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Epidemiology of Foodborne Norovirus Outbreaks, United States, 2001–2008
research-article
Author(s):
Aron J. Hall
,
Valerie G. Eisenbart ,
Amy Lehman Etingüe ,
L. Hannah Gould ,
Ben A. Lopman ,
Umesh D. Parashar
Publication date (Print):
October 2012
Journal:
Emerging Infectious Diseases
Publisher:
Centers for Disease Control and Prevention
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There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
In the United States, the leading cause of foodborne illness is norovirus; an average of 1 foodborne norovirus outbreak is reported every day. The more we know about how this virus is spread and in which foods, the better we can ward off future outbreaks. A recent study identified the most common sources of foodborne norovirus outbreaks as ready-to-eat foods that contain fresh produce and mollusks that are eaten raw, such as oysters. Most implicated foods had been prepared in restaurants, delicatessens, and other commercial settings and were most often contaminated by an infected food worker. Although possible contamination during production, harvesting, or processing cannot be overlooked, food safety during meal preparation should be emphasized. Food handlers should wash their hands, avoid bare-handed contact with ready-to-eat foods, and not work when they are sick.
Abstract
Keywords: norovirus, foodborne disease, outbreaks, attribution, United States, viruses
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Most cited references26
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Norwalk Virus Shedding after Experimental Human Infection
Robert L. Atmar, Antone Opekun, Mark Gilger … (2008)
Noroviruses are the most common cause of epidemic gastroenteritis in the United States ( 1 ). Although in vitro replication systems for these viruses have recently been described ( 2 , 3 ), human noroviruses cannot readily be grown in cell culture, and no small animal model of human norovirus infection is available. Much of what is known about these viruses has by necessity been learned from experimental human infection and from observational studies of naturally acquired infection. Norwalk virus is the prototype strain in the genus Norovirus, and many of the human experimental infection studies have used this strain ( 4 – 9 ). We describe the duration and magnitude of virus shedding in persons infected with Norwalk virus after experimental inoculation. Materials and Methods Virus Inoculum Liquid feces from persons who participated in a previous Norwalk virus challenge study ( 8 ) were screened to identify samples with high concentrations of Norwalk virus RNA (>107 reverse transcription–PCR [RT-PCR] U/mL). The participants were recontacted and screened for health (results within normal limits for liver function, tuberculosis skin test [negative], and chest radiographs; negative serologic test results for hepatitis A, B, and C, retroviruses [HIV-1, HIV-2, and human T-lymphotropic virus 1 and 2], and syphilis [nonreactive rapid plasma regain]). The new challenge inoculum (lot 42399) was prepared from liquid feces of 1 participant by clarification, centrifugation, and serial filtration through filters with progressively smaller pore size to a final 0.45-μm filter size. The inoculum, which contained no other enteric viruses or adventitious agents, was packaged and stored at –80°C. Challenge Protocol Challenge studies were conducted from September 2004 through October 2006. Healthy adults (18–50 years of age) provided informed consent and successfully completed a test of understanding. In addition, eligible persons were secretor positive (because secretor-negative persons are resistant to Norwalk virus infection; 9 , 10 ), had screening laboratory study