Maharaj K. Bhan

Great diversity of group A rotavirus strains and high prevalence of mixed rotavirus infections in India.

ABSTRACT We previously observed a marked diversity of rotavirus strains and a high prevalence of the uncommon serotype G9 in a small survey of rotavirus strains collected from six centers in India. In the present study, we characterized a larger collection of strains from children hospitalized with severe diarrhea in seven Indian cities between 1996 and 1998. A total of 287 strains were G and P genotyped by reverse transcription-PCR, and some were further characterized by electropherotyping and subgrouping. Of the four strains common globally, three were found in only 43% of samples (P[8], G1, 15%; P[4], G2, 22%; P[8], G4, 6%), whereas G9 strains made up 17% of the total. Three different G9 strains were present: a P[8], G9 strain, which displayed the long electropherotype and subgroup II VP6 specificity, and two P[6], G9 strains, one with the long electropherotype and subgroup II specificity and the other with the short electropherotype and subgroup I specificity. Marked diversity was observed among strains collected from different cities and collected over time. Of the 253 strains that were fully typed, 54 (21%) had a mixed G or P genotype. Serotype G2 strains were detected more often in infections caused by single strains than in mixed infections (P < 0.05), whereas serotype G1 strains were found more often in mixed infections than in infections caused by single strains (P < 0.05). The diversity of rotavirus strains and the high prevalence of mixed infections confirm trends reported earlier and help to better characterize the strains of rotavirus circulating in India. Vaccines under development should clearly target G9 strains, and G9 should be included as one of the common global serotypes.

Zinc with oral rehydration therapy reduces stool output and duration of diarrhea in hospitalized children: a randomized controlled trial.

Objectives The authors evaluated the effect of zinc treatment as an adjunct to oral rehydration therapy on stool output and diarrheal duration in children with acute noncholera diarrhea with dehydration. Methods This double-blind, randomized, controlled trial was conducted at two urban hospitals in New Delhi. A total of 287 dehydrated male patients, ages 3 to 36 months, with diarrhea for ≤ 72 hours were enrolled. They were assigned to zinc or placebo by a randomization scheme stratified by age (≤ or >12 months) and weight for height (65%–80% or >80% National Centre for Health Statistics median). Participants in the zinc group received 15 mg (≤12 months) or 30 mg (>12 months) elemental zinc daily in three divided doses for 14 days. The main outcome measures were stool output and diarrheal duration. Results Zinc treatment reduced total stool output (ratio of geometric means, 0.69; 95% confidence interval [CI]: 0.48, 0.99) and stool output per day of diarrhea (ratio of geometric means, 0.76; 95% CI: 0.59, 0.98). The risk of continued diarrhea was lower (relative hazards, 0.76; 95% CI: 0.59, 0.97) and the proportion of diarrheal episodes lasting ≥ 5 days (odds ratio, 0.49; 95% CI: 0.25, 0.97) or ≥ 7 days was less (odds ratio, 0.09; 95% CI: 0.01, 0.73) in the zinc group. Conclusions This study demonstrates a beneficial effect of zinc administered during acute diarrhea on stool output, diarrheal duration, and proportion of episodes lasting more than 7 days. The effects are large enough to merit routine use of zinc during acute diarrhea in developing countries.

Management of the severely malnourished child: perspective from developing countries

Careful assessment and appropriate treatment and rehabilitation using standard protocols that are easy to follow reduce morbidity and mortality

Research priorities to reduce global mortality from newborn infections by 2015.

