Incidence of Norovirus-Associated Medical Encounters among Active Duty United States Military Personnel and Their Dependents

BackgroundNorovirus is a leading cause of gastroenteritis episodes and outbreaks in US military deployments, but estimates of endemic disease burden among military personnel in garrison are lacking.MethodsDiagnostic codes from gastroenteritis-associated medical encounters of active duty military personnel and their beneficiaries from July 1998–June 2011 were obtained from the Armed Forces Health Surveillance Center. Using time-series regression models, cause-unspecified encounters were modeled as a function of encounters for specific enteropathogens. Model residuals (representing unexplained encounters) were used to estimate norovirus-attributable medical encounters. Incidence rates were calculated using population data for both active duty and beneficiary populations.ResultsThe estimated annual mean rate of norovirus-associated medically-attended visits among active duty personnel and their beneficiaries was 292 (95% CI: 258 to 326) and 93 (95% CI: 80 to 105) encounters per 10,000 persons, respectively. Rates were highest among beneficiaries <5 years of age with a median annual rate of 435 (range: 318 to 646) encounters per 10,000 children. Norovirus was estimated to cause 31% and 27% of all-cause gastroenteritis encounters in the active duty and beneficiary populations, respectively, with over 60% occurring between November and April. There was no evidence of any lag effect where norovirus disease occurred in one population before the other, or in one beneficiary age group before the others.ConclusionsNorovirus is a major cause of medically-attended gastroenteritis among non-deployed US military active duty members as well as in their beneficiaries.     

Incidence of Norovirus and Other Viral Pathogens That Cause Acute Gastroenteritis (AGE) among Kaiser Permanente Member Populations in the United States, 2012–2013

Noroviruses and other viral pathogens are increasingly recognized as frequent causes of acute gastroenteritis (AGE). However, few laboratory-based data are available on the incidence of AGE caused by viral pathogens in the U.S. This study examined stool specimens submitted for routine clinical diagnostics from patients enrolled in Kaiser Permanente (KP) health plans in metro Portland, OR, and the Maryland, District of Columbia, and northern Virginia geographic areas to estimate the incidence of viral enteropathogens in these populations. Over a one-year study period, participating laboratories randomly selected stools submitted for routine clinical diagnostics for inclusion in the study along with accompanying demographic and clinical data. Selected stools were tested for norovirus, rotavirus, sapovirus, and astrovirus using standardized real-time RT-PCR protocols. Each KP site provided administrative data which were used in conjunction with previously published data on healthcare utilization to extrapolate pathogen detection rates into population-based incidence rates. A total of 1,099 specimens collected during August 2012 to September 2013 were included. Mean age of patients providing stool specimens was 46 years (range: 0–98 years). Noroviruses were the most common viral pathogen identified among patients with AGE (n = 63 specimens, 6% of specimens tested). In addition, 22 (2%) of specimens were positive for rotavirus; 19 (2%) were positive for sapovirus; and 7 (1%) were positive for astrovirus. Incidence of norovirus-associated outpatient visits was 5.6 per 1,000 person-years; incidence of norovirus disease in the community was estimated to be 69.5 per 1,000 person-years. Norovirus incidence was highest among children <5 years of age (outpatient incidence = 25.6 per 1,000 person-years; community incidence = 152.2 per 1,000 person-years), followed by older adults aged >65 years (outpatient incidence = 7.8 per 1,000 person-years; community incidence = 75.8 per 1,000 person-years). Outpatient incidence rates of rotavirus, sapovirus, and astrovirus were 2.0, 1.6, 0.6 per 1,000 person-years, respectively; community incidence rates for these viruses were 23.4, 22.5, and 8.5 per 1,000 person-years, respectively. This study provides the first age-group specific laboratory-based community and outpatient incidence rates for norovirus AGE in the U.S. Norovirus was the most frequently detected viral enteropathogen across the age spectrum with the highest rates of norovirus disease observed among young children and, to a lesser extent, the elderly. These data provide a better understanding of the norovirus disease burden in the United States, including variations within different age groups, which can help inform the development, targeting, and future impacts of interventions, including vaccines.     

