Pneumococcal population genomics changes during the early time period of conjugate vaccine uptake in southern India.

Streptococcus pneumoniae is a major cause of invasive disease of young children in low- and middle-income countries. In southern India, pneumococcal conjugate vaccines (PCVs) that can prevent invasive pneumococcal disease began to be used more frequently after 2015. To characterize pneumococcal evolution during the early time period of PCV uptake in southern India, genomes were sequenced and selected characteristics were determined for 402 invasive isolates collected from children <5 years of age during routine surveillance from 1991 to 2020. Overall, the prevalence and diversity of vaccine type (VT) and non-vaccine type (NVT) isolates did not significantly change post-uptake of PCV. Individually, serotype 1 and global pneumococcal sequence cluster (GPSC or strain lineage) 2 significantly decreased, whereas serotypes 6B, 9V and 19A and GPSCs 1, 6, 10 and 23 significantly increased in proportion post-uptake of PCV. Resistance determinants to penicillin, erythromycin, co-trimoxazole, fluoroquinolones and tetracycline, and multidrug resistance significantly increased in proportion post-uptake of PCV and especially among VT isolates. Co-trimoxazole resistance determinants were common pre- and post-uptake of PCV (85 and 93 %, respectively) and experienced the highest rates of recombination in the genome. Accessory gene frequencies were seen to be changing by small amounts across the frequency spectrum specifically among VT isolates, with the largest changes linked to antimicrobial resistance determinants. In summary, these results indicate that as of 2020 this pneumococcal population was not yet approaching a PCV-induced equilibrium and they highlight changes related to antimicrobial resistance. Augmenting PCV coverage and prudent use of antimicrobials are needed to counter invasive pneumococcal disease in this region.

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries.

BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8-68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7-48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4-34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5-94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7-84·3) compared with those without HIV (61·0%, 51·6-69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF).

Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease: A Diagnostic Accuracy Study for Pediatric Tuberculosis.

INTRODUCTION: An estimated 1.2 million children develop tuberculosis (TB) every year with 240,000 dying because of missed diagnosis. Existing tools suffer from lack of accuracy and are often unavailable. Here, we describe the scientific and clinical methodology applied in RaPaed-TB, a diagnostic accuracy study. METHODS: This prospective diagnostic accuracy study evaluating several candidate tests for TB was set out to recruit 1000 children <15 years with presumptive TB in 5 countries (Malawi, Mozambique, South Africa, Tanzania, India). Assessments at baseline included documentation of TB signs and symptoms, TB history, radiography, tuberculin skin test, HIV testing and spirometry. Respiratory samples for reference standard testing (culture, Xpert Ultra) included sputum (induced/spontaneous) or gastric aspirate, and nasopharyngeal aspirate (if <5 years). For novel tests, blood, urine and stool were collected. All participants were followed up at months 1 and 3, and month 6 if on TB treatment or unwell. The primary endpoint followed NIH-consensus statements on categorization of TB disease status for each participant. The study was approved by the sponsor's and all relevant local ethics committees. DISCUSSION: As a diagnostic accuracy study for a disease with an imperfect reference standard, Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease (RaPaed-TB) was designed following a rigorous and complex methodology. This allows for the determination of diagnostic accuracy of novel assays and combination of testing strategies for optimal care for children, including high-risk groups (ie, very young, malnourished, children living with HIV). Being one of the largest of its kind, RaPaed-TB will inform the development of improved diagnostic approaches to increase case detection in pediatric TB.

Clinical Spectrum of Children With Multisystem Inflammatory Syndrome Associated With SARS-CoV-2 Infection.

OBJECTIVES: To compare the clinical profile, treatment, and outcomes of PCR-positive and PCR-negative antibody-positive critically ill children with multisystem inflammatory syndrome (MIS-C). METHODS: This retrospective observational study was done at a tertiary care coronavirus disease 19 (COVID-19) pediatric intensive care unit in India. The baseline characteristics, clinical profile, treatment, and outcomes in seventeen critically ill children diagnosed with MIS-C were analyzed from 1 July to 31 October, 2020. RESULTS: Sixteen out of 17 children presented with hypotensive shock and respiratory distress. Mean (SD) age of PCR-negative antibody-positive and PCR-positive children was 11 (4.4) and 5 (3.7) years, respectively (P=0.007). The former group had significantly higher mean (SD) D-dimer levels [16,651 (14859) ng/mL vs 3082 (2591) ng/mL; P=0.02]. All received intensive care management and steroid therapy; 7 children received intravenous immunoglobulin. 14 children survived and 3 died. CONCLUSIONS: The outcome of children with MIS-C was good if recognized early and received intensive care.

