Publications by authors named "Marion P G Koopmans"

163 Publications

Are presymptomatic SARS-CoV-2 infections in nursing home residents unrecognized symptomatic infections? Sequence and metadata from weekly testing in an extensive nursing home outbreak.

Age Ageing 2021 May 7. Epub 2021 May 7.

Department of Internal Medicine, section of Geriatric Medicine, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Background: Sars-CoV-2 outbreaks resulted in a high case fatality rate in nursing homes (NH) worldwide. It is unknown to which extent presymptomatic residents and staff contribute to the spread of the virus.

Aims: To assess the contribution of asymptomatic and presymptomatic residents and staff in SARS-CoV-2 transmission during a large outbreak in a Dutch NH.

Methods: Observational study in a 185-bed NH with two consecutive testing strategies: testing of symptomatic cases only, followed by weekly facility-wide testing of staff and residents regardless of symptoms. Nasopharyngeal and oropharyngeal testing with RT-PCR for SARs-CoV-2, including sequencing of positive samples, was conducted with a standardized symptom assessment.

Results: 185 residents and 244 staff participated. Sequencing identified one cluster. In the symptom-based test strategy period 3/39 residents were presymptomatic versus 38/74 residents in the period of weekly facility-wide testing (p-value<0.001). In total, 51/59 (91.1%) of SARS-CoV-2 positive staff was symptomatic, with no difference between both testing strategies (p-value 0.763). Loss of smell and taste, sore throat, headache or myalga was hardly reported in residents compared to staff (p-value <0.001). Median Ct-value of presymptomatic residents was 21.3, which did not differ from symptomatic (20.8) or asymptomatic (20.5) residents (p-value 0.624).

Conclusions: Symptoms in residents and staff are insufficiently recognized, reported or attributed to a possible SARS-CoV-2 infection. However, residents without (recognized) symptoms showed the same potential for viral shedding as residents with symptoms. Weekly testing was an effective strategy for early identification of SARS-Cov-2 cases, resulting in fast mitigation of the outbreak.
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http://dx.doi.org/10.1093/ageing/afab081DOI Listing
May 2021

Monitoring SARS-CoV-2 Circulation and Diversity through Community Wastewater Sequencing, the Netherlands and Belgium.

Emerg Infect Dis 2021 05;27(5):1405-1415

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a major global health problem, and public health surveillance is crucial to monitor and prevent virus spread. Wastewater-based epidemiology has been proposed as an addition to disease-based surveillance because virus is shed in the feces of ≈40% of infected persons. We used next-generation sequencing of sewage samples to evaluate the diversity of SARS-CoV-2 at the community level in the Netherlands and Belgium. Phylogenetic analysis revealed the presence of the most prevalent clades (19A, 20A, and 20B) and clustering of sewage samples with clinical samples from the same region. We distinguished multiple clades within a single sewage sample by using low-frequency variant analysis. In addition, several novel mutations in the SARS-CoV-2 genome were detected. Our results illustrate how wastewater can be used to investigate the diversity of SARS-CoV-2 viruses circulating in a community and identify new outbreaks.
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http://dx.doi.org/10.3201/eid2705.204410DOI Listing
May 2021

Novel opportunities for NGS-based one health surveillance of foodborne viruses.

One Health Outlook 2020 22;2:14. Epub 2020 Jun 22.

Viroscience Department, Erasmus Medical Centre, Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Foodborne viral infections rank among the top 5 causes of disease, with noroviruses and hepatitis A causing the greatest burden globally. Contamination of foods by infected food handlers or through environmental pollution are the main sources of foodborne illness, with a lesser role for consumption of products from infected animals. Viral partial genomic sequencing has been used for more than two decades to track foodborne outbreaks and whole genome or metagenomics next-generation-sequencing (NGS) are new additions to the toolbox of food microbiology laboratories. We discuss developments in the field of targeted and metagenomic NGS, with an emphasis on application in food virology, the challenges and possible solutions towards future routine application.
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http://dx.doi.org/10.1186/s42522-020-00015-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993515PMC
June 2020

viromeBrowser: A Shiny App for Browsing Virome Sequencing Analysis Results.

