Theme Editorial: Controlled Human Infection Models: Exploring the landscape in India

Controlled Human Infection Models (CHIMs) refers to the intentional introduction of an infectious agent into a healthy volunteer to deliberately induce the infection under regulated conditions. These studies can be useful in discovering the origin and development of a disease, its immunological responses and natural course, as well as in the evaluation of interventions. CHIMs have yielded data that have informed the development process of several vaccines in recent years. Infectious diseases contribute substantially to the global burden of disease and therefore research and development in the context of infectious diseases is a high priority.

Direct and Indirect Costs of Pediatric Gastroenteritis in Vellore, India.

Objective: To determine costs of pediatric gastroenteritis in out-patient and in-patient facilities. Methods: Cross-sectional survey of children with acute gastroenteritis attending out-patient clinic (n=30) or admitted in the ward (n=30) for management in the Christian Medical College, Vellore, India from July-September 2014 to estimate direct (drugs, tests, consultation/hospitalization) and indirect (travel, food, lost wages) costs associated with the episode. Results: Median direct and indirect costs were Rs 590 and Rs 190 for out-patient management and Rs 7258 and Rs. 610 for hospitalization, constituting 1.1% and 11% of median annual household income, respectively. Conclusions: Escalating healthcare costs need tracking for evaluation of interventions.

Direct Medical Costs in Children with Rotavirus and Non-rotavirus Diarrhea Admitted to a Pediatric Intensive Care Unit and High Dependency Unit in Delhi.

Objective: To estimate direct medical costs of diarrheal hospitalization of children <5 years admitted in pediatric intensive care unit (PICU) or high dependency unit (HDU). Methods: Analysis of medical records and hospital bills of 84 children during two time frames, 2005-08 and 2012-14. Results: Direct medical costs in PICU increased from INR 17,941 to INR 50,663 per child for rotavirus diarrhea and INR 11,614 to INR 27,106 for non-rotavirus diarrhea, and in HDU from approximately INR 5,800 to INR 10,500 per child for all-cause diarrhea between the two time frames. Conclusions: Costs of PICU and HDU care are high and should be included in cost-effectiveness analysis of vaccination.

Leveraging the National Rotavirus Surveillance Network for Monitoring Intussusception.

Objective: To assess feasibility of monitoring intussusception by hospitals participating in the National Rotavirus Surveillance Network. Methods: Questionnaire-based survey in 28 hospitals. One hospital with electronic records selected for detailed data analysis. Results: There was 75% response to the questionnaire. Few network hospitals were suitable for monitoring intussusception in addition to ongoing activities, but there was at least one potential sentinel hospital in each region. The hospital selected for detailed data analysis of cases of intussusception reported an incidence rate of 112 per 100,000 child years in infants. Over 90% of intussusceptions were managed without surgery. Conclusions: Selection of sentinel hospitals for intussusception surveillance is feasible and necessary, but will require training, increased awareness and referral.

Leveraging the National Rotavirus Surveillance Network for Monitoring Intussusception.

Objective: To assess feasibility of monitoring intussusception by hospitals participating in the National Rotavirus Surveillance Network. Methods: Questionnaire-based survey in 28 hospitals. One hospital with electronic records selected for detailed data analysis. Results: There was 75% response to the questionnaire. Few network hospitals were suitable for monitoring intussusception in addition to ongoing activities, but there was at least one potential sentinel hospital in each region. The hospital selected for detailed data analysis of cases of intussusception reported an incidence rate of 112 per 100,000 child years in infants. Over 90% of intussusceptions were managed without surgery. Conclusions: Selection of sentinel hospitals for intussusception surveillance is feasible and necessary, but will require training, increased awareness and referral.

Profile and Trends of Rotavirus Gastroenteritis in Under-five Children in India (2012-2014): Preliminary Report of the Indian National Rotavirus Surveillance Network.

Objective: To estimate the burden of rotavirus-associated gastroenteritis in India. Methods: Hospital-based surveillance network was established, with clinical evaluation and laboratory testing for rotavirus among children aged below 5 years hospitalized with acute gastroenteritis. Results: Between September 2012 and December 2014, stool samples from 10207 children were tested and rotavirus was detected in 39.6% of cases. Infections were more commonly seen among younger children (<2 years). Detection rates were higher during cooler months of September – February. Among rotavirus infected-children, 64.0% had severe or very severe disease. G1P[8] was the predominant rotavirus genotype (62.7%) observed during the surveillance period. Conclusions: Surveillance data highlights the high rotavirus disease burden and emphasizes the need for close monitoring to reduce morbidity and mortality associated with rotavirus gastroenteritis in India.

Rotavirus-specific Salivary and Fecal IgA in Indian Children and Adults.

