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The live attenuated tetravalent CYD-TDV vaccine (Dengvaxia) is effective but has scarcely been used due to safety concerns among seronegative recipients. Rapid diagnostic tests (RDTs) which can accurately determine individual dengue serostatus are needed for use in pre-vaccination screening. This study aimed to determine the performance of existing RDTs (which have been designed to detect levels of immunoglobulin G, IgG, associated with acute post-primary dengue) when repurposed for detection of previous dengue infection (where concentrations of IgG are typically lower). A convenience sample of four-hundred-and-six participants including 217 children were recruited during a community serosurvey. Whole blood was collected by phlebotomy and tested using Bioline Dengue IgG/IgM (Abbott) and Standard Q Dengue IgM/IgG (SD Biosensor) RDTs in the field. Serum samples from the same individuals were also tested at National Health Laboratory. The Panbio indirect IgG ELISA was used as a reference test. Reference testing determined that 370 (91.1%) participants were dengue IgG seropositive. Both assays were highly specific (100.0%) but had low sensitivity (Bioline = 21.1% and Standard Q = 4.6%) when used in the field. Sensitivity was improved when RDTs were used under laboratory conditions, and when assays were allowed to run beyond manufacturer recommendations and read at a delayed time-point, but specificity was reduced. Efforts to develop RDTs with high sensitivity and specificity for prior dengue infection which can be operationalised for pre-vaccination screening are ongoing. Performance of forthcoming candidate assays should be tested under field conditions with blood samples, as well as in the laboratory.

BackgroundChest radiography is the standard for diagnosing pediatric lower respiratory infections in low-income and middle-income countries. A method for interpreting pediatric chest radiographs for research endpoints was recently updated by the World Health Organization (WHO) Chest Radiography in Epidemiological Studies project. Research in India required training local physicians to interpret chest radiographs following the WHO method.ObjectiveTo describe the methodology for training Indian physicians and evaluate the training’s effectiveness.Materials and methodsTwenty-nine physicians (15 radiologists and 14 pediatricians) from India were trained by two WHO Chest Radiography in Epidemiological Studies members over 3 days in May 2019. Training materials were adapted from WHO Chest Radiography in Epidemiological Studies resources. Participants followed WHO methodology to interpret 60 unique chest radiographs before and after the training. Participants needed to correctly classify ≥80% of radiographs for primary endpoint pneumonia on the post-training test to be certified to interpret research images. We analyzed participant performance on both examinations.ResultsTwenty-six of 29 participants (89.7%) completed both examinations. The average score increased by 9.6% (95% confidence interval [CI] 5.0–14.1%) between examinations (P<0.001). Participants correctly classifying ≥80% of images for primary endpoint pneumonia increased from 69.2% (18/26) on the pretraining to 92.3% (24/26) on the post-training examination (P=0.003). The mean scores of radiologists and pediatricians on the post-training examination were not statistically different (P=0.43).ConclusionOur results demonstrate this training approach using revised WHO definitions and tools was successful, and that non-radiologists can learn to apply these methods as effectively as radiologists. Such capacity strengthening is important for enabling research to support national policy decision-making in these settings. We recommend future research incorporating WHO chest radiograph methodology to consider modelling trainings after this approach.

Background Scabies and impetigo are endemic in many tropical, low- and middle-income countries. Mass drug administration (MDA) with ivermectin has emerged as a control strategy for these conditions. In 2019, Timor-Leste Ministry of Health planned to implement MDA including ivermectin for the control of lymphatic filariasis, so we undertook a baseline assessment of scabies and impetigo to better understand local epidemiology and contribute to future surveys assessing the impact of MDA. Methods A cross-sectional school survey was conducted in April–May 2019 at six primary schools in a semi-urban (Dili) and two rural (Ermera and Manufahi) settings. Children under 19 years of age present at school on survey days were eligible to participate, of whom we enrolled 1183. Trained health workers interviewed and examined 1043 participants to clinically diagnose scabies using the 2020 International Alliance for the Control of Scabies (IACS) diagnostic criteria, as well as impetigo. Prevalence was adjusted for age and sex. Mixed-effects logistic regression models were used to analyse odds of scabies and impetigo infection. All models accounted for clustering at the school level through the use of random effect terms. Population attributable risk of scabies as a cause of impetigo was also estimated. Results The overall weighted prevalence of scabies was 30.6%. Children in rural Manufahi were more likely to have scabies than those in semi-urban Dili (53.6% vs 28.2%, adjusted odds ratio [AOR] 3.5). Most cases of scabies were mild (3 to 10 lesions), and lesions were usually distributed on more than one body region. Scabies prevalence was lower among 10 to 14 year olds compared to 5 to 9 year olds. Overall weighted prevalence of impetigo was 11.3%. Relative to Dili, children in rural Ermera and Manufahi were twice as likely to have impetigo. Impetigo was twice as common in children with scabies than in those without, corresponding to an attributable risk of scabies as a cause of impetigo of 22.7%. Conclusions Scabies and impetigo prevalence in Timor-Leste is among the highest reported globally, particularly in rural areas. Scabies infestation was strongly associated with impetigo. Comprehensive control strategies are urgently needed in Timor-Leste. Graphical Abstract

