Association of in utero HIV exposure with child brain structure and language development: a South African birth cohort study.

BACKGROUND: There is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not understood and neuroimaging studies are lacking. We aimed to investigate the cortical brain structure of children who are HIV-exposed and uninfected (HEU) compared to HIV-unexposed (HU) children and to examine the relationship with neurodevelopment. METHODS: The Drakenstein Child Health birth cohort study enrolled pregnant women from a high HIV prevalence area in South Africa with longitudinal follow-up of mother-child pairs. High-resolution magnetic resonance imaging scans from 162 children (70 HEU; 92 HU) were acquired at 2-3 years of age. All HEU children were born to mothers taking antiretroviral therapy. Measures of brain structure (cortical thickness and surface area) in the prefrontal cortex regions were extracted from T1-weighted images and compared between groups using multivariate analysis of variance and linear regression. Child development, assessed using the Bayley Scales of Infant and Toddler Development-III, was correlated with cortical structure, and mediation analyses were performed. RESULTS: Analyses demonstrated an association between HIV exposure and cortical thickness across the prefrontal cortex (p = 0.035). Children who were HEU had thicker cortices in prefrontal regions, with significantly greater cortical thickness in the medial orbitofrontal cortex (mOFC) bilaterally compared to HU children (3.21 mm versus 3.14 mm, p = 0.009, adjusted effect size 0.44 [95% CI 0.12 to 0.75]). Estimates held across multiple sensitivity analyses. There were no group differences in cortical surface area. Language scores, which were lower in HEU versus HU children (81.82 versus 86.25, p = 0.011, effect size - 0.44 [95% CI - 0.78 to - 0.09]), negatively correlated with prefrontal cortical thickness in both groups. Cortical thickness in the mOFC mediated the relationship between HIV exposure and poor language outcomes (Sobel test p = 0.032). CONCLUSIONS: In this cohort study, exposure to HIV during pregnancy was associated with altered cortical structure in early life. Our findings indicate that differences in cortical thickness development in the prefrontal region in children who are HEU may be a pathway leading to language impairment. Longitudinal studies are needed to determine the lasting impact.

Adoption of C-reactive protein rapid tests for the management of acute childhood infections in hospitals in the Netherlands and England: a comparative health systems analysis.

BACKGROUND: The adoption of C-reactive protein point-of-care tests (CRP POCTs) in hospitals varies across Europe. We aimed to understand the factors that contribute to different levels of adoption of CRP POCTs for the management of acute childhood infections in two countries. METHODS: Comparative qualitative analysis of the implementation of CRP POCTs in the Netherlands and England. The study was informed by the non-adoption, abandonment, spread, scale-up, and sustainability (NASSS) framework. Data were collected through document analysis and qualitative interviews with stakeholders. Documents were identified by a scoping literature review, search of websites, and through the stakeholders. Stakeholders were sampled purposively initially, and then by snowballing. Data were analysed thematically. RESULTS: Forty-one documents resulted from the search and 46 interviews were conducted. Most hospital healthcare workers in the Netherlands were familiar with CRP POCTs as the tests were widely used and trusted in primary care. Moreover, although diagnostics were funded through similar Diagnosis Related Group reimbursement mechanisms in both countries, the actual funding for each hospital was more constrained in England. Compared to primary care, laboratory-based CRP tests were usually available in hospitals and their use was encouraged in both countries because they were cheaper. However, CRP POCTs were perceived as useful in some hospitals of the two countries in which the laboratory could not provide CRP measures 24/7 or within a short timeframe, and/or in emergency departments where expediting patient care was important. CONCLUSIONS: CRP POCTs are more available in hospitals in the Netherlands because of the greater familiarity of Dutch healthcare workers with the tests which are widely used in primary care in their country and because there are more funding constraints in England. However, most hospitals in the Netherlands and England have not adopted CRP POCTs because the alternative CRP measurements from the hospital laboratory are available in a few hours and at a lower cost.

Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases. METHODS: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness. RESULTS: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock. CONCLUSION: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology.