Ultrasound gel as a source of hospital outbreaks: Indian experience and literature review.

Purpose: Hospital outbreaks are observed increasingly worldwide with various organisms from different sources such as contaminated ultrasound gel, intravenous (IV) fluids and IV medications. Among these, ultrasound gel is one of the most commonly reported sources for Burkholderia cepacia complex (Bcc) outbreaks. In this study, we describe our experience on investigation and the management of Bcc bacteraemia outbreak due to contaminated ultrasound gel from a tertiary care centre, South India. Materials and Methods: Over a 10-day period in October 2016, seven children in our Paediatric intensive care unit (ICU) were found to have bacteraemia with Bcc isolated from their blood culture. Repeated isolation of the same organism with similar antimicrobial susceptibility pattern over a short incubation period from the same location, confirmed the outbreak. An active outbreak investigation, including environmental surveillance, was carried out to find the source and control the outbreak. Isolates were subjected to multi-locus sequence typing (MLST) and global eBURST (goeBURST) analysis. Results: Environmental surveillance revealed contaminated ultrasound gel as the source of infection. MLST and goeBURST analysis confirmed that the outbreak was caused by a novel sequence type 1362 with the same clonal complex CC517. The outbreak was controlled by stringent infection control measures, withdrawal of contaminated ultrasound gel from regular usage and implementing the practice of using ultrasonogram (USG) probe cover for USG screening and guided procedures. Conclusion: This report highlights the importance of early identification of an outbreak, prompt response of the ICU and infection control teams, sound environmental and epidemiological surveillance methods to identify the source and stringent infection control measures to control the outbreak. Contaminated ultrasound gel can be a potential source for healthcare-associated infection, which cannot be overlooked.

A systematic review of antimicrobial resistance of typhoidal Salmonella in India.

Background & objectives: The temporal trends in the development of antimicrobial resistance (AMR) among Salmonella Typhi and Salmonella Paratyphi in India have not been systematically reported. We aimed to systematically review the temporal AMR trends (phenotypic and molecular mechanisms) in bacterial isolates from patients with enteric fever over two decades in India. Methods: To identify trends in AMR in India, resistance patterns among 4611 individual S. Typhi isolates and 800 S. Paratyphi A isolates, reported from 1992 to 2017 in 40 publications, were analysed. Molecular resistance determinants were extracted from 22 publications and also reviewed in accordance with the PRISMA guidelines. Articles were sourced using a predefined search strategy from different databases. Results: The analyses suggested that multidrug-resistant (MDR) enteric fever was declining in India and being replaced by fluoroquinolone (FQ) resistance. Mutations in gyrA and parC were key mechanisms responsible for FQ resistance, whereas MDR was largely driven by resistance determinants encoded on mobile genetic elements (plasmids, transposons). Interpretation & conclusions: The results reflect the effect of antimicrobial pressure which has been driving AMR in typhoidal Salmonella in India. Understanding these trends is important in planning future approaches to therapy, which serve as a baseline for assessment of the impact of new typhoid conjugate vaccines against these resistant organisms.

Clonal similarities and sequence-type diversity of invasive and carriage Streptococcus pneumoniae in India among children under 5 Years.

