http://repub.eur.nl/res/aut/24131/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/34217/ 2011-05-01T00:00:00Z Background: New variant strains of norovirus have emerged worldwide in recent years, evolving by mutation much like influenza viruses. These strains have been associated with a notable increase in the number of annual norovirus outbreaks. However, the impact of such increased norovirus activity on morbidity and mortality is not clear because norovirus infection is rarely specifically registered. Methods: We studied trends of gastroenteritis with unspecified cause in medical registrations (ie, general practitioner [GP] visits, hospitalizations, and deaths) and their association with known temporal trends in norovirus outbreaks in the Netherlands. Using weekly counts in the elderly (aged 65+ years) from 1999 through 2006, we applied Poisson regression analyses adjusted for additional pathogens and seasonal trends (linear, sine, and cosine terms). Results: In the elderly, each notified norovirus outbreak was associated with an estimated 26 unspecified gastroenteritis GP visits (95% confidence interval = 17-34), 2.2 unspecified gastroenteritis hospitalizations (1.6-2.7), and 0.14 unspecified gastroenteritis deaths (0.08-0.21). For the heaviest norovirus season (2004-2005), these models attributed up to 3804 unspecified gastroenteritis GP visits, 318 unspecified gastroenteritis hospitalizations, and 21 unspecified gastroenteritis deaths to norovirus outbreaks among a total elderly population of 2.3 million. DISCUSSION:: The recent increase in norovirus outbreak activity is associated with increases of unspecified gastroenteritis morbidity and even deaths in the elderly. Norovirus should not be regarded as an infection with trivial health risks. Copyright http://repub.eur.nl/res/pub/34096/ 2011-03-01T00:00:00Z Although norovirus infection is generally known to be a mild disease, there is some evidence for severe outcome. An outbreak in a Dutch psychiatric institution, originating from pilgrims returning from Lourdes (France), provided an opportunity for performing a retrospective cohort study in order to identify risk factors for norovirus disease and excess mortality. Relative risks (RR) including 95% confidence intervals (CI) showed that attending the pilgrimage (RR 20, 95% CI 14-30) and age >70 (RR 17, 95% CI 12-22) were risk factors for symptomatic infection. In a subset of patients, for whom more detailed information was available, the use of statins was associated with norovirus disease when adjusted for underlying condition (adjusted odds ratio 39, 95% CI 12-130). Mortality was higher in cases infected during the pilgrimage compared to other residents (RR 209, 95% CI 47-938). Norovirus disease can lead to severe outcome. The newly identified risk of statins for contracting norovirus disease may have considerable consequences for the Western world and needs prospective confirmation. http://repub.eur.nl/res/pub/21345/ 2010-11-17T00:00:00Z Halfway into the past century molecular biology emerged as a science, and it has evolved and grown very rapidly since. As a result of their very nature, infectious diseases have always had the attention of physicians and scientists, and the possibilities for research offered by molecular biology were pre-eminently suitable for studying the causative agents of these infectious diseases, and especially for studying viruses. Noroviruses cause sudden onset gastro-intestinal illness in humans. Their ability to cause large scale outbreaks of debilitating illness, even if of quickly passing nature, has made them into a relevant topic of study. Rapid developments in molecular biology have generated diagnostic tools which enabled many labs in the world to perform norovirus diagnostics, and to perform sequence analyses of the detected strains. These sequence data form a very valuable basis for studies of the molecular epidemiology of noroviruses. By linking the sequence data to classical epidemiological data, such as time and place of illness, number of people affected, etc., a platform is made for unveiling information describing for example the spread of the virus, the impact, and the prevalence. The work presented in this thesis aims to further current knowledge of norovirus by studying its molecular epidemiology, to better enable taking public health actions aimed at decreasing the impact of disease. http://repub.eur.nl/res/pub/21613/ 2010-11-01T00:00:00Z Norovirus (NoV) infection in immunocompromised patients may lead to prolonged norovirus shedding. Here, we demonstrate the involvement of three chronic shedders in hospital outbreaks. Combined epidemiological and molecular evidence suggests that in one case, NoV transmission occurred at least 17 days after the first diagnosis. http://repub.eur.nl/res/pub/20183/ 2010-08-30T00:00:00Z Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0×10-3 mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern. http://repub.eur.nl/res/pub/27662/ 2010-06-01T00:00:00Z Sapoviruses (SaVs) belong to the Caliciviridae family and can cause gastroenteritis in humans and swine. Despite extensive testing, human sapoviruses have been found only in sporadic cases and in one mixed outbreak in children between 1994 and 2007 in the Netherlands. Here we describe a change in sapovirus epidemiology in the Netherlands resulting in sapovirus outbreaks and infections in adults. From November 2007 to January 2009, 478 outbreaks of acute gastroenteritis were reported to the National Institute for Public Health and the Environment in the Netherlands as a part of ongoing surveillance. Sapoviruses were found to be the most likely cause of 19 outbreaks (4%). During the same 2-year period, sapovirus infections were reported in Sweden, Slovenia, and Hungary. In the Netherlands, further characterization of outbreak strains showed that 12 (63%) sapovirus outbreaks were caused by genotype I.2 viruses. Most patients were adults older than 60 years (range, 1 to 100 years). Phylogenetic analysis using all presently available SaV sequences showed high homology between genotype I.2 strains detected in different geographical regions (Sweden, Slovenia, Taiwan, Japan, and Russia) since 2007. These first reported outbreaks of sapovirus infections