Search

Background Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) is the state-of-the-art diagnostic for norovirus. Cycle threshold (Ct), an indicator of viral load, may be associated with symptomatic disease as well as demographic and outbreak characteristics. Methods Data on (1) outbreak and sporadic cases and (2) asymptomatic controls in the United States and Latin America were analyzed. With multivariate regression models, we assessed relationships between various factors and Ct values, and we calculated odds ratios (ORs) for the presence of symptoms and attributable fractions of norovirus. Receiver-operating characteristic analysis was performed to define an optimal Ct cutoff to identify disease-causing infections. Results Cycle threshold values were lower (ie, higher viral loads) among symptomatic cases (model-adjusted mean ± standard error: 25.3 ± 1.2) compared with asymptomatic controls (28.5 ± 1.4). Cycle threshold values were significantly different across age groups, norovirus genogroups, timing of specimen collection, outbreak settings, and transmission modes. Genogroup II (GII) Ct values were associated with presence of symptoms (OR = 1.1), allowing us to estimate that 16% of diarrheal disease was attributable to norovirus. The optimized Ct cutoff led to poor sensitivity and specificity for genogroup I and GII. Conclusions Cycle threshold values were associated with host, pathogen, and outbreak factors. Cycle threshold values may not effectively distinguish disease-causing infection for individual patients, but they are useful for epidemiological studies aiming to attribute disease.

In April 2012, the Jordan Ministry of Health investigated an outbreak of lower respiratory illnesses at a hospital in Jordan; 2 fatal cases were retrospectively confirmed by real-time reverse transcription polymerase chain reaction (rRT-PCR) to be the first detected cases of Middle East respiratory syndrome (MERS-CoV).Epidemiologic and clinical characteristics of selected potential cases were assessed through serum blood specimens, medical record reviews, and interviews with surviving outbreak members, household contacts, and healthcare personnel. Cases of MERS-CoV infection were identified using 3 US Centers for Disease Control and Prevention serologic tests for detection of anti-MERS-CoV antibodies.Specimens and interviews were obtained from 124 subjects. Seven previously unconfirmed individuals tested positive for anti-MERS-CoV antibodies by at least 2 of 3 serologic tests, in addition to 2 fatal cases identified by rRT-PCR. The case-fatality rate among the 9 total cases was 22%. Six subjects were healthcare workers at the outbreak hospital, yielding an attack rate of 10% among potentially exposed outbreak hospital personnel. There was no evidence of MERS-CoV transmission at 2 transfer hospitals having acceptable infection control practices.Novel serologic tests allowed for the detection of otherwise unrecognized cases of MERS-CoV infection among contacts in a Jordanian hospital-associated respiratory illness outbreak in April 2012, resulting in a total of 9 test-positive cases. Serologic results suggest that further spread of this outbreak to transfer hospitals did not occur. Most subjects had no major, underlying medical conditions; none were on hemodialysis. Our observed case-fatality rate was lower than has been reported from outbreaks elsewhere.

Key Points Question Is rotavirus vaccination in the United States associated with a decrease in hospitalization and emergency department visits for rotavirus in children? Findings This case-control vaccine effectiveness study included 1193 children with rotavirus infection and 9620 controls younger than 5 years with acute gastroenteritis in 7 US inpatient and emergency departments from 2010 to 2016. Both vaccines studied were associated with decreased inpatient visits and severe infections and among younger children. Meaning These findings suggest that rotavirus vaccines continue to perform well, particularly among important target populations, continuing the justification of rotavirus vaccination in US infants., This case-control study assesses US vaccine effectiveness for 2 rotavirus vaccines in preventing rotavirus inpatient and emergency department visits among children younger than 5 years., Importance Rotavirus vaccines have been recommended for universal US infant immunization for more than 10 years, and understanding their effectiveness is key to the continued success of the US rotavirus vaccine immunization program. Objective To assess the association of RotaTeq (RV5) and Rotarix (RV1) with inpatient and emergency department (ED) visits for rotavirus infection. Design, Setting, and Participants This case-control vaccine effectiveness study was performed at inpatient and ED clinical settings in 7 US pediatric medical institutions from November 1, 2009, through June 30, 2016. Children younger than 5 years seeking medical care for acute gastroenteritis were enrolled. Clinical and epidemiologic data, vaccination verification, and results of stool sample tests for laboratory-confirmed rotavirus were collected. Data were analyzed from November 1, 2009, through June 30, 2016. Main Outcomes and Measures Rotavirus vaccine effectiveness for preventing rotavirus-associated inpatient and ED visits over time for each licensed vaccine, stratified by clinical severity and age. Results Among the 10 813 children included (5927 boys [54.8%] and 4886 girls [45.2%]; median [range] age, 21 [8-59] months), RV5 and RV1 analyses found that compared with controls, rotavirus-positive cases were more often white (RV5, 535 [62.2%] vs 3310 [57.7%]; RV1, 163 [43.1%] vs 864 [35.1%]), privately insured (RV5, 620 [72.1%] vs 4388 [76.5%]; RV1, 305 [80.7%] vs 2140 [87.0%]), and older (median [range] age for RV5, 26 [8-59] months vs 21 [8-59] months; median [range] age for RV1, 22 [8-59] months vs 19 [8-59] months) but did not differ by sex. Among 1193 rotavirus-positive cases and 9620 rotavirus-negative controls, at least 1 dose of any rotavirus vaccine was 82% (95% CI, 77%-86%) protective against rotavirus-associated inpatient visits and 75% (95% CI, 71%-79%) protective against rotavirus-associated ED visits. No statistically significant difference during this 7-year period was observed for either rotavirus vaccine. Vaccine effectiveness against inpatient and ED visits was 81% (95% CI, 78%-84%) for RV5 (3 doses) and 78% (95% CI, 72%-82%) for RV1 (2 doses) among the study population. A mixed course of both vaccines provided 86% (95% CI, 74%-93%) protection. Rotavirus patients who were not vaccinated had severe infections 4 times more often than those who were vaccinated (74 of 426 [17.4%] vs 28 of 605 [4.6%]; P