Raising AWaRe-ness of Antimicrobial Stewardship Challenges in Pediatric Emergency Care: Results from the PERFORM Study Assessing Consistency and Appropriateness of Antibiotic Prescribing Across Europe.

BACKGROUND: Optimization of antimicrobial stewardship is key to tackling antimicrobial resistance, which is exacerbated by overprescription of antibiotics in pediatric emergency departments (EDs). We described patterns of empiric antibiotic use in European EDs and characterized appropriateness and consistency of prescribing. METHODS: Between August 2016 and December 2019, febrile children attending EDs in 9 European countries with suspected infection were recruited into the PERFORM (Personalised Risk Assessment in Febrile Illness to Optimise Real-Life Management) study. Empiric systemic antibiotic use was determined in view of assigned final "bacterial" or "viral" phenotype. Antibiotics were classified according to the World Health Organization (WHO) AWaRe classification. RESULTS: Of 2130 febrile episodes (excluding children with nonbacterial/nonviral phenotypes), 1549 (72.7%) were assigned a bacterial and 581 (27.3%) a viral phenotype. A total of 1318 of 1549 episodes (85.1%) with a bacterial and 269 of 581 (46.3%) with a viral phenotype received empiric systemic antibiotics (in the first 2 days of admission). Of those, the majority (87.8% in the bacterial and 87.0% in the viral group) received parenteral antibiotics. The top 3 antibiotics prescribed were third-generation cephalosporins, penicillins, and penicillin/ß-lactamase inhibitor combinations. Of those treated with empiric systemic antibiotics in the viral group, 216 of 269 (80.3%) received ≥1 antibiotic in the "Watch" category. CONCLUSIONS: Differentiating bacterial from viral etiology in febrile illness on initial ED presentation remains challenging, resulting in a substantial overprescription of antibiotics. A significant proportion of patients with a viral phenotype received systemic antibiotics, predominantly classified as WHO Watch. Rapid and accurate point-of-care tests in the ED differentiating between bacterial and viral etiology could significantly improve antimicrobial stewardship.

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study.

BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.

Effects on child and adolescent health of climate change mitigation policies: A systematic review of modelling studies.

There is a growing body of modelling evidence that demonstrates the potential for immediate and substantial benefits to adult health from greenhouse gas mitigation actions, but the effects on the health of younger age groups is largely unknown. We conducted a systematic review to identify the available published evidence of the modelled effects on child and adolescent health (≤18 years of age) of greenhouse gas mitigation. We searched six databases of peer-reviewed studies published between January 1, 1990 and July 27, 2022, screened 27,282 original papers and included 23 eligible papers. All included studies were set in high- and middle-income countries; and all studies modelled the effects of interventions that could mitigate greenhouse gas emissions and improve air quality. Most of the available evidence suggests positive benefits for child and adolescent respiratory health from greenhouse gas mitigation actions that simultaneously reduce air pollution (specifically PM2.5 and nitrogen dioxide). We found scant evidence on child and adolescent health from regions more vulnerable to climate change, or on mitigation interventions that could affect exposures other than air pollution.

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study.

Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

External validation of a multivariable prediction model for identification of pneumonia and other serious bacterial infections in febrile immunocompromised children.

