Beryl Primrose Gladstone

Protective Effect of Natural Rotavirus Infection in an Indian Birth Cohort

BACKGROUND More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected). METHODS We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3. RESULTS Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P[8], the most common viral strain, there was no evidence of homotypic protection. CONCLUSIONS Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.).

Molecular and Spatial Epidemiology of Cryptosporidiosis in Children in a Semiurban Community in South India

ABSTRACT Cryptosporidium spp. are a leading cause of diarrhea in Indian children, but there are no data for prevalent species or subgenotypes. Genetic characterization of Cryptosporidium spp. by PCR-restriction fragment length polymorphism and spatial analysis of cases using Geographical Information Systems technology was carried out for 53 children with cryptosporidial diarrhea in an urban slum. The two most common species were C. hominis (81%) and C. parvum (12%). Other species identified were C. felis and C. parvum (mouse genotype). Five subgenotypes were identified at the Cpgp40/15 locus. Subgenotype Ia predominated among C. hominis isolates, and all C. parvum isolates were subgenotype Ic. C. hominis infection was associated with a greater severity of diarrhea. Sequencing of the Cpgp40/15 alleles of C. felis and C. parvum (mouse genotype) revealed similarities to subgenotype IIa and C. meleagridis, respectively. Space-time analysis revealed two clusters of infection due to C. hominis Ia, with a peak in February 2005. This is the first study to demonstrate space-time clustering of a single subgenotype of C. hominis in a setting where cryptosporidiosis is endemic. Molecular characterization and spatial analysis have the potential to further the understanding of disease and transmission in the community.

Disease and economic burden of rotavirus diarrhoea in India

We used published and unpublished studies and national statistics to estimate the number of deaths, hospitalizations, and outpatient visits due to rotavirus diarrhoea and the associated national economic burden of disease in India. Annually in India, rotavirus diarrhoea causes an estimated 122,000-153,000 deaths, 457,000-884,000 hospitalizations, and 2 million outpatient visits in children <5 years of age. India spends Rs 2.0-3.4 billion (US

Understanding Reduced Rotavirus Vaccine Efficacy in Low Socio-Economic Settings

41-72 million) annually in medical costs to treat rotavirus diarrhoea. The use of specific interventions against rotavirus, such as newly available vaccines, would help prevent much of this large disease and economic burden.

Infant morbidity in an Indian slum birth cohort

Introduction Rotavirus vaccine efficacy ranges from >90% in high socio-economic settings (SES) to 50% in low SES. With the imminent introduction of rotavirus vaccine in low SES countries, understanding reasons for reduced efficacy in these settings could identify strategies to improve vaccine performance. Methods We developed a mathematical model to predict rotavirus vaccine efficacy in high, middle and low SES based on data specific for each setting on incidence, protection conferred by natural infection and immune response to vaccination. We then examined factors affecting efficacy. Results Vaccination was predicted to prevent 93%, 86% and 51% of severe rotavirus gastroenteritis in high, middle and low SES, respectively. Also predicted was that vaccines are most effective against severe disease and efficacy declines with age in low but not high SES. Reduced immunogenicity of vaccination and reduced protection conferred by natural infection are the main factors that compromise efficacy in low SES. Discussion The continued risk of severe disease in non-primary natural infections in low SES is a key factor underpinning reduced efficacy of rotavirus vaccines. Predicted efficacy was remarkably consistent with observed clinical trial results from different SES, validating the model. The phenomenon of reduced vaccine efficacy can be predicted by intrinsic immunological and epidemiological factors of low SES populations. Modifying aspects of the vaccine (e.g. improving immunogenicity in low SES) and vaccination program (e.g. additional doses) may bring improvements.

Neonatal Infection with G10P[11] Rotavirus Did Not Confer Protection against Subsequent Rotavirus Infection in a Community Cohort in Vellore, South India

Objective: To establish incidence rates, clinic referrals, hospitalisations, mortality rates and baseline determinants of morbidity among infants in an Indian slum. Design: A community-based birth cohort with twice-weekly surveillance. Setting: Vellore, South India. Subjects: 452 newborns recruited over 18 months, followed through infancy. Main outcome measures: Incidence rates of gastrointestinal illness, respiratory illness, undifferentiated fever, other infections and non-infectious morbidity; rates of community-based diagnoses, clinic visits and hospitalisation; and rate ratios of baseline factors for morbidity. Results: Infants experienced 12 episodes (95% confidence interval (CI) 11 to 13) of illness, spending about one fifth of their infancy with an illness. Respiratory and gastrointestinal symptoms were most common with incidence rates (95% CI) of 7.4 (6.9 to 7.9) and 3.6 (3.3 to 3.9) episodes per child-year. Factors independently associated with a higher incidence of respiratory and gastrointestinal illness were age (3–5 months), male sex, cold/wet season and household involved in beedi work. The rate (95% CI) of hospitalisation, mainly for respiratory and gastrointestinal illness, was 0.28 (0.22 to 0.35) per child-year. Conclusions: The morbidity burden due to respiratory and gastrointestinal illness is high in a South Indian urban slum, with children ill for approximately one fifth of infancy, mainly with respiratory and gastrointestinal illnesses. The risk factors identified were younger age, male sex, cold/wet season and household involvement in beedi work.