Background Acute gastroenteritis (AGE) is a frequent sequela in children undergoing hematopoietic cell transplant (HCT). Although rotavirus and norovirus have been implicated as important causes of AGE, the frequency of other pathogens is unknown. Little data exist on longitudinal prevalence of infectious AGE in HCT. Methods From February 2015 to May 2016, subjects Results Thirty-one patients were enrolled at four sites (Seattle: 13, Kansas City: 8, Oakland: 6, Nashville: (4) with median age 5 (IQR 3–10) years. Two hundred sixteen samples were obtained with median 7 samples/subject. During the first 100 days, 29 (94%) subjects met the AGE definition. Thirty-six single pathogen detections occurred in 16 (52%) subjects. Clostridium difficile was the most frequent pathogen (Figure 1), with 14 detections in nine patients, all ≥3 years; 50% of detections were asymptomatic. Seven (50%) detections occurred at HCT onset and none received targeted C. difficile therapy. Sapovirus was detected nine times in four patients, with seven (78%) detections associated with AGE symptoms. Rotavirus was detected nine times, during five symptomatic episodes, in three patients. Adenovirus was detected four times in three patients and all were symptomatic. Conclusion We longitudinally characterized the etiology of infectious AGE in children undergoing HCT. Despite the majority of patients meeting the definition for AGE, only half had a pathogen detected, suggesting that differentiating infectious vs. noninfectious AGE (e.g., medication induced) in this population is difficult. Although all subjects with adenovirus and most with sapovirus were symptomatic, asymptomatic C. difficile detection was common. Interestingly, norovirus was not detected. Further investigation of AGE is warranted in this population. Disclosures All authors: No reported disclosures.

Background Norovirus is a leading cause of acute gastroenteritis (AGE) in all age groups. Although at least 28 different genotypes infecting humans have been reported, most outbreaks over the last 15 years have been caused by genogroup II (GII) viruses, of which GII.4 viruses have caused more than 50%. Since clinical differences between different genotypes are poorly understood, we sought to compare clinical characteristics in children infected with GII.4 and non-GII.4 viruses. Methods Children between 15 days and 17 years who presented with AGE defined as diarrhea (≥3 loose stools in a 24 hour period) or vomiting (≥1 episodes in a 24 hour period) within 10 days duration were recruited in outpatient, emergency, and inpatient settings in Nashville, TN, during 2012–2015. Stool specimens were tested by RT-qPCR for GI and GII norovirus. Norovirus-positive specimens were genotyped by sequencing of a partial region of the capsid gene. In this study, we excluded children infected with GI, mixed GI/GII and non-typeable GII viruses. Results Of 3,705 AGE subjects enrolled, 2,892 (78%) specimens were collected, 637 (22%) tested norovirus-positive (567 [89%] GII, 62 [10%] GI, and 8 [1%] mixed GI/GII). Of the 567 GII viruses, 461 (81%) were able to be genotyped and of those 238/461 (51.6%) were typed as GII.4 and 223/461 (48.3%) were typed as other GII genotypes (non-GII.4, primarily GII.3 [65/ 461, 14.1%], GII.6 [48/461, 10.4%] and GII.7 [36/461, 7.8%]). Over three AGE seasons, GII.4 represented 64/117 (54%), 79/178 (44%), and 71/166 (57%), of the GII infections, respectively. Compared with non-GII.4 subjects, GII.4 subjects were more likely to be younger (15.5 vs. 21.3 months, P < 0.01), and less likely to attend daycare (23% vs. 39%, P < 0.01). GII.4 subjects also were more likely to present with diarrhea (75% vs. 57%, P < 0.01) and had higher median modified Vesikari score (7 vs. 6, P < 0.01). Conclusion Children infected with GII.4 viruses were younger, less likely to attend child care, more likely to present with diarrhea, and had a more severe illness compared with those with non-GII.4 infections. These data provide important information on the genotype distribution of norovirus in children with AGE in Tennessee and highlight GII.4 as the most prevalent strain. Disclosures N. Halasa, sanofi pasteur: Investigator, Research support. GSK: Consultant, Consulting fee. Moderna: Consultant, Consulting fee.

Background Viral infections are a significant cause of severe acute respiratory illnesses (ARI) in young children. Understanding the current epidemiology of these viruses is important for informing treatment and prevention measures. We describe the New Vaccine Surveillance Network (NVSN) and report preliminary results from 2015 to 2016. Methods Prospective active surveillance for hospitalized ARI was conducted from November 1, 2015 to June 30, 2016 among children Results Among 2,974 hospitalized children with ARI whose specimens were tested for viruses, 2,228 (75%) were 1 virus detected in 234 (8%). RSV was detected in 1,039 (35%) children with ARI, HMPV in 245 (8%), influenza in 104 (4%), and PIV-1, PIV-2, and PIV-3 in 49 (2%), 2 ( Conclusion During the 2015–2016 season, viral detections were common in young children hospitalized for ARI at seven US sites. NVSN combines clinical data with current molecular laboratory techniques to describe respiratory virus epidemiology in cases of hospitalized pediatric ARI in order to inform current and future prevention, treatment, and healthcare utilization measures. Disclosures N. Halasa, Sanofi Pasteur: Investigator, Research support. GSK: Consultant, Consulting fee. Moderna: Consultant, Consulting fee. J. Englund, Gilead: Consultant and Investigator, Consulting fee and Research support. Novavax: Investigator, Research support. GlaxoSmithKline: Investigator, Research support. Alios: Investigator, Research support. MedImmune: Investigator, Research support. J. V. Williams, Quidel: Board Member, Consulting fee. GlaxoSmithKline: Consultant, Consulting fee.

Background We investigated clinical influenza testing and treatment in children hospitalized with acute respiratory illness (ARI) who had distinct respiratory syndromes. Methods Children Results Among 2,134 children with available ICD10 codes, on preliminary analysis 1,119 (52%) had influenza testing ordered by a clinician: 111 (10%) were positive, and 57 (51%) of 111 received antiviral treatment. Of the 2,134, 858 (40%) had one of the four mutually exclusive syndromes (table). Hospital clinical testing per clinician discretion was influenza positive in 16 of the 858 children (percent positivity per syndrome ranged from Conclusion Understanding testing and treatment practices by clinical syndrome may help to identify missed opportunities for influenza diagnosis and treatment. Table: Disclosures J. Englund, Gilead: Consultant and Investigator, Consulting fee and Research support. Novavax: Investigator, Research support. GlaxoSmithKline: Investigator, Research support. Alios: Investigator, Research support. MedImmune: Investigator, Research support. N. B. Halasa, sanofi pasteur: Investigator, Research support. GSK: Consultant, Consulting fee. Moderna: Consultant, Consulting fee.

