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1.  Burden and Typing of Rotavirus Group A in Children with Acute Gastroenteritis in Shiraz, Southern Iran 
Background
Human Rotavirus is a significant cause of severe gastroenteritis in infants and young children worldwide. In recent years, Rotavirus genotyping by RT-PCR has provided valuable information about the diversity of Rotaviruses circulating worldwide. The purpose of the present study is to monitor the prevalence of the different G types of Rotaviruses circulating in Shiraz, Southern Iran and detect any uncommon or novel types.
Methods
During the period from December 2007 to November 2008, a total of 138 stool samples were collected from children less than 5 years old who were hospitalized for acute gastroenteritis. Rotavirus-associated diarrhea was investigated in fecal specimens with enzyme immunoassays (EIA). Rotavirus-positive specimens were typed by the Nested RT-PCR and by using different types of specific primers.
Results
Out of the 138 collected samples, 34.78% (48 cases) tested positive for Rotavirus. The frequency of G1, G2 and G4 types was 6.25%, 2.08% and 27.08%, respectively. Mixed and non-typeable infections were detected in 33.34% and 31.25% of hospitalized children with acute diarrhea, respectively. This is the first time mixed Rotavirus infections with G1/G3 have been reported in Iran.
Conclusion
The high frequency of Rotavirus detection indicates the severity and the burden of Rotavirus disease may be able to reduce through the implementation of an effective vaccine and continual surveillance for the detection of Rotavirus genotypes circulating in other regions of Iran.
Regarding to the noticeable frequency of non-typeable and mixed infections, it is suggested to use the other specific primers and further studies to detection of other novel and unusual types.
PMCID: PMC3482325  PMID: 23115715
Human Rotavirus; Diarrhea; Hospitalized children; G types
2.  Rotavirus Antigenemia in Children Is Associated with Viremia 
PLoS Medicine  2007;4(4):e121.
Background
Antigenemia is commonly detected in rotavirus-infected children. Although rotavirus RNA has been detected in serum, definitive proof of rotavirus viremia has not been shown. We aimed to analyze a defined patient population to determine if infectious virus could be detected in sera from children with rotavirus antigenemia.
Methods and Findings
Serum samples obtained upon hospitalization from children with gastroenteritis (57 stool rotavirus-positive and 41 rotavirus-negative), children with diagnosed bronchiolitis of known (n = 58) or unknown (n = 17) viral etiology, children with noninfectious, nonchronic conditions (n = 17), and healthy adults (n = 28) were tested for rotavirus antigen by enzyme immunoassay (EIA). Results of serum antigen testing were assessed for association with clinical and immunological attributes of the children. Rotavirus antigenemia was detected in 90% (51/57) of children with rotavirus-positive stools, in 89% (8/9) of children without diarrhea but with rotavirus-positive stools, in 12% (2/17) of children with bronchiolitis of unknown etiology without gastroenteritis, and in 12% (5/41) of children with gastroenteritis but with rotavirus-negative stools. Antigenemia was not detected in sera from children with noninfectious nonchronic conditions, children with bronchiolitis of known etiology and no gastroenteritis, or healthy adults. Neither age nor timing of serum collection within eight days after onset of gastroenteritis significantly affected levels of antigenemia, and there was no correlation between antigenemia and viral genotype. However, there was a negative correlation between serum rotavirus antigen and acute rotavirus-specific serum IgA (r = −0.44, p = 0.025) and IgG (r = −0.40, p = 0.01) titers. We examined 11 antigen-positive and nine antigen-negative sera for infectious virus after three blind serial passages in HT-29 cells using immunofluorescence staining for rotavirus structural and nonstructural proteins. Infectious virus was detected in 11/11 (100%) sera from serum antigen-positive children and in two out of nine (22%) sera samples from antigen-negative children (p = 0.002).
Conclusions
Most children infected with rotavirus are viremic. The presence of viremia is directly related to the detection of antigenemia and is independent of the presence of diarrhea. Antigenemia load is inversely related to the titer of antirotavirus antibody in the serum. The finding of infectious rotavirus in the blood suggests extraintestinal involvement in rotavirus pathogenesis; however, the impact of rotavirus viremia on clinical manifestations of infection is unknown.
A study of 57 children with rotavirus-positive stools found that most were viremic, and that the presence of viremia was directly related to antigenemia and independent of the presence of diarrhea.
Editors' Summary
Background.
Rotavirus is a type of virus that is the commonest cause of severe diarrhea among children worldwide. It is passed from one person to another when virus present in the stool of an infected person is swallowed by another individual. The infection causes vomiting, watery diarrhea, and fever; many children need to be hospitalized as a result and globally more than 600,000 children are thought to die as a result of rotavirus infections per year. Evidence from single case descriptions of infected children have suggested that rotavirus might also cause symptoms outside of the gut—for example, in the lungs or brain. Previous studies have found fragments of rotavirus, for example RNA or parts of virus protein, in tissues outside of the gut such as liver, kidney, blood, and heart. However, simply finding fragments such as RNA or protein does not necessarily mean that rotavirus infects these tissues.
Why Was This Study Done?
These researchers wanted to find out whether rotavirus was present in the blood of infected children. If evidence of rotavirus in the blood was found, this might help explain why some children infected with rotavirus have symptoms affecting organs other than the gut.
What Did the Researchers Do and Find?
In this study, five groups of patients were recruited and tests were done on each to find out whether infectious rotavirus was present in their bloodstream, and also whether the researchers could detect rotavirus components in blood using antibodies against particular parts of the rotavirus particle. The five groups of patients that were compared included children hospitalized with gastroenteritis; children hospitalized with noninfectious conditions; healthy adult laboratory workers; children with lung infections from known viruses; and finally children with lung infections of unknown cause. The researchers found that among the children with gastroenteritis who had rotavirus in their stool, 90% also had evidence of rotavirus particles in their bloodstream. By contrast, control individuals (either children who were hospitalized with noninfectious conditions or healthy adults) did not have rotavirus particles in blood. A small proportion of children with gastroenteritis but no rotavirus in their stool did have rotavirus particles in blood. Interestingly, a small proportion of the children who had lung infections (but in whom no known virus had been identified as the cause) showed evidence of rotavirus in their bloodstreams. Finally, in a group of 11 children with evidence of rotavirus particles in their bloodstreams, all were found to also have infectious virus present in the blood.
What Do These Findings Mean?
These results show that rotavirus is able to spread beyond the gut and into the bloodstream. The finding that rotavirus can spread into the bloodstream may explain some earlier suggestions that rotavirus is responsible for symptoms outside of the gut. However, it is not yet clear how commonly children with rotavirus have other symptoms resulting from the virus spreading into their bloodstream.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040121.
Read the related PLoS Medicine Perspective article by David Candy
Information from the World Health Organization Initiative for Vaccine Research on rotavirus disease burden; see also the Rotavirus Vaccine Program, a partnership that aims to develop rotavirus vaccines appropriate for use in developing countries
Information from the US Centers for Disease Control and Prevention about rotavirus
Health Encyclopedia entry from the UK's NHS Direct on Rotavirus
doi:10.1371/journal.pmed.0040121
PMCID: PMC1852122  PMID: 17439294
3.  Molecular characterization of rotavirus isolates from select Canadian pediatric hospitals 
BMC Infectious Diseases  2012;12:306.
Background
We report the first multi-site rotavirus genotype analysis in Canada. Prior to this study, there was a dearth of rotavirus G and P genotyping data in Canada. Publically funded universal rotavirus vaccination in Canada started in 2011 and has been introduced by four provinces to date. Uptake of rotavirus vaccines in Canada prior to 2012 has been very limited. The aim of this study was to describe the genotypes of rotavirus strains circulating in Canada prior to widespread implementation of rotavirus vaccine by genotyping samples collected from selected paediatric hospitals. Secondly we identified rotavirus strains that differed genetically from those included in the vaccines and which could affect vaccine effectiveness.
