Burden of Norovirus and Rotavirus in Children after Rotavirus Vaccine Introduction,Cochabamba, Bolivia

The effectiveness of rotavirus vaccine in the field may set the stage for a changing landscape of diarrheal illness affecting children worldwide. Norovirus and rotavirus are the two major viral enteropathogens of childhood. This study describes the prevalence of norovirus and rotavirus 2 years after widespread rotavirus vaccination in Cochabamba, Bolivia. Stool samples from hospitalized children with acute gastroenteritis (AGE) and outpatients aged 5–24 months without AGE were recruited from an urban hospital serving Bolivia''s third largest city. Both viruses were genotyped, and norovirus GII.4 was further sequenced. Norovirus was found much more frequently than rotavirus. Norovirus was detected in 69/201 (34.3%) of specimens from children with AGE and 13/71 (18.3%) of those without diarrhea. Rotavirus was detected in 38/201 (18.9%) of diarrheal specimens and 3/71 (4.2%) of non-diarrheal specimens. Norovirus GII was identified in 97.8% of norovirus-positive samples; GII.4 was the most common genotype (71.4% of typed specimens). Rotavirus G3P[8] was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P[4] was second most prevalent (16.0% of typed specimens). This community is likely part of a trend toward norovirus predominance over rotavirus in children after widespread vaccination against rotavirus.     

Rotavirus prevalence in the primary care setting in Nicaragua after universal infant rotavirus immunization

Nicaragua was the first developing nation to implement universal infant rotavirus immunization with the pentavalent rotavirus vaccine (RV5). Initial studies of vaccine effectiveness in Nicaragua and other developing nations have focused on the prevention of hospitalizations and severe rotavirus diarrhea. However, rotavirus diarrhea is more commonly treated in the primary care setting, with only 1-3% of rotavirus cases receiving hospital care. We measured the prevalence of rotavirus infection in primary care clinics in León, Nicaragua, after introduction of the immunization program. In the post-vaccine period, 3.5% (95% confidence interval = 1.9-5.8) of children seeking care for diarrhea tested positive for rotavirus. A high diversity of rotavirus genotypes was encountered among the few positive samples. In conclusion, rotavirus was an uncommon cause of childhood diarrhea in this primary care setting after implementation of a rotavirus immunization program.     

Rotavirus vaccines

The past few years have seen important developments in understanding the epidemiological and virological characteristics of rotaviruses, and rapid progress has been made in rotavirus vaccine development, but further challenges remain before a vaccine is introduced into widespread use. The licensure of the first rotavirus vaccine, a tetravalent rhesus-based rotavirus vaccine, in the United States in 1998, marked a significant advance in preventing the morbidity associated with rotavirus diarrhea. The association between the tetravalent rhesus-based rotavirus vaccine and intussusception has created significant hurdles as well as new opportunities to study the pathogenesis of rotavirus and rotavirus vaccine infection. Several other rotavirus vaccine candidates are in late stages of development, and results from trials have been encouraging.     

A Prospective Hospital-based Surveillance to Estimate Rotavirus Disease Burden in Bhutanese Children under 5 Years of Age

As part of efforts to develop an informed policy for rotavirus vaccination, this prospective study was conducted to estimate the burden of rotavirus diarrhea among children less than 5 years old attended to the Department of Pediatrics, Jigme Dorji Wangchuk National Referral Hospital (JDWNRH), Thimphu, Bhutan. The duration of the study was three years, extending from February 2010 through December 2012. We estimated the frequency of hospitalization in the pediatric ward and dehydration treatment unit (DTU) for diarrhea and the number of events attributable to rotavirus infection among children under 5 years of age. During the study period, a total of 284 children (1 in 45) were hospitalized in the pediatric ward, and 2,220 (1 in 6) in the DTU with diarrhea among children residing in the Thimphu district. Group A rotavirus was detected in 32.5% and 18.8% of the stool samples from children hospitalized in the pediatric ward, respectively. Overall, 22.3% of the stool samples were rotavirus-positive, and the majority (90.8%) of them was detected in children under 2 years of age. From this study, we estimated that the annual incidence of hospitalization in the pediatric ward and DTU due to rotavirus diarrhea was 2.4/1000 (95% CI 1.7–3.4) and 10.8/1000 (95% CI 9.1–12.7) children, respectively. This study revealed that rotavirus is a major cause of diarrhea in Bhutanese children in Thimphu district and since no study has been performed previously, represents an important finding for policy discussions regarding the adoption of a rotavirus vaccine in Bhutan.     