We compared rotavirus detection rates in children with acute gastroenteritis (AGE) and in healthy controls using enzyme immunoassays (EIAs) and semiquantitative real-time reverse transcription PCR (qRT-PCR). We calculated rotavirus vaccine effectiveness using different laboratory-based case definitions to determine which best identified the proportion of disease that was vaccine preventable. Of 648 AGE patients, 158 (24%) were EIA positive, and 157 were also qRT-PCR positive. An additional 65 (10%) were qRT-PCR positive but EIA negative. Of 500 healthy controls, 1 was EIA positive and 24 (5%) were qRT-PCR positive. Rotavirus vaccine was highly effective (84% [95% CI 71%–91%]) in EIA-positive children but offered no significant protection (14% [95% CI −105% to 64%]) in EIA-negative children for whom virus was detected by qRT-PCR alone. Children with rotavirus detected by qRT-PCR but not by EIA were not protected by vaccination, suggesting that rotavirus detected by qRT-PCR alone might not be causally associated with AGE in all patients.

To determine the medical costs of laboratory-confirmed rotavirus hospitalizations and emergency department (ED) visits and estimate the economic impact of the rotavirus vaccine program.During 4 rotavirus seasons (2006-2009), children3 years of age hospitalized or seen in the ED with laboratory-confirmed rotavirus were identified through active population-based rotavirus surveillance in three US counties. Medical costs were obtained from hospital and physician billing data, and factors associated with increased costs were examined. Annual national costs were estimated using rotavirus hospitalization and ED visit rates and medical costs for rotavirus hospitalizations and ED visits from our surveillance program for pre- (2006-2007) and post-vaccine (2008-2009) time periods.Pre-vaccine, for hospitalizations, the median medical cost per child was $3581, the rotavirus hospitalization rate was 22.1/10,000, with an estimated annual national cost of $91 million. Post-vaccine, the median medical cost was $4304, the hospitalization rate was 6.3/10,000 and the estimated annual national cost was $31 million. Increased costs were associated with study site, age3 months, underlying medical conditions and an atypical acute gastroenteritis presentation. For ED visits, the pre-vaccine median medical cost per child was $574, the ED visit rate was 291/10,000 resulting in an estimated annual national cost of $192 million. Post-vaccine, the median medical cost was $794, the ED visit rate was 71/10,000 with an estimated annual national cost of $65 million.After implementation of rotavirus immunization, the total annual medical costs decreased from $283 million to $96 million, an annual reduction of $187 million.

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

Rotavirus vaccine introduction in the United States in 2006 led to substantial declines in rotavirus detections during 2007 to 2010. To further evaluate the long-term impact of the vaccine program, we assessed trends in rotavirus testing and detection in the 2010 to 2011 and 2011 to 2012 seasons compared with prevaccine seasons from 2000 to 2006.We examined data from July 2000 to June 2012 from 50 to 70 laboratories reporting to the National Respiratory and Enteric Viruses Surveillance System to compare rotavirus season timing and peak activity in the pre- and postvaccine introduction eras. To assess trends in rotavirus testing and detection, we restricted the analyses to 25 laboratories that consistently reported for ≥ 26 weeks for each season from 2000 to 2012.The threshold for the start of the rotavirus season was never achieved nationally during the 2011 to 2012 season, and the 2010 to 2011 season was 8 weeks shorter in duration than the prevaccine baseline. During these seasons, nationally, the number of positive rotavirus tests declined 74%-90% compared with the prevaccine baseline and the total number of tests performed annually declined 28%-36%. The annual proportion positive at the 25 consistently reporting laboratories remained below 10% in both seasons compared with a prevaccine baseline median of 26%. A pattern of biennial increases in rotavirus activity emerged during the 5 postvaccine seasons from 2007 to 2012, but activity remained substantially below prevaccine levels.A substantial and sustained decline in rotavirus activity below the prevaccine baseline was observed in all 5 postvaccine introduction years, affirming the long-term health benefits of the US rotavirus vaccination program.

Background. We assessed vaccine effectiveness (VE) for RotaTeq (RV5; 3 doses) and Rotarix (RV1; 2 doses) at reducing rotavirus acute gastroenteritis (AGE) inpatient and emergency department (ED) visits in US children. Methods. We enrolled children

Background Case-control studies are often performed to estimate postlicensure vaccine effectiveness (VE), but the enrollment of controls can be challenging, time-consuming, and costly. We evaluated whether children enrolled in the same hospital-based diarrheal surveillance used to identify rotavirus cases but who test negative for rotavirus (test-negative controls) can be considered a suitable alternative to nondiarrheal hospital or community-based control groups (traditional controls). Methods We compared calculated VE estimates as a function of varying values of true VE, attack rates of rotavirus and nonrotavirus diarrhea in the population, and sensitivity and specificity of the rotavirus enzyme immunoasssay. We also searched the literature to identify rotavirus VE studies that used traditional and test-negative control groups and compared VE estimates obtained using the different control groups. Results Assuming a 1% attack rate for severe rotavirus diarrhea, a 3% attack rate for severe nonrotavirus diarrhea in the population, a test sensitivity of 96%, and a specificity of 100%, the calculated VE estimates using both the traditional and test-negative control groups closely approximated the true VE for all values from 30% to 100%. As true VE decreased, the traditional case-control approach slightly overestimated the true VE and the test-negative case-control approach slightly underestimated this estimate, but the absolute difference was only ±0.2 percentage points. Field VE estimates from 10 evaluations that used both traditional and test-negative control groups were similar regardless of control group used. Conclusions The use of rotavirus test-negative controls offers an efficient and cost-effective approach to estimating rotavirus VE through case-control studies.

