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Wittmann S, Jorgensen R, Oostenbrink R, et al., 2023, Heart rate and respiratory rate in predicting risk of serious bacterial infection in febrile children given antipyretics: prospective observational study, European Journal of Pediatrics
<jats:title>Abstract</jats:title><jats:p>Clinical algorithms used in the assessment of febrile children in the Paediatric Emergency Departments are commonly based on threshold values for vital signs, which in children with fever are often outside the normal range. Our aim was to assess the diagnostic value of heart and respiratory rate for serious bacterial infection (SBI) in children after temperature lowering following administration of antipyretics. A prospective cohort of children presenting with fever between June 2014 and March 2015 at the Paediatric Emergency Department of a large teaching hospital in London, UK, was performed. Seven hundred forty children aged 1 month–16 years presenting with a fever and ≥ 1 warning signs of SBI given antipyretics were included. Tachycardia or tachypnoea were defined by different threshold values: (a) APLS threshold values, (b) age-specific and temperature-adjusted centiles charts and (c) relative difference in <jats:italic>z</jats:italic>-score. SBI was defined by a composite reference standard (cultures from a sterile site, microbiology and virology results, radiological abnormalities, expert panel). Persistent tachypnoea after body temperature lowering was an important predictor of SBI (OR 1.92, 95% CI 1.15, 3.30). This effect was only observed for pneumonia but not other SBIs. Threshold values for tachypnoea > 97th centile at repeat measurement achieved high specificity (0.95 (0.93, 0.96)) and positive likelihood ratios (LR + 3.25 (1.73, 6.11)) and may be useful for ruling in SBI, specifically pneumonia. Persistent tachycardia was not an independent predictor of SBI and had limited value as a diagnostic test.</jats:p><jats:p><jats:italic> Conclusion</jats:italic>: Among children given antipyretics, tachypnoea at repeat measurement had some value in predicting SBI and was useful to rule in pneumo
Kuiper R, Wright VJ, Habgood-Coote D, et al., 2023, Bridging a diagnostic Kawasaki disease classifier from a microarray platform to a qRT-PCR assay, Pediatric Research, Vol: 93, Pages: 559-569, ISSN: 0031-3998
BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier. METHODS: We designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier. RESULTS: The performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924-1.00] vs 0.992 [95% CI: 0.978-1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections. CONCLUSION: We successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory. IMPACT: A diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory.
Channon-Wells S, Vito O, McArdle AJ, et al., 2023, Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study, The Lancet Rheumatology, ISSN: 2665-9913
Eleftheriou D, Moraes YC, Purvis C, et al., 2023, Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol, TRIALS, Vol: 24
Krupickova S, Voges I, Mohiaddin R, et al., 2023, Short-term outcome of late gadolinium changes detected on cardiovascular magnetic resonance imaging following coronavirus disease 2019 Pfizer/BioNTech vaccine-related myocarditis in adolescents, PEDIATRIC RADIOLOGY, ISSN: 0301-0449
Dewez JE, Pembrey L, Nijman RG, et al., 2022, Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians., PLoS One, Vol: 17, Pages: 1-22, ISSN: 1932-6203
BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicia
Neumann E, Schreeck F, Herberg J, et al., 2022, How paediatric drug development and use could benefit from OMICs: A c4c expert group white paper, British Journal of Clinical Pharmacology, Vol: 88, Pages: 5017-5033, ISSN: 0306-5251
The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good-quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages.