Objective: To compare serum, salivary and fecal IgA responses in infants and adults following rotavirus vaccination. Study design: Laboratory testing of samples from clinical trials. Setting: Medical College Hospital. Participants: 13 healthy adult volunteers not given vaccine, 20 healthy adult volunteers given one dose of bovine rotavirus tetravalent vaccine (Shantha Biotechnics), and 88 infants given 3 or 5 doses of Rotarix. Outcome measures: Serum, salivary and fecal IgA at one or more time points. Methods: IgA antibodies were estimated in serum, saliva and fecal samples by enzyme-linked immunosorbent assay, and normalized to total IgA in saliva. Results: In naturally infected adult volunteers, comparing serum and salivary IgA showed significant positive correlation (r=0.759; P=0.003). Of 20 vaccinated adults, complete samples showing change were available for 10; among them there was a significant positive correlation (P<0.05) between pre-vaccination serum and pre-vaccination salivary IgA but not between post-vaccination serum and post-vaccination salivary IgA. Of 88 infants given 3 or 5 doses of vaccine, 13 had more than 4-fold IgA response in serum, saliva and fecal samples, 6 had a 2-4 fold increases in all specimens. There was weak correlation between seroconversion rates measured by serum and salivary antibody responses. Salivary and stool assays were able to detect seroconversion in a few children in whom there was no detectable response in serum. Conclusions: Evaluation of multiple samples is useful for intensive experimental study designs and may help improve our understanding of the induction and dynamics of immune responses to rotavirus vaccination.

Racecadotril in the Management of Rotavirus and Non-rotavirus Diarrhea in Under-five Children: Two Randomized, Double-blind, Placebo-controlled Trials.

Objective: To study the effect of racecadotril on reduction in the duration of acute rotavirus and non-rotavirus diarrhea. Design: Two randomized double-blind placebo-controlled trials Setting: Community-based trial in an urban area in Vellore, hospital-based trial at a secondary hospital in Vellore Participants: 199 and 130 3-59 month old children in the community- and hospital-based trials, respectively. Methods: Racecadotril (1.5 mg/kg/dose, thrice a day for three days) or placebo were given to manage acute diarrhea in both trials. Main outcome measure: Median duration of diarrhea. Results: Among 124 children completing the hospital trial, the median duration of diarrhea was 25 h in both arms (P=0.5); median total stool weight was 74 g/kg and 53.5 g/kg in racecadotril group and placebo group, respectively (P=0.4); and average fluid intake per day was 3.6 mL/kg/h and 3mL/kg/h in racecadotril and placebo arms, respectively (P=0.3). Among rotavirus-positive children, median duration of diarrhea was 26.9 h and 30.2 h in racecadotril and placebo arms, respectively (P=0.7). In the community, 196 completed the trial, the median duration of diarrhea was 2 days for both arms (P=0.8) and rotavirus positive children had similar outcomes with median diarrheal duration of 3 d in both arms (P=0.4). Conclusion: Treatment with racecadotril did not reduce diarrheal duration, stool volume or the requirement for fluid replacement in children with acute gastroenteritis, both with and without rotavirus infection.

Expanded Indian National Rotavirus Surveillance Network in the Context of Rotavirus Vaccine Introduction.

Objective: To extend a nation-wide rotavirus surveillance network in India, and to generate geographically representative data on rotaviral disease burden and prevalent strains. Design: Hospital-based surveillance. Setting: A comprehensive multicenter, multi-state hospital based surveillance network was established in a phased manner involving 28 hospital sites across 17 states and two union territories in India. Patients: Cases of acute diarrhea among children below 5 years of age admitted in the participating hospitals. Results: During the 28-month study period between September 2012 and December 2014, 11898 children were enrolled and stool samples from 10207 children admitted with acute diarrhea were tested; 39.6% were positive for rotavirus. Highest positivity was seen in Tanda (60.4%) and Bhubaneswar (60.4%) followed by Midnapore (59.5%). Rotavirus infection was seen more among children aged below 2 years with highest (46.7%) positivity in the age group of 12-23 months. Cooler months of September – February accounted for most of the rotavirus-associated gastroenteritis, with highest prevalence seen during December – February (56.4%). 64% of rotavirus-infected children had severe to very severe disease. G1 P[8] was the predominant rotavirus strain (62.7%) during the surveillance period. Conclusions: The surveillance data highlights the high rotaviral disease burden in India. The network will continue to be a platform for monitoring the impact of the vaccine.

Rotavirus in India: Forty Years of Research.

