Self-controlled risk interval study of rotavirus vaccine safety: Findings and implications.

BACKGROUND: The self-controlled case series (SCCS) is often used to monitor vaccine safety. The evaluation of intussusception after the rotavirus vaccine is complicated because the baseline rate varies with age. Time-varying baseline risk adjustments with data from unexposed cohorts are utilised. Self-controlled risk interval (SCRI), with a shorter observation period, can also mitigate the problem by studying a control period close to the risk period. OBJECTIVE: An Indian rotavirus vaccine has previously been studied using SCCS. The risk of intussusception in the high-risk windows (21 days after vaccination) was comparable to the background risk. The aim was to re-analyse data of an existing SCCS study using alternate statistical methods to examine vaccine safety. METHODS: We examined the mean age of intussusception in the vaccinated and the unvaccinated. We performed an SCRI analysis of the surveillance data from the SCCS study, limiting the observation period to 180 days. We analysed the time-to-intussusception from the last vaccination. Finally, we performed an SCCS analysis, excluding unvaccinated cases from the analysis. RESULTS: We found that the mean age of intussusception was significantly lower in the vaccinated (205 days) compared to the unvaccinated (223 days) (p-value 0.0026). The Incident Risk Ratio (IRR) on SCRI analysis was 1.62 (95% CI 1.07-2.44). There were significantly more intussusceptions in the first 30 days after vaccination compared to the next 30-day window. (92 vs 63 p-value = 0.009). We found that excluding unvaccinated infants from the SCCS analysis demonstrated significantly increased risk for the risk period 1-21 days after the 3rd dose (IRR 2.47, 95% CI 1.70-3.59). The risks of intussusception were missed in traditional SCCS analysis using unvaccinated infants as controls. CONCLUSION: Traditional risk adjustments using data from unexposed cohorts in SCCS may not be appropriate for investigating the risk of intussusception where vaccination lowers the mean age of intussusception.

Health Insurance: Drawing inspiration from chit funds to pool health risks efficiently.

The provision of government-funded public health services in India is grossly inadequate and 48.2% of "total health expenditure" for India is paid "out of pocket" [1]. When the total health expenditure in a household exceeds 10% of the annual income, it is considered catastrophic health expenditure (CHE) [2].

Mean core to peripheral temperature difference and mean lactate levels in first 6 hours of hospitalisation as two indicators of prognosis: an observational cohort study.

BACKGROUND: To study mean core to peripheral temperature difference (CPTD) and the mean lactate levels over the first 6 h of admission to hospital, as indicators of prognosis in critically ill children. METHODS: A prospective observational study in a tertiary level Pediatrics ICU in Delhi, India. Seventy eight paediatric patients from 1 month to 12 years were studied. Children with physical trauma, post-surgical patients and patients with peripheral vascular disease were excluded. Core temperature (skin over temporal artery) to peripheral temperature (big toe) difference was measured repeatedly every minute over 6 h and mean of temperature difference was calculated. Pediatric Risk of Mortality (PRISM) II, lactate clearance and mean lactate levels during that time were also studied. In-hospital mortality was used as the outcome measure. RESULTS: Mean temperature difference During the first 6 h after admission the mean temperature difference was 9.37 ± 2 °C in those who died and 3.71 ± 2.27 °C in those who survived (p < 0.0001). The area under the receiver operating curve (AUROC) was 0.953 (p < 0.0001). The comparable AUROC of PRISM II was 0.999 (p < 0.0001). Mean Lactate Mean lactate level in the first 6 h was 7.1 ± 2.02 mg/dl in those who died compared to 2.86 ± 0.87 mg/dl in those who survived (p < 0.0001). The AUROC curve for mean lactate was 0.989 (95% CI = 0.933 to 0.999; p < 0.0001). AUROC for the lactate clearance was 0.682 (p = 0.0214). CONCLUSIONS: The mean core to peripheral temperature difference over the first 6 h is an easy-to-use and non-invasive method that is useful to predict mortality in children admitted to the Pediatric ICU. The mean lactate during the first 6 h of Pediatric ICU admission is a better index of prognosis than the lactate clearance over the same time period. They may be used as components of a scoring system to predict mortality.

Mother-to-Child Transfer of Reactivated Varicella-Zoster Virus DNA and Varicella-Zoster IgG in Pregnancy.