Geographic Information Systems and Genotyping in Identification of Rotavirus G12 Infections in Residents of an Urban Slum with Subsequent Detection in Hospitalized Children: Emergence of G12 Genotype in South India

BACKGROUND Various observational studies have suggested that neonatal rotavirus infection confers protection against diarrhea due to subsequent rotavirus infection. We examined the incidence of rotavirus infection and diarrhea during the first 2 years of life among children infected with the G10P[11] rotavirus strain during the neonatal period and those not infected with rotavirus. METHODS Children were recruited at birth and were followed up at least twice weekly. Stool samples, collected every 2 weeks for surveillance and at each episode of diarrhea, were screened by enzyme-linked immunosorbent assay and were genotyped by polymerase chain reaction. RESULTS Among 33 children infected neonatally with G10P[11] and 300 children not infected with rotavirus, there was no significant difference in the rates of rotavirus-positive diarrhea (rate ratio [RR], 1.05 [95% confidence interval [CI], 0.61-1.79]), moderate or severe rotavirus-positive diarrhea (RR, 1.42 [95% CI, 0.73-2.78]), or asymptomatic rotavirus shedding (RR, 1.25 [95% CI, 0.85-1.83]). CONCLUSION Neonatal G10P[11] infection with a strain resembling a vaccine candidate did not confer protection against subsequent rotavirus infection or diarrhea of any severity in this setting.

Rotavirus Infection in the Neonatal Nurseries of a Tertiary Care Hospital in India

ABSTRACT Rotavirus infections by G12 strains in several countries have recently been described. In this study, we report the emergence of G12 strains in south India. Fourteen cases of G12 infection were identified between June and September 2005. G12 was seen in combination with P[6], P[8], or nontypeable P type. Nine cases, including five symptomatic infections and four asymptomatic infections, were identified as part of routine surveillance for rotavirus infections in a birth cohort in the community between June and July 2005. Significant temporal and time-space clustering of eight of these cases represents a possible recent introduction of a new rotavirus VP7 genotype. Previous rotavirus infections had been documented for six of the nine children in the community. In the following 2 months, five cases of G12 infection were identified among children presenting to a referral hospital with diarrhea. This is the first description of symptomatic and asymptomatic G12 infections in children in the community. The detection of G12 strains from different parts of the world in recent years suggests the possibility of its emergence as an important global genotype. Monitoring of cocirculating rotavirus strains and detection of emerging strains is important in the context of the availability of rotavirus vaccines.

Burden of Illness in the First 3 Years of Life in an Indian Slum

Background: The majority of neonatal rotavirus infections are believed to be asymptomatic, and protection from subsequent infection and disease has been reported in neonatally infected children. In this study, we present the results of a 4-year prospective surveillance in the neonatal nurseries of a tertiary care hospital in south India. Methods: Stool samples from neonates admitted for >48 hours either with gastrointestinal (GI) symptoms or with nonenteric pathology were screened for rotavirus. Careful assessment of clinical data was carried out. G- and P-typing for all symptomatic rotavirus positive cases and equal number of asymptomatic controls from the same month was determined by reverse transcription polymerase chain reaction. Results: Rotavirus was detected in 43.9% of 1411 neonates, including those with and without gastrointestinal disease. Rotavirus detection was significantly higher among neonates with GI disease (55.5%) than asymptomatic neonates (44.4%) (P < 0.001). Rotavirus was seen in association with diarrhea, vomiting, feed intolerance, necrotizing enterocolitis, hematochezia, gastroesophageal reflux, and abdominal distension. Diarrhea was significantly more frequent in neonates with rotavirus infection (P < 0.001) whereas uninfected neonates developed significantly more feeding intolerance (P < 0.001). Significantly greater proportion of term neonates with GI disease were positive for rotavirus than preterm neonates (P < 0.001). G10P[11] was the most common genotype associated with both symptomatic and asymptomatic infections. Conclusions: This study documents the high rates of rotavirus infection in the neonatal nurseries and the continuing detection of the G10P[11] strain associated with GI disease in Vellore.

Investigation of the environment and of mothers in transmission of rotavirus infections in the neonatal nursery.

The morbidity and mortality in a cohort of 452 children followed up from birth up to 3 years of age, in an urban slum in India, is described. These children were recruited and followed from March 2002 to September 2006. A prospective morbidity survey was established. There were 1162 child-years of follow-up. The average morbidity rate was 11.26 episodes/child-year. Respiratory infections caused 58.3 and diarrheal disease 18.4% of the illnesses. Respiratory illnesses resulted in 48, 67.5 and 50 days of illnesses, and there were 3.6, 1.64 and 1.16 diarrheal episodes per child in the 3 years, respectively. There were five deaths in the cohort in the 3 years of follow-up. Of the 77 drop-outs 44 were contacted for mortality data. The morbidity in the area is high, comparable to other studies. The mortality is low, and is attributed to the facilitated access to care.