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Interest in causes of mortality of free-ranging, native North American lagomorphs has grown with the emergence of rabbit hemorrhagic disease virus 2 (RHDV2). Over the years 2013-2022, the Southeastern Cooperative Wildlife Disease Study received 119 Sylvilagus spp. case submissions from the central and eastern United States, comprising 147 rabbits. Most (86%) of these submissions occurred after detecting RHDV2 in the United States in 2020. Laboratory data from these rabbits were retrospectively evaluated for major causes, contributors to mortality, and pathogen detections. Gross and histologic examination was performed for 112 rabbits. Common primary causes of death included trauma ( n  = 49), bacterial disease ( n  = 31), emaciation ( n  = 6), and parasitism ( n  = 6). Among the 32 rabbits with bacterial disease, 12 were diagnosed with tularemia and 7 with pasteurellosis. Rabbits with pasteurellosis had disseminated abscessation, septicemia, and/or polyserositis. Less commonly, cutaneous fibroma ( n  = 2), notoedric mange ( n  = 2), encephalitozoonosis ( n  = 2), neoplasia (round-cell sarcoma; n  = 1), and congenital abnormalities ( n  = 1) were diagnosed. RHDV2 was not detected in 123 rabbits tested. Although RHDV2 has not been detected in wild lagomorphs in the eastern United States, detections in domestic rabbits from the region emphasize the need for continued surveillance. Furthermore, continued surveillance for Francisella tularensis informs public health risk. Overall, increased knowledge of Sylvilagus spp. health furthers our understanding of diseases affecting these important prey and game species., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. In this study, we used colonization with the model commensal murine norovirus (MNV; strain CR6) to interrogate host-directed mechanisms of viral regulation, and we show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In addition to restricting CR6 replication to the intestinal tract, we show that STAT1 regulates antiviral CD4 + and CD8 + T cell responses and prevents systemic viral-induced tissue damage and disease. Despite altered T cell responses that resemble those that mediate lethal immunopathology in systemic viral infections in STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound limited viral replication, preventing virus-induced tissue damage and death without impacting the generation of inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa and that uncontrolled viral replication mediates disease rather than the concomitant development of dysregulated antiviral T cell responses in STAT1-deficient mice. IMPORTANCE The intestinal microbiota is a collection of bacteria, archaea, fungi, and viruses that colonize the mammalian gut. Coevolution of the host and microbiota has required development of immunological tolerance to prevent ongoing inflammatory responses against intestinal microbes. Breakdown of tolerance to bacterial components of the microbiota can contribute to immune activation and inflammatory disease. However, the mechanisms that are necessary to maintain tolerance to viral components of the microbiome, and the consequences of loss of tolerance, are less well understood. Here, we show that STAT1 is integral for preventing escape of a commensal-like virus, murine norovirus CR6 (MNV CR6), from the gut and that in the absence of STAT1, mice succumb to infection-induced disease. In contrast to the case with other systemic viral infections, mortality of STAT1-deficient mice is not driven by immune-mediated pathology. Our data demonstrate the importance of host-mediated geographical restriction of commensal-like viruses.

Background: To guide decision-making on immunisation programmes for ageing adults in Europe, one of the aims of the Vaccines and InfecTious diseases in the Ageing popuLation (IMI2-VITAL) project is to assess the burden of disease (BoD) of (potentially) vaccine-preventable diseases ((P)VPD). We aimed to identify the available data sources to calculate the BoD of (P)VPD in participating VITAL countries and to pinpoint data gaps. Based on epidemiological criteria and vaccine availability, we prioritized (P) VPD caused by Extra-intestinal pathogenic Escherichia coli (ExPEC), norovirus, respiratory syncytial virus, Staphylococcus aureus, and pneumococcal pneumonia., Methods: We conducted a survey on available data (e.g. incidence, mortality, disability-adjusted life years (DALY), quality-adjusted life years (QALY), sequelae, antimicrobial resistance (AMR), etc.) among national experts from European countries, and carried out five pathogen-specific literature reviews by searching MEDLINE for peer-reviewed publications published between 2009 and 2019., Results: Morbidity and mortality data were generally available for all five diseases, while summary BoD estimates were mostly lacking. Available data were not always stratified by age and risk group, which is especially important when calculating BoD for ageing adults. AMR data were available in several countries for S. aureus and ExPEC., Conclusion: This study provides an exhaustive overview of the available data sources and data gaps for the estimation of BoD of five (P) VPD in ageing adults in the EU/EAA, which is useful to guide pathogen-specific BoD studies and contribute to calculation of (P)VPDs BoD.

Viral diseases, whether of animals or humans, are normally considered as problems to be managed. However, in Australia, two viruses have been used as landscape-scale therapeutics to control European rabbits (Oryctolagus cuniculus), the preeminent invasive vertebrate pest species. Rabbits have caused major environmental and agricultural losses and contributed to extinction of native species. It was not until the introduction of Myxoma virus that effective control of this pest was obtained at a continental scale. Subsequent coevolution of rabbit and virus saw a gradual reduction in the effectiveness of biological control that was partially ameliorated by the introduction of the European rabbit flea to act as an additional vector for the virus. In 1995, a completely different virus, Rabbit hemorrhagic disease virus (RHDV), escaped from testing and spread through the Australian rabbit population and again significantly reduced rabbit numbers and environmental impacts. The evolutionary pressures on this virus appear to be producing quite different outcomes to those that occurred with myxoma virus and the emergence and invasion of a novel genotype of RHDV in 2014 have further augmented control. Molecular studies on myxoma virus have demonstrated multiple proteins that manipulate the host innate and adaptive immune response; however the molecular basis of virus attenuation and reversion to virulence are not yet understood.

Rabbit hemorrhagic disease virus (RHDV) is the causative agent of rabbit hemorrhagic disease (RHD), and its infection results in mortality of 70-90% in farmed and wild rabbits. RHDV is thought to replicate strictly in rabbits. However, there are also reports showing that gene segments from the RHDV genome or antibodies against RHDV have been detected in other animals. Here, we report the detection and isolation of a RHDV from diseased Alpine musk deer ( Moschus sifanicus ). The clinical manifestations in those deer were sudden death without clinical signs and hemorrhage in the internal organs. To identify the potential causative agents of the disease, we used sequence independent single primer amplification (SISPA) to detect gene segments from viruses in the tissue samples collected from the dead deer. From the obtained sequences, we identified some gene fragments showing very high nucleotide sequence similarity with RHDV genome. Furthermore, we identified caliciviral particles using an electron microscope in the samples. The new virus was designated as RHDV GS/YZ. We then designed primers based on the genome sequence of an RHDV strain CD/China to amplify and sequence the whole genome of the virus. The genome of the virus was determined to be 7437 nucleotides in length, sharing the highest genome sequence identity of 98.7% with a Chinese rabbit strain HB. The virus was assigned to the G2 genotype of RHDVs according to the phylogenetic analyses based on both the full-length genome and VP60 gene sequences. Animal experiments showed that GS/YZ infection in rabbits resulted in the macroscopic and microscopic lesions similar to that caused by the other RHDVs. This is the first report of RHDV isolated from Alpine musk deer, and our findings extended the epidemiology and host range of RHDV.

