Phenotyping of Lewis and secretor HBGA from saliva and detection of new FUT2 gene SNPs from young children from the Amazon presenting acute gastroenteritis and respiratory infection.

The Histo-blood group antigens (HBGA) are host genetic factors associated with susceptibility to rotavirus (RV) and human norovirus (HuNoV), the major etiological agents of viral acute gastroenteritis (AGE) worldwide. The FUT2 gene expressing the alpha-1, 2-L- fucosyltransferase enzyme is important for gut HBGA expression, and also provides a composition of the phenotypic profile achieved through mutations occurring in populations with different evolutionary histories; as such, it can be considered a genetic population marker. In this study, Lewis and secretor HBGA phenotyping was performed using 352 saliva samples collected from children between three months and five years old born in the Amazon (Brazil, Venezuela and English Guyana) presenting AGE or acute respiratory infection (ARI), the latter considered as control samples. The total of children phenotyped as secretors was 323, corresponding to 91.80%. From these, 207 (58.80%) had a Le (a + b+) profile. The HBGA profiles were equally found in children with AGE as well as with ARI. The rs1047781 of the FUT2 gene was not detected in DNA from saliva cells with a Le (a+b+) profile. However, mutations not yet described in the FUT2 gene were observed: missense 325A>T, 501C>T, 585C>T, 855A>T and missense substitutions 327C>T [S (Ser) > C (Cys)], 446 T>C [L(Leu) > P(Pro)], 723C>A [N(Asn) > K(Lys)], 724A>T [I(Ile) > F(Phe)], 736C>A [H(His) > N(Asn)]. The SNP distribution in the FUT2 gene of the analyzed samples was very similar to that described in Asian populations, including indigenous tribes.

Sustained Decline in Acute Gastroenteritis-Associated Hospitalizations and Outpatient Visits Among American Indian/Alaska Native Children After Rotavirus Vaccine Introduction, 2001-2014.

We examined the uptake of rotavirus vaccine and compared trends in acute gastroenteritis (AGE)-associated hospitalizations and outpatient visits among American Indian and Alaska Native (AI/AN) children aged <5 years before and after introduction of the rotavirus vaccine. The rates of AGE-associated hospitalization and outpatient visits among AI/AN children remained below prevaccine levels.

Impact on affected families and society of severe rotavirus infections in Swedish children assessed in a prospective cohort study.

BACKGROUND: Few prospective cohort studies have estimated the overall impact of severe rotavirus gastroenteritis (RVGE) leading to hospitalization on families and society. We assessed human and economic resources needed to care for an affected average child aged <5 years in Sweden. METHODS: The study was conducted in Astrid Lindgren Children's Hospital which serves approximately 14% of all Swedish children <5 years of age. All children admitted with acute gastroenteritis in the study period were tested for rotavirus. Health care consumption was collected prospectively and publically available unit costs used to calculate direct costs. Non-medical and indirect costs were collected in interviews with families using a standardized questionnaire during the hospital stay and approximately 14 days post-discharge. RESULTS: 144/206 children (70%) with laboratory-confirmed RVGE were included. The median age was 14 months. The average total cost per hospitalized child was €3894, of which €2169 (56%) was due to direct healthcare-related costs (including Emergency Department visits and in-patient care), €104 (2%) to non-medical direct costs and €1621 (42%) to indirect costs due to productivity loss. Carers of children with severe RVGE were absent from work on average five days per study child: four days during hospitalization of affected child and one day due to gastroenteritis in the carer. CONCLUSIONS: Costs for RVGE are dominated by direct costs which are similar to some other countries in Europe, but indirect costs due to productivity loss are also important, and should be considered in decisions to introduce rotavirus vaccines into national vaccination programmes.

Sustained Reduction of Childhood Diarrhea-Related Mortality and Hospitalizations in Mexico After Rotavirus Vaccine Universalization.

BACKGROUND: Mexico implemented routine childhood vaccination against rotavirus in 2007. We describe trends in hospitalization and deaths from diarrhea among children aged <5 years in Mexico before and 7 years after implementation of rotavirus vaccination. METHODS: We obtained data on deaths and hospitalizations from diarrhea, from January 2003 through December 2014, in Mexican children <5 years of age. We compared diarrhea-related mortality and hospitalizations in the postvaccine era with the prevaccine baseline from 2003 to 2006. RESULTS: Compared with the prevaccine baseline, we observed a 53% reduction (95% confidence interval [CI], 47%-58%) in diarrhea-related mortality and a 47% reduction (95% CI, 45%-48%) in diarrhea-related hospitalizations in postvaccine years, translating to 959 deaths and 5831 hospitalizations averted every year in Mexican children aged <5 years. Prevaccine peaks in diarrhea-related mortality and hospitalizations during the rotavirus season months were considerably diminished in postvaccine years, with greater declines observed during the rotavirus season compared with non-rotavirus season months. CONCLUSIONS: We document a substantial and sustained decline in diarrhea-related hospitalizations and deaths in Mexican children associated with implementation of rotavirus vaccination. These results highlight the public health benefits that could result in countries that adopt rotavirus vaccination into their national immunization programs.