Rotavirus was first identified as a human pathogen just over 40 years ago, and work on this pathogen in India started shortly thereafter. Subsequent studies have confirmed its pre-eminent role in gastroenteritis in children in India. Standardized surveillance has enabled the documentation of the high burden of disease, and has demonstrated that there is considerable geographic and temporal variation in strain circulation. Internationally licensed vaccines, vaccine candidates based on indigenous strains and out-licensed strains have been tested for safety, immunogenicity and efficacy; three vaccines are now licensed in India and are used in the private sector. Public sector vaccination has begun, and it will be path-breaking for Indian vaccinologists to measure impact of vaccine introduction in terms of safety and effectiveness. So far, India has kept pace with international epidemiologic and vaccine research on rotavirus, and these efforts should continue.

Study of Common Illnesses Before and After Vaccination: A Risk-interval Approach.

Objective: To compare the proportion of children who developed a specified illness in the 7 day post-vaccination window, with the background rate of the same event in the 7 day pre-vaccination window. Study design: Risk interval approach (Self-controlled caseseries). Setting: Well Baby Clinic of Christian Medical College, Vellore. Participants: 1602 healthy infants and under-six children presenting for routine vaccination. Outcome measures: Episode of any illness. Methods: The interviewer enquired about any adverse event or illness experienced by the child for each day of the week preceding the administration of age-appropriate vaccines. A second interview (telephonic) was conducted by the same interviewer one week following vaccine administration to enquire about adverse event(s) experienced by the child for each day of the subsequent week using a similar protocol. Results: With multiple vaccines delivered at appropriate ages, common childhood illnesses that could be reported as adverse events following immunization, except fever (RR=5.7, 95% CI=4.50-7.35), occurred at higher rates pre-vaccination. Risk Ratios of fever following whole cell (RR=9.3, 95% CI=6.43-13.52) and acellular (RR=8.5, 95% CI=3.82-18.91) vaccines were similar, with both showing a decreasing trend with increasing age. The gastrointestinal adverse event profile [diarrhea (RR=0.6, 95% CI=0.14-2.51) and vomiting (RR=1.0, 95% CI=0.14-7.10)] for rotavirus vaccine was similar pre- and post-immunization. Conclusions: Since most adverse events to vaccines are also common childhood illnesses, estimating the background rates of common illnesses is important to accurately ascertain a causal relationship.

Effects of Elevated Blood Lead Levels in Preschool Children in Urban Vellore.

Objectives: To study the burden and associated risk factors for elevated blood lead levels among pre-school children (15-24 months) in urban Vellore, and to study its effects on child cognition and anemia. Design: An investigative study through Mal-ED cohort. Setting: Eight adjacent urban slums in Vellore, Tamil Nadu. Participants: 251 babies recruited through Mal-ED Network. Outcome measures: Blood lead levels using Graphite Furnace Atomic Absorption Spectrophotometry method at 15 and 24 mo; hemoglobin estimation by azidemethemoglobin method; cognitive levels using Bayley Scales of Infant Development III. Results: Around 45% of children at 15 months and 46.4% at 24 months had elevated blood lead levels (>10 μg/dL). Among children who had elevated blood lead levels at 15 months, 69.2% (45/65) continued to have elevated levels at 24 months. After adjusting for potential confounders, children from houses having a piped drinking water supply and houses with mud or clay floors were at significantly higher risk of having elevated blood lead levels at 15 months. Thirty one percent (21/67) of the children with elevated blood lead levels had poor cognitive scores. Children with elevated blood lead levels at 15 months had higher risk (Adjusted OR 1.80; 95% CI 0.80 - 3.99) of having poorer cognitive scores at 24 months. More than half of the children (57%) were anemic at 15 months of age, and elevated blood lead levels were not significantly associated with anemia. Conclusions: Elevated blood lead levels are common among preschool children living in urban slums of Vellore. Poorer conditions of the living environment are associated with elevated lead levels.

Prevalence & risk factors for soil transmitted helminth infection among school children in south India.

Background & objectives: Soil-transmitted helminths (STH) are a major public health problem in tropical and sub-tropical countries, affecting the physical growth and cognitive development in school-age children. This study was aimed to assess the prevalence and risk factors of STH infection among school children aged 6 -14 yr in Vellore and Thiruvanamalai districts in south India. Methods: Children aged 6-14 yr, going to government and government aided schools (n=33, randomly selected) in Vellore and Thiruvanamalai districts were screened to estimate the prevalence of STH, and a case control study was done on a subset to assess the risk factors for the infection. Results: The prevalence of STH was 7.8 per cent, varying widely in schools from 0 to 20.4 per cent, in 3706 screened children. Hookworm (8.4%) rates were high in rural areas, while Ascaris (3.3%) and Trichuris (2.2%) were more prevalent among urban children. Consumption of deworming tablets (OR=0.25, P<0.01) offered protection, while residing in a field hut (OR=6.73, P=0.02) and unhygienic practices like open air defaecation (OR=5.37, P<0.01), keeping untrimmed nails (OR=2.53, P=0.01) or eating food fallen on the ground (OR=2.52, P=0.01) were important risk factors for STH infection. Interpretation & conclusions: Our study indicated that school children with specific risk factors in the studied area were vulnerable subpopulation with elevated risk of STH infection. Identifying risk factors and dynamics of transmission in vulnerable groups can help to plan for effective prevention strategies.

