Project description:BackgroundPneumonia is a leading cause of mortality in children <5 years globally. Early identification of hospitalized children with pneumonia who may fail antibiotics could improve outcomes. We conducted a secondary analysis from the Malawi CPAP IMPACT trial evaluating risk factors for antibiotic failure among children hospitalized with pneumonia.MethodsParticipants were 1-59 months old with World Health Organization-defined severe pneumonia and hypoxemia, severe malnutrition, and/or HIV exposure/infection. All participants received intravenous antibiotics per standard care. First-line antibiotics were benzylpenicillin and gentamicin for five days. Study staff assessed patients for first-line antibiotic failure daily between days 3-6. When identified, patients failing antibiotics were switched to second-line ceftriaxone. Analyses excluded children receiving ceftriaxone and/or deceased by hospital day two. We compared characteristics between patients with and without treatment failure and fit multivariable logistic regression models to evaluate associations between treatment failure and admission characteristics.ResultsFrom June 2015-March 2018, 644 children were enrolled and 538 analyzed. Antibiotic failure was identified in 251 (46.7%) participants, and 19/251 (7.6%) died. Treatment failure occurred more frequently with severe malnutrition (50.2% (126/251) vs 28.2% (81/287), p<0.001) and amongst those dwelling ≥10km from a health facility (22.3% (56/251) vs 15.3% (44/287), p = 0.026). Severe malnutrition occurred more frequently among children living ≥10km from a health facility than those living <10km (49.0% (49/100) vs 35.7% (275/428), p = 0.014). Children with severe malnutrition (adjusted odds ratio (aOR) 2.2 (95% CI 1.52, 3.24), p<0.001) and pre-hospital antibiotics ((aOR 1.47, 95% CI 1.01, 2.14), p = 0.043) had an elevated aOR for antibiotic treatment failure.ConclusionSevere malnutrition and pre-hospital antibiotic use predicted antibiotic treatment failure in this high-risk severe pneumonia pediatric population in Malawi. Our findings suggest addressing complex sociomedical conditions like severe malnutrition and improving pneumonia etiology diagnostics will be key for better targeting interventions to improve childhood pneumonia outcomes.

Project description:Pneumonia is the leading cause of child mortality under five years of age worldwide. For pneumonia with chest indrawing in children aged 3-59 months, injectable penicillin and hospitalization was the recommended treatment. This increased the health care cost and exposure to nosocomial infections. We compared the clinical and cost outcomes of a seven day treatment with oral amoxicillin with the first 48 h of treatment given in the hospital (hospital group) or at home (home group).We conducted an open-label, multi-center, two-arm randomized clinical trial at six tertiary hospitals in India. Children aged 3 to 59 months with chest indrawing pneumonia were randomized to home or hospital group. Clinical outcomes, treatment adherence, and patient safety were monitored through home visits on day 3, 5, 8, and 14 with an additional visit for the home group at 24 h. Clinical outcomes included treatment failure rates up to 7 days (primary outcome) and between 8-14 days (secondary outcome) using the intention to treat and per protocol analyses. Cost outcomes included direct medical, direct non-medical and indirect costs for a random 17% subsample using the micro-costing technique.1118 children were enrolled and randomized to home (n = 554) or hospital group (n = 564). Both groups had similar baseline characteristics. Overall treatment failure rate was 11.5% (per protocol analysis). The hospital group was significantly more likely to fail treatment than the home group in the intention to treat analysis. Predictors with increased risk of treatment failure at any time were age 3-11 months, receiving antibiotics within 48 h prior to enrolment and use of high polluting fuel. Death rates at 7 or 14 days did not differ significantly. (Difference -0.0%; 95% CI -0.5 to 0.5). The median total treatment cost was Rs. 399 for the home group versus Rs. 602 for the hospital group (p < 0.001), for the same effect of 5% failure rate at the end of 7 days of treatment in the random subsample.Home based oral amoxicillin treatment was equivalent to hospital treatment for first 48 h in selected children of chest indrawing pneumonia and was cheaper. Consistent with the recent WHO simplified guidelines, management with home based oral amoxicillin for select children with only fast breathing and chest-indrawing can be a cost effective intervention.ClinicalTrials.gov NCT01386840, registered 25th June 2011 and the Indian Council of Medical Research REFCTRI/2010/000629.