Impact and Effectiveness of Monovalent Rotavirus Vaccine in Armenian Children.

BACKGROUND: The Republic of Armenia was 1 of the 2 earliest countries in the Newly Independent States to introduce rotavirus vaccine into its national immunization program to reduce the burden of rotavirus disease (documented to cause 38% of acute gastroenteritis hospitalizations [AGE] among children aged <5 years). In November 2012, RV1 (Rotarix) was introduced for Armenian infants at ages 6 and 12 weeks. METHODS: The established active surveillance system at 2 hospitals in the capital, Yerevan, whereby children aged <5 years hospitalized for AGE have stool sample tested for rotavirus antigen, was used to assess trends in rotavirus hospitalizations. Immunization records on children enrolled after vaccine introduction were obtained from clinics, and vaccine effectiveness (VE) was estimated using children with AGE who test negative for rotavirus as controls for the rotavirus-positive cases. RESULTS: Among infants, rotavirus hospitalizations were reduced by 48% within the first year after introduction, and by ≥75% in years 2 and 3 following introduction. Reductions of ≥30% in other young children too old to have been vaccinated suggest additional benefit through indirect protection; overall in year 3, rotavirus hospitalizations were reduced by 69% among children aged <5 years. The overall VE of 2 RV1 doses in protecting against rotavirus hospitalization (any severity) was 62% (95% confidence interval [CI], 36%-77%) among children aged 6-23 months; 68% (95% CI, 24%-86%) among those aged 6-11 months, and 60% (95% CI, 20%-80%) in children aged 12-23 months. Against more severe rotavirus disease, VE was 79% (95% CI, 55%-90%) and similarly high in both age groups. CONCLUSIONS: RV1 is effective in young Armenian children and substantially reduced rotavirus hospitalizations shortly after introduction.

Real-World Effectiveness of Pentavalent Rotavirus Vaccine Among Bedouin and Jewish Children in Southern Israel.

BACKGROUND: Pentavalent rotavirus vaccine (RV5) was introduced into the Israeli National Immunization Program in January 2011. We determined RV5 vaccine effectiveness (VE) in southern Israel, a region characterized by 2 distinct populations: Bedouins living in a low- to middle-income, semirural setting, and Jews living in a high-income, urban setting. METHODS: We enrolled vaccine-eligible children who visited the emergency department (ED) or were hospitalized due to acute gastroenteritis (AGE) during the first 3 rotavirus seasons after RV5 vaccine introduction (2011-2013). Fecal specimens were tested for rotavirus by enzyme immunoassay and genotyped. Vaccination among laboratory-confirmed rotavirus cases was compared with rotavirus-negative AGE controls. Regression models were used to calculate VE estimates by age, clinical setting, and ethnicity. RESULTS: Of 515 enrolled patients, 359 (70%) were Bedouin. Overall, 185 (36%) patients were rotavirus positive; 79 of 119 (66%) were G1P[8] genotype. The adjusted VE for a full 3-dose course of RV5 against ED visit or hospitalization was 63% (95% confidence interval [CI], 38%-78%). RV5 provided G1P[8] genotype-specific effectiveness of 78% (95% CI, 58%-88%). By age, RV5 VE was 64% (95% CI, 21%-84%) and 71% (95% CI, 39%-86%) among children aged 6-11 months and 12-23 months, respectively. By clinical setting, RV5 VE was 59% (95% CI, 23%-78%) against hospitalization, and 67% (95% CI, 11%-88%) against ED visit. The adjusted VE of a full RV5 course among Bedouin children was 62% (95% CI, 29%-79%). CONCLUSIONS: RV5 significantly protected against rotavirus-associated ED visits and hospitalizations in a diverse population of vaccine-eligible children living in southern Israel.

Changes in hospitalisations for acute gastroenteritis in Australia after the national rotavirus vaccination program.