Management of Children with Severe Acute Malnutrition: Experience of Nutrition Rehabilitation Centers in Uttar Pradesh, India.

Objective: To assess the effectiveness of facility-based care for children with severe acute malnutrition (SAM) in Nutrition Rehabilitation Centers (NRC). Design: Review of data. Setting: 12 NRCs in Uttar Pradesh, India. Participants: Children admitted to NRCs (Jan 1, 2010 - Dec 31, 2011). Intervention: Detection and treatment of SAM with locallyadapted protocols. Outcomes: Survival, default, discharge, and recovery rates. Results: 54.6% of the total 1,229 children admitted were boys, 81.6% were in the age group 6-23 months old, 86% belonged to scheduled tribes, scheduled castes, or other backward castes, and 42% had edema or medical complications. Of the 1,181 program exits, 14 (1.2%) children died, 657 (47.2%) children defaulted, and 610 (51.7%) children were discharged The average (SD) weight gain was 12.1 (7.3) g/kg body weight/day and the average (SD) length of stay was 13.2 (5.6) days. 206 (46.8%) children were discharged after recovery (weight gain ≥15%) while 324 (53.2%) were discharged, non-recovered (weight gain <15%) Conclusions: NRCs provide life-saving care for children with SAM; however, the protocols and therapeutic foods currently used need to be improved to ensure the full recovery of all children admitted.

Survey of ethical issues reported by Indian medical students: basis for design of a new curriculum.

Education in ethics is now a formal part of the undergraduate medical curriculum. However, most courses are structured around principles and case studies more appropriate to western countries. The cultures and practices of countries like India differ from those of western countries. It is, therefore, essential that our teaching should address the issues which are the most relevant to our setting. An anonymised, questionnaire-based, cross-sectional survey of medical students was carried out to get a picture of the ethical problems faced by students in India. The data were categorised into issues related to professional behaviour and ethical dilemmas. Unprofessional behaviour was among the issues reported as a matter of concern by a majority of the medical students. The survey highlights the need to design the curriculum in a way that reflects the structure of medical education in India, where patients are not always considered socio-culturally equal by students or the medical staff. This perspective must underpin any further efforts to address education in ethics in India.

Protection is not just about preventing disease: vaccine equity and ethics in the developing world.

Vaccines are intended to prevent disease. In 1798, Jenner used the principle of an animal virus that caused a localised lesion but afforded protection against severe disease. This started the practice of “vaccination”. The idea of preventing disease and avoiding unnecessary suffering is attractive, but since vaccines are generally given to prevent disease in people who do not already have it, they must not themselves cause disease, or at least no more than acceptable discomfort.

Adherent Escherichia coli in colorectal mucosal biopsies: A histological and ultrastructural evaluation.

Background: Colorectal mucosal biopsies occasionally demonstrate the presence of bacteria adherent to the epithelium. This study evaluated the histological and ultrastructural correlates of such bacterial adherence. Materials and Methods: Rectal mucosal biopsies from eight patients in whom histopathological examination of biopsies had earlier demonstrated adherent bacteria were examined by electron microscopy and by bacterial culture. Colorectal biopsies of 69 patients with adherent bacteria detected histologically were retrospectively evaluated for histological changes at sites proximal and distant to adherent bacteria. Results: Escherichia coli of different serogroups were isolated from 7 of 8 rectal biopsies demonstrating bacterial adherence. All isolates showed diffuse or focal adherence to HEp-2 cell monolayers. Ultrastructural changes noted included microvillus damage, pedestal formation, actin web condensation, and protrusions of the apical cytoplasm of epithelial cells into the lumen towards the bacteria. Histological changes noted at light microscopy included reduction in epithelial cell height, focal epithelial cell degeneration, cryptitis and neutrophil infiltration at sites of bacterial adherence whereas these were usually absent at sites distant to adherent bacteria. Bacterial adherence was noted more often in biopsies from Crohn's disease patients than in patients without this diagnosis (P < 0.001). Conclusion: Adherent Escherichia coli in colorectal biopsies were associated with focal epithelial damage and showed an association with Crohn's disease.