Methods
Stool specimens were collected by opportunity sampling of children with gastroenteritis who presented to emergency departments. Samples were genotyped for G (VP7) genotypes and P (VP4) genotypes by hemi-nested multiplex PCR methods. Phylogenetic analysis was carried out on Canadian G9 strains to investigate their relationship to G9 strains that have circulated in other regions of the world.
Results
348 samples were collected, of which 259 samples were rotavirus positive and genotyped. There were 34 rotavirus antigen immunoassay negative samples genotyped using PCR-based methods. Over the four rotavirus seasons, 174 samples were G1P[8], 45 were G3P[8], 22 were G2P[4], 13 were G9P[8], 3 were G4P[8] and 2 were G9P[4]. Sequence analysis showed that all Canadian G9 isolates are within lineage III.
Conclusions
Although a limited number of samples were obtained from a median of 4 centres during the 4 years of the study, it appears that currently approved rotavirus vaccines are well matched to the rotavirus genotypes identified at these hospitals. Further surveillance to monitor the emergence of rotavirus genotypes in Canada is warranted.
doi:10.1186/1471-2334-12-306
PMCID: PMC3519651  PMID: 23153184
4.  Emergence of unusual human rotavirus strains in Salento, Italy, during 2006–2007 
Background
In recent years, rotavirus genotyping by RT-PCR has provided valuable information about the diversity of rotaviruses (RV) circulating throughout the world.
The purpose of the present study was to monitor the prevalence of the different G and P genotypes of rotaviruses circulating in Salento and detect any uncommon or novel types.
Methods
During the period from January 2006 to December 2007, a total of 243 rotavirus positive stool samples were collected from children with diarrhoea admitted to four Hospitals in the province of Lecce (Copertino, Galatina, Gallipoli and Tricase).
All the specimens were tested for RV by real time PCR and genotyped for VP7 (G-type) and VP4 (P-type) gene by reverse transcription (RT) and multiplex PCR using different type specific primers.
Results
In course of this study we identified 4 common G&P combinations viz. G2P[8], G1P[8], G2P[4] and G9P[8] amongst 59.8% of the typeable rotavirus positives.
Rotavirus G2P[8] was recognized as the most widespread genotype during the sentinel-based survey in Salento.
The detection of other novel and unusual strains, such as G2P[10], G4P[10], G8P[4], G9P[11] and G10P[8] is noteworthy.
Furthermore, a significant number of mixed infections were observed during the survey period but G3P[8] rotaviruses were not detected.
Conclusion
This study highlights the genetic diversity among rotaviruses isolated from children in Salento and the emergence of some novel strains. Therefore, it is highly essential to continuously monitor for these strains so as to assess the impact of vaccines on RV strains circulating in Salento and understand the effect of strain variation on efficacy of presently available vaccines.
doi:10.1186/1471-2334-9-43
PMCID: PMC2676288  PMID: 19368717
5.  Molecular Characterization of Rotavirus in Ireland: Detection of Novel Strains Circulating in the Population 
Journal of Clinical Microbiology  2000;38(9):3370-3374.
A collection of three hundred thirty rotavirus-positive stool samples from children with diarrhea in the southern and eastern regions of Ireland between 1997 and 1999 were submitted to the Molecular Diagnostics Unit of the Cork Institute of Technology, Cork, Ireland, for investigation. These strains were characterized by several methods, including polyacrylamide gel electropherotyping and G and P genotyping. A subset of the G types was confirmed by nucleic acid sequencing. The most prevalent types found in this collection included G1P[8] (n = 106; 32.1%), G2P[4] (n = 94; 28.5%), and G4P[8] (n = 37; 11.2%). Novel strains were also detected, including G1P[4] (n = 19; 5.8%), and G4P[4] (n = 2; 0.6%). Interestingly, mixed infections accounted for 18.8% (n = 62) of the total collection, with only 3% (n = 10) which were not G and/or P typeable. Significantly, six G8 and five G9 strains were identified as part of mixed infections. These strains have not previously been identified in Irish children, suggesting a greater diversity in rotavirus strains currently circulating in Ireland.
PMCID: PMC87388  PMID: 10970385
6.  The molecular epidemiology of circulating rotaviruses: three-year surveillance in the region of Monastir, Tunisia 
BMC Infectious Diseases  2011;11:266.
Background
Rotavirus infection is the most common cause of severe, dehydrating, gastroenteritis among children worldwide. In developing countries, approximately 1440 children die from rotavirus infections each day, with an estimated 527,000 annually. In infants, rotavirus is estimated to cause more than 2 million hospitalizations every year depending on the income level of the country.
The purpose of this study was to estimate the proportion of rotavirus gastroenteritis and identify the distribution of circulating G and P genotype rotavirus strains among children consulting several dispensaries in the region of Monastir (outpatients departments) or admitted to Monastir University Hospital (inpatients department) with acute gastroenteritis.
Methods
This study was undertaken during a 3-year period from April 2007 to April 2010 in Tunisian children under 13 suffering from acute gastroenteritis. Group A rotaviruses were detected in stools by ELISA and genotyped using multiplex reverse transcription PCRs with type-specific primers on the basis of their outer capsid proteins. Statistical analyses were performed with SPSS software, version 19.
Results
Of the 435 stool samples from children with acute gastroenteritis, 27.6% were positive for rotavirus A. The predominant G type was G1 (37.5%), followed by G3 (25%), G2 (17.5%), G4 (12.5%), G9 (2.5%) and three mixed-G infections G3G4 (2.5%) were identified.
Only P[8] (80.8%), P[4] (16.7%) and P[9] (0.8%) genotypes were found. The predominant single G/P combination was G1P[8] (37.5%), followed by G3P[8] (25%), G2P[4] (16.7%), G4P[8] (12.5%), G9P[8] (1.7%) and one case of the unusual combination G9P[9] (0.8%). The G-mixed types G3G4 combined with P[8] (2.5%). Infants less than 3 months of age were most frequently affected. The prevalence of rotavirus infection peaked in the winter season, when temperatures were low, and decreased in summer.
Conclusions
Rotavirus gastroenteritis is a common disease associated with significant morbidity, mortality, and economic burden. Epidemiological knowledge of rotavirus is critical for the development of effective preventive measures, including vaccines.
These data will help to make informed decisions as to whether rotavirus vaccine should be considered for inclusion in Tunisia's National Immunisation Programme.
doi:10.1186/1471-2334-11-266
PMCID: PMC3193173  PMID: 21967503
7.  Incidence and Clinical Characteristics of Group A Rotavirus Infections among Children Admitted to Hospital in Kilifi, Kenya  
PLoS Medicine  2008;5(7):e153.
Background
Rotavirus, predominantly of group A, is a major cause of severe diarrhoea worldwide, with the greatest burden falling on young children living in less-developed countries. Vaccines directed against this virus have shown promise in recent trials, and are undergoing effectiveness evaluation in sub-Saharan Africa. In this region limited childhood data are available on the incidence and clinical characteristics of severe group A rotavirus disease. Advocacy for vaccine intervention and interpretation of effectiveness following implementation will benefit from accurate base-line estimates of the incidence and severity of rotavirus paediatric admissions in relevant populations. The study objective was to accurately define the incidence and severity of group A rotavirus disease in a resource-poor setting necessary to make informed decisions on the need for vaccine prevention.