Background: Pneumococcal pneumonia is one of the major causes of mortality in children less than 5 years in Asia, especially in India. Available PCVs have less serotype coverage in India compared to western countries. Moreover, the baseline pneumococcal serotype and sequence type data is limited and available data doesn't represent the entire India. With this background we aimed to characterize invasive and carriage isolates of S. pneumoniae from a tertiary care hospital in South India. Materials and Methods: A total of 221 S. pneumoniae isolates, invasive (n=138) and carriage (n=83) between the time period of 2012-2018 were included. Isolates was identified and confirmed using standard laboratory protocols. Serotyping was performed by Customized sequential multiplex PCR and MLST as described in www.pubmlst.org. Results: The major serotypes were 19F, 6B, 14, 6A and 19A and the sequence types (ST) were ST63, 236 and 230. Predominant STs in invasive was ST 63 whereas in carriage were ST4894 and 1701. High level ST diversity in carriage was observed. Majority of the STs were SLVs or DLVs of previously reported STs or PMEN clones. Phylogenetic analyses of the STs revealed gradual expansion of three PMEN CCs CC320, 63 and 230. Conclusion: The vaccine serotypes were the predominant ones found to be associated with IPD, PMEN clones, new STs and antimicrobial resistance. Accordingly, PCV13 is expected to provide invasive serotype coverage of 75% in Indian children less than 5 years. This study provides baseline serotype and sequence type data prior to the introduction of PCV in South India.

Immunochromatography in CSF improves data on surveillance of S. pneumoniae meningitis in India.

INTRODUCTION: Streptococcus pneumoniae is a significant cause of childhood bacterial meningitis in India. The United States Food and Drug Administration has licensed an immunochromatographic (ICT) test, Binax®NOW™, to detect the C polysaccharide antigen of S. pneumoniae in cerebrospinal fluids (CSF). Accurate etiological diagnosis of bacterial meningitis in India is essential for effective treatment strategies and preventive interventions. MATERIALS AND METHODS: CSF samples from 2081 children admitted, with clinically suspected bacterial meningitis at 11 sentinel sites of hospital based sentinel surveillance network for bacterial meningitis in India between September 2009 and December 2016 were tested with ICT. Concurrent CSF cultures were processed using standard procedures. RESULTS AND DISCUSSION: S. pneumoniae was detected thrice the number of times by ICT than by CSF culture, with a sensitivity and specificity of 100% and 95.3% respectively. This rapid ICT test proves to be of immense use as a diagnostic test for meningitis patients with/without prior antibiotic treatment, especially in facilities with limited laboratory infrastructure in resource limited settings.

Early Childhood Neurodevelopmental Outcomes in Infants Exposed to Infectious Syphilis In Utero.

BACKGROUND: There are minimal neurodevelopmental follow-up data for infants exposed to syphilis in utero. METHODS: This is an inception cohort study of infants exposed to syphilis in utero. We reviewed women with reactive syphilis serology in pregnancy or at delivery in Edmonton (Canada), 2002 through 2010 and describe the neurodevelopmental outcomes of children with and without congenital syphilis. RESULTS: There were 39 births to women with reactive syphilis serology, 9 of whom had late latent syphilis (n = 4), stillbirths (n = 2) or early neonatal deaths (n = 3), leaving 30 survivors of which 11 with and 7 without congenital syphilis had neurodevelopmental assessment. Those with congenital syphilis were all born to women with inadequate syphilis treatment before delivery. Neurodevelopmental impairment was documented in 3 of 11 (27%) infants with congenital syphilis and one of 7 (14%) without congenital syphilis with speech language delays in 4 of 11 (36%) with congenital syphilis and 3 of 7 (42%) without congenital syphilis. CONCLUSIONS: Infants born to mothers with reactive syphilis serology during pregnancy are at high risk for neurodevelopmental impairment, whether or not they have congenital syphilis, so should all be offered neurodevelopmental assessments and early referral for services as required.

Extremely High Mortality Rates in Patients with Carbapenem-resistant, Hypermucoviscous Klebsiella pneumoniae Blood Stream Infections.

