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Neonates and children in low-income and middle-income countries (LMICs) contribute to the highest number of sepsis-associated deaths globally. Interventions to prevent sepsis mortality are hampered by a lack of comprehensive epidemiological data and pathophysiological understanding of biological pathways. In this review, we discuss the challenges faced by LMICs in diagnosing sepsis in these age groups. We highlight a role for multi-omics and health care data to improve diagnostic accuracy of clinical algorithms, arguing that health-care systems urgently need precision medicine to avoid the pitfalls of missed diagnoses, misdiagnoses, and overdiagnoses, and associated antimicrobial resistance. We discuss ethical, regulatory, and systemic barriers related to the collection and use of big data in LMICs. Technologies such as cloud computing, artificial intelligence, and medical tricorders might help, but they require collaboration with local communities. Co-partnering (joint equal development of technology between producer and end-users) could facilitate integration of these technologies as part of future care-delivery systems, offering a chance to transform the global management and prevention of sepsis for neonates and children.

Summary Background The Gambia introduced seven-valent pneumococcal conjugate vaccine (PCV7) in August 2009, followed by PCV13 in May, 2011, using a schedule of three primary doses without a booster dose or catch-up immunisation. We aimed to assess the long-term impact of PCV on disease incidence. Methods We did 10 years of population-based surveillance for invasive pneumococcal disease (IPD) and WHO defined radiological pneumonia with consolidation in rural Gambia. The surveillance population included all Basse Health and Demographic Surveillance System residents aged 2 months or older. Nurses screened all outpatients and inpatients at all health facilities using standardised criteria for referral. Clinicians then applied criteria for patient investigation. We defined IPD as a compatible illness with isolation of Streptococcus pneumoniae from a normally sterile site (cerebrospinal fluid, blood, or pleural fluid). We compared disease incidence between baseline (May 12, 2008–May 11, 2010) and post-vaccine years (2016–2017), in children aged 2 months to 14 years, adjusting for changes in case ascertainment over time. Findings We identified 22 728 patients for investigation and detected 342 cases of IPD and 2623 cases of radiological pneumonia. Among children aged 2–59 months, IPD incidence declined from 184 cases per 100 000 person-years to 38 cases per 100 000 person-years, an 80% reduction (95% CI 69–87). Non-pneumococcal bacteraemia incidence did not change significantly over time (incidence rate ratio 0·88; 95% CI, 0·64–1·21). We detected zero cases of vaccine-type IPD in the 2–11 month age group in 2016–17. Incidence of radiological pneumonia decreased by 33% (95% CI 24–40), from 10·5 to 7·0 per 1000 person-years in the 2–59 month age group, while pneumonia hospitalisations declined by 27% (95% CI 22–31). In the 5–14 year age group, IPD incidence declined by 69% (95% CI −28 to 91) and radiological pneumonia by 27% (95% CI −5 to 49). Interpretation Routine introduction of PCV13 substantially reduced the incidence of childhood IPD and pneumonia in rural Gambia, including elimination of vaccine-type IPD in infants. Other low-income countries can expect substantial impact from the introduction of PCV13 using a schedule of three primary doses. Funding Gavi, The Vaccine Alliance; Bill & Melinda Gates Foundation; UK Medical Research Council; Pfizer Ltd.

Background Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. Methods We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus–associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. Findings In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. Interpretation Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. Funding Bill & Melinda Gates Foundation.

Background An improved understanding of childhood pneumonia etiology is required to inform prevention and treatment strategies. Lung aspiration is the gold standard specimen for pneumonia diagnostics. We report findings from analyses of lung and pleural aspirates collected in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods The PERCH study enrolled children aged 1–59 months hospitalized with World Health Organization–defined severe or very severe pneumonia in 7 countries in Africa and Asia. Percutaneous transthoracic lung aspiration (LA) and pleural fluid (PF) aspiration was performed on a sample of pneumonia cases with radiological consolidation and/or PF in 4 countries. Venous blood and nasopharyngeal/oropharyngeal swabs were collected from all cases. Multiplex quantitative polymerase chain reaction (PCR) and routine microbiologic culture were applied to clinical specimens. Results Of 44 LAs performed within 3 days of admission on 622 eligible cases, 13 (30%) had a pathogen identified by either culture (5/44) or by PCR (11/29). A pathogen was identified in 12/14 (86%) PF specimens tested by either culture (9/14) or PCR (9/11). Bacterial pathogens were identified more frequently than viruses. All but 1 of the cases with a virus identified were coinfected with bacterial pathogens. Streptococcus pneumoniae (9/44 [20%]) and Staphylococcus aureus (7/14 [50%]) were the predominant pathogens identified in LA and PF, respectively. Conclusions Bacterial pathogens predominated in this selected subgroup of PERCH participants drawn from those with radiological consolidation or PF, with S. pneumoniae and S. aureus the leading pathogens identified., Lung aspiration (LA) and pleural fluid (PF) aspiration were performed on a subgroup of PERCH pneumonia cases with radiological consolidation or PF collection. Bacterial pathogens predominated (Streptococcus pneumoniae in LA, Staphylococcus aureus in PF), in contrast to overall PERCH findings.

Background Oxygen is vital in the treatment of illnesses in children and adults, yet is lacking in many low and middle-income countries health care settings. Oxygen concentrators (OCs) can increase access to oxygen, compared to conventional oxygen cylinders. We investigated the costs and critical success factors of OCs in three hospitals in Fiji, and extrapolated these to estimate the oxygen delivery cost to all Sub-Divisional hospitals (SDH) nationwide. Methods Data sources included key personnel interviews, and data from SDH records, Ministry of Health and Medical Services, and a non-governmental organisation. We used Investment Logic Mapping (ILM) to define key issues. An economic case was developed to identify the investment option that optimised value while incorporating critical success factors identified through ILM. A fit-for-purpose analysis was conducted using cost analysis of four short-listed options. Sensitivity analyses were performed by altering variables to show the best or worst case scenario. All costs are presented in Fijian dollars. Results Critical success factors identifed included oxygen availability, safety, ease of use, feasibility, and affordability. Compared to the status quo of having only oxygen cylinders, an option of having a minimum number of concentrators with cylinder backup would cost $434,032 (range: $327,940 to $506,920) over 5 years which would be 55% (range: 41 to 64%) of the status quo cost. Conclusion Introducing OCs into all SDHs in Fiji would reduce overall costs, while ensuring identified critical success factors are maintained. This study provides evidence for the benefits of OCs in this and similar settings.