Viral haemorrhagic disease (VHD) and colibacillosis are common diseases in rabbits that cause economic losses worldwide. The effect of colibacillosis on the immune response of vaccinated rabbits against rabbit haemorrhagic disease virus (RHDV) was studied. Four groups (G1-G4) were included. G1 was the negative control group; G2 was the RHDV vaccine group; G3 was the E. coli-infected group; and G4 was the E. coli-infected + RHDV vaccine group. The E. coli infection and RHDV vaccination were simultaneously performed, with another previous infection, 3 days before vaccination. At 28 days post-vaccination (PV), the rabbits (G2-G4) were challenged intramuscularly with 0.5 ml of RHDV at a dose of 10 3 50% median lethal dose (LD 50 )/rabbit. The rabbits were observed for clinical signs, body weight gain and mortality rates. Tissue, blood, serum, and faecal samples and rectal swabs were collected at 3, 5, 7, 14, 21 and 28 days PV. Significant clinical signs and mortality and a decrease in BW were observed in the infected + RHDV vaccine group. On the 3 rd day post-infection (PI), compared with all the other groups, the vaccinated group (G2) had significantly upregulated hepatic tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels; however, the infected + RHDV vaccine group had significantly higher intestinal levels of TNF-α and IL-6 than the other groups. Furthermore, E. coli infection in vaccinated rabbits led to immunosuppression, as shown by significant decreases (P < 0.05) in heterophil phagocytic activity, the CD4+/CD8+ ratio, and HI antibody responses to RHDV and a significant increase in the heterophil to lymphocyte (H/L) ratio. In conclusion, colibacillosis leads to immunosuppression involving a shift in the equilibrium of cytokines and reduced weight gain and mortality in vaccinated rabbits and could be a contributing factor in RHDV vaccination failure in rabbit farming., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Neutropenic diets were adopted as a way to decrease the infection risks in immunocompromised individuals, but these diets result in significant restrictions in the variety and types of foods an individual may consume. We used a controlled before-and-after study design in consecutive pediatric and young adult patients who underwent hematopoietic stem cell transplant at our center between January 1, 2014, and December 31, 2014. From January through June, all patients were placed on a traditional neutropenic diet; on July 1, we liberalized the bone marrow transplant (BMT) diet to a modified BMT diet. We compared the incidence of bloodstream infections in the first 100 days post-transplant, incidence of norovirus in the first 100 days, total parenteral nutrition days through day 100, incidence of grade 3 to 4 graft-versus-host disease at day 100, gastrointestinal graft-versus-host disease (any stage), and 100-day overall survival. In addition, we administered an investigator-created survey to evaluate food cravings, nausea, diet limitations, and subjective quality of life. In total, 102 patients underwent hematopoietic stem cell transplant during the study period. Forty-nine (48%) received the neutropenic diet and 53 (52%) the BMT diet. Other than more males receiving the neutropenic diet (67% versus 47%, P = 0.05), there were no statistical demographic and outcome differences between the 2 groups. Additionally, 46 subjects (45%) completed the investigator-created questionnaire. There was no difference in the perceived food cravings, nausea, diet limitations, and subjective quality of life between the 2 cohorts. These data demonstrate noninferiority of the modified BMT diet over the traditional neutropenic diet. We believe the food safety-based diet offers a greater variety of food, which may assist in the transition to a normal diet., (Copyright © 2019. Published by Elsevier Inc.)

Background: Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. Clarifying the viral, host, and environmental factors (epidemiologic triad) associated with severe outcomes can help target public health interventions., Methods: Acute norovirus outbreaks reported to the National Outbreak Reporting System (NORS) in 2009-2016 were linked to laboratory-confirmed norovirus outbreaks reported to CaliciNet. Outbreaks were analyzed for differences in genotype (GII.4 vs non-GII.4), hospitalization, and mortality rates by timing, setting, transmission mode, demographics, clinical symptoms, and health outcomes., Results: A total of 3747 norovirus outbreaks were matched from NORS and CaliciNet. Multivariable models showed that GII.4 outbreaks (n = 2353) were associated with healthcare settings (odds ratio [OR], 3.94 [95% confidence interval {CI}, 2.99-5.23]), winter months (November-April; 1.55 [95% CI, 1.24-1.93]), and older age of cases (≥50% aged ≥75 years; 1.37 [95% CI, 1.04-1.79]). Severe outcomes were more likely among GII.4 outbreaks (hospitalization rate ratio [RR], 1.54 [95% CI, 1.23-1.96]; mortality RR, 2.77 [95% CI, 1.04-5.78]). Outbreaks in healthcare settings were also associated with higher hospitalization (RR, 3.22 [95% CI, 2.34-4.44]) and mortality rates (RR, 5.65 [95% CI, 1.92-18.70])., Conclusions: Severe outcomes more frequently occurred in norovirus outbreaks caused by GII.4 and those in healthcare settings. These results should help guide preventive interventions for targeted populations, including vaccine development., (Published by Oxford University Press for the Infectious Diseases Society of America 2018.)

Disability adjusted life years (DALYs) have been used since the 1990s. It is a composite measure of years of life lost with years lived with disability. Essentially, one DALY is the equivalent of a year of healthy life lost if a person had not experienced disease. Norovirus is the most common cause of gastrointestinal diseases worldwide. Norovirus activity varies from one season to the next for reasons not fully explained. Infection with norovirus is generally not severe, and is normally characterized as mild and self-limiting with no long-term sequelae. In this study, we model a range of estimates of DALYs for community cases of norovirus in England and Wales. We estimated a range of DALYs for norovirus to account for mixing of the severity of disease and the range of length of illness experienced by infected people. Our estimates were between 1159 and 4283 DALYs per year, or 0.3⁻1.2 years of healthy life lost per thousand cases of norovirus. These estimates provide evidence that norovirus leads to a considerable level of ill health in England and Wales. This information will be helpful should candidate norovirus vaccines become available in the future., Competing Interests: The authors declare no conflict of interest.

Objective: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking., Method: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group., Results: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/μL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy., Conclusion: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI., (Copyright © 2018. Published by Elsevier Inc.)

Background: Prior to 2010, the lagoviruses that cause rabbit hemorrhagic disease (RHD) in European rabbits (Oryctolagus cuniculus) and European brown hare syndrome (EBHS) in hares (Lepus spp.) were generally genus-specific. However, in 2010, rabbit hemorrhagic disease virus 2 (RHDV2), also known as Lagovirus europaeus GI.2, emerged and had the distinguishing ability to cause disease in both rabbits and certain hare species. The mountain hare (Lepus timidus) is native to Sweden and is susceptible to European brown hare syndrome virus (EBHSV), also called Lagovirus europaeus GII.1. While most mountain hare populations are found on the mainland, isolated populations also exist on islands. Here we investigate a mortality event in mountain hares on the small island of Hallands Väderö where other leporid species, including rabbits, are absent., Results: Post-mortem and microscopic examination of three mountain hare carcasses collected from early November 2016 to mid-March 2017 revealed acute hepatic necrosis consistent with pathogenic lagovirus infection. Using immunohistochemistry, lagoviral capsid antigen was visualized within lesions, both in hepatocytes and macrophages. Genotyping and immunotyping of the virus independently confirmed infection with L. europaeus GI.2, not GII.1. Phylogenetic analyses of the vp60 gene grouped mountain hare strains together with a rabbit strain from an outbreak of GI.2 in July 2016, collected approximately 50 km away on the mainland., Conclusions: This is the first documented infection of GI.2 in mountain hares and further expands the host range of GI.2. Lesions and tissue distribution mimic those of GII.1 in mountain hares. The virus was most likely initially introduced from a concurrent, large-scale GI.2 outbreak in rabbits on the adjacent mainland, providing another example of how readily this virus can spread. The mortality event in mountain hares lasted for at least 4.5 months in the absence of rabbits, which would have required virus circulation among mountain hares, environmental persistence and/or multiple introductions. This marks the fourth Lepus species that can succumb to GI.2 infection, suggesting that susceptibility to GI.2 may be common in Lepus species. Measures to minimize the spread of GI.2 to vulnerable Lepus populations therefore are prudent.