Background Group A rotaviruses (RVA) are a significant cause of pediatric gastroenteritis worldwide. The New Vaccine Surveillance Network (NVSN) has conducted active surveillance for RVA at pediatric hospitals and emergency departments at 3-7 geographically diverse sites in the United States since 2006. Methods Over 6 consecutive years, from 2008 to 2013, 1523 samples from NVSN sites that were tested positive by a Rotaclone enzyme immunoassay were submitted to the Centers for Disease Control and Prevention for genotyping. Results In the 2009, 2010, and 2011 seasons, genotype G3P[8] was the predominant genotype throughout the network, with a 46%-84% prevalence. In the 2012 season, G12P[8] replaced G3P[8] as the most common genotype, with a 70% prevalence, and this trend persisted in 2013 (68.0% prevalence). Vaccine (RotaTeq; Rotarix) strains were detected in 0.6%-3.4% of genotyped samples each season. Uncommon and unusual strains (eg, G8P[4], G3P[24], G2P[8], G3P[4], G3P[6], G24P[14], G4P[6], and G9P[4]) were detected sporadically over the study period. Year, study site, and race were found to be significant predictors of genotype. Conclusions Continued active surveillance is needed to monitor RVA genotypes in the United States and to detect potential changes since vaccine licensure.

Group A rotaviruses (RVs) are 11-segmented, double-stranded RNA viruses and are primary causes of gastroenteritis in young children. Despite their medical relevance, the genetic diversity of modern human RVs is poorly understood, and the impact of vaccine use on circulating strains remains unknown. In this study, we report the complete genome sequence analysis of 58 RVs isolated from children with severe diarrhea and/or vomiting at Vanderbilt University Medical Center (VUMC) in Nashville, TN, during the years spanning community vaccine implementation (2005 to 2009). The RVs analyzed include 36 G1P[8], 18 G3P[8], and 4 G12P[8] Wa-like genogroup 1 strains with VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5/6 genotype constellations of I1-R1-C1-M1-A1-N1-T1-E1-H1. By constructing phylogenetic trees, we identified 2 to 5 subgenotype alleles for each gene. The results show evidence of intragenogroup gene reassortment among the cocirculating strains. However, several isolates from different seasons maintained identical allele constellations, consistent with the notion that certain RV clades persisted in the community. By comparing the genes of VUMC RVs to those of other archival and contemporary RV strains for which sequences are available, we defined phylogenetic lineages and verified that the diversity of the strains analyzed in this study reflects that seen in other regions of the world. Importantly, the VP4 and VP7 proteins encoded by VUMC RVs and other contemporary strains show amino acid changes in or near neutralization domains, which might reflect antigenic drift of the virus. Thus, this large-scale, comparative genomic study of modern human RVs provides significant insight into how this pathogen evolves during its spread in the community.

In 2009, three children were hospitalized in Rochester, NY, with sequence-confirmed G8P[4] rotavirus gastroenteritis—the first U.S. detection of this uncommon strain more typically found in Africa. Continued monitoring of G8P[4] and other rotavirus genotypes not represented in current vaccines is essential to assess whether vaccination will result in an increase in prevalence of these strains.

During the 2008–2009 rotavirus season of the Centers for Disease Control and Prevention New Vaccine Surveillance Network, one case of paediatric acute gastroenteritis associated with a rotavirus G14P[24] strain was identified. This was the first detection of the genotype G14 and P[24] in humans, and the first detection of the G14P[24] combination. To gain an insight into the origins and the evolution of this strain, we determined the complete ORF sequences of all 11 genes. A majority of the genes identified were similar to the simian strain TUCH, except for the VP1 and VP7 genes that clustered only distantly with the bovine and equine strains, respectively. In addition, this strain carried AU-1-like NSP2 and NSP4 genes. Using codon-partitioning and protein-based phylogenetic approaches, we determined that the VP7 genotype of strain 2009727118 was actually G3; therefore, the proposed full genomic classification of the 2009727118 strain is G3-P[24]-I9-R2-C3-M3-A9-N3-T3-E3-H6. These findings indicate the possibility that the 2009727118 strain originated by interspecies transmission and multiple reassortment events involving human, bovine and equine rotaviruses, resulting in the introduction of some genes into the genome of simian rotaviruses. Additionally, we found evidence of mutational saturation in the third codon position of the VP7 ORF which presented an issue with homoplasy in phylogenetic analyses.

We sought to determine whether maternal vaccination during pregnancy was associated with a reduced risk of laboratory-confirmed influenza hospitalizations in infants6 months old. Active population-based, laboratory-confirmed influenza surveillance was conducted in children hospitalized with fever and/or respiratory symptoms in 3 US counties from November through April during the 2002 through 2009 influenza seasons. The exposure, influenza vaccination during pregnancy, and the outcome, positive/negative influenza testing among their hospitalized infants, were compared using logistic regression analyses. Among 1510 hospitalized infants6 months old, 151 (10%) had laboratory-confirmed influenza and 294 (19%) mothers reported receiving influenza vaccine during pregnancy. Eighteen (12%) mothers of influenza-positive infants and 276 (20%) mothers of influenza-negative infants were vaccinated (unadjusted odds ratio, 0.53; 95% confidence interval, 0.32-0.88 and adjusted odds ratio, 0.52; 95% confidence interval, 0.30-0.91). Infants of vaccinated mothers were 45-48% less likely to have influenza hospitalizations than infants of unvaccinated mothers. Our results support the current influenza vaccination recommendation for pregnant women.

Rotavirus vaccine was recommended for routine use in US infants in 2006. Before the introduction of vaccine, rotavirus was the most common cause of severe gastroenteritis in children5 years of age in the United States.We reviewed published data to summarize the US experience during the first 3 years of its rotavirus vaccination program.Rotavirus seasons have been delayed and diminished in magnitude during the postvaccine era compared with the prevaccine era. Hospitalizations, emergency department visits, and outpatient visits due to gastroenteritis have declined dramatically in children5 years of age including in children age-ineligible to have received vaccine, suggesting indirect benefits of vaccination. Rotavirus vaccine has been widely accepted by pediatricians. Vaccine coverage is steadily increasing but remains lower than coverage levels of other routine infant immunizations.The implementation of routine childhood immunization against rotavirus has rapidly and dramatically reduced the large health burden of rotavirus gastroenteritis in US children. Continued monitoring of rotavirus diarrhea is needed to determine if immunity wanes as vaccinated children get older and to better quantify the indirect benefits of vaccination. Ongoing surveillance will also enable monitoring of the long-term impact of vaccination on rotavirus epidemiology.