Background: Newborn infections are responsible for approximately one-third of the estimated 4.0 million neonatal deaths that occur globally every year. Appropriately targeted research is required to guide investment in effective interventions, especially in low resource settings. Setting global priorities for research to address neonatal infections is essential and urgent. Methods: The Department of Child and Adolescent Health and Development of the World Health Organization (WHO/CAH) applied the Child Health and Nutrition Research Initiative (CHNRI) priority-setting methodology to identify and stimulate research most likely to reduce global newborn infection-related mortality by 2015. Technical experts were invited by WHO/CAH to systematically list and then use standard methods to score research questions according to their likelihood to (i) be answered in an ethical way, (ii) lead to (or improve) effective interventions, (iii) be deliverable, affordable, and sustainable, (iv) maximize death burden reduction, and (v) have an equitable effect in the population. The scores were then weighted according to the values provided by a wide group of stakeholders from the global research priority-setting network. Findings: On a 100-point scale, the final priority scores for 69 research questions ranged from 39 to 83. Most of the 15 research questions that received the highest scores were in the domain of health systems and policy research to address barriers affecting existing cost-effective interventions. The priority questions focused on promotion of home care practices to prevent newborn infections and approaches to increase coverage and quality of management of newborn infections in health facilities as well as in the community. While community-based intervention research is receiving some current investment, rigorous evaluation and cost analysis is almost entirely lacking for research on facility-based interventions and quality improvement. Interpretation: Given the lack of progress in improving newborn survival despite the existence of effective interventions, it is not surprising that of the top ranked research priorities in this article the majority are in the domain of health systems and policy research. We urge funding agencies and investigators to invest in these research priorities to accelerate reduction of neonatal deaths, particularly those due to infections.

Improving the performance of enteric vaccines in the developing world

Vaccines against important enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in some populations. The application of new technologies and diverse scientific disciplines are needed to realize the promise of truly universal and effective solutions to combat those and other enteric diseases.

Celiac disease with mild to moderate histologic changes is a common cause of chronic diarrhea in Indian children.

Objectives: In developed countries, small bowel histology in coeliac disease is a spectrum, ranging from normal with increased intraepithelial lymphocytes to the classic flat mucosa. In developing countries, mild to moderate enteropathies in children with chronic diarrhea and growth failure are assumed to be caused by tropical sprue, persistent infections, or malnutrition with bacterial overgrowth. We report the prevalence and histology of coeliac disease in children with chronic diarrhea at a tertiary referral hospital in North India. Methods: Two hundred fifty-nine children with symptoms indicating coeliac disease attended the All India Institute of Medical Sciences. Histology was graded after a modified Marsh classification. Serum immunoglobulin A anti-endomysial antibodies (AEA) were assayed using indirect immunofluorescence. Subjects with abnormal histology and positive AEA were put on a gluten free diet (GFD). Coeliac disease was diagnosed on small intestinal biopsy changes and a clinical response to a GFD. Results: Severe enteropathies were present in 63 (24%) subjects, and 58 (92%) responded to a GFD. Sixty-six (25%) had moderate histologic changes, 61 responding to a GFD. AEA was positive in 56 of 63 patients with severe and 65 of 66 with moderate enteropathies. Fifty-seven children had mild enteropathies, and 19 of 20 with positive AEA responded clinically to a GFD. Conclusions: Coeliac disease is more common than previously believed. It presents a variable histology, and diagnoses may be missed or delayed if based only on severe enteropathies. Serology is a useful adjunct to diagnosis, and diagnostic criteria need to be developed appropriately for coeliac disease in developing countries despite limited facilities.

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life

UNLABELLED Rotavirus gastroenteritis is one of the leading causes of diarrhea in Indian children less than 2 years of age. The 116E rotavirus strain was developed as part of the Indo-US Vaccine Action Program and has undergone efficacy trials. This paper reports the efficacy and additional safety data in children up to 2 years of age. In a double-blind placebo controlled multicenter trial, 6799 infants aged 6-7 weeks were randomized to receive three doses of an oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6, 10, and 14 weeks. The primary outcome was severe (≥11 on the Vesikari scale) rotavirus gastroenteritis. Efficacy outcomes and adverse events were ascertained through active surveillance. We randomly assigned 4532 and 2267 subjects to receive vaccine and placebo, respectively, with over 96% subjects receiving all three doses of the vaccine or placebo. The per protocol analyses included 4354 subjects in the vaccine and 2187 subjects in the placebo group. The overall incidence of severe RVGE per 100 person years was 1.3 in the vaccine group and 2.9 in the placebo recipients. Vaccine efficacy against severe rotavirus gastroenteritis in children up to 2 years of age was 55.1% (95% CI 39.9 to 66.4; p<0.0001); vaccine efficacy in the second year of life of 48.9% (95% CI 17.4 to 68.4; p=0.0056) was only marginally less than in the first year of life [56.3% (95% CI 36.7 to 69.9; p<0.0001)]. The number of infants needed to be immunized to prevent one episode of severe RVGE in the first 2 years of life was 40 (95% CI 28.0 to 63.0) and for RVGE of any severity, it was 21 (95% CI 16.0 to 32.0). Serious adverse events were observed at the same rates in the two groups. None of the eight intussusception events occurred within 30 days of a vaccine dose and all were reported only after the third dose. The sustained efficacy of the 116E in the second year of life is reassuring. CLINICAL TRIAL REGISTRY The trial is registered with Clinical Trial Registry-India (# CTRI/2010/091/000102) and Clinicaltrials.gov (# NCT01305109).