Community Diarrhea Incidence Before and After Rotavirus Vaccine Introduction in Nicaragua

We estimated the incidence of watery diarrhea in the community before and after introduction of the pentavalent rotavirus vaccine in León, Nicaragua. A random sample of households was selected before and after rotavirus vaccine introduction. All children < 5 years of age in selected households were eligible for inclusion. Children were followed every 2 weeks for watery diarrhea episodes. The incidence rate was estimated as numbers of episodes per 100 child-years of exposure time. A mixed effects Poisson regression model was fit to compare incidence rates in the pre-vaccine and vaccine periods. The pre-vaccine cohort (N = 726) experienced 36 episodes per 100 child-years, and the vaccine cohort (N = 826) experienced 25 episodes per 100 child-years. The adjusted incidence rate ratio was 0.60 (95% confidence interval [CI] 0.40, 0.91) during the vaccine period versus the pre-vaccine period, indicating a lower incidence of watery diarrhea in the community during the vaccine period.     

Rotavirus infections in traveler's diarrhea

We tried to isolate rotaviruses from travelers with diarrhea arriving at Nagoya International Airport. 1. Ten cases revealed positive for rotavirus out of 334 diarrheal patients tested during a period from 1985 to 1988. 2. Most of the rotavirus positive cases were in their forties or in their fifties. 3. Geographic distribution of the infected area of the cases was not concentrated with specific countries. 4. Diarrhea was the most frequent clinical manifestations of the cases. 5. There was no cluster in seasonal distribution of the cases.     

Rotavirus in travelers' diarrhea: study of an adult student population in Mexico.

The role of rotavirus in adult diarrhea was evaluated in 165 students attending a Mexican university. Students were divided into three groups: newly arrived summer students from the United Sttes, regular students from the United States, and Mexican and Venezuelan students. Ninety-one students with diarrhea and 74 corresponding, matched, asymptomatic control students were included in the study. The frequency of rotavirus in stools was determined by electron microscopy with use of the pseudoreplica technique. Twenty-five percent of those who were ill and 12% of the controls had rotavirus in their stools. A significantly (P less than 0.05) greater number of newly arrived United States summer students with diarrhea had rotavirus in their stool than did matched controls (26% vs. 3%). There was no significant difference in rate of recovery of bacterial pathogens from rotavirus-positive and rotavirus-negative stools (52% vs. 53%) from students with diarrhea. Although significantly more rotavirus was identified from ill American summer students than from controls, the role of rotavirus as a cause of diarrhea in these students could not be established in all cases since bacterial pathogens were also commonly found in stool.     

Rotavirus

Since their discovery in the 1970s, the human rotaviruses have been recognized as the most important cause of acute infectious gastroenteritis among infants and children worldwide. Rotavirus has been found to infect almost all mammalian and avian species tested, and is primarily a disease of the young. In humans, rotavirus is the most frequent gastrointestinal pathogen in infants and children less than 2 years of age. In developing countries, the attack rate peaks at 6 months of age, whereas in developed areas of the world the virus is most commonly found among children 6-12 months of age. Rotavirus displays a marked seasonality in temperate climates, with the number of cases peaking in the colder winter months. In tropical climates, this seasonality is not as apparent, and infection may occur year round. Symptoms of rotavirus infection are non-specific and include vomiting and diarrhoea, occasionally accompanied by a low grade fever. Dehydration is more common with rotavirus infection than with most bacterial pathogens, and is the most common cause of death related to rotavirus infection. Treatment is non-specific and includes the use of oral rehydration therapy, especially in developing countries where malnutrition is common. Strategies for the prevention of rotavirus infection are dependent on advances in the understanding of the molecular biology of the rotavirus. The genetic structure of the virus has been extensively studied, and a number of the structural proteins have been identified. The neutralization antigens, located on VP4 and VP7, may be important in conferring immunity to rotavirus in vivo. Two animal-derived and several reassortant rotavirus vaccines are currently being evaluated in field studies, and a number of other candidate vaccines are being tested in vitro and in animal studies.     