OBJECTIVE: To externally validate and update the Feverkids tool clinical prediction model for differentiating bacterial pneumonia and other serious bacterial infections (SBIs) from non-SBI causes of fever in immunocompromised children. DESIGN: International, multicentre, prospective observational study embedded in PErsonalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM). SETTING: Fifteen teaching hospitals in nine European countries. PARTICIPANTS: Febrile immunocompromised children aged 0-18 years. METHODS: The Feverkids clinical prediction model predicted the probability of bacterial pneumonia, other SBI or no SBI. Model discrimination, calibration and diagnostic performance at different risk thresholds were assessed. The model was then re-fitted and updated. RESULTS: Of 558 episodes, 21 had bacterial pneumonia, 104 other SBI and 433 no SBI. Discrimination was 0.83 (95% CI 0.71 to 0.90) for bacterial pneumonia, with moderate calibration and 0.67 (0.61 to 0.72) for other SBIs, with poor calibration. After model re-fitting, discrimination improved to 0.88 (0.79 to 0.96) and 0.71 (0.65 to 0.76) and calibration improved. Predicted risk <1% ruled out bacterial pneumonia with sensitivity 0.95 (0.86 to 1.00) and negative likelihood ratio (LR) 0.09 (0.00 to 0.32). Predicted risk >10% ruled in bacterial pneumonia with specificity 0.91 (0.88 to 0.94) and positive LR 6.51 (3.71 to 10.3). Predicted risk <10% ruled out other SBIs with sensitivity 0.92 (0.87 to 0.97) and negative LR 0.32 (0.13 to 0.57). Predicted risk >30% ruled in other SBIs with specificity 0.89 (0.86 to 0.92) and positive LR 2.86 (1.91 to 4.25). CONCLUSION: Discrimination and calibration were good for bacterial pneumonia but poorer for other SBIs. The rule-out thresholds have the potential to reduce unnecessary investigations and antibiotics in this high-risk group.

Air pollution and child health impacts of decarbonization in 16 global cities: Modelling study.

Most research on the air pollution-related health effects of decarbonization has focused on adults. We assess the potential health benefits that could be achieved in children and young people in a global sample of 16 cities through global decarbonization actions. We modelled annual average concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at 1x1 km resolution in the cities using a general circulation/atmospheric chemistry model assuming removal of all global combustion-related emissions from land transport, industries, domestic energy use and power generation. We modelled the impact on childhood asthma incidence and adverse birth outcomes (low birthweight, pre-term births) using published exposure-response relationships. Removal of combustion emissions was estimated to decrease annual average PM2.5 by between 2.9 µg/m3 (8.4%) in Freetown and 45.4 µg/m3 (63.7%) in Dhaka. For NO2, the range was from 0.3 ppb (7.9%) in Freetown to 18.8 ppb (92.3%) in Mexico City. Estimated reductions in asthma incidence ranged from close to zero in Freetown, Tamale and Harare to 149 cases per 100,000 population in Los Angeles. For pre-term birth, modelled impacts ranged from a reduction of 135 per 100,000 births in Dar es Salaam to 2,818 per 100,000 births in Bhubaneswar and, for low birthweight, from 75 per 100,000 births in Dar es Salaam to 2,951 per 100,000 births in Dhaka. The large variations chiefly reflect differences in the magnitudes of air pollution reductions and estimated underlying disease rates. Across the 16 cities, the reduction in childhood asthma incidence represents more than one-fifth of the current burden, and an almost 10% reduction in pre-term and low birthweight births. Decarbonization actions that remove combustion-related emissions contributing to ambient PM2.5 and NO2 would likely lead to substantial but geographically-varied reductions in childhood asthma and adverse birth outcomes, though there are uncertainties in causality and the precision of estimates.

Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

Are children with prolonged fever at a higher risk for serious illness? A prospective observational study.

OBJECTIVES: To describe the characteristics and clinical outcomes of children with fever ≥5 days presenting to emergency departments (EDs). DESIGN: Prospective observational study. SETTING: 12 European EDs. PATIENTS: Consecutive febrile children <18 years between January 2017 and April 2018. INTERVENTIONS: Children with fever ≥5 days and their risks for serious bacterial infection (SBI) were compared with children with fever <5 days, including diagnostic accuracy of non-specific symptoms, warning signs and C-reactive protein (CRP; mg/L). MAIN OUTCOME MEASURES: SBI and other non-infectious serious illness. RESULTS: 3778/35 705 (10.6%) of febrile children had fever ≥5 days. Incidence of SBI in children with fever ≥5 days was higher than in those with fever <5 days (8.4% vs 5.7%). Triage urgency, life-saving interventions and intensive care admissions were similar for fever ≥5 days and <5 days. Several warning signs had good rule in value for SBI with specificities >0.90, but were observed infrequently (range: 0.4%-17%). Absence of warning signs was not sufficiently reliable to rule out SBI (sensitivity 0.92 (95% CI 0.87-0.95), negative likelihood ratio (LR) 0.34 (0.22-0.54)). CRP <20 mg/L was useful for ruling out SBI (negative LR 0.16 (0.11-0.24)). There were 66 cases (1.7%) of non-infectious serious illnesses, including 21 cases of Kawasaki disease (0.6%), 28 inflammatory conditions (0.7%) and 4 malignancies. CONCLUSION: Children with prolonged fever have a higher risk of SBI, warranting a careful clinical assessment and diagnostic workup. Warning signs of SBI occurred infrequently but, if present, increased the likelihood of SBI. Although rare, clinicians should consider important non-infectious causes of prolonged fever.

