Shamim Qazi

Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis.

Summary Background The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. Methods We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. Findings We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3–13·9 million) episodes of severe and 3·0 million (2·1–4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265 000 (95% CI 160 000–450 000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. Interpretation Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. Funding WHO.

Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries

Background The recent series of reviews conducted within the Global Action Plan for Pneumonia and Diarrhoea (GAPPD) addressed epidemiology of the two deadly diseases at the global and regional level; it also estimated the effectiveness of interventions, barriers to achieving high coverage and the main implications for health policy. The aim of this paper is to provide the estimates of childhood pneumonia at the country level. This should allow national policy–makers and stakeholders to implement proposed policies in the World Health Organization (WHO) and UNICEF member countries. Methods We conducted a series of systematic reviews to update previous estimates of the global, regional and national burden of childhood pneumonia incidence, severe morbidity, mortality, risk factors and specific contributions of the most common pathogens: Streptococcus pneumoniae (SP), Haemophilus influenzae type B (Hib), respiratory syncytial virus (RSV) and influenza virus (flu). We distributed the global and regional–level estimates of the number of cases, severe cases and deaths from childhood pneumonia in 2010–2011 by specific countries using an epidemiological model. The model was based on the prevalence of the five main risk factors for childhood pneumonia within countries (malnutrition, low birth weight, non–exclusive breastfeeding in the first four months, solid fuel use and crowding) and risk effect sizes estimated using meta–analysis. Findings The incidence of community–acquired childhood pneumonia in low– and middle–income countries (LMIC) in the year 2010, using World Health Organizations definition, was about 0.22 (interquartile range (IQR) 0.11–0.51) episodes per child–year (e/cy), with 11.5% (IQR 8.0–33.0%) of cases progressing to severe episodes. This is a reduction of nearly 25% over the past decade, which is consistent with observed reductions in the prevalence of risk factors for pneumonia throughout LMIC. At the level of pneumonia incidence, RSV is the most common pathogen, present in about 29% of all episodes, followed by influenza (17%). The contribution of different pathogens varies by pneumonia severity strata, with viral etiologies becoming relatively less important and most deaths in 2010 caused by the main bacterial agents – SP (33%) and Hib (16%), accounting for vaccine use against these two pathogens. Conclusions In comparison to 2000, the primary epidemiological evidence contributing to the models of childhood pneumonia burden has improved only slightly; all estimates have wide uncertainty bounds. Still, there is evidence of a decreasing trend for all measures of the burden over the period 2000–2010. The estimates of pneumonia incidence, severe morbidity, mortality and etiology, although each derived from different and independent data, are internally consistent – lending credibility to the new set of estimates. Pneumonia continues to be the leading cause of both morbidity and mortality for young children beyond the neonatal period and requires ongoing strategies and progress to reduce the burden further.

Oral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study*

BACKGROUND Injectable penicillin is the recommended treatment for WHO-defined severe pneumonia (lower chest indrawing). If oral amoxicillin proves equally effective, it could reduce referral, admission, and treatment costs. We aimed to determine whether oral amoxicillin and parenteral penicillin were equivalent in the treatment of severe pneumonia in children aged 3-59 months. METHODS This multicentre, randomised, open-label equivalency study was undertaken at tertiary-care centres in eight developing countries in Africa, Asia, and South America. Children aged 3-59 months with severe pneumonia were admitted for 48 h and, if symptoms improved, were discharged with a 5-day course of oral amoxicillin. 1702 children were randomly allocated to receive either oral amoxicillin (n=857) or parenteral penicillin (n=845) for 48 h. Follow-up assessments were done at 5 and 14 days after enrollment. Primary outcome was treatment failure (persistence of lower chest indrawing or new danger signs) at 48 h. Analyses were by intention-to-treat and per protocol. FINDINGS Treatment failure was 19% in each group (161 patients, pencillin; 167 amoxillin; risk difference -0.4%; 95% CI -4.2 to 3.3) at 48 h. Infancy (age 3-11 months; odds ratio 2.72, 95% CI 1.95 to 3.79), very fast breathing (1.94, 1.42 to 2.65), and hypoxia (1.95, 1.34 to 2.82) at baseline predicted treatment failure by multivariate analysis. INTERPRETATION Injectable penicillin and oral amoxicillin are equivalent for severe pneumonia treatment in controlled settings. Potential benefits of oral treatment include decreases in (1) risk of needle-borne infections; (2) need for referral or admission; (3) administration costs; and (4) costs to the family.

Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trial

BACKGROUND WHO case management guidelines for severe pneumonia involve referral to hospital for treatment with parenteral antibiotics. If equally as effective as parenteral treatment, home-based oral antibiotic treatment could reduce referral, admission, and treatment costs. Our aim was to determine whether home treatment with high-dose oral amoxicillin and inpatient treatment with parenteral ampicillin were equivalent for the treatment of severe pneumonia in children. METHODS This randomised, open-label equivalency trial was done at seven study sites in Pakistan. 2037 children aged 3-59 months with severe pneumonia were randomly allocated to either initial hospitalisation and parenteral ampicillin (100 mg/kg per day in four doses) for 48 h, followed by 3 days of oral amoxicillin (80-90 mg/kg per day; n=1012) or to home-based treatment for 5 days with oral amoxicillin (80-90 mg/kg per day in two doses; n=1025). Follow-up assessments were done at 1, 3, 6, and 14 days after enrollment. The primary outcome was treatment failure (clinical deterioration) by day 6. Analyses were done per protocol and by intention to treat. This trial is registered, ISRCTN95821329. FINDINGS In the per-protocol population, 36 individuals were excluded from the hospitalised group and 37 from the ambulatory group, mainly because of protocol violations or loss to follow-up. There were 87 (8.6%) treatment failures in the hospitalised group and 77 (7.5%) in the ambulatory group (risk difference 1.1%; 95% CI -1.3 to 3.5) by day 6. Five (0.2%) children died within 14 days of enrollment, one in the ambulatory group and four in the hospitalised group. In each case, treatment failure was declared before death and the antibiotic had been changed. None of the deaths were considered to be associated with treatment allocation; there were no serious adverse events reported in the trial. INTERPRETATION Home treatment with high-dose oral amoxicillin is equivalent to currently recommended hospitalisation and parenteral ampicillin for treatment of severe pneumonia without underlying complications, suggesting that WHO recommendations for treatment of severe pneumonia need to be revised.

Community case management of pneumonia: at a tipping point?

Pneumonia is the leading cause of child mortality globally. Community case management (CCM) of pneumonia by community health workers is a feasible, effective strategy to complement facility-based management for areas that lack access to facilities. We surveyed experts in the 57 African and Asian countries with the highest levels and rates of childhood mortality to assess current policies, implementation and plans regarding CCM of pneumonia. About one-third (20/54) of countries reported policies supporting CCM for pneumonia, and another third (18/54) reported no policy against the strategy. Half (27/54) the countries reported some implementation of CCM for pneumonia, but often on a small scale. A few countries sustain a large-scale programme. Programmes, community health workers and policy parameters varied greatly among implementing countries. About half (12/26) of non-implementing countries are planning to move ahead with the strategy. Momentum is gathering for CCM for pneumonia as a strategy to address the pneumonia treatment gap and help achieve Millennium Development Goal 4. Challenges remain to: (1) introduce this strategy into policy and implement it in high pneumonia burden countries; (2) increase coverage of this strategy in countries currently implementing it; and (3) better define and monitor implementation at the country level.

