Prior infection with intestinal coronaviruses moderates symptom severity and mortality in patients with COVID-19: A hypothesis and preliminary evidence.

The pandemic of acute respiratory illness caused by the novel betacoronavirus SARS-CoV-2, officially designated COVID-19, has attained the proportions of a global health crisis. Though all nations of the world have been affected by this disease, there have been marked cross-national variations in prevalence, severity and mortality rates. Various explanations, based on demographic, social and climatic factors, have been suggested to account for this variability, but these remain unverified to date. Based on recent research findings suggesting that human enterocytes may serve as a point of entry for SARS-CoV-2, leading to intestinal viral replication, this paper puts forward the hypothesis that prior intestinal infection with coronaviruses, either symptomatic or asymptomatic, may moderate this process and minimize the severity of SARS-CoV-2 infection. This hypothesis is supported by evidence on the gastrointestinal manifestations of SARS-CoV-2 and related infections, on the geographical patterns observed in the variability of COVID-19 mortality, and on the occurrence and geographical distribution of outbreaks of diarrheal disease, as well as asymptomatic infection, with human coronaviruses as verified by direct or serological testing. Preliminary supporting evidence based on national and international health statistics is presented, along with suggestions on more robust methods by which this hypothesis may be tested. If the proposal put forth in this paper can be confirmed either wholly or in part, it would have significant implications in terms of strategies aimed at minimizing the severity of COVID-19 in a clinical setting.

First isolation and whole-genome characterization of a G9P[14] rotavirus strain from a diarrheic child in Egypt.

An unusual group A rotavirus (RVA) strain (RVA/Human-tc/EGY/AS997/2012/G9[14]) was isolated for the first time in a faecal sample from a 6-month-old child who was hospitalized for treatment of acute gastroenteritis in Egypt in 2012. Whole-genome analysis showed that the strain AS997 had a unique genotype constellation: G9-P[14]-I2-R2-C2-M2-A11-N2-T1-E2-H1. Phylogenetic analysis indicated that the strain AS997 had the consensus P[14] genotype constellation with the G9, T1 and H1 reassortment. This suggests either a mixed gene configuration originated from a human Wa-like strain and a P[14]-containing animal virus, or that this P[14] could have been acquired via reassortment of human strains only. The study shows the possible roles of interspecies transmission and multiple reassortment events leading to the generation of novel rotavirus genotypes and underlines the importance of whole-genome characterization of rotavirus strains in surveillance studies.

Bovine Colostrum in the Treatment of Acute Diarrhea in Children: A Double-Blinded Randomized Controlled Trial.

OBJECTIVES: To evaluate the effect of bovine colostrum (BC) on the treatment of children with acute diarrhea attending the outpatient clinic. METHODS: This double-blind randomized controlled trial was conducted on 160 children with diarrhea; 80 cases were randomly treated with BC group and 80 cases randomly received placebo (placebo group). All cases were investigated for bacterial causes of diarrhea (Salmonella spp, Shigella spp, diarrheagenic E. coli (DEC), Campylobacter spp., and Vibrio cholerae) as well as for Rotavirus antigen in stool. RESULTS: After 48 h, the BC group had a significantly lower frequency of vomiting, diarrhea and Vesikari scoring compared with the placebo group (p = 0.000, p = 0.000, p = 0.000, respectively), whether it was due to Rotavirus or E. coli infection. CONCLUSIONS: BC is effective in the treatment of acute diarrhea and can be considered as adjuvant therapy in both viral and bacterial diarrhea to prevent diarrhea-related complications.

El Niño-Southern oscillation and under-5 diarrhea in Botswana.

Childhood diarrheal disease causes significant morbidity and mortality in low and middle-income countries, yet our ability to accurately predict diarrhea incidence remains limited. El Niño-Southern Oscillation (ENSO) has been shown to affect diarrhea dynamics in South America and Asia. However, understanding of its effects in sub-Saharan Africa, where the burden of under-5 diarrhea is high, remains inadequate. Here we investigate the connections between ENSO, local environmental conditions, and childhood diarrheal disease in Chobe District, Botswana. Our results demonstrate that La Niña conditions are associated with cooler temperatures, increased rainfall, and higher flooding in the Chobe region during the rainy season. In turn, La Niña conditions lagged 0-5 months are associated with higher than average incidence of under-5 diarrhea in the early rainy season. These findings demonstrate the potential use of ENSO as a long-lead prediction tool for childhood diarrhea in southern Africa.

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

BACKGROUND: Rotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech). OBJECTIVES: To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children. SEARCH METHODS: On 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty. MAIN RESULTS: Fifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac. RV1 Children vaccinated and followed up the first year of life In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence). RV5 Children vaccinated and followed up the first year of life In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence). Children vaccinated and followed up for two years In low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence). Rotavac Children vaccinated and followed up the first year of life Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up. Children vaccinated and followed up for two years Rotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence). No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence). There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint. AUTHORS' CONCLUSIONS: RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events. 21 October 2019 Up to date All studies incorporated from most recent search All published trials found in the last search (4 Apr, 2018) were included and 15 ongoing studies are currently awaiting completion (see 'Characteristics of ongoing studies').