Treatment and Prevention of Rotavirus Infection in Children

Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. No antiviral therapy is available. Treatment of rotavirus gastroenteritis is limited to rehydration therapy. Recently, therapies, such as probiotics, have been developed as adjuncts to rehydration therapy. Two effective rotavirus vaccines are available and recommended for routine immunization of all infants. These vaccines have been introduced in both developed and developing countries. As rotavirus vaccines are implemented, studies that assess health impact, indirect benefits, and strain changes after the introduction of rotavirus vaccine have been reported. In the United States, rotavirus vaccination has led to dramatic drops in severe rotavirus-related hospitalizations and has reduced emergency room visits. Herd immunity has also been noted after routine rotavirus immunization. There have been no significant strain shifts or escape mutants noted since the introduction of rotavirus vaccines.     

Identification of a Ruminant Origin Group B Rotavirus Associated with Diarrhea Outbreaks in Foals

Equine rotavirus group A (ERVA) is one of the most common causes of foal diarrhea. Starting in February 2021, there was an increase in the frequency of severe watery to hemorrhagic diarrhea cases in neonatal foals in Central Kentucky. Diagnostic investigation of fecal samples failed to detect evidence of diarrhea-causing pathogens including ERVA. Based on Illumina-based metagenomic sequencing, we identified a novel equine rotavirus group B (ERVB) in fecal specimens from the affected foals in the absence of any other known enteric pathogens. Interestingly, the protein sequence of all 11 segments had greater than 96% identity with group B rotaviruses previously found in ruminants. Furthermore, phylogenetic analysis demonstrated clustering of the ERVB with group B rotaviruses of caprine and bovine strains from the USA. Subsequent analysis of 33 foal diarrheic samples by RT-qPCR identified 23 rotavirus B-positive cases (69.69%). These observations suggest that the ERVB originated from ruminants and was associated with outbreaks of neonatal foal diarrhea in the 2021 foaling season in Kentucky. Emergence of the ruminant-like group B rotavirus in foals clearly warrants further investigation due to the significant impact of the disease in neonatal foals and its economic impact on the equine industry.     

Rotavirus carriage, asymptomatic infection, and disease in the first two years of life. I. Virus shedding

From September 1979 to July 1980 inclusive, rotaviruses were prospectively detected by electron microscopy (EM) and ELISA in 82 (29%) of 283 children under two years of age who were admitted to a general pediatric ward in Paris. Rotavirus was found in 43 (36%) of 119 children with diarrhea and in 40 (24%) of 164 children without diarrhea; thus of 83 children shedding rotavirus, 40 (48%) were not diarrheic. Virus shedding that was not associated with diarrhea was observed in 71% of neonates, in 50% of one- to six-month-old children, and in 26% of 7-24-month-old children. Rotavirus shedding was statistically correlated (P less than .01) only with those cases of diarrhea with fever and vomiting ( DFV syndrome). Consequently, relative risk (RR) for the DFV syndrome in patients who were shedding virus was 2.07 (P less than .001) vs. 0.95 for other types of diarrhea. These observations show that asymptomatic rotaviral infection is not an infrequent occurrence; that the association between rotavirus and diarrhea is not necessarily an etiologic one; and that the DFV syndrome appears as a major clinical expression of rotaviral disease. Consequently, recovery of rotavirus from feces is of little diagnostic significance since it does not give a differentiation between rotavirus-induced and rotavirus-associated diarrhea.     

Rotavirus infection following post‐transplantation cyclophosphamide based haploidentical hematopoietic cell transplantation in children is associated with hemophagocytic syndrome and high mortality

We evaluated the incidences and consequences of rotavirus induced diarrhea in a cohort of 115 patients undergoing T‐cell replete haploidentical transplantation. Four out of 115 patients developed rotavirus‐induced diarrhea between 47 and 147 days. The incidence of rotavirus infection was 9.7% in children compared to none in adults (P = .01). This was 25.3% in those with GVHD compared to 1.2% in those without GVHD (P = .001). Rotavirus infection was followed by post–transplantation hemophagocytic syndrome (PTHPS) at a median of 4 days (range, 3‐10 days) in all four patients. Three patients succumbed to the complications related to PTHPS. Only one patient, who is long‐term survivor, was able to eliminate this virus after 2 weeks. Children undergoing T‐replete haploidentical hematopoietic cell transplantation who develop GVHD are at a higher risk of community‐acquired rotavirus infection which was strongly associated with PTHPS with poor outcome.     