Background: Mobile devices provide new opportunities for the prevention of overweight and obesity in children. We aimed to co-create and test an app that provided comprehensible feedback to parents on their child's growth and delivered a suite of age-specific information about nutrition and activity. Methods: A two-phased approach was used to co-create the digital growth tool - See How They Grow - and test its feasibility. Phase one used focus groups and a national online survey to gather requirements and build the app. Phase two involved testing the app over 12-weeks, with parents or carers of children aged ≤ 2-years. All research activities were undertaken exclusively through the app. Participants were recruited using social media and hard copy materials. Findings: Four focus groups and 101 responses to the national survey informed the features and functions to include in the final app. Two hundred and twenty-five participants downloaded the app, resulting in 208 eligible participants. Non-Māori/Non-Pacific (78%) and Māori (14%) had the highest downloads. Fifty-four per cent of participants were parents of children under 6-months. These participants were more likely to regularly use the app than those with children older than 6-months (64% vs 36%, P =0.011). Over half of the participants entered three measures (n=101, 48%). Of those that completed the follow-up survey (n=101, 48%), 72 reported that the app helped them better understand how to interpret growth charts. Interpretation: With minor modifications, the app could be an effective tool to support parents understanding of growth trajectories and what they mean for their children. A larger trial is needed to evaluate if the app can have a measurable impact on increasing knowledge and behaviour, and therefore on preventing childhood overweight and obesity. Funding Statement: This study was funded through a contestable funding round by Cure Kids, the National Science Challenge: a Better Start and Precision Driven Health. The funders had no influence on the design, implementation, interpretation or reporting of the study findings. Declaration of Interests: None. Ethics Approval Statement: The study has Ethics approval from the NZ Auckland University Human Participants Ethics Committee; Co-creation and Development Study Reference 020166, Feasibility Study Reference 022248. All participants gave consent to participate. The feasibility study was registered on the Australia New Zealand Clinical Trial registration (ACTRN12619000905167).

Background: In 2013 the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) to recommend home-based treatment rather than hospital admission. We analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-groups with high odds of mortality, who might continue to benefit from hospital management. Methods: PERCH enrolled 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using logistic regression. Findings: Among 2189 cases with LCWI pneumonia, 76 (3·6%) died. Mortality was higher in infants compared to children 12-59 months of age (OR 2·03, 95%CI 1·05-3·93), in children with oxygen saturation

Background Human parainfluenza virus (hPIV) is a common virus in childhood acute lower respiratory infections (ALRI). However, no estimates have been made to quantify the global burden of hPIV in childhood ALRI. We aimed to estimate the global and regional hPIV-associated and hPIV-attributable ALRI incidence, hospital admissions, and mortality for children younger than 5 years and stratified by 0–5 months, 6–11 months, and 12–59 months of age. Methods We did a systematic review of hPIV-associated ALRI burden studies published between Jan 1, 1995, and Dec 31, 2020, found in MEDLINE, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Global Health Library, three Chinese databases, and Google search, and also identified a further 41 high-quality unpublished studies through an international research network. We included studies reporting community incidence of ALRI with laboratory-confirmed hPIV; hospital admission rates of ALRI or ALRI with hypoxaemia in children with laboratory-confirmed hPIV; proportions of patients with ALRI admitted to hospital with laboratory-confirmed hPIV; or in-hospital case–fatality ratios (hCFRs) of ALRI with laboratory-confirmed hPIV. We used a modified Newcastle-Ottawa Scale to assess risk of bias. We analysed incidence, hospital admission rates, and hCFRs of hPIV-associated ALRI using a generalised linear mixed model. Adjustment was made to account for the non-detection of hPIV-4. We estimated hPIV-associated ALRI cases, hospital admissions, and in-hospital deaths using adjusted incidence, hospital admission rates, and hCFRs. We estimated the overall hPIV-associated ALRI mortality (both in-hospital and out-hospital mortality) on the basis of the number of in-hospital deaths and care-seeking for child pneumonia. We estimated hPIV-attributable ALRI burden by accounting for attributable fractions for hPIV in laboratory-confirmed hPIV cases and deaths. Sensitivity analyses were done to validate the estimates of overall hPIV-associated ALRI mortality and hPIV-attributable ALRI mortality. The systematic review protocol was registered on PROSPERO (CRD42019148570). Findings 203 studies were identified, including 162 hPIV-associated ALRI burden studies and a further 41 high-quality unpublished studies. Globally in 2018, an estimated 18·8 million (uncertainty range 12·8–28·9) ALRI cases, 725 000 (433 000–1 260 000) ALRI hospital admissions, and 34 400 (16 400–73 800) ALRI deaths were attributable to hPIVs among children younger than 5 years. The age-stratified and region-stratified analyses suggested that about 61% (35% for infants aged 0–5 months and 26% for 6–11 months) of the hospital admissions and 66% (42% for infants aged 0–5 months and 24% for 6–11 months) of the in-hospital deaths were in infants, and 70% of the in-hospital deaths were in low-income and lower-middle-income countries. Between 73% and 100% (varying by outcome) of the data had a low risk in study design; the proportion was 46–65% for the adjustment for health-care use, 59–77% for patient groups excluded, 54–93% for case definition, 42–93% for sampling strategy, and 67–77% for test methods. Heterogeneity in estimates was found between studies for each outcome. Interpretation We report the first global burden estimates of hPIV-associated and hPIV-attributable ALRI in young children. Globally, approximately 13% of ALRI cases, 4–14% of ALRI hospital admissions, and 4% of childhood ALRI mortality were attributable to hPIV. These numbers indicate a potentially notable burden of hPIV in ALRI morbidity and mortality in young children. These estimates should encourage and inform investment to accelerate the development of targeted interventions. Funding Bill & Melinda Gates Foundation.