Hagedoorn NN, Boeddha NP, Kohlfuerst DS, et al., 2022, Hemostasis proteins in invasive meningococcal and nonmeningococcal infections: a prospective multicenter study., Pediatric Critical Care Medicine, Vol: 23, Pages: e543-e554, ISSN: 1529-7535
OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens (Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus, and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci (n = 83), pneumococci (n = 64), S. aureus (n = 50), and GAS (n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score). Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens (p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic
Boeddha NPP, Atkins L, de Groot R, et al., 2022, Group A streptococcal disease in paediatric inpatients: a European perspective, EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199
Tan CD, van der Walle EEPL, Vermont CL, et al., 2022, Correction to: Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4211-4214, ISSN: 0340-6199
van der Velden FJS, de Vries G, Martin A, et al., 2022, Febrile illness in high-risk children: a prospective, international observational study, EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199
Tan CD, van der Walle EEPL, Vermont CL, et al., 2022, Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4199-4209, ISSN: 0340-6199
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 guideline
Pennisi I, Moniri A, Miscourides N, et al., 2022, Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-chip platform, BIOSENSORS & BIOELECTRONICS, Vol: 216, ISSN: 0956-5663
Tan CD, El Ouasghiri S, von Both U, et al., 2022, Sex differences in febrile children with respiratory symptoms attending European emergency departments: An observational multicenter study., PLoS One, Vol: 17, Pages: 1-11, ISSN: 1932-6203
OBJECTIVE: To assess sex differences in presentation and management of febrile children with respiratory symptoms attending European Emergency Departments. DESIGN AND SETTING: An observational study in twelve Emergency Departments in eight European countries. PATIENTS: Previously healthy children aged 0-<18 years with fever (≥ 38°C) at the Emergency Department or in the consecutive three days before Emergency Department visit and respiratory symptoms were included. MAIN OUTCOME MEASURES: The main outcomes were patient characteristics and management defined as diagnostic tests, treatment and admission. Descriptive statistics were used for patient characteristics and management stratified by sex. Multivariable logistic regression analyses were performed for the association between sex and management with adjustment for age, disease severity and Emergency Department. Additionally, subgroup analyses were performed in children with upper and lower respiratory tract infections and in children below five years. RESULTS: We included 19,781 febrile children with respiratory symptoms. The majority were boys (54%), aged 1-5 years (58%) and triaged as low urgent (67%). Girls presented less frequently with tachypnea (15% vs 16%, p = 0.002) and increased work of breathing (8% vs 12%, p<0.001) compared with boys. Girls received less inhalation medication than boys (aOR 0.82, 95% CI 0.74-0.90), but received antibiotic treatment more frequently than boys (aOR 1.09, 95% CI 1.02-1.15), which is associated with a higher prevalence of urinary tract infections. Amongst children with a lower respiratory tract infection and children below five years girls received less inhalation medication than boys (aOR 0.77, 95% CI 0.66-0.89; aOR 0.80, 95% CI 0.72-0.90). CONCLUSIONS: Sex differences concerning presentation and management are present in previously healthy febrile children with respiratory symptoms presenting to the Emergency Department. Future research should focus on whethe
Piccinelli E, Bautista-Rodriguez C, Herberg J, et al., 2022, Segmental and global longitudinal strain differences between Kawasaki disease and multi-system inflammatory syndrome in children, CARDIOLOGY IN THE YOUNG, ISSN: 1047-9511
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Pennisi I, Moniri A, Miscourides N, et al., 2022, Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-a-chip technology, Publisher: MedRxiv
<h4>ABSTRACT</h4> The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between tr
Jackson H, Calle IR, Broderick C, et al., 2022, Characterisation of the blood RNA host response underpinning severity in COVID-19 patients, Scientific Reports, Vol: 12, ISSN: 2045-2322
Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.
Borensztajn DM, Hagedoorn NN, Carrol ED, et al., 2022, Febrile children with comorbidities at the emergency department - a multicentre observational study, European Journal of Pediatrics, Vol: 181, Pages: 3491-3500, ISSN: 0340-6199
We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3–1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2–3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1–2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1–2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8–7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7–2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2–6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5–24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1–6.9) or PICU admission (aOR 9.7, 6.1–15.5).
Cunnington AJ, Digital Diagnostics for Africa Network, 2022, The potential of digital molecular diagnostics for infectious diseases in sub-Saharan Africa, PLOS Digital Health, Vol: 1, ISSN: 2767-3170
There is a large gap between diagnostic needs and diagnostic access across much of sub-Saharan Africa, particularly for infectious diseases which inflict a substantial burden of morbidity and mortality. Accurate diagnostics are essential for the correct treatment of individuals and provide vital information underpinning disease surveillance, prevention, and control strategies. Digital molecular diagnostics combine the high sensitivity and specificity of molecular detection with point-of-care format and mobile connectivity. Recent developments in these technologies create an opportunity for a radical transformation of the diagnostic ecosystem. Rather than trying to emulate diagnostic laboratory models in resource-rich settings, African countries have the potential to pioneer new models of healthcare designed around digital diagnostics. This article describes the need for new diagnostic approaches, highlights advances in digital molecular diagnostic technology, and outlines their potential for tackling infectious diseases in sub-Saharan Africa. It then addresses the steps which will be necessary for development and implementation of digital molecular diagnostics. Although the focus is on infectious diseases in sub-Saharan Africa, many of the principles apply to other resource limited settings and to non-communicable diseases.
