Yalda Lucero

Norovirus illness is a global problem: emergence and spread of norovirus GII.4 variants, 2001-2007.

BACKGROUND Noroviruses (NoVs) are the most common cause of viral gastroenteritis. Their high incidence and importance in health care facilities result in a great impact on public health. Studies from around the world describing increasing prevalence have been difficult to compare because of differing nomenclatures for variants of the dominant genotype, GII.4. We studied the global patterns of GII.4 epidemiology in relation to its genetic diversity. METHODS Data from NoV outbreaks with dates of onset from January 2001 through March 2007 were collected from 15 institutions on 5 continents. Partial genome sequences (n=775) were collected, allowing phylogenetic comparison of data from different countries. RESULTS The 15 institutions reported 3098 GII.4 outbreaks, 62% of all reported NoV outbreaks. Eight GII.4 variants were identified. Four had a global distribution--the 1996, 2002, 2004, and 2006b variants. The 2003Asia and 2006a variants caused epidemics, but they were geographically limited. Finally, the 2001 Japan and 2001 Henry variants were found across the world but at low frequencies. CONCLUSIONS NoV epidemics resulted from the global spread of GII.4 strains that evolved under the influence of population immunity. Lineages show notable (and currently unexplained) differences in geographic prevalence. Establishing a global NoV network by which data on strains with the potential to cause pandemics can be rapidly exchanged may lead to improved prevention and intervention strategies.

Two year review of intestinal intussusception in six large public hospitals of Santiago, Chile.

Background. A need for updated information on different aspects of idiopathic intussusception resurged after the Rotashield experience. Variability of incidence rates worldwide and the possibility of a more severe outcome among infants that have intussusception at a younger age are two issues that remain unclear. We aimed to provide updated information on clinical aspects of intussusception in a large population of Chilean children <2 years of age, including a best estimate of incidence rate and a comparative analysis of the clinical evolution for children younger and older than 6 months of age. Methods. Several sources of information were used to recollect all intussusception cases 0 to 24 months of age treated in six public pediatric hospitals of the Metropolitan area during years 2000 and 2001 and to obtain updated estimates of the population covered by these hospitals. A thorough chart review of intussusception cases was performed using a standardized case report form. Results. A total of 50 and 45 intussusception cases were detected for 2000 and 2001, respectively, and estimated intussusception rates for children 0 to 24 months and for the subgroup <12 months of age were 35 and 32 per 100 000, and 55 and 47 per 100 000. The monthly distribution of intussusception cases differed for both years without an identifiable reason, and no association between intussusception and rotavirus infection was observed. No intussusception-associated death was recorded. Overall complications occurred in 21% of children, and infants younger than 6 months of age did not have more complications or a more prolonged hospital stay than older children. Conclusions. Idiopathic intussusception is not uncommon among Chilean infants with incidence rates similar to those reported in the United States. There was no clear association with preexisting rotavirus infection and occurrence of complications was not related to young age.

Rotarix®: vaccine performance 6 years postlicensure

Rotarix® was first licensed in 2004 and rapidly introduced into private and public markets worldwide. In a previous 2009 article, we reviewed the impact of rotavirus-associated disease, the rationale for different vaccines, prelicensure efficacy studies and cost–effectiveness studies for Rotarix. As of September 2011, Rotarix had been licensed in 123 countries in the Americas, Europe, Australia, Africa and Asia, of which 27 have incorporated the vaccine into national or regional immunization programs. The current review intends to provide the reader with further insight into this vaccine, focusing mainly on the new information obtained after a 6-year postlicensure period. This review will provide only a brief summary of prelicensure studies extensively discussed in the previous publication and refer, in more depth, to the worldwide experience with the vaccine, vaccine impact, and safety observed in effectiveness and observational studies, including a particular analysis on protection against rotavirus G2P[4].

Symptomatic and Asymptomatic Rotavirus and Norovirus Infections During Infancy in a Chilean Birth Cohort

Background: Rotavirus and more recently norovirus have been recognized as 2 of the most common causes of acute diarrhea in children. Comparative analysis of these infections in a birth cohort has not been performed and can provide relevant insight on clinical and viral behaviors. Methods: Mother-infant pairs from middle-low socioeconomic background living in the Metropolitan Region of Chile are being followed for 18 months in 2 outpatient clinics. Infants are evaluated monthly for asymptomatic excretion of rotavirus and norovirus and during acute diarrhea episodes (ADE) for rotavirus, norovirus, and bacterial enteropathogens. Severity of ADE is evaluated using the Vesikari score. Results: Between July 1, 2006 and September 1, 2008 a total of 198 children were followed for a mean of 15.7 months. Asymptomatic rotavirus and norovirus infections were detected in 1.3% and 8% of 2278 stool samples compromising 14% and 57% of infants, respectively. Incidence of ADE was approximately 0.8 for the first year of life and approximately 0.6 for the 13 to 18 month age group. Rotavirus and norovirus were detected in 15% and 18% of 145 ADE evaluated. Mean Vesikari score was 10.4 and 7.4 for rotavirus and norovirus respectively (P = 0.01) and severity was not associated with age of patients for either virus. Reinfections were more common for norovirus asymptomatic episodes: 44% versus 19% (P = 0.01) and borderline for symptomatic episodes: 40% versus 11% (P = 0.08). Rotavirus genotype G9P8 and norovirus genogroup II (GII) predominated although most asymptomatic episodes for both viruses were nontypable. None of 19 symptomatic GII norovirus infections had a previous documented GII infection compared with 10 of 31 asymptomatic GII infections (OR = 0. 95% CL = 0, 0.59; P = 0.008). Conclusions: Children had suffered a mean of approximately 1.4 ADE by 18 months of age of which 15% and 18% were caused by rotavirus and norovirus, respectively. In general rotavirus infections were more severe than norovirus infections and for both viruses severity was not related to age. Norovirus reinfections were significantly more common than rotavirus reinfections but for GII norovirus a primary infection seems to confer protection against clinically significant reinfections.