CONTEXTE: Le rotavirus entraîne plus de décès liés à la diarrhée chez les enfants de moins de cinq ans que tout autre agent unique dans les pays où la mortalité infantile est élevée. C'est également une cause fréquente d'hospitalisations liées à la diarrhée dans les pays où la mortalité infantile est faible. Les vaccins antirotavirus préqualifiés par l'Organisation mondiale de la santé (OMS) comprennent un vaccin monovalent (RV1 ; Rotarix, GlaxoSmithKline), un vaccin pentavalent (RV5 ; RotaTeq, Merck) et plus récemment un autre vaccin monovalent (Rotavac, Bharat Biotech). OBJECTIFS: Évaluer les vaccins antirotavirus préqualifiés par l'OMS (RV1, RV5 et Rotavac) pour leur efficacité et leur innocuité chez les enfants. STRATÉGIE DE RECHERCHE DOCUMENTAIRE: Le 4 avril 2018, nous avons effectué une recherche dans MEDLINE (via PubMed), le registre spécialisé du groupe de travail Cochrane sur les maladies infectieuses (the Cochrane Infectious Diseases Group), CENTRAL (publié dans la Bibliothèque Cochrane), Embase, LILACS, et BIOSIS. Nous avons également effectué des recherches dans le système d'enregistrement international des essais cliniques (ICTRP) de l'OMS, ClinicalTrials.gov, les rapports d'essais cliniques trouvés sur les sites Web des fabricants, les références des études incluses et les revues systématiques pertinentes. CRITÈRES DE SÉLECTION: Nous avons sélectionné des essais cliniques contrôlés randomisés (ECR) chez des enfants comparant des vaccins antirotavirus préqualifiés pour utilisation par l'OMS à un placebo ou à aucune intervention. RECUEIL ET ANALYSE DES DONNÉES: Deux auteurs de la revue ont évalué de façon indépendante l'éligibilité à l'essai et évalué les risques de biais. Un auteur de la revue a extrait les données et un deuxième auteur les a vérifiées par recoupement. Nous avons combiné des données dichotomiques en utilisant le risque relatif (RR) et l'intervalle de confiance à 95 % (IC). Nous avons stratifié l'analyse par taux de mortalité par pays et utilisé GRADE pour évaluer la valeur probante des données. RÉSULTATS PRINCIPAUX: Cinquante­cinq essais ont satisfait aux critères d'inclusion et enrôlé 216 480 participants au total. Trente­six essais cliniques (119 114 participants) ont évalué le RV1, 15 essais cliniques (88 934 participants) le RV5 et quatre essais cliniques (8432 participants) le Rotavac. RV1 Enfants vaccinés et suivis au cours de leur première année de vie Dans les pays à faible mortalité, le RV1 prévient 84 % des cas graves de diarrhée à rotavirus (RR 0,16, IC à 95 % : 0,09 à 0,26 ; 43 779 participants, 7 essais ; données de bonne valeur probante) et probablement 41 % des cas de diarrhée sévère toutes causes confondues (RR 0,59, IC à 95 % : 0,47 à 0,74 ; 28 051 participants, 3 essais ; données de valeur probante moyenne). Dans les pays à forte mortalité, le RV1 prévient 63 % des cas graves de diarrhée à rotavirus (RR 0,37, IC à 95 % : 0,23 à 0,60 ; 6114 participants, 3 essais ; données de bonne valeur probante) et 27 % des cas graves de diarrhée toutes causes confondues (RR 0,73, IC à 95 % : 0,56 à 0,95 ; 5639 participants, 2 essais ; données de bonne valeur probante). Enfants vaccinés et suivis pendant deux ans Dans les pays à faible mortalité, le RV1 prévient 82 % des cas graves de diarrhée à rotavirus (RR 0,18, IC à 95 % : 0,14 à 0,23 ; 36 002 participants, 9 essais ; données de bonne valeur probante) et probablement 37 % des épisodes graves de diarrhée toutes causes confondues (rapport des taux 0,63, IC à 95 % : 0,56 à 0,71 ; 39 091 participants, 2 essais ; données de valeur probante moyenne). Dans les pays à forte mortalité, le RV1 prévient probablement 35 % des cas graves de diarrhée à rotavirus (RR 0,65, IC à 95 % : 0,51 à 0,83 ; 13 768 participants, 2 essais ; données de bonne valeur probante) et 17 % des cas graves de diarrhée toutes causes confondues (RR 0,83, IC à 95 % : 0,72 à 0,96 ; 2764 participants, 1 essai ; données de valeur probante moyenne). Aucune augmentation du risque d'événements indésirables graves (EIG) n'a été décelée (RR 0,88 IC à 95 % 0,83 à 0,93 ; données de bonne valeur probante). On a signalé 30 cas d'invagination (intussusception) intestinale chez 53 032 enfants après la vaccination RV1 et 28 cas chez 44 214 enfants après l'administration d'un placebo ou l'absence d'intervention (RR 0,70, IC à 95 % : 0,46 à 1,05 ; données de faible valeur probante). RV5 Enfants vaccinés et suivis au cours de leur première année de vie Dans les pays à faible mortalité, le RV5 prévient probablement 92 % des cas graves de diarrhée à rotavirus (RR 0,08, IC à 95 % : 0,03 à 0,22 ; 4 132 participants, 5 essais ; données de valeur probante moyenne). Nous n'avons pas identifié d'études sur les diarrhées graves toutes causes confondues dans les pays à faible mortalité. Dans les pays à forte mortalité, le RV5 prévient 57 % des cas de diarrhée à rotavirus grave (RR 0,43, IC à 95 % : 0,29 à 0,62 ; 5916 participants, 2 essais ; données de bonne valeur probante), mais il n'y a probablement que peu voire pas de différence entre vaccin et placebo pour la diarrhée grave toutes causes confondues (RR 0,80, IC à 95 % : 0,58 à 1,11 ; 1 essai, 4085 participants ; données de valeur probante moyenne). Enfants vaccinés et suivis pendant deux ans Dans les pays à faible mortalité, le RV5 prévient 82 % des cas graves de diarrhée à rotavirus (RR 0,18, IC à 95 % : 0,08 à 0,39 ; 7318 participants, 4 essais ; données de valeur probante moyenne). Nous n'avons pas identifié d'études sur les diarrhées graves toutes causes confondues dans les pays à faible mortalité. Dans les pays à forte mortalité, le RV5 prévient 41 % des cas graves de diarrhée à rotavirus (RR 0,59, IC à 95 % : 0,43 à 0,82 ; 5 885 participants, 2 essais ; données de bonne valeur probante) et 15 % des cas graves de diarrhée toutes causes confondues (RR 0,85, IC à 95 % : 0,75 à 0,98 ; 5977 participants, 2 essais ; données de bonne valeur probante). Aucune augmentation du risque d'évènements indésirables graves (EIG) n'a été décelée (RR 0,93 IC à 95 % 0,86 à 1,01 ; données de valeur probante moyenne à bonne). Il y a eu 16 cas d'invagination chez 43 629 enfants après la vaccination RV5 et 20 cas chez 41 866 enfants après le placebo (RR 0,77, IC à 95 % : 0,41 à 1,45 ; données de faible valeur probante). Rotavac Enfants vaccinés et suivis au cours de leur première année de vie Le Rotavac n'a fait l'objet d'aucun ECR dans les pays à faible mortalité infantile. En Inde, pays à forte mortalité, le Rotavac prévient probablement 57 % des cas graves de diarrhée à rotavirus (RR 0,43, IC à 95 % : 0,30 à 0,60 ; 6799 participants, données de valeur probante moyenne) ; l'essai n'a pas fait état de diarrhée grave toutes causes confondues à un an de suivi. Enfants vaccinés et suivis pendant deux ans Le Rotavac prévient probablement 54 % des cas graves de diarrhée à rotavirus en Inde (RR 0,46, IC à 95 % : 0,35 à 0,60 ; 6541 participants, 1 essai ; données de valeur probante moyenne) et 16 % des cas graves de diarrhée toutes causes confondues (RR 0,84, IC à 95 % : 0,71 à 0,98 ; 6799 participants, 1 essai ; données de valeur probante moyenne). Aucune augmentation du risque d'évènements indésirables graves (EIG) n'a été décelée (RR 0,93 95 % IC 0,85 à 1,02 ; données de valeur probante moyenne). Il y a eu huit cas d'invagination intestinale chez 5 764 enfants après la vaccination par Rotavac et trois cas chez 2 818 enfants après le placebo (RR 1,33, IC à 95 % : 0,35 à 5,02 ; données de très faible valeur probante). Il n'y avait pas suffisamment de données probante indiquant un effet sur la mortalité attribuable à un vaccin antirotavirus (198 381 participants, 44 essais ; données de valeur probante faible à très faible), car les essais n'étaient pas assez puissants pour détecter un effet à ce paramètre. CONCLUSIONS DES AUTEURS: Les vaccins RV1, RV5 et Rotavac préviennent les épisodes de diarrhée à rotavirus. Bien que l'estimation de l'effet relatif soit plus faible dans les pays à forte mortalité que dans les pays à faible mortalité, le nombre d'épisodes évités est plus élevé dans ces pays car le risque de base est beaucoup plus élevé. Nous n'avons trouvé aucun risque accru d'événements indésirables graves.