Viruses 2021 03 9;13(3). Epub 2021 Mar 9.

Viroscience Department, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Experiments in which complex virome sequencing data is generated remain difficult to explore and unpack for scientists without a background in data science. The processing of raw sequencing data by high throughput sequencing workflows usually results in contigs in FASTA format coupled to an annotation file linking the contigs to a reference sequence or taxonomic identifier. The next step is to compare the virome of different samples based on the metadata of the experimental setup and extract sequences of interest that can be used in subsequent analyses. The viromeBrowser is an application written in the opensource R shiny framework that was developed in collaboration with end-users and is focused on three common data analysis steps. First, the application allows interactive filtering of annotations by default or custom quality thresholds. Next, multiple samples can be visualized to facilitate comparison of contig annotations based on sample specific metadata values. Last, the application makes it easy for users to extract sequences of interest in FASTA format. With the interactive features in the viromeBrowser we aim to enable scientists without a data science background to compare and extract annotation data and sequences from virome sequencing analysis results.
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http://dx.doi.org/10.3390/v13030437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999463PMC
March 2021

Towards a sensitive and accurate interpretation of molecular testing for SARS-CoV-2: a rapid review of 264 studies.

Euro Surveill 2021 03;26(10)

Global Outbreak Alert and Response Network (GOARN), Geneva, Switzerland.

BackgroundSensitive molecular diagnostics and correct test interpretation are crucial for accurate COVID-19 diagnosis and thereby essential for good clinical practice. Furthermore, they are a key factor in outbreak control where active case finding in combination with isolation and contact tracing are crucial.AimWith the objective to inform the public health and laboratory responses to the pandemic, we reviewed current published knowledge on the kinetics of SARS-CoV-2 infection as assessed by RNA molecular detection in a wide range of clinical samples.MethodsWe performed an extensive search on studies published between 1 December 2019 and 15 May 2020, reporting on molecular detection and/or isolation of SARS-CoV-2 in any human laboratory specimen.ResultsWe compiled a dataset of 264 studies including 32,515 COVID-19 cases, and additionally aggregated data points (n = 2,777) from sampling of 217 adults with known infection timeline. We summarised data on SARS-CoV-2 detection in the respiratory and gastrointestinal tract, blood, oral fluid, tears, cerebrospinal fluid, peritoneal fluid, semen, vaginal fluid; where provided, we also summarised specific observations on SARS-CoV-2 detection in pregnancy, infancy, children, adolescents and immunocompromised individuals.ConclusionOptimal SARS-CoV-2 molecular testing relies on choosing the most appropriate sample type, collected with adequate sampling technique, and with the infection timeline in mind. We outlined knowledge gaps and directions for future well-documented systematic studies.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.10.2001134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953531PMC
March 2021

Street RABV Induces the Cholinergic Anti-inflammatory Pathway in Human Monocyte-Derived Macrophages by Binding to nAChr α7.

Front Immunol 2021 19;12:622516. Epub 2021 Feb 19.

Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.

Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8 T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.
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http://dx.doi.org/10.3389/fimmu.2021.622516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933221PMC
February 2021

Guillain-Barré Syndrome in Suriname; Clinical Presentation and Identification of Preceding Infections.

Front Neurol 2021 10;12:635753. Epub 2021 Feb 10.

Department of Viroscience, Erasmus Medical Center, Rotterdam, Netherlands.