results that were within normal limits (liver and renal function, blood counts), had negative serologic results for hepatitis and HIV, had no serious chronic diseases, had no history of nonbacterial gastroenteritis within 3 months of inoculation or of bacterial or protozoal enteric infection within 1 month (based on 3 negative enteric cultures and fecal ova and parasite studies in the 4-week preinoculation screening period), were not exposed to persons considered to be at risk for more severe norovirus infection (e.g., immunocompromised patients, the elderly, and children), and were not employed in jobs identified as having high risk for transmission to other persons (e.g., food service, healthcare, and airline industries). On the day of inoculation, participants were admitted to the Baylor College of Medicine General Clinical Research Center and orally received different dosages of inoculum (10-fold dilutions ranging from 4.8 to 4,800 RT-PCR units) or placebo in the early evening. Inoculated participants remained in the Center for a minimum of 96 hours and at discharge had experienced no watery feces or vomiting for at least 18 hours. Participants’ clinical signs and symptoms were evaluated every 4 hours while they were in the Center, and all fecal samples were collected and refrigerated immediately. Within 24 hours of collection, the samples were transported to the laboratory for processing and stored at –70oC until analyzed. After patient discharge, all fecal samples were collected daily for 21 days and then weekly for up to 5 additional weeks (for a total observation time of up to 8 weeks postinoculation). The samples were delivered to the laboratory within a day of collection and were processed and stored as described above. Participants were educated about the importance of hand washing and hand hygiene at the beginning of the study, and these concepts were reinforced at each study visit. The clinical protocol was reviewed and approved by the Institutional Review Board at Baylor College of Medicine, and an Investigational New Drug application describing the clinical protocol and study inoculum was reviewed by the US Food and Drug Administration. Laboratory Studies Norwalk virus–specific antigen was detected by sandwich ELISA, using Norwalk virus–specific antiserum, as previously described ( 8 ), and Norwalk virus–specific antibody was detected by ELISA, using Norwalk virus–like particles as antigen, as previously described ( 8 ). Norwalk virus RNA was detected in fecal specimens by using either an immunomagnetic capture (IMC) RT-PCR assay ( 11 ) or quantitated by real-time RT-PCR (qRT-PCR) with RNA transcripts as a standard ( 2 ). The primers used for the IMC RT-PCR assay were the antisense Norwalk virus p35 (5′-CTT GTT GGT TTG AGG CCA TAT-3′) and the sense Norwalk virus p36 (5′-ATA AAA GTT GGC ATG AAC A-3′); probe was a 5′ digoxigenin-labeled Norwalk virus p69 (5′-GGC CTG CCA TCT GGA TTG CC-3′). For the qRT-PCR assay, a 10% fecal sample was diluted 1,000-fold and heated to 95oC for 5 min ( 12 ); 20 μL of heated sample was analyzed in duplicate wells. The primers for the qRT-PCR assay were the antisense Norwalk virus p165 (5′-CAT AAT CAC CTA CAT CCA TCT CAG ATG-3′, which is complementary to Norwalk virus nt 4689–4715) and the sense primer Norwalk virus p166 (5′-CGG CCT CAC CAG AAT TGG-3′, which is complementary to Norwalk virus nt 4641–4658); the probe was Norwalk virus p167 (5′-FAM/CGA GGT TGT GGC CCA AGA TTT GCT AG/TAMRA-3′, which is complementary to nt 4660–4685). For determination of a virus titer, both wells had to show amplification. The limits of detection for the IMC RT-PCR and qRT-PCR assays were ≈15 × 103 and ≈40 × 106 copies/g feces, respectively. Definitions Infection was defined as seroresponse (4-fold rise in titer