Rotavirus A Infections in Community Childhood Diarrhea in the Brazilian Semiarid Region During Postvaccination Era.

BACKGROUND: Rotavirus A (RVA) is one of the leading causes of acute gastroenteritis worldwide; however, few studies assessed RVA genetics with community surveillance. OBJECTIVES: This study aimed to investigate clinical data, genetic diversity, and coinfection patterns of RVA infections in children from 2 to 36 months old with or without community childhood diarrhea in the Brazilian semiarid region during postvaccination era. METHODS: We enrolled and collected socioeconomic/clinical information using a standardized questionnaire and fecal samples from 291 children. Viral RNA samples were extracted and analyzed using quantitative reverse transcription polymerase chain reaction to establish the diagnosis of RVA. Sequencing of VP7 and VP4 (VP8*) regions and phylogenetic analysis were performed. RESULTS: RVA-negative diagnosis was associated with children 24 to 36 months old with complete vaccination schedule. Genotype G1P[8] was the most prevalent (57%), whereas unusual genotypes including G1P[4], G2P[8], and G3P[9] were also detected. G1- and P[8]-positive samples showed high degrees of similarity with the vaccine strain. RVA coinfections were frequently observed, and enteroaggregative Escherichia coli was the most prevalent copathogen. CONCLUSIONS: These results demonstrate that genotype G1P[8] is the most prevalent strain. VP7 and/or VP8* gene segments arising from RV1 vaccine strain were documented in these children, suggesting shedding or herd vaccination. Moreover, our study indicates full vaccination is important for protection against RVA infections.