Prevalence of rotavirus and norovirus antibodies in non-human primates

Rotavirus and norovirus are associated with a substantial burden of diarrheal disease in humans and some animals, but their role in acute viral gastroenteritis in non-human primates has not been established. We examined sera from five species of Old and New World monkeys and chimpanzees for antibodies to rotavirus and norovirus by enzyme immunoassays using RRV and three recombinant human norovirus capsid proteins, respectively. Most (88%) of the 3 Old World monkey species (mangabey, pigtail, and rhesus) and apes were seropositive for rotavirus. Norovirus antibody was prevalent in the three monkey species, with 53% (44/83) and 58% (48/83) seropositive for GI and GII strains, respectively. Eleven (92%) of the 12 chimpanzees tested were seropositive for GI norovirus. Given the high rate of infection with both viruses, the role of these agents in causing acute gastroenteritis in non-human primates and the value of these animals as models of infection and disease need to be assessed.     

Molecular epidemiology of norovirus in South Korea

Norovirus is a major cause of viral gastroenteritis and a common cause of foodborne and waterborne outbreaks. Norovirus outbreaks are responsible for economic losses, most notably to the public health and food industry field. Norovirus has characteristics such as low infectious dose, prolonged shedding period, strong stability, great diversity, and frequent genome mutations. Besides these characteristics, they are known for rapid and extensive spread in closed settings such as hospitals, hotels, and schools. Norovirus is well known as a major agent of food-poisoning in diverse settings in South Korea. For these reasons, nationwide surveillance for norovirus is active in both clinical and environmental settings in South Korea. Recent studies have reported the emergence of variants and novel recombinants of norovirus. In this review, we summarized studies on the molecular epidemiology and nationwide surveillance of norovirus in South Korea. This review will provide information for vaccine development and prediction of new emerging variants of norovirus in South Korea. [BMB Reports 2015; 48(2): 61-67]     

Norovirus disease: changing epidemiology and host susceptibility factors

Noroviruses cause the majority of acute viral gastroenteritis cases that occur worldwide. The increased recognition of noroviruses as the cause of outbreaks and sporadic disease is due to the recent availability of improved norovirus-specific diagnostics. Transmission of these viruses is facilitated by their high prevalence in the community, shedding of infectious virus particles from asymptomatic individuals and the high stability of the virus in the environment. Currently, the spectrum of clinical disease and the understanding of host susceptibility factors are changing. Cases of chronic norovirus gastroenteritis have been observed in transplant recipients and unusual clinical presentations have been recognized in otherwise healthy adults that are under physical stress. Recently, noroviruses were found to bind to gut-expressed carbohydrates, leading to a correlation between a person's genetically determined carbohydrate expression and their susceptibility to Norwalk virus infection. Greater community surveillance and further investigation of carbohydrate receptor-binding properties could provide further insights into norovirus transmission, susceptibility and pathogenesis, and should aid in developing vaccines and antiviral therapies for this common viral disease.     