from preinoculation baseline to 30-day serum sample, as measured by ELISA) or fecal virus excretion as detected by RT-PCR or presence of antigen. Viral gastroenteritis was defined as illness with moderate diarrhea (alone) for any continuous 24-hour period (moderate diarrhea is >200 g of watery feces that immediately take the shape of the collection container) or 1 vomiting episode plus 1 of the following: abdominal cramps or pain, nausea, bloating, loose feces (if not fulfilling the definition of diarrhea), fever (oral temperature >37.6°C), myalgia, or headache. Results A total of 16 persons inoculated with Norwalk virus met the criteria for having Norwalk virus infection. Of these, 11 (69%) met the predefined definition for viral gastroenteritis. The 5 who did not meet this predefined definition had >3 symptoms that did not include vomiting or >200 g of watery diarrhea. All 11 participants with viral gastroenteritis had abdominal cramps, nausea, and vomiting; 5 of these participants also had >200 g of watery diarrhea, and 1 had 37.6oC (n = 4), and chills (n = 3). The 5 participants who did not fulfill the criteria for gastroenteritis had nausea (n = 5), anorexia (n = 5), malaise (n = 4), abdominal cramps (n = 3), myalgia (n = 3), headache (n = 3), temperature >37.6oC (n = 2), chills (n = 2), and watery diarrhea 4-fold rise in serum antibody level, and all but 2 also shed virus as measured by antigen ELISA (Table). Virus shedding as measured by IMC RT-PCR was first detected a median of 36 hours (range 18–110 hours) after inoculation and lasted a median of 28 days after inoculation (range 13–56 days). Norwalk virus was detected in fecal samples of 7 participants 3–14 hours before onset of any clinical signs or symptoms. Presymptomatic shedding was more common in persons who did not meet the definition of clinical gastroenteritis than in those who did (4/5 vs. 3/11, respectively, p = 0.11, 2-tailed Fisher exact test). Virus shedding as measured by antigen ELISA was first detected ≈33 hours (median 42 hours) after inoculation and was last detected 10 days (median 7 days) after inoculation. Median values of the onset and resolution of virus shedding, as measured by IMC RT-PCR or antigen ELISA, were similar for the participants who had clinical gastroenteritis compared with those of persons who did not meet the definition of gastroenteritis (Table). Table Fecal virus shedding among 16 participants inoculated with Norwalk virus* Participant no. Estimated Norwalk virus inoculum dose (RT-PCR units) First–last study days† postinoculation when symptoms present First–last study days IMC
RT-PCR positive Day peak virus titer (character of feces) Peak qRT-PCR virus titer (log10/g) First–last study days postinoculation when antigen positive Met clinical definition of gastroenteritis Had diarrhea and vomiting 706 4,800 2 2–28‡ 2 (liquid) 11.1 2–9 707 4,800 2–4 1–30‡ 2 (liquid) 9.5 4–8 710 4,800 1–2 2–30‡ 5 (solid) 10.9 2–7 722 48 2 2–48 4 (solid) 11.7 2–8 724 4.8 2–3 2–56 3 (solid) 11.4 2–6 Had vomiting only 701 4,800 1–2 1–29‡ 4 (solid) 10.8 3–10 720§ 48 2 2–56 4 (solid) 11.5 2–9 721 48 1–3 2–21 4 (solid) 11.7 2–10 723 48 2 1–50 4 (solid) 12.2 2–6 731 4.8 2–3 5–10 5 (solid) 10.0 None 732 4.8 2–3 2–15 3 (solid) 11.9 2–6 Median – 2 2–30‡ 4 (solid) 11.4 2–8 Did not meet clinical definition of gastroenteritis 703 4,800 2–3 1–32‡ 2 (solid) 10.7 2–9 704 4,800 2–3 4–21‡ 5 (solid) 9.2 5–7 715§ 48 2–3 1–28 3 (solid) 11.7 2–5 716§ 48 2–3 1–20 4 (unformed) 10.1 3–7 717 48 3 4–13 4 (solid) 9.3 None Median – 2–3 1–21‡ 4 (solid) 10.1 2–7 *RT–PCR, reverse transcription–PCR; IMC, immunomagnetic capture; qRT-PCR, quantitative PCR.
†Study days are reported as calendar days; study day 1 began ≈5–6 h postinoculation.
‡Fecal samples only collected for 30 d postinoculation.