In low-to-middle-income countries (LMICs), enteric pathogens contribute to child malnutrition, affecting nutrient absorption, inducing inflammation, and causing diarrhoea. This is a substantial problem in LMICs due to high disease burden, poor sanitation and nutritional status, and the cyclical nature of pathogen infection and malnutrition. This relationship remains understudied in Timor-Leste. In our pilot study of enteric pathogens and malnutrition in Dili, Timor-Leste (July 2019–October 2020), we recruited 60 infants in a birth cohort from Hospital Nacional Guido Valadares (HNGV) with up to four home visits. We collected faecal samples and details of demographics, anthropometrics, diet and food practices, and animal husbandry. Additionally, we collected faecal samples, diagnostics, and anthropometrics from 160 children admitted to HNGV with a clinical diagnosis of severe diarrhoea or severe acute malnutrition (SAM). We tested faeces using the BioFire® FilmArray® Gastrointestinal Panel. We detected high prevalence of enteric pathogens in 68.8% (95%CI 60.4–76.2%) of infants at home, 88.6% of SAM cases (95%CI 81.7–93.3%) and 93.8% of severe diarrhoea cases (95%CI 67.7–99.7%). Diarrhoeagenic Escherichia coli and Campylobacter spp. were most frequently detected. Pathogen presence did not significantly differ in birth cohort diarrhoeal stool, but hospital data indicated associations between Salmonella and Shigella and diarrhoea. We observed wasting in 18.4% (95%CI 9.2–32.5%) to 30.8% (95%CI 17.5–47.7%) of infants across home visits, 57.9% (95%CI 34.0–78.9%) of severe diarrhoea cases, and 92.5% (95%CI 86.4–96.2%) of SAM cases. We associated bottle feeding with increased odds of pathogen detection when compared with exclusive breastfeeding at home (OR 8.3, 95%CI 1.1–62.7). We detected high prevalence of enteric pathogens and signs of malnutrition in children in Dili. Our pilot is proof of concept for a study to fully explore the risk factors and associations between enteric pathogens and malnutrition in Timor-Leste.

IntroductionHistoric disruption in health infrastructure combined with data from a recent vaccine coverage survey suggests there are likely significant immunity gaps to vaccine preventable diseases and high risk of outbreaks in Timor-Leste. Community-based serological surveillance is an important tool to augment understanding of population-level immunity achieved through vaccine coverage and/or derived from prior infection.Methods and analysisThis national population-representative serosurvey will take a three-stage cluster sample and aims to include 5600 individuals above 1 year of age. Serum samples will be collected by phlebotomy and analysed for measles IgG, rubella IgG, SARS-CoV-2 antispike protein IgG, hepatitis B surface antibody and hepatitis B core antigen using commercially available chemiluminescent immunoassays or ELISA. In addition to crude prevalence estimates and to account for differences in Timor-Leste’s age structure, stratified age-standardised prevalence estimates will be calculated, using Asia in 2013 as the standard population. Additionally, this survey will derive a national asset of serum and dried blood spot samples which can be used for further investigation of infectious disease seroepidemiology and/or validation of existing and novel serological assays for infectious diseases.Ethics and disseminationEthical approval has been obtained from the Research Ethics and Technical Committee of the Instituto Nacional da Saúde, Timor-Leste and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research, Australia. Co-designing this study with Timor-Leste’s Ministry-of-Health and other relevant partner organisations will allow immediate translation of findings into public health policy, which may include changes to routine immunisation service delivery and/or plans for supplementary immunisation activities.

The World Health Organization (WHO)-defined radiological pneumonia is a preferred endpoint in pneumococcal vaccine efficacy and effectiveness studies in children. Automating the WHO methodology may support more widespread application of this endpoint. We trained a deep learning model to classify pneumonia CXRs in children using the World Health Organization (WHO)'s standardized methodology. The model was pretrained on CheXpert, a dataset containing 224,316 adult CXRs, and fine-tuned on PERCH, a pediatric dataset containing 4,172 CXRs. The model was then tested on two pediatric CXR datasets released by WHO. We also compared the model's performance to that of radiologists and pediatricians. The average area under the receiver operating characteristic curve (AUC) for primary endpoint pneumonia (PEP) across 10-fold validation of PERCH images was 0.928; average AUC after testing on WHO images was 0.977. The model's classification performance was better on test images with high inter-observer agreement; however, the model still outperformed human assessments in AUC and precision-recall spaces on low agreement images. A deep learning model can classify pneumonia CXR images in children at a performance comparable to human readers. Our method lays a strong foundation for the potential inclusion of computer-aided readings of pediatric CXRs in vaccine trials and epidemiology studies.