Global Economic Burden of Norovirus Gastroenteritis

BackgroundDespite accounting for approximately one fifth of all acute gastroenteritis illnesses, norovirus has received comparatively less attention than other infectious pathogens. With several candidate vaccines under development, characterizing the global economic burden of norovirus could help funders, policy makers, public health officials, and product developers determine how much attention and resources to allocate to advancing these technologies to prevent and control norovirus.MethodsWe developed a computational simulation model to estimate the economic burden of norovirus in every country/area (233 total) stratified by WHO region and globally, from the health system and societal perspectives. We considered direct costs of illness (e.g., clinic visits and hospitalization) and productivity losses.ResultsGlobally, norovirus resulted in a total of $4.2 billion (95% UI: $3.2–5.7 billion) in direct health system costs and $60.3 billion (95% UI: $44.4–83.4 billion) in societal costs per year. Disease amongst children <5 years cost society $39.8 billion, compared to $20.4 billion for all other age groups combined. Costs per norovirus illness varied by both region and age and was highest among adults ≥55 years. Productivity losses represented 84–99% of total costs varying by region. While low and middle income countries and high income countries had similar disease incidence (10,148 vs. 9,935 illness per 100,000 persons), high income countries generated 62% of global health system costs. In sensitivity analysis, the probability of hospitalization had the largest impact on health system cost estimates ($2.8 billion globally, assuming no hospitalization costs), while the probability of missing productive days had the largest impact on societal cost estimates ($35.9 billion globally, with a 25% probability of missing productive days).ConclusionsThe total economic burden is greatest in young children but the highest cost per illness is among older age groups in some regions. These large costs overwhelmingly are from productivity losses resulting from acute illness. Low, middle, and high income countries all have a considerable economic burden, suggesting that norovirus gastroenteritis is a truly global economic problem. Our findings can help identify which age group(s) and/or geographic regions may benefit the most from interventions.     

Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors

Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED₅₀ of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.     

Campylobacter Infection in Children in Malawi Is Common and Is Frequently Associated with Enteric Virus Co-Infections

Background

Campylobacter species are the most common cause of bacterial gastroenteritis in the developed world. However, comparatively few studies have determined the epidemiological features of campylobacteriosis in resource-poor settings.

Methods

A total of 1,941 faecal specimens collected from symptomatic (diarrhoeic) children and 507 specimens from asymptomatic (non-diarrhoeic) children hospitalised in Blantyre, Malawi, between 1997 and 2007, and previously tested for the presence of rotavirus and norovirus, was analysed for C. jejuni and C. coli using a real time PCR assay.

Results

Campylobacter species were detected in 415/1,941 (21%) of diarrhoeic children, with C. jejuni accounting for 85% of all cases. The median age of children with Campylobacter infection was 11 months (range 0.1–55 months), and was significantly higher than that for children with rotavirus and norovirus (6 months and 7 months respectively; P<0.001). Co-infection with either rotavirus or norovirus was noted in 41% of all cases in the diarrhoeic group. In contrast, the detection rate of Campylobacter in the non-diarrhoeic group was 14%, with viral co-infection identified in 16% of children with Campylobacter. There was no association between Campylobacter detection rate and season over the 10 year period.

Discussion

Using molecular detection methodology in hospitalised Malawian children, we have demonstrated a high prevalence of Campylobacter infection, with frequent viral co-infection. The burden of Campylobacter infection in young African children may be greater than previously recognised.     

Economic Cost of Campylobacter,Norovirus and Rotavirus Disease in the United Kingdom

Objectives

To estimate the annual cost to patients, the health service and society of infectious intestinal disease (IID) from Campylobacter, norovirus and rotavirus.

Design

Secondary data analysis.

Setting

The United Kingdom population, 2008–9.

Main outcome measures

Cases and frequency of health services usage due to these three pathogens; associated healthcare costs; direct, out-of-pocket expenses; indirect costs to patients and caregivers.

Results

The median estimated costs to patients and the health service at 2008–9 prices were: Campylobacter £50 million (95% CI: £33m–£75m), norovirus £81 million (95% CI: £63m–£106m), rotavirus £25m (95% CI: £18m–£35m). The costs per case were approximately £30 for norovirus and rotavirus, and £85 for Campylobacter. This was mostly borne by patients and caregivers through lost income or out-of-pocket expenditure. The cost of Campylobacter-related Guillain-Barré syndrome hospitalisation was £1.26 million (95% CI: £0.4m–£4.2m).

Conclusions

Norovirus causes greater economic burden than Campylobacter and rotavirus combined. Efforts to control IID must prioritise norovirus. For Campylobacter, estimated costs should be considered in the context of expenditure to control this pathogen in agriculture, food production and retail. Our estimates, prior to routine rotavirus immunisation in the UK, provide a baseline vaccine cost-effectiveness analyses.     

