Factors predicting mortality in hospitalised HIV-negative children with lower-chest-wall indrawing pneumonia and implications for management.

INTRODUCTION: In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no 'danger signs', to recommend home-based treatment. 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 but may not be admitted by staff implementing the 2012 guidelines. We compare the proportion of deaths identified using the criteria in the 2012 guidelines, and the proportion of deaths identified using an alternative set of criteria from our model. METHODS: PERCH enrolled a cohort of 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia (without obvious cyanosis, inability to feed, vomiting, convulsions, lethargy or head nodding) between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using predictive logistic regression. Malnutrition was defined as mid-upper-arm circumference <125mm or weight-for-age z-score <-2. RESULTS: Among 2189 cases, 76 (3·6%) died. Mortality was associated with oxygen saturation <92% (aOR 3·33, 1·99-5·99), HIV negative but exposed status (4·59, 1·81-11·7), moderate or severe malnutrition (6·85, 3·22-14·6) and younger age (infants compared to children 12-59 months old, OR 2·03, 95%CI 1·05-3·93). At least one of three risk factors: hypoxaemia, HIV exposure, or malnutrition identified 807 children in this population, 40% of LCWI pneumonia cases and identified 86% of the children who died in hospital (65/76). Risk factors identified using the 2012 WHO treatment guidelines identified 66% of the children who died in hospital (n = 50/76). CONCLUSIONS: Although it focuses on treatment failure in hospital, this study supports the proposal for better risk stratification of children with LCWI pneumonia. Those who have hypoxaemia, any malnutrition or those who were born to HIV positive mothers, experience poorer outcomes than other children with LCWI pneumonia. Consistent identification of these risk factors should be prioritised and children with at least one of these risk factors should not be managed in the community.

Phenotypic and molecular characterization of beta-lactam resistant Multidrug-resistant Enterobacterales isolated from patients attending six hospitals in Northern Nigeria.

Infections caused by multi-drug resistant Enterobacterales (MDR-E) are difficult to treat and cause significant mortality, especially in developing countries. This study characterized the phenotypic and genotypic profiles of 49 randomly selected beta-lactam resistant MDR-E previously isolated from patients being managed in hospitals in Nigeria using whole genome sequencing. The study isolates exhibited 85.5% resistance to 3rd generation cephalosporins and 65.3% resistance to carbapenems. The blaTEM-1B (29, 59.2%), blaCTX-M-15 (38, 77.6%), and blaNDM-1 (17, 51.5%) were the most common penicillinase, ESBL, and carbapenem resistant genes across isolates, respectively. Seventeen (45%) of blaCTX-M-15 was carried on the insertion sequence ISEc9 while blaNDM-1 (11, 64.7%) were associated with ISEc33. None of the 21 plasmids detected were associated with ß-lactamase genes. Higher resistance rates were found in E. coli ST-88 (n = 2) and the high-risk ST-692 (n = 2). For Klebsiella species, the high-risk clones ST-476 (n = 8) and ST-147 (n = 3) predominated and had higher phenotypic resistance rates and higher number of AMR genes. The mechanisms and pattern of antibiotic resistance differ from patterns previously described with isolates harbouring a wide range of AMRGs. The detection of several chromosomally mediated carbapenemases in our study also represents a significant finding that warrants further investigation to better understand its' implications for clinical practice and public health. The selected MDR-Es were found to be pan-susceptible to tigecycline and had very low resistance to fosfomycin, suggesting a potential for these as empiric treatments. A surveillance approach incorporating both conventional laboratory techniques and modern molecular techniques is essential for the comprehensive characterization of the emergence and dissemination of antimicrobial resistance in Enterobacterales infections within Nigeria.

Tackling antimicrobial resistance across sub-Saharan Africa: current challenges and implications for the future.

