Identifying risk of death in children hospitalized with community-acquired pneumonia.

Objective: To externally validate a tool developed by the Pneumonia Research Partnership to Assess WHO Recommendations study group for identification of the risk of death in children hospitalized with community-acquired pneumonia, the PREPARE tool. Methods: We did a secondary analysis of data collected during hospital-based surveillance of children with community-acquired pneumonia in northern India from January 2015 to February 2022. We included children aged 2-59 months with pulse oximetry assessment. We used multivariable backward stepwise logistic regression analysis to assess the strength of association of the PREPARE variables (except hypothermia) with pneumonia-related death. We estimated sensitivity, specificity, and positive and negative likelihood ratios of the PREPARE score at cut-off scores ≥ 3, ≥ 4 and ≥ 5. Findings: Of 10 943 children screened, 6745 (61.6%) were included in our analysis, of whom 93 (1.4%) died. Age of < 1 year, female sex, weight-for-age < -3 standard deviations, respiratory rate of ≥ 20 breaths/min higher than the age-specific cut-off, and lethargy, convulsions, cyanosis and blood oxygen saturation < 90% were associated with death. In the validation, the PREPARE score had the highest sensitivity (79.6%) with concurrent highest specificity (72.5%) to identify hospitalized children at risk of death from community-acquired pneumonia at a cut-off score of ≥ 5. Area under curve was 0.82 (95% confidence interval: 0.77-0.86). Conclusion: The PREPARE tool with pulse oximetry showed good discriminatory ability on external validation in northern India. The tool can be used to assess risk of death of hospitalized children aged 2-59 months with community-acquired pneumonia for early referral to higher-level facilities.

Assessment of interleukin 1 receptor antagonist (IL-1RA) levels in children with and without community acquired pneumonia: a hospital based case-control study.

The primary objective was to compare serum interleukin-1 receptor antagonist (IL-1RA) levels in cases of community acquired pneumonia (CAP) and healthy age-gender-matched controls. The secondary objective was to compare serum IL-1RA levels in cases which were positive or negative for Streptococcus pneumoniae in the blood by real-time-polymerase chain reaction (RT-PCR). Hospitalized children with World Health Organization defined CAP, aged 2-59 months, were included as cases. Healthy controls were recruited from the immunization clinic of the hospital. Enzyme-linked immunosorbent assay (ELISA) test was used to detect serum IL-1RA levels. Identification of S.pneumoniae in blood was done by RT-PCR. From October 2019 to October 2021, 330 cases (123, 37.27% female) and 330 controls (151, 45.75% females) were recruited. Mean serum IL-1RA levels (ng/ml) were 1.36 ± 0.95 in cases and 0.25 ± 0.25 in controls (p < 0.001). Within cases, serum IL-1RA levels were significantly higher in those whose RT-PCR was positive for S.pneumoniae. Thus serum IL-1RA levels may be evaluated as a surrogate marker of S.pneumoniae in future studies.

The main purpose of the study was to compare the levels of a protein in the blood that is part of the immune system, called interleukin-1 receptor antagonist (IL-1RA) which binds to the same site in the body as an antibody does when it is fighting certain diseases, like pneumonia. We then compared the levels of this protein, IL-1RA, in hospitalized cases of community acquired pneumonia (CAP), caused from exposure to germs in the community, rather than obtained or contracted in a hospital, to that found in healthy people or 'controls' recruited from an immunization clinic. Cases and controls were matched for age and gender. The secondary objective of our study was to compare the level of IL-1RA protein in the blood in cases that were positive for the bacteria Streptococcus pneumoniae measured in the blood by a molecular test called real-time-polymerase chain reaction which can detect a very small amounts of a protein that is uniquely found in the S.pneumoniae bacteria that causes CAP. This case­control study was conducted in a large teaching institution that receives referrals from the other hospitals in northern India. It was found that serum IL-1RA levels were raised in cases of CAP, especially those which were possibly due to S.pneumoniae.

Predicting Mortality and Use of RISC Scoring System in Hospitalized Under-Five Children Due to WHO Defined Severe Community Acquired Pneumonia.