BACKGROUND: Infections caused by carbapenem resistant K. pneumoniae are increasing and associated with high mortality rates. There are increasing reports of hypermucoviscous/ hypervirulent K. pneumoniae isolated from various sources. However, there is limited data on the prevalence of hypermucoviscous strains among carbapenem-resistant K. pneumoniae from invasive infections in India and its association with mortality. rmpA, rmpA2 and magA genes are associated with these hypervirulent strains. In this study, we investigate the prevalence of hypermucoviscous strains amongst carbapenem resistant K. pneumoniae isolated from blood culture. Association of mortality rate with meropenem minimum inhibitory concentration and hypermucoviscous strains are determined. METHODS: 86 non-repetitive carbapenem resistant K. pneumoniae isolated from bacteremia underwent E-test for meropenem minimum inhibitory concentration (MIC) determination and PCR for detection of carbapenamase genes. String test, PCR for rmpA, rmpA2 and magA were performed for characterisation of hypervirulent strains. Results: 31.3% of the 86 isolates displayed hypermucoviscous phenotype as indicated by a positive string test. Among the two genotypic markers, 7% were positive for rmpA2 and all were negative for rmpA and magA. 74.1% and 67.9% mortality were seen among string test positives and isolates meropenem MIC of ≥16µg/ml respectively (p 0.036 and 0.008 respectively). Isolates with both string positivity and meropenem MIC of ≥16µg/ml had a very high mortality rate of 84.2%. CONCLUSION: String test, aids prediction of disease severity, and is independently associated with increased mortality in invasive carbapenem resistant K.pneumoniae health care-acquired infections. High meropenem MIC is a significant risk factor for mortality. Combination of string positive carbapenem resistant hypermucoviscous K. pneumoniae resulted in mortality rate of 84.2%. It is important to monitor prevalence of carbapenem resistant hypermucoviscous/hypervirulent K. pneumoniae among invasive isolates especially in a setting with high resistance rates as combination of increased virulence and decreased susceptibility to antimicrobials results in worse outcomes.

Clinical and Bacterial Risk Factors for Mortality in Children With Carbapenem-resistant Enterobacteriaceae Bloodstream Infections in India.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are an increasing cause of nosocomial infection in hospitalized children worldwide. Few studies have investigated risk factors for mortality in children with CRE bloodstream infection (BSI). Data are particularly scarce in areas where NDM and OXA carbapenemases predominate. Here, we investigate mortality rates, clinical and microbiologic risk factors for mortality in 50 pediatric patients with CRE BSI in India. METHODS: Children younger than 17 years old with meropenem-resistant Klebsiella pneumoniae or Escherichia coli isolated from blood culture in 2014 and 2015 were identified from laboratory records. Clinical records were systematically reviewed for each child to establish mortality at 30 days and clinical details. Bacterial isolates were subjected to meropenem E test and multiplex polymerase chain reaction to determine carbapenemase gene. Data were analyzed to establish clinical and bacterial risk factors for mortality. RESULTS: All CRE BSI were hospital-acquired or associated with healthcare. A total of 84% of children had an underlying comorbidity and 46% had a malignancy. K. pneumoniae was the most common bacteria isolated; NDM was the most common carbapenemase gene detected. The mortality rate was 52%. Significant risk factors for mortality included intensive care admission, intubation, inotropic support and respiratory source. Failure to clear bacteremia and a minimum inhibitory concentration > 8 mg/L for the isolate was associated with a statistically significant increase in mortality. Mortality rates were significantly lower when two or more effective drugs were used in combination. CONCLUSIONS: CRE BSI affects children with multiple comorbidities and repeated admissions to hospital. The mortality rate is high; combination therapy may be beneficial.

Estimation of the burden of pandemic(H1N1)2009 in developing countries: experience from a tertiary care center in South India.

BACKGROUND: The burden of the pandemic (H1N1) 2009 influenza might be underestimated if detection of the virus is mandated to diagnose infection. Using an alternate approach, we propose that a much higher pandemic burden was experienced in our institution. METHODOLOGY/PRINCIPAL FINDINGS: Consecutive patients (n = 2588) presenting to our hospital with influenza like illness (ILI) or severe acute respiratory infection (SARI) during a 1-year period (May 2009-April 2010) were prospectively recruited and tested for influenza A by real-time RT-PCR. Analysis of weekly trends showed an 11-fold increase in patients presenting with ILI/SARI during the peak pandemic period when compared with the pre-pandemic period and a significant (P<0.001) increase in SARI admissions during the pandemic period (30 ± 15.9 admissions/week) when compared with pre-pandemic (7 ± 2.5) and post-pandemic periods (5 ± 3.8). However, Influenza A was detected in less than one-third of patients with ILI/SARI [699 (27.0%)]; a majority of these (557/699, 79.7%) were Pandemic (H1N1)2009 virus [A/H1N1/09]. An A/H1N1/09 positive test was correlated with shorter symptom duration prior to presentation (p = 0.03). More ILI cases tested positive for A/H1N1/09 when compared with SARI (27.4% vs. 14.6%, P = 0.037). When the entire study population was considered, A/H1N1/09 positivity was associated with lower risk of hospitalization (p<0.0001) and ICU admission (p = 0.013) suggesting mild self-limiting illness in a majority. CONCLUSION/SIGNIFICANCE: Analysis of weekly trends of ILI/SARI suggest a higher burden of the pandemic attributable to A/H1N1/09 than estimates assessed by a positive PCR test alone. The study highlights methodological consideration in the estimation of burden of pandemic influenza in developing countries using hospital-based data that may help assess the impact of future outbreaks of respiratory illnesses.