Count every newborn; A measurement improvement roadmap for coverage data

BackgroundThe Every Newborn Action Plan (ENAP), launched in 2014, aims to end preventable newborn deaths and stillbirths, with national targets of ≤12 neonatal deaths per 1000 live births and ≤12 stillbirths per 1000 total births by 2030. This requires ambitious improvement of the data on care at birth and of small and sick newborns, particularly to track coverage, quality and equity.MethodsIn a multistage process, a matrix of 70 indicators were assessed by the Every Newborn steering group. Indicators were graded based on their availability and importance to ENAP, resulting in 10 core and 10 additional indicators. A consultation process was undertaken to assess the status of each ENAP core indicator definition, data availability and measurement feasibility. Coverage indicators for the specific ENAP treatment interventions were assigned task teams and given priority as they were identified as requiring the most technical work. Consultations were held throughout.ResultsENAP published 10 core indicators plus 10 additional indicators. Three core impact indicators (neonatal mortality rate, maternal mortality ratio, stillbirth rate) are well defined, with future efforts needed to focus on improving data quantity and quality. Three core indicators on coverage of care for all mothers and newborns (intrapartum/skilled birth attendance, early postnatal care, essential newborn care) have defined contact points, but gaps exist in measuring content and quality of the interventions. Four core (antenatal corticosteroids, neonatal resuscitation, treatment of serious neonatal infections, kangaroo mother care) and one additional coverage indicator for newborns at risk or with complications (chlorhexidine cord cleansing) lack indicator definitions or data, especially for denominators (population in need). To address these gaps, feasible coverage indicator definitions are presented for validity testing. Measurable process indicators to help monitor health service readiness are also presented. A major measurement gap exists to monitor care of small and sick babies, yet signal functions could be tracked similarly to emergency obstetric care.ConclusionsThe ENAP Measurement Improvement Roadmap (2015-2020) outlines tools to be developed (e.g., improved birth and death registration, audit, and minimum perinatal dataset) and actions to test, validate and institutionalise proposed coverage indicators. The roadmap presents a unique opportunity to strengthen routine health information systems, crosslinking these data with civil registration and vital statistics and population-based surveys. Real measurement change requires intentional transfer of leadership to countries with the greatest disease burden and will be achieved by working with centres of excellence and existing networks.

Chest radiography in children aged 2-59 months diagnosed with non-severe pneumonia as defined by World Health Organization: descriptive multicentre study in Pakistan

Abstract Objectives To evaluate the chest radiographs of children diagnosed with non-severe pneumonia on the basis of the current World Health Organization guidelines (fast breathing alone) for radiological evidence of pneumonia. Design Descriptive analysis. Setting Outpatient departments of six hospitals in four cities in Pakistan. Participants 2000 children with non-severe pneumonia were enrolled; 1932 children were selected for chest radiography. Interventions Two consultant radiologists used standardised WHO definitions to evaluate chest radiographs; no clinical information was made available to them. If they disagreed, the radiographs were read by a third radiologist; the final classification was based on agreement between two of the three radiologists. Main outcome measures Presence or absence of pneumonia on radiographs. Results Chest radiographs were reported normal in 1519 children (82%). Radiological evidence of pneumonia was reported in only 263 (14%) children, most of whom had interstitial pneumonitis. Lobar consolidation was present in only 26 children. The duration of illness did not correlate significantly with the presence of radiological changes (relative risk 1.17, 95% confidence interval 0.91 to 1.49). Conclusion Most children diagnosed with non-severe pneumonia on the basis of the current WHO definition had normal chest radiographs.