BACKGROUND: Pneumonia acquired in the community is a leading cause of hospitalization and death in under-five children. Predicting mortality in children remains a challenge. There is a need of consolidated scoring system to predict mortality in under-five children in developing nations. METHODS: This is a hospital-based prospective nested case-control study, conducted in a tertiary care teaching hospital of north India. Included were under-five hospitalized children due to WHO defined severe community acquired pneumonia (CAP). Those who did not survive were categorized as cases, while those who were discharged were categorized as controls. RESULTS: The mortality rate among the recruited 180 hospitalized children with severe CAP was 9.4%. The mortality in under-five children was higher among infants, children who resided in rural areas and were unimmunized or partially immunized for the present age. Mortality was also statistically significantly higher among under-five children with weight for age and weight for length/height below -2Z score; SpO2 < 90% at room air at admission, cyanosis, convulsion, high C-reactive protein (CRP), blood culture positive sepsis and end point consolidation. These predictors were found to be independent risk factors for the mortality after analyzing in multivariate model while presence of wheeze and exclusive breast feeding for first six months of life were found to be protective. The receiver operating characteristic (ROC) curve for respiratory index of severity in children (RISC) score has area under curve (AUC) 0.91 while AUC of RISC score with King George's Medical University (KGMU) modification has 0.88 for prediction of mortality. At the cut-off level of 3, the sensitivity of the RISC score in predicting mortality was 94.1% while the specificity was 73.6%. However, the sensitivity of the RISC score with KGMU modification in predicting mortality at cut-off level of 3 was 88.4% with a specificity of 74.8%. CONCLUSION: Various predictors for mortality under-five children are young age, malnutrition, cyanosis, high CRP, blood culture positive sepsis and end point consolidation. It is also possible to predict mortality using RISC score which comprises simple variables and can be easily used at centers of periphery. Similar accuracy had been also found through the use of an age independent modified score (RISC score with KGMU modification).Lay summaryPneumonia is a primary cause of hospitalization as well as death among the children under the age of five. A variety of severity or mortality predicting scores have been produced for adults, but such scores for children are scarce. Furthermore, their utility in developing nations has not been proven. This is a hospital-based prospective study. Included were children under five (2 to 59 months) hospitalized due to severe community acquired pneumonia (CAP) defined as per World Health Organization (WHO) and were not hospitalized in last 14 days elsewhere. Those who did not survive were classified as cases while those who were discharged were classified as controls. A total of 200 consecutively hospitalized children with severe CAP based on WHO were screened and 180 children were recruited. Among recruited children, the percentage of mortality was 9.4% while 90.6% were discharged. The mortality was higher among children younger than 12 months, those belonged to rural area and were unimmunized or partially immunized for the present age. Mortality was also higher among under-five children with severe malnutrition, anemia, SpO2 < 90% at room air at admission, cyanosis, convulsion, thrombocytopenia, high CRP, blood culture positive sepsis and end point consolidation. After assessing in a multivariate model, these predictors were determined to be independent risk factor for death, while wheezing and exclusive breast feeding throughout the first six months of life were found to be protective. The receiver operating characteristic (ROC) curve for respiratory index of severity in children (RISC) score has an area under curve (AUC) of 0.91 while AUC of RISC score with King George's Medical University (KGMU) modification was 0.88 for the prediction of death in under-five children hospitalized due to severe CAP.

Global Hunger Index does not really measure hunger - An Indian perspective.

The Global Hunger Index (GHI) is calculated and disseminated annually. India, which is the 5th largest economy in the world and has a good ranking in many other indicators, has a poor ranking based on this index. After a critical review of the appropriateness of the indicators used in GHI, the Indian Council of Medical Research has the viewpoint that the indicators of undernourishment, stunting, wasting and child mortality do not measure hunger per se. Referring to this index as a Hunger Index, and thereby ranking countries is not appropriate, since many of the measures that are used to evolve an index that measures hunger are probably contextual. Countries should therefore evolve their own measures that are suitable for their own context.

Serotypes of Streptococcus pneumoniae in Children Aged <5 Years Hospitalized With or Without Pneumonia in Developing and Emerging Countries: A Descriptive, Multicenter Study.