ObjectiveAs children hospitalised with community-acquired pneumonia (CAP) are at risk of persistent chest radiograph (CXR) abnormalities and respiratory sequelae, we investigated factors associated with incomplete CXR resolution at 4 weeks and 12 months post-discharge in children from populations at high-risk of chronic lung disease.DesignSecondary analysis−multicentre, placebo-controlled, randomised controlled trial.Settings and patients324 children aged 3 months to ≤5 years hospitalised with radiographic-confirmed CAP were enrolled from seven hospitals in Australia, New Zealand and Malaysia. After 1–3 days of intravenous antibiotics, then 3 days of oral amoxicillin–clavulanate, they were randomised to extended (13–14 days) or standard (5–6 days) courses of antibiotics.InterventionCXRs were performed at admission, 4 weeks, and 12 months post-discharge and reviewed in a blinded manner.Main outcome measuresRadiographic changes of pneumonia at 4 weeks and 12 months post-discharge compared with admission CXRs.ResultsAmong children with interpretable CXRs, incomplete resolution was seen in 42/253 (17%) at 4 weeks, and 29/212 (14%) at 12 months. Characteristics at admission associated with incomplete CXR resolution at 4 weeks were previous pneumonia hospitalisation (adjusted odds ratio [ORadj])=6.46, 95% confidence interval [CI] 2.21 to 18.85) and increasing age (ORadj=0.60 per-year, 95% CI 0.38 to 0.94). Continuing respiratory symptoms/signs at 4 weeks post-discharge was also associated with incomplete resolution (OR=5.63, 95% CI 2.38 to 13.32). At 12 months, previous pneumonia hospitalisation was associated with persistent incomplete CXR resolution (OR=4.03, 95 % CI 1.25 to 13.02).ConclusionIn high-risk settings, younger age, those with previous pneumonia hospitalisation, or ongoing respiratory symptoms/signs 4 weeks post-discharge from hospitalised CAP may be associated with incomplete CXR resolution. Consequently, follow-up imaging and monitoring may be warranted in these children.

IntroductionAcute lower respiratory infections (ALRIs) remain the leading causes of repeated hospitalisations among young disadvantaged Australian and New Zealand First Nations and Timorese children. Severe (hospitalised) and recurrent ALRIs in the first years of life are associated with future chronic lung diseases (eg, bronchiectasis) and impaired lung function. Despite the high burden and long-term consequences of severe ALRIs, clinical, evidence-based and feasible interventions (other than vaccine programmes) that reduce ALRI hospitalisations in children are limited. This randomised controlled trial (RCT) will address this unmet need by trialling a commonly prescribed macrolide antibiotic (azithromycin) for 6–12 months. Long-term azithromycin was chosen as it reduces ALRI rates by 50% in Australian and New Zealand First Nations children with chronic suppurative lung disease or bronchiectasis. The aim of this multicentre, international, double-blind, placebo-containing RCT is to determine whether 6–12 months of weekly azithromycin administered to Australian and New Zealand First Nations and Timorese children after their hospitalisation with an ALRI reduces subsequent ALRIs compared with placebo. Our primary hypothesis is that children receiving long-term azithromycin will have fewer medically attended ALRIs over the intervention period than those receiving placebo.Methods and analysisWe will recruit 160 Australian and New Zealand First Nations and Timorese children aged <2 years to a parallel, superiority RCT across four hospitals from three countries (Australia, New Zealand and Timor-Leste). The primary outcome is the rate of medically attended ALRIs during the intervention period. The secondary outcomes are the rates and proportions of children with ALRI-related hospitalisation, chronic symptoms/signs suggestive of underlying chronic suppurative lung disease or bronchiectasis, serious adverse events, and antimicrobial resistance in the upper airways, and cost-effectiveness analyses.Ethics and disseminationThe Human Research Ethics Committees of the Northern Territory Department of Health and Menzies School of Health Research (Australia), Health and Disability Ethics Committee (New Zealand) and the Institute National of Health-Research Technical Committee (Timor-Leste) approved this study. The study outcomes will be disseminated to academic and medical communities via international peer-reviewed journals and conference presentations, and findings reported to health departments and consumer-based health organisations.Clinical trial registrationAustralia New Zealand Clinical Trial Registry ACTRN12619000456156.

[...]COVID-19 testing in LMICs needs massive upscaling and outreach. [...]pandemic lockdown strategies should maintain vital access to care and be tailored to the particular social, economic and health environments of LMICs. Hypoxaemia as a mortality risk factor in acute lower respiratory infections in children in low and middle-income countries: systematic review and meta-analysis.

Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1–59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6–97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3–65·6) of causes, whereas bacteria accounted for 27·3% (23·3–31·6) and Mycobacterium tuberculosis for 5·9% (3·9–8·3). Viruses were less common (54·5%, 95% CrI 47·4–61·5 vs 68·0%, 62·7–72·7) and bacteria more common (33·7%, 27·2–40·8 vs 22·8%, 18·3–27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4–34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus–enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. Bill & Melinda Gates Foundation.