European rabbits (Oryctolagus cuniculus) are severely affected by rabbit haemorrhagic disease (RHD). Caused by a lagovirus, the disease leads to losses in the rabbit industry and has implications for wildlife conservation. Past RHD outbreaks have been caused by GI.1/RHDV genotype viruses. A new virus belonging to the GI.2/RHDV2/b genotype emerged in 2010, quickly spreading and replacing the former in several countries; however, limited data are available on its pathogenicity and epidemiological factors. The present work extends these issues and evaluates cross-protection between both genotypes. Ninety-four and 88 domestic rabbits were challenged with GI.2/RHDV2/b and GI.1b/RHDV variant isolates, respectively. Cross-protection was determined by a second challenge on survivors with the corresponding strain. Mortality by GI.2/RHDV2/b was highly variable due to unknown individual factors, whereas mortality by GI.1b/RHDV was associated with age. Mortality in rabbits < 4 weeks old was 84%, higher than previously reported. Cross-protection was not identical between the two viruses because the ratio of mortality rate ratios for the first and second challenges was 3.80 ± 2.68 times higher for GI.2/RHDV2/b than it was for GI.1b/RHDV. Rabbit susceptibility to GI.2/RHDV2/b varied greatly and appeared to be modulated by the innate functionality of the immune response and/or its prompt activation by other pathogens. GI.1b/RHDV pathogenicity appeared to be associated with undetermined age-related factors. These results suggest that GI.2/RHDV2/b may interact with other pathogens at the population level but does not satisfactorily explain the GI.1b/RHDV virus's quick replacement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mortality caused by rabbit haemorrhagic disease virus (RHDV) in wild rabbits is reduced in parts of Australia where the related, non-pathogenic calicivirus RCV-A1 is endemic. Laboratory experiments previously showed that prior infection with RCV-A1 enabled rabbits to better withstand subsequent infection with highly virulent RHDV, and this was assumed to explain higher survival. Here, we analyse serological data from the field suggesting that reduced mortality rates among wild rabbits may also result from rabbits previously infected with RCV-A1 having a reduced likelihood of RHDV infection. We discuss the possible mechanisms underlying this finding and its implications. The methods we describe for analysing field data gave far greater insights into epidemiological processes and virus interactions than gained from reporting basic seroprevalence rates alone., (© 2017 Blackwell Verlag GmbH.)

Norovirus is a leading cause of childhood vomiting and diarrhea in the United States and globally. Although most illnesses caused by norovirus are self-resolving, severe outcomes may occur from dehydration, including hospitalization and death. A vast majority of deaths from norovirus occur in developing countries. Immunocompromised children are at risk for more severe outcomes. Treatment of norovirus illness is focused on early correction of dehydration and maintenance of fluid status and nutrition. Hand hygiene, exclusion of ill individuals, and environmental cleaning are important for norovirus outbreak prevention and control, and vaccines to prevent norovirus illness are currently under development., (Published by Elsevier Inc.)

Human noroviruses are highly efficient in person to person transmission thus associated with explosive outbreaks of acute gastroenteritis. Outbreak control is limited to disinfection and isolation measures. Strategies to control the spread of noroviruses should be developed and models to study norovirus transmission will greatly facilitate this. Here, a mouse-to-mouse transmission model, in which mice develop acute murine norovirus (MNV)-induced diarrhea, was used to explore the role of interferon lambda (IFN-λ) in the control of a norovirus infection. Sentinel AG129 mice [deficient in IFN-α/β and IFN-γ receptors] that were co-housed with MNV-infected mice shedding high amounts of virus in their stool, developed a MNV-infection with associated diarrhea. Inoculation of such sentinel mice with an IFN-λ expression plasmid resulted in the production of circulating IFN-λ and upregulation of the expression of IFN-stimulated genes (ISGs) of the gut. Injection of the IFN-λ-expressing plasmid to sentinels prevents MNV-induced disease upon exposure to MNV-infected mice, as well as MNV replication in the small intestine, the associated signs of inflammation and the mounting of a specific IgG-based immune response. This demonstrates that IFN-λ can alone mediate protection against transmission of norovirus. The development of a simple delivery method for IFN-λ could be explored as a strategy to control norovirus outbreaks and protect vulnerable populations such as the elderly and immunocompromised., (Copyright © 2017. Published by Elsevier B.V.)

Background: In the regular wildlife monitoring action carried out in the summer of the past few years at the Berlenga Island, wild rabbits (Oryctolagus cuniculus) have been repeatedly found dead. However, the origin of those deaths was never investigated. Our aim was to investigate the cause of death of 11 rabbits collected between April and May 2016., Results: While screening samples from rabbit carcasses for the major viral rabbit pathogens, five tested positive to RHDV2 but all were negative for RHDV and myxoma virus (MYXV). For six RHDV2-negative specimens, emaciation and parasitism were considered the most probable cause of death. Lesions identified in the RHDV2-positive rabbits included non-suppurative diffuse hepatic necrosis and pulmonary lesions varying from congestion and oedema of the lungs to interstitial pneumonia. Sequencing analysis of the vp60 gene obtained from two specimens showed identical vp60 sequences. Comparison with other known RHDV2 strains from public databases through BLAST analysis revealed a closer similarity with strains from Alentejo collected during 2013. Maximum Likelihood and Bayesian phylogenetic analysis showed that the 2016 strains from the archipelago have a higher resemblance with a group of strains mostly collected in the South of Portugal between 2013 and 2014., Conclusion: The results suggest that RHDV2 may have been introduced on the Berlenga Island a few years ago, having evolved separately from mainland strains due to insularity.