A saving grace of the COVID-19 pandemic in high-income and upper middle-income countries has been the relative sparing of children. As the disease spreads across low-income and middle-income countries (LMICs), long-standing system vulnerabilities may tragically manifest, and we worry that children will be increasingly impacted, both directly and indirectly. Drawing on our shared child pneumonia experience globally, we highlight these potential impacts on children in LMICs and propose actions for a collective response. Current data suggest children are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but are less likely than adults to become severely ill.1–4 Although at first glance these data appear reassuring, the child pneumonia, and broader global child health, experience provides a forewarning of what may be coming in LMICs. High-income countries (HICs) have an under-5 pneumonia mortality rate of 3 per 100 000.5 In contrast, the rate in LMICs is 200 per 100 000 population, with pneumonia the leading infectious cause of under-5 death globally.5 While yet unknown, COVID-19, a viral pneumonia syndrome, may impact children in LMICs more severely than what has been observed to date. The risk factors for poor outcomes in pneumonia …

Background In 1997, The Gambia introduced three primary doses of Haemophilus influenzae type b (Hib) conjugate vaccine without a booster in its infant immunisation programme along with establishment of a population-based surveillance on Hib meningitis in the West Coast Region (WCR). This surveillance was stopped in 2002 with reported elimination of Hib disease. This was re-established in 2008 but stopped again in 2010. We aimed to re-establish the surveillance in WCR and to continue surveillance in Basse Health and Demographic Surveillance System (BHDSS) in the east of the country to assess any shifts in the epidemiology of Hib disease in The Gambia. Methods In WCR, population-based surveillance for Hib meningitis was re-established in children aged under-10 years from 24 December 2014 to 31 March 2017, using conventional microbiology and Real Time Polymerase Chain Reaction (RT-PCR). In BHDSS, population-based surveillance for Hib disease was conducted in children aged 2-59 months from 12 May 2008 to 31 December 2017 using conventional microbiology only. Hib carriage survey was carried out in pre-school and school children from July 2015 to November 2016. Results In WCR, five Hib meningitis cases were detected using conventional microbiology while another 14 were detected by RT-PCR. Of the 19 cases, two (11%) were too young to be protected by vaccination while seven (37%) were unvaccinated. Using conventional microbiology, the incidence of Hib meningitis per 100 000-child-year (CY) in children aged 1-59 months was 0.7 in 2015 (95% confidence interval (CI) = 0.0-3.7) and 2.7 (95% CI = 0.7-7.0) in 2016. In BHDSS, 25 Hib cases were reported. Nine (36%) were too young to be protected by vaccination and five (20%) were under-vaccinated for age. Disease incidence peaked in 20122013 at 15 per 100 000 CY and fell to 5-8 per 100 000 CY over the subsequent four years. The prevalence of Hib carriage was 0.12% in WCR and 0.38% in BHDSS. Conclusions After 20 years of using three primary doses of Hib vaccine without a booster Hib transmission continues in The Gambia, albeit at low rates. Improved coverage and timeliness of vaccination are of high priority for Hib disease in settings like Gambia, and there are currently no clear indications of a need for a booster dose.

Background Whether digitally recorded lung sounds are associated with radiographic pneumonia or clinical outcomes among children in low-income and middle-income countries is unknown. We sought to address these knowledge gaps. Methods We enrolled 1 to 59 month old children hospitalized with pneumonia at eight African and Asian Pneumonia Etiology Research for Child Health sites in six countries, recorded digital stethoscope lung sounds, obtained chest radiographs, and collected clinical outcomes. Recordings were processed and classified into binary categories positive or negative for adventitial lung sounds. Listening and reading panels classified recordings and radiographs. Recording classification associations with chest radiographs with World Health Organization (WHO)-defined primary endpoint pneumonia (radiographic pneumonia) or mortality were evaluated. We also examined case fatality among risk strata. Results Among children without WHO danger signs, wheezing (without crackles) had a lower adjusted odds ratio (aOR) for radiographic pneumonia (0.35, 95% confidence interval (CI): 0.15, 0.82), compared to children with normal recordings. Neither crackle only (no wheeze) (aOR: 2.13, 95% CI: 0.91, 4.96) or any wheeze (with or without crackle) (aOR: 0.63, 95% CI: 0.34, 1.15) were associated with radiographic pneumonia. Among children with WHO danger signs no lung recording classification was independently associated with radiographic pneumonia, although trends toward greater odds of radiographic pneumonia were observed among children classified with crackle only (no wheeze) or any wheeze (with or without crackle). Among children without WHO danger signs, those with recorded wheezing had a lower case fatality than those without wheezing (3.8% vs. 9.1%, p = .03). Conclusions Among lower risk children without WHO danger signs digitally recorded wheezing is associated with a lower odds for radiographic pneumonia and with lower mortality. Although further research is needed, these data indicate that with further development digital auscultation may eventually contribute to child pneumonia care.

Background Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods We measured serum CRP levels in cases with World Health Organization–defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for “confirmed” bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to “RSV pneumonia” (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results Among 601 human immunodeficiency virus (HIV)–negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. Conclusions Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.

Summary In the Pneumonia Etiology Research for Child Health study, abnormal chest radiographs (CXRs) in cases were associated with hypoxemia, crackles, tachypnea, and fever. Overall, 54% of CXRs were abnormal (site range, 35%–64%). Consolidation on CXR was associated with an increased risk of mortality., Background. Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. Methods. The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)–defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. Results. CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%–64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. Conclusions. Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.

Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias.

Background It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. Methods We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1–59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. Results Of 3772 induced sputum specimens, 2608 (69%) had 25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, 25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. Conclusions Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children aged 1-59 months. METHODS: Data from 1802 human immunodeficiency virus (HIV)-negative children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic. RESULTS: Predictors of mortality, across 7 low- and middle-income countries, were age