Rotavirus infection in a geriatric population

An outbreak of gastroenteritis affected 19 of 34 geriatric patients and four of 23 staff assigned to the ward in a period of 3 1/2 weeks in January 1980. Fourteen of the 19 patients with gastroenteritis (17 were tested properly) and four of the ten asymptomatic patients (five asymptomatic patients were not tested) showed evidence of rotavirus infection by virus positivity and/or a significant antibody response to rotavirus. One of the four staff members with gastroenteritis showed serologic evidence (three were tested) of rotavirus infection. Nine of the 18 asymptomatic staff members (two remaining staff members were not tested) showed a fourfold rise in antibody to rotavirus but four had antibody titers of 1:32 or more. The patients had diarrhea for a mean of 2.6 days. Most of them had five or fewer diarrheal stools in one day. Six patients had a severe illness and two died. Thirteen of 15 symptomatic patients who had serum samples, collected during the acute and convalescent phases, tested manifested high titers (greater than or equal to 1:32) of complement-fixing antibody to rotavirus antigen.     

Rotavirus vaccines: targeting the developing world

For the past 2 decades, rotavirus infection, the most common cause of severe diarrhea in children, has been a priority target for vaccine development. This decision to develop rotavirus vaccines is predicated on the great burden associated with fatal rotavirus disease (i.e., 440,000 deaths/year), the firm scientific basis for developing live oral vaccines, the belief that increased investment in development at this time could speed the introduction of vaccines in developing countries, and the appreciation that implementation of a vaccine program should result in a measurable decrease in the number of hospitalizations and deaths associated with rotavirus disease within 2-3 years. RotaShield (Wyeth-Ayerst), the first rotavirus vaccine licensed in the United States, was withdrawn after 9 months because of a rare association of the vaccine with the development of intussusception. In the developing world, this vaccine could still have had a measurable effect, because the benefits of preventing deaths due to rotavirus disease would have been substantially greater than the rare risk of intussusception. Two live oral vaccines being prepared by GlaxoSmithKline and Merck have completed large-scale clinical trials. The GlaxoSmithKline vaccine has been licensed in Mexico and the Dominican Republic, and the Merck vaccine could be licensed in the United States within 1 year; several other candidate vaccines are in earlier stages of testing. However, many challenges remain before any of these vaccines can be incorporated into childhood immunization programs in the developing world. First, vaccine efficacy, which has already been demonstrated in children in industrialized and middle-income countries, needs to be proven in poor developing countries in Africa and Asia. The safety of vaccines with regard to the associated risk of intussusception must be demonstrated as well. Novel financing strategies will be needed to ensure that new vaccines are affordable and available in the developing world. Decision makers and parents in developing countries need to know about this disease that has little name recognition and is rarely diagnosed. Finally, for the global effort toward the prevention of rotavirus disease to be successful, special efforts will be required in India, China, and Indonesia, because one-third of all deaths due to rotavirus disease occur in these countries, and because these countries depend almost entirely on vaccines manufactured domestically.     

Rotavirus carriage, asymptomatic infection, and disease in the first two years of life. II. Serological response

Serological response to rotavirus and virus shedding were prospectively studied in 179 children (neonatal to 24-month-old) upon admission to a hospital during an 11-month period. Analysis of the evolution of IgG and IgM ELISA titers revealed 24 cases of rotaviral disease (serological response and diarrhea), 13 cases of asymptomatic infection (serological response and no diarrhea), 36 cases of virus carriage (absence of a serological response), three cases of past infection, and six possible cases of nosocomial infection. Rotaviral disease was encountered two out of three times and was characterized by diarrhea associated with fever and vomiting. Asymptomatic rotaviral infection and disease, observed from the neonatal period onwards, affected 2% of neonates, 20% of one- to six-month-old children, and 37% of 7-24-month-old children. In contrast, virus carriage occurred in 27%, 19%, and 14% of those children respectively. Altogether these results indicate that during the period 1-24 months of age, when asymptomatic rotaviral infection and disease were prevalent, approximately two of 10 children had rotaviral disease, one of 10 had asymptomatic infection, two of 10 were virus carriers, and five of 10 were not infected with rotavirus.     

Serum antibody as a marker of protection against natural rotavirus infection and disease

To determine whether naturally acquired serum IgA and IgG antibodies were associated with protection against rotavirus infection and illness, a cohort of 200 Mexican infants was monitored weekly for rotavirus excretion and diarrhea from birth to age 2 years. Serum samples collected during the first week after birth and every 4 months were tested for anti-rotavirus IgA and IgG. Children with an IgA titer >1:800 had a lower risk of rotavirus infection (adjusted relative risk [aRR], 0.21; P<.001) and diarrhea (aRR, 0. 16; P=.01) and were protected completely against moderate-to-severe diarrhea. However, children with an IgG titer >1:6400 were protected against rotavirus infection (aRR, 0.51; P<.001) but not against rotavirus diarrhea. Protective antibody titers were achieved after 2 consecutive symptomatic or asymptomatic rotavirus infections. These findings indicate that serum anti-rotavirus antibody, especially IgA, was a marker of protection against rotavirus infection and moderate-to-severe diarrhea.     