Background: No data are available on clinical manifestations and course of norovirus gastroenteritis (NVE) in intestinal allograft (from intestinal and multivisceral transplant recipients, ITR) compared to native intestine (from other allograft recipients, nITR)., Methods: This was a retrospective study of solid organ transplant recipients with NVE at two centers from January 1, 2010 to April 1, 2014. Chi-square, t-test, linear and logistic regression analyses were done to compare NVE in ITR vs nITR patients., Results: The ITR (45 patients) were compared to nITR (107 patients). ITR were younger (odds ratio [OR]=0.90; P<.0001), less likely to receive anti-lymphocyte induction therapy (OR=0.15; P<.0001), and had shorter time from transplant to NVE (OR=0.99; P=.008). On presentation ITR had less frequent nausea (OR=0.11; P<.0001) or vomiting (OR=0.36; P=.01), higher white blood cell count (OR=1.09; P=.001), and higher glomerular filtration rate (OR=1.02; P<.0001). ITR were less likely to receive anti-motility agents (OR=9.6; P<.0001). ITR were more likely to stay longer on intravenous (IV) fluids (OR=1.18; P<.0001); have recurrent NVE (OR=4.25; P<.0001); have longer hospital stay (OR=1.07; P<.0001); develop acute rejection (OR=5.1; P=.006); and have lower overall survival (OR=0.28; P=.006)., Conclusions: Compared to nITR, the ITR with NVE were significantly younger, had less nausea and vomiting at presentation, received less anti-motility agents, required more IV fluids, and had longer hospital stay. A trend was seen for lower survival with NVE in ITR., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Norovirus (NoV) is gaining recognition as an important cause of diarrhea among solid organ transplant (SOT) recipients, but existing studies have been limited by a small sample size., Methods: We conducted a retrospective study of all adult SOT recipients diagnosed with NoV between 2006 and 2013 and compared their data to that of adult SOT recipients with diarrhea who tested negative for NoV during that time., Results: A total of 192 patients with diarrhea had stool NoV testing as part of their work-up during the study period; of these patients, 35% (67) tested positive for NoV. Of patients with diarrhea without NoV, Clostridium difficile (25%) and cytomegalovirus (12%) were the most commonly identified infectious cause of diarrhea. Diarrheal duration was significantly protracted in NoV patients, with an average of 241 days vs 75 days in the control group (P=.0007). One patient death and 2 graft failures were related to the NoV illness within the first month after the onset of diarrhea, and 30% of NoV patients had a ≥20% increase in creatinine within 1 year of diagnosis. These outcomes did not differ significantly from those of SOT patients with diarrhea in the non-NoV group., Conclusions: NoV is a common cause of diarrhea among SOT recipients at our institution and is responsible for a very prolonged course of chronic diarrhea., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Rabbit hemorrhagic disease virus (RHDVb) is the new variant of the classical RHDV, a virulent pathogen responsible for an acute disease in young rabbits. The virus invades internal organs, especially the liver, spleen, kidneys, and gut; prevents coagulation; and causes liver necrosis. This eventually leads to quick death of the animal because of hemorrhage. In this study, we evaluated the effects of a new vaccine against RHDVb in rabbits at a young age, after experimental infection using four different viral isolates. Our findings show that the vaccine had a protective effect with survival rates reaching 80-100% against the different isolates. These results suggest that this vaccine, when applied to young animals, is an effective tool to protect against the disease caused by RHDVb in rabbitries.

Noroviruses are a leading cause of gastroenteritis across the world in all age groups and are linked to increased hospitalization and mortality in children, the elderly and immunocompromised. The development of specific antiviral treatment for norovirus gastroenteritis is urgently needed. We explored in a mouse model whether an inhibitor of norovirus replication could be used therapeutically post murine norovirus (MNV)-infection of mice. Using the MNV, we previously discovered that the viral polymerase inhibitor 2'-C-methylcytidine (2CMC) is able to protect against diarrhea and mortality in mice when used prophylactically and to block the transmission of MNV between mice. Here, we investigated whether 2CMC could be used therapeutically, starting treatment between 12 h and 3 days post-infection with 2CMC. Post-exposure treatment of MNV-infected mice with 2CMC was efficient up to 2 days after infection, preventing norovirus-induced diarrhea, delaying and reducing MNV shedding in stool of treated mice. Rehydration of 2CMC-treated animals did not result in a further improvement of the disease evolution compared to antiviral treatment only. The presence of MNV antigens and inflammation in the small intestine of infected mice inversely correlated with the effectiveness of delayed antiviral treatment. Anti-MNV IgGs were detected in re-challenged mice 10 weeks after the first contact, these protected the mice from re-infection. We here demonstrate the benefit of antiviral treatment in ongoing norovirus infections., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Diarrhoeal diseases are major contributors to the global burden of disease, particularly in children. However, comprehensive estimates of the incidence and mortality due to specific aetiologies of diarrhoeal diseases are not available. The objective of this study is to provide estimates of the global and regional incidence and mortality of diarrhoeal diseases caused by nine pathogens that are commonly transmitted through foods., Methods and Findings: We abstracted data from systematic reviews and, depending on the overall mortality rates of the country, applied either a national incidence estimate approach or a modified Child Health Epidemiology Reference Group (CHERG) approach to estimate the aetiology-specific incidence and mortality of diarrhoeal diseases, by age and region. The nine diarrhoeal diseases assessed caused an estimated 1.8 billion (95% uncertainty interval [UI] 1.1-3.3 billion) cases and 599,000 (95% UI 472,000-802,000) deaths worldwide in 2010. The largest number of cases were caused by norovirus (677 million; 95% UI 468-1,153 million), enterotoxigenic Escherichia coli (ETEC) (233 million; 95% UI 154-380 million), Shigella spp. (188 million; 95% UI 94-379 million) and Giardia lamblia (179 million; 95% UI 125-263); the largest number of deaths were caused by norovirus (213,515; 95% UI 171,783-266,561), enteropathogenic E. coli (121,455; 95% UI 103,657-143,348), ETEC (73,041; 95% UI 55,474-96,984) and Shigella (64,993; 95% UI 48,966-92,357). There were marked regional differences in incidence and mortality for these nine diseases. Nearly 40% of cases and 43% of deaths caused by these nine diarrhoeal diseases occurred in children under five years of age., Conclusions: Diarrhoeal diseases caused by these nine pathogens are responsible for a large disease burden, particularly in children. These aetiology-specific burden estimates can inform efforts to reduce diarrhoeal diseases caused by these nine pathogens commonly transmitted through foods.

Background: Noroviruses (NoVs) are the most common cause of acute gastroenteritis (AGE) causing both sporadic and outbreak-associated illness. Norovirus (NoV) infections occur across all ages but certain sub-groups are considered at increased risk due to heightened transmission and/or symptom severity. Older adults are potentially at high risk of NoV-associated illness due to frequent outbreaks in long-term care facilities (LTCFs) and severe health outcomes following infection. Elucidation of NoV risk among older adults will support prevention, treatment and control efforts., Methods: We conducted a systematic literature review to summarize the published risk estimates of NoV-associated illness, hospitalization and death among individuals aged 65 years and older. A structured search using defined NoV and gastroenteritis (GE) terms was performed in the PubMed and EMBASE databases of human studies published between January 1, 2003 and May 16, 2013., Results: We identified 39 studies from high income (HI) and upper-middle income (UMI) countries. Thirty-six percent of publications provided risk estimates based on laboratory-confirmed or epidemiologically-linked population-based surveillance data using molecular diagnostic methods. Over the study period, estimated annual NoV rates and extrapolated number of cases among older adults in HI and UMI countries were: 29-120/10,000 or 1.2-4.8 million NoV-associated illnesses; 18-54/10,000 or 723,000-2.2 million NoV-associated outpatient visits; 1-19/10,000 or 40,00-763,000 NoV-associated inpatient visits; 0.04-0.32/10,000 or 2000-13,000 NoV-associated deaths. NoV was responsible for approximately 10-20 % of GE hospitalizations and 10-15 % of all-cause GE deaths among older adults. Older adults experienced a heightened risk of nosocomial infections. Those in LTCFs experience frequent NoV outbreaks and the range in attack rates was 3-45 %, case hospitalization rates 0.5-6 % and case fatality rates 0.3-1.6 %., Conclusions: Older adults are at increased risk of severe NoV-associated health outcomes. NoV-associated hospitalization rates were higher, more severe, resulted in longer stays and incurred greater costs than for younger patients. NoV-associated mortality rates were approximately 200 % higher among individuals 65 years and older compared to <5 years. The burden of NoV among older adults is expected to rise along with societal aging and increased need for institutionalized care. NoV prevention in older adults, including potential vaccination, may significantly impact risk of severe illness.