The seasonality of diarrheal pathogens: A retrospective study of seven sites over three years.

BACKGROUND: Pediatric diarrhea can be caused by a wide variety of pathogens, from bacteria to viruses to protozoa. Pathogen prevalence is often described as seasonal, peaking annually and associated with specific weather conditions. Although many studies have described the seasonality of diarrheal disease, these studies have occurred predominantly in temperate regions. In tropical and resource-constrained settings, where nearly all diarrhea-associated mortality occurs, the seasonality of many diarrheal pathogens has not been well characterized. As a retrospective study, we analyze the seasonal prevalence of diarrheal pathogens among children with moderate-to-severe diarrhea (MSD) over three years from the seven sites of the Global Enteric Multicenter Study (GEMS), a case-control study. Using data from this expansive study on diarrheal disease, we characterize the seasonality of different pathogens, their association with site-specific weather patterns, and consistency across study sites. METHODOLOGY/PRINCIPAL FINDINGS: Using traditional methodologies from signal processing, we found that certain pathogens peaked at the same time every year, but not at all sites. We also found associations between pathogen prevalence and weather or "seasons," which are defined by applying modern machine-learning methodologies to site-specific weather data. In general, rotavirus was most prevalent during the drier "winter" months and out of phase with bacterial pathogens, which peaked during hotter and rainier times of year corresponding to "monsoon," "rainy," or "summer" seasons. CONCLUSIONS/SIGNIFICANCE: Identifying the seasonally-dependent prevalence for diarrheal pathogens helps characterize the local epidemiology and inform the clinical diagnosis of symptomatic children. Our multi-site, multi-continent study indicates a complex epidemiology of pathogens that does not reveal an easy generalization that is consistent across all sites. Instead, our study indicates the necessity of local data to characterizing the epidemiology of diarrheal disease. Recognition of the local associations between weather conditions and pathogen prevalence suggests transmission pathways and could inform control strategies in these settings.

A randomized, open-labelled, non-inferiority phase 4 clinical trial to evaluate the immunogenicity and safety of the live, attenuated, oral rotavirus vaccine, ROTAVAC® in comparison with a licensed rotavirus vaccine in healthy infants.

BACKGROUND: ROTAVAC® (nHRV), derived naturally from the human 116E rotavirus (RV) neonatal strain, was licensed in India in 2015 based on promising results of a phase 3, safety and efficacy vaccine trial. As a pre-requisite for WHO prequalification, we compared the immunogenicity and safety of ROTAVAC® to those of a WHO-prequalified, Rotarix®. METHODS: We conducted a multicentre, open-labeled, randomized phase 4 clinical trial where 464 infants, 6-8 weeks of age were equally randomized to receive as licensed, the complete regimen of ROTAVAC® (3 doses; Group I) or Rotarix® (2 doses; Group II). Antibody responses (serum anti-RV Immunoglobulin A [IgA]) were measured by enzyme-linked immunosorbent assay (ELISA). The primary analysis was an assessment of non-inferiority of ROTAVAC® to Rotarix® for geometric mean concentration (GMC) for infants who received the complete regimen of either vaccine. RESULTS: The GMC for Group I was 20.4 (95%CI: 17.6, 23.6) and that for Group II was 24.8 (95%CI: 20.3, 30.3), the GMC ratio was 0.82 (95% CI: 0.64, 1.05), thus meeting the non-inferiority criterion. Site-wise analysis of GMC titres revealed that one site had a peculiar pre-vaccination titre affecting only ROTAVAC® post-vaccination GMCs. Seroconversion rates were 35.3% (95%CI: 29.0, 41.9) and 31.0% (95%CI: 25.1, 37.4) for Groups I and Group II, respectively. There was no substantive difference in safety profiles between both vaccines. CONCLUSIONS: The complete regimen of ROTAVAC® demonstrated immunological non-inferiority to the complete regimen of Rotarix® with a clinically acceptable safety profile. Because the demand for RV vaccines is increasing as more countries are expanding their immunization schedules, the lack of need of a buffering agent, low dose volume (0.5 mL), non-interference with other concomitantly administered vaccines, and conformance with WHO-prequalification requirements provide ROTAVAC® the potential for widespread global usage. Post completion of this study, ROTAVAC® is now a WHO-prequalified vaccine. CLINICAL TRIALS REGISTRATION: (CTRI Number: CTRI/2015/12/006428).

Vaccines for preventing rotavirus diarrhoea: vaccines in use.