Stress-induced subclinical reactivation of varicella-zoster virus (VZV) has been studied previously. However, subclinical reactivation of VZV induced by the stress of pregnancy has not been investigated. The objective was to study varicella DNA and varicella antibody levels in mothers and their newborn babies. VZV immunoglobulin G (IgG) levels in 350 mother-newborn dyads were studied using indirect enzyme-linked immunosorbent assay testing. A subset of 73 dyads was selected, DNA was isolated from the serum samples, and quantitative polymerase chain reaction (qPCR) was performed. Nearly 15% (14.6%) mothers tested were positive for varicella antibodies (>100 mIU/dL) and 16% were borderline (<100 and >50 mIU/dL). Approximately 16.9% of the babies were positive, and 18% were in borderline. Among those tested for VZV-DNA, 70% of mothers with low VZ-IgG (<100 mIU/dL) and 11.32% of those with high VZ-IgG (>100 mIU/dL) were positive for DNA. Among the newborns, 60% of those with low VZ-IgG and 15% of those with high VZ-IgG were positive for DNA. Mothers who have had VZV infection in the past can transmit VZV DNA to their babies.

Measuring disability in an urban slum community in India using the Washington Group questionnaire.

BACKGROUND: The UN recommends that the 'Washington Group questionnaire (WGQ) on functioning' is used for data collection on disability. There are few studies on the WGQ from India. OBJECTIVE: To evaluate the prevalence of disability in a community-health project, using this tool: to examine if the use of the WGQ identifies more people with disability than the tools used previously. METHOD: We performed a systematic sample survey using the WGQ in the community-health project covering a population of 50,000 residents. The questionnaire was administered to 2203 individuals. RESULTS: The age and sex distribution of the sample studied matched the National Census data 2011. The study identified 41 individuals with a disability. The prevalence of disability in our sample was 1.86% (95% CI 1.3%-2.43%) compared to 2.21% in India-Census-2011. Receiver operating characteristic (ROC) curve showed that disability was more prevalent after the age of 44 years (p-value <0.0001 and AUC 0.806). The odds ratio of disability was 10.1 above this age compared with those below that age (95% CI: 5.1 to 20). CONCLUSION: Use of the WGQ did not yield better data on disability prevalence than that identified by the Census. Another study, this one in Telangana, south India, by the London School of Hygiene & Tropical Medicine found that self-reporting identifies only a third of the cases of disability. More direct and leading questions are needed to empower the disabled in developing countries to identify barriers which prevent their full participation in society.

Reply to Comment on Dhiman, R. et al. Correlation of Non-Polio Acute Flaccid Paralysis Rate with Pulse Polio Frequency in India. Int. J. Environ. Res. Public Health 2018, 15, 1755.

We thank the authors for their interest in our paper [...].

Correlation between Non-Polio Acute Flaccid Paralysis Rates with Pulse Polio Frequency in India.

The last case of polio from India was reported in 2011. That year, the non-polio acute flaccid paralysis (NPAFP) rate in India was 13.35/100,000, where the expected rate is 1⁻2/100,000. A previous study of data from 2000 to 2010 has detailed the NPAFP rate in a state correlated with the pulse polio rounds conducted there, and the strongest correlation with the NPAFP rate was found when the number of doses from the previous 4 years were used. However, a simple association being found with regression analysis does not prove a causal relationship. After publication of those findings, as the threat of polio had lessened, the number of rounds of OPV administration was brought down. The present study has been done to look at data till the end of 2017, to see if the incidence of NPAFP declined with this reduction in polio immunization rounds. We used polio surveillance data acquired by the Government of India from 2000⁻2017. Correlation of the NAFP rate to the number of polio rounds in the state was examined, and the cumulative effect of polio doses administered in previous years was sought. NPAFP rate correlated with the OPV pulse polio rounds in that year (R = 0.46; p < 0.001), and the NPAFP rate started to decrease from 2012 when the number of pulse polio rounds had decreased. NPAFP rates in the states of Uttar Pradesh (UP) and Bihar were the highest in the country. Looking at the high-NPAFP states of UP and Bihar, we found that the correlation coefficient was strongest when doses used over 5 years was considered (R = 0.76; p < 0.001). The response to the reduction in OPV rounds (de-challenging) adds credence to the assumption that OPV was responsible for the change in the NPAFP rate. Now that India has been polio-free for over 6 years, we propose that we may be able to reduce NPAFP by further reducing pulse polio rounds.

Revised World Health Organization (WHO)'s causality assessment of adverse events following immunization-a critique.