Seroepidemiologic evaluation of antibodies to rotavirus as correlates of the risk of clinically significant rotavirus diarrhea in rural Bangladesh.

A case-control study was conducted among children and adult women in rural Bangladesh to evaluate whether serologic immunity to rotavirus was associated with a lower risk of rotavirus diarrhea of sufficient severity to cause patients to seek medical care. Acute-phase sera from 219 cases of rotavirus diarrhea, detected among patients treated in three diarrheal treatment centers, were compared with sera from 477 contemporaneously selected community controls. Overall, serum IgG antirotavirus antibody titers were nearly one-fourth as high in cases as in controls (107 vs. 417 units/ml; P less than .001). Among persons aged greater than or equal to 8 months, in whom titers of maternal antirotavirus antibodies should have been negligible, even the lowest range of detectable titers (100-200 units/ml) was associated with a substantial (75%, P less than .05) reduction of the risk of rotavirus diarrhea. We conclude that titers of serum IgG antirotavirus antibodies induced by earlier infection were inversely related to the risk of clinically significant rotavirus diarrhea.     

Incidence of diarrhea caused by rotavirus infections in rural Zhengding, China: prospective, population-based surveillance

Rotavirus is the pathogen most commonly associated with severe gastroenteritis in young children in the People's Republic of China, yet there are few population-based data on the incidence of rotavirus infection. The present study investigated the burden of rotavirus diarrhea and rotavirus infections in rural China, according to age. Population-based surveillance was used to study the incidence of rotavirus infection among children <5 years of age in 4 townships of Zhengding County, Hebei Province, China. The total population in the catchment area in 2002 was 75,630 individuals, including 2997 children aged <5 years. Stool samples were obtained and were tested for rotavirus antigen by use of an enzyme-linked immunosorbent assay. During 2002, a total of 2010 cases of diarrhea were detected among children <5 years of age. The incidence of treated cases of diarrhea was 671 cases/1000 children/year for children <5 years of age, and it was highest for children <12 months of age (1467 cases/1000 children/year). The estimated incidence of rotavirus infection was 151 cases/1000 children/year for children <5 years of age. The highest incidence of rotavirus infection was among children aged 1-2 years (340 cases/1000 children/year). Widespread immunization of children against rotavirus before 6 months of age should be considered for the control of rotavirus diarrhea.     

Rotavirus vaccines: Current controversies and future directions

Rotaviruses are the most important cause of pediatric gastroenteritis worldwide. In August 1998, a new rotavirus vaccine was licensed for general use in the United States. However, 14 months later, the vaccine was withdrawn from the market because of serious gastrointestinal side effects. This paper discusses the need for a rotavirus vaccine, the development of the first rotavirus vaccine, and the safety issues that led to the recall of that vaccine.     

Rotavirus outbreak on a pediatric oncology floor: possible association with toys

BACKGROUND: Several outbreaks of rotavirus gastroenteritis have occurred in hospitals and day care centers. In the spring of 1997, an outbreak of rotavirus occurred on our pediatric unit. Aggressive infection control measures were instituted, and potential lapses in infection control were assessed. METHODS: Memorial Sloan-Kettering Cancer Center is a 434-bed cancer hospital in New York City. The pediatric unit is a 42-bed ward with both bone marrow transplant patients and non-bone marrow transplant oncology patients. Nosocomially acquired rotavirus was defined as diarrhea, vomiting, or gastrointestinal upset with onset 48 hours or more after hospital admission, accompanied by a positive enzyme immunoassay for rotavirus antigen. RESULTS: Between February 24 and April 4, 1997, 8 patients on the pediatric unit had nosocomial rotavirus. Aggressive infection control measures were instituted. Patients with rotavirus were cohorted and placed on contact precautions (strict handwashing, gloves, and gown). Investigation by the infection control team revealed that communal toys in the playroom were not being cleaned according to the weekly protocol. CONCLUSIONS: An outbreak of nosocomial rotavirus occurred on our pediatric oncology unit. Shared toys may have served as fomites in the transmission of rotavirus.