Vaccine efficacy is measured in randomized, prelicensure clinical trials where vaccination typically affords only direct protection to the vaccinated individual. Vaccine effectiveness is measured in postlicensure observational studies where vaccination might provide indirect benefits to a population as a whole in addition to directly protecting the vaccinated individual. The potential discrepancy in effectiveness and efficacy estimates would depend on the postlicensure study design. We developed a mathematical model to assess the impact of indirect benefits on vaccine effectiveness as measured by the common cohort study design under scenarios of homogenous and heterogenous vaccine allocation. We found that under the cohort design, effectiveness estimates equaled efficacy if either the indirect effects were assumed to be negligible or vaccine allocation in the community was homogenous. However, in presence of indirect benefits, effectiveness estimates would be biased upward compared with vaccine efficacy if one of the two sub-populations in the same study had a higher rate of vaccination. Because of indirect effects of vaccination, even in studies where other biases can be eliminated, the presence of distinct sub-populations with varying rates of vaccination can lead to discrepancies between effectiveness and efficacy estimates.

To the Editor: After the substantial decrease in acute gastroenteritis (AGE) in children caused by rotavirus after introduction of 2 rotavirus vaccines (1), norovirus has become the leading cause of medically attended AGE in US children

Background. Because a previous rotavirus vaccine was associated with intussusception, new rotavirus vaccines are monitored postlicensure for any such association. Accurate background intussusception rates are needed to determine whether the number of cases observed after vaccination exceeds that expected by chance. Previously, intussusception rates were obtained from inpatient discharge databases. We sought to determine the rate of intussusception among infants managed only with short-stay or emergency department care. Methods. Intussusception cases occurring in infants were identified retrospectively at 3 children's hospitals from January 2001 through March 2006, a period without rotavirus vaccine use, by a search of discharge, billing, and radiology databases for International Classification of Diseases, Ninth Revision, Clinical Modification code 560.0 (intussusception) and procedure codes and by review of medical records. Results. Of 156 infants with intussusception fulfilling Brighton level 1 criteria, 81 (52%) were billed as inpatients, 68 (44%) as short-stay patients, and 7 (4%) as emergency department patients only. The use of only inpatients assigned code 560.0 underestimated the total number of level 1 cases at the hospitals by 44%. The mean annual intussusception rate for the hospitals' catchment counties was 49.3 cases per 100,000 live births (inpatient cases: 27.1 cases per 100,000 live births; short-stay or emergency department cases: 22.3 cases per 100,000 live births). Conclusions. Intussusception rates based solely on inpatient discharge databases could underestimate the true incidence of level 1 intussusception by >40%. Background rates used for assessment of risk after vaccination should account for cases managed only with short-stay or emergency department care.

Purpose To investigate whether concurrent vaccinations (≥2 vaccinations on consecutive days) are associated with hospitalization risk among U.S. military personnel. Methods We analyzed Defense Medical Surveillance System data from January 1998 through December 2003 for 117,876 active component U.S. military personnel. We performed a time-to-event analysis of a historical cohort using a Cox proportional hazards model comparing hospitalizations during a 120-day postvaccination exposure interval to hospitalizations within a 120-day pre-exposure interval. We excluded personnel who were deployed during these intervals and those having hospitalizations 60 days prior to the concurrent vaccination exposure. Hazards ratios (HRs) with 95% confidence intervals were calculated, adjusting for demographic, occupational, health, and calendar variables. Results We analyzed 19,743 persons having concurrent vaccinations. Receiving two or more vaccinations concurrently was not statistically associated with the adjusted risk of hospitalization (HR = 0.90 [0.75, 1.09]). Furthermore, no statistically significant associations were detected for 3 concurrent vaccinations (HR = 0.86 [0.58, 1.28]), 4 concurrent vaccinations (HR = 1.08, [0.66, 1.74]), or five or more concurrent vaccinations (HR = 0.86 [0.49, 1.51]). Conclusions No evidence was found that the concurrent receipt of multiple vaccinations is related to hospitalization risk among this sample of U.S. military personnel.

Purpose Understanding the completeness and accuracy of U.S. military anthrax vaccination data is important to the design and interpretation of studies to assess the safety of anthrax vaccine. We estimated the agreement between electronically recorded anthrax vaccination data in the Defense Medical Surveillance System (DMSS) versus anthrax vaccination data abstracted from hardcopy medical charts in a representative sample of the U.S. military from 1998 to 2004. Methods Medical chart abstractions were conducted at 28 military treatment facilities for 4201 personnel. Abstracted anthrax vaccination data for 1817 personnel, representing 7400 anthrax vaccine doses, were compared with electronically captured data in the DMSS from 1998 to 2004. Sensitivity, positive predictive value (PPV), specificity and negative predictive value (NPV) were calculated using weighted analyses. Results Weighted person-level analysis revealed DMSS sensitivity = 93.8% (95%CI = 91.1, 95.8), specificity = 87.0% (79.0, 92.3), PPV = 85.6% (77.2, 91.3) and NPV = 94.5% (91.7, 96.4). Report of anthrax vaccination within a ±7 days window in both medical chart and DMSS electronic data had a sensitivity of 88.3% (85.4, 90.7) and a PPV of 86.6% (84.9, 88.2) in the vaccine dose-level analysis. Conclusions These results support that anthrax vaccination data captured by the DMSS are adequate for post-marketing surveillance investigations in the U.S. military and are of comparable quality to data captured by other vaccine safety databases. Copyright © 2007 John Wiley & Sons, Ltd.