Trobisch A, Schweintzger NA, Kohlfurst DS, et al., 2022, Osteoarticular infections in pediatric hospitals in Europe: a prospective cohort study from the EUCLIDS consortium, Frontiers in Pediatrics, Vol: 10, Pages: 1-12, ISSN: 2296-2360
Background: Pediatric osteoarticular infections (POAIs) are serious diseases requiring early diagnosis and treatment.Methods: In this prospective multicenter cohort study, children with POAIs were selected from the European Union Childhood Life-threatening Infectious Diseases Study (EUCLIDS) database to analyze their demographic, clinical, and microbiological data.Results: A cohort of 380 patients with POAIs, 203 with osteomyelitis (OM), 158 with septic arthritis (SA), and 19 with both OM and SA, was analyzed. Thirty-five patients were admitted to the Pediatric Intensive Care Unit; out of these, six suffered from shock, one needed an amputation of the right foot and of four left toes, and two had skin transplantation. According to the Pediatric Overall Performance Score, 36 (10.5%) showed a mild overall disability, 3 (0.8%) a moderate, and 1 (0.2%) a severe overall disability at discharge. A causative organism was detected in 65% (247/380) of patients. Staphylococcus aureus (S. aureus) was identified in 57.1% (141/247) of microbiological confirmed cases, including 1 (0.7%) methicillin-resistant S. aureus (MRSA) and 6 (4.2%) Panton-Valentine leukocidin (PVL)-producing S. aureus, followed by Group A Streptococcus (18.2%) and Kingella kingae (8.9%). K. kingae and PVL production in S. aureus were less frequently reported than expected from the literature.Conclusion: POAIs are associated with a substantial morbidity in European children, with S. aureus being the major detected pathogen. In one-third of patients, no causative organism is identified. Our observations show an urgent need for the development of a vaccine against S. aureus and for the development of new microbiologic diagnostic guidelines for POAIs in European pediatric hospitals.
Hagedoorn NN, Zachariasse JM, Borensztajn D, et al., 2022, Shock Index in the early assessment of febrile children at the emergency department: a prospective multicentre study, Archives of Disease in Childhood, Vol: 107, Pages: 116-122, ISSN: 0003-9888
OBJECTIVE: (1) To derive reference values for the Shock Index (heart rate/systolic blood pressure) based on a large emergency department (ED) population of febrile children and (2) to determine the diagnostic value of the Shock Index for serious illness in febrile children. DESIGN/SETTING: Observational study in 11 European EDs (2017-2018). PATIENTS: Febrile children with measured blood pressure. MAIN OUTCOME MEASURES: Serious bacterial infection (SBI), invasive bacterial infection (IBI), immediate life-saving interventions (ILSIs) and intensive care unit (ICU) admission. The association between high Shock Index (>95th centile) and each outcome was determined by logistic regression adjusted for age, sex, referral, comorbidity and temperature. Additionally, we calculated sensitivity, specificity and negative/positive likelihood ratios (LRs). RESULTS: Of 5622 children, 461 (8.2%) had SBI, 46 (0.8%) had IBI, 203 (3.6%) were treated with ILSI and 69 (1.2%) were ICU admitted. High Shock Index was associated with SBI (adjusted OR (aOR) 1.6 (95% CI 1.3 to 1.9)), ILSI (aOR 2.5 (95% CI 2.0 to 2.9)), ICU admission (aOR 2.2 (95% CI 1.4 to 2.9)) but not with IBI (aOR: 1.5 (95% CI 0.6 to 2.4)). For the different outcomes, sensitivity for high Shock Index ranged from 0.10 to 0.15, specificity ranged from 0.95 to 0.95, negative LRs ranged from 0.90 to 0.95 and positive LRs ranged from 1.8 to 2.8. CONCLUSIONS: High Shock Index is associated with serious illness in febrile children. However, its rule-out value is insufficient which suggests that the Shock Index is not valuable as a screening tool for all febrile children at the ED.
Tan CD, Hagedoorn NN, Dewez JE, et al., 2022, Rapid Viral Testing and Antibiotic Prescription in Febrile Children With Respiratory Symptoms Visiting Emergency Departments in Europe, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 41, Pages: 39-44, ISSN: 0891-3668
Borensztajn D, Hagedoorn NN, Carrol E, et al., 2022, Characteristics and management of adolescents attending the ED with fever: a prospective multicentre study, BMJ Open, Vol: 12, ISSN: 2044-6055
Objective Most studies on febrile children have focused on infants and young children with serious bacterial infection (SBI). Although population studies have described an increased risk of sepsis in adolescents, little is known about febrile adolescents attending the emergency department (ED). We aimed to describe patient characteristics and management of febrile adolescents attending the ED.Design and setting The MOFICHE/PERFORM study (Management and Outcome of Febrile Children in Europe/Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union), a prospective multicentre study, took place at 12 European EDs. Descriptive and multivariable regression analyses were performed, comparing febrile adolescents (12–18 years) with younger children in terms of patient characteristics, markers of disease severity (vital signs, clinical alarming signs), management (diagnostic tests, therapy, admission) and diagnosis (focus, viral/bacterial infection).Results 37 420 encounters were included, of which 2577 (6.9%) were adolescents. Adolescents were more often triaged as highly urgent (38.9% vs 34.5%) and described as ill appearing (23.1% vs 15.6%) than younger children. Increased work of breathing and a non-blanching rash were present less often in adolescents, while neurological signs were present more often (1% vs 0%). C reactive protein tests were performed more frequently in adolescents and were more often abnormal (adjusted OR (aOR) 1.7, 95% CI 1.5 to 1.9). Adolescents were more often diagnosed with SBI (OR 1.8, 95% CI 1.6 to 2.0) and sepsis/meningitis (OR 2.3, 95% CI 1.1 to 5.0) and were more frequently admitted (aOR 1.3, 95% CI 1.2 to 1.4) and treated with intravenous antibiotics (aOR 1.7, 95% CI 1.5 to 2.0).Conclusions Although younger children presented to the ED more frequently, adolescents were more often diagnosed with SBI and sepsis/meningitis. Our data emphasise the importance of awareness of severe infections
Hoggart C, Shimizu C, Galassini R, et al., 2021, Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease, European Journal of Human Genetics, Vol: 29, Pages: 1734-1744, ISSN: 1018-4813
Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.