A descriptive study was performed between 1 January 2010 and 31 December 2011 to estimate the incidence of norovirus outbreaks in hospitals and nursing homes in Catalonia (Spain). Epidemiological surveys were done for each outbreak. Norovirus was confirmed using RT-PCR. The incidence of outbreaks/106 person-years by centre, and the attack rate, were calculated. Statistically significant differences were calculated using odds ratio (ORs) and 95% confidence intervals (CIs). Person-to-person transmission was responsible for 81·5% (22/27) of outbreaks. The incidence in the population was 156·7 outbreaks/106 person-years. The incidence by centre was 1·3% per year and was greater in hospitals (2·6%) than in nursing homes (0·9%) (OR 3·2, 95% CI 1·5-6·9). The global attack rate in residents and staff was 34·7% (816/2348). The mortality rate was 0·25% (2/816). Genogroup GII.4 caused 66·7% of outbreaks. Norovirus GII.4 outbreaks cause significant morbidity affecting both patients and staff.

Norovirus infection in humans typically results in acute gastroenteritis but may also occur in many animal species. Noroviruses are recognized as one of the most common causes of acute gastroenteritis in the world, being responsible for almost 20% of all cases. Despite their prevalence and impact, our knowledge of the norovirus life cycle and the pathological processes associated with norovirus-induced disease is limited. Whilst infection of the intestine is the norm, extraintestinal spread and associated pathologies have also been described. In addition, long-term chronic infections are now recognized as a significant cause of morbidity and mortality in the immunocompromised. This review aims to summarize the current state of knowledge with respect to norovirus pathology and the underlying mechanisms that have been characterized to date., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Objective: To estimate and compare disease burden attributable to six gastrointestinal pathogens (norovirus, rotavirus, Campylobacter, non-typhoidal Salmonella, Giardia, and Cryptosporidium) in Australia, 2010., Methods: We estimated the number of acute gastroenteritis (AGE) cases and deaths, disability-adjusted life years (DALYs), and DALY/case for each pathogen. We included AGE cases that did not require medical care. Sequelae were included for Campylobacter (Guillain-Barré syndrome, reactive arthritis (ReA), irritable bowel syndrome (IBS)) and Salmonella (ReA, IBS)., Results: We estimated 16626069 AGE cases in Australia in 2010 (population 22 million). Of the pathogens studied, most AGE cases were attributed to norovirus (2180145), Campylobacter (774003), and Giardia (614740). Salmonella caused the fewest AGE cases (71255) but the most AGE deaths (90). The DALY burden was greatest for Campylobacter (18222 DALYs) and Salmonella (3856 DALYs), followed by the viral and protozoal pathogens. The average DALY/case was greatest for Salmonella (54.1 DALY/1000 cases), followed by Campylobacter (23.5 DALY/1000 cases)., Conclusions: The pathogen causing the greatest disease burden varied according to the metric used, however DALYs are considered most useful given the incorporation of morbidity, mortality, and sequelae. These results can be used to prioritize public health interventions toward Salmonella and Campylobacter infections and to measure the impact of these interventions.

Rabbit hemorrhagic disease is caused by a calicivirus, rabbit hemorrhagic disease virus (RHDV), which is responsible for high mortality in domestic and wild European rabbits (Oryctolagus cuniculus). RHDV strains were sequenced from wild European rabbits (Oryctolagus cuniculus algirus) collected in the Azorean island of Pico, Portugal. Phylogenetic analyses showed that the Pico RHDV strains diverge from all of the others described so far, but cluster with the genogroups 1-5 (G1-G5). The genetic distance between the Pico RHDV sequences and each G1, G2 and G3-G5 genogroup (~0.08) is compatible with an RHDV introduction at least 17 years ago. Our results show that in Pico, RHDV is the outcome of an independent evolution from the original RHDV strain that appeared in its European rabbit population. These are the first sequences of RHDV obtained in the subspecies O. c. algirus, outside of its original region, the Iberian Peninsula. Furthermore, we discuss the risk of rabbit translocations from the Azores to the Iberian Peninsula, where the rabbit wild populations are suffering high mortalities.

Human noroviruses are a major cause of food-borne illness, accountable for 50% of all-etiologies outbreaks of acute gastroenteritis (in both developing and developed countries). There is no vaccine or antiviral drug for the prophylaxis or treatment of norovirus-induced gastroenteritis. We recently reported the inhibitory effect of 2'-C-methylcytidine (2CMC), a hepatitis C virus polymerase inhibitor, on the in vitro replication of murine norovirus (MNV). Here we evaluated the inhibitory effect of 2CMC on in vitro human norovirus replication through a Norwalk virus replicon model and in a mouse model by using AG129 mice orally infected with MNV. Survival, weight, and fecal consistency were monitored, and viral loads in stool samples and organs were quantified. Intestines were examined histologically. 2CMC reduced Norwalk virus replicon replication in a dose-dependent manner and was able to clear cells of the replicon. Treatment of MNV-infected AG129 mice with 2CMC (i) prevented norovirus-induced diarrhea; (ii) markedly delayed the appearance of viral RNA and reduced viral RNA titers in the intestine, mesenteric lymph nodes, spleen, lungs, and stool; (iii) completely prevented virus-induced mortality; and (iv) resulted in protective immunity against a rechallenge. We demonstrate for the first time that a small-molecule inhibitor of norovirus replication protects from virus-induced disease and mortality in a relevant animal model. These findings pave the way for the development of potent and safe antivirals as prophylaxis and therapy of norovirus infection.

Estimation of pathogen-specific causes of child diarrhea deaths is needed to guide vaccine development and other prevention strategies. We did a systematic review of articles published between 1990 and 2011 reporting at least one of 13 pathogens in children <5 years of age hospitalized with diarrhea. We included 2011 rotavirus data from the Rotavirus Surveillance Network coordinated by WHO. We excluded studies conducted during diarrhea outbreaks that did not discriminate between inpatient and outpatient cases, reporting nosocomial infections, those conducted in special populations, not done with adequate methods, and rotavirus studies in countries where the rotavirus vaccine was used. Age-adjusted median proportions for each pathogen were calculated and applied to 712 000 deaths due to diarrhea in children under 5 years for 2011, assuming that those observed among children hospitalized for diarrhea represent those causing child diarrhea deaths. 163 articles and WHO studies done in 31 countries were selected representing 286 inpatient studies. Studies seeking only one pathogen found higher proportions for some pathogens than studies seeking multiple pathogens (e.g. 39% rotavirus in 180 single-pathogen studies vs. 20% in 24 studies with 5-13 pathogens, p<0.0001). The percentage of episodes for which no pathogen could be identified was estimated to be 34%; the total of all age-adjusted percentages for pathogens and no-pathogen cases was 138%. Adjusting all proportions, including unknowns, to add to 100%, we estimated that rotavirus caused 197 000 [Uncertainty range (UR) 110 000-295 000], enteropathogenic E. coli 79 000 (UR 31 000-146 000), calicivirus 71 000 (UR 39 000-113 000), and enterotoxigenic E. coli 42 000 (UR 20 000-76 000) deaths. Rotavirus, calicivirus, enteropathogenic and enterotoxigenic E. coli cause more than half of all diarrheal deaths in children <5 years in the world.