§Watery feces with mass 100 × 106 copies/g until at least day 14 (Figure 1). Persons who met the clinical definition of gastroenteritis had a higher median peak of virus shedding than those who did not have gastroenteritis (250 × 109 vs. 12 × 109 genomic copies/g feces, p = 0.08, Wilcoxon rank sum), and the average total number of viral genomic copies measured in the feces over the first 2 weeks after inoculation also was higher in the clinical gastroenteritis group (1013.3 vs. 1012.4, p = 0.056, Student t test). The virus concentrations in feces collected later after inoculation were low (range 225,000–40 × 106 genomic copies/g). Correlation between virus titer in feces and optical density results obtained in the antigen ELISA was strong (r = 0.823, Pearson correlation, p 1011 norovirus copies/g feces, whereas the peak fecal virus titer observed by Ozawa et al. ( 18 ) in symptomatic and asymptomatic food handlers was ≈10-fold lower. Each of these studies was of persons with naturally acquired norovirus infection. However, the median peak viral load observed in our study (1011) was much higher than the 107–108 median viral loads reported in the prior studies ( 17 , 18 ). Lee et al. ( 19 ) noted higher viral loads in patients who had more prolonged symptoms (>4 days) associated with infection caused by GII.4 norovirus. Amar et al. ( 20 ) also reported viral loads to be higher in persons who had symptomatic gastroenteritis than in those who had been asymptomatic for at least 3 weeks. Our findings suggest that clinical gastroenteritis was associated with higher peak virus shedding and higher total virus shedding during the first 2 weeks after inoculation. Although we did not see an association of peak virus titer with symptom duration, the median duration of symptoms averaged only ≈1 day in our study. Potential reasons for the different results observed in other studies include the manner in which samples were collected (single samples vs. serial collection), the real-time assays used (generic assays designed to be broadly reactive vs. assay designed specifically for Norwalk virus detection), virulence of the infecting strains, differences in the populations studied (e.g., age, immune status), and the small number of infected persons who did not have clinical gastroenteritis in our study. The development of more sensitive methods to detect noroviruses has been associated with a corresponding increase in the duration of recognized virus shedding ( 1 , 8 ). For example, Rockx et al. ( 21 ) found norovirus in fecal samples for >3 weeks in ≈25% of infected persons, and Murata et al. ( 22 ) found norovirus in fecal samples for up to 6 weeks in infected infants. In contrast, at least half of the participants in our study still had Norwalk virus in fecal samples after 4 weeks and 2 had virus still present at 8 weeks; we cannot exclude the possibility that these 2 persons shed for a longer period. Determination of whether the virus is still infectious must await the development of more sensitive and reproducible methods for norovirus cultivation than are currently available ( 23 ).
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Novel Surveillance Network for Norovirus Gastroenteritis Outbreaks, United States1
Everardo Vega, Leslie Barclay, Nicole Gregoricus … (2011)
Noroviruses are the primary cause of epidemic viral gastroenteritis and the leading cause of foodborne outbreaks in the United States (1–3). Although the course of disease is in most cases self-limiting, young, elderly, and immunocompromised persons are at risk for complications caused by severe vomiting and diarrhea (4–8). In addition to the clinical impact of norovirus disease, the economic effects in lost wages, time, and intervention procedures (e.g., clean-up costs and recalls) can be significant (9–11). Although norovirus outbreaks occur year-round, they are more common during the winter months (12–14). Noroviruses are genetically classified into 5 genogroups, GI–GV, with GI and GII strains responsible for most human disease (2,15). GII viruses can be further divided into at least 19 genotypes, of which GII.4 is responsible for >85% of outbreaks (14,16), although other genotypes and viruses continue to circulate and cause sporadic disease in children (17–19). Over the past 15 