BACKGROUND: Improving knowledge regarding Streptococcus pneumoniae distribution in pneumonia cases is important to better target preventive and curative measures. The objective was to describe S. pneumoniae serotypes in children with or without pneumonia. METHODS: It was a case-control study carried out in 8 developing and emerging countries between 2010 and 2014. Cases were children aged <5 years admitted to the hospital for pneumonia. Controls were children admitted for surgery or routine outpatient care. RESULTS: In nasopharyngeal samples, S. pneumoniae were detected in 68.2% of the cases and 47.5% of the controls (P < .001). Nasopharyngeal carriage was associated with a higher risk of being a case in 6/8 study sites (adjusted odds ratio ranged from 0.71 [95% confidence interval [CI], .39-1.29; P = .26] in India [Pune/Vadu] to 11.86 [95% CI, 5.77-24.41; P < .001] in Mongolia). The 13-valent pneumococcal conjugate vaccine (PCV13) serotypes were more frequently detected in cases with nasopharyngeal carriage (67.1%) than in controls with nasopharyngeal carriage (54.6%), P < .001. Streptococcus pneumoniae was detected in blood by polymerase chain reaction in 8.3% of the cases. Of 34 cases with an S. pneumoniae serotype detected in blood, 27 (79%) had the same serotype in the nasopharyngeal sample. CONCLUSIONS: The results confirm the assumption that the isolate carrying or causing disease in an individual is of the same serotype. Most serotypes independently associated with nasopharyngeal carriage or pneumonia are covered by PCV13, suggesting that increased PCV coverage would reduce the burden of S. pneumoniae-related pneumonia.

Micronutrient-fortified infant cereal improves Hb status and reduces iron-deficiency anaemia in Indian infants: an effectiveness study.

Anaemia affects approximately 69 % of Indian children aged 6-12 months, with Fe deficiency (ID) being a common cause. The effectiveness of micronutrient-fortified infant cereal in improving Fe status and neurodevelopment was evaluated in non-anaemic and mildly anaemic Indian infants. An intervention group (IC) enrolled at age 6 months consumed 50 g/d of rice-based cereal providing 3·75 mg Fe/d as ferrous fumarate for 6 months (n 80) and was compared with a matched static cross-sectional control group (CG) without intervention enrolled at age 12 months (n 80). Mean Hb was higher in IC (118·1 (sd 10·2) g/l) v. CG (109·5 (sd 16·4) g/l) at age 12 months (adjusted mean difference: 9·7 g/l; 95 % CI 5·1, 14·3; P < 0·001), while geometric mean serum ferritin tended to be higher (27·0 (-1 sd 13·4, +1 sd 54·4) v. 20·3 (-1 sd 7·5, +1 sd 55·0) ng/ml); P = 0·085) and soluble transferrin receptor was lower (1·70 (-1 sd 1·19, +1 sd 2·43) v. 2·07 (-1 sd 1·29, +1 sd 3·33) mg/l; P = 0·014). Anaemia (23 v. 45 %; P = 0·007) and ID (17 v. 40 %; P = 0·003) were lower in IC v. CG. Bayley Scales of Infant and Toddler Development Third Edition scores for language (P = 0·003), motor development (P = 0·018), social-emotional (P = 0·004) and adaptive behaviour (P < 0·001), but not cognitive development (P = 0·980), were higher in IC v. CG. No significant difference in anthropometric Z-scores was observed between the groups. Consuming a micronutrient-fortified infant cereal daily for 6 months during complementary feeding promoted better Fe status while reducing the risk for anaemia and ID and was associated with superior neurodevelopmental scores.

Effectiveness of various communication strategies for improving childhood pneumonia case management: a community based behavioral open labeled trial in rural Lucknow, Uttar Pradesh, India.