Although recognized as the leading cause of epidemic acute gastroenteritis across all age groups, norovirus has remained poorly characterized with respect to its endemic disease incidence. Use of different methods, including attributable proportion extrapolation, population-based surveillance, and indirect modeling, in several recent studies has considerably improved norovirus disease incidence estimates for the United States. Norovirus causes an average of 570-800 deaths, 56,000-71,000 hospitalizations, 400,000 emergency department visits, 1.7-1.9 million outpatient visits, and 19-21 million total illnesses per year. Persons >65 years of age are at greatest risk for norovirus-associated death, and children <5 years of age have the highest rates of norovirus-associated medical care visits. Endemic norovirus disease occurs year round but exhibits a pronounced winter peak and increases by ≤ 50% during years in which pandemic strains emerge. These findings support continued development and targeting of appropriate interventions, including vaccines, for norovirus disease.

The endemic non-pathogenic Australian rabbit calicivirus RCV-A1 is known to provide some cross protection to lethal infection with the closely related Rabbit Haemorrhagic Disease Virus (RHDV). Despite its obvious negative impacts on viral biocontrol of introduced European rabbits in Australia, little is known about the extent and mechanisms of this cross protection. In this study 46 rabbits from a colony naturally infected with RCV-A1 were exposed to RHDV. Survival rates and survival times did not correlate with titres of serum antibodies specific to RCV-A1 or cross reacting to RHDV, but were instead influenced by the time between infection with the two viruses, demonstrating for the first time that the cross protection to lethal RHDV infection is transient. These findings are an important step towards a better understanding of the complex interactions of co-occurring pathogenic and non-pathogenic lagoviruses.

Although deaths are often reported in the context of norovirus outbreaks, clinical and epidemiologic characteristics of the decedents prior to death are not well established. Through a literature review of published reports of deaths associated with norovirus infection, we identified and summarized 158 norovirus-associated deaths in 12 countries from 1988 to 2011., (Published by Mosby, Inc.)

Noroviruses are an important cause of acute gastroenteritis in humans. We incorporated new insights gained over the past decade in an updated estimate of the disease burden of (foodborne) norovirus illness in The Netherlands in 2009. The disease outcomes - non-consulting cases, visiting a general practitioner, hospitalization and mortality - and the foodborne proportion were derived from cohort studies, surveillance data and literature. Age-specific incidence estimates were applied to the population age distribution in The Netherlands in 2009. The general population incidence was 3800/100 000 (95% CI 2670–5460), including 0.4 fatal cases/100 000,resulting in 1622 (95% CI 966–2650) disability-adjusted life-years in a population of 16.5 million [corrected].The updated burden of norovirus is over twofold higher than previously estimated, due in particular to the new insights in case-fatality ratios. Results suggest that the burden of norovirus institutional outbreaks is relatively small compared to the burden of community-acquired norovirus infections.

Rabbit haemorrhagic disease is a major tool for the management of introduced, wild rabbits in Australia. However, new evidence suggests that rabbits may be developing resistance to the disease. Rabbits sourced from wild populations in central and southeastern Australia, and domestic rabbits for comparison, were experimentally challenged with a low 60 ID50 oral dose of commercially available Czech CAPM 351 virus - the original strain released in Australia. Levels of resistance to infection were generally higher than for unselected domestic rabbits and also differed (0-73% infection rates) between wild populations. Resistance was lower in populations from cooler, wetter regions and also low in arid regions with the highest resistance seen within zones of moderate rainfall. These findings suggest the external influences of non-pathogenic calicivirus in cooler, wetter areas and poor recruitment in arid populations may influence the development rate of resistance in Australia.

Context: Norovirus outbreaks are common among vulnerable, elderly populations in US nursing homes., Objectives: To assess whether all-cause hospitalization and mortality rates are increased during norovirus outbreak vs nonoutbreak periods in nursing homes, and to identify factors associated with increased risk., Design, Setting, and Participants: A retrospective cohort study of Medicare-certified nursing homes in Oregon, Wisconsin, and Pennsylvania that reported at least 1 confirmed or suspected norovirus outbreak to the Centers for Disease Control and Prevention's National Outbreak Reporting System (NORS), January 2009 to December 2010. Deaths and hospitalizations occurring among residents of these nursing homes were identified through the Medicare Minimum Data Set (MDS)., Main Outcome Measures: Rates of all-cause hospitalization and mortality during outbreak compared with nonoutbreak periods were estimated using a random-effects Poisson regression model controlling for background seasonality in both outcomes., Results: The cohort consisted of 308 nursing homes that reported 407 norovirus outbreaks to NORS. Per MDS, 67 730 hospitalizations and 26 055 deaths occurred in these homes during the 2-year study. Hospitalization rates were 124.0 (95% CI, 119.4-129.1) vs 109.5 (95% CI, 108.6-110.3) hospitalizations per nursing home−year during outbreak vs nonoutbreak periods, yielding a seasonally adjusted rate ratio (RR) of 1.09 (95% CI, 1.05-1.14). Similarly, mortality rates were 53.7 (95% CI, 50.6-57.0) vs 41.9 (95% CI, 41.4-42.4) deaths per nursing home−year in outbreak vs nonoutbreak periods (seasonally adjusted RR, 1.11; 95% CI, 1.05-1.18). The increases in hospitalizations and mortality were concentrated in the first 2 weeks (week 0 and 1) and the initial week (week 0) of the outbreak, respectively. Homes with lower daily registered nurse (RN) hours per resident (<0.75) had increased mortality rates during norovirus outbreaks compared with baseline (RR, 1.26; 95% CI, 1.14-1.40), while no increased risk (RR, 1.03; 95% CI, 0.96-1.12) was observed in homes with higher daily RN hours per resident (P = .007 by likelihood ratio test); the increase in hospitalization rates did not show a similar pattern., Conclusion: Norovirus outbreaks were associated with significant concurrent increases in all-cause hospitalization and mortality in nursing homes.

Background: Norovirus enteritis (NVE) can be fatal in frail patients. High blood lactate levels indicate hypoperfusion and predict mortality in many infectious diseases. The objective was to determine the frequency and association with mortality of elevated lactate levels in patients with community-onset NVE., Methods: A retrospective cohort study was performed. All hospitalized adult patients with community-onset NVE verified by polymerase chain reaction during the period August 2008 to June 2009 were included. Vital signs and venous lactate on arrival, co-morbid conditions, and time of death were registered. The outcome measure was 30-day all-cause mortality., Results: Eighty-two patients with a median age of 77 y (interquartile range (IQR) 53-86 y) were included, of whom 47 (57%) were female and 49 (60%) had at least 1 major co-morbid condition. Lactate levels were above the upper limit of normal (ULN; 1.6 mmol/l) in 45 patients (55%). The overall 30-day mortality rate was 7% (6/82). Mortality was 18% (5/28) with lactate ≥ 2.4 mmol/l (> 50% above the ULN) on admission compared to 2% (1/54) with lactate < 2.4 mmol/l (p < 0.05). Patients who died had a higher median lactate level compared to survivors: 4.5 (IQR 2.7-7.9) mmol/l vs 1.7 (IQR 1.3-2.5) mmol/l, respectively (p < 0.01). The adjusted odds ratio for death within 30 days for a 1 mmol/l increase in lactate was 2.5 (95% confidence interval 1.003-6.3, p = 0.049)., Conclusions: We observed a high proportion of patients with elevated lactate levels in community-onset NVE. Lactate elevation could predict mortality. Measurement of blood lactate may be a valuable tool in the clinical management of patients with a suspected norovirus infection.