The World Health Organisation (WHO) has recently revised how adverse events after immunization (AEFI) are classified. Only reactions that have previously been acknowledged in epidemiological studies to be caused by the vaccine, are classified as a vaccine-product-related-reaction. Deaths observed during post-marketing surveillance are not considered as "consistent with causal association with vaccine", if there was no statistically significant increase in deaths recorded during the small Phase 3 trials that preceded it. Of course, vaccines that caused deaths in the control-trials stage would not be licensed. After licensure, deaths and all new serious adverse reactions are labelled as 'coincidental deaths' or 'unclassifiable', and the association with vaccine is not acknowledged. The resulting paradox is evident. The definition of causal association has also been changed. It is now used only if there is "no other factor intervening in the processes." Therefore, if a child with an underlying congenital heart disease (other factor), develops fever and cardiac decompensation after vaccination, the cardiac failure would not be considered causally related to the vaccine. The Global Advisory Committee on Vaccine Safety has documented many deaths in children with pre-existing heart disease after they were administered the Pentavalent vaccine. The WHO now advises precautions when vaccinating such children and this has reduced the risk of death. Using the new definition of causal association, this relationship would not be acknowledged and lives would be put at risk. In view of the above, it is necessary that the AEFI manual be revaluated and revised urgently. AEFI reporting is said to be for vaccine safety. Child safety (safety of children) rather than vaccine safety (safety for vaccines) needs to be the emphasis.

Evaluation of the Protection Provided by Hepatitis B Vaccination in India.

OBJECTIVE: In India, Hepatitis B vaccination is recommended at 6 wk except for hospital-deliveries. The authors examined protection afforded by the birth dose. METHODS: A case-control study was done. HBsAg and HBcAb were tested in 2671 children, 1 to 5 y and HBsAb was evaluated in a subset of 1413 children. Vaccination history was recorded. Cases were HBsAg carriers. In another analysis, children who got infected (HBsAg and/or HBcAb positive) were considered as cases. Exposed were the unvaccinated. In another analysis, exposed were those vaccinated without the birth dose. RESULTS: The odds ratio (OR) for HBsAg positivity with birth vaccination was 0.35 (95% CI 0.19-0.66); while with vaccination at 6 wk was 0.29 (95%CI 0.14-0.61), both compared to unvaccinated. Birth vaccination has no added protection when compared to the unvaccinated. Unvaccinated children in index study had HBsAg positivity of 4.38%. The number needed to treat (NNT) to prevent one case of HBsAg positivity was 32.6 (95% CI, 20.9 to 73.6). The odds of getting HBV infection was 0.42 (CI 0.25-0.68) with birth dose and 0.49 (CI 0.30-0.82) without the birth dose compared to the unvaccinated. Protective antibody (HBsAb) was present in about 70% of the vaccinated. In the unimmunised, in the first 2 y HBsAb protection was present in 40%. The odds ratio (OR) for HBsAb in the fully vaccinated between 4 and 5 y was 1.4 (95%CI 0.9-2.18) compared to the unvaccinated. CONCLUSIONS: The present study lends support to the pragmatic approach of the Government to vaccinate babies born at home starting at 6 wk.

Infanrix hexa and sudden death: a review of the periodic safety update reports submitted to the European Medicines Agency.

There have been a number of spontaneous reports of sudden unexpected death soon after the administration of Infanrix hexa (combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenza type B vaccine). The manufacturer, GlaxoSmithKline (GSK), submits confidential periodic safety update reports (PSURs) on Infanrix hexa to the European Medicines Agency (EMA). The latest is the PSUR 19. Each PSUR contains an analysis of observed/expected sudden deaths, which shows that the number of observed deaths soon after immunisation is lower than that expected by chance. This commentary focuses on that aspect of the PSUR which has a bearing on policy decisions. We analysed the data provided in the PSURs. It is apparent that the deaths acknowledged in the PSUR 16 were deleted from the PSUR 19. The number of observed deaths soon after vaccination among children older than one year was significantly higher than that expected by chance once the deleted deaths were restored and included in the analysis. The manufacturer must explain the figures that have been submitted to the regulatory authorities. The procedures undertaken by the EMA to evaluate the manufacturer's claims in the PSUR need to be reviewed. The Drugs Controller General of India nearly automatically accepts drugs and vaccines approved by the EMA. There is a need to reappraise the reliance on due diligence by the EMA.

Platelet Distribution Width to Platelet Count Ratio as an Index of Severity of Illness.