Background. Few data exist describing pertussis epidemiology among infants and children in low- and middle-income countries to guide preventive strategies. Methods. Children 1–59 months of age hospitalized with World Health Organization–defined severe or very severe pneumonia in 7 African and Asian countries and similarly aged community controls were enrolled in the Pneumonia Etiology Research for Child Health study. They underwent a standardized clinical evaluation and provided nasopharyngeal and oropharyngeal swabs and induced sputum (cases only) for Bordetella pertussis polymerase chain reaction. Risk factors and pertussis-associated clinical findings were identified. Results. Bordetella pertussis was detected in 53 of 4200 (1.3%) cases and 11 of 5196 (0.2%) controls. In the age stratum 1–5 months, 40 (2.3% of 1721) cases were positive, all from African sites, as were 8 (0.5% of 1617) controls. Pertussis-positive African cases 1–5 months old, compared to controls, were more often human immunodeficiency virus (HIV) uninfected-exposed (adjusted odds ratio [aOR], 2.2), unvaccinated (aOR, 3.7), underweight (aOR, 6.3), and too young to be immunized (aOR, 16.1) (all P ≤ .05). Compared with pertussis-negative African cases in this age group, pertussis-positive cases were younger, more likely to vomit (aOR, 2.6), to cough ≥14 days (aOR, 6.3), to have leukocyte counts >20 000 cells/µL (aOR, 4.6), and to have lymphocyte counts >10 000 cells/µL (aOR, 7.2) (all P ≤ .05). The case fatality ratio of pertussis-infected pneumonia cases 1–5 months of age was 12.5% (95% confidence interval, 4.2%–26.8%; 5/40); pertussis was identified in 3.7% of 137 in-hospital deaths among African cases in this age group. Conclusions. In the postneonatal period, pertussis causes a small fraction of hospitalized pneumonia cases and deaths; however, case fatality is substantial. The propensity to infect unvaccinated infants and those at risk for insufficient immunity (too young to be vaccinated, premature, HIV-infected/exposed) suggests that the role for maternal vaccination should be considered along with efforts to reduce exposure to risk factors and to optimize childhood pertussis vaccination coverage.

Summary Background Little information is available about the effect of pneumococcal conjugate vaccines (PCVs) in low-income countries. We measured the effect of these vaccines on invasive pneumococcal disease in The Gambia where the 7-valent vaccine (PCV7) was introduced in August, 2009, followed by the 13-valent vaccine (PCV13) in May, 2011. Methods We conducted population-based surveillance for invasive pneumococcal disease in individuals aged 2 months and older who were residents of the Basse Health and Demographic Surveillance System (BHDSS) in the Upper River Region, The Gambia, using standardised criteria to identify and investigate patients. Surveillance was done between May, 2008, and December, 2014. We compared the incidence of invasive pneumococcal disease between baseline (May 12, 2008–May 11, 2010) and after the introduction of PCV13 (Jan 1, 2013–Dec 31, 2014), adjusting for changes in case ascertainment over time. Findings We investigated 14 650 patients, in whom we identified 320 cases of invasive pneumococcal disease. Compared with baseline, after the introduction of the PCV programme, the incidence of invasive pneumococcal disease decreased by 55% (95% CI 30–71) in the 2–23 months age group, from 253 to 113 per 100 000 population. This decrease was due to an 82% (95% CI 64–91) reduction in serotypes covered by the PCV13 vaccine. In the 2–4 years age group, the incidence of invasive pneumococcal disease decreased by 56% (95% CI 25–75), from 113 to 49 cases per 100 000, with a 68% (95% CI 39–83) reduction in PCV13 serotypes. The incidence of non-PCV13 serotypes in children aged 2–59 months increased by 47% (−21 to 275) from 28 to 41 per 100 000, with a broad range of serotypes. The incidence of non-pneumococcal bacteraemia varied little over time. Interpretation The Gambian PCV programme reduced the incidence of invasive pneumococcal disease in children aged 2–59 months by around 55%. Further surveillance is needed to ascertain the maximum effect of the vaccine in the 2–4 years and older age groups, and to monitor serotype replacement. Low-income and middle-income countries that introduce PCV13 can expect substantial reductions in invasive pneumococcal disease. Funding GAVI's Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP), Bill & Melinda Gates Foundation, and the UK Medical Research Council.

Summary Background Global child mortality reduced substantially during the Millennium Development Goal period (2000–15). We aimed to estimate morbidity, mortality, and prevalence of risk factors for child pneumonia at the global, regional, and national level for developing countries for the Millennium Development Goal period. Methods We estimated the incidence, number of hospital admissions, and in-hospital mortality due to all-cause clinical pneumonia in children younger than 5 years in developing countries at 5-year intervals during the Millennium Development Goal period (2000–15) using data from a systematic review and Poisson regression. We estimated the incidence and number of cases of clinical pneumonia, and the pneumonia burden attributable to HIV for 132 developing countries using a risk-factor-based model that used Demographic and Health Survey data on prevalence of the various risk factors for child pneumonia. We also estimated pneumonia mortality in young children using data from multicause models based on vital registration and verbal autopsy. Findings Globally, the number of episodes of clinical pneumonia in young children decreased by 22% from 178 million (95% uncertainty interval [UI] 110–289) in 2000 to 138 million (86–226) in 2015. In 2015, India, Nigeria, Indonesia, Pakistan, and China contributed to more than 54% of all global pneumonia cases, with 32% of the global burden from India alone. Between 2000 and 2015, the burden of clinical pneumonia attributable to HIV decreased by 45%. Between 2000 and 2015, global hospital admissions for child pneumonia increased by 2·9 times with a more rapid increase observed in the WHO South-East Asia Region than the African Region. Pneumonia deaths in this age group decreased from 1·7 million (95% UI 1·7–2·0) in 2000 to 0·9 million (0·8–1·1) in 2015. In 2015, 49% of global pneumonia deaths occurred in India, Nigeria, Pakistan, Democratic Republic of the Congo, and Ethiopia collectively. All key risk factors for child pneumonia (non-exclusive breastfeeding, crowding, malnutrition, indoor air pollution, incomplete immunisation, and paediatric HIV), with the exception of low birthweight, decreased across all regions between 2000 and 2015. Interpretation Globally, the incidence of child pneumonia decreased by 30% and mortality decreased by 51% during the Millennium Development Goal period. These reductions are consistent with the decrease in the prevalence of some of the key risk factors for pneumonia, increasing socioeconomic development and preventive interventions, improved access to care, and quality of care in hospitals. However, intersectoral action is required to improve socioeconomic conditions and increase coverage of interventions targeting risk factors for child pneumonia to accelerate decline in pneumonia mortality and achieve the Sustainable Development Goals for health by 2030. Funding Bill & Melinda Gates Foundation.