Guillain-Barré syndrome (GBS) is associated with various types of preceding infections including and cytomegalovirus, but there is also an association with arthropod borne viruses (arboviruses), such as Zika virus, that are endemic in tropical regions. Here we present the clinical characteristics of 12 GBS patients from Suriname that were hospitalized between the beginning of 2016 and half 2018. Extensive diagnostic testing was performed for pathogens that are commonly associated with GBS, but also for arboviruses, in order to identify the preceding infection that might have led to GBS. With this extensive testing algorithm, we could identify a recent infection in six patients of which four of them had evidence of a recent Zika virus or dengue virus infection. These results suggest that arboviruses, specifically Zika virus but possibly also dengue virus, might be important causative agents of GBS in Suriname. Furthermore, we found that more accessibility of intravenous immunoglobulins or plasma exchange could improve the treatment of GBS in Suriname.
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http://dx.doi.org/10.3389/fneur.2021.635753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902883PMC
February 2021

Genome Sequence of a Strain from a Farmed Mink in The Netherlands.

Microbiol Resour Announc 2021 Feb 25;10(8). Epub 2021 Feb 25.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.

We report the genome sequence of a strain identified from a fecal sample from a farmed mink () in The Netherlands that was tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using real-time PCR (RT-PCR). The viral genome sequence was obtained using agnostic deep sequencing.
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http://dx.doi.org/10.1128/MRA.01451-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909093PMC
February 2021

Hand hygiene and glove use in nursing homes before and after an intervention.

Infect Control Hosp Epidemiol 2021 Feb 9:1-3. Epub 2021 Feb 9.

Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

We investigated whether an intervention to improve hand hygiene compliance in nursing homes changed glove use. Hand hygiene compliance increased, but substitution of hand hygiene with gloves did not decrease. We observed a reduction of inappropriately unchanged gloves after exposure to body fluids.Clinical trials identifier: Netherlands Trial Register, trial NL6049 (NTR6188): https://www.trialregister.nl/trial/6049.
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http://dx.doi.org/10.1017/ice.2020.1415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873455PMC
February 2021

Neutrophil extracellular traps persist at high levels in the lower respiratory tract of critically ill COVID-19 patients.

J Infect Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.

SARS-CoV-2 induced lower respiratory tract (LRT) disease can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill COVID-19 patients. Plasma NET levels peaked early after ICU admission and correlated with SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma. Baseline plasma NET quantity correlated with disease severity, but was not associated with soluble markers of thrombosis nor with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from fatal COVID-19 patients. Thus, NETs are produced and retained in the LRT of critical COVID-19 patients and could contribute to SARS-CoV-2-induced ARDS pathology.  .
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http://dx.doi.org/10.1093/infdis/jiab053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928807PMC
January 2021

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19).

Nat Commun 2021 01 11;12(1):267. Epub 2021 Jan 11.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.

Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5-11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4-17.2). Multivariate analyses identify viral loads above 7 log RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.
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http://dx.doi.org/10.1038/s41467-020-20568-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801729PMC
January 2021

Severe Acute Respiratory Syndrome Coronavirus 2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman.

J Pediatric Infect Dis Soc 2020 Dec 26. Epub 2020 Dec 26.

Department of Neonatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood.

Methods: Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy.

Results: RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts.

Conclusions: Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.
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http://dx.doi.org/10.1093/jpids/piaa153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798999PMC
December 2020

Susceptibility of rabbits to SARS-CoV-2.

Emerg Microbes Infect 2021 Dec;10(1):1-7

Viroscience department, Erasmus Medical Center, Rotterdam, the Netherlands.

Transmission of severe acute respiratory coronavirus-2 (SARS-CoV-2) between livestock and humans is a potential public health concern. We demonstrate the susceptibility of rabbits to SARS-CoV-2, which excrete infectious virus from the nose and throat upon experimental inoculation. Therefore, investigations on the presence of SARS-CoV-2 in farmed rabbits should be considered.
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http://dx.doi.org/10.1080/22221751.2020.1868951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832544PMC
December 2021

An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells.

EMBO J 2021 03 11;40(5):e105912. Epub 2021 Jan 11.