Methods and Findings
Between 2002 and 2004 we conducted prospective surveillance for group A rotavirus infection at Kilifi District Hospital in coastal Kenya. Children < 13 y of age were eligible as “cases” if admitted with diarrhoea, and “controls” if admitted without diarrhoea. We calculated the incidence of hospital admission with group A rotavirus using data from a demographic surveillance study of 220,000 people in Kilifi District. Of 15,347 childhood admissions 3,296 (22%) had diarrhoea, 2,039 were tested for group A rotavirus antigen and, of these, 588 (29%) were positive. 372 (63%) rotavirus-positive cases were infants. Of 620 controls 19 (3.1%, 95% confidence interval [CI] 1.9–4.7) were rotavirus positive. The annual incidence (per 100,000 children) of rotavirus-positive admissions was 1,431 (95% CI 1,275–1,600) in infants and 478 (437–521) in under-5-y-olds, and highest proximal to the hospital. Compared to children with rotavirus-negative diarrhoea, rotavirus-positive cases were less likely to have coexisting illnesses and more likely to have acidosis (46% versus 17%) and severe electrolyte imbalance except hyponatraemia. In-hospital case fatality was 2% among rotavirus-positive and 9% among rotavirus-negative children.
Conclusions
In Kilifi > 2% of children are admitted to hospital with group A rotavirus diarrhoea in the first 5 y of life. This translates into over 28,000 vaccine-preventable hospitalisations per year across Kenya, and is likely to be a considerable underestimate. Group A rotavirus diarrhoea is associated with acute life-threatening metabolic derangement in otherwise healthy children. Although mortality is low in this clinical research setting this may not be generally true in African hospitals lacking rapid and appropriate management.
Combining prospective hospital-based surveillance with demographic data in Kilifi, Kenya, James Nokes and colleagues assess the burden of rotavirus diarrhea in young children.
Editors' Summary
Background.
Rotavirus is a leading global cause of diarrhea in babies and young children. Indeed, most children become infected at least once with this virus before their fifth birthday. Rotavirus is usually spread by children or their caregivers failing to wash their hands properly after going to the toilet and then contaminating food or drink. The symptoms of rotavirus infection—diarrhea, vomiting, and fever—are usually mild, but if the diarrhea is severe it can quickly lead to dehydration. Mild to moderate dehydration can be treated at home by providing the patient with plenty of fluids or with a special rehydration drink that replaces lost water and salts. However, for infants or toddlers who become severely dehydrated, rehydration with intravenous fluids (fluids injected directly into a vein) in hospital may be essential. Unfortunately, in developing countries in sub-Saharan Africa and elsewhere, this treatment is not widely available and every year more than half a million young children die from rotavirus infections.
Why Was This Study Done?
Two rotavirus vaccines that could reduce this burden of disease are currently undergoing clinical trials to determine their effectiveness in sub-Saharan Africa. However, very little is known about the incidence of severe rotavirus infections among children living in this region (that is, how many children develop severe disease every year) or about the clinical characteristics of the disease here. Public-health officials need this baseline information before they can make informed decisions about the mass introduction of rotavirus vaccination and to help them judge whether the intervention has been successful if it is introduced. In this study, the researchers examine the incidence and clinical characteristics of rotavirus infections (specifically, group A rotavirus [GARV] infections; there are several different rotaviruses but GARV causes most human infections) among children admitted to the district hospital in Kilifi, Kenya.
What Did the Researchers Do and Find?
During the 3-year study, more than 15,000 children under the age of 13 years were admitted to Kilifi District Hospital, a little under a quarter of whom had severe diarrhea. Nearly a third of the patients admitted with diarrhea who were tested had a GARV-specific protein in their stools (faeces); by contrast, only three in 100 children admitted without diarrhea showed any evidence of GARV infection. Two-thirds of the GARV-positive children were infants (under 1 year old). Using these figures and health surveillance data (records of births, deaths, and causes of death) collected in the area around the hospital, the researchers calculated that the annual incidence (per 100,000 children) of GARV-positive hospital admissions in the region was 1,431 for infants and 478 for children under age 5 years. Children with GARV-positive diarrhea were less likely to have other illnesses (for example, malnutrition) than those admitted with GARV-negative diarrhea, the researchers report, but were more likely to have life-threatening complications such as severe dehydration and salt imbalances in their blood. However, despite being more ill on admission, only 1 in 50 children with GARV-positive diarrhea died, compared to nearly 1 in 10 of the children with GARV-negative diarrhea; the GARV-positive children also left hospital quicker than those who were GARV-negative.
What Do These Findings Mean?
These findings indicate that severe GARV-positive diarrhea is a major cause of hospital admission among otherwise healthy young children in the Kilifi region of Kenya. By the time they are 5 years old, the researchers estimate that 1 in 50 of the children living in this region will have been admitted to hospital with severe GARV-positive diarrhea. Because rotavirus vaccines prevent virtually all severe rotavirus-associated disease (at least in developed countries where their effectiveness has been extensively tested), the researchers estimate that vaccination might prevent more than 28,000 hospitalizations annually across Kenya; however, this prediction assumes that it is valid to extrapolate from the data obtained from this one district hospital to the entire country.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050153.
The US Centers for Disease Control and Prevention provides information about rotavirus infections, surveillance, and vaccination (in English and Spanish)
The UK National Health Service Direct health encyclopedia provides information on rotavirus infections
MedlinePlus also provides links to information on rotavirus (in English and Spanish)
The African Rotavirus Surveillance Network is working to improve knowledge about rotavirus infections in Africa
The Rotavirus Vaccine Program aims to reduce child illness and death from diarrhea by increasing the availability of rotavirus vaccines in developing countries (in English and Spanish)
PATH, a nonprofit international organization that aims to create sustainable, culturally relevant solutions to global health problems, also provides detailed information on rotavirus surveillance and disease burden
doi:10.1371/journal.pmed.0050153
PMCID: PMC2488191  PMID: 18651787
8.  Molecular Epidemiology of Rotavirus Strains Circulating among Children with Gastroenteritis in Iran 
Iranian Journal of Pediatrics  2012;22(1):63-69.
Objective
This study was conducted to evaluate the prevalence of rotavirus disease and to investigate the genotypes of rotavirus strains causing acute gastroenteritis among children aged <5 years old in Marvdasht, Iran.
Methods
One hundred and forty-one children, aged 1 month to 5 years, afflicted with severe diarrhea were enrolled during January 2007 to December 2008. Their stool samples were studied with enzyme immunoassays (EIA) for group A rotaviruses. Rotavirus-positive specimens were genotyped by the Nested RT-PCR using different types of specific primers.
Findings
Out of total collected samples rotavirus infection was detected in 40 (28.37%). Of the rotavirus episodes, 72.91% occurred during the first 2 years of life (P=0.038). The highest prevalence of infection was identified in summer (52.50%) and the lowest in winter (7.50%). The most common clinical features included diarrhea (96.25%), vomiting (82.50%) and fever (45.0%). Mixed genotypes were the predominant G type (60.0%), followed by non-typeable (12.50%), G2 (12.50%), G4 (10.0%) and G1 (5.0%) genotypes. G3/G8 mixed infection is the first of these rotavirus genotypes to be reported in Iran.
Conclusion
Regarding high frequency of rotavirus infection, continuous surveillance is needed to inform diarrhea prevention programs as well as to provide information about the occurrence of new rotavirus strains. This will assist policy makers in decision making on rotavirus vaccine introduction.
PMCID: PMC3448217  PMID: 23056861
Rotavirus; Gastroenteritis; Genotyping; Children; Epidemiology
9.  Prevalence of Rotavirus Genotypes in Children Younger than 5 Years of Age before the Introduction of a Universal Rotavirus Vaccination Program: Report of Rotavirus Surveillance in Turkey 
PLoS ONE  2014;9(12):e113674.
Background
Group A rotaviruses are the most common causative agent of acute gastroenteritis among children less than 5 years of age throughout the world. This sentinel surveillance study was aimed to obtain baseline data on the rotavirus G and P genotypes across Turkey before the introduction of a universal rotavirus vaccination program.