INTRODUCTION: Antimicrobial resistance (AMR) is a concern as this increases morbidity, mortality, and costs, with sub-Saharan Africa having the highest rates globally. Concerns with rising AMR have resulted in international, Pan-African, and country activities including the development of national action plans (NAPs). However, there is variable implementation across Africa with key challenges persisting. AREAS COVERED: Consequently, there is an urgent need to document current NAP activities and challenges across sub-Saharan Africa to provide future guidance. This builds on a narrative review of the literature. EXPERT OPINION: All surveyed sub-Saharan African countries have developed their NAPs; however, there is variable implementation. Countries including Botswana and Namibia are yet to officially launch their NAPs with Eswatini only recently launching its NAP. Cameroon is further ahead with its NAP than these countries; though there are concerns with implementation. South Africa appears to have made the greatest strides with implementing its NAP including regular monitoring of activities and instigation of antimicrobial stewardship programs. Key challenges remain across Africa. These include available personnel, expertise, capacity, and resources to undertake agreed NAP activities including active surveillance, lack of focal points to drive NAPs, and competing demands and priorities including among donors. These challenges are being addressed, with further co-ordinated efforts needed to reduce AMR.

A multicentre point prevalence study of antibiotics utilization in hospitalized patients in an urban secondary and a tertiary healthcare facilities in Nigeria: findings and implications.

OBJECTIVES: The understanding of antimicrobial utilization patterns is pertinent to successful implementation of the National Action Plans on Antimicrobial Resistance (AMR). There is, however, limited information on antibiotics utilization in Nigeria. This study was undertaken to build on existing information and provide direction for appropriate interventions including Antibiotics Stewardship Programs (ASP). METHOD: A Point Prevalence Study (PPS) was conducted in two public urban health facilities in Lagos, Nigeria using a design adapted from the European Center for Disease Prevention and Control (ECDC) and Global-PPS surveys. RESULTS: The prevalence of antibiotics use was 80.6% administered mostly parenterally (83.1% of total prescriptions) with concerns with extended surgical antibiotics prophylaxis. The mostly used antibiotics in the secondary hospital were parenteral metronidazole (32.4%), ceftriaxone (27.5%), and amoxicillin + clavulanate (8.2%) while the mostly used in the tertiary hospital were ceftriaxone (25.3%), parenteral metronidazole (19.1%), and amoxicillin + clavulanate (9.3%). There was an appreciable lack of specific functional capacities, policies, and processes to promote appropriate antimicrobial use in both hospitals. CONCLUSIONS: There is high rate of antibiotics utilization in these facilities with lack of institutional frameworks and processes for ensuring appropriate antibiotic use. The study provides the information needed to improve future antimicrobial use in hospitals and reduce AMR.

The Etiology of Childhood Pneumonia in The Gambia: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Pneumonia remains the leading cause of death in young children globally. The changing epidemiology of pneumonia requires up-to-date data to guide both case management and prevention programs. The Gambia study site contributed a high child mortality, high pneumonia incidence, low HIV prevalence, Haemophilus influenzae type b and pneumococcal conjugate vaccines-vaccinated rural West African setting to the Pneumonia Etiology Research for Child Health (PERCH) Study. METHODS: The PERCH study was a 7-country case-control study of the etiology of hospitalized severe pneumonia in children 1-59 months of age in low and middle-income countries. Culture and nucleic acid detection methods were used to test nasopharyngeal/oropharyngeal swabs, blood, induced sputum and, in selected cases, lung or pleural fluid aspirates. Etiology was determined by integrating case and control data from multiple specimens using the PERCH integrated analysis based on Bayesian probabilistic methods. RESULTS: At The Gambia study site, 638 cases of World Health Organization-defined severe and very severe pneumonia (286 of which were chest radiograph [CXR]-positive and HIV-negative) and 654 age-frequency matched controls were enrolled. Viral causes predominated overall (viral 58% vs. bacterial 28%), and of CXR-positive cases respiratory syncytial virus (RSV) accounted for 37%, Streptococcus pneumoniae 13% and parainfluenza was responsible for 9%. Nevertheless, among very severe cases bacterial causes dominated (77% bacterial vs. 11% viral), led by S. pneumoniae (41%); Mycobacterium tuberculosis, not included in "bacterial", accounted for 9%. 93% and 80% of controls ≥1 year of age were, respectively, fully vaccinated for age against Haemophilus influenzae and S. pneumoniae. CONCLUSIONS: Viral causes, notably RSV, predominated in The Gambia overall, but bacterial causes dominated the severest cases. Efforts must continue to prevent disease by optimizing access to existing vaccines, and to develop new vaccines, notably against RSV. A continued emphasis on appropriate case management of severe pneumonia remains important.