BACKGROUND: Rotavirus results in more diarrhoea-related deaths in children under five years than any other single agent in countries with high childhood mortality. It is also a common cause of diarrhoea-related hospital admissions in countries with low childhood mortality. Rotavirus vaccines that have been prequalified by the World Health Organization (WHO) include a monovalent vaccine (RV1; Rotarix, GlaxoSmithKline), a pentavalent vaccine (RV5; RotaTeq, Merck), and, more recently, another monovalent vaccine (Rotavac, Bharat Biotech). OBJECTIVES: To evaluate rotavirus vaccines prequalified by the WHO (RV1, RV5, and Rotavac) for their efficacy and safety in children. SEARCH METHODS: On 4 April 2018 we searched MEDLINE (via PubMed), the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (published in the Cochrane Library), Embase, LILACS, and BIOSIS. We also searched the WHO ICTRP, ClinicalTrials.gov, clinical trial reports from manufacturers' websites, and reference lists of included studies and relevant systematic reviews. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) in children comparing rotavirus vaccines prequalified for use by the WHO versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and assessed risks of bias. One review author extracted data and a second author cross-checked them. We combined dichotomous data using the risk ratio (RR) and 95% confidence interval (CI). We stratified the analysis by country mortality rate and used GRADE to evaluate evidence certainty. MAIN RESULTS: Fifty-five trials met the inclusion criteria and enrolled a total of 216,480 participants. Thirty-six trials (119,114 participants) assessed RV1, 15 trials (88,934 participants) RV5, and four trials (8432 participants) Rotavac.RV1 Children vaccinated and followed up the first year of life In low-mortality countries, RV1 prevents 84% of severe rotavirus diarrhoea cases (RR 0.16, 95% CI 0.09 to 0.26; 43,779 participants, 7 trials; high-certainty evidence), and probably prevents 41% of cases of severe all-cause diarrhoea (RR 0.59, 95% CI 0.47 to 0.74; 28,051 participants, 3 trials; moderate-certainty evidence). In high-mortality countries, RV1 prevents 63% of severe rotavirus diarrhoea cases (RR 0.37, 95% CI 0.23 to 0.60; 6114 participants, 3 trials; high-certainty evidence), and 27% of severe all-cause diarrhoea cases (RR 0.73, 95% CI 0.56 to 0.95; 5639 participants, 2 trials; high-certainty evidence).Children vaccinated and followed up for two yearsIn low-mortality countries, RV1 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.14 to 0.23; 36,002 participants, 9 trials; high-certainty evidence), and probably prevents 37% of severe all-cause diarrhoea episodes (rate ratio 0.63, 95% CI 0.56 to 0.71; 39,091 participants, 2 trials; moderate-certainty evidence). In high-mortality countries RV1 probably prevents 35% of severe rotavirus diarrhoea cases (RR 0.65, 95% CI 0.51 to 0.83; 13,768 participants, 2 trials; high-certainty evidence), and 17% of severe all-cause diarrhoea cases (RR 0.83, 95% CI 0.72 to 0.96; 2764 participants, 1 trial; moderate-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.88 95% CI 0.83 to 0.93; high-certainty evidence). There were 30 cases of intussusception reported in 53,032 children after RV1 vaccination and 28 cases in 44,214 children after placebo or no intervention (RR 0.70, 95% CI 0.46 to 1.05; low-certainty evidence).RV5 Children vaccinated and followed up the first year of life In low-mortality countries, RV5 probably prevents 92% of severe rotavirus diarrhoea cases (RR 0.08, 95% CI 0.03 to 0.22; 4132 participants, 5 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 57% of severe rotavirus diarrhoea (RR 0.43, 95% CI 0.29 to 0.62; 5916 participants, 2 trials; high-certainty evidence), but there is probably little or no difference between vaccine and placebo for severe all-cause diarrhoea (RR 0.80, 95% CI 0.58 to 1.11; 1 trial, 4085 participants; moderate-certainty evidence).Children vaccinated and followed up for two yearsIn low-mortality countries, RV5 prevents 82% of severe rotavirus diarrhoea cases (RR 0.18, 95% CI 0.08 to 0.39; 7318 participants, 4 trials; moderate-certainty evidence). We did not identify studies reporting on severe all-cause diarrhoea in low-mortality countries. In high-mortality countries, RV5 prevents 41% of severe rotavirus diarrhoea cases (RR 0.59, 95% CI 0.43 to 0.82; 5885 participants, 2 trials; high-certainty evidence), and 15% of severe all-cause diarrhoea cases (RR 0.85, 95% CI 0.75 to 0.98; 5977 participants, 2 trials; high-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.86 to 1.01; moderate to high-certainty evidence). There were 16 cases of intussusception in 43,629 children after RV5 vaccination and 20 cases in 41,866 children after placebo (RR 0.77, 95% CI 0.41 to 1.45; low-certainty evidence).Rotavac Children vaccinated and followed up the first year of life Rotavac has not been assessed in any RCT in countries with low child mortality. In India, a high-mortality country, Rotavac probably prevents 57% of severe rotavirus diarrhoea cases (RR 0.43, 95% CI 0.30 to 0.60; 6799 participants, moderate-certainty evidence); the trial did not report on severe all-cause diarrhoea at one-year follow-up.Children vaccinated and followed up for two yearsRotavac probably prevents 54% of severe rotavirus diarrhoea cases in India (RR 0.46, 95% CI 0.35 to 0.60; 6541 participants, 1 trial; moderate-certainty evidence), and 16% of severe all-cause diarrhoea cases (RR 0.84, 95% CI 0.71 to 0.98; 6799 participants, 1 trial; moderate-certainty evidence).No increased risk of serious adverse events (SAE) was detected (RR 0.93 95% CI 0.85 to 1.02; moderate-certainty evidence). There were eight cases of intussusception in 5764 children after Rotavac vaccination and three cases in 2818 children after placebo (RR 1.33, 95% CI 0.35 to 5.02; very low-certainty evidence).There was insufficient evidence of an effect on mortality from any rotavirus vaccine (198,381 participants, 44 trials; low- to very low-certainty evidence), as the trials were not powered to detect an effect at this endpoint. AUTHORS' CONCLUSIONS: RV1, RV5, and Rotavac prevent episodes of rotavirus diarrhoea. Whilst the relative effect estimate is smaller in high-mortality than in low-mortality countries, there is a greater number of episodes prevented in these settings as the baseline risk is much higher. We found no increased risk of serious adverse events.