Prospective characterization of norovirus compared with rotavirus acute diarrhea episodes in chilean children.

Background: Rotavirus and more recently noroviruses are recognized as main causes of moderate to severe acute diarrhea episodes (ADE) in children ≤5 years of age. Comparing epidemiologic and clinical features of norovirus to rotavirus ADE will aid in the decision-making process required to develop norovirus vaccines. Methods: Surveillance for ADE occurring in children ≤5 years of age was implemented in the emergency department (ED) and ward of a large hospital in Santiago and Valparaiso, and in 4 outpatient clinics in Santiago. A stool sample was obtained within 48 hours of consultation for rotavirus detection by enzyme-linked immunosorbent assay and noroviruses by enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction. For ED and hospital rotavirus and norovirus ADE parents were instructed to monitor clinical findings associated with severity until the end of the episode. The 20-point Vesikari score was used to determine disease severity. Results: Between July 2006 and October 2008 rotavirus and noroviruses were detected in 331 (26%) and 224 (18%) of 1913 ADE evaluated. The proportion of rotavirus-positive samples in hospital ward, ED, and outpatient clinic was 40%, 26% to 30%, and 13% compared with 18%, 17% to 19%, and 14% for noroviruses. Mean age and 25%–75% interquartile interval of children with rotavirus and norovirus ADE were remarkably similar, 15.6 months (9–20), and 15.5 months (9–19), respectively. Rotavirus cases displayed an autumn-winter peak followed 2 to 3 months later by the norovirus peak. The mean (interquartile) for the Vesikari score was 12.9 (11–15) and 11.9 (9–14.5) for rotavirus (N = 331) and norovirus (N = 224) ADE, respectively, P = 0.003. Compared with norovirus, rotavirus ADE were more common in the 11 to 16 severity score interval (P = 0.006), had a higher maximum stool output in a given day (P = 0.01) and more frequent fever (P < 0.0001). Duration of diarrhea, presence, duration and intensity of vomiting, and intensity of fever did not differ between viruses. Mixed rotavirus and norovirus infections were uncommon (<1%) and not clinically more severe. Clinical severity of ADE in young infants was similar for rotavirus and lower (P = 0.03) for noroviruses compared with older children. Conclusion: Noroviruses are a significant cause of moderate to severe endemic ADE in Chilean children. Although significantly less severe than rotavirus as a group, most norovirus episodes were moderate to severe clinically. An effective norovirus vaccine would be of significant additional benefit to the current rotavirus vaccine in decreasing disease burden associated with ADE.

Dynamics of Helicobacter pylori detection in stools during the first 5 years of life in Chile, a rapidly developing country.

Background: Helicobacter pylori colonization/infection can be transitory or persistent, conditions that have not been thoroughly evaluated in young children. We aimed to characterize the dynamics of H. pylori stool detection and to determine host and environmental factors and symptoms associated with persistence. Method: In a 5-year cohort study, we followed-up infants from birth with clinic visits every 3 months. Symptoms and environmental risk factor survey and a stool sample for H. pylori antigen detection were requested in every visit. Secretor/ABH histo-blood group phenotype was determined in saliva. Results: Overall, 218 of 1456 (15%) stool samples were positive for H. pylori and 39 of 96 (41%) children had at least 1 positive sample. Stool detection was transitory in 16 of 39 (41%), persistent in 19 (49%) and undetermined in 4 (10%) children. Persistence was acquired largely during the first 24 months (17/19 cases) and was associated with nonsecretor phenotype (32% versus 0% for transitory infection; P = 0.02) and daycare attendance (67% versus 26% for never infected; P = 0.019). Symptoms possibly associated with persistence were referred in only 1 child. Conclusions: Nearly 20% of this Chilean cohort had persistent H. pylori stool sample detections during the first 5 years of life, acquired mostly during the first 24 months. Persistence was significantly associated with nonsecretor phenotype and daycare attendance, and possibly associated gastrointestinal symptoms were rare. This relatively common group of young children with persistent H. pylori colonization/infection will require further study.