Immunogenicity, safety, and reactogenicity of the 10-valent pneumococcal non-typeable Hemophilus influenzae protein D conjugate vaccine (PHiD-CV) when co-administered with the DTPw-HBV/Hib vaccine in Indian infants: a single-blind, randomized, controlled study.

In India, pneumococcal diseases are major causes of child mortality, and effective vaccines against Streptococcus pneumoniae are needed. This single-blind, randomized study assessed the immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Hemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) co-administered with DTPw-HBV/Hib in Indian infants as 3-dose primary vaccination course. A total of 360 infants were randomized (2:1) to receive either PHiD-CV co-administered with DTPw-HBV/Hib (PHiD-CV group) or a Hib vaccine co-administered with DTPw-HBV (control group) at 6, 10, and 14 weeks of age. For each vaccine pneumococcal serotype, the percentage of infants in the PHiD-CV group with antibody concentrations ≥ 0.2 µg/mL one month after the third vaccine dose was at least 98.3%, except for serotypes 6B (77.7%) and 23F (89.5%), and opsonophagocytic activity titers ≥ 8 were measured in at least 95.7% of infants, except for serotypes 1 (90.5%) and 6B (84.5%). In addition, all the infants in the PHiD-CV group were seroprotected against diphtheria, tetanus, Hib, and hepatitis B or seropositive for antibodies against pertussis and NTHi protein D (except one infant). Incidences of solicited local and general symptoms were comparable between groups, except for fever (axillary temperature ≥ 37.5°C), which seemed to occur more frequently in the PHiD-CV group. In conclusion, PHiD-CV was shown to be immunogenic and well-tolerated when co-administered with DTPw-HBV/Hib in Indian infants.

Immunogenicity of a single dose of tetravalent meningococcal serogroups A, C, W-135, and Y conjugate vaccine administered to 2- to 10-year-olds is noninferior to a licensed-ACWY polysaccharide vaccine with an acceptable safety profile.

BACKGROUND: Meningococcal disease remains an important cause of invasive bacterial infections in children less than 5 years of age. Immunogenicity and safety of the investigational ACWY vaccine conjugated with tetanus toxoid (ACWY-TT, GlaxoSmithKline Biologicals) were evaluated in 1501 healthy 2- to 10-year-old children in the Philippines, India, Lebanon, and Saudi Arabia. METHODS: Children were randomized (3:1) to receive ACWY-TT or licensed tetravalent meningococcal polysaccharide vaccine (Mencevax, GlaxoSmithKline, Men-PS). Diary cards were used to collect solicited symptoms for 4 days after vaccination. Serious adverse events were reported for 6 months. Serum bactericidal activity (rSBA, rabbit complement) was measured before and 1 month after vaccination in the first 75% of subjects enrolled in each country. RESULTS: The statistical criteria for noninferiority in terms of rSBA vaccine responses were reached. Exploratory analyses showed that postvaccination rSBA titers ≥ 1:8 and ≥ 1:128 were significantly higher after ACWY-TT than Men-PS for serogroups C, W-135, and Y, and rSBA vaccine responses and geometric mean antibody titers were significantly higher for all 4 serogroups after administration of ACWY-TT. Noninferiority in terms of incidences of grade 3 general symptoms was not demonstrated. ACWY-TT was well tolerated with grade 3 events reported in <1% of subjects per group. No serious adverse events were considered related to vaccination. CONCLUSION: ACWY-TT was immunogenic in children between 2 to 10 years of age with a clinically acceptable safety profile that resembled licensed Men-PS. These data support a positive benefit/risk ratio for the ACWY-TT vaccine.

Chronic growth faltering amongst a birth cohort of Indian children begins prior to weaning and is highly prevalent at three years of age.