Project description:BackgroundPneumonia is a leading cause of morbidity and mortality in children younger than five years of age. Most deaths occur during infancy and in low-income countries. Daily zinc supplements have been reported to prevent acute lower respiratory tract infection (LRTI) and reduce child mortality. This is an update of a review first published in 2010.ObjectivesTo evaluate the effectiveness of zinc supplementation in the prevention of pneumonia in children aged two to 59 months.Search methodsWe searched CENTRAL (Issue 21 October 2016), MEDLINE (1966 to October 2016), Embase (1974 to October 2016), LILACS (1982 to October 2016), CINAHL (1981 to October 2016), Web of Science (1985 to October 2016) and IMSEAR (1980 to October 2016).Selection criteriaRandomised controlled trials (RCTs) evaluating zinc supplementation for the prevention of pneumonia in children aged from 2 months to 59 months.Data collection and analysisTwo review authors independently assessed trial quality and extracted data.Main resultsWe did not identify any new studies for inclusion in this update. We included six studies that involved 5193 participants.Analysis showed that zinc supplementation reduced the incidence of pneumonia by 13% (fixed-effect risk ratio (RR) 0.87; 95% confidence interval (CI) 0.81 to 0.94, six studies, low-quality evidence) and prevalence of pneumonia by 41% (random-effects RR 0.59; 95% CI 0.35 to 0.99, one study, n = 609, low-quality evidence). On subgroup analysis, we found that zinc reduced the incidence of pneumonia defined by specific clinical criteria by 21% (i.e. confirmation by chest examination or chest radiograph) (fixed-effect RR 0.79; 95% CI 0.0.71 to 0.88, four studies, n = 3261), but had no effect on lower specificity pneumonia case definition (i.e. age-specific fast breathing with or without lower chest indrawing) (fixed-effect RR 0.95; 95% CI 0.86 to 1.06, four studies, n = 1932).Authors' conclusionsZinc supplementation in children is associated with a reduction in the incidence and prevalence of pneumonia.

Project description:BackgroundPneumonia causes about 0.9 million deaths worldwide each year. The World Health Organization (WHO) guidelines for the standard management of severe pneumonia requires parenteral ampicillin every 6 hours and once-daily parenteral gentamicin for 5 to 7 days. Although this treatment has contributed to the reduction of mortality, it requires nursing interventions every 6 hours for 7 days. Further intervention trials should be conducted to search for alternate antibiotics with better adherence, reduced cost, and reduced hospital stay. Parenteral amoxicillin is an effective alternative to ampicillin, as it has a longer half-life and broader coverage.ObjectiveThe aim of this clinical trial is to compare the efficacy of a dose of injectable amoxicillin every 12 hours plus a once-daily dose of injectable gentamicin with a dose of injectable ampicillin every 6 hours plus a once-daily dose of injectable gentamicin in children hospitalized for severe pneumonia.MethodsThis randomized, controlled, open-label, noninferiority trial is being conducted in Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh. A sample size of 308 children with severe pneumonia will give adequate power to this study. Children aged 2 to 59 months are randomized to either intravenous ampicillin or intravenous amoxicillin, plus intravenous gentamicin in both study arms. The monitoring of the patients is carried out according to the WHO protocol for the treatment of severe pneumonia. The primary objective is the rate of treatment failure, defined by the persistence of danger signs of severe pneumonia beyond 48 hours or deterioration within 24 hours of initiation of the therapy. The secondary objectives are (1) improvement in or the resolution of danger signs since enrollment, (2) length of hospital stay, (3) death during hospitalization, and (4) rate of nosocomial infections.ResultsEnrollment in the study started on January 1, 2018, and ended on October 31, 2019. Data entry and analysis are in progress. Findings from the study are expected to be disseminated in October 2020.ConclusionsOur study's findings will improve compliance with the use of antibiotics that require less frequent doses for the treatment of severe pneumonia.Trial registrationClinicalTrials.gov NCT03369093; https://clinicaltrials.gov/ct2/show/NCT03369093.International registered report identifier (irrid)DERR1-10.2196/17735.

Project description:BackgroundFirst dose oral co-trimoxazole and referral are recommended for WHO-defined severe pneumonia. Difficulties with referral compliance are reported in many low-resource settings, resulting in low access to appropriate treatment. The objective in this study was to assess whether community case management by lady health workers (LHWs) with oral amoxicillin in children with severe pneumonia was equivalent to current standard of care.MethodsIn Haripur district, Pakistan, 28 clusters were randomly assigned with stratification in a 1:1 ratio to intervention and control clusters by use of a computer-generated randomisation sequence. Children were included in the study if they were aged 2-59 months with WHO-defined severe pneumonia and living in the study area. In the intervention clusters, community-based LHWs provided mothers with oral amoxicillin (80-90 mg/kg per day or 375 mg twice a day for infants aged 2-11 months and 625 mg twice a day for those aged 12-59 months) with specific guidance on its use. In control clusters, LHWs gave the first dose of oral co-trimoxazole (age 2-11 months, sulfamethoxazole 200 mg plus trimethoprim 40 mg; age 12 months to 5 years, sulfamethoxazole 300 mg plus trimethoprim 60 mg) and referred the children to a health facility for standard of care. Participants, carers, and assessors were not masked to treatment assignment. The primary outcome was treatment failure by day 6. Analysis was per protocol with adjustment for clustering within groups by use of generalised estimating equations. This study is registered, number ISRCTN10618300.FindingsWe assigned 1995 children to treatment in 14 intervention clusters and 1477 in 14 control clusters, and we analysed 1857 and 1354 children, respectively. Cluster-adjusted treatment failure rates by day 6 were significantly reduced in the intervention clusters (165 [9%] vs 241 [18%], risk difference -8·9%, 95% CI -12·4 to -5·4). Further adjustment for baseline covariates made little difference (-7·3%, -10·1 to -4·5). Two deaths were reported in the control clusters and one in the intervention cluster. Most of the risk reduction was in the occurrence of fever and lower chest indrawing on day 3 (-6·7%, -10·0 to -3·3). Adverse events were diarrhoea (n=4) and skin rash (n=1) in the intervention clusters and diarrhoea (n=3) in the control clusters.InterpretationCommunity case management could result in a standardised treatment for children with severe pneumonia, reduce delay in treatment initiation, and reduce the costs for families and health-care systems.FundingUnited States Agency for International Development (USAID).