Let's just ask them. Perspectives on urban dwelling and air quality: A cross-sectional survey of 3,222 children, young people and parents.

This research aimed to capture and synthesise the views of children, young people, parents and expectant parents (CYPP) about the cities where they live, with a specific focus on air pollution (AP), in order to support the generation of evidence-informed policy that reflects CYPP's perspectives, ultimately contributing to the development of child-centered, healthier, sustainable cities. The Children, Cities and Climate (CCC) project used targeted social media adverts to recruit CYPP to complete an online survey with a combination of open and closed questions in order to collect perceptions about air quality in their home cities, the main sources of AP, and how they would improve their cities. The survey was completed by 3,222 CYPP in 59 of the most polluted cities in 14 countries. Nearly two in five (39%) CYPP cited AP as one of the worst things about their city, with motor transport perceived as the main contributor. CYPP reported differing views on whether their cities were becoming better (43%) or worse (34%) places to live (33% reported it was 'staying the same'). Numerous specific ideas to improve cities and urban air quality emerged, alongside an emphasis on also addressing structural barriers to change. A clear set of principles that should guide how city leaders act was also described, including the need to engage with young people meaningfully. CYPPs articulated good and bad experiences of urban living and perceived AP and traffic as pressing concerns. They provided a clear set of suggestions for improving their cities. Further efforts to engage young people on these issues are warranted.

Adoption of C-reactive protein point-of-care tests for the management of acute childhood infections in primary care in the Netherlands and England: a comparative health systems analysis.

BACKGROUND: The use of point of care (POC) tests varies across Europe, but research into what drives this variability is lacking. Focusing on CRP POC tests, we aimed to understand what factors contribute to high versus low adoption of the tests, and also to explore whether they are used in children. METHODS: We used a comparative qualitative case study approach to explore the implementation of CRP POC tests in the Netherlands and England. These countries were selected because although they have similar primary healthcare systems, the availability of CRP POC tests in General Practices is very different, being very high in the former and rare in the latter. The study design and analysis were informed by the non-adoption, abandonment, spread, scale-up and sustainability (NASSS) framework. Data were collected through a review of documents and interviews with stakeholders. Documents were identified through a scoping literature review, search of websites, and stakeholder recommendation. Stakeholders were selected purposively initially, and then by snowballing. Data were analysed thematically. RESULTS: Sixty-five documents were reviewed and 21 interviews were conducted. The difference in the availability of CRP POC tests is mainly because of differences at the wider national context level. In the two countries, early adopters of the tests advocated for their implementation through the generation of robust evidence and by engaging with all relevant stakeholders. This led to the inclusion of CRP POC tests in clinical guidelines in both countries. In the Netherlands, this mandated their reimbursement in accordance with Dutch regulations. Moreover, the prevailing better integration of health services enabled operational support from laboratories to GP practices. In England, the funding constraints of the National Health Service and the prioritization of alternative and less expensive antimicrobial stewardship interventions prevented the development of a reimbursement scheme. In addition, the lack of integration between health services limits the operational support to GP practices. In both countries, the availability of CRP POC tests for the management of children is a by-product of the test being available for adults. The tests are less used in children mainly because of concerns regarding their accuracy in this age-group. CONCLUSIONS: The engagement of early adopters combined with a more favourable and receptive macro level environment, including the role of clinical guidelines and their developers in determining which interventions are reimbursed and the operational support from laboratories to GP practices, led to the greater adoption of the tests in the Netherlands. In both countries, CRP POC tests, when available, are less used less in children. Organisations considering introducing POC tests into primary care settings need to consider how their implementation fits into the wider health system context to ensure achievable plans.