Rotavirus gastroenteritis in India, 2011–2013: Revised estimates of disease burden and potential impact of vaccines

While improvements in oral rehydration use and access to healthcare have contributed to impressive gains in child survival, diarrheal diseases remain the second most important cause of child mortality in India. Pathogen specific disease rates, while key to deciding on the utility of specific public health interventions such as vaccines, are extremely difficult to obtain in developing country settings with less than optimal health access, diagnostic services and information systems. This study combined disease burden within five cohorts of infants followed up for diarrheal morbidity with data from the nationally representative Indian Rotavirus Surveillance Network and applies rates of rotavirus related events to UNICEF birth and mortality estimates for India. These estimates, while limited by the lack of data from nationally representative population based studies, use methods consistent with those employed by the World Health Organization Child Health Epidemiology Reference Group. We estimate that 11.37 million episodes of rotavirus gastroenteritis occur each year in India, requiring 3.27 million outpatient visits and 872,000 inpatient admissions when health access is unconstrained, resulting in a need for Rs. 10.37 billion each year in direct costs. An estimated 78,000 rotavirus-associated deaths occur annually of which 59,000 occur in the first 2 years of life. Introduction of a rotavirus vaccine of similar efficacy to the Rotavac in the national immunization program would result in 686,277 fewer outpatient visits, 291,756 fewer hospitalizations and 26,985 fewer deaths each year in India, assuming no indirect effects for the vaccine.

Genomic Characterization of Nontypeable Rotaviruses and Detection of a Rare G8 Strain in Delhi, India

ABSTRACT In the present investigation we molecularly characterized nontypeable rotavirus strains previously identified during surveillance in New Delhi, India. The majority of strains were demonstrated to belong to genotype G1 (54.5%) or P[8] (77.8%) on the basis of nucleotide sequencing of fragments from their VP7 and VP4 genes. The other genotypes detected included G2, G8, G9, G12, and P[4]. A G8P[6] strain, strain DS108, was detected for the first time in northern India. The VP7 gene of DS108 was most homologous with the VP7 gene of a bovine G8 strain, strain A5 (98.9%), indicating its bovine parentage. In contrast, the VP4 gene had a high degree of nucleotide sequence homology (92.9% to 99.1%) with the VP4 genes of human P[6] strains. The VP6 gene and nonstructural genes (NSP1 to NSP3 and NSP5) were most homologous with the VP6 gene and nonstructural genes of human rotaviruses belonging to the DS1 genogroup. Interestingly, the NSP4 gene of DS108 clustered within genotype E6 that until now had only two representative strains, both with G12P[6] specificity (strains RV176-00 and N26-02). Together, these results indicate that G8 strain DS108 belongs to the DS1 genogroup and could be the result of the acquisition of the VP7, VP4, and NSP4 genes by a human G2P[4] strain from more than one donor, similar to the evolution of G12P[6] strain RV176-00. The present study highlights the importance of characterizing multiple genes of nontypeable rotavirus strains to detect novel strains and get a more complete picture of rotavirus evolution.

A pilot test of the addition of zinc to the current case management package of diarrhea in a primary healthcare setting

Zinc is recommended for the treatment of acute diarrhea in children but the effect of its introduction on drug and oral rehydration solution use is unclear. Government care providers, private practitioners and community workers were trained to distribute zinc and oral rehydration solution to children seeking care for diarrhea. Periodic surveys showed that village-based workers became a common source of diarrhea treatment and private practitioners were used less. Zinc was used in approximately half of the episodes; the prescription and use rates of oral rehydration solution packets increased from 7% at baseline to 44.9% 6 months later. Reduction in use of drugs during diarrhea ranged from 34% for tablets to 64% for injections 6 months later. The cost of treatment to families declined significantly. These findings need confirmation in a randomized controlled trial.