BACKGROUND: Community acquired pneumonia is responsible for 16% of under 5 mortality in India, probably due to delayed recognition and qualified care seeking. Therefore these deaths could possibly be averted by creating community awareness and promoting care seeking from qualified physicians in the government system. The objective of study was to assess the effectiveness of facility-based and village-based behavior change communication interventions delivered to community using validated information, education and communication materials, along with infrastructural strengthening of health facilities, for change in care seeking from government system for community acquired pneumonia in rural Lucknow, India. METHOD: Community based open labeled behavioral trial in 2 by 2 factorial design was conducted in eight rural blocks of Lucknow, northern India. Trained community health workers conducted Pneumonia Awareness Sessions once a month for the care givers of children using validated information, education and communication materials either at the villages or at government health facilities. Prior infrastructural strengthening of public health facilities was done to provide optimal care to cases. Pre packed pneumonia drug kits were provided which had amoxicillin, paracetamol and an instruction card on their use as well as pictorial representation of danger signs of pneumonia. RESULTS: Study lasted from October 2015 to September 2018. Adherence to conduct of facility-based intervention was 93.0% (279/300) and to village-based intervention was 73.4% (7638/10410). In village-based intervention there was 79.3% (p < 0.0001) increase from a baseline of 3.3% (14/420) and facility-based intervention 68.9% (p = 0.02) increase from a baseline of 5.35% (21/392) in cases of possible pneumonia treated at government health facilities. CONCLUSION: Conduct of structured pneumonia awareness session using validated information, education and communication material at village level with infrastructural strengthening resulted in improved qualified care seeking from government facilities for community acquired pneumonia. TRIAL REGISTRATION: AEARCTR-0003137, retrospectively registered on 10/July/2018.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.

BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. METHODS: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. FINDINGS: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. INTERPRETATION: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. FUNDING: The Bill & Melinda Gates Foundation.

To assess the effectiveness of various communication strategies for improving childhood pneumonia case management: study protocol of a community based behavioral open labeled trial in rural Lucknow, Uttar Pradesh, India.

BACKGROUND: Community Acquired Pneumonia (CAP) is the leading cause of childhood morbidity and mortality worldwide including India. Many of these deaths can be averted by creating awareness in community about early symptoms of CAP and by ensuring availability of round the clock, quality health care. The objective was to assess the effectiveness of an innovative package of orienting doctors and community health workers about community perceptions on CAP barriers to qualified health care seeking, plus infrastructural strengthening by (i) providing "Pneumonia Drug Kit" (PDK) (ii) establishing "Pneumonia Management Corner" (PMC) at additional primary health center (PHCs) and (iii) "Pneumonia Management Unit" (PMU) at Community health center (CHCs) along with one of 4 different behavior change communication interventions: 1. Organizing Childhood Pneumonia Awareness Sessions (PAS) for caregivers of children < 5 years of age during a routine immunization day at PHCs and CHCs by Auxillary Nurse Midwives (ANM) 2. Organizing PAS on Village Health and Nutrition Day only once a month in villages by Accredited Social Health Activist (ASHA) 3. Combination of both Interventions 1 & 2 4. Usual Care as measured by number of clinical pneumonia cases-treated by ANM/doctors with PDK or treated at either PMC or PMU. METHODS: Prospective community based open labeled behavioral trial (2 by 2 factorial design) conducted in 8 rural blocks of Lucknow district. Community survey will be done by multistage cluster sampling to collect information on changes in types of health care providers' service utilization for ARI/CAP pre and post intervention. DISCUSSION: CAP is one of the leading killers of childhood deaths worldwide. Studies have reported that recognition of pneumonia and its danger signs is poor among caregivers. The proposed study will assess effectiveness of various communication strategies for improving childhood pneumonia case management interventions at mother/community level, health worker and health center level. The project will generate demand and improve supply of quality of care of CAP and thus result in reduced mortality in Lucknow district. Since the work will be done in partnership with government, it can be scaled up. TRIAL REGISTRATION: This study has been registered retrospectively in the AEARCT Registry and the registration number is: AEARCTR-0003137 .

Microorganisms Associated With Pneumonia in Children <5 Years of Age in Developing and Emerging Countries: The GABRIEL Pneumonia Multicenter, Prospective, Case-Control Study.