水源性诺如病毒

诺如病毒是导致人类病毒性急性腹泻的主要病原,常常造成严重的公共卫生与食品安全事件,而水体是诺如病毒传播的重要载体。对水源性诺如病毒的环境抗性、浓缩和检测方法、流行病学以及目前对于水体中诺如病毒检测存在的突出问题和未来的发展方向进行了综述和展望。     

Phylogenetic analysis of norovirus isolates involved in some Canadian gastroenteritis outbreaks in 2004 and 2005

Noroviruses are recognized as the most common cause of nonbacterial gastroenteritis worldwide. In this study, we investigated the molecular epidemiology of noroviral isolates in Canada from 2004 to 2005 by sequencing the RNA polymerase gene and capsid N-terminal/shell (N/S) domain. Norovirus genogroups I and II were thus found to have co-circulated in Canada during the studied period, with a higher incidence of genogroup II (95.7%). The GII-4 or Lordsdale subgroup was the predominant genotype, suggesting that norovirus genogroup II is the major cause of viral gastroenteritis in Canada, as it is in many other countries. Phylogenetic analyses of the RNA polymerase gene and the capsid N/S domain indicated different genotypes for 2 strains, suggesting probable genetic recombination. Sequencing of the norovirus polymerase gene may reflect actual classification but should be supported by sequence information obtained from the capsid gene.     

World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010

Illness and death from diseases caused by contaminated food are a constant threat to public health and a significant impediment to socio-economic development worldwide. To measure the global and regional burden of foodborne disease (FBD), the World Health Organization (WHO) established the Foodborne Disease Burden Epidemiology Reference Group (FERG), which here reports their first estimates of the incidence, mortality, and disease burden due to 31 foodborne hazards. We find that the global burden of FBD is comparable to those of the major infectious diseases, HIV/AIDS, malaria and tuberculosis. The most frequent causes of foodborne illness were diarrheal disease agents, particularly norovirus and Campylobacter spp. Diarrheal disease agents, especially non-typhoidal Salmonella enterica, were also responsible for the majority of deaths due to FBD. Other major causes of FBD deaths were Salmonella Typhi, Taenia solium and hepatitis A virus. The global burden of FBD caused by the 31 hazards in 2010 was 33 million Disability Adjusted Life Years (DALYs); children under five years old bore 40% of this burden. The 14 subregions, defined on the basis of child and adult mortality, had considerably different burdens of FBD, with the greatest falling on the subregions in Africa, followed by the subregions in South-East Asia and the Eastern Mediterranean D subregion. Some hazards, such as non-typhoidal S. enterica, were important causes of FBD in all regions of the world, whereas others, such as certain parasitic helminths, were highly localised. Thus, the burden of FBD is borne particularly by children under five years old–although they represent only 9% of the global population–and people living in low-income regions of the world. These estimates are conservative, i.e., underestimates rather than overestimates; further studies are needed to address the data gaps and limitations of the study. Nevertheless, all stakeholders can contribute to improvements in food safety throughout the food chain by incorporating these estimates into policy development at national and international levels.

Summary Points

• Thirty-one foodborne hazards caused 600 (95% uncertainty interval [UI] 420–960) million foodborne illnesses and 420,000 (95% UI 310,000–600,000) deaths in 2010.
• The global burden of FBD caused by the 31 hazards studied was 33 (95% UI 25–46) million DALYs in 2010.
• The most frequent causes of foodborne illness were diarrheal disease agents; particularly norovirus and Campylobacter spp.
• Foodborne diarrheal disease agents, particularly non-typhoidal Salmonella enterica, caused 230,000 (95% UI 160,000–320,000) deaths
• Other major causes of FBD deaths were Salmonella Typhi, Taenia solium, hepatitis A virus and aflatoxin.
• 40% of the FBD burden was among children under 5 years old.
• The African (AFR), South-East Asian (SEAR) and Eastern Mediterranean (EMR) D subregions had the highest FBD burden.
• Diarrheal disease agents were the leading cause of FBD burden in most subregions, and non-typhoidal Salmonella enterica caused an important burden in all subregions, particularly in the subregions in Africa.
• Other main causes of diarrheal FBD burden were enteropathogenic Escherichia coli, enterotoxigenic Escherichia coli and Vibrio cholerae in low-income subregions, and Campylobacter spp. in high-income subregions.
• The burden of aflatoxin was high in the AFR D, Western Pacific (WPR) B and SEAR B subregions, whereas dioxins caused the highest burden in SEAR D, EMR D and European (EUR) A and C subregions.
• In the South-East Asian subregions, there was a considerable burden of Salmonella Typhi; the burden of Opisthorchis spp. was concentrated in the SEAR B region, where the seafoodborne trematodes Paragonimus spp. and Clonorchis sinensis were also important.
• In Central and South American (AMR B and AMR D) subregions, T. solium and Toxoplasma gondii contributed significantly to the FBD burden.
• These estimates should inform policy development at national and international levels to improve food safety throughout the food chain.