OBJECTIVE: To evaluate the impact of the Australian rotavirus vaccination program on both rotavirus and all-cause acute gastroenteritis (AGE) hospitalisations and to compare outcomes in Indigenous and non-Indigenous people. DESIGN AND SETTING: Retrospective analysis of the Australian Institute of Health and Welfare National Hospital Morbidity database for hospitalisations coded as rotavirus and all-cause AGE, between 1 July 2001 and 30 June 2010. MAIN OUTCOME MEASURES: Age-specific hospitalisation rates in Indigenous and non-Indigenous people, before and after the introduction of the vaccine program in July 2007. RESULTS: There was a 71% decline in rotavirus-coded hospitalisations of children aged < 5 years between periods before and after rotavirus vaccination (from 261 per 100,000 to 75 per 100,000). There was also a 38% decline in non-rotavirus coded AGE hospitalisations (from 1419 per 100,000 to 880 per 100,000). This represented more than 7700 hospitalisations of children aged < 5 years being averted in the financial year 2009-10. Reductions were also observed in the 5-19-years age group, suggesting that transmission of virus was reduced at a population level. Decreases in hospitalisations of Indigenous children were smaller than those for the general population, and fluctuated by location and year. CONCLUSIONS: These data show a sustained and substantial decline in severe rotavirus disease and all-cause AGE since the introduction of rotavirus vaccination, most pronounced in the target age group, but with evidence of herd immunity. The impact of rotavirus vaccination in Indigenous children in hyperendemic settings was less remarkable.

Clinical characteristics of obstructive uropathy associated with rotavirus gastroenteritis in Japan.

AIMS: Rotavirus gastroenteritis is severe and often results in dehydration and pre-renal azotemia. However, we have encountered four children with acute obstructive uropathy associated with acute rotavirus gastroenteritis, and several similar cases have been reported. Therefore, the aim of the present study was to clarify the epidemiology and clinical features of acute obstructive uropathy associated with acute rotavirus gastroenteritis in Japanese children. PATIENTS AND METHODS: We sent questionnaires to all members of the Japanese Society for Nephrology and all authors who had published case reports of this disease in Japan, inquiring about patient age at diagnosis, sex, the type of stones, laboratory data and other factors. RESULTS: 21 reported patients were evaluable, ranging from 0.4 to 3 years. The sex distribution showed a strong male prevalence. Oliguria had appeared about 7 days after the onset of gastroenteritis. Most of the patients showed hyperuricemia and hyponatremia. The stones consisted mainly of ammonium acid urate. The patients were discharged with normal renal function. CONCLUSION: Although obstructive uropathy associated with rotavirus gastroenteritis is very rare, this disease condition should be explored when anuria is refractory to sufficient fluid replacement therapy or when oliguria persists despite recovery of the gastrointestinal symptoms.

Baseline estimates of diarrhea-associated mortality among United States children before rotavirus vaccine introduction.

OBJECTIVES: Deaths due to diarrhea among US children declined substantially from the 1960s through the 1980s, but have not been recently assessed. We examined diarrhea-associated mortality among young US children from 1992 to 2006 to establish baseline estimates through which the effect of rotavirus vaccines, introduced in 2006, can be assessed. METHODS: National Center for Health Statistics multiple cause-of-death mortality data were used to examine diarrhea-associated deaths and death rates among US children 1 to 59 months of age during 1992-2006. The winter residual method was used to indirectly estimate the annual number of diarrhea-associated deaths attributable to rotavirus. RESULTS: An average of 369 diarrhea-associated deaths/year (3320 total deaths) occurred among US children 1 to 59 months of age during 1992-1998 and 2005-2006. The diarrhea-associated death rate increased 40% between the first 3 and last 2 years of the study period, from an average of 1.6 deaths per 100,000 to 2.3 deaths per 100,000. Black children died at almost 4 times the rate of white children. Diarrhea-associated deaths showed a winter seasonal pattern similar to that of rotavirus, particularly among children 4 to 23 months of age. Using indirect methods, we estimated 25 yearly rotavirus-associated deaths during the study period. Rotavirus vaccination could potentially prevent 21 of these deaths annually. CONCLUSIONS: Diarrhea-associated mortality among US children stabilized but appears to be increasing in recent years. Rotavirus was associated with a small but significant number of preventable deaths. The national multiple cause-of-death data should prove useful for assessing mortality impact of rotavirus vaccination in the United States.

Detection of G3P[3] and G3P[9] rotavirus strains in American Indian children with evidence of gene reassortment between human and animal rotaviruses.