Norovírus no município de São Paulo, 2010-2016: estudo transversal sobre a principal causa de gastroenterite infantil / Norovirus en el Municipio de São Paulo, Brasil, 2010-2016: estudio transversal sobre la principal causa de gastroenteritis infantil / Norovirus in São Paulo city, Brazil, 2010-2016: a cross-sectional study of the leading cause of gastroenteritis in children

Objetivo: descrever casos de doença diarreica aguda por norovírus em crianças menores de 5 anos do município de São Paulo, Brasil. Métodos: estudo transversal com dados provenientes da Vigilância Epidemiológica das Gastroenterites Causadas por Rotavírus; foi definido como caso o paciente internado em unidade sentinela por doença diarreica aguda e identificação laboratorial do norovírus como agente etiológico, entre os anos de 2010 e 2016. Resultados: durante o período estudado, a proporção de casos de norovírus em menores de 5 anos de idade ultrapassou a proporção de casos de rotavírus, agente considerado predominante na infância; o norovírus foi associado a 28,4% do total de casos notificados, ocorrendo o ano todo, principalmente nos meses mais quentes. Conclusão: norovírus foi o principal agente etiológico identificado em crianças menores de 5 anos com doença diarreica aguda no município de São Paulo.

Objetivo: describir casos de enfermedad diarreica aguda por Norovirus en niños menores de 5 años provenientes del Municipio de São Paulo, Brasil. Métodos: Estudio transversal con datos de la Vigilancia Epidemiológica de las Gastroenteritis causadas por Rotavirus. Se definió como caso el paciente internado en unidad centinela por enfermedad diarreica aguda e identificación de laboratorio del Norovirus como agente etiológico entre los años de 2010 y 2016. Resultados: Durante el período estudiado, la proporción de casos de Norovirus en menores de 5 años superó la proporción de casos de Rotavirus, agente considerado predominante en la infancia. El Norovirus fue asociado al 28,4% del total de los casos notificados, ocurriendo todo el año, principalmente en los meses más cálidos. Conclusión: el Norovirus fue el principal agente etiológico identificado en niños menores de 5 años con enfermedad diarreica aguda en el Municipio de São Paulo.

Objective: to describe cases of acute diarrheal disease caused by norovirus in children under 5 years old in São Paulo city, Brazil. Methods: this was a cross-sectional study using data from Epidemiological Surveillance of Gastroenteritis due to Rotavirus; cases were defined as patients hospitalized in a sentinel unit because of acute diarrheal disease and laboratory identification of norovirus as the etiological agent between 2010 and 2016. Results: during the study period, the proportion of norovirus cases in children under 5 years old exceeded the proportion of Rotavirus, an agent considered predominant in childhood; norovirus was associated with 28.4% of total reported cases, occurring all year round, especially in warmer months. Conclusion: norovirus was the leading etiological agent identified in children under 5 years old with acute diarrheal disease in São Paulo city.

Prevalence and clinical profile of rotavirus A infection among diarrhoeal children and phylogenetic analysis with vaccine strains in Chengdu, West China, 2009-2014.

OBJECTIVES: Rotaviruses are the most common cause of severe diarrhoeal disease in young children. However, little is known about the epidemiological and clinical profile of rotavirus A (RVA) in diarrhoeal children or the efficacy of Lanzhou lamb rotavirus vaccine (LLR) in Chengdu, China. This study aimed to determine the prevalence and clinical profile of RVA in diarrhoeal children and provide gene analysis information for RVA vaccination programmes. METHODS: A total of 1121 faecal samples were collected from outpatient children with diarrhoea between 2009 and 2014. RT-PCR was performed to detect RVA infection and other gastroenteritis viruses. VP4 and VP7 genes of 13 RVA strains were sequenced to compare their similarity with vaccine strains. RESULTS: The overall RVA infection rate was 17.48%. G1 (54.72%) and G3 (18.87%) were the predominant G genotypes; P[8] (72.36%) and P[4] (11.38%) were the main P genotypes. Sixteen genotypes were identified; G1P[8] (57.33%) and G9P[8] (12.00%) were the most prevalent. The proportion of coinfection with RVA and other gastroenteritis viruses was 18.88%. RVA was mostly detected in winter and in diarrhoeal children 1-2 years of age. The genotypes of Rotarix and RotaTeq vaccines were consistent with RVA strains prevalent in Sichuan and shared high identity. CONCLUSIONS: RVA was one of the major aetiological agents of diarrhoeal children in Chengdu. Genotype distribution differed within each year and the gene analysis implied low efficacy of LLR. Continuous epidemiological monitoring of RVA is essential for the national vaccination programme.

Rotavirus vaccination takes seasonal signature of childhood diarrhea back to pre-sanitation era in Brazil.