Methods
Rotavirus antigen-positive samples were collected from 2102 children less than 5 years of age who attended hospitals participating in the Turkish Rotavirus Surveillance Network. Rotavirus antigen was detected in the laboratories of participating hospitals by commercial serological tests such as latex agglutination, immunochromatographic test or enzyme immunoassay. Rotavirus G and P genotypes were determined by reverse transcription polymerase chain reaction (RT-PCR) using consensus primers detecting the VP7 and VP4 genes, followed by semi-nested type-specific multiplex PCR.
Results
RT-PCR found rotavirus RNA in 1644 (78.2%) of the samples tested. The highest rate of rotavirus positivity (38.7%) was observed among children in the 13 to 24 month age group, followed by children in the age group of 25 to 36 months (28.3%). A total of eight different G types, six different P types, and 42 different G–P combinations were obtained. Four common G types (G1, G2, G3, and G9) and two common P types (P[8] and P[4]) accounted for 95.1% and 98.8% of the strains, respectively. G9P[8] was the most common G/P combination found in 40.5% of the strains followed by G1P[8] (21.6%), G2P[8] (9.3%), G2P[4] (6.5%), G3P[8] (3.5%), and finally, G4P[8] (3.4%). These six common genotypes included 83.7% of the strains tested in this study. The rate of uncommon genotypes was 14%.
Conclusion
The majority of the strains analyzed belonged to the G1–G4 and G9 genotypes, suggesting high coverage of current rotavirus vaccines. This study also demonstrates a dramatic increase in G9 genotype across the country.
doi:10.1371/journal.pone.0113674
PMCID: PMC4249891  PMID: 25437502
10.  Prevalence and Molecular Genotyping of Group A Rotaviruses in Iranian Children 
Rotavirus is the leading cause of acute gastroenteritis in worldwide young children. Effective vaccines to prevent rotavirus infection are currently available, although their clinical use is still limited, and rotavirus still causes many episodes of infantile gastroenteritis, mainly during the winter season. The aim of this study was to evaluate the prevalence of rotavirus infection in children aged <5-years-old who were hospitalised for gastroenteritis. One hundred and sixty-three stool samples from hospitalised children (<5-years-old) complicated with severe diarrhoea, in two hospitals in Jahrom City, Iran were collected from 2009 to 2010. Antigenic prevalence of rotavirus group A was distinguished by enzyme immunoassay. The antigen of group A rotavirus was diagnosed by EIA in 75 of 163 collected samples. The genotype of EIA-positive samples was determined by nested RT-PCR. The frequency of rotavirus genotypes G1, G2, G3, G4 and G9 was 17.33, 13.34, 2.67, 30.66 and 2.67 %, respectively. Also, the frequency of mixed and non-typable genotypes was detected in 2.67 and 30.66 %, respectively. G1/G8 mixed infection was the first of these rotavirus genotypes to be reported in Iran. Detection of high prevalence of group A rotavirus infection in hospitalised children with diarrhoea, and determination of circulating rotavirus genotypes in this region of Iran, provide useful data for formulating effective vaccines; especially for infants less than 5-years-old.
doi:10.1007/s13337-012-0070-7
PMCID: PMC3550810  PMID: 23729998
Rotavirus; Prevalence; Molecular genotyping; RT-PCR
11.  Genetic Diversity of Circulating Rotavirus Strains in Tanzania Prior to the Introduction of Vaccination 
PLoS ONE  2014;9(5):e97562.
Background
Tanzania currently rolls out vaccination against rotavirus-diarrhea, a major cause of child illness and death. As the vaccine covers a limited number of rotavirus variants, this study describes the molecular epidemiology of rotavirus among children under two years in Dar es Salaam, Tanzania, prior to implementation of vaccination.
Methods
Stool specimens, demographic and clinical information, were collected from 690 children admitted to hospital due to diarrhea (cases) and 545 children without diarrhea (controls) during one year. Controls were inpatient or children attending child health clinics. Rotavirus antigen was detected using ELISA and positive samples were typed by multiplex semi-nested PCR and sequencing.
Results
The prevalence of rotavirus was higher in cases (32.5%) than in controls (7.7%, P<0.001). The most common G genotypes were G1 followed by G8, G12, and G4 in cases and G1, G12 and G8 in controls. The Tanzanian G1 variants displayed 94% similarity with the Rotarix vaccine G1 variant. The commonest P genotypes were P[8], P[4] and P[6], and the commonest G/P combination G1 P[8] (n = 123), G8 P[4] and G12 P[6]. Overall, rotavirus prevalence was higher in cool (23.9%) than hot months (17.1%) of the year (P = 0.012). We also observed significant seasonal variation of G genotypes. Rotavirus was most frequently found in the age group of four to six months. The prevalence of rotavirus in cases was lower in stunted children (28.9%) than in non-stunted children (40.1%, P = 0.003) and lower in HIV-infected (15.4%, 4/26) than in HIV-uninfected children (55.3%, 42/76, P<0.001).
Conclusion
This pre-vaccination study shows predominance of genotype G1 in Tanzania, which is phylogenetically distantly related to the vaccine strains. We confirm the emergence of genotype G8 and G12. Rotavirus infection and circulating genotypes showed seasonal variation. This study also suggests that rotavirus may not be an opportunistic pathogen in children infected with HIV.
doi:10.1371/journal.pone.0097562
PMCID: PMC4028215  PMID: 24844631
12.  Genetic diversity of porcine group A rotavirus strains in the UK 
Veterinary Microbiology  2014;173(1-2):27-37.
Highlights
•This is the first study of rotavirus genotypes circulating in UK pigs.•Rotavirus transmission between pigs and humans is not thought to be common in the UK.•Human rotavirus genotype P[8] found in a UK pig.•The uncommon rotavirus genotype P[32] is widespread in UK pig herds.
Rotavirus is endemic in pig farms where it causes a loss in production. This study is the first to characterise porcine rotavirus circulating in UK pigs. Samples from diarrheic pigs with rotavirus enteritis obtained between 2010 and 2012 were genotyped in order to determine the diversity of group A rotavirus (GARV) in UK pigs. A wide range of rotavirus genotypes were identified in UK pigs: six G types (VP7); G2, G3, G4, G5, G9 and G11 and six P types (VP4); P[6], P[7], P[8], P[13], P[23], and P[32]. With the exception of a single P[8] isolate, there was less than 95% nucleotide identity between sequences from this study and any available rotavirus sequences.
The G9 and P[6] genotypes are capable of infecting both humans and pigs, but showed no species cross-over within the UK as they were shown to be genetically distinct, which suggested zoonotic transmission is rare within the UK. We identified the P[8] genotype in one isolate, this genotype is almost exclusively found in humans. The P[8] was linked to a human Irish rotavirus isolate in the same year. The discovery of human genotype P[8] rotavirus in a UK pig confirms this common human genotype can infect pigs and also highlights the necessity of surveillance of porcine rotavirus genotypes to safeguard human as well as porcine health.
doi:10.1016/j.vetmic.2014.06.030
PMCID: PMC4158422  PMID: 25123085
Rotavirus; Porcine; Phylogenetic; Zoonosis
13.  Changing profile of rotavirus genotypes in Bangladesh, 2006–2012 
BMC Infectious Diseases  2013;13:320.
Background
Rotavirus is the leading cause of severe diarrhea in infants and young children worldwide including Bangladesh. Unlike what was seen in high-income countries, the licensed rotavirus vaccines did not show high efficacy in Bangladeshi trials. We assessed rotavirus prevalence and genotypes in Bangladesh over six-year period to provide baseline information on the rotavirus burden and changing profile in the country.