Persistent and Transient Helicobacter pylori Infections in Early Childhood

BACKGROUND Helicobacter pylori, the main cause of peptic ulcer disease and gastric cancer in adult populations, is generally acquired during the first years of life. Infection can be persistent or transient and bacterial and host factors determining persistence are largely unknown and may prove relevant for future disease. METHODS Two cohorts of healthy Chilean infants (313 total) were evaluated every 3 months for 18-57 months to determine pathogen- and host-factors associated with persistent and transient infection. RESULTS One-third had at least one positive stool ELISA by age 3, with 20% overall persistence. Persistent infections were acquired at an earlier age, associated with more household members, decreased duration of breastfeeding, and nonsecretor status compared to transient infections. The cagA positive strains were more common in persistent stools, and nearly 60% of fully characterized persistent stool samples amplified cagA/vacAs1m1. Persistent children were more likely to elicit a serologic immune response, and both infection groups had differential gene expression profiles, including genes associated with cancer suppression when compared to healthy controls. CONCLUSIONS These results indicate that persistent H. pylori infections acquired early in life are associated with specific host and/or strain profiles possibly associated with future disease occurrence.

An update on management of severe acute infectious gastroenteritis in children

This article focuses on clinical and diagnostic aspects relevant to severe acute infectious gastroenteritis in children and will update treatment strategies focused on, although not limited to, anti-infective therapy. For the purposes of this article we will consider severe acute infectious gastroenteritis as follows: watery diarrhea accompanied by, or at high risk for, moderate to severe dehydration due to abrupt onset of vomiting that reduces oral intake, and/or frequent emission of liquid stools, or moderate to severe dysenteric/bloody diarrhea with moderate to high-grade fever. The article will not include food poisoning associated with bacterial toxins and will only briefly discuss oral rehydration strategies and intravenous solutions. The article will also briefly discuss current preventive measures against rotavirus gastroenteritis through vaccination, a topic that has been extensively discussed elsewhere.

Development and validation of a microarray for the confirmation and typing of norovirus RT-PCR products

Noroviruses are implicated in many worldwide institutional, food and waterborne outbreaks each year. Genetic typing of isolates is valuable for monitoring outbreak spread as well as variation in circulating strains. Microarrays have the potential to provide rapid genotype information for norovirus samples. The NoroChip v3.0 provides an oligonucleotide hybridization platform to screen for over 600 potential interactions in each experiment. The NoroChip v3.0 was developed at Health Canada and validated in seven international partner laboratories. Each laboratory validated the NoroChip v3.0 using norovirus amplicons routinely characterized in their testing protocols. Fragments from the capsid region (region C) and a 2.4 kb amplicon spanning polymerase and capsid sequences (region AD) were validated in six of the partner laboratories and provided correct genogroup typing information (GI or GII) when hybridized to the NoroChip v3.0. Results indicate that the current limiting factor for implementing the NoroChip v3.0 as a strain typing tool is the difficulty obtaining a long, specific amplicon from all circulating norovirus strains. Data obtained with the longer region AD amplicon provided the best discrimination between norovirus strains.

DQ2, DQ7 and DQ8 Distribution and Clinical Manifestations in Celiac Cases and Their First-Degree Relatives.

HLA-linked genes are relevant to celiac disease (CD); the potential genetic differences present worldwide are not fully understood. Previous results suggest that the distribution of HLA-DQ2/DQ7/DQ8 in Chile may differ from that in Europe and North America. In celiac patients and their first-degree relatives (FDRS), we assessed their clinical, serological and histological characteristics, determined HLA-DQ2, HLA-DQ7 and HLA-DQ8 alleles and genotypes, and evaluated the relations between them. A total of 222 individuals were assessed (56 cases, 166 FDRs). 16.9% of FDRs were tTG positive; 53.6% of them showed overweight/obesity and 3% undernourishment; they spontaneously declared being asymptomatic, but detailed questioning revealed that 60.7% experienced symptoms, which had not been investigated. DQ2 was present in 53.9% and 43.9.0% of cases and FDRs (p < 0.05). The most frequent genotype distribution was DQ2/DQ7 (fr 0.392 (cases) and 0.248 (FDRs), respectively, p < 0.02). The next most common genotypes were HLA-DQ2/DQ8 (fr 0.236 in FDRs and 0.176 in cases, p < 0.05). 3.92% cases were not HLA-DQ2/DQ8 carriers. Among tTG positive FDRs, 57.4%, 22.3% and 20.2% carried DQ2, DQ7 and DQ8, respectively. In cases, 72.7% of the biopsies classified Marsh ≥3 carried at least one DQ2; 91.7% of DQ2/DQ2 and 88.3% of DQ2/DQ7 were Marsh ≥3. Thus, DQ2 frequency is lower than reported; the higher frequency found for DQ8 and DQ7 concur with recent publications from Argentine and Brazil. These results suggest that although CD may manifest clinically in ways similar to those described in other populations, some genetic peculiarities in this region deserve further study.