OBJECTIVES: This study aimed to examine the previously unknown long-term spatio-temporal patterns in diarrheal morbidity and mortality across age groups and geography in Brazil under the light of evolving socioeconomic factors and interventions. METHODS: Nationwide mortality (1979-2014) and hospitalization (1998-2014) data were obtained from the Brazilian Ministry of Health. Analyses of long-term secular trends and seasonality of diarrheal morbidity and mortality were performed in EPIPOI (www.epipoi.info). RESULTS: For most states, the primary peak in mortality risk among children under 5 years occurred from December-April (summer/early autumn) from 1979-1988. From 2000-2005 (before the 2006 implementation of rotavirus vaccination), the pattern switched to June-October (winter/early spring). By 2007-2014, the peak in mortality shifted back towards summer/early autumn. A similar pattern was observed for hospitalizations. These patterns were particularly apparent in non-equatorial regions of the country. In contrast, the risk of diarrhea-related death among older children (5-19 years) did not demonstrate well-defined seasonality or spatial patterns. CONCLUSIONS: Rotavirus vaccination policies were associated with a shift in the timing of seasonal peaks in children under 5, reminiscent of the summer diarrhea period common decades prior. Additionally, young children were shown to have distinct disease patterns compared to other age groups, suggesting different etiologies.

Assessing gut microbiota perturbations during the early phase of infectious diarrhea in Vietnamese children.

Diarrheal diseases remain the second most common cause of mortality in young children in developing countries. Efforts have been made to explore the impact of diarrhea on bacterial communities in the human gut, but a thorough understanding has been impeded by inadequate resolution in bacterial identification and the examination of only few etiological agents. Here, by profiling an extended region of the 16S rRNA gene in the fecal microbiome, we aimed to elucidate the nature of gut microbiome perturbations during the early phase of infectious diarrhea caused by various etiological agents in Vietnamese children. Fecal samples from 145 diarrheal cases with a confirmed infectious etiology before antimicrobial therapy and 54 control subjects were analyzed. We found that the diarrheal fecal microbiota could be robustly categorized into 4 microbial configurations that either generally resembled or were highly divergent from a healthy state. Factors such as age, nutritional status, breastfeeding, and the etiology of the infection were significantly associated with these microbial community structures. We observed a consistent elevation of Fusobacterium mortiferum, Escherichia, and oral microorganisms in all diarrheal fecal microbiome configurations, proposing similar mechanistic interactions, even in the absence of global dysbiosis. We additionally found that Bifidobacterium pseudocatenulatum was significantly depleted during dysenteric diarrhea regardless of the etiological agent, suggesting that further investigations into the use of this species as a dysentery-orientated probiotic therapy are warranted. Our findings contribute to the understanding of the complex influence of infectious diarrhea on gut microbiome and identify new opportunities for therapeutic interventions.

Gastroenteritis agudas y virus entéricos: impacto de la detección de norovirus / Acute gastroenteritis and enteric viruses: Impact on the detection of norovirus

Introducción: El norovirus es el segundo agente causal de las gastroenteritis agudas víricas en niños después del rotavirus. Su prevalencia está subestimada debido a que no se realiza habitualmente un diagnóstico específico. El estudio de los diagnósticos microbiológicos, realizados antes y después de la fecha de implantación de un test de detección de un microorganismo concreto, permite estimar el porcentaje de casos no diagnosticados con anterioridad (por la no implantación) y los que se dejarían de diagnosticar en caso de su supresión. En este artículo estudiamos la epidemiología de las gastroenteritis agudas por virus antes y después de la implantación del test CerTest Norovirus GI+GII. Material y métodos: Estudio observacional de cohortes retrospectivo realizado en pacientes menores de 15 años con gastroenteritis aguda desde enero de 2013 hasta abril de 2015. Se dividió la muestra en 2 grupos; en el primero la búsqueda se limitó a adenovirus y rotavirus y en el segundo la determinación de norovirus se incorporó al diagnóstico sistemático. Se incluyó a 604 pacientes, 313 en el primer grupo y 291 en el segundo. Resultados: Las características demográficas fueron similares en ambos grupos. Se identificaron 58/313 (18,5%) virus entéricos en el primer grupo y 97/291 (33,3%) en el segundo. Del segundo grupo 31 muestras fueron positivas para norovirus, siendo 12 (4,1%) positivas exclusivamente para norovirus. No se encontraron diferencias significativas en las características clínicas de los virus intestinales. Conclusiones: Se observó un aumento real del 4,1% en el porcentaje de casos con agente etiológico identificado al implementar la técnica diagnóstica CerTest Norovirus GI+GII. El rotavirus sigue siendo la causa más frecuente de gastroenteritis aguda en nuestro medio, seguido de cerca por el norovirus (AU)

Introduction: Norovirus is the second cause of acute viral gastroenteritis in infants after rotavirus. However, its prevalence is underestimated because a specific diagnosis is not usually performed. The comparative study of microbiological diagnostics, performed before and after the implementation date of a test for detecting a particular microorganism, allows the estimation of the percentage of cases not properly diagnosed earlier (for non-implementation of the test) and those that would be left to diagnose if the test is removed. In this paper we study the epidemiology of acute gastroenteritis virus before and after the implantation of the Norovirus GI+GII CerTest. Material and methods: An observational retrospective cohort study was conducted on patients under 15 years old with acute gastroenteritis, from January 2013 to April 2015. The sample was divided into two groups. In the first group, the search was limited to adenovirus and rotavirus, and in the second one, the determination of norovirus became part of the systematic diagnosis. The study included 604 patients, 313 in the first group and 291 in the second one. Results: Demographic characteristics were similar in both groups. In the first group, 58/313 (18.5%) enteric viruses were identified and in the second group, 97/291 (33.3%). In the second group, 31 positive cases for norovirus were identified, but only 12 (4.1%) of them were positive exclusively for this virus. No significant differences were found in clinical features of intestinal viruses. Conclusions: An actual increase of 4.1% was observed in the cases with an identified aetiological agent after implementing the Norovirus GI+GII CerTest diagnostic technique. The most common cause of acute gastroenteritis is rotavirus, closely followed by norovirus (AU)

Efficacy and Safety of Saccharomyces boulardii in Acute Rotavirus Diarrhea: Double Blind Randomized Controlled Trial from a Developing Country.