Viroscience Department, Erasmus University Medical Center, Rotterdam, The Netherlands.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which may result in acute respiratory distress syndrome (ARDS), multiorgan failure, and death. The alveolar epithelium is a major target of the virus, but representative models to study virus host interactions in more detail are currently lacking. Here, we describe a human 2D air-liquid interface culture system which was characterized by confocal and electron microscopy and single-cell mRNA expression analysis. In this model, alveolar cells, but also basal cells and rare neuroendocrine cells, are grown from 3D self-renewing fetal lung bud tip organoids. These cultures were readily infected by SARS-CoV-2 with mainly surfactant protein C-positive alveolar type II-like cells being targeted. Consequently, significant viral titers were detected and mRNA expression analysis revealed induction of type I/III interferon response program. Treatment of these cultures with a low dose of interferon lambda 1 reduced viral replication. Hence, these cultures represent an experimental model for SARS-CoV-2 infection and can be applied for drug screens.
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http://dx.doi.org/10.15252/embj.2020105912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883112PMC
March 2021

Genome Sequences of Seven Strains from Chickens in The Netherlands.

Microbiol Resour Announc 2020 Nov 19;9(47). Epub 2020 Nov 19.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.

We report seven chicken megrivirus genome sequences identified in chicken fecal samples from a broiler farm in The Netherlands. The sequences were determined using metagenomic sequencing and would expand our understanding of the genome diversity of megriviruses.
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http://dx.doi.org/10.1128/MRA.01207-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679105PMC
November 2020

Phylogenetic Investigation of Norovirus Transmission between Humans and Animals.

Viruses 2020 11 10;12(11). Epub 2020 Nov 10.

Department of Viroscience, Erasmus MC, Wytemaweg 80, 3015CN Rotterdam, The Netherlands.

Norovirus infections are a leading cause of acute gastroenteritis worldwide, affecting people of all ages. There are 10 norovirus genogroups (GI-GX) that infect humans and animals in a host-specific manner. New variants and genotypes frequently emerge, and their origin is not well understood. One hypothesis is that new human infections may be seeded from an animal reservoir, as human noroviruses have occasionally been detected in animal species. The majority of these sequences were identified as older GII.4 variants, but a variety of other GIIs and GIs have been detected as well. While these sequences share at least 94% nt similarity with human strains, most of them are >98% identical to human strains. The fact that these strains were detected in animals after they had been detected through human surveillance to be already circulating in humans suggests human-to-animal transmission.
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http://dx.doi.org/10.3390/v12111287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698157PMC
November 2020

Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans.

Science 2021 01 10;371(6525):172-177. Epub 2020 Nov 10.

Department of Viroscience, Erasmus MC, WHO Collaborating Centre for Arbovirus and Viral Hemorrhagic Fever Reference and Research, Rotterdam, Netherlands.

Animal experiments have shown that nonhuman primates, cats, ferrets, hamsters, rabbits, and bats can be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, SARS-CoV-2 RNA has been detected in felids, mink, and dogs in the field. Here, we describe an in-depth investigation using whole-genome sequencing of outbreaks on 16 mink farms and the humans living or working on these farms. We conclude that the virus was initially introduced by humans and has since evolved, most likely reflecting widespread circulation among mink in the beginning of the infection period, several weeks before detection. Despite enhanced biosecurity, early warning surveillance, and immediate culling of animals in affected farms, transmission occurred between mink farms in three large transmission clusters with unknown modes of transmission. Of the tested mink farm residents, employees, and/or individuals with whom they had been in contact, 68% had evidence of SARS-CoV-2 infection. Individuals for which whole genomes were available were shown to have been infected with strains with an animal sequence signature, providing evidence of animal-to-human transmission of SARS-CoV-2 within mink farms.
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http://dx.doi.org/10.1126/science.abe5901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857398PMC
January 2021

Unravelling the modes of transmission of SARS-CoV-2 during a nursing home outbreak: looking beyond the church super-spread event.