years, new GII.4 variants have been identified; several have been associated with a global increase in the number of outbreaks (15). The last pandemic GII.4 variant, GII.4 2006b or GII.4 Minerva, was identified in late 2005/early 2006 and has been the predominant outbreak strain in the United States since then. The successive displacement of GII.4 variants suggests that population immunity is driving the evolution of GII.4 viruses (20,21), and the emergence of a new variant will cause an increase in the number of outbreaks in an immunologically naive population. It is not fully understood why some GII.4 variants become pandemic whereas others do not. The combination of novel antigenic sites in protruding regions of the capsid (centered around amino acids 295 and 396) and the change or expansion of a susceptible population may be responsible for the emergence of pandemic variants (20,22). The latter theory has been supported by the discovery that different norovirus strains may have different histo–blood group antigen (HBGA) binding patterns and that nonsecretors are not susceptible to infection with certain genotypes or variants (23). Most mutations between genotypes and variants occur in the P2 region of the major capsid viral protein (VP), VP1, which contains the HBGA binding sites. Since 2008, all 50 states have had the laboratory capacity for norovirus testing; the Centers for Disease Control and Prevention (CDC) National Calicivirus Laboratory (NCL) provides laboratory support to states that do not have in-house capacity for norovirus strain typing. Recent studies on the molecular epidemiology of norovirus in the US have been based on specimens from a subset of outbreaks that were submitted to CDC (13,24,25). To enhance and harmonize norovirus outbreak surveillance, CDC and its state partners have developed a national norovirus outbreak surveillance network, CaliciNet. CaliciNet was developed to improve standardized typing of norovirus outbreaks, assist in linking geographically different clusters of norovirus illness, allow rapid classification and identification of new norovirus strains, and establish a comprehensive strain surveillance network in the United States. In this article, we describe the CaliciNet network and report first-year results, including the identification of a new GII.4 norovirus variant. Materials and Methods CaliciNet CaliciNet is a novel electronic laboratory surveillance network of local and state public health laboratories in the United States, coordinated by CDC. CaliciNet participants perform molecular typing of norovirus strains by using standardized laboratory protocols for reverse transcription PCR (RT-PCR) followed by DNA sequence analysis of the amplicons. A customized CaliciNet database developed in Bionumerics version 5.1 (Applied Maths, Austin, TX, USA) includes norovirus sequence and basic epidemiologic information (Table 1), which are submitted electronically via a secure connection to the CaliciNet server at CDC. Both epidemiologic and sequence data can then be used to help link multistate outbreaks to a common source (e.g., contaminated food). To ensure high-quality data entry, submissions to the CaliciNet server are performed by certified laboratory personnel of the participating state or local health laboratories, and final quality assurance/quality control is performed at CDC. Table 1 Epidemiologic data fields required for upload to CaliciNet* Required CaliciNet fields Description LabOBNumber Year, outbreak, and number Outbreak date Begin date of outbreak Outbreak city City where outbreak occurred Outbreak state State where outbreak occurred Outbreak setting Select outbreak setting† Outbreak country Country where outbreak occurred Transmission Foodborne, person-to-person, waterborne Conventional RT-PCR Results of RT-PCR‡ Sequence experiment Sequence of region D§ *RT-PCR, reverse transcription PCR.
†Child care center, cruise ships, hospital, long-term care facility, party or event, restaurant, school and community, correctional center.
‡Region C or D.