Febrile illness in high-risk children: a prospective, international observational study.

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the 'Biomarker Validation in HR patients' database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1-4.6)) and HIV (OR 10.4 (95% CI 2.0-54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3-0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522).   Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known: • Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom. • Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New: • Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective. • The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers.

G6PD testing and radical cure for Plasmodium vivax in Cambodia: A mixed methods implementation study.

INTRODUCTION: Cambodia aims to eliminate malaria by 2025, however tackling Plasmodium vivax (P.v) presents multiple challenges. The prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency has prevented the deployment of 8-aminoquinolones for "radical cure", due to the risk of severe haemolysis. Patients with P. vivax have therefore continued to experience recurrent relapses leading to cumulative health and socioeconomic burden. The recent advent of point of care testing for G6PD deficiency has made radical cure a possibility, however at the time of the study lack of operational experience and guidance meant that they had not been introduced. This study therefore aimed to design, implement and evaluate a new care pathway for the radical cure of P.vivax. METHODS: This implementation study took place in Pursat province, Western Cambodia. The interventions were co-developed with key stakeholders at the national, district, and local level, through a continuous process of consultations as well as formal meetings. Mixed methods were used to evaluate the feasibility of the intervention including its uptake (G6PD testing rate and the initiation of primaquine treatment according to G6PD status); adherence (self-reported); and acceptability, using quantitative analysis of primary and secondary data as well as focus group discussions and key informant interviews. RESULTS: The co-development process resulted in the design of a new care pathway with supporting interventions, and a phased approach to their implementation. Patients diagnosed with P.v infection by Village Malaria Workers (VMWs) were referred to local health centres for point-of-care G6PD testing and initiation of radical cure treatment with 14-day or 8-week primaquine regimens depending on G6PD status. VMWs carried out follow-up in the community on days 3, 7 and 14. Supporting interventions included training, community sensitisation, and the development of a smartphone and tablet application to aid referral, follow-up and surveillance. The testing rate was low initially but increased rapidly over time, reflecting the deliberately cautious phased approach to implementation. In total 626 adults received G6PD testing, for a total of 675 episodes. Of these 555 occurred in patients with normal G6PD activity and nearly all (549/555, 98.8%) were initiated on PQ14. Of the 120 with deficient/intermediate G6PD activity 61 (50.8%) were initiated on PQ8W. Self-reported adherence was high (100% and 95.1% respectively). No severe adverse events were reported. The pathway was found to be highly acceptable by both staff and patients. The supporting interventions and gradual introduction were critical to success. Challenges included travel to remote areas and mobility of P.v patients. CONCLUSION: The new care pathway with supporting interventions was highly feasible with high levels of uptake, adherence and acceptability in this setting where high prevalence of G6PD deficiency is high and there is a well-established network of VMWs. Scaling up of the P.v radical cure programme is currently underway in Cambodia and a decline in reduction in the burden of malaria is being seen, bringing Cambodia a step closer to elimination.

Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study.

Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0-18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0-2.3). Management per ED varied as follows: use of diagnostic tests 14-83%, antibiotic treatment 23-54%, admission 34-86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0-38%), partial adherence occurred in 56% (484/868, range 35-77%). CONCLUSION: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. WHAT IS KNOWN: • Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. • There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence. WHAT IS NEW: • Full guideline adherence is limited, whereas partial guideline adherence is moderate in febrile children below 3 months across Europe. • Guideline revision including new biomarkers is needed to improve management in young febrile children.

Early neurodevelopment of HIV-exposed uninfected children in the era of antiretroviral therapy: a systematic review and meta-analysis.