Clin Infect Dis 2020 Oct 29. Epub 2020 Oct 29.

Department of Infectious Disease Control, Municipal Public Health Service Rotterdam-Rijnmond, Rotterdam, the Netherlands.

Background: An outbreak of COVID-19 in a nursing home in the Netherlands, following an on-site church service held on March 8 th, 2020, triggered an investigation to unravel sources and chain(s) of transmission.

Methods: Epidemiological data were collected from registries and through a questionnaire among church attendees. Symptomatic residents and healthcare workers (HCWs) were tested for SARS-CoV-2 by RT-PCR and subjected to whole genome sequencing (WGS). Sequences from a selection of people from the same area were included as community reference.

Results: After the church service, 30 of 39 attendees (77%) developed symptoms; 14 were tested and were positive for COVID-19 (11 residents and 3 non-residents). In the following five weeks, 62 of 300 residents (21%) and 30 of 640 HCWs (5%) tested positive for COVID-19; 21 of 62 residents (34%) died. The outbreak was controlled through a cascade of measures. WGS of samples from residents and HCWs identified a diversity of sequence types, grouped into eight clusters. Seven resident church attendees all were infected with distinct viruses, four of which belonged to two larger clusters in the nursing home.

Conclusions: Although initial investigation suggested the church service as source of the outbreak, detailed analysis showed a more complex picture, most consistent with widespread regional circulation of the virus in the weeks before the outbreak, and multiple introductions into the nursing home before the visitor ban. The findings underscore the importance of careful outbreak investigations to understand SARS-CoV-2 transmission to develop evidence-based mitigation measures.
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http://dx.doi.org/10.1093/cid/ciaa1664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665385PMC
October 2020

Human Noroviruses Attach to Intestinal Tissues of a Broad Range of Animal Species.

J Virol 2021 01 13;95(3). Epub 2021 Jan 13.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands

Human noroviruses are the most common nonbacterial cause of gastroenteritis outbreaks, with new variants and genotypes frequently emerging. The origin of these new viruses is unknown; however, animals have been proposed as a potential source, as human noroviruses have been detected in animal species. Here, we investigated the potential of animals to serve as a reservoir of human noroviruses by testing norovirus attachment to formalin-fixed intestinal tissues of a range of potential reservoir animals. We set up a novel method to study norovirus binding using fluorescein isothiocyanate (FITC)-labeled virus-like particles (VLPs). In humans, noroviruses interact with histo-blood group antigens (HBGAs), carbohydrates that are expressed, among others, on the epithelial lining of the gastrointestinal tract. In animals, this interaction is not well understood. To test if virus binding depends on HBGAs, we characterized the HBGA phenotype in animal tissues by immunohistochemistry. With the exception of the black-headed gull and the straw-colored fruitbat, we observed the attachment of several human norovirus genotypes to the intestinal epithelium of all tested animal species. However, we did not find an association between the expression of a specific HBGA phenotype and virus-like particle (VLP) attachment. We show that selected human noroviruses can attach to small-intestinal tissues across species, supporting the hypothesis that human noroviruses can reside in an animal reservoir. However, whether this attachment can subsequently lead to infection needs to be further assessed. Noroviruses are a major cause of acute gastroenteritis in humans. New norovirus variants and recombinants (re)emerge regularly in the human population. From animal experiments and surveillance studies, it has become clear that at least seven animal models are susceptible to infection with human strains and that domesticated and wild animals shed human noroviruses in their feces. As virus attachment is an important first step for infection, we used a novel method utilizing FITC-labeled VLPs to test for norovirus attachment to intestinal tissues of potential animal hosts. We further characterized these tissues with regard to their HBGA expression, a well-studied norovirus susceptibility factor in humans. We found attachment of several human strains to a variety of animal species independent of their HBGA phenotype. This supports the hypothesis that human strains could reside in an animal reservoir.
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http://dx.doi.org/10.1128/JVI.01492-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925106PMC
January 2021

Automated download and clean-up of family-specific databases for kmer-based virus identification.