OBJECTIVE: To study the efficacy and safety of Saccharomyces boulardii (SB) in acute childhood rotavirus diarrhea. METHODS: Children (3 months to 5 years) with WHO-defined acute watery diarrhea and stool rotavirus positive (n = 60) were randomized into intervention (n = 30) and control (n = 30) groups. The intervention group received SB (500 mg/day) for 5 days. RESULTS: The median duration (hours) of diarrhea was significantly shorter in the intervention group (60 vs. 89; 95% CI: -41.2 to - 16.8). A significantly shorter duration of hospitalization (74 vs. 91; 95% CI: -33.46 to - 0.54) was also seen in the intervention group, but no significant difference was seen for fever and vomiting. There was also no difference between the two groups in the proportion of children requiring parenteral rehydration and persistence of diarrhea lasting beyond day 7. There was no report of any adverse events. CONCLUSIONS: The present trial showed that SB is effective and safe in acute rotavirus diarrhea.

Correlation of Clinical Outcomes With Multiplex Molecular Testing of Stool From Children Admitted to Hospital With Gastroenteritis in Botswana.

BACKGROUND: Diarrheal disease is a leading cause of death for young children. Most pediatric gastroenteritis is caused by viral pathogens; consequently, current recommendations advocate against routine antibacterial therapy if children present without bloody stools. METHODS: In this prospective cohort study, we enrolled children with severe acute gastroenteritis admitted to hospital in Botswana. Details of presenting history, physical examination, and course in the hospital were recorded. Stool samples were characterized using a 15 pathogen polymerase chain reaction assay. RESULTS: There were 671 participants with a median age of 8.3 months; 77 (11%) had severe acute malnutrition. Only 74 children had bloody stools, of whom 48 (65%) had a detectable bacterial pathogen, compared to 195 of 592 (33%) of those without. There were 26 deaths (3.9%). Covariates associated with death in multivariable logistic regression were the detection of any of Campylobacter/Shigella/enterotoxigenic Escherichia coli (odds ratio [OR] 2.57, 95% confidence interval [CI] 1.07-6.17), severe acute malnutrition (OR 4.34, 95% CI 1.79-10.5), and antibiotic therapy (OR 8.82, 95% CI 2.03-38.2). There was no significant association between bloody stools and death, and the effect of Campylobacter/Shigella/enterotoxigenic E. coli infection on death was not modified by the presence of bloody stools. CONCLUSIONS: Detection of bacterial enteropathogens is associated with increased mortality in children in sub-Saharan Africa. Unfortunately, most children with these infections do not have bloody stools, and bloody dysentery was not found to be associated with worse outcomes. Clinical trials evaluating outcomes associated with more aggressive diagnostic strategies in children presenting with severe acute gastroenteritis in sub-Saharan Africa should be undertaken.

Unusual rotavirus genotypes among children with acute diarrhea in Saudi Arabia.

BACKGROUND: Human rotavirus A (human RV-A) is the most common cause of viral gastroenteritis in infants. The objective of the study was to characterize the G and P genotypes among clinical rotavirus isolates from children with acute diarrhea admitted to a tertiary care hospital in Riyadh, Saudi Arabia. METHODS: From 2011 to 2012, 541 pediatric patients with acute diarrhea were tested for rotavirus infection. RNA extractions from the fecal specimens were done by commercial kit. RT-PCR and sequencing techniques were used to detect the prevalent genotypes. Phylogenetic analysis by Maximum Likelihood method was used to study the clustering of the circulating genotypes. RESULTS: The data showed that 171/541 (31.6%) faecal samples were positive for human RVA and majority were children aged below 2 years. From the G and P [types] detected it was seen that (a) 171 minus 43 ie. 128 rotavirus positives were G typed successfully (b) 171 minus 20 ie. 151 rotavirus positives were P typed successfully; (c) overall G [P] nature was determined for 113 rotavirus positives out of 171. VP4 genotyping showed that majority of the positives 146/151 (96.7%) were P [8]; 4/151 (2.6%) were P [4]; 1/151 (0.66%) was P [6]. The dominant strains included G1P [8] 70/113 (61.9%); G9P [8] 19/113 (16.8%); G12P [8] 7/113 (6.2%) and G3P [8] 5/113 (4.4%) while the uncommon strains detected from Saudi Arabia during the study were G1P [4] 1/113 (0.88%) and G12P [6] 1/113 (0.88%). Phylogenetic tree, based on VP4/VP7 sequence analysis, revealed that G1P [8] was distinctly related to homologous strains included in human RV-A vaccine strains. Nevertheless, the uncommon genotypes G1P [4] and G12P [6] were clustered with isolates from other countries such as Bangladesh, China, Japan, Thailand and Philippines. CONCLUSIONS: More studies will be required to further focus on newly emerging genotypes in our region together with the seasonality of rotavirus infection in the region, especially after January 2013 when the rotavirus vaccination has become part of routine childhood immunizations.