The distribution and evolution of human rotavirus strains is important for vaccine development and effectiveness. In settings where rotavirus vaccine coverage is high, vaccine pressure could select for replacement of common strains (similar to those included in rotavirus vaccines) with uncommon strains, some of which could be generated by reassortment between human and animal rotaviruses. Between 2002 and 2004, a phase-III rotavirus vaccine clinical trial was conducted among American Indian children of the Navajo and White Mountain Apache tribes, which are known to be at high risk for rotavirus diarrhea. We evaluated the rotavirus strains collected from study participants who received placebo during the trial to determine the distribution of rotavirus genotypes and to detect emerging strains that contribute to disease and could influence rotavirus vaccine effectiveness. Three uncommon strains of human rotavirus, two G3P[3] and one G3P[9] strains were detected in stools of children aged 3 to 6 months of age. Segments of all 11 rotavirus genes were sequenced and genotyped by comparison of cognate gene fragments with reference strains. The G3P[3] strains had similar genotypes to each other and to reference dog and cat strains. The G3P[9] strain had similar genotypes to cow, cat and dog reference strains. Genetic analyses of these three strains support the known diversity generating mechanisms of rotavirus.

Rotavirus gastroenteritis in the Northern Territory, 1995-2004.

OBJECTIVE: To present data on rotavirus notifications in the Northern Territory to provide knowledge about the local epidemiology of rotavirus gastroenteritis that can be used to inform the use and funding of rotavirus vaccines. DESIGN: Retrospective analysis of data from the Northern Territory Notifiable Diseases Database. PARTICIPANTS AND SETTING: Patients with cases of rotavirus infection notified to the NT Centre for Disease Control from 1 January 1995 to 31 December 2004. MAIN OUTCOME MEASURES: Patterns of rotavirus notifications over time; infection rates in Indigenous versus non-Indigenous children aged 0-5 years; age groups infected with rotavirus. RESULTS: Numbers of rotavirus notifications over the period 1995-2004 show annual, monthly and regional variability. The rotavirus notification rate for Indigenous children aged 0-5 years was 2.75 per 100 per year, compared with 0.98 for non-Indigenous children, with a relative risk for Indigenous children of 2.17 (95% CI, 1.97-2.39) over the 10 years. Indigenous children infected with rotavirus were younger than non-Indigenous children, with median ages of 11 months and 16 months, respectively. Rotavirus gastroenteritis occurred in outbreaks, transmitted over months throughout the NT. CONCLUSION: Large numbers of cases of rotavirus gastroenteritis affecting Indigenous and non-Indigenous children in the NT are notified every year. The rate in Indigenous children may be decreasing relative to non-Indigenous children. An effective rotavirus vaccine could prevent significant morbidity.

Characterisation of rotaviruses from children treated at a London hospital during 1996: emergence of strains G9P2A[6] and G3P2A[6].

Rotavirus strains from 171 patients treated in 1996 at a children's hospital in London were characterised. Use of a panel of typing monoclonal antibodies for serotypes G1-4 identified 105 (61%) of the strains. The majority, 90 strains (86%), were serotype G1. Characterisation of G (VP7) and P (VP4) types using reverse transcription-polymerase chain reaction was more efficient, and 167 of 171 (98%) of the strains were identified this way. The predominant strains were G1P1A[8] (55%) and G4P1A[8] (17%), which are prevalent throughout the world; however, a significant number of cases were associated with genotypes not recorded previously in the United Kingdom. There were 21 (13%) cases associated with G9P2A[6] and 11 (6%) cases associated with G3P2A[6]. The majority (seven of 10) cases of infection in children older than 3 years of age were caused by these two genotypes. A majority (15/21) of G9P2A[6] strains were recovered from children admitted to the hospital, and five children were sufficiently dehydrated to necessitate intravenous rehydration.

Perinatal risk factors for infant hospitalization with viral gastroenteritis.