Background: Pneumonia, the leading infectious cause of child mortality globally, mainly afflicts developing countries. This prospective observational study aimed to assess the microorganisms associated with pneumonia in children aged <5 years in developing and emerging countries. Methods: A multicenter, case-control study by the GABRIEL (Global Approach to Biological Research, Infectious diseases and Epidemics in Low-income countries) network was conducted between 2010 and 2014 in Cambodia, China, Haiti, India (2 sites), Madagascar, Mali, Mongolia, and Paraguay. Cases were hospitalized children with radiologically confirmed pneumonia; controls were children from the same setting without any features suggestive of pneumonia. Nasopharyngeal swabs were collected from all subjects; 19 viruses and 5 bacteria were identified by reverse-transcription polymerase chain reaction. Associations between microorganisms and pneumonia were quantified by calculating the adjusted population attributable fraction (aPAF) after multivariate logistic regression analysis adjusted for sex, age, time period, other pathogens, and site. Results: Overall, 888 cases and 870 controls were analyzed; ≥1 microorganism was detected in respiratory samples in 93.0% of cases and 74.4% of controls (P < .001). Streptococcus pneumoniae, Mycoplasma pneumoniae, human metapneumovirus, rhinovirus, respiratory syncytial virus (RSV), parainfluenza virus 1, 3, and 4, and influenza virus A and B were independently associated with pneumonia; aPAF was 42.2% (95% confidence interval [CI], 35.5%-48.2%) for S. pneumoniae, 18.2% (95% CI, 17.4%-19.0%) for RSV, and 11.2% (95% CI, 7.5%-14.7%) for rhinovirus. Conclusions: Streptococcus pneumoniae, RSV, and rhinovirus may be the major microorganisms associated with pneumonia infections in children <5 years of age from developing and emerging countries. Increasing S. pneumoniae vaccination coverage may substantially reduce the burden of pneumonia among children in developing countries.

Interplay of cytokines in preterm birth.

Preterm infants (i.e., born before <37 wk of gestation) are at increased risk of morbidity and mortality and long-term disabilities. Global prevalence of preterm birth (PTB) varies from 5 to 18 per cent. There are multiple aetiological causes and factors associated with PTB. Intrapartum infections are conventionally associated with PTB. However, maternal genotype modulates response to these infections. This review highlights the association of cytokine gene polymorphisms and their levels with PTB. Varying PTB rates across the different ethnic groups may be as a result of genetically mediated varying cytokines response to infections. Studies on genetic variations in tumour necrosis factor-alpha, interleukin-1 alpha (IL-1α), IL-1ß, IL-6, IL-10 and toll-like receptor-4 genes and their association with PTB, have been reviewed. No single polymorphism of the studied genes was found to be associated with PTB. However, increased maternal levels of IL-1ß and IL-6 and low levels of IL-10 have been found to be associated with PTB.

A Mutagenic Primer Assay for Genotyping of the CRHR1 Gene Rare Variant rs1876828 (A/G) in Asians: A Cost-Effective SNP Typing.

BACKGROUND: Today, the genetic and genomic research entered in a new era of high-throughput genotyping technology. However, mutagenic polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is still a choice of genotyping method in molecular epidemiological research. It has been extensively used for the detection of risk alleles, if the target SNP has no natural discriminating restriction site. We undertook this study to develop a mutagenic primer assay for a CRHR1 rare gene variant: rs1876828 (A/G) and to determine their allele frequency in north Indian children. METHODS: The mutagenic primers were designed and assay conditions were optimized to perform mutagenic PCR-RFLP in 550 subjects. The efficiency of assay and results were validated by sequencing. RESULTS: This study demonstrated that the mutagenic primer assay is feasible and applicable to discriminate CRHR1 gene rare variant rs1876828 (A/G) and the "frequency of allele "G" was 100% in north Indian asthmatics as well as normal subjects. CONCLUSION: This method can be used for both large- and small-scale study of complex genetic, where CRHR1 gene plays the pivotal roles.

Recurrent benign copy number variants & issues in interpretation of variants of unknown significance identified by cytogenetic microarray in Indian patients with intellectual disability.