in adults in the Netherlands were remarkable. Detection of identical genotypes in many samples might suggest that these viruses have the same origin, and since the infection is spreading fast, the prevalence of sapovirus infection may be increasing. The incidence of sapovirus infections in these countries suggests that a substantial part of Europe is affected by this virus. Copyright http://repub.eur.nl/res/pub/20756/ 2010-05-01T00:00:00Z Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0×10-3 mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern. © 2010 Siebenga et al. http://repub.eur.nl/res/pub/24625/ 2009-09-01T00:00:00Z Background. Noroviruses (NoVs) are the most common cause of viral gastroenteritis. Their high incidence and importance in health care facilities result in a great impact on public health. Studies from around the world describing increasing prevalence have been difficult to compare because of differing nomenclatures for variants of the dominant genotype, GII.4. We studied the global patterns of GII.4 epidemiology in relation to its genetic diversity. Methods. Data from NoV outbreaks with dates of onset from January 2001 through March 2007 were collected from 15 institutions on 5 continents. Partial genome sequences (n = 775) were collected, allowing phylogenetic comparison of data from different countries. Results. The 15 institutions reported 3098 GII.4 outbreaks, 62% of all reported NoV outbreaks. Eight GII.4 variants were identified. Four had a global distribution-the 1996, 2002, 2004, and 2006b variants. The 2003Asia and 2006a variants caused epidemics, but they were geographically limited. Finally, the 2001 Japan and 2001Henry variants were found across the world but at low frequencies. Conclusions. NoV epidemics resulted from the global spread of GII.4 strains that evolved under the influence of population immunity. Lineages show notable (and currently unexplained) differences in geographic prevalence. Establishing a global NoV network by which data on strains with the potential to cause pandemics can be rapidly exchanged may lead to improved prevention and intervention strategies. http://repub.eur.nl/res/pub/29106/ 2008-10-01T00:00:00Z During a 2-year survey in an academic hospital, 8 (8.4%) of all norovirus (NoV)-positive patients showed prolonged norovirus illness and shedding (duration, 21-182 days). All patients had underlying illnesses, resulting in some level of immunodeficiency in 5. Four patients were admitted to the hospital with gastroenteritis, 2 acquired norovirus while hospitalized, and 2 were outpatients. Genotypes GII.4 and GIIb-GII.3 were found. Reinfection occurred in 3 patients. Full capsid sequences were determined from strains detected in sequentially collected stool specimens to study evolution. The greatest number of amino acid mutations in a given patient was 11; they were detected in NoV isolates recovered over a 119-day period and were mapped to positions at or near putative antigenic sites. In the patient with most severe immune dysfunction, only 5 amino acids mutated over 182 days, suggesting immune-driven selection. The severe impact on patients and hospitals and the potential role of prolonged shedders as a reservoir for viral antigenic variants lead us to stress the importance of confinement of outbreaks of NoV infection that occur in hospitals. http://repub.eur.nl/res/pub/29910/ 2008-08-01T00:00:00Z The Roland Morris Disability Questionnaire (RMDQ-24) and the VAS spine score have been regularly used to measure functional outcome in patients with back pain. The RMDQ-24 is primarily used in degenerative disease of the spine and the VAS Spine is used in trauma patients. The aim of this study is to compare these scores and to see if there is a correlation in patients with a traumatic thoracolumbar spinal fracture. Prospective cohort study comparing the RMDQ-24 and the VAS spine score in patients with a traumatic type A fracture thoracolumbar spine fracture. Fifteen non-operatively patients (group one) completed 118 questionnaires and 17 operatively treated patients (group two) completed 140 questionnaires. Group one scored an average of 6.6 and 65.9 for the RMDQ-24 and VAS Spine, in group two this was 5.1 and 82.9. Spearman's correlation test showed a significant correlation, in group one 0.83 and for the second group 0.87. RMDQ-24 and VAS Spine have a strong positive correlation in measuring disability in a group of patients with back pain because of a spinal fracture. In both non-operatively and operatively treated groups this correlation is significant. http://repub.eur.nl/res/pub/35238/ 2007-09-01T00:00:00Z Noroviruses are the causative agents of the majority of viral gastroenteritis outbreaks in humans. During the past 15 years, noroviruses of genotype GGII.4 have caused four epidemic seasons of viral gastroenteritis, during which four novel variants (termed epidemic variants) emerged and displaced the resident viruses. In order to understand the mechanisms and biological advantages of these epidemic variants, we studied the genetic changes in the capsid proteins of GGII.4 strains over this period. A representative sample was drawn from 574 GGII.4 outbreak strains collected over 15 years of systematic surveillance in The Netherlands, and capsid genes were sequenced for a total of 26 strains. The three-dimensional structure was predicted by homology modeling, using the Norwalk virus (Hu/NoV/GGI.1/Norwalk/1968/US) capsid as a reference. The highly significant preferential accumulation and fixation of mutations (nucleotide and amino acid) in the protruding part of the capsid protein provided strong evidence for the occurrence of genetic drift and selection. Although subsequent new epidemic variants differed by up to 25 amino acid mutations, consistent changes were observed in only five positions. Phylogenetic analyses showed that each variant descended from its chronologic predecessor, with the exception of the 2006b variant, which is more closely related to the 2002 variant than to the 2004 variant. The consistent association between the observed genetic findings and changes in epidemiology leads to the conclusion that population immunity plays a role in the epochal evolution of GGII.4 norovirus strains. Copyright