CONTEXT: A tetravalent vaccine against rotavirus, the most commonly identified etiologic agent of viral gastroenteritis (GE), has recently been licensed for use in the United States. OBJECTIVE: To evaluate whether specific groups of infants might be at sufficiently high risk to warrant a focused rotavirus vaccine policy, we investigated perinatal risk factors for hospitalization with viral GE and rotavirus in the first year of life. DESIGN: Population-based, case-control study. SETTING: Washington State linked birth certificate and hospital discharge abstracts from 1987 through 1995. PATIENTS: Infants, 1 through 11 months of age, hospitalized for viral GE (N = 1606) were patients in this study. Control subjects were 8084 nonhospitalized infants, frequency-matched to patients on year of birth. PRIMARY OUTCOME MEASURE: Maternal and infant characteristics associated with infant hospitalization for viral GE. RESULTS: We found a significant association between birth weight and the risk for hospitalization. Very low birth weight infants (<1500 g) were at the highest risk (odds ratio [OR] 2.6; 95% confidence interval [CI]: 1.6,4.1);, low birth weight infants (1500-2499 g), at intermediate risk (OR 1.6; 95% CI: 1.3,2.1); and large infants (>4000 g), at reduced risk (OR 0.8; 95% CI: 0.6,0.9). Other characteristics associated with GE hospitalization were male gender (OR 1.4; 95% CI: 1.3,1.6); maternal smoking (OR 1.2; 95% CI: 1.1,1. 4); unmarried mother (OR 1.2; 95% CI: 1.1,1.4); Medicaid insurance (OR 1.4; 95% CI: 1.3,1.7); and maternal age <20 years (OR 1.2; 95% CI: 1.0,1.5). Infants born October through December were at decreased risk for hospitalization (OR 0.8; 95% CI: 0.7,0.9), as were infants born to Asian mothers (OR 0.5; 95% CI: 0.3,0.7), and infants born to mothers >34 years of age (OR 0.7; 95% CI: 0.6,0.9). Using these factors, the area under a receiver operating characteristic curve was 0.63. Therefore, to achieve a sensitivity of 90% in identifying high-risk infants, specificity would fall to 10%. Subanalyses of children admitted for viral GE during the peak of the Northwest rotavirus season (January to March) and children with confirmed rotavirus infection demonstrated similar risk factors and receiver operating characteristic curves. CONCLUSION: We conclude that a focused rotavirus vaccination policy using readily identifiable potential high-risk groups would be unlikely to prevent most infant hospitalizations associated with rotavirus infection. However, the safety of rotavirus vaccine in low birth weight and premature infants must be established, because these children appear to be at greater risk for hospitalization with viral GE and rotavirus.

Epidemiology and microbiology of diarrhoea in young Aboriginal children in the Kimberley region of Western Australia.

Infectious diarrhoea is common in young Australian Aborigines and is one of the main causes for their unsatisfactory health standards with consequent widespread failure to thrive and undernutrition. Most published reports relate to patients in hospital or to hospital admission statistics and give little indication of the extent or severity of diarrhoeal disease in children in Aboriginal communities. The present investigation involved more than 100 Aboriginal children up to 5 years of age living in remote communities in the tropical north of Western Australia who were studied prospectively over a 12-month period.

A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population.

A double-blind, randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of a rhesus rotavirus vaccine and RIT 4237, a bovine rotavirus vaccine, in a Navajo population. Infants aged 2-5 months were randomized to receive one dose of either 10(4) pfu of the rhesus rotavirus vaccine or 10(8) pfu of the RIT 4237 vaccine or placebo. Eleven (10.2%) of 108 infants in the rhesus vaccine group, 11 (10.4%) of 106 in the RIT 4237 group, and 9 (8.4%) of 107 in the placebo group experienced rotavirus diarrhea during the follow-up period of 17 months. Thus, in this population, neither vaccine was efficacious in preventing rotavirus diarrhea.

Rotavirus diarrhea in Jewish and Bedouin children in the Negev region of Israel: epidemiology, clinical aspects and possible role of malnutrition in severity of illness.

We conducted a 1-year prospective study in the Negev region of southern Israel to determine the epidemiologic and clinical patterns of rotavirus diarrhea. A total of 605 patients were studied, 392 Bedouins and 213 Jews, 441 of whom had diarrhea (449 episodes) and 164 did not. Rotavirus was the most common organism detected in children with diarrhea (63 of 444; 14%) but was rarely found in controls (3 of 163; 2%) (P less than 0.001). In 22% (12 of 54) of the rotavirus-positive patients, at least one other organism was also detected. The rate of rotavirus detection decreased as age increased, from 18% in the first year to 8% in the third year of life. Hospitalization with rotavirus diarrhea occurred more frequently in the summer. However, during winter, when diarrhea was less prevalent in the community, the proportion of cases associated with rotavirus was higher. Compared with controls, malnourished children were more likely to be hospitalized. However, rotavirus was detected in similar proportions among well-nourished and malnourished cases with diarrhea. The most prevalent rotavirus serotype was type 1 (in 69%), followed by types 4 and 2 (18 and 13%, respectively). We estimated that during the study period, approximately 2% of all Bedouin infants vs. only 0.2% of Jewish infants were hospitalized with rotavirus disease in their first year of life. Clinical signs and symptoms and stool appearance were not useful in predicting rotavirus detection. Malnutrition seems to be an important indicator of disease severity, which may explain why the toll of rotavirus-associated morbidity and mortality is particularly high among children in developing countries.