Background: Because there may be substantial hidden mortality caused by common seasonal pathogens, we estimated the number of deaths in elderly persons attributable to viruses and bacteria for which robust weekly laboratory surveillance data were available., Methods: On weekly time series (1999-2007) we used regression models to associate total death counts in individuals aged 65-74, 75-84, and ≥85 years (a population of 2.5 million) with pathogen circulation-influenza A (season-specific), influenza B, respiratory syncytial virus (RSV), parainfluenza, enterovirus, rotavirus, norovirus, Campylobacter, and Salmonella-adjusted for extreme outdoor temperatures., Results: Influenza A and RSV were significantly (P < .05) associated with mortality in all studied age groups; influenza B and parainfluenza were additionally associated in those aged ≥75 years, and norovirus was additionally associated in those aged ≥85 years. The proportions of deaths attributable to seasonal viruses were 6.8% (≥85 years), 4.4% (75-84 years), and 1.4% (65-74 years), but with great variations between years. Influenza occasionally showed lower impact than some of the other viruses., Conclusions: The number of different pathogens associated with mortality in the older population increases with increasing age. Besides influenza A and RSV, influenza B, parainfluenza and norovirus may also contribute substantially to elderly mortality.

Background: Globally, gastroenteritis is recognized as an important contributor to mortality among children, but population-based data on gastroenteritis deaths among adults and the contributions of specific pathogens are limited. We aimed to describe trends in gastroenteritis deaths across all ages in the United States and specifically estimate the contributions of Clostridium difficile and norovirus., Methods: Gastroenteritis-associated deaths in the United States during 1999-2007 were identified from the National Center for Health Statistics multiple-cause-of-death mortality data. All deaths in which the underlying cause or any of the contributing causes listed gastroenteritis were included. Time-series regression models were used to identify cause-unspecified gastroenteritis deaths that were probably due to specific causes; seasonality of model residuals was analyzed to estimate norovirus-associated deaths., Results: Gastroenteritis mortality averaged 39/1000000 person-years (11 255 deaths per year) during the study period, increasing from 25/1 000 000 person-years in 1999-2000 to 57/1 000 000 person-years in 2006-2007 (P < .001). Adults aged ≥ 65 years accounted for 83% of gastroenteritis deaths (258/1 000 000 person-years). C. difficile mortality increased 5-fold from 10/1 000 000 person-years in 1999-2000 to 48/1 000 000 person-years in 2006-2007 (P < .001). Norovirus contributed to an estimated 797 deaths annually (3/1 000 000 person-years), with surges by up to 50% during epidemic seasons associated with emergent viral strains., Conclusions: Gastroenteritis-associated mortality has more than doubled during the past decade, primarily affecting the elderly. C. difficile is the main contributor to gastroenteritis-associated deaths, largely accounting for the increasing trend, and norovirus is probably the second leading infectious cause. These findings can help guide appropriate clinical management strategies and vaccine development.

Background: Noroviruses (NoVs) are the most common cause of epidemic gastroenteritis; however, the relative impacts of individual factors underlying severe illness are poorly understood. This report reviews published NoV outbreak reports to quantify hospitalization and mortality rates and assess their relationship with outbreak setting, transmission route, and strain., Methods: Using a string of terms related to "norovirus" and "outbreak," we 2435 nonduplicate articles identified in PubMed, EMBASE, and Web of Knowledge published between January 1993 and June 2011. Inclusion criteria included outbreaks with a minimum of 2 ill persons with a common exposure and at least 1 reverse-transcription polymerase chain reaction-confirmed case of NoV disease. Univariate analyses were performed, and multivariable models were fitted to estimate the independent effect of each factor., Results: We analyzed 843 NoV outbreaks reported in 233 published articles from 45 countries. Based upon 71724 illnesses, 501 hospitalizations, and 45 deaths, overall hospitalization and mortality rates were 0.54% and 0.06%, respectively. In multivariate analysis, genogroup 2 genotype 4 (GII.4) NoV strains were associated with higher hospitalization (incidence rate ratio [IRR], 9.4; 95% confidence interval [CI], 6.1-14.4; P< .001) and mortality rates (IRR, 3.1; 95% CI, 1.3-7.6; P = .01). Deaths were much more likely to occur in outbreaks occurring in healthcare facilities (IRR, 60; 95% CI, 6-109; P = .01)., Conclusions: Our review suggests that hospitalizations and deaths were more likely in outbreaks associated with GII.4 viruses, independent of other factors, and underscores the importance of developing vaccines against GII.4 viruses to prevent severe disease outcomes.

The purpose of this study was to review documented outbreaks of enteric illness associated with nosocomial norovirus infections and to identify modes of transmission, morbidity and mortality patterns, and recommendations for control. Searches of electronic databases, public health publications, and federal, state/provincial public health websites were completed for 1 January 2000 to 31 December 2010. Computer-aided searches of literature databases and systematic searches of government websites identified 54 relevant outbreak reports. Transmission routes included person-to-person (18.5%), foodborne (3.7%) and in the majority (77.8%) the route was unknown. Actions taken during the outbreak to control infection included restricting the movements of patients and staff (22.5%), enhanced environmental cleaning (13.6%) and hand hygiene (10.3%). Rapid identification of norovirus outbreaks in hospitals is vital for the immediate implementation of infection control measures and isolation of infected individuals in this mainly immunocompromised population. Studies that statistically evaluate infection control measures are needed.

1. Identifying general patterns of how and why survival rates vary across space and time is necessary to truly understand population dynamics of a species. However, this is not an easy task given the complexity and interactions of processes involved, and the interpopulation differences in main survival determinants. 2. Here, using European rabbits (Oryctolagus cuniculus) as a model and information from local studies, we investigated whether we could make inferences about trends and drivers of survival of a species that are generalizable to large spatio-temporal scales. To do this, we first focused on overall survival and then examined cause-specific mortalities, mainly predation and diseases, which may lead to those patterns. 3. Our results show that within the large-scale variability in rabbit survival, there exist general patterns that are explained by the integration of factors previously known to be important at the local level (i.e. age, climate, diseases, predation or density dependence). We found that both inter- and intrastudy survival rates increased in magnitude and decreased in variability as rabbits grow old, although this tendency was less pronounced in populations with epidemic diseases. Some causes leading to these higher mortalities in young rabbits could be the stronger effect of rainfall at those ages, as well as, other death sources like malnutrition or infanticide. 4. Predation is also greater for newborns and juveniles, especially in population without diseases. Apart from the effect of diseases, predation patterns also depended on factors, such as, density, season, and type and density of predators. Finally, we observed that infectious diseases also showed general relationships with climate, breeding (i.e. new susceptible rabbits) and age, although the association type varied between myxomatosis and rabbit haemorrhagic disease. 5. In conclusion, large-scale patterns of spatio-temporal variability in rabbit survival emerge from the combination of different factors that interrelate both directly and through density dependence. This highlights the importance of performing more comprehensive studies to reveal combined effects and complex relationships that help us to better understand the mechanisms underlying population dynamics., (© 2011 The Authors. Journal of Animal Ecology © 2011 British Ecological Society.)