BACKGROUND: The benefit of zinc as an adjunct therapy for severe pneumonia is not established. We assessed the benefit of adjunct zinc therapy for severe pneumonia in children and determined whether the study children were zinc deficient. METHODS: This was a randomized, parallel group, double-blind, placebo-controlled trial with an allocation ratio of 1:1 conducted in children with severe pneumonia to evaluate the efficacy of daily zinc as an adjunct treatment in preventing 'treatment failure' (presence of any sign of severe pneumonia) on day-5 and day-10 and in reducing the time to resolution of signs of severe pneumonia. Six hundred and four children 2-59 months of age presenting with severe pneumonia at six urban and rural health care facilities in The Gambia were individually randomised to receive placebo (n = 301) or zinc (n = 303) for seven days. To determine if the study children were zinc deficient, supplementation was continued in a randomly selected subgroup of 121 children from each arm for six months post-enrolment, and height-gain, nutritional status, plasma zinc concentrations, and immune competence were compared. RESULTS: Percentage of treatment failure were similar in placebo and zinc arms both on day 5 (14.0% vs 14.1%) and day 10 (5.2% vs 5.9%). The time to recovery from lower chest wall indrawing and sternal retraction was longer in the placebo compared to zinc arm (24.4 vs 23.0 hours; P = 0.011 and 18.7 vs 11.0 hours; P = 0.006 respectively). The time to resolution for all respiratory symptoms of severity was not significantly different between placebo and zinc arms (42.3 vs 30.9 hours respectively; P = 0.242). In the six months follow-up sub-group, there was no significant difference in height gain, height-for-age and weight-for-height Z-scores, mid upper arm circumference, plasma zinc concentrations, and anergy at six months post-enrolment. CONCLUSIONS: In this population, zinc given as an adjunct treatment for severe pneumonia showed no benefit in treatment failure rates, or clinically important benefit in time to recovery from respiratory symptoms and showed marginal benefit in rapidity of resolution of some signs of severity. This finding does not support routine use of zinc as an adjunct treatment in severe pneumonia in generally zinc replete children. TRIAL REGISTRATION: ISRCTN33548493.

Background.Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods.We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1–59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). Results.One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of Conclusions.The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice.

Background We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries. Methods We tested blood by PCR for the pneumococcal autolysin gene in children aged 1–59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization–defined severe or very severe pneumonia or were age-frequency–matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls. Results In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%–11.5% among cases and 5.3%–10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus. Discussion The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases.

Pneumonia is a major killer of children worldwide. It is responsible for 19% of under-five-year-old mortality, of which 70% occurs in sub-Saharan Africa and South East Asia. A substantial proportion of deaths attributed to pneumonia is caused by failure to recognise factors at presentation that affect prognosis. The present study was aimed to assess for factors at presentation that determine mortality among children with WHO ARI defined severe pneumonia. This was a prospective observational study of consecutive children aged 2 to 59 months admitted with severe pneumonia at a major health centre in rural Gambia to de- termine the risk factors for mortality using logistic regression analysis. Four hundred and twenty (27.6%) out of the 1517 under- five admissions during the study period fulfilled the criteria of severe pneumonia using the WHO ARI criteria. Fifteen of the 420 cases died giving case fatality of 36 per 1000 admissions, with pneumonia accounting for 21.4% of all 70 deaths during the period. Although age ranges 12-23 months and 36-47 months, overcrowding, hypothermia at presentation, oedematous PEM, severe wasting, grunting respiration, convulsion, somnolence and hypoxaemia were significantly associated with mortality (p < 0.05); only convulsions ( OR = 16.64, 95% CI 1.028-1.033) and severe wasting (OR = 5.05, 95% CI 1.459-20.484,) were independent determinants of mortality. We conclude that children with severe pneumonia who in addition have severe wasting and convulsion are at increased risks of dying and should be managed in better equipped secondary or tertiary health facilities.

National facility-based neonatal mortality audits are an important source of data to identify areas for improvement of service delivery and outcome of care.To examine admissions to the neonatal unit, Edward Francis Small Teaching Hospital, Banjul, The Gambia and make recommendations for programme action to reduce mortality through improvements in the quality of care, particularly with respect to suspected neonatal infections.Case notes were reviewed for all neonates admitted to the neonatal unit during a 5-year period (1 January 2009 to 31 December 2013) to assess outcome and quality of care. Data for 2009 were subsequently excluded because of the low proportion of records retrieved.Of the 4944 admissions between 1 January 2010 and 31 December 2013, 1734 infants (35%) died, with 57% of all deaths occurring within the first 48 hours of admission. There were 1267 early neonatal deaths (deaths occurring during the first 7 days of life), 67% of which occurred during the first 48 hours of life. Independent predictors of neonatal death in the multivariable analysis were; maternal lack of antenatal care, non-teaching hospital delivery, admission weight1500 g, abnormal blood glucose concentration ( 2.6 mmol/L or6.9 mmol/L) and hypothermia (axillary temperature36.5 ˚C). Forty-eight per cent of newborns had point-of-admission hypothermia. Possible severe bacterial infection (pSBI) accounted for 44% (2166/4944) of admissions, prematurity/low birthweight for 27% (1340/4944) and intrapartum-related conditions for 20%. Only 5% (104/2166) of pSBI cases had at least one supportive investigation; 41 had a chest radiograph, 26 had a blood culture and 43 had a lumbar puncture. Although 94% of the newborns received intravenous antibiotics, 55% of those who did lacked clinical evidence of pSBI and had no diagnostic work-up.Priority areas for action include infection prevention and improved diagnosis and management. There is also scope to reduce hypothermia with feasible interventions particularly targeting preterm infants. Improved patient records and audit data with linked action and accountability are interventions which could prevent such deaths of newborns in The Gambia and other developing countries.