§Region D is the preferred sequence, but region C is also accepted. CaliciNet certification for participants is a 2-step process that involves evaluation of data entry and analysis of sequences and a laboratory panel test. Each laboratory must pass an annual proficiency test. The laboratory certification and proficiency test consists of analyzing a panel of fecal samples by real-time RT-PCR and conventional RT-PCR analysis followed by bidirectional sequencing as described below. Certified participants are then authorized to upload norovirus outbreak data consisting of >2 samples per outbreak to the national CaliciNet database (Table 1). GII.4 sequences with >2% and 3% difference in region C or D, respectively, and >10% difference with all other noroviruses are further analyzed at CDC by amplification of the VP1 or P2 region. Outbreaks All outbreaks submitted to CaliciNet and the NCL from October 2009 through March 2010 were genotyped by region D analysis (26). To verify GII.4 New Orleans variants, a subset of outbreaks from CaliciNet participating laboratories and 2 specimens from each outbreak received at the NCL from October 2009 through May 2010 were analyzed by using the P2 region as described below. Viral RNA Extraction Viral RNA was extracted from clarified 10% fecal suspensions in phosphate-buffered saline with the MagMax-96 Viral RNA Isolation Kit (Ambion, Foster City, CA, USA) on an automated KingFisher magnetic particle processor (Thermo Fisher Scientific, Pittsburgh, PA, USA) according to the manufacturer’s instructions and eluted into 100 µL of elution buffer (10 mmol/L Tris pH 8.0 and 1 mmol/L EDTA). Extracted RNA was stored at –80°C until further use. Real-time RT-PCR Viral RNA was tested for GI and GII noroviruses in a duplex format by using the AgPath-ID One-Step RT-PCR Kit (Applied Biosystems, Foster City, CA, USA) on a 7500 Realtime PCR platform (Applied Biosystems). The final reaction mix of 25 µL consisted of 400 nmol/L of each oligonucleotide primer, Cog1F, Cog1R, Cog2F, and Cog2R, and 200 nmol/L of each TaqMan Probe Ring 2 (27) and Ring 1C (28) (Table 2). Cycling conditions included reverse transcription for 10 min at 45°C and denaturation for 10 min at 95°C, followed by 40 cycles of 15 s at 95°C and 1 min at 60°C. Table 2 Oligonucleotide primers and probes used for detection and genotype identification of norovirus strains submitted to CaliciNet* Primer or probe name RT-PCR target Sequence, 5′ → 3′ Reference TVN-L1 ORF2–ORF3 GGG TGT GTT GTG GTG TTG T26VN (29) L1 ORF2–ORF3 GGG TGT GTT GTG GTG TTG This study EVP2F P2 (GII.4 specific) GTR CCR CCH ACA GTT GAR TCA This study EVP2R P2 (GII.4 specific) CCG GGC ATA GTR GAY CTR AAG AA This study Cap D1 Region D GII TGT CTR STC CCC CAG GAA TG (26) Cap C Region D GII CCT TYC CAK WTC CCA YGG (26) Cap D3 Region D GII TGY CTY ITI CCH CAR GAA TGG (26) Cog 2F ORF1–ORF2 junction (GII) CAR GAR BCN ATG TTY AGR TGG ATG AG (27) Cog 2R ORF1–ORF2 junction (GII) TCG ACG CCA TCT TCA TTC ACA (27) Ring 2 ORF1–ORF2 junction (GII) Cy5-TGG GAG GGC GAT CGC AAT CT-BHQ (27) Ring 1C ORF1–ORF2 junction (GI) FAM-AGA TYG CGI TCI CCT GTC CA-BHQ (28) Cog 1F ORF1–ORF2 junction (GI) CGY TGG ATG CGI TTY CAT GA (27) Cog 1R ORF1–ORF2 junction (GI) CTT AGA CGC CAT CAT CAT TYA C (27) *RT-PCR, reverse transcription PCR; ORF, open reading frame. Region D RT-PCR The QIAGEN One-Step RT-PCR Kit (QIAGEN, Valencia, CA, USA) was used for region D amplification in a 25-µL reaction volume. RNAse Inhibitor (Applied Biosystems) was added to a final concentration of 15–20 units/reaction. Oligonucleotide primers CapD1, CapD3, and CapC were added to a final concentration of 1 µmol/L each (Table 2). RT-PCR conditions included reverse transcription at 42°C for 30 min and denaturation at 95°C for 15 min, followed by 40 cycles of 30 s at 94°C, 30 s at 40°C, and 30 s at 72°C. A final elongation step was run for 10 min at 72°C. P2 Region Amplification The P2 region was amplified by using the SuperScript III One-Step RT-PCR with Platinum Taq High Fidelity Kit (Invitrogen, Carlsbad, CA, USA). The final reaction volume of 25 µL consisted of 4 µmol/L of EVP2F and EVP2R (Table 2). RT-PCR conditions included reverse transcription at 55°C for 30 min and denaturation at 94°C for 2 min, followed by 40 cycles of PCR at 94°C for 15 s, 55°C for 30 s, 68°C for 1 min, and a final extension step of 68°C for 5 min. Amplification and Cloning of GII.4 New Orleans Novel GII.4 New Orleans sequences were identified by region D sequence analysis and further analyzed by amplification of complete open