Methods
This study was conducted from June 2006 to May 2012 in Matlab, Bangladesh. Group A rotaviruses were detected in stools collected from diarrhea patients by ELISA and genotyped using multiplex reverse transcription PCR followed by nucleotide sequencing.
Results
Of the 9678 stool samples, 20.3% were positive for rotavirus. The most predominant genotype was G1P[8] (22.4%), followed by G9P[8] (20.8%), G2P[4] (16.9%) and G12P[8] (10.4%). Mixed infections were detected in 14.2% of the samples. Emergence of an unusual strain, G9P[4] was documented during 2011–12. Several amino acid mismatches in the antigenic epitopes of VP7 and VP4 between Bangladeshi and the vaccine strains were identified.
Conclusions
Our study provides important information on rotavirus genotypes that should be considered for the selection and introduction of rotavirus vaccines in Bangladesh.
doi:10.1186/1471-2334-13-320
PMCID: PMC3723515  PMID: 23855423
Rotavirus; Diarrhea; Vaccine; Bangladesh; Genotype; Epitope
14.  Rotavirus genotypes associated with childhood severe acute diarrhoea in southern Ghana: a cross-sectional study 
Virology Journal  2013;10:287.
Background
Rotavirus immunization has been effective in developed countries where genotype G1P[8] is the predominant rotavirus strain. Knowledge of circulating strains in a population before introduction of rotavirus immunization program will be useful in evaluating the effect of the intervention.
Methods
Rotavirus was identified by enzyme immuno-assay (EIA) on stool specimens of children (age 0 – 59 months) hospitalized with acute gastroenteritis from August 2007 to February 2011 in Accra, Ghana. Rotavirus positive specimens were further characterized by polyacrylamide gel electrophoresis (PAGE) and reverse-transcriptase polymerase chain reaction (RT-PCR).
Results
Of the 2277 acute gastroenteritis hospitalizations 1099 (48.2%) were rotavirus-positive by EIA. Of the 1099 cases 977 (89%) were PAGE positive. All EIA positive specimens were further subjected to RT-PCR and 876 (79.7%) had sufficient material for characterization. Of these 876 cases, 741 (84.6%) were assigned G genotype, 709 (80.9%) P genotype, and 624 (71.2%) both G and P genotypes. We identified 8 G genotypes (G1, G2, G3, G4, G8, G9, G10, G12) and 3 P genotypes (P[4], P[6], P[8]). G1 (50.9%), G2 (18.8%), G3 (12.8%), P[8] (36.1%) and P[6] (30.7%) were the most prevalent. The most prevalent genotype combination was G1P[8] (28%). Mixed G (7.3%) and P (24.2%) genotypes were not uncommon. There was year-by-year and seasonal variations for most genotypes.
Conclusion
There is great diversity of rotavirus strains in children with severe gastroenteritis in southern Ghana. Even though cross-protection with vaccine-induced immunity occurs, continued strain surveillance is recommended after the introduction of rotavirus vaccine in the national immunization program.
doi:10.1186/1743-422X-10-287
PMCID: PMC3848793  PMID: 24034588
Rotavirus; Gastroenteritis; Diarrhoea; Genotypes; Ghana; Immunization
15.  Epidemiology and Genetic Diversity of Rotavirus Strains in Children with Acute Gastroenteritis in Lahore, Pakistan 
PLoS ONE  2013;8(6):e67998.
Pakistan harbors high disease burden of gastro-enteric infections with majority of these caused by rotavirus. Unfortunately, lack of proper surveillance programs and laboratory facilities have resulted in scarcity of available data on rotavirus associated disease burden and epidemiological information in the country. We investigated 1306 stool samples collected over two years (2008–2009) from hospitalized children under 5 years of age for the presence of rotavirus strains and its genotypic diversity in Lahore. The prevalence rate during 2008 and 2009 was found to be 34% (n = 447 out of 1306). No significant difference was found between different age groups positive for rotavirus (p>0.05). A subset of EIA positive samples was further screened for rotavirus RNA through RT-PCR and 44 (49.43%) samples, out of total 89 EIA positive samples, were found positive. G and P type prevalence was found as follows: G1P [4] = 3(6.81%); G1P [6] = 9(20.45%); G1P [8] = 1(2.27%); G2P [4] = 21(47.72%); G2P [8] = 1(2.27%); G9P [4] = 1(2.27%); G9P [6] = 1(2.27%) and G9P [8] = 7(15.90%). Phylogenetic analysis revealed that the VP7 and VP4 sequences clustered closely with the previously detected strains in the country as well as Belgian rotaviruses. Antigenic characterization was performed by analyzing major epitopes in the immunodominant VP7 and VP4 gene segments. Although the neutralization conferring motifs were found variable between the Pakistani strains and the two recommended vaccines strains (Rotarix™ and RotaTeq™), we validate the use of rotavirus vaccine in Pakistan based on the proven and recognized vaccine efficacy across the globe. Our findings constitute the first report on rotavirus’ genotype diversity, their phylogenetic relatedness and epidemiology during the pre-vaccination era in Lahore, Pakistan and support the immediate introduction of rotavirus vaccine in the routine immunization program of the country.
doi:10.1371/journal.pone.0067998
PMCID: PMC3692488  PMID: 23825693
16.  Etiological study of enteric viruses and the genetic diversity of norovirus, sapovirus, adenovirus, and astrovirus in children with diarrhea in Chongqing, China 
BMC Infectious Diseases  2013;13:412.
Background
Enteric viruses are a major cause of diarrhea in children, especially those <5 years old. Identifying the viral agents is critical to the development of effective preventive measures. This study aimed to determine the prevalence of common enteric viruses in children <5 years old presented with diarrhea to the Children’s Hospital of Chongqing Medical University.
Methods
Five hundred fecal samples were collected between August and November 2010 from children <5 years of age who presented with acute diarrhea at the Children’s Hospital of Chongqing Medical University. All samples were tested for rotaviruses A, B, and C, noroviruses GI and GII, adenovirus, sapovirus, and astrovirus using enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction (RT-PCR), or PCR. Partial sequences of norovirus, sapovirus, adenovirus, and astrovirus were phylogenetically analyzed to determine the genotype.
Results
Enteric viruses were detected in 302 of the 500 children who presented with acute diarrhea (277/477; 58.07%) and persistent diarrhea (5/23; 21.74%). In 277 samples from children with acute diarrhea in whom at least one viral agent was found, rotavirus A was the most frequent virus identified (132 cases; 27.67%), followed by norovirus GII in 130 cases (27.25%), adenovirus in 30 cases (6.29%), sapovirus in 9 cases (1.89%) and astrovirus in one case (0.21%). Twenty-two of the norovirus GII-positive cases were randomly selected for genotyping. GII/4 was the predominant strain, followed by GII/6, GII/2, GII/3, and GII/7. Sapovirus was classified into four genotypes: GI/1 was predominant, followed by GI/2, GII/1, and GIV. The predominant adenovirus was type 41. Mixed infections were found in 25 cases, all of which presented with acute diarrhea (25/477; 5.24%). Viruses were positive in 5/23 (21.74%) cases with persistent diarrhea. Neither rotavirus B, rotavirus C, nor norovirus GI were found in any of the samples.
Conclusions
Enteric viruses are a major cause of diarrhea in children <5 years old in Chongqing. Rotavirus A is the most common etiological agent, follow by norovirus.
doi:10.1186/1471-2334-13-412
PMCID: PMC3766652  PMID: 24004442
17.  Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis 
PLoS Medicine  2012;9(10):e1001330.
A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.
Background
To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.
Methods and Findings
We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates.
We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.