BACKGROUND: There are 15·4 million children who are HIV-exposed and uninfected worldwide. Early child development crucially influences later academic and socioeconomic factors. However, the neurodevelopmental outcomes of HIV-exposed uninfected (HEU) children in the era of maternal antiretroviral therapy (ART) remain unclear. We aimed to examine the effects of in-utero exposure to HIV and ART on child neurodevelopment. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, Africa-Wide Information, PsycInfo, and Global Health databases from inception to May 27, 2020, for studies from the past two decades reporting neurodevelopment of HEU children aged 0-5 years compared with HIV-unexposed (HU) children (aim 1), and effects of different maternal ART regimens on neurodevelopment of HEU children (aim 2). We did narrative syntheses for both aims, and a random-effects meta-analysis of high-quality studies comparing HEU children and HU children, to obtain weighted pooled estimates of effect sizes. This study was registered with PROSPERO, CRD42018075910. FINDINGS: We screened 35 527 records and included 45 articles from 31 studies. Overall, 12 (57%) of 21 studies comparing HEU children and HU children found worse neurodevelopment in HEU children in at least one domain. Study design and methodological quality were variable, with heterogeneity across populations. Meta-analysis included eight high-quality studies comparing 1856 HEU children with 3067 HU children at ages 12-24 months; among HEU children with available data, 1709 (99%) of 1732 were exposed to ART. HEU children had poorer expressive language (effect size -0·17 [95% CI -0·27 to -0·07], p=0·0013) and gross motor function (-0·13 [-0·20 to -0·07], p<0·0001) than HU children, but similar cognitive development (-0·06 [-0·19 to 0·06], p=0·34), receptive language development (-0·10 [-0·23 to 0·03], p=0·14), and fine motor skills (-0·05 [-0·15 to 0·06], p=0·36). Results suggested little or no evidence of an effect of specific maternal ART regimens on neurodevelopment; study heterogeneity prevented meta-analysis. INTERPRETATION: HEU children are at risk of subtle impairments in expressive language and gross motor development by age 2 years. We found no consistent effect of maternal ART regimens analysed, although evidence was scarce. We highlight the need for large high-quality longitudinal studies to assess the neurodevelopmental trajectories of HEU children and to investigate underlying mechanisms to inform intervention strategies. FUNDING: Wellcome Trust and Medical Research Council.

The response to COVID-19 among drug retail outlets in Indonesia: A cross-sectional survey of knowledge, attitudes, and practices.

Background: Pharmacists have been at the frontline of the COVID-19 response in Indonesia, providing medicines, advice, and referral services often in areas with limited healthcare access. This study aimed to explore their knowledge, attitudes, and practices during the pandemic, so that we can be better prepared for future emergencies. Methods: A cross-sectional online survey of community pharmacists and pharmacy technicians in Indonesia was conducted between July and August 2020. The dataset was analysed descriptively, and logistic regression was used to explore willingness to participate in COVID-19 interventions. Findings: 4716 respondents participated in the survey. Two-thirds (66·7%) reported knowing only "a little" about COVID-19 and around a quarter (26·6%) said they had not received any COVID-19 guidelines. Almost all were concerned about being infected (97·2%) and regularly took steps to protect themselves and their clients (87·2%). Stock-outs of Personal Protective Equipment (PPE) and other products (32·3%) was the main reason for not taking any precautions. Around a third (37·7%) mentioned having dispensed antibiotics to clients suspected of having COVID-19. To support COVID-19 response efforts, most respondents were willing to provide verbal advice to clients (97·8%), distribute leaflets to clients (97·7%), and participate in surveillance activities (88·8%). Older respondents, those identifying as male, and those working in smaller outlets were more willing to provide information leaflets. Those working in smaller outlets were also more willing to engage in outbreak surveillance. Interpretation: Drug retail outlets continue to operate at the frontline of disease outbreaks and pandemics around the world. These providers have an important role to play by helping to reduce the burden on facilities and providing advice and treatment. To fulfil this role, drug retail outlets require regular access to accurate guidelines and steady supplies of PPE. Calls for drug retail outlet staff to plat in response efforts including the provision of information to clients and surveillance could ease escalating pressures on the health system during future outbreaks. Funding: This study was funded by a grant from the Department of Foreign Affairs and Trade, Australia, under the Stronger Health Systems for Health Security Scheme.