The Farafenni Health and Demographic Surveillance System (Farafenni HDSS) is located 170 km from the coast in a rural area of The Gambia north of the River Gambia. It was set up in 1981 by the UK Medical Research Council Laboratories to generate demographic and health information required for the evaluation of a village-based primary health care programme in 40 villages. Regular updates of demographic events and residency status have subsequently been conducted every 4 months. The surveillance area was extended in 2002 to include Farafenni Town and surrounding villages to support randomized controlled trials. With over three decades of prospective surveillance and through specific scientific investigations the platform (population approximately 50000) has generated data on: morbidity and mortality due to malaria in children and during pregnancy; non-communicable disease among adults; reproductive health; and levels and trends in childhood and maternal mortality. Other information routinely collected includes causes of death through verbal autopsy and household socioeconomic indicators. The current portfolio of the platform includes tracking Millennium Development Goal 4 (MDG4) attainments in rural Gambia and cause-of-death determination. (c) The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Background. Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods. Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. Results. MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62–0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. Conclusions. Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Background. Detection of pneumococcus by lytA polymerase chain reaction (PCR) in blood had poor diagnostic accuracy for diagnosing pneumococcal pneumonia in children in 9 African and Asian sites. We assessed the value of blood lytA quantification in diagnosing pneumococcal pneumonia. Methods. The Pneumonia Etiology Research for Child Health (PERCH) case-control study tested whole blood by PCR for pneumococcus in children aged 1-59 months hospitalized with signs of pneumonia and in age-frequency matched community controls. The distribution of load among PCR-positive participants was compared between microbiologically confirmed pneumococcal pneumonia (MCPP) cases, cases confirmed for nonpneumococcal pathogens, nonconfirmed cases, and controls. Receiver operating characteristic analyses determined the "optimal threshold" that distinguished MCPP cases from controls. Results. Load was available for 290 of 291 cases with pneumococcal PCR detected in blood and 273 of 273 controls. Load was higher in MCPP cases than controls (median, 4.0 × 10 3 vs 0.19 × 10 3 copies/mL), but overlapped substantially (range, 0.16-989.9 × 10 3 copies/mL and 0.01-551.9 × 10 3 copies/mL, respectively). The proportion with high load (≥2.2 log 10 copies/mL) was 62.5% among MCPP cases, 4.3% among nonconfirmed cases, 9.3% among cases confirmed for a nonpneumococcal pathogen, and 3.1% among controls. Pneumococcal load in blood was not associated with respiratory tract illness in controls (P = .32). High blood pneumococcal load was associated with alveolar consolidation on chest radiograph in nonconfirmed cases, and with high ( > 6.9 log 10 copies/mL) nasopharyngeal/oropharyngeal load and C-reactive protein ≥40 mg/L (both P < .01) in nonconfirmed cases but not controls. Conclusions. Quantitative pneumococcal PCR in blood has limited diagnostic utility for identifying pneumococcal pneumonia in individual children, but may be informative in epidemiological studies.

Over the last 20–30 years, enormous reductions have occurred in the absolute and relative burden of pneumonia mortality in young children around the world. Only 20 years ago, when the population of young children was approximately 625 million, approximately 1.7 million young children died from pneumonia before their 5th birthday (Figure 1) [1–4]. Mortality from pneumonia among children aged 670 million [1, 2, 5]. This remarkable improvement in child survival and health has resulted from advances in social conditions and economic development [6] but has also been influenced by at least 4 pivotal innovations: (1) the development of a global vaccination program, the World Health Organization’s Expanded Program on Immunizations (begun in 1974), which created the architecture around which country investments, donor funding, program strategies, and outcome measurements could be envisioned and implemented; (2) the global consensus to focus funding, programs, and momentum on 6 development targets articulated by the United Nations General Assembly through the Millennium Development Goals (MDGs, agreed upon in 2000) with MDG4 targeting child survival; (3) the advent of large, health-focused nongovernmental organizations; and (4) the founding of the Global Alliance for Vaccines and Immunization (the Gavi Alliance, formally launched at the World Economic Forum in January 2000), a multilateral funding organization that has allowed for an unprecedented pace of introduction and expanded use of life-saving vaccines in low-income countries. In part, as a result of this multidimensional, multisectoral consensus approach enacted through critical large-scale investments in prevention, protection, and treatment, pneumonia mortality has fallen substantially in many parts of the world because the most fatal of the pathogens and the underlying conditions that put children at risk are being targeted.

The Pneumonia Etiology Research for Child Health study was conducted across 7 diverse research sites and relied on standardized clinical and laboratory methods for the accurate and meaningful interpretation of pneumonia etiology data. Blood, respiratory specimens, and urine were collected from children aged 1–59 months hospitalized with severe or very severe pneumonia and community controls of the same age without severe pneumonia and were tested with an extensive array of laboratory diagnostic tests. A standardized testing algorithm and standard operating procedures were applied across all study sites. Site laboratories received uniform training, equipment, and reagents for core testing methods. Standardization was further assured by routine teleconferences, in-person meetings, site monitoring visits, and internal and external quality assurance testing. Targeted confirmatory testing and testing by specialized assays were done at a central reference laboratory.

In pneumonia, specimens are rarely obtained directly from the infection site, the lung, so the pathogen causing infection is determined indirectly from multiple tests on peripheral clinical specimens, which may have imperfect and uncertain sensitivity and specificity, so inference about the cause is complex. Analytic approaches have included expert review of case-only results, case–control logistic regression, latent class analysis, and attributable fraction, but each has serious limitations and none naturally integrate multiple test results. The Pneumonia Etiology Research for Child Health (PERCH) study required an analytic solution appropriate for a case–control design that could incorporate evidence from multiple specimens from cases and controls and that accounted for measurement error. We describe a Bayesian integrated approach we developed that combined and extended elements of attributable fraction and latent class analyses to meet some of these challenges and illustrate the advantage it confers regarding the challenges identified for other methods.

Background Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. Methods IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children Results A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%–0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as “possibly related” to the procedure. Conclusions The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a lowrisk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety.

In 2012, an outbreak of Neisseria meningitidis serogroup W135 occurred in The Gambia. The attack rate was highest among young children. The associated risk factors were male sex, contact with meningitis patients, and difficult breathing. Enhanced surveillance facilitates early epidemic detection, and multiserogroup conjugate vaccine could reduce meningococcal epidemics in The Gambia.

Coxsackieviruses (CV) A1, CV-A19 and CV-A22 have historically comprised a distinct phylogenetic clade withinEnterovirus(EV)C. Several novel serotypes that are genetically similar to these three viruses have been recently discovered and characterized. Here, we report the coding sequence analysis of two genotypes of a previously uncharacterized serotype EV-C113 from Bangladesh and demonstrate that it is most similar to CV-A22 and EV-C116 within the capsid region. We sequenced novel genotypes of CV-A1, CV-A19 and CV-A22 from Bangladesh and observed a high rate of recombination within this group. We also report genomic analysis of the rarely reported EV-C104 circulating in the Gambia in 2009. All available EV-C104 sequences displayed a high degree of similarity within the structural genes but formed two clusters within the non-structural genes. One cluster included the recently reported EV-C117, suggesting an ancestral recombination between these two serotypes. Phylogenetic analysis of all available complete genome sequences indicated the existence of two subgroups within this distinctEnterovirus Cclade: one has been exclusively recovered from gastrointestinal samples, while the other cluster has been implicated in respiratory disease.

