Adverse Events Following Immunization- The Known Unknowns and Black Box

Although vaccines are one of the most rigorously tested biological products, the safety concerns persist globally. The vaccine safety concerns linked to measles, pentavalent and human papillomavirus (HPV) vaccines have affected the vaccine coverage significantly in past. While surveillance of adverse events following immunization (AEFI) is part of the national immunization program mandate, it suffers from challenges and biases related to reporting, completeness, and quality. Some conditions of concern, termed as adverse events of special interest (AESI) following vaccination, mandated specialised studies to prove/disprove the association. The AEFIs/AESIs are usually caused by one of the four pathophysiologic mechanisms, but for several AEFIs/AESIs, the exact pathophysiology remains elusive. For the causality assessment of AEFIs, a systematic process with checklists and algorithm are followed to classify into one of the four causal association categories. While the causal association primarily banks on epidemiological observations for several AEFIs, the emerging evidences indicate roles of underlying genetic, gender, age and other pro-inflammatory risk factors for AEFIs and AESIs. The emerging evidences suggest role of antigenic mimicry, autoantibody(ies) and underlying genetic susceptibility for the AEFIs/AESIs. The uncertainty about the frequency, profile, interval, and severity of AEFIs/AESIs and variations across the population, ambiguity about the exact pathophysiology mechanism, absence of definite markers, suggest a possible black box effect of the vaccines. Unless these unanswered questions concerning the AEFIs/AESIs are addressed appropriately and communicated to the stakeholders (professionals, care providers, beneficiaries, general public and media), the anti-vaccine movement shall keep challenging the vaccine and vaccination program.

Multicenter Studies: Relevance, Design and Implementation

Multicenter studies are essential in clinical and public health research with several advantages compared to single-center studies. Multicenter studies are attractive and advantageous, allowing quicker recruitment, diverse population coverage and increased generalizability. However, these studies often suffer from methodological, implementation and statistical challenges that can compromise the validity of the study. To meet the technical and interpretative integrity, a multicenter study must be conducted with sound study design, uniform implementation methodology, assured standardization, high-quality data and appropriate statistical considerations. A systematic site selection, rigorous study protocols, stringent quality assurance measures and appropriate analytical approach are indispensable to ensure high internal validity and minimize inter-site variability. For effective implementation of multicenter study, a well-organized coordination center and functional governance mechanism are critical. Transparent and effective network communication among the investigators with cultural sensitivities assists in building productive collaboration. This manuscript summarizes the design, organization, implementation and governance aspects of multicenter studies.

An Introduction to Qualitative and Mixed Methods Study Designs in Health Research

With the recognition of different population behavior and relevance of socio-cultural factors in health, health services and public health program contexts, qualitative research is increasingly being used in health research, including clinical trials. Qualitative research follows an inductive framework to explore and gain an in-depth understanding of the phenomena, especially why and how aspects, through techniques including interviews, focus groups and observations. It analyzes the textual data collected following one of the common analysis approaches: grounded theory, phenomenology, ethnography or participatory action research. Despite the divergence in principles, mixed methods research designs systematically combine the quantitative and qualitative methods for a comprehensive understanding on the issue. The commonly used mixed methods designs variably combine the purpose, priority, sequence, embedding and data integration. Mixed methods analysis requires strategic synthesis of the results to gain comprehensive knowledge for appropriate clinical or public health action.

Impact of Neonatal Resuscitation Capacity Building of Birth Attendants on Stillbirth Rate at Public Health Facilities in Uttar Pradesh, India

Objective: To document the impact of neonatal resuscitationcapacity building of birth attendants at district and sub-districtlevel on fresh stillbirth within the public health system in India.Design: An implementation research using pre-post studydesign.Setting: 3 high-infant and neonatal mortality districts (Gonda,Aligarh and Raebareli) of Uttar Pradesh, India.Participants: Pregnant women who delivered at the healthfacilities and their newborns.Interventions: An intervention package with (i) training onessential newborn care resuscitation; (ii) skill laboratoriesestablishment for peer-interactive learning; (iii) betterdocumentation; and (iv) supportive supervision was implementedat all health facilities in the districts.Main outcome measures: Impact on fresh stillbirth rates andresuscitation practices were documented at 42 health facilities(Gonda-17, Aligarh-8 and Raebareli-17) over 12-18 months.Results: Out of the 3.3% (4431/133627) newborns requiringresuscitation, 58.5% (n=2599) were completely revived, 19%(n=842) had some features of hypoxic insult after birth and 1.4%(n=62) were stillbirths. There was 15.6% reduction in still birth ratein the three districts with the intervention package.Conclusion: The reduction in still birth rate and improvement innewborn resuscitation efforts in the three districts indicatedfeasibility of implementation and scalability of the interventionpackage. However sustenance of the impact over longer periodneeds documentation