reading frame 2. Extracted RNA from fecal samples underwent cDNA synthesis with a TVN-L1 primer (29) (Table 2) for 60 min at 50°C by using the Superscript III cDNA synthesis kit (Invitrogen). The reaction mixture was purified by using the DNA Clean and Concentrator-5 (Zymo Research, Orange, CA, USA). The cDNA was amplified by using oligonucleotides (0.5 µmol/L each) L1 and Cog2F (Table 2), using the Phusion PCR Kit with the addition of 3% dimethyl sulfoxide (Finnzymes, Woburn, MA, USA). PCR conditions included denaturation at 98°C for 30 s followed by 40 cycles of 98°C for 10 s, 48°C for 30 s, and 72°C for 1.5 min. A final elongation step was run at 72°C for 10 min. PCR products of ≈2.5 kb were gel purified and cloned by using a TOPO-TA Cloning Kit (Invitrogen). Five clones of each strain were fully sequenced bidirectionally and their respective consensus sequences were submitted to GenBank. The accession no. for GII.4 New Orleans is GU445325. DNA Sequencing All amplicons were purified with the QIAquick Gel Extraction or PCR Purification Kits (QIAGEN) and sequenced by using the BigDye Terminator Kit version 1.1 (Applied Biosystems). Sequence reactions were cleaned up by using the BigDye Xterminator Kit (Applied Biosystems) and analyzed on a 3130XL Automated Sequencer (Applied Biosystems). Phylogenetic Analysis VP1 or P2 sequences were aligned by using MEGA4 software (30). Maximum-likelihood phylogenetic analysis of VP1 amino acids were run in PhyML version 3.0 (www.atgc-montpellier.fr/phyml/binaries.php) by using the LG amino acids replacement matrix (31). The initial tree was the best of 5 random trees, and branches were supported by 100 bootstrap replicates. Branches with bootstrap support 50% during the winter months. Compared with known GII.4 viruses, GII.4 New Orleans had several changes in key amino acids in the P2 region of VP1 and around the sites that have been shown to be important in HBGA binding (20). Because most GII.4 variants that have been identified since 2004 are conserved at these sites, it has been speculated that mutations that change the HBGA binding pattern would decrease the fitness of the virus (36). During the last transitional period when GII.4 Minerva (GII.4 2006b) was identified, another GII.4 variant was co-circulating (21,37). CaliciNet uses the same software as the US bacterial enteric pathogen surveillance network (PulseNet) (38), but it is customized with plug-ins to add CaliciNet-specific functionality. CaliciNet uses sequence data, whereas PulseNet is based on pulsed-field gel electrophoresis restriction digestion patterns of bacterial enteric pathogens. Current typing regions of CaliciNet target small regions of the norovirus genome, which makes it difficult to discern closely related norovirus strains, although the implications to human health may be significant. Our data and data from other studies (39) demonstrated that P2 region analysis enables more sensitive identification of new GII.4 variant strains compared with currently used CaliciNet regions. Use of these analyses would increase the sensitivity of outbreak surveillance to track strains that are part of a single outbreak and likely to have a common source. Hence, P2 is under consideration to be included in CaliciNet. Like CaliciNet, the Foodborne Viruses in Europe network (FBVE) uses a central database to which users can submit norovirus sequences (40). Compared with the FBVE network, CaliciNet focuses primarily on noroviruses, is not web-based, and is based on a secured network connection to CaliciNet servers at CDC where the states log on as clients, enabling them to upload, view, and query outbreak data submitted by other states. CaliciNet also organizes training workshops and sends standardized protocols and annual proficiency panels to its members. The benefit of the FBVE network is that it can be more easily expanded to include laboratories outside its network, whereas to date CaliciNet allows only participants from state and local health laboratories in the US to participate. The success of CaliciNet in linking multistate outbreaks to a common source (e.g., contaminated food) will depend on joint efforts of state and local epidemiologists to rapidly identify the likely common source and on CaliciNet laboratories for the timely upload of