A genetic polymorphism affecting FUT2 secretor status in approximately one-quarter of humans of European descent affects the expression of histo-blood group antigens on the mucosal epithelia of human respiratory, genitourinary, and digestive tracts. These histo-blood group antigens serve as host receptor sites necessary for attachment and infection of some pathogens, including norovirus.We investigated whether an association exists between FUT2 secretor status and laboratory-confirmed rotavirus infections in US children.Multicenter case-control observational study involving active surveillance at 6 US pediatric medical institutions in the inpatient and emergency department clinical settings. We enrolled 1564 children younger than 5 years with acute gastroenteritis (diarrhea and/or vomiting) and 818 healthy controls frequency matched by age and month, from December 1, 2011, through March 31, 2013.Paired fecal-saliva specimens were tested for rotavirus and for secretor status. Comparisons were made between rotavirus test-positive cases and healthy controls stratified by ethnicity and vaccination status. Adjusted multivariable analyses assessed the preventive association of secretor status against severe rotavirus gastroenteritis.One (0.5%) of 189 rotavirus test-positive cases was a nonsecretor, compared with 188 (23%) of 818 healthy control participants (P .001). Healthy control participants of Hispanic ethnicity were significantly less likely to be nonsecretors (13%) compared with healthy children who were not of Hispanic ethnicity (25%) (P .001). After controlling for vaccination and other factors, children with the nonsecretor FUT2 polymorphism appeared statistically protected (98% [95% CI, 84%-100%]) against severe rotavirus gastroenteritis.Severe rotavirus gastroenteritis was virtually absent among US children who had a genetic polymorphism that inactivates FUT2 expression on the intestinal epithelium. We observed a strong epidemiologic association among children with rotavirus gastroenteritis compared with healthy control participants. The exact cellular mechanism behind this epidemiologic association remains unclear, but evidence suggests that it may be rotavirus genotype specific. The lower prevalence of nonsecretors among Hispanic children may translate to an enhanced burden of rotavirus gastroenteritis among this group. Our findings may have bearing on our full understanding of rotavirus infections and the effects of vaccination in diverse populations.

BACKGROUND During the past decade, substantial declines in overall childhood mortality from diarrhea have been documented among Chinese children, but the last detailed assessment of rotavirus-specific mortality in China was conducted in 2002. To provide policy makers with up-to-date information, we examined rotavirus-related mortality in children

PURPOSE OF REVIEW We discuss recent advances in the understanding of acquired immunity and susceptibility to the two major pediatric enteric viral pathogens, norovirus and rotavirus. RECENT FINDINGS The prominent decline in severe rotavirus gastroenteritis in areas with mature rotavirus vaccination programmes has correspondingly unmasked the significant burden of disease associated with norovirus gastroenteritis among children. As epidemiologists and vaccinologists set their sights on this next vaccine target, we provide an update on norovirus vaccine development.In addition to these developments regarding acquired immunity, refinements to our understanding of innate susceptibility to norovirus has advanced. Significant recent advances now describe similar immunologic mechanisms in understanding susceptibility for both norovirus and rotavirus, involving histo-blood group antigenic associations, which may also prove to be genotype specific. SUMMARY This information can potentially be used to tailor both applied and developmental efforts to public health interventions against these important pediatric enteric viral pathogens.

(See the Editorial Commentary by Debbink on pages 1639–41.) Norovirus is associated with nearly one-fifth of acute gastroenteritis (AGE) cases worldwide and is the leading cause of pediatric AGE in countries with universal rotavirus vaccination [1, 2]. Norovirus causes 200 000 pediatric deaths each year in developing countries [3]. Though rarely fatal in developed countries, norovirus AGE causes substantial morbidity and is responsible for 20 million cases annually in the United States alone [4]. The illness is characterized by sudden onset of severe vomiting and dehydrating diarrhea lasting 1–3 days [5]. Its high transmissibility makes norovirus an important public health concern, particularly in closed settings such as long-term care facilities, schools and child care centers, and military barracks [5, 6]. Human susceptibility to norovirus infection is thought to be at least partially dependent upon an individual's fucosyltransferase 2 (FUT2) genotype [7–16]. FUT2 controls the secretion of ABO histo-blood group antigens (HBGAs) at the gut surface. These carbohydrates serve as binding ligands and presumed receptors for caliciviruses, the virus family that includes norovirus [7]. However, in vitro and in silico studies have shown that noroviruses bind to HBGAs in a strain-specific manner [8, 9]. At least 1 functional FUT2 allele is present in 70%–80% of individuals, who are referred to as FUT2 “secretors” [17]. FUT2 is inactivated in the remaining 20%–30% (“nonsecretors”) by homozygous 428G > A nonsense mutations in European and African populations, or less common variants such as the 385A > T missense mutation found in Asian populations [17]. Individuals of Meso-American descent rarely carry these inactivating mutations [10, 17]. In challenge studies, FUT2 nonsecretors have demonstrated resistance to specific noroviruses, developing neither symptoms nor antibody response to norovirus genotypes GI.1 or GII.4 [11, 12, 18]. In epidemiologic studies, FUT2 nonsecretors have demonstrated significantly lower susceptibility to symptomatic infection by some norovirus genotypes (GI.1, GII.3, GII.4) [13–15, 18] but not others (GI.3, GII.3) [15, 16]. Although numerous outbreak studies have shown increased susceptibility of FUT2 secretors to specific noroviruses, the impact of FUT2 on overall risk of sporadic norovirus in racially/ethnically diverse populations has not been examined. Furthermore, secretor genetics in relation to asymptomatic shedding of norovirus has not been studied in populations in which the nonsecretor genotype is common. Finally, although in vitro work suggests that A and B blood group antigens may modify risk of norovirus infection in secretor individuals [8], this question has not been well addressed in epidemiologic studies. With norovirus vaccines currently in development [2], understanding population patterns of susceptibility to this pathogen is crucial. Our study utilizes a large, prospective, geographically diverse AGE surveillance network to identify sporadic pediatric norovirus infections. We use these surveillance data to determine the relationship of FUT2 secretor status to symptomatic and asymptomatic norovirus infection and modification of that relationship by non-O blood group types, and to describe FUT2 secretor status in the United States by racial/ethnic background.