Pediatric Appropriate Evaluation Protocol for India (PAEP-India): Tool for Assessing Appropriateness of Pediatric Hospitalization

Objectives: To develop and assess Pediatric AppropriatenessEvaluation Protocol for India (PAEP-India) for inter-rater reliabilityand appropriateness of hospitalization.Design: Cross-sectional study.Setting: The available PAEP tools were reviewed and adaptedfor Indian context by ten experienced pediatricians followingsemi-Delphi process. Two PAEP-India tools; newborn (?28 days)and children (>28 days-18 years) were developed. These PAEP-India tools were applied to cases to assess appropriateness ofadmission and inter-rater reliability between assessors.Participants: Two sets of case records were used: (i) 274cases from five medical colleges in Delhi-NCR [?28 days (n=51);>28 days to 18 years (n=223)]; (ii) 622 infants who werehospitalized in 146 health facilities and were part of a cohort (n=30688) from two southern Indian states.Interventions: Each case-record was evaluated by twopediatricians in a blinded manner using the appropriate PAEP-India tools, and ‘admission criteria’ were categorized asappropriate, inappropriate or indeterminate.Main outcome measures: The proportion of appropriatehospitalizations and inter-rater reliability between assessors(using kappa statistic) were estimated for the cases.Results: 97.8% hospitalized cases from medical colleges werelabelled as appropriate by both reviewers with inter-rateragreement of 98.9% (k=0.66). In the southerm Indian set ofinfants, both reviewers labelled 80.5% admissions as appropriatewith inter-rater agreement of 96.1% (k= 0.89).Conclusions: PAEP-India (newborn and child) tools are simple,objective and applicable in diverse settings and highly reliable.These tools can potentially be used for deciding admissionappropriateness and hospital stay and may be evaluated later forusefulness for cost reimbursements for insurance proposes.

Alpha 1 Antitrypsin Deficiency in Children with Chronic Liver Disease in North India.

Objective: We attempted to determine the role of alpha-1- antitrypsin (AAT) deficient variants as an etiologic factor for chronic liver disease in North Indian children. Design: This study investigated 1700 children (682 retrospectively and 1018 prospectively) (840 CLD, 410 neonatal cholestasis and 450 without liver disease) for AAT deficiency. Setting: Tertiary referral center, All India Institute of Medical Sciences, New Delhi. Patients: Of 1250 liver disease patients, 98 (7.8%) were suspected to be AAT deficient on the basis of screening tests (low serum AAT levels and/or absent/faint alpha-1- globulin band on serum agarose electrophoresis and/or diastase resistant PAS positive granules on liver biopsy). Main outcome measures: AAT deficient Z or S allele in suspected patients. Results: Z or S allele was not observed on phenotyping (1700 subjects), or with PCR-RFLP, SSCP and sequencing done in 50 of 98 suspected AAT deficient patients. A novel mutation G-to-A at position 333 in exon V was found in two siblings having positive immunohistochemistry for AAT on liver biopsy, both of whom had significant liver disease with portal hypertension. Conclusion: In conclusion, AAT deficiency as an etiologic factor for chronic liver disease in childhood appeared to be uncommon in North India.

Infantile Hookworm Disease.

Hookworm infection is common but has rarely been reported in neonates or infants. Two cases of hookworm infestation in early infancy are described. The infants presented with malena, severe pallor, lethargy and failure to gain weight. Initial stool examination was non-contributory and diagnosis was made by upper gastrointestinal endoscopy

Non-alcoholic fatty liver disease and childhood obesity.

Obesity has emerged as a significant global health problem in the pediatric population. Pediatric liver disease is a serious complication of childhood obesity. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver--simple steatosis, NASH/ steatohepatitis--fat with in.ammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. The important message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.

Acute cysticercal meningitis--missed diagnosis.

Neurocysticercosis is the commonest CNS parasitic disease worldwide but cysticercal meningoencephalitis is relatively rare, especially in Indian patients. We herein report a girl with cysticercal meningitis that was initially not suspected and later diagnosed on the basis of cerebrospinal fluid (CSF) eosinophilia. The need for CSF examination with wright-giemsa staining to avoid missing CSF eosinophilia is discussed.

Pneumomediastinum and subcutaneous emphysema in acute miliary tuberculosis.

Pneumomediastinum and subcutaneous emphysema are rare complications of miliary tuberculosis in children. In this report, a 5-year-old girl with miliary tuberculosis complicated by pneumomediastinum and subcutaneous emphysema, is presented and relevant literature is discussed.