OBJECTIVE: To prospectively validate association between the ratio of platelet distribution width (PDW)/platelet count (PCT) and pediatric intensive care unit (PICU) mortality. METHODS: The study was done in the pediatric intensive care unit (PICU). Platelet indices in the first sample taken after admission were used. In this case control analysis, cases were the patients who died in PICU and the survivors served as controls. Consecutive 209 eligible patients over a period of 15 mo from January 2014 through March 2015 were included. Exposure was PDW/PC above 0.07. Of them 174 survived and 35 died. RESULTS: The mean PDW for survivors was 16.77 (±0.92) and for those who died it was 17.33 (±1.03) (p 0.0015). Mean platelet count (PC) for survivors was 3,46,000 (±1,64,700) and for those who died it was 1,75,800 (±1,61,500) (p < 0.001). PDW/PC for survivors was 0.12 (±0.46) and for those who died it was 0.336 (±0.53) (p 0.0014). Using the cut-off of 0.07 for PDW/PC described by Golwala et al., 77.14% above the cut-off died, compared to 22.85% below that cut-off. The odds ratio (OR) for death was 10.6 (95% CI: 4.48 to 25.12). The area under the receiver operating curve (ROC) curve for PDW/PC ratio was 0.81. CONCLUSIONS: The ratio of PDW/PC, higher than 0.07 in the first sample after admission can be considered as an independent predictor of mortality with sensitivity and specificity of 77.1% and 77.5%, respectively. It may be a useful component for inclusion in composite scores for predicting mortality.

Nasal Continuous Positive Airway Pressure in Bronchiolitis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of nasal continuous positive airway pressure (nCPAP) in decreasing respiratory distress in bronchiolitis. DESIGN: Randomized controlled trial. SETTING: Tertiary-care hospital in New Delhi, India. Participants: 72 infants (age <1y) hospitalized with a clinical diagnosis of bronchiolitis were randomized to receive standard care, or nCPAP in addition to standard care, in the first hour after admission. 23 parents refused to give consent for participation. 2 infants did not tolerate nCPAP. PARTICIPANTS: 72 infants (age <1y) hospitalized with a clinical diagnosis of bronchiolitis were randomized to receive standard care, or nCPAP in addition to standard care, in the first hour after admission. 23 parents refused to give consent for participation. 2 infants did not tolerate nCPAP. INTERVENTION: The outcome was assessed after 60 minutes. If nCPAP was not tolerated or the distress increased, the infant was switched to standard care. Analysis was done on intention-to-treat basis. MAIN OUTCOME MEASURES: Change in respiratory rate, Silverman-Anderson score and a Modified Pediatric Society of New Zealand Severity Score. RESULTS: 14 out of 32 in nCPAP group and 5 out of 35 in standard care group had change in respiratory rate ≥10 (P=0.008). The mean (SD) change in respiratory rate [8.0 (5.8) vs 5.1 (4.0), P=0.02] in Silverman-Anderson score [0.78 (0.87) vs 0.39 (0.73), P=0.029] and in Modified Pediatric Society of New Zealand Severity Score [2.5 (3.01) vs. 1.08 (1.3), P=0.012] were significantly different in the nCPAP and standard care groups, respectively. CONCLUSIONS: nCPAP helped reduce respiratory distress significantly compared to standard care.

Correlation of Infant Gender with Postpartum Maternal and Paternal Depression and Exclusive Breastfeeding Rates.

INTRODUCTION: Male bias in India has resulted in an altered sex ratio. It also results in maternal postpartum depression (PPD) and lower breastfeeding rates. We studied depression among fathers in this context. METHODS: Edinburgh postnatal depression scale (EPDS) questionnaire was administered to 479 parents separately. Breastfeeding on day 7 was determined. RESULTS: Depression was significantly higher in fathers of girls. Mean EPDS score was 5.86 ± 4.98 versus 2.5 ± 2.64 (p < 0.001). Concordance between parents was significant (r = 0.95, p < 0.001). Boys were more likely to be exclusively breastfed (64.46% versus 35.54%, p < 0.001). In second-order births, if the first born was a girl and second baby was again a girl, 23% were exclusively breastfed compared with 86% if it was boy after a girl (p < 0.001). Among parents who had EPDS scores ≥11, no babies were exclusively breastfed. Among the 25 babies who received no breast milk, 21 were girls and 4 were boys (p < 0.042). The multiple logistic regression analysis indicated that birth of girls (OR 0.269, 95% CI 0.076-0.953), high EPDS score in mothers (OR = 0.080, 95% CI 0.026-0.249), and high EPDS score in fathers (OR = 0.096, 95% CI 0.031-0.299) were associated with lower breastfeeding rates. CONCLUSION: Paternal depression correlates closely with maternal PPD and low exclusive breastfeeding of girls. Breastfeeding has implications for survival of girls. Efforts are needed to support the parents of girl children with PPD and such support must extend to fathers to improve survival.