BACKGROUND & OBJECTIVES: Cytogenetic microarray (CMA) is now recommended as a first-tier clinical diagnostic test in cases with idiopathic intellectual disability and/or developmental delay (ID/DD). Along with clinically relevant variants, CMA platforms also identify variants of unknown significance (VUS). This study was done to look for utility and various issues in interpretation of copy number variants (CNVs) in Indian patients with ID/DD. METHODS: The CMA was performed in 86 Indian patients with idiopathic ID/DD with or without dysmorphic features. CNV was reported if copy number gain was >400 kb in size and copy number loss was > 200 kb in size. RESULTS: Pathogenic CNVs were found in 18 of 86 (20.9%) patients. One large (14 Mb size) de novo heterozygous copy number gain was found in one patient. VUS (total 31) were present in 17 of 86 (19.7%) patients. Five novel recurrent benign CNVs were also present in our patients. INTERPRETATION & CONCLUSIONS: Our findings highlight the difficulties in interpretation of CNVs identified by CMA. More Indian data on VUS and recurrent benign CNVs will be helpful in the interpretation of CMA in patients with ID/DD.

Association of interleukin genes polymorphism with asthma susceptibility in Indian children: a case-control study.

BACKGROUND: Interleukins (IL) 4 and 13 genes and their receptors (R) are the key cytokines which amplify inflammatory reactions in asthma. OBJECTIVE: This study aimed to investigate the association of IL 4, 4 R, 13 and 13 R genes polymorphism with asthma in Indian children. METHODS: In this hospital-based case-control study, included were children aged 1-15 years recruited as diagnosed cases of bronchial asthma, according to EPR 2007 and excluded were subjects with other respiratory diseases. Children with no present or past history of asthma were enrolled as controls. Spirometry was done in cases age ≥ 6 years. Gene-gene interaction was evaluated using binary logistic regression. RESULTS: From October 2010 to July 2013, 275 cases and 275 controls were recruited. Gene-gene interactions between C1112T in IL 13 and Ile50Val in IL 4 R gene polymorphisms were found to be statistically significant (OR = 2.37, 95% CI = 1.04-5.42, p = 0.040). Individuals with CT and GG genotype of C1112T in IL 13 and Ile50Val in IL 4 R were at twice the risk for the development of asthma compared to individuals with both non-risk genotypes. CONCLUSION: The data suggests that gene-gene interactions between IL 13 and IL 4 R genes may play an important role in asthma among Indian children.

CFTR Gene Mutations and Asthma in Indian Children: A Case-Control Study.

Cystic Fibrosis Trans membrane conductance regulator (CFTR) gene is an asthma susceptibility gene. In the present study we investigated the possible association of CFTR gene mutations in Indian asthmatic children as compared to controls. The study included 250 asthmatics and 250 age and sex matched controls. Case to control ratio for sample size was 1:1. Genotyping was performed for 24 CFTR gene mutations by ARMS-PCR and PCR-RFLP method. Among 24 CFTR gene mutations, heterozygous allele of R553X mutation was found in 4 (1.6 %) asthmatic cases and 2 (0.8 %) controls. Value of FVC and FEV1/FVC ratio were significantly lower in heterozygous individuals (p value <0.05). No significant difference was observed in the genotype and allele frequency of R553X mutation (OR = 1.339, 95 % CI = 0.755-2.374, p value = 0.685). Furthermore, all wild type homozygous alleles were observed in remaining 23 CFTR gene mutations. Our data concludes that R553X mutation was not significantly associated in Indian asthmatic children.

Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial.

BACKGROUND: In north India, vitamin A deficiency (retinol <0·70 µmol/L) is common in pre-school children and 2-3% die at ages 1·0-6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality. METHODS: Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200,000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6-72 months. Annually, one centre per block was randomly selected and visited by a study team 1-5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100,000 visits, 25,000 deaths at ages 1·0-6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547. FINDINGS: Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] µmol/L, increase 0·10 [SE 0·01] µmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 µmol/L 6%vs 13%, decrease 7% [SE 1%]), as was that of Bitot's spots (1·4%vs 3·5%, decrease 2·1% [SE 0·7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0-6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89-1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected. INTERPRETATION: DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20-30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5-16, p=0·00015), reliably contradicting the hypothesis of no effect. FUNDING: UK Medical Research Council, USAID, World Bank (vitamin A donated by Roche).