Bioinformatics 2021 May;37(5):705-710

Department of Viroscience, Erasmus University Medical Centre, 3000 CA Rotterdam, The Netherlands.

Summary: Here, we present an automated pipeline for Download Of NCBI Entries (DONE) and continuous updating of a local sequence database based on user-specified queries. The database can be created with either protein or nucleotide sequences containing all entries or complete genomes only. The pipeline can automatically clean the database by removing entries with matches to a database of user-specified sequence contaminants. The default contamination entries include sequences from the UniVec database of plasmids, marker genes and sequencing adapters from NCBI, an E.coli genome, rRNA sequences, vectors and satellite sequences. Furthermore, duplicates are removed and the database is automatically screened for sequences from green fluorescent protein, luciferase and antibiotic resistance genes that might be present in some GenBank viral entries, and could lead to false positives in virus identification. For utilizing the database, we present a useful opportunity for dealing with possible human contamination. We show the applicability of DONE by downloading a virus database comprising 37 virus families. We observed an average increase of 16 776 new entries downloaded per month for the 37 families. In addition, we demonstrate the utility of a custom database compared to a standard reference database for classifying both simulated and real sequence data.

Availabilityand Implementation: The DONE pipeline for downloading and cleaning is deposited in a publicly available repository (https://bitbucket.org/genomicepidemiology/done/src/master/).

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa857DOI Listing
May 2021

Spatial risk analysis for the introduction and circulation of six arboviruses in the Netherlands.

Parasit Vectors 2020 Sep 10;13(1):464. Epub 2020 Sep 10.

Wildlife Ecology & Conservation Group, Wageningen University & Research, Wageningen, The Netherlands.

Background: Arboviruses are a growing public health concern in Europe, with both endemic and exotic arboviruses expected to spread further into novel areas in the next decades. Predicting where future outbreaks will occur is a major challenge, particularly for regions where these arboviruses are not endemic. Spatial modelling of ecological risk factors for arbovirus circulation can help identify areas of potential emergence. Moreover, combining hazard maps of different arboviruses may facilitate a cost-efficient, targeted multiplex-surveillance strategy in areas where virus transmission is most likely. Here, we developed predictive hazard maps for the introduction and/or establishment of six arboviruses that were previously prioritized for the Netherlands: West Nile virus, Japanese encephalitis virus, Rift Valley fever virus, tick-borne encephalitis virus, louping-ill virus and Crimean-Congo haemorrhagic fever virus.

Methods: Our spatial model included ecological risk factors that were identified as relevant for these arboviruses by an earlier systematic review, including abiotic conditions, vector abundance, and host availability. We used geographic information system (GIS)-based tools and geostatistical analyses to model spatially continuous datasets on these risk factors to identify regions in the Netherlands with suitable ecological conditions for arbovirus introduction and establishment.

Results: The resulting hazard maps show that there is spatial clustering of areas with either a relatively low or relatively high environmental suitability for arbovirus circulation. Moreover, there was some overlap in high-hazard areas for virus introduction and/or establishment, particularly in the southern part of the country.

Conclusions: The similarities in environmental suitability for some of the arboviruses provide opportunities for targeted sampling of vectors and/or sentinel hosts in these potential hotspots of emergence, thereby increasing the efficient use of limited resources for surveillance.
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http://dx.doi.org/10.1186/s13071-020-04339-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488554PMC
September 2020

Orthohantavirus Pathogenesis and Cell Tropism.

Front Cell Infect Microbiol 2020 4;10:399. Epub 2020 Aug 4.

Department of Viroscience, Erasmus University Medical Center, Rotterdam, Netherlands.