Group A Rotaviruses (RVA) are double stranded RNA viruses that are a significant cause of acute pediatric gastroenteritis. Beginning in 2006 and 2008, respectively, two vaccines, Rotarix™ and RotaTeq®, have been approved for use in the USA for prevention of RVA disease. The effects of possible vaccine pressure on currently circulating strains in the USA and their genome constellations are still under investigation. In this study we report 33 complete RVA genomes (ORF regions) collected in multiple cities across USA during 2006 – 2009, including 8 collected from children with verified receipt of 3 doses of rotavirus vaccine. The strains included 16 G1P[8], 10 G3P[8], and 7 G9P[8]. All 33 strains had a Wa like backbone with the consensus genotype constellation of G(1/3/9)-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. From maximum likelihood based phylogenetic analyses, we identified 3 to7 allelic constellations grouped mostly by respective G types, suggesting a possible allelic segregation based on the VP7 gene of RVA primarily for the G3 and G9 strains. The vaccine failure strains showed similar grouping for all genes in G9 strains and most genes of G3 strains suggesting that these constellations were necessary to evade vaccine-derived immune protection. Substitutions in the antigenic region of VP7 and VP4 genes were also observed for the vaccine failure strains which could possibly explain how these strains escape vaccine induced immune response. This study helps elucidate how RVA strains are currently evolving in the population post vaccine introduction and supports the need for continued RVA surveillance.

To the Editor: Group A rotaviruses (RVAs) are a leading cause of acute gastroenteritis-associated deaths among children

Background Although antiviral therapy is recommended for hospitalized patients with suspected or confirmed influenza, clinicians often rely on test results to determine management. Rapid influenza diagnostic tests (RIDTs) have suboptimal sensitivity; use of molecular assays may improve care. We evaluated clinical influenza testing and antiviral treatment practices in hospitalized children. Methods Children aged Results Of 2267 children, 1165 (51%) had clinical diagnostic testing on upper respiratory samples: 276 (24%) by RIDT alone, 780 (67%) by molecular testing alone, and 109 (9%) by both. The use of molecular testing alone varied by site, from 10% to 100% of samples tested. Of 116 (10%) children testing positive for influenza, 60 (52%) were treated; by site, treatment of children positive for influenza ranged from 25% to 83%. Antiviral treatment was given to 16/20 (80%) of those admitted ≤2 days from symptom onset vs. 44/96 (46%) children admitted >2 days after onset. Among 94 children tested by one method who were positive, >80% had samples collected in the emergency department or on day of admission, and 47 started treatment (Figure, A): 16/37 (43%) and 31/57 (54%) were treated when tested by RIDT alone and molecular testing alone, respectively. Of those positive children treated, 7/16 (44%) tested by RIDT vs. 22/31 (71%) by molecular testing started treatment on the day of testing (Figure, B). Conclusion Half of hospitalized children with ARI who tested positive for influenza received antiviral treatment. Although there was high variability in testing and treatment by site, in positive patients who were treated the use of molecular testing appeared to be associated with prompt antiviral therapy. Understanding clinician reasons for relatively low treatment overall will require further investigation. Disclosures J. Englund, Gilead: Consultant and Investigator, Research support Chimerix: Investigator, Research support Alios: Investigator, Research support Novavax: Investigator, Research support MedImmune: Investigator, Research support GlaxoSmithKline: Investigator, Research support N. B. Halasa, sanofi pasteur: Research Contractor, Research support Astra Zeneca: Research Contractor, Grant recipient

Background While nearly 2 million children are brought to emergency department (ED) annually due to vomiting and/or diarrhea from acute gastroenteritis (AGE), it is estimated that 90% of AGE cases do not seek medical care. We sought to determine whether the disease severity and enteropathogen burden of disease of children with AGE brought for ED care is different from those cared for at home. Methods Subjects were prospectively recruited by the APPETITE team in pediatric EDs in 2 urban centers and via HealthLink, a province-wide nurse telephone advice line. Eligibility criteria included: < 18 years old, AGE defined by ≥ 3 episodes of vomiting or diarrhea in the preceding 24 hours, and < 7 days of symptoms. The primary outcome was index encounter disease severity quantified using the modified Vesikari Scale (MVS) score. To eliminate the impact of the index encounter on the score we excluded the index ED visit and intervention from all calculations. Secondary objectives included the enteropathogen burden of disease. Two rectal swabs and stool were collected and tested for enteropathogens by enteric bacterial culture, Luminex xTAG GPP, and a 5-virus in-house RT-qPCR panel. Results Between December 9, 2014 and December 31, 2016, 1,623 participants were enrolled with 81.5% from the EDs. Median age was 20.1 months. Children who went to ED were less likely to have a family physician (62 vs. 82%, P < 0.001), more likely to have clinical dehydration (Clinical Dehydration Scale score 3 vs 1, P < 0.001) and vomiting (91 vs. 85%, P = 0.004), previously received IV fluids (4.1 vs. 0.7%, P = 0.001) or been admitted (5.4 vs. 1.3%, P = 0.002). The MVS score was similar between groups when the contribution of the index visit to the score was excluded (8.1 vs. 7.8, P = 0.15). Participants recruited in the ED were not significantly more likely to have bacterial pathogens (8.0 vs. 3.7%, P = 0.09) but were less likely to have viral pathogens identified (64.1 vs. 80.7, P < 0.001). Conclusion Children presenting for ED care had disease severity scores that were similar to children managed at home when the contribution of the index ED visit was accounted for. Viral pathogens were more common in AGE receiving care at home while those presenting to the ED and potentially have a clinically greater likelihood of having a bacterial enteropathogen. Disclosures All authors: No reported disclosures.