     

RotaC: A web-based tool for the complete genome classification of group A rotaviruses

Background  

Group A rotaviruses are the most common cause of severe diarrhea in infants and children worldwide and continue to have a major global impact on childhood morbidity and mortality. In recent years, considerable research efforts have been devoted to the development of two new live, orally administered vaccines. Although both vaccines have proven to confer a good protection against severe rotavirus gastroenteritis, these vaccines will have to be screened and may have to be updated regularly to reflect temporal and spatial genotype fluctuations. In this matter, the genetic characterization of circulating and new emerging rotavirus strains will need to be compulsory and accurate. An extended classification system for rotaviruses in which all the 11 genomic RNA segments are used, has been proposed recently. The use of this classification system will help to elucidate the role of gene reassortments in the generation of genetic diversity, host range restriction, co-segregation of certain gene segments, and in adaptation to a new host species.     

Detection of Norovirus Capsid Protein in Authentic Standards and in Stool Extracts by Matrix-Assisted Laser Desorption Ionization and Nanospray Mass Spectrometry

Mass spectrometry (MS) represents a rapid technique for the identification of microbial monocultures, and its adaptation to the detection of pathogens in real-world samples is a public health and homeland security priority. Norovirus, a leading cause of gastroenteritis in the world, is difficult to monitor because it cannot be cultured outside the human body. The detection of norovirus capsid protein was explored using three common MS-based methods: scanning of intact proteins, peptide mass fingerprinting, and peptide sequencing. Detection of intact target protein was limited by poor selectivity and sensitivity. Detection of up to 16 target peptides by peptide mass fingerprinting allowed for the reproducible and confident (P < 0.05) detection of the 56-kDa norovirus capsid protein in the range of 0.1 × 10⁻¹² to 50 × 10⁻¹² mol in authentic standards of recombinant norovirus virus-like particles (VLPs). To explore assay performance in complex matrixes, a non-gel-based, rapid method (2 to 3 h) for virus extraction from human stool was evaluated (72% ± 12% recovery), and additional analyses were performed on norovirus-free stool extracts fortified with VLPs. Whereas peptide mass fingerprinting was rendered impractical by sample interferences, peptide sequencing using nanospray tandem MS facilitated unambiguous identification of ≥250 fmol of capsid protein in stool extracts. This is the first report on MS-based detection of norovirus, accomplished by using structurally identical, noninfective VLPs at clinically relevant concentrations. It represents an important milestone in the development of assays for surveillance of this category B bioterrorism agent.     

Household Catastrophic Healthcare Expenditure and Impoverishment Due to Rotavirus Gastroenteritis Requiring Hospitalization in Malaysia

Background

While healthcare costs for rotavirus gastroenteritis requiring hospitalization may be burdensome on households in Malaysia, exploration on the distribution and catastrophic impact of these expenses on households are lacking.

Objectives

We assessed the economic burden, levels and distribution of catastrophic healthcare expenditure, the poverty impact on households and inequities related to healthcare payments for acute gastroenteritis requiring hospitalization in Malaysia.