Conclusions
Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rotavirus causes severe diarrhea and vomiting. It is responsible for a large number of hospitalizations among young children in developed countries (an estimated 60,000 hospitalizations per year in the US in 2005, for example). In poor countries, rotavirus is a major cause of death in children under five. In 1998, the first rotavirus vaccine, called RotaShield, was approved in the US by the Food and Drug Administration. Shortly after the vaccine became widely used, doctors noticed a small increase in a problem called intussusception among the vaccinated infants. Intussusception is a rare type of bowel obstruction that occurs when the bowel telescopes in on itself. Prompt treatment of intussusception normally leads to full recovery, but some children with the condition need surgery, and when the disease is left untreated it can be fatal. Because intussusception is a serious condition and because very few children die from rotavirus infection in the United States, the US authorities stopped recommending vaccination with RotaShield in 1999. The manufacturer withdrew the vaccine from the market shortly thereafter.
Since then, two new vaccines (named Rotarix and RotaTeq) have been developed. Before they were approved in the US and elsewhere, they were extensively tested for any adverse side effects, especially intussusception. No increase in the risk for intussusception was found in these studies, and both are now approved and recommended for vaccination of infants around the world.
Why Was This Study Done?
Since 2006, hundreds of thousands of infants have been vaccinated with Rotarix or RotaTeq, with safety being closely monitored. Some countries have reported a small increase in intussusception (one to four additional cases per 100,000 vaccinated infants, compared with one per 2,000 of cases that occur in unvaccinated children). This increase is much lower than the one seen previously with RotaShield. In response to these findings, authorities in the US and other developed countries as well as the World Health Organization declared that the benefits of the vaccine outweigh the risks of the small number of additional intussusception cases in both developed and poor countries. However, because older infants have a higher risk of naturally occurring intussusception, they decided that the course of vaccination (three oral doses for Rotarix and two for RotaTeq) should be initiated before 15 weeks of age and completed before the age of 32 weeks. This is usually not a problem in countries with easy access to health facilities. However, in many poor countries where delays in infant vaccination are common, giving the vaccine only to very young children means that many others who could benefit from its protection will be excluded. In this study, the researchers examined the risks and benefits of rotavirus vaccination in poor countries where most of the rotavirus deaths occur. Specifically, they looked at the benefits and risks if the age restrictions were removed, with a particular emphasis on allowing infants to initiate rotavirus immunization even if they arrive after 15 weeks of age.
What Did the Researchers Do and Find?
The researchers used the most recent estimates for how well the vaccines protect children in Africa and Asia from becoming infected with rotavirus, how many deaths from rotavirus infection can be avoided by vaccination, how many additional cases of intussusception will likely occur in vaccinated children, and what proportion of children would be excluded from rotavirus vaccination because they are too old when they come to a health facility for their infant vaccination. They then estimated the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination in two scenarios. The first one (the restricted scenario) corresponds to previous guidelines from WHO and others, in which rotavirus vaccination needs to be initiated before 15 weeks and the full series completed before 32 weeks. The second one (called the unrestricted scenario) allows rotavirus vaccination of children alongside current routinely administered vaccines up to three years of age, recognizing that most children receive their vaccination by 1 year of life.
The researchers estimated that removing the age restriction would prevent an additional 154 rotavirus deaths for each intussusception death caused by the vaccine. Under the unrestricted scenario, roughly a third more children would get vaccinated, which would prevent an additional approximately 47,000 death from rotavirus while causing approximately 300 additional intussusception deaths.
They also calculated some best- and worst-case scenarios. The worst-case scenario assumed a much higher risk of intussusception for children receiving their first dose after 15 weeks of life than what has been seen anywhere, and also that an additional 20% of children with intussusception would die from it than what was already assumed in their routine scenario (again, a higher number than seen in reality). In addition, it assumes a lower protection from rotavirus death for the vaccine than has been observed in children vaccinated so far. In this pessimistic case, the number of rotavirus deaths prevented was 24 for each intussusception death caused by the vaccine.
What Do These Findings Mean?
If one accepts that deaths caused by a vaccine are not fundamentally different from deaths caused by a failure to vaccinate, then these results show that the benefits of lifting the age restriction for rotavirus vaccine clearly outweigh the risks, at least when only examining mortality outcomes. The calculations are valid only for low-income countries in Africa and Asia where both vaccination delays and deaths from rotavirus are common. The risk-benefit ratio will be different elsewhere. There are also additional risks and benefits that are not included in the study's estimates. For example, early vaccination might be seen as less of an urgent priority when this vaccine can be had at a later date, leaving very young children more vulnerable. On the other hand, when many children in the community are vaccinated, even the unvaccinated children are less likely to get infected (what is known as “herd immunity”), something that has not been taken into account in the benefits here. The results of this study (and its limitations) were reviewed in April 2012 by WHO's Strategic Advisory Group of Experts. The group then recommended that, while early vaccination is still strongly encouraged, the age restriction on rotavirus vaccination should be removed in countries where delays in vaccination and rotavirus mortality are common so that more vulnerable children can be vaccinated and deaths from rotavirus averted.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001330.
The World Health Organization provides information on rotavirus
Wikipedia has information on rotavirus vaccine and intussusception (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control and Prevention rotavirus vaccination page includes a link to frequently asked questions
PATH Rotavirus Vaccine Access and Delivery has timely, useful updates on status of rotavirus vaccines globally
doi:10.1371/journal.pmed.1001330
PMCID: PMC3479108  PMID: 23109915
18.  Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis 
PLoS Medicine  2011;8(4):e1001024.
A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age.
Background
In 2006, Brazil began routine immunization of infants <15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators.
Methods and Findings
National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007–2009) were compared with expected rates calculated from pre-vaccine years (2002–2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea-related mortality and admissions among children <5 y of age were 22% (95% confidence interval 6%–44%) and 17% (95% confidence interval 5%–27%) lower than expected, respectively. A cumulative total of ∼1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children <5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%–28%) and admissions (21%–25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period.
Conclusions
After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrheal disease, usually caused by infectious agents, is the second major cause of death in children aged under five years. As highlighted in a recent PLoS Medicine series, access to clean water and improved sanitation is the key to the primary prevention of diarrheal illnesses. Yet despite the targets of Millennium Development Goal 7 to half the number of people without access to clean water or improved sanitation by 2015, over one billion people worldwide do not currently have access to clean water and over two billion do not currently have access to improved sanitation.
Since enteric viruses are primarily transmitted directly from one person to another, they cannot be controlled completely by improvements in sanitation. Therefore, although not replacing the urgent need to provide access to clean water and improved sanitation for all, vaccination programs that protect young children against some infections that cause diarrhea, such as rotavirus, which accounts for one-third of all child deaths caused by diarrhea, are a pragmatic way forward. As large clinical trials have shown the safety and efficacy of rotavirus vaccines in population settings, in July 2009, the World Health Organization recommended including rotavirus vaccines into every country's national immunization programs.
Why Was This Study Done?
Although the protective effect of rotavirus vaccines has been assessed in various high-, middle-, and low-income settings, for reasons that remain unclear, the efficacy of live, oral rotavirus vaccines appears to be dependent on geographical location and correlated to the socioeconomic status of the population. Because of these concerns, evaluating the health impact of large-scale rotavirus vaccine programs and ensuring their equity in a real-world setting (rather than in clinical trial conditions) is important.
Therefore, the researchers addressed this issue by conducting this study to evaluate the effect of rotavirus vaccination on mortality and hospital admissions for diarrhea due to all causes among young children in the five regions of Brazil. The researchers chose to do this study in Brazil because of the high incidence of diarrhea-related deaths and hospital admissions and because five years ago, in July 2006, the Brazilian Ministry of Health introduced the single-strain rotavirus vaccine simultaneously in all 27 states through its national immunization program—allowing for “before” and “after” intervention analysis.