Neonatal sepsis: A major global public health challenge

Neonatal mortality is increasingly recognized as an important global public health challenge that must be addressed if we are to reduce child health disparities between rich and poor countries. Most of the estimated 4 million neonatal deaths per year occur in low and middle income countries. Three conditions: infection, birth asphyxia, and consequences of premature birth/low birth weight, are responsible for majority of these deaths. More than one-third are estimated to be due to severe infections, and a quarter are due to the clinical syndrome of neonatal sepsis/pneumonia. Case fatality rates for neonatal infections remain high among both hospitalized newborns and those in the community. In general, the identification and treatment of newborns with infection is unsatisfactory in many developing country settings. Because sick newborns present with nonspecific signs and symptoms, a clinical diagnosis of neonatal sepsis is difficult in even the most sophisticated settings. Many factors contribute to the high mortality due to infections, including under-recognition of illness, delay in care seeking at the household level, and lack of access to both appropriately trained health workers and to high quality services to manage sepsis. Even if quality services are available, the cost of treatment is beyond the reach of many families. It is particularly poignant that many neonatal deaths occur in the community, without the newborn ever having contact with the appropriate health services. At the turn of this new century, leaders throughout the world committed to working together to meet Eight Millennium Development Goals related to poverty reduction, expanded educational opportunities, gender equality, environmental sustainability, and improved health. Without addressing the causes of neonatal mortality and developing improved strategies for prevention, diagnosis and treatment, it will be impossible to meet Millennium Development Goal 4—to reduce child mortality by two-thirds between 1990 and 2015. Over the past several years, attempts have been made to raise awareness of the contribution of neonatal problems to overall infant mortality and to promote strategies to reduce mortality at the country level. Sixteen evidence-based cost-effective interventions have been identified to reduce neonatal mortality, during the preconception, antenatal, intrapartum and postnatal periods. Included among these is community-based case management of pneumonia. The evidence for effectiveness of community-based interventions for management of neonatal sepsis is less widely accepted. The purpose of this supplement is to evaluate available evidence on the burden of disease, etiology, antimicrobial resistance, and potential options for management of neonatal sepsis at the community level. The first 3 papers in this supplement resulted from a comprehensive review of the literature on neonatal sepsis commissioned by the Department of Child and Adolescent Health and Development, World Health Organization (WHO). Thaver and Zaidi report the findings from a review of community-based studies from developing countries to estimate rates of infections and infection-specific mortality. It is clear from this review that data from developing countries are limited in both quality and quantity. Zaidi et al review information about pathogens associated with neonatal sepsis in developing countries. Community-based data are almost completely lacking for the early neonatal period (ie, newborns in the first week of life). Most published data are from hospitals where Klebsiella species, E. coli, and Staphylococcus aureus are the most common causes of infection. Antimicrobial resistance patterns of neonatal pathogens are reported in another paper by Thaver et al These authors cite concerns about the emerging resistance of Klebsiella and E. coli to commonly used antibiotics. Although community-based data were scarce, lower antimicrobial resistance levels in the community are encouraging. Bhutta et al reviewed case management approaches for neonatal sepsis in the community settings of low resource countries. Despite limitations, these approaches hold promise for reducing neonatal mortality in such settings. In 2 papers, Darmstadt et al describe available data on use of oral and injectable antibiotics for the management of neonatal sepsis. They present advantages and disadvantages of various antibiotics

Community case management of severe pneumonia with oral amoxicillin in children aged 2-59 months in Haripur district, Pakistan: a cluster randomised trial.

BACKGROUND First 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. METHODS In 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. FINDINGS We 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. INTERPRETATION Community 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. FUNDING United States Agency for International Development (USAID).

Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-59 months in low resource settings: multicentre randomised controlled trial (SPEAR study)

Objective To evaluate whether five days’ treatment with injectable ampicillin plus gentamicin compared with chloramphenicol reduces treatment failure in children aged 2-59 months with community acquired very severe pneumonia in low resource settings. Design Open label randomised controlled trial. Setting Inpatient wards within tertiary care hospitals in Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen, and Zambia. Participants Children aged 2-59 months with WHO defined very severe pneumonia. Intervention Chloramphenicol versus a combination of ampicillin plus gentamicin. Main outcome measures Primary outcome measure was treatment failure at five days. Secondary outcomes were treatment failure defined similarly among all participants evaluated at 48 hours and at 10 and 21 days. Results More children failed treatment with chloramphenicol at day 5 (16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10 and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110 children (11.5%), with the most common organisms being Staphylococcus aureus (n=47) and Streptococcus pneumoniae (n=22). In subgroup analysis, bacteraemia with any organism increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to 3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death (5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin group. No difference was found in treatment failure for children with S aureus bacteraemia in the two groups, but the power to detect a difference in this subgroup analysis was low. Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen saturation <90%), receiving chloramphenicol, being female, and poor immunisation status. Conclusion Injectable ampicillin plus gentamicin is superior to injectable chloramphenicol for the treatment of community acquired very severe pneumonia in children aged 2-59 months in low resource settings. Trial registration Current Controlled Trials ISRCTN39543942.