Methods

A two-year prospective, hospital-based study was conducted from 2008 to 2010 in an urban (Kuala Lumpur) and rural (Kuala Terengganu) setting in Malaysia. All children under the age of 5 years admitted for acute gastroenteritis were included. Patients were screened for rotavirus and information on healthcare expenditure was obtained.

Results

Of the 658 stool samples collected at both centers, 248 (38%) were positive for rotavirus. Direct and indirect costs incurred were significantly higher in Kuala Lumpur compared with Kuala Terengganu (US$222 Vs. US$45; p<0.001). The mean direct and indirect costs for rotavirus gastroenteritis consisted 20% of monthly household income in Kuala Lumpur, as compared with only 5% in Kuala Terengganu. Direct medical costs paid out-of-pocket caused 141 (33%) households in Kuala Lumpur to experience catastrophic expenditure and 11 (3%) households to incur poverty. However in Kuala Terengganu, only one household (0.5%) experienced catastrophic healthcare expenditure and none were impoverished. The lowest income quintile in Kuala Lumpur was more likely to experience catastrophic payments compared to the highest quintile (87% vs 8%). The concentration index for out-of-pocket healthcare payments was closer to zero at Kuala Lumpur (0.03) than at Kuala Terengganu (0.24).

Conclusions

While urban households were wealthier, healthcare expenditure due to gastroenteritis had more catastrophic and poverty impact on the urban poor. Universal rotavirus vaccination would reduce both disease burden and health inequities in Malaysia.     

诺如病毒检测方法研究进展

诺如病毒是引起人类非细菌性胃肠炎的主要病原之一,具有很高的传染性和变异性,可导致严重的公共卫生问题,尤其在抵抗力弱的人群中有很高的发病率,因此开发快速、准确的检测技术对预防和控制诺如病毒的传播是非常重要的。本文综述了近年来RT-PCR、环介导等温扩增、实时荧光定量PCR、巢式PCR、ELISA、免疫层析、基因芯片等技术在诺如病毒检测中的应用及发展趋势。     

Predominance of Norovirus and Sapovirus in Nicaragua after Implementation of Universal Rotavirus Vaccination

Background

Despite significant reduction of rotavirus (RV) infections following implementation of RotaTeq vaccination in Nicaragua, a large burden of patients with diarrhea persists.

Methods

We conducted a community- and hospital-based study of the burden of RV, norovirus (NV) and sapovirus (SV) infections as cause of sporadic acute gastroenteritis (GE) among 330 children ≤ 5 years of age between September 2009 and October 2010 in two major cities of Nicaragua with a RotaTeq coverage rate of 95%.

Results

We found that NV, SV and RV infections altogether accounted for 45% of cases of GE. Notably, NV was found in 24% (79/330) of the children, followed by SV (17%, 57/330) and RV (8%, 25/330). The detection rate in the hospital setting was 27%, 15% and 14% for NV, SV and RV respectively, whereas in the community setting the detection rate of RV was < 1%. Among each of the investigated viruses one particular genogroup or genotype was dominant; GII.4 (82%) for NV, GI (46%) for SV and G1P[8] (64%) in RV. These variants were also found in higher proportions in the hospital setting compared to the community setting. The GII.4.2006 Minerva strain circulating globally since 2006 was the most common among genotyped NV in this study, with the GII.4-2010 New Orleans emerging in 2010.

Conclusions

This study shows that NV has become the leading viral cause of gastroenteritis at hospital and community settings in Nicaragua after implementation of RV vaccination.     

Rotavirus vaccines: recent developments and future considerations

Two new vaccines have recently been shown to be safe and effective in protecting young children against severe rotavirus gastroenteritis. Although both vaccines are now marketed worldwide, it is likely that improvements to these vaccines and/or the development of future generations of rotavirus vaccines will be desirable. This Review addresses recent advances in our knowledge of rotavirus, the host immune response to rotavirus infection and the efficacy and safety of the new vaccines that will be helpful for improving the existing rotavirus vaccines, or developing new rotavirus vaccines in the future.