Orthohantaviruses are zoonotic viruses that are naturally maintained by persistent infection in specific reservoir species. Although these viruses mainly circulate among rodents worldwide, spill-over infection to humans occurs. Orthohantavirus infection in humans can result in two distinct clinical outcomes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). While both syndromes develop following respiratory transmission and are associated with multi-organ failure and high mortality rates, little is known about the mechanisms that result in these distinct clinical outcomes. Therefore, it is important to identify which cell types and tissues play a role in the differential development of pathogenesis in humans. Here, we review current knowledge on cell tropism and its role in pathogenesis during orthohantavirus infection in humans and reservoir rodents. Orthohantaviruses predominantly infect microvascular endothelial cells (ECs) of a variety of organs (lungs, heart, kidney, liver, and spleen) in humans. However, in this review we demonstrate that other cell types (e.g., macrophages, dendritic cells, and tubular epithelium) are infected as well and may play a role in the early steps in pathogenesis. A key driver for pathogenesis is increased vascular permeability, which can be direct effect of viral infection in ECs or result of an imbalanced immune response in an attempt to clear the virus. Future studies should focus on the role of identifying how infection of organ-specific endothelial cells as well as other cell types contribute to pathogenesis.
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http://dx.doi.org/10.3389/fcimb.2020.00399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438779PMC
August 2020

Setting a baseline for global urban virome surveillance in sewage.

Sci Rep 2020 08 13;10(1):13748. Epub 2020 Aug 13.

Viroscience Department, Erasmus Medical Center, Rotterdam, The Netherlands.

The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective.
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http://dx.doi.org/10.1038/s41598-020-69869-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426863PMC
August 2020

SARS-CoV-2-Specific Antibody Detection for Seroepidemiology: A Multiplex Analysis Approach Accounting for Accurate Seroprevalence.

J Infect Dis 2020 10;222(9):1452-1461

Centre for Immunology of Infectious Diseases and Vaccines, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

Background: The COVID-19 pandemic necessitates better understanding of the kinetics of antibody production induced by infection with SARS-CoV-2. We aimed to develop a high-throughput multiplex assay to detect antibodies to SARS-CoV-2 to assess immunity to the virus in the general population.

Methods: Spike protein subunits S1 and receptor binding domain, and nucleoprotein were coupled to microspheres. Sera collected before emergence of SARS-CoV-2 (n = 224) and of non-SARS-CoV-2 influenza-like illness (n = 184), and laboratory-confirmed cases of SARS-CoV-2 infection (n = 115) with various severities of COVID-19 were tested for SARS-CoV-2-specific IgG concentrations.

Results: Our assay discriminated SARS-CoV-2-induced antibodies and those induced by other viruses. The assay specificity was 95.1%-99.0% with sensitivity 83.6%-95.7%. By merging the test results for all 3 antigens a specificity of 100% was achieved with a sensitivity of at least 90%. Hospitalized COVID-19 patients developed higher IgG concentrations and the rate of IgG production increased faster compared to nonhospitalized cases.

Conclusions: The bead-based serological assay for quantitation of SARS-CoV-2-specific antibodies proved to be robust and can be conducted in many laboratories. We demonstrated that testing of antibodies against multiple antigens increases sensitivity and specificity compared to single-antigen-specific IgG determination.
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http://dx.doi.org/10.1093/infdis/jiaa479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454740PMC
October 2020

Increased hand hygiene compliance in nursing homes after a multimodal intervention: A cluster randomized controlled trial (HANDSOME).

Infect Control Hosp Epidemiol 2020 10 4;41(10):1169-1177. Epub 2020 Aug 4.

Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Objective: To assess the effect of a multimodal intervention on hand hygiene compliance (HHC) in nursing homes.

Design, Setting, And Participants: HHC was evaluated using direct, unobtrusive observation in a cluster randomized controlled trial at publicly funded nursing homes in the Netherlands. In total, 103 nursing home organizations were invited to participate; 18 organizations comprising 33 nursing homes (n = 66 nursing home units) participated in the study. Nursing homes were randomized into a control group (no intervention, n = 30) or an intervention group (multimodal intervention, n = 36). The primary outcome measure was HHC of nurses. HHC was appraised at baseline and at 4, 7, and 12 months after baseline. Observers and nurses were blinded.