What Did the Researchers Do and Find?
The researchers obtained data on diarrheal deaths and hospital admissions in children aged under five years for the period 2002–2005 and 2007–2009 and data on rotavirus vaccination rates. The researchers got the data on diarrhea deaths from the Brazilian Mortality Information System—the national database of information collected from death certificates that covers 90% of all deaths in Brazil. The data on hospital admissions came from the electronic Hospital Information System of Brazil's Unified Health System (Sistema Unico de Saúde, SUS)—the publicly funded health-care system that covers roughly 70% of the hospitalizations and includes information on all admissions (from public hospitals and some private hospitals) authorized for payment by the Unified Health System. The researchers got regional rotavirus vaccination coverage estimates for 2007–2009 from the information department of the Ministry of Health, and estimated coverage of the two doses of oral rotavirus vaccine by taking the annual number of second doses administered divided by the number of infants in the region.
In 2007, an estimated 80% of infants received two doses of rotavirus vaccine, and by 2009, this proportion rose to 84% of children younger than one year of age. The researchers found that in the three years following the introduction of rotavirus vaccination, diarrhea-related mortality rates and admissions among children aged under five years were respectively 22% and 17% lower than expected, with a cumulative total of 1,500 fewer diarrhea deaths and 130,000 fewer admissions. Furthermore, the largest reductions in deaths and admissions were among children who had the highest rates of vaccination (less than two years of age), and the lowest reductions were among children who were not eligible for vaccination during the study period (aged 2–4 years).
What Do These Findings Mean?
These findings suggest that the introduction of rotavirus vaccination in all areas of Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children aged under five years. These real-world impact data are consistent with the clinical trials and strengthen the evidence base for rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
These findings have important global policy implications. In middle-income countries, such as Brazil, that are not eligible for financial support from donors, the potential reductions in admissions and other health-care costs will be important for cost-effectiveness considerations to justify the purchase of these still relatively expensive vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001024
PLoS Medicine has published a series on water and sanitation
More information is available from the World Health Organization on diarrheal illness in children
More information is available about rotavirus vaccines from the World Health Organization, the US Centers for Disease Control and Prevention, and the Rotavirus Vaccine Program
doi:10.1371/journal.pmed.1001024
PMCID: PMC3079643  PMID: 21526228
19.  Intussusception incidence among infants in the UK and Republic of Ireland: A pre-rotavirus vaccine prospective surveillance study 
Vaccine  2013;31(38):4098-4102.
Highlights
•The pre-rotavirus vaccine incidence of intussusception among UK and Irish infants was 24.8 and 24.2/100,000 live births.•The highest incidence (50.3/100,000 live births) occurred in the fifth month of life (for England).•A seasonal trend in intussusception was observed with the incidence significantly increased during winter and spring.•Baseline rates will inform rotavirus vaccine-safety policy by enabling comparison with post-introduction incidence.
Introduction
Intussusception, an abdominal emergency in young children, has been linked to a previous vaccine used to prevent rotavirus gastroenteritis. Although this vaccine was withdrawn, recent studies have suggested a potential, very small increased risk of intussusception following the administration of newly developed rotavirus vaccines. We aimed to determine the baseline incidence of intussusception among infants in the UK and Republic of Ireland – prior to the imminent introduction of the rotavirus vaccine into the UK schedule this year.
Methods
Prospective, active surveillance via the established British Paediatric Surveillance Unit (BPSU) was carried out from March 2008 to March 2009. Clinicians across 101 National Health Service (and equivalent) hospitals, including 27 paediatric surgical centres, reported cases admitted for intussusception in the UK and Republic of Ireland. The standard Brighton Collaboration case definition was used with only definite cases included for incidence estimation.
Results
The study response rate was 94.5% (379 questionnaires received out of 401 case notifications). A total of 250 definite cases of intussusception were identified. The annual incidence among infants in the UK and Republic of Ireland was 24.8 (95% CI: 21.7–28.2) and 24.2 (95% CI: 15.0–37.0) per 100,000 live births. In the UK, the highest incidence occurred in Northern Ireland (40.6, 95% CI: 21.0–70.8), followed by Scotland (28.7, 95% CI: 17.5–44.3), England (24.2, 95% CI: 20.9–27.9), then Wales (16.9, 95% CI: 6.8–34.8). In England, regional incidence was highest in London and lowest in the West Midlands. By age, the highest incidence (50.3/100,000 live births, 95% CI: 33.4–72.7) occurred in the fifth month of life (for England). A seasonal trend in the presentation of intussusception was observed with the incidence significantly (p = 0.001) increased during winter and spring.
Conclusion
The baseline rates obtained in this study will inform rotavirus vaccine-safety policy by enabling comparison with post-introduction incidence.
doi:10.1016/j.vaccine.2013.06.084
PMCID: PMC3988919  PMID: 23871447
BPSU, British Paediatric Surveillance Unit; NHS, National Health Service; ONS, Office for National Statistics; Intussusception; Incidence; Surveillance; BPSU; Vaccine safety
20.  Sentinel Hospital-Based Surveillance for Assessment of Burden of Rotavirus Gastroenteritis in Children in Pakistan 
PLoS ONE  2014;9(10):e108221.
Objectives
To determine the burden and molecular epidemiology of rotavirus gastroenteritis in children hospitalized with severe acute watery diarrhea in Pakistan prior to introduction of rotavirus vaccine.
Methods
A cross-sectional study was carried out over a period of two years from 2006 – 2008 at five sentinel hospitals in the cities of Karachi, Lahore, Rawalpindi, and Peshawar. Stool samples collected from children under five years of age hospitalized with severe acute watery diarrhea were tested for rotavirus antigen via enzyme immunoassay (EIA) (IDEA REF K6020 Oxoid Ltd (Ely), Cambridge, United Kingdom). A subset of EIA positive stool samples were further processed for genotyping.
Results
6679 children were enrolled and stool specimens of 2039 (30.5%) were positive for rotavirus. Rotavirus positivity ranged from 16.3% to 39.4% in the 5 hospitals with highest positivity in Lahore. 1241 (61%) of all rotavirus cases were in infants under one year of age. Among the strains examined for G-serotypes, the occurrence of G1, G2, G9 and G4 strains was found to be 28%, 24%, 14% and 13%, respectively. Among P-types, the most commonly occurring strains were P6 (31.5%) followed by P8 (20%) and P4 (12%). Prevalent rotavirus genotype in hospitalized children of severe diarrhea were G1P[8] 11.6% (69/593), followed by G2P[4] 10.4% (62/593), and G4P[6] 10.1% (60/593).
Conclusions
Approximately one third of children hospitalized with severe gastroenteritis in urban centers in Pakistan have rotavirus. Introduction of rotavirus vaccine in Pakistan's national immunization program could prevent many severe episodes and diarrheal deaths.
doi:10.1371/journal.pone.0108221
PMCID: PMC4189951  PMID: 25295613
21.  Diversity of Group A Human Rotavirus Types Circulating over a 4-Year Period in Madrid, Spain 
Journal of Clinical Microbiology  2004;42(4):1609-1613.