BACKGROUND: Poor growth of children in developing countries is a major public health problem associated with mortality, morbidity and developmental delay. We describe growth up to three years of age and investigate factors related to stunting (low height-for-age) at three years of age in a birth cohort from an urban slum. METHODS: 452 children born between March 2002 and August 2003 were followed until their third birthday in three neighbouring slums in Vellore, South India. Field workers visited homes to collect details of morbidity twice a week. Height and weight were measured monthly from one month of age in a study-run clinic. For analysis, standardised z-scores were generated using the 2006 WHO child growth standards. Risk factors for stunting at three years of age were analysed in logistic regression models. A sensitivity analysis was conducted to examine the effect of missing values. RESULTS: At age three years, of 186 boys and 187 girls still under follow-up, 109 (66%, 95% Confidence interval 58-73%) boys and 93 (56%, 95% CI 49-64%) girls were stunted, 14 (8%, 95% CI 4-13%) boys and 12 (7%, 95% CI 3-11%) girls were wasted (low weight-for-height) and 72 (43%, 95% CI 36-51) boys and 66 (39%, 95% CI 31-47%) girls were underweight (low weight-for-age). In total 224/331 (68%) children at three years had at least one growth deficiency (were stunted and/or underweight and/or wasted); even as early as one month of age 186/377 (49%) children had at least one growth deficiency. Factors associated with stunting at three years were birth weight less than 2.5 kg (OR 3.63, 95% CI 1.36-9.70) 'beedi-making' (manual production of cigarettes for a daily wage) in the household (OR 1.74, 95% CI 1.05-2.86), maternal height less than 150 cm (OR 2.02, 95% CI 1.12-3.62), being stunted, wasted or underweight at six months of age (OR 1.75, 95% CI 1.05-2.93) and having at least one older sibling (OR 2.00, 95% CI 1.14-3.51). CONCLUSION: A high proportion of urban slum dwelling children had poor growth throughout the first three years of life. Interventions are needed urgently during pregnancy, early breastfeeding and weaning in this population.

Does 3-day course of oral amoxycillin benefit children of non-severe pneumonia with wheeze: a multicentric randomised controlled trial.

BACKGROUND: WHO-defined pneumonias, treated with antibiotics, are responsible for a significant proportion of childhood morbidity and mortality in the developing countries. Since substantial proportion pneumonias have a viral etiology, where children are more likely to present with wheeze, there is a concern that currently antibiotics are being over-prescribed for it. Hence the current trial was conducted with the objective to show the therapeutic equivalence of two treatments (placebo and amoxycillin) for children presenting with non-severe pneumonia with wheeze, who have persistent fast breathing after nebulisation with salbutamol, and have normal chest radiograph. METHODOLOGY: This multi-centric, randomised placebo controlled double blind clinical trial intended to investigate equivalent efficacy of placebo and amoxicillin and was conducted in ambulatory care settings in eight government hospitals in India. Participants were children aged 2-59 months of age, who received either oral amoxycillin (31-54 mg/Kg/day, in three divided doses for three days) or placebo, and standard bronchodilator therapy. Primary outcome was clinical failure on or before day- 4. PRINCIPAL FINDINGS: We randomized 836 cases in placebo and 835 in amoxycillin group. Clinical failures occurred in 201 (24.0%) on placebo and 166 (19.9%) on amoxycillin (risk difference 4.2% in favour of antibiotic, 95% CI: 0.2 to 8.1). Adherence for both placebo and amoxycillin was >96% and 98.9% subjects were followed up on day- 4. Clinical failure was associated with (i) placebo treatment (adjusted OR = 1.28, 95% CI: 1.01 to1.62), (ii) excess respiratory rate of >10 breaths per minute (adjusted OR = 1.51, 95% CI: 1.19, 1.92), (iii) vomiting at enrolment (adjusted OR = 1.49, 95% CI: 1.13, 1.96), (iv) history of use of broncho-dilators (adjusted OR = 1.71, 95% CI: 1.30, 2.24) and (v) non-adherence (adjusted OR = 8.06, 95% CI: 4.36, 14.92). CONCLUSIONS: Treating children with non-severe pneumonia and wheeze with a placebo is not equivalent to treatment with oral amoxycillin. TRIAL REGISTRATION: ClinicalTrials.gov NCT00407394.