Impact of the introduction of pneumococcal conjugate vaccination on invasive pneumococcal disease and pneumonia in The Gambia: 10 years of population-based surveillance.

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.

The Etiology of Pneumonia From Analysis of Lung Aspirate and Pleural Fluid Samples: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

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.

The development and implementation of an oxygen treatment solution for health facilities in low and middle-income countries.

BACKGROUND: Oxygen reduces mortality from severe pneumonia and is a vital part of case management, but achieving reliable access to oxygen is challenging in low and middle-income country (LMIC) settings. We developed and field tested two oxygen supply solutions suitable for the realities of LMIC health facilities. METHODS: A Health Needs Assessment identified a technology gap preventing reliable oxygen supplies in Gambian hospitals. We used simultaneous engineering to develop two solutions: a Mains-Power Storage (Mains-PS) system consisting of an oxygen concentrator and batteries connected to mains power, and a Solar-Power Storage (Solar-PS) system (with batteries charged by photovoltaic panels) and evaluated them in health facilities in The Gambia and Fiji to assess reliability, usability and costs. RESULTS: The Mains-PS system delivered the specified ≥85% (±3%) oxygen concentration in 100% of 1-2 weekly measurements over 12 months, which was available to 100% of hypoxaemic patients, and 100% of users rated ease-of-use as at least 'good' (90% very good or excellent). The Solar-PS system delivered ≥85% ± 3%) oxygen concentration in 100% of 1-2 weekly measurements, was available to 100% of patients needing oxygen, and 100% of users rated ease-of-use at least very good.Costs for the systems (in US dollars) were: PS$9519, Solar-PS standard version $20 718. The of oxygen for a standardised 30-bed health facility using 1.7 million litres of oxygen per year was: for cylinders 3.2 cents (c)/L in The Gambia and 6.8 c/L in Fiji, for the PS system 1.2 c/L in both countries, and for the Solar-PS system 1.5 c/L in both countries. CONCLUSIONS: The oxygen systems developed and tested delivered high-quality, reliable, cost-efficient oxygen in LMIC contexts, and were easy to operate. Reliable oxygen supplies are achievable in LMIC health facilities like those in The Gambia and Fiji.

Digital auscultation in PERCH: Associations with chest radiography and pneumonia mortality in children.

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 59monthold 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.

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

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 <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.

Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study.

INTRODUCTION: Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. METHODS: Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1-59 months had WHO severe or very severe pneumonia; age-matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. RESULTS: Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. CONCLUSIONS: Listening panel and case-control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries.

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

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

Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

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.

Safety of Induced Sputum Collection in Children Hospitalized With Severe or Very Severe Pneumonia.

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 <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. 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 low-risk 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.

Standardized Interpretation of Chest Radiographs in Cases of Pediatric Pneumonia From the PERCH Study.

BACKGROUND.: Chest radiographs (CXRs) are a valuable diagnostic tool in epidemiologic studies of pneumonia. The World Health Organization (WHO) methodology for the interpretation of pediatric CXRs has not been evaluated beyond its intended application as an endpoint measure for bacterial vaccine trials. METHODS.: The Pneumonia Etiology Research for Child Health (PERCH) study enrolled children aged 1-59 months hospitalized with WHO-defined severe and very severe pneumonia from 7 low- and middle-income countries. An interpretation process categorized each CXR into 1 of 5 conclusions: consolidation, other infiltrate, both consolidation and other infiltrate, normal, or uninterpretable. Two members of a 14-person reading panel, who had undertaken training and standardization in CXR interpretation, interpreted each CXR. Two members of an arbitration panel provided additional independent reviews of CXRs with discordant interpretations at the primary reading, blinded to previous reports. Further discordance was resolved with consensus discussion. RESULTS.: A total of 4172 CXRs were obtained from 4232 cases. Observed agreement for detecting consolidation (with or without other infiltrate) between primary readers was 78% (κ = 0.50) and between arbitrators was 84% (κ = 0.61); agreement for primary readers and arbitrators across 5 conclusion categories was 43.5% (κ = 0.25) and 48.5% (κ = 0.32), respectively. Disagreement was most frequent between conclusions of other infiltrate and normal for both the reading panel and the arbitration panel (32% and 30% of discordant CXRs, respectively). CONCLUSIONS.: Agreement was similar to that of previous evaluations using the WHO methodology for detecting consolidation, but poor for other infiltrates despite attempts at a rigorous standardization process.

Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study.

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 <10 SECs per low-power field (LPF) and 2350 (62%) 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, <10 SECs per LPF (but not >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.

Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study.

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.

Density of Upper Respiratory Colonization With Streptococcus pneumoniae and Its Role in the Diagnosis of Pneumococcal Pneumonia Among Children Aged <5 Years in the PERCH Study.

BACKGROUND.: Previous studies suggested an association between upper airway pneumococcal colonization density and pneumococcal pneumonia, but data in children are limited. Using data from the Pneumonia Etiology Research for Child Health (PERCH) study, we assessed this potential association. METHODS.: PERCH is a case-control study in 7 countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. Cases were children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia. Controls were randomly selected from the community. Microbiologically confirmed pneumococcal pneumonia (MCPP) was confirmed by detection of pneumococcus in a relevant normally sterile body fluid. Colonization density was calculated with quantitative polymerase chain reaction analysis of nasopharyngeal/oropharyngeal specimens. RESULTS.: Median colonization density among 56 cases with MCPP (MCPP cases; 17.28 × 106 copies/mL) exceeded that of cases without MCPP (non-MCPP cases; 0.75 × 106) and controls (0.60 × 106) (each P < .001). The optimal density for discriminating MCPP cases from controls using the Youden index was >6.9 log10 copies/mL; overall, the sensitivity was 64% and the specificity 92%, with variable performance by site. The threshold was lower (≥4.4 log10 copies/mL) when MCPP cases were distinguished from controls who received antibiotics before specimen collection. Among the 4035 non-MCPP cases, 500 (12%) had pneumococcal colonization density >6.9 log10 copies/mL; above this cutoff was associated with alveolar consolidation at chest radiography, very severe pneumonia, oxygen saturation <92%, C-reactive protein ≥40 mg/L, and lack of antibiotic pretreatment (all P< .001). CONCLUSIONS.: Pneumococcal colonization density >6.9 log10 copies/mL was strongly associated with MCPP and could be used to improve estimates of pneumococcal pneumonia prevalence in childhood pneumonia studies. Our findings do not support its use for individual diagnosis in a clinical setting.

The Effect of Antibiotic Exposure and Specimen Volume on the Detection of Bacterial Pathogens in Children With Pneumonia.

BACKGROUND.: Antibiotic exposure and specimen volume are known to affect pathogen detection by culture. Here we assess their effects on bacterial pathogen detection by both culture and polymerase chain reaction (PCR) in children. METHODS.: PERCH (Pneumonia Etiology Research for Child Health) is a case-control study of pneumonia in children aged 1-59 months investigating pathogens in blood, nasopharyngeal/oropharyngeal (NP/OP) swabs, and induced sputum by culture and PCR. Antibiotic exposure was ascertained by serum bioassay, and for cases, by a record of antibiotic treatment prior to specimen collection. Inoculated blood culture bottles were weighed to estimate volume. RESULTS.: Antibiotic exposure ranged by specimen type from 43.5% to 81.7% in 4223 cases and was detected in 2.3% of 4863 controls. Antibiotics were associated with a 45% reduction in blood culture yield and approximately 20% reduction in yield from induced sputum culture. Reduction in yield of Streptococcus pneumoniae from NP culture was approximately 30% in cases and approximately 32% in controls. Several bacteria had significant but marginal reductions (by 5%-7%) in detection by PCR in NP/OP swabs from both cases and controls, with the exception of S. pneumoniae in exposed controls, which was detected 25% less frequently compared to nonexposed controls. Bacterial detection in induced sputum by PCR decreased 7% for exposed compared to nonexposed cases. For every additional 1 mL of blood culture specimen collected, microbial yield increased 0.51% (95% confidence interval, 0.47%-0.54%), from 2% when volume was ≤1 mL to approximately 6% for ≥3 mL. CONCLUSIONS.: Antibiotic exposure and blood culture volume affect detection of bacterial pathogens in children with pneumonia and should be accounted for in studies of etiology and in clinical management.