The incidence and distribution of human rotavirus G types among children under 5 years old with acute gastroenteritis were determined over a 4-year period (1998 to 2002) by using monoclonal antibodies and reverse transcription-PCR methods. Rotavirus was detected in 1,155 (31%) of 3,760 specimens tested. Rotavirus was studied in every month of the 48-month survey period. Rotavirus activity occurred mainly (51%) in the typically cooler months in Spain (November to February). The age distribution of rotavirus-positive cases showed that 90% of patients (1,038 of 1,155) were under 2 years old. Rotavirus types were determined for 576 of 1,155 patients (50%). G1 was the main genotype detected (53%), and the second most common was G4 (24%). The G2, G9, and G3 rotavirus types were detected in 14, 6, and 2% of the cases, respectively. Dual infections were detected in only 0.6%. The seasonal distribution of genotypes showed a significant genotypic shift: whereas G4 strains predominated (57%) during the 1998 to 2000 seasons, the G1 gradually increased to account for 75% in the 2000 to 2002 seasons. In addition, the present study reports the first detection of the G9 genotype in human fecal samples in Spain. Therefore, additional types may be required for vaccine development strategies that currently target only types G1 to G4.
doi:10.1128/JCM.42.4.1609-1613.2004
PMCID: PMC387563  PMID: 15071013
22.  Annual incidence, serotype distribution, and genetic diversity of human astrovirus isolates from hospitalized children in Melbourne, Australia. 
Journal of Clinical Microbiology  1996;34(7):1750-1753.
The incidence of astrovirus infection in children under 5 years of age hospitalized for acute gastroenteritis in Melbourne, Australia, during 1995 was determined. Astrovirus was detected in 16 fecal specimens by Northern (RNA) dot blot analysis of RNA isolated from feces with an astrovirus-specific cDNA probe. The incidence of astrovirus infection was determined as 4.2% (16 of 378 total samples) compared with rates of 63.2, 3.7, and 4.2% for rotavirus, adenovirus, and all bacterial pathogens, respectively. Astrovirus was detected during the winter season and mainly in infants between 6 and 12 months of age. Serotyping of samples was carried out by reverse transcriptase PCR and direct sequencing of a 348-bp region of the capsid protein gene. Type 1 strains predominated (11 of 13 typeable samples), although type 4 isolates were also detected. Astrovirus was retrospectively identified in 13 fecal samples collected from hospitalized infants between 1980 and 1985 and shown to contain small viruses by electron microscopy. Type 1 isolates were again the most common, although a type 5 strain was also found. Comparative sequence analysis indicated that type 1 astroviruses exhibited up to 7% sequence divergence over a 15-year period; however, all mutations were silent. The incidence of astrovirus reported here indicates that the virus is a significant cause of severe diarrhea in young children. The genetic analysis also provides important molecular epidemiological information relevant to the development of preventative therapies.
PMCID: PMC229107  PMID: 8784582
23.  Rotavirus Strain Diversity in Blantyre, Malawi, from 1997 to 1999 
Journal of Clinical Microbiology  2001;39(3):836-843.
In a 2-year study of viral gastroenteritis in children in Blantyre, Malawi, the diversity of rotavirus strains was investigated by using electropherotyping, reverse transcription-PCR amplification of the VP7 and VP4 genes (G and P genotyping), and nucleotide sequencing. Of 414 rotavirus strains characterized, the following strain types were identified: P[8], G1 (n = 111; 26.8%); P[6], G8 (n = 110; 26.6%); P[8], G3 (n = 93; 22.5%); P[4], G8 (n = 31; 7.5%); P[8], G4 (n = 21; 5.1%); P[6], G3 (n = 12; 2.9%); P[6], G1 (n = 7; 1.7%); P[6], G9 (n = 3; 0.7%); P[6], G4 (n = 3; 0.7%); P[4], G3 (n = 1; 0.2%); and mixed (n = 15; 3.6%). While all strains could be assigned a G type, seven strains (1.7%) remained P nontypeable. The majority of serotype G8 strains and all serotype G9 strains had short electropherotype profiles. All remaining typeable strains had long electropherotypes. Divergent serotype G1 rotaviruses, which contained multiple base substitutions in the 9T-1 primer binding site, were commonly identified in the second year of surveillance. Serotype G2 was not identified. Overall, G8 was the most frequently identified VP7 serotype (n = 144; 34.8%) and P[8] was the most frequently detected VP4 genotype (n = 227; 54.8%). Partial sequence analysis of the VP4 gene of genotype P[8] rotaviruses identified three distinct clusters, which predominantly (but not exclusively) comprised strains belonging to a distinct VP7 serotype (G1, G3, or G4). As a result of mutations in the 1T-1 primer binding site, strains belonging to each cluster required a separate primer for efficient typing. One cluster, represented by P[8], G4 strain OP354, was highly divergent from the established Wa and F45 VP4 P[8] lineages. As is the case for some other countries, the diversity of rotaviruses in Malawi implies that rotavirus vaccines in development will need to protect against a wider panel of serotypes than originally envisioned.
doi:10.1128/JCM.39.3.836-843.2001
PMCID: PMC87838  PMID: 11230392
24.  Characterization of novel VP7, VP4, and VP6 genotypes of a previously untypeable group A rotavirus 
Virology  2009;385(1):58-67.
Rotavirus is the most common cause of acute gastroenteritis among infants and young children throughout the world, but rotavirus cases in developing countries account for nearly all of the ∼600,000 annual deaths. We studied the epidemiology of rotavirus in 22 rural communities in northern coastal Ecuador over a five-year period. From 250 rotavirus positive stool specimens, the percentage that could not be RT-PCR genotyped for VP4 and VP7 was 77% and 63%, respectively. The possibility of sample degradation was considered but discounted after an experimental examination of rotavirus stability and EM visualization of rotavirus-like particles in several untypeable samples. Finally, alternate primers were used to amplify Ecu534, a sample that was untypeable using most published VP4 and VP7 primers. Characterization of the VP7, VP4, and VP6 full gene segments revealed novel genotypes and nucleotide mismatches with most published primer sequences. When considered with other findings, our results suggest that primer mismatch may be a widespread cause of genotyping failure, and might be particularly problematic in countries with greater rotavirus diversity. The novel sequences described in this study have been given GenBank accession numbers EU805775 (VP7), EU805773 (VP4), EU805774 (VP6) and the RCWG has assigned them novel genotypes G20P[28]I13, respectively.
doi:10.1016/j.virol.2008.11.026
PMCID: PMC2729439  PMID: 19131083
rotavirus; novel genotype; genotyping failure; primer design; RT-PCR; Ecuador
25.  Molecular Characterization of Equine Rotavirus in Ireland▿  
Journal of Clinical Microbiology  2008;46(10):3346-3354.
Group A rotaviruses are important causative agents of severe, acute dehydrating diarrhea in foals. A total of 86 rotavirus-positive fecal samples, collected from diarrheic foals from 11 counties in three of the four provinces of Ireland, were obtained from the Irish Equine Centre in Kildare during a 7-year (1999 to 2005) passive surveillance study and were characterized molecularly to establish the VP7 (G type) and VP4 (P type) antigenic specificities. Fifty-eight samples (67.5%) were found to contain G3 viruses, while in 26 samples (30.2%) the rotaviruses were typed as G14 and in 2 samples (2.3%) there was a mixed infection, G3 plus G14. All samples except for two, which were untypeable, were characterized as P[12]. Fifty-eight percent of the samples were obtained from County Kildare, the center of the Irish horse industry, where an apparent shift from G3P[12] to G14P[12] was observed in 2003. By sequence analysis of the VP7 protein, the G3 Irish strains were shown to resemble viruses of the G3A subtype (H2-like) (97.1 to 100% amino acid [aa] identity), while the G14 Irish strains displayed 93.9 to 97.1% aa identity to other G14 viruses. In the VP8* fragment of the VP4 protein, the P[12] Irish viruses displayed high conservation (92.3 to 100% aa) with other equine P[12] viruses. Worldwide, G3P[12] and G14P[12] are the most prevalent equine rotavirus strains, and G3P[12] vaccines have been developed for prevention of rotavirus-associated diarrhea in foals. Investigations of the VP7/VP4 diversity of the circulating equine viruses and the dynamics of strain replacement are important for better assessing the efficacies of the vaccines.
doi:10.1128/JCM.00995-08
PMCID: PMC2566120  PMID: 18716232

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