Intervention: Audits regarding hand hygiene (HH) materials and personal hygiene rules, 3 live lessons, an e-learning program, posters, and a photo contest. We used a new method to teach the nurses the WHO-defined 5 moments of HH: Room In, Room Out, Before Clean, and After Dirty.

Results: HHC increased in both arms. The increase after 12 months was larger for units in the intervention arm (from 12% to 36%) than for control units (from 13% to 21%) (odds ratio [OR], 2.10; confidence interval [CI], 1.35-3.28). The intervention arm exhibited a statistically significant increase in HHC at 4 of the 5 WHO-defined HH moments. At follow-up, HHC in the intervention arm remained statistically significantly higher (OR, 1.93; 95% CI, 1.59-2.34) for indications after an activity (from 37% to 39%) than for indications before an activity (from 14% to 27%).

Conclusions: The HANDSOME intervention is successful in improving HHC in nursing homes.
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http://dx.doi.org/10.1017/ice.2020.319DOI Listing
October 2020

SARS-CoV-2 is transmitted via contact and via the air between ferrets.

Nat Commun 2020 07 8;11(1):3496. Epub 2020 Jul 8.

Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands.

SARS-CoV-2, a coronavirus that emerged in late 2019, has spread rapidly worldwide, and information about the modes of transmission of SARS-CoV-2 among humans is critical to apply appropriate infection control measures and to slow its spread. Here we show that SARS-CoV-2 is transmitted efficiently via direct contact and via the air (via respiratory droplets and/or aerosols) between ferrets, 1 to 3 days and 3 to 7 days after exposure respectively. The pattern of virus shedding in the direct contact and indirect recipient ferrets is similar to that of the inoculated ferrets and infectious virus is isolated from all positive animals, showing that ferrets are productively infected via either route. This study provides experimental evidence of robust transmission of SARS-CoV-2 via the air, supporting the implementation of community-level social distancing measures currently applied in many countries in the world and informing decisions on infection control measures in healthcare settings.
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http://dx.doi.org/10.1038/s41467-020-17367-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343828PMC
July 2020

Human Paramyxovirus Infections Induce T Cells That Cross-React with Zoonotic Henipaviruses.

mBio 2020 07 7;11(4). Epub 2020 Jul 7.

Erasmus MC, Department of Viroscience, Rotterdam, the Netherlands

Humans are infected with paramyxoviruses of different genera early in life, which induce cytotoxic T cells that may recognize conserved epitopes. This raises the question of whether cross-reactive T cells induced by antecedent paramyxovirus infections provide partial protection against highly lethal zoonotic Nipah virus infections. By characterizing a measles virus-specific but paramyxovirus cross-reactive human T cell clone, we discovered a highly conserved HLA-B*1501-restricted T cell epitope in the fusion protein. Using peptides, tetramers, and single cell sorting, we isolated a parainfluenza virus-specific T cell clone from a healthy adult and showed that both clones cleared Nipah virus-infected cells. We identified multiple conserved hot spots in paramyxovirus proteomes that contain other potentially cross-reactive epitopes. Our data suggest that, depending on HLA haplotype and history of paramyxovirus exposures, humans may have cross-reactive T cells that provide protection against Nipah virus. The effect of preferential boosting of these cross-reactive epitopes needs to be further studied in light of paramyxovirus vaccination studies. Humans encounter multiple paramyxoviruses early in life. This study shows that infection with common paramyxoviruses can induce T cells cross-reactive with the highly pathogenic Nipah virus. This demonstrates that the combination of paramyxovirus infection history and HLA haplotype affects immunity to phylogenetically related zoonotic paramyxoviruses.
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http://dx.doi.org/10.1128/mBio.00972-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343989PMC
July 2020