Project description:BackgroundDespite the fact that a large proportion of children with fever in Africa present at primary health care facilities, few studies have been designed to specifically study the causes of uncomplicated childhood febrile illness at this level of care, especially in areas like Zanzibar that has recently undergone a dramatic change from high to low malaria transmission.MethodsWe prospectively studied the aetiology of febrile illness in 677 children aged 2-59 months with acute uncomplicated fever managed by IMCI (Integrated Management of Childhood Illness) guidelines in Zanzibar, using point-of-care tests, urine culture, blood-PCR, chest X-ray (CXR) of IMCI-pneumonia classified patients, and multiple quantitative (q)PCR investigations of nasopharyngeal (NPH) (all patients) and rectal (GE) swabs (diarrhoea patients). For comparison, we also performed NPH and GE qPCR analyses in 167 healthy community controls. Final fever diagnoses were retrospectively established based on all clinical and laboratory data. Clinical outcome was assessed during a 14-day follow-up. The utility of IMCI for identifying infections presumed to require antibiotics was evaluated.FindingsNPH-qPCR and GE-qPCR detected ≥1 pathogen in 657/672 (98%) and 153/164 (93%) of patients and 158/166 (95%) and 144/165 (87%) of controls, respectively. Overall, 57% (387/677) had IMCI-pneumonia, but only 12% (42/342) had CXR-confirmed pneumonia. Two patients were positive for Plasmodium falciparum. Respiratory syncytial virus (24.5%), influenza A/B (22.3%), rhinovirus (10.5%) and group-A streptococci (6.4%), CXR-confirmed pneumonia (6.2%), Shigella (4.3%) were the most common viral and bacterial fever diagnoses, respectively. Blood-PCR conducted in a sub-group of patients (n = 83) without defined fever diagnosis was negative for rickettsiae, chikungunya, dengue, Rift Valley fever and West Nile viruses. Antibiotics were prescribed to 500 (74%) patients, but only 152 (22%) had an infection retrospectively considered to require antibiotics. Clinical outcome was generally good. However, two children died. Only 68 (11%) patients remained febrile on day 3 and three of them had verified fever on day 14. An additional 29 (4.5%) children had fever relapse on day 14. Regression analysis determined C-reactive Protein (CRP) as the only independent variable significantly associated with CXR-confirmed pneumonia.ConclusionsThis is the first study on uncomplicated febrile illness in African children that both applied a comprehensive laboratory panel and a healthy control group. A majority of patients had viral respiratory tract infection. Pathogens were frequently detected by qPCR also in asymptomatic children, demonstrating the importance of incorporating controls in fever aetiology studies. The precision of IMCI for identifying infections requiring antibiotics was low.

Project description:BackgroundDue to increasing antimicrobial resistance in low-resource settings, strategies to rationalize antibiotic treatment of children unlikely to have a bacterial infection are needed. This study's objective was to utilize a database of placebo treated Malawian children with World Health Organization (WHO) fast breathing pneumonia to develop a prognostic risk score that could aid antibiotic decision making.MethodsWe conducted a secondary analysis of children randomized to the placebo group of the Innovative Treatments in Pneumonia (ITIP) fast breathing randomized, controlled, noninferiority trial. Participants were low-risk HIV-uninfected children 2-59 months old with WHO fast breathing pneumonia in Lilongwe, Malawi. Study endpoints were treatment failure, defined as either disease progression at any time on or before Day 4 of treatment or disease persistence on Day 4, or relapse, considered as the recurrence of pneumonia or severe disease among previously cured children between Days 5 and 14. We utilized multivariable linear regression and stepwise model selection to develop a model to predict the probability of treatment failure or relapse.ResultsTreatment failure or relapse occurred in 11.5% (61/526) of children included in this analysis. The final model incorporated the following predictors: heart rate terms, mid-upper arm circumference, malaria status, water source, family income, and whether or not a sibling or other child in the household received childcare outside the home. The model's area under the receiver operating characteristic score was 0.712 (95% confidence interval 0.66, 0.78) and it explained 6.1% of the variability in predicting treatment failure or relapse (R2, 0.061). For the model to categorize all children with treatment failure or relapse correctly, 77% of children without treatment failure or relapse would require antibiotics.ConclusionThe model had inadequate discrimination to be appropriate for clinical application. Different strategies will likely be required for models to perform accurately among similar pediatric populations.

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Antibiotic therapy versus no antibiotic therapy for children aged 2 to 59 months with WHO-defined non-severe pneumonia and wheeze.

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