Group A rotaviruses (RVs) remain a leading cause of childhood gastroenteritis worldwide. Although the G/P types of locally circulating RVs can vary from year to year and differ depending upon geographical location, those with G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8] specificities typically dominate. Little is known about the evolution and diversity of G2P[4] RVs and the possible role that widespread vaccine use has had on their increased frequency of detection. To address these issues, we analyzed the 12 G2P[4] RV isolates associated with a rise in RV gastroenteritis cases at Vanderbilt University Medical Center (VUMC) during the 2010-2011 winter season. Full-genome sequencing revealed that the isolates had genotype 2 constellations typical of DS-1-like viruses (G2P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2). Phylogenetic analyses showed that the genome segments of the isolates were comprised of two or three different subgenotype alleles; this enabled recognition of three distinct clades of G2P[4] viruses that caused disease at VUMC in the 2010-2011 season. Although the three clades cocirculated in the same community, there was no evidence of interclade reassortment. Bayesian analysis of 328 VP7 genes of G2 viruses isolated in the last 39 years indicate that existing G2 VP7 gene lineages continue to evolve and that novel lineages, as represented by the VUMC isolates, are constantly being formed. Moreover, G2 lineages are characteristically shaped by lineage turnover events that introduce new globally dominant strains every 7 years, on average. The ongoing evolution of G2 VP7 lineages may give rise to antigenic changes that undermine vaccine effectiveness in the long term. IMPORTANCE Little is known about the diversity of cocirculating G2 rotaviruses and how their evolution may undermine the effectiveness of rotavirus vaccines. To expand our understanding of the potential genetic range exhibited by rotaviruses circulating in postvaccine communities, we analyzed part of a collection of rotaviruses recovered from pediatric patients in the United States from 2010 to 2011. Examining the genetic makeup of these viruses revealed they represented three segregated groups that did not exchange genetic material. The distinction between these three groups may be explained by three separate introductions. By comparing a specific gene, namely, VP7, of the recent rotavirus isolates to those from a collection recovered from U.S. children between 1974 and 1991 and other globally circulating rotaviruses, we were able to reconstruct the timing of events that shaped their ancestry. This analysis indicates that G2 rotaviruses are continuously evolving, accumulating changes in their genetic material as they infect new patients.

Prior to the introduction of rotavirus vaccines in 2006, rotavirus was the leading cause of severe gastroenteritis among US children

Since the introduction of rotavirus vaccines for universal vaccination of infants in the United States (RotaTeq [RV5], Merck Vaccines, Whitehouse Station, New Jersey; Rotarix [RV1], GlaxoSmithKline Biologicals, Rixensart, Belgium), vaccination against rotavirus has resulted in substantial declines in severe gastroenteritis among US children [1–5]. Rotavirus infection is not limited to the intestine and is associated with antigenemia in approximately one-half of children hospitalized with rotavirus gastroenteritis [6–9]. Furthermore, rotavirus has been isolated in cell culture from the sera of infected children, thus confirming that the existence of viremia and the potential for systemic illness exists [6]. Wild-type rotavirus has been detected in cerebrospinal fluid by polymerase chain reaction and electron microscopy in cases of seizure occurring with diarrhea [10–13]. Clinical neurologic illness has been linked to rotavirus infection in numerous studies and case reports [14–19]. One of the largest, a multicenter study of 1359 patients hospitalized with laboratory-confirmed rotavirus in Canada from 2005 to 2007, reported that 7% of these subjects experienced a seizure [20]. A retrospective cohort analysis at a single US hospital from 2002 to 2006 reported that 6 of 34 children (18%) hospitalized with rotavirus-associated seizures spent at least 1 day in an intensive care unit, and a lumbar puncture was performed on 20 of these 34 children (59%) [21]. Gastroenteritis-associated seizures often occur in clusters (>1 seizure in 24 hours) and while the child is afebrile [22]. These events may be more likely than febrile seizures to prompt emergent care, invasive diagnostic procedures, and follow-up medical care and/or medication, and are not included in guidelines addressing the management of children with simple febrile seizures [23–25]. With the clinically observed relationship between natural rotavirus infections and seizures, we studied a retrospective cohort of children enrolled in the Vaccine Safety Datalink (VSD) to investigate whether a protective association exists between receipt of rotavirus vaccination and being hospitalized or receiving care at an emergency department (ED) for seizure the year following vaccination.

Surveillance for rotavirus-associated diarrhea after implementation of rotavirus vaccination can assess vaccine effectiveness and identify disease-associated genotypes. During active vaccine postlicensure surveillance in the United States, we found a novel rotavirus genotype, G14P[24], in a stool sample from a child who had diarrhea. Unusual rotavirus strains may become more prevalent after vaccine implementation.

Background\ud \ud We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era.\ud \ud Methods\ud \ud Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (household-contact characteristics).\ud \ud Results\ud \ud Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was

In 2006–07, 77 cases of gastroenteritis in Rochester, NY, USA were associated with rotavirus genotype G12P[8]. Sequence analysis identified a high degree of genetic relatedness among the VP7 and VP4 genes of the Rochester G12P[8] strains and between these strains and currently circulating human G12P[8] strains. Out of 77 samples, two and seven unique nucleotide sequences were identified for VP7 and VP4 genes, respectively. Rochester strain VP7 genes were found to occupy the G12-III lineage and VP4 genes clustered within the P[8]-3 lineage. Six strains contained non-synonymous nucleotide substitutions that produced amino acid changes at 6 sites in the VP8 ∗ region of the VP4 gene. Two sites (amino acids 242 and 246) were located in or near a described trypsin cleavage site. Selection analyses identified one positively selected VP7 site (107) and strong purifying selection at 58 sites within the VP7 gene as well as 2 of the 6 variant sites (79 and 218) in VP4.

Background. Although rotavirus and norovirus cause nearly 40% of severe endemic acute gastroenteritis (AGE) in children

The objective of this study is to determine the vaccine effectiveness (VE) of the pentavalent rotavirus vaccine (RV5) for preventing rotavirus-related hospitalizations and emergency department (ED) visits during the 2006–07 and 2007–08 rotavirus seasons using two study designs. Active, prospective population-based surveillance was conducted to identify cases of laboratory-confirmed rotavirus-related hospitalizations and ED visits to be used in case-cohort and case-control designs. VE was calculated using one comparison group for the case-cohort method and two comparison groups for the case-control method. The VE estimates produced by the three analyses were similar. Three doses of RV5 were effective for preventing rotavirus-related hospitalizations and ED visits in each analysis, with VE estimated as 92% in all three analyses. Two doses of RV5 were also effective, with VE ranging from 79% to 83%. A single dose was effective in the case-cohort analysis, but was not significant in either of the case-control analyses. The case-cohort and the case-control study designs produced the same VE point estimates for completion of the three dose series. Two and three doses of RV5 were effective in preventing rotavirus-related hospitalizations and ED visits.