outbreak sequences to the national CaliciNet database. Although CaliciNet has selected region D as its preferred sequence region, a region C and soon a P2 region sequence database will be maintained to enable exchange of information with other norovirus surveillance networks. Because the region D assay targets a genetically highly heterogeneous region of VP1, the performance of this assay will be closely monitored over time, and necessary changes will be implemented to improve assay sensitivity and specificity. Future CaliciNet expansion will include other gastroenteritis viruses, such as sapovirus and astrovirus, as well as add capability for CaliciNet members to submit fecal samples from patients involved in norovirus-negative outbreaks to CDC for further testing, including novel pathogen discovery sequencing technologies (18). CaliciNet was launched in March 2009 and helped in the rapid identification of a new GII.4 variant. P2 analysis confirmed that this variant was divergent from previous GII.4 viruses. The widespread presence of GII.4 New Orleans across the US coupled with the decreasing prevalence of the GII.4 Minerva variant, which has been the major cause of outbreaks during 2006–2009, suggests gradual strain displacement. Data from the 2009–2010 winter season showed the importance of CaliciNet and its future potential for norovirus surveillance in the US. To enhance norovirus surveillance globally, CaliciNet will collaborate with other norovirus surveillance networks, such as ViroNet in Canada and the global norovirus network, NoroNet (15), to better predict or determine norovirus epidemiologic or outbreak trends. International surveillance of viral foodborne outbreaks is essential because of the increasing globalization of the food industry. Additional members of the Calicivirus network who contributed data (state represented): Chao-Yang Pan, Tasha Padilla (CA); Justin Nucci, Mary-Kate Cichon (CO); Gregory Hovan (DE); Precilia Calimlim, Cheryl-Lynn Daquip (HI); Edward Simpson (IN); Amanda Bruesch, Kari Getz (ID); Jonathan Johnston, Julie Haendiges (MD); Heather Grieser, John Martha (ME); Laura Mosher (MI); Elizabeth Cebelinski (MN); Alisha M. Nadeau, Fengxiang Gao (NH); Ondrea Shone (NJ); Frederick Gentry (NM); Gino Battaglioli (NY), Eric Brandt, Rebekah Carmen, Steven York (OH); Andrea Maloney (SC); Amy M. Woron, Christina Moore (TN); Chun Wang (TX); Valarie Devlin (VT); Tim Davis, Tonya Danz, and Jose Navidad (WI).
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The roles of Clostridium difficile and norovirus among gastroenteritis-associated deaths in the United States, 1999-2007.
U. Parashar, B. Lopman, Trent McDonald … (2012)
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. 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. 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. 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.
Author and article information
Journal
Journal ID (nlm-ta): Emerg Infect Dis
Journal ID (iso-abbrev): Emerging Infect. Dis
Journal ID (publisher-id): EID
Title:
Emerging Infectious Diseases
Publisher:
Centers for Disease Control and Prevention
ISSN
(Print):
1080-6040
ISSN
(Electronic):
1080-6059
Publication date
(Print):
October
2012
Volume: 18
Issue: 10
Pages: 1566-1573
Affiliations
[-1-1]Centers for Disease Control and Prevention, Atlanta, Georgia, USA (A.J. Hall, V.G.
Eisenbart, A. Lehman Etingüe, L.H. Gould, B.A. Lopman, U.D. Parashar);
[-2-1]Centers for Disease Control and Prevention, Atlanta, Georgia, USA (A.J. Hall, V.G.
Eisenbart, A. Lehman Etingüe, L.H. Gould, B.A. Lopman, U.D. Parashar);
Author notes
Address for correspondence: Aron J. Hall, Centers for Disease Control and Prevention,
1600 Clifton Rd NE, Mailstop A34, Atlanta, GA 30333, USA; email:
ajhall@
123456cdc.gov
Address for correspondence: Aron J. Hall, Centers for Disease Control and Prevention,
1600 Clifton Rd NE, Mailstop A34, Atlanta, GA 30333, USA; email:
ajhall@
123456cdc.gov
Article
Publisher ID: 12-0833DOI: 10.3201/eid1810.120833
PMC ID: 3471645
PubMed ID: 23017158
SO-VID: bc94baba-0f58-4d32-8a99-42b6596d90ec
History
Categories
Subject:
CME
Subject:
Research
Subject:
Research
ScienceOpen disciplines: Infectious disease & Microbiology
Data availability:
ScienceOpen disciplines: Infectious disease & Microbiology