In Tonga, pneumococcal conjugate vaccine is not a scheduled immunization. We identified all children in Tonga with invasive pneumococcal disease from 2010 to 2013. The average annual invasive pneumococcal disease incidence rate was 113/100,000 (

Setting: Greater Banjul and Upper River Regions, The Gambia.\ud \ud Objective: To investigate tractable social, environmental and nutritional risk factors for childhood pneumonia.\ud \ud Design: A case-control study examining the association of crowding, household air pollution (HAP) and nutritional factors with pneumonia was undertaken in children aged 2–59 months: 458 children with severe pneumonia, defined according to the modified WHO criteria, were compared with 322 children with non-severe pneumonia, and these groups were compared to 801 neighbourhood controls. Controls were matched by age, sex, area and season.\ud \ud Results: Strong evidence was found of an association between bed-sharing with someone with a cough and severe pneumonia (adjusted OR [aOR] 5.1, 95%CI 3.2–8.2, P < 0.001) and non-severe pneumonia (aOR 7.3, 95%CI 4.1–13.1, P < 0.001), with 18% of severe cases estimated to be attributable to this risk factor. Malnutrition and pneumonia had clear evidence of association, which was strongest between severe malnutrition and severe pneumonia (aOR 8.7, 95%CI 4.2–17.8, P < 0.001). No association was found between pneumonia and individual carbon monoxide exposure as a measure of HAP.\ud \ud Conclusion: Bed-sharing with someone with a cough is an important risk factor for severe pneumonia, and potentially tractable to intervention, while malnutrition remains an important tractable determinant.

SETTING: A 42-bed hospital operated by the Medical Research Council (MRC) Unit in The Gambia. OBJECTIVE: To devise, test and evaluate a cost-efficient uninterrupted oxygen system in the MRC Hospital. DESIGN: Oxygen cylinders were replaced with oxygen concentrators as the primary source of oxygen. An uninterruptable power supply (UPS) ensured continuity of power. Hospital staff were trained on the use of the new system. Eight years post-installation, an analysis of concentrator maintenance needs and costs was conducted and user feedback obtained to assess the success of the system. RESULTS: The new system saved at least 51% of oxygen supply costs compared to cylinders, with savings likely to have been far greater due to cylinder leakages. Users indicated that the system is easier to use and more reliable, although technical support and staff training are still needed. CONCLUSION: Oxygen concentrators offer long-term cost savings and an improved user experience compared to cylinders; however, some technical support and maintenance are needed to upkeep the system. A UPS dedicated to oxygen concentrators is an appropriate solution for settings where power interruptions are frequent but short in duration. This approach can be a model for health systems in settings with similar infrastructure.

Background The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide. Methods and Findings We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (, The substantial global burden of influenza infections in children is revealed by Lafond and colleagues. Children in developing countries are 3 times more likely to be hospitalised and treatments vary. This study highlights the need for vaccination programs in the young., Editors' Summary Background Acute lower respiratory infections—bacterial and viral infections of the lungs and airways (the tubes that take oxygen-rich air to the lungs)—are major causes of illness and death in children worldwide. Pneumonia (infection of the lungs) alone is responsible for 15% of deaths among children under five years old and kills nearly one million young children every year. Globally, infections with respiratory syncytial virus and with Streptococcus pneumoniae are associated with about 25% and 18.3%, respectively, of all episodes of severe respiratory infection in young children. Another infectious organism that contributes to the global burden of respiratory disease among children is the influenza virus. Every year, millions of people become infected with this virus, which infects the airways and causes symptoms that include a high temperature, tiredness and weakness, general aches and pains, and a dry chesty cough. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) nevertheless kill about half a million people annually, with the highest burden of severe disease being experienced by elderly people and by children under five years old. Why Was This Study Done? Annual immunization (vaccination) can reduce an individual’s risk of catching influenza, but before a country implements this preventative measure, policymakers need reliable estimates of the burden of influenza in their country. Although such estimates have been calculated for resource-rich countries with temperate climates, where influenza largely occurs in the winter, few estimates of influenza burden are available for resource-limited countries, which has hampered informed consideration of vaccination for influenza prevention in many settings. Recently, however, there has been a global expansion of systematic surveillance and testing for influenza virus among patients admitted to hospital for severe respiratory infection. Here, the researchers use this expanded surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide between 1982 and 2012. Specifically, they undertake a systematic review to identify published research articles on influenza-associated respiratory disease in hospitalized children, and, by aggregating the data from these articles with data collected by hospital-based influenza surveillance, they calculate a pooled estimate of the proportion of children hospitalized with respiratory disease who are positive for influenza. What Did the Researchers Do and Find? Using predefined search criteria, the researchers identified 108 published research articles that provided information on influenza-associated respiratory illness among hospitalized children. In addition, the Global Respiratory Hospitalizations–Influenza Proportion Positive (GRIPP) working group provided 37 hospital-based influenza surveillance datasets. By aggregating the data from these sources using a statistical approach called meta-analysis, the researchers calculated that, overall, influenza was associated with 9.5% of hospitalizations for severe respiratory infection among children under 18 years old worldwide, ranging from 4.8% among children under six months old to 16.4% among children aged 5–17 years. The researchers also calculated that, on average over the study period, influenza resulted in about 374,000 hospitalizations annually among children under one year old (including 228,000 hospitalizations among children less than six months old) and nearly one million hospitalizations annually among children under five years old. Finally, the researchers calculated that influenza-associated hospitalization rates among children under five years old over the study period were more than three times higher in resource-limited countries than in industrialized countries (150 and 48 hospitalizations, respectively, per 100,000 children per year). What Do These Findings Mean? Differences in hospitalization practices, in applications of case definitions, and in influenza testing protocols between settings may affect the accuracy of these findings. Specifically, the approach taken by the researchers may mean that their estimate of the total burden of severe respiratory disease due to influenza is an underestimate of the true situation. Even so, these findings suggest that influenza is an important contributor to hospitalizations for severe respiratory illness among children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could, therefore, reduce the contribution that influenza makes to hospitalizations for respiratory infections among children. Importantly, the estimates of the burden of influenza provided by these findings can now be used by countries considering influenza vaccination programs for children and/or pregnant women to help them investigate the possible health and cost implications of such programs and should also stimulate further research into the development of effective influenza vaccines for young children. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001977. The UK National Health Service Choices website provides information about respiratory infections, seasonal influenza, influenza vaccination, and influenza vaccination in children The World Health Organization provides information on seasonal influenza (in several languages) and on influenza vaccines The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects seasonal influenza, including information about vaccination, and about children, influenza, and vaccination; its website contains a short video about personal experiences of influenza Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)

