptors, respectively. Here, we asked whether binding to avian-type receptors enhances influenza virus pathogenicity. We tested two 2009 pandemic H1N1 viruses possessing HA-222G (isolated from severe cases) and two viruses that possessed HA-222D. In glycan arrays, viruses possessing HA-222D preferentially bound to human-type receptors, while those encoding HA-222G bound to both avian- and human-type receptors. This difference in receptor binding correlated with efficient infection of viruses possessing HA-222G, compared to those possessing HA-222D, in human lung tissue, including alveolar type II pneumocytes, which express avian-type receptors. In a nonhuman primate model, infection with one of the viruses possessing HA-222G caused lung damage more severe than did infection with a virus encoding HA-222D, although these pathological differences were not observed for the other virus pair with either HA-222G or HA-222D. These data demonstrate that the acquisition of avian-type receptor-binding specificity may result in more-efficient infection of human alveolar type II pneumocytes and thus more-severe lung damage. Collectively, these findings suggest a new mechanism by which influenza viruses may become more pathogenic in mammals, including humans.

Resistance was not associated with oseltamivir use or more severe disease., In Norway in January 2008, unprecedented levels of oseltamivir resistance were found in 12 of 16 influenza viruses A (H1N1) tested. To investigate the epidemiologic and clinical characteristics of these viruses, we used sequence analysis to test all available subtype H1N1 viruses from the 2007–08 season for resistance. Questionnaires from physicians provided information on predisposing diseases, oseltamivir use, symptoms, and complications. Clinical data were obtained for 265 patients. In total, 183 (67.3%) of 272 viruses were oseltamivir resistant. Resistance was not associated with prior use of antiviral drugs. Symptoms and hospitalization rates did not differ for patients infected with a resistant or a susceptible virus. Oseltamivir-resistant influenza viruses A (H1N1) did not show diminished capability to spread in the absence of selective pressure. The ability of these viruses to sustain their fitness and spread among persons should be considered when shaping future strategies for treating and preventing seasonal and pandemic influenza.

Background A new A(H1N1) influenza virus was detected in April 2009. The virus is now causing a pandemic of influenza. The article presents an overview of symptoms, complications, vulnerable groups, diagnosis and treatment. Material and methods The overview is based on literature identified through a search in PubMed (using PubMed's own search strategy) and on official reports from WHO and the disease control centres of EU and the USA. Results The new influenza A(H1N1) has so far mainly affected young people, only few people over 60 years. The clinical presentation is similar to that of ordinary influenza; but nausea, vomiting and diarrhoea seem to be more common. The reported risk of complications and case fatality are low, but hospitalisation, pneumonia and deaths have occurred, also in previously healthy young individuals. Antiviral treatment with oseltamivir or zanamivir is likely to be as effective as in ordinary influenza. Interpretation Mild cases may be underrepresented in the published literature. It is important to keep up-to-date on international reports on the nature of the disease in order to best prepare clinicians to diagnose and treat patients when the epidemic hits Norway with full force.

The objective of the study was to compare the mortality in HIV infected individuals to the general population, and to explore the relative contribution of HIV to mortality before and after the introduction of highly active antiretroviral therapy (HAART). All HIV patients attending Ullevål University Hospital, Oslo, Norway before (cohort 1) and after (cohort 2) the introduction of HAART were included. Causes of deaths were classified as HIV related or not. Mortality in the Norwegian general population was standardized according to the distribution of age and gender in our cohorts. Ratios between mortality in our cohorts and the standardized mortality were calculated. The risk ratio (RR) for 5-y mortality compared to the general population was 22.6 (95% confidence interval (CI), 19.5-26.4) in cohort 1 (n = 782), and 3.96 (95% CI 2.25-6.97) in cohort 2 (n = 398). The non-HIV related mortality RR was 4.42 (95% CI 3.18-6.13) in cohort1 and 0.89 (95% CI 0.29-2.76) in cohort 2. Higher age and low CD4 cell count were associated with increased mortality. Thus, in the HAART era the mortality in HIV patients was reduced by 80%. However, the mortality in the HAART era was still 4 times higher than in the general population.

Tick-borne encephalitis (TBE) is the most important viral tick-borne disease in Europe and can cause severe disease in humans. In Norway, human cases have been reported only from the southern coast. The aim of this study was to investigate the prevalence of tick-borne encephalitis virus (TBEV) in questing Ixodes ricinus ticks from the north-western part of Norway. A total of 4509 ticks were collected by flagging in May and June 2014. A subpopulation of 2220 nymphs and 162 adult ticks were analysed by real-time PCR and positive samples were confirmed by pyrosequencing. The estimated prevalence of TBEV was 3.08% among adult ticks from Sekken in More og Romsdal County and 0.41% among nymphs from both Hitra and Froya in Sor-Trondelag County. This study indicates that TBEV might be more widespread than the distribution of reported human cases suggests.