Population deworming every 6 months with albendazole in 1 million pre-school children in North India: DEVTA, a cluster-randomised trial.

BACKGROUND: In north India many pre-school children are underweight, many have intestinal worms, and 2-3% die at ages 1·0-6·0 years. We used the state-wide Integrated Child Development Service (ICDS) infrastructure to help to assess any effects of regular deworming on mortality. METHODS: Participants in this cluster-randomised study were children in catchment areas of 8338 ICDS-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks were cluster-randomly allocated in Oxford between 6-monthly vitamin A (retinol capsule of 200,000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of albendazole effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6-72 months. Annually, one centre per block was randomly selected and visited by a study team 1-5 months after any trial deworming to sample faeces (for presence of worm eggs, reliably assessed only after mid-study), weigh children, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100,000 visits, 25,000 deaths at age 1·0-6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547. FINDINGS: Estimated compliance with 6-monthly albendazole was 86%. Among 2589 versus 2576 children surveyed during the second half of the study, nematode egg prevalence was 16% versus 36%, and most infection was light. After at least 2 years of treatment, weight at ages 3·0-6·0 years (standardised to age 4·0 years, 50% male) was 12·72 kg albendazole versus 12·68 kg control (difference 0·04 kg, 95% CI -0·14 to 0·21, p=0·66). Comparing the 36 albendazole-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0-6·0 years during the 5-year study were 3·00 (SE 0·07) albendazole versus 3·16 (SE 0·09) control, difference 0·16 (SE 0·11, mortality ratio 0·95, 95% CI 0·89 to 1·02, p=0·16), suggesting absolute risks of dying between ages 1·0 and 6·0 years of roughly 2·5% albendazole versus 2·6% control. No specific cause of death was significantly affected. INTERPRETATION: Existing ICDS village staff can be organised to deliver simple pre-school interventions sustainably for many years at low cost, but regular deworming had little effect on mortality in this lightly infected pre-school population. FUNDING: UK Medical Research Council, USAID, World Bank (albendazole donated by GlaxoSmithKline).

Performance criteria for verbal autopsy-based systems to estimate national causes of death: development and application to the Indian Million Death Study.

BACKGROUND: Verbal autopsy (VA) has been proposed to determine the cause of death (COD) distributions in settings where most deaths occur without medical attention or certification. We develop performance criteria for VA-based COD systems and apply these to the Registrar General of India's ongoing, nationally-representative Indian Million Death Study (MDS). METHODS: Performance criteria include a low ill-defined proportion of deaths before old age; reproducibility, including consistency of COD distributions with independent resampling; differences in COD distribution of hospital, home, urban or rural deaths; age-, sex- and time-specific plausibility of specific diseases; stability and repeatability of dual physician coding; and the ability of the mortality classification system to capture a wide range of conditions. RESULTS: The introduction of the MDS in India reduced the proportion of ill-defined deaths before age 70 years from 13% to 4%. The cause-specific mortality fractions (CSMFs) at ages 5 to 69 years for independently resampled deaths and the MDS were very similar across 19 disease categories. By contrast, CSMFs at these ages differed between hospital and home deaths and between urban and rural deaths. Thus, reliance mostly on urban or hospital data can distort national estimates of CODs. Age-, sex- and time-specific patterns for various diseases were plausible. Initial physician agreement on COD occurred about two-thirds of the time. The MDS COD classification system was able to capture more eligible records than alternative classification systems. By these metrics, the Indian MDS performs well for deaths prior to age 70 years. The key implication for low- and middle-income countries where medical certification of death remains uncommon is to implement COD surveys that randomly sample all deaths, use simple but high-quality field work with built-in resampling, and use electronic rather than paper systems to expedite field work and coding. CONCLUSIONS: Simple criteria can evaluate the performance of VA-based COD systems. Despite the misclassification of VA, the MDS demonstrates that national surveys of CODs using VA are an order of magnitude better than the limited COD data previously available.