Smoke from biomass fuels is a risk factor for pneumonia, the leading cause of child death worldwide. Although particulate matter (PM) is the metric of choice for studying the health effects of biomass smoke, measuring children's PM exposure is difficult. Carbon monoxide (CO), which is easier to measure, can be used as a proxy for PM exposure. We measured the exposure of children ≤ 5 years of age in The Gambia to CO using small, passive, color stain diffusion tubes. We conducted multiple CO measurements on a subset of children to measure day-to-day exposure variability. Usual CO exposure was modeled using a mixed effects model, which also included individual and household level exposure predictors. Mean measured CO exposure for 1181 children (n=2263 measurements) was 1.04 ± 1.46 p.p.m., indicating that the Gambian children in this study on average have a relatively low CO exposure. However, 25% of children had exposures of 1.3 p.p.m. or higher. CO exposure was higher during the rainy months (1.33 ± 1.62 p.p.m.). Burning insect coils, using charcoal, and measurement done in the rainy season were associated with higher exposure. A parsimonious model with fuel, season, and other PM sources as covariates explained 39% of between-child variation in exposure and helped remove within-child variability.

To describe how through a DSS in a rural area of The Gambia it has been possible to measure substantial reductions in child mortality rates and how we investigated whether the decline paralleled the registered fall in malaria incidence in the country. METHODS: Demographic surveillance data spanning 19.5 years (1 April 1989-30 September 2008) from 42 villages around the town of Farafenni The Gambia were used to estimate childhood mortality rates for neonatal infant child (1-4 years) and under-5 age groups. Data were presented in five a priori defined time periods and annual rates per 1000 live births were derived from Kaplan-Meier survival probabilities. RESULTS: From 1989-1992 to 2004-2008 under-5 mortality declined by 56% (95% CI: 48-63%) from 165 (95% CI: 151-181) per 1000 live births to 74 (95% CI: 65-84) per 1000 live births. In 1- to 4-year-olds mortality during the period 2004-2008 was 69% (95% CI: 60-76%) less than in 1989-1992. The corresponding mortality decline in infants was 39% (95% CI: 23-52%); in neonates it was 38% (95% CI: 13-66%). The derived annual under-5 mortality rates declined from 159 per 1000 live births in 1990 to 45 per 1000 live births in 2008 thus implying an attainment of MDG4 seven years in advance of the target year of 2015. CONCLUSION: Achieving MDG4 is possible in poor rural areas of Africa through widespread deployment of relatively simple measures that improve child survival such as immunisation and effective malaria control. (c) 2011 Blackwell Publishing Ltd.

Pneumonia remains the leading cause of death in young children worldwide. Global pneumonia control depends on a good understanding of the aetiology of pneumonia. Percutaneous transthoracic aspiration culture is much more sensitive than blood culture in identifying the aetiological agents of pneumonia. However, the procedure is not widely practised because of lack of familiarity with it and concerns about potential adverse events. We review the diagnostic usefulness and safety of this procedure over 25 years of its use in research and routine practice at the UK Medical Research Council (MRC), The Gambia, and give a detailed description of the procedure itself. Published materials were identified from the MRC's publication database and systematic searches using the PubMed/Medline and Google search engines. Data from a current pneumonia aetiology study in the unit are included together with clinical experience of staff practising at the unit over the period covered in this review. A minimum of 500 lung aspirates were performed over the period of review. Lung aspiration produces a greater yield of diagnostic bacterial isolates than blood culture. It is especially valuable clinically when pathogens not covered by standard empirical antibiotic treatment, such as Mycobacterium tuberculosis and Staphylococcus aureus, are identified. There have been no deaths following the procedure in our setting and a low rate of other complications, all transient. Lung aspiration is currently the most sensitive method for diagnosing pneumonia in children. With appropriate training and precautions it can be safely used for routine diagnosis in suitable referral hospitals.

Zinc deficiency is widespread and tends to mirror the distribution of infectious diseases prevalent in the developing world. Despite numerous observational studies suggesting a key role for zinc in human immunity and an involvement in disease pathogenesis, the underlying mechanisms remain poorly understood, and zinc intervention trials across a range of diseases have yielded mixed results. There is suggestive evidence that zinc supplementation may reduce initial susceptibility to pneumonia (i.e. preventive), but interpretation is confounded by the use of varied and imprecise diagnostic criteria. Evidence for a therapeutic (i.e. lower pneumonia severity and duration) effect of adjunctive zinc in pre- existing disease is less secure and similarly confounded. In neither case has there been substantive research into the putative mechanisms by which zinc could be beneficial. Animal studies suggest a beneficial role for zinc in T cell immunity; with deficiency resulting in involution of the thymus, which is the seat of T cell development. Here we review the evidence that zinc may play a critical role in human infectious diseases immunity through effects on T cell generation and mediation of cytokine production. Additional mechanisms may involve a role in the removal of metabolic toxins via free radical scavenger molecules for which zinc is an essential cofactor. We review the theory and existing evidence to support that zinc supplementation promotes the induction of T cell immunity to control infection and ameliorate immunopathology including excess inflammation. This is a potential route by which respiratory tissue regeneration may be achieved following respiratory tract infections in children benefiting from zinc adjunct therapy.

Hypoxaemia is a common problem causing child deaths in developing countries, but the cost-effective ways to address hypoxaemia are ignored by current global strategies. Improving oxygen supplies and the detection of hypoxaemia has been shown to reduce death rates from childhood pneumonia by up to 35%, and to be cheaper per life saved than other effective initiatives such as conjugate pneumococcal vaccines. Oxygen concentrators provide the cheapest and most consistent source of oxygen in health facilities where power supplies are reliable. To implement and sustain oxygen concentrators requires strengthening of health systems, with clinicians, teachers, administrators and technicians working together. Programmes built around the use of pulse oximetry and oxygen concentrators are an entry point for improving quality of care, and are a unique example of successful integration of appropriate technology into clinical care. This paper is a practical and up-to-date guide for all involved in purchasing, using and maintaining oxygen concentrators in developing countries.