Rabbit haemorrhagic disease (RHD) is an acute fatal disease of domestic and wild European rabbits (Oryctolagus cuniculus) caused by RHD virus (RHDV). Accurate assessment of immunity is of great importance for the conservation and control of wild rabbits. We evaluated a competitive ELISA (cELISA) against isotype ELISAs for assessing the protective immunity against the disease by challenging 50 wild-caught rabbits with a lethal dose of RHDV. Death or survival to the challenge was used as a criterion to determine the performance characteristics of the assay for the assessment of immunity in rabbits. At 1:10 dilution, a serum exhibiting ≥ 25% inhibition (1:10(25)) was regarded as the presence of RHDV-specific antibodies. Eleven of 16 (68.8%) rabbits with antibodies at 1:10(25) (<1:40) died of RHD. When the cut-off was moved from 25% to 50% inhibition (1:10(50)) at 1:10 serum dilution, the assay sensitivity, specificity and accuracy for the protective immunity were improved from 84%, 54.2% and 69.4% to 84%, 100% and 91.8%, respectively. We also demonstrated at the epitope amino acid sequence level why the presence of the RHDV-cross reactive benign rabbit calicivirus, which interfered with isotype ELISAs, had little impact on the specificity of the cELISA for the diagnosis of RHDV infection. The presence of RHDV-specific antibody at 1:10(50) by the cELISA is a reliable indicator for the protective immunity. In contrast to isotype ELISAs, the cELISA is a valuable specific tool for monitoring the herd immunity to RHD for the conservation and management of wild rabbits in the field., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Rabbit hemorrhagic disease virus (RHDV) causes lethal fulminant hepatitis closely resembling acute liver failure (ALF) in humans. In this study, we investigated whether cardiotrophin-1 (CT-1), a cytokine with hepatoprotective properties, could attenuate liver damage and prolong survival in virus-induced ALF. Twenty-four rabbits were infected with 2 × 10(4) hemagglutination units of RHDV. Twelve received five doses of CT-1 (100 μg/kg) starting at 12 h postinfection (hpi) (the first three doses every 6 h and then two additional doses at 48 and 72 hpi), while the rest received saline. The animals were analyzed for survival, serum biochemistry, and viral load. Another cohort (n = 22) was infected and treated similarly, but animals were sacrificed at 30 and 36 hpi to analyze liver histology, viral load, and the expression of factors implicated in liver damage and repair. All infected rabbits that received saline died by 60 hpi, while 67% of the CT-1-treated animals survived until the end of the study. Treated animals showed improved liver function and histology, while the viral loads were similar. In the livers of CT-1-treated rabbits we observed reduction of oxidative stress, diminished PARP1/2 and JNK activation, and decreased inflammatory reaction, as reflected by reduced expression of tumor necrosis factor alpha, interleukin-1β, Toll-like receptor 4, VCAM-1, and MMP-9. In addition, CT-1-treated rabbits exhibited marked upregulation of TIMP-1 and increased expression of cytoprotective and proregenerative growth factors, including platelet-derived growth factor B, epidermal growth factor, platelet-derived growth factor receptor β, and c-Met. In conclusion, in a lethal form of acute viral hepatitis, CT-1 increases animal survival by attenuating inflammation and activating cytoprotective mechanisms, thus representing a promising therapy for ALF of viral origin.

Norovirus has been associated with excess deaths. A retrospective study of mortality following norovirus enteritis (NVE) was undertaken. All hospitalized adult patients with a stool sample positive for norovirus genogroup II on polymerase chain reaction, treated at Sahlgrenska University Hospital, Gothenburg, Sweden between August 2008 and June 2009, were included as cases (N = 598, aged 18-101 years). Matched controls without enteritis (N = 1196) were selected for comparison. Medical records were reviewed and deaths up to 90 days following positive sampling were noted, as well as comorbidities and length of hospital stay. Thirty- and 90-day survival rates were calculated. Total 30-day mortality was 7.6% and no deaths were recorded in cases aged 18-59 years. Thirty-day mortality was higher in cases with underlying medical conditions compared with those without these comorbidities (age 60-101 years: 89.5% vs 94.7% alive at Day 30, respectively; P < 0.05). In cases aged > 80 years, mortality was higher in those with community-onset NVE (N = 64) compared with hospital-onset NVE (N = 305) (81.2% vs 90.2% alive at Day 30, respectively; P < 0.05), and compared with controls (N = 128) (81.2% vs 91.4% alive at Day 30, respectively; P < 0.05). Median length of hospital stay was 20 [interquartile range (IQR) 12-29] days for cases with hospital-onset NVE, and seven (IQR 2-13) days for controls (P < 0.001). In conclusion, community-onset NVE requiring hospitalization was associated with higher mortality compared with hospital-onset NVE and matched controls in hospitalized elderly patients., (Copyright © 2011 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

This paper describes morbidity and mortality parameters for Campylobacter spp., Salmonella spp., enterohaemorrhagic Escherichia coli, Listeria spp., norovirus infections and their primary associated sequelae [Guillain-Barré syndrome (GBS), haemolytic uraemic syndrome, reactive arthropathies and Reiter's syndrome]. Data from a period of 4 years were obtained from three national databases to estimate percentage of reported cases hospitalized, mean annual hospitalization incidence rate, frequency of hospitalization by age and sex, and number of deaths. The length of hospital stay, discharge disposition, hospitalization age, and number of diagnoses per case were also extracted and summarized. In addition, we estimated that each year in Canada, there are between 126 and 251 cases of Campylobacter-associated GBS. This study provides morbidity and mortality estimates for the top enteric pathogens in Canada, including their associated sequelae, which can contribute to the quantification of the burden of illness.

Outbreaks of viral gastroenteritis occur regularly in residential care facilities (RCFs), with norovirus being the most common agent. Notification of outbreaks to public health authorities is encouraged in Australia, although there is limited evidence that this results in public health benefit. The aim of this study was to investigate if prompt notification of suspected norovirus outbreaks to public health authorities is associated with a reduction in either the duration or attack rate of outbreaks. Viral gastroenteritis outbreaks notified from Queensland RCFs between 2004 and 2007 were analysed. Foodborne outbreaks were excluded, along with 6 outbreaks where viruses other than norovirus were identified as the causative agent. Of the 264 remaining outbreaks, 70.8% were laboratory-confirmed as being due to norovirus. The average time to notification was 4 days and the average duration of outbreaks was 12 days. Outbreaks notified promptly (within 1 day) were of significantly shorter duration compared with outbreaks notified within 2-3 days (P < 0.02) or 4 or more days (P < 0.001). Early notification of outbreaks was not significantly associated with a reduced attack rate, however there was a significantly higher attack rate in facilities with less than 150 individuals at risk compared with facilities with 150 or more individuals at risk (30% versus 18%, respectively; P < 0.001). The shorter duration of promptly notified outbreaks provides some evidence to support recommendations from best practice guidelines for prompt notification of outbreaks by RCFs. However, further research is needed to unravel the interplay of factors that may influence the severity of viral gastroenteritis outbreaks in RCFs.

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 2·0, 95% CI 1·4-3·0) and age >70 (RR 1·7, 95% CI 1·2-2·2) 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 3·9, 95% CI 1·2-13·0). Mortality was higher in cases infected during the pilgrimage compared to other residents (RR 20·9, 95% CI 4·7-93·8). 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.