Li HK, Kaforou M, Rodriguez-Manzano J, et al., 2021, Discovery and validation of a 3-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations; a case-control then observational cohort study, The Lancet Microbe, Vol: 2, Pages: 594-603, ISSN: 2666-5247
Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We sought to derive and validate a blood transcriptional signature to detect viral infections including COVID-19 among adults with suspected infection presenting to the Emergency Department (ED).Methods: Blood RNA sequencing was performed on a discovery cohort of adults attending the ED with suspected infection who had subsequently-confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes were subjected to feature selection to derive the most parsimonious discriminating signature. RT-qPCR validation of the signature was then performed in a prospective cohort of ED patients presenting with undifferentiated fever, and a second case-control cohort of ED patients with COVID-19 or bacterial infection. Signature performance was assessed by calculating area under receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.Findings: A 3-gene transcript signature was derived from the discovery cohort of 56 bacterial and 27 viral infection cases. In the validation cohort of 200 cases, the signature differentiated bacterial from viral infections with an AUC-ROC of 0.976 (95% CI: 0.919-1.000), sensitivity 97.3% and specificity of 100%. The AUC-ROC for C-reactive protein (CRP) and leucocyte count (WCC) was 0.833 (95% CI: 0.694-0.944) and 0.938 (95% CI: 0.840-0.986) respectively. The signature achieved higher net benefit in decision curve analysis than either CRP or WCC for discriminating viral infections from all other cases. In the second validation analysis the signature discriminated 35 bacterial infections from 34 SARS-CoV-2 positive COVID-19 infections with AUC-ROC of 0.953 (95% CI: 0.893-0.992), sensitivity 88.6% and specificity of 94.1%.Interpretation: This novel 3-gene signature discriminates viral i
Boeddha NP, Driessen GJ, Hagedoorn NN, et al., 2021, Detectable a disintegrin and metalloproteinase with thrombospondin motifs-1 in serum is associated with adverse outcome in pediatric sepsis., Critical Care Explorations, Vol: 3, Pages: 1-12, ISSN: 2639-8028
IMPORTANCE: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking. OBJECTIVES: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome. DESIGN: Data from two prospective cohort studies. SETTING AND PARTICIPANTS: Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission). MAIN OUTCOMES AND MEASURES: Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay. RESULTS: In cohort 1 (n = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; p = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; p = 0.04). In cohort 2 (n = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; p = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; p = 0.003), which was mostly attributable to patients with Neisseria meningitidis. CONCLUSIONS AND RELEVANCE: In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with deat
Borenzstajn D, Hagedoorn N, Carrol ED, et al., 2021, A NICE combination for predicting hospitalisation at the Emergency Department: a European multicentre observational study of febrile children, The Lancet Regional Health - Europe, Vol: 8, ISSN: 2666-7762
BackgroundProlonged Emergency Department (ED) stay causes crowding and negatively impacts quality of care. We developed and validated a prediction model for early identification of febrile children with a high risk of hospitalisation in order to improve ED flow.MethodsThe MOFICHE study prospectively collected data on febrile children (0–18 years) presenting to 12 European EDs. A prediction models was constructed using multivariable logistic regression and included patient characteristics available at triage. We determined the discriminative values of the model by calculating the area under the receiver operating curve (AUC).FindingsOf 38,424 paediatric encounters, 9,735 children were admitted to the ward and 157 to the PICU. The prediction model, combining patient characteristics and NICE alarming, yielded an AUC of 0.84 (95%CI 0.83-0.84).The model performed well for a rule-in threshold of 75% (specificity 99.0% (95%CI 98.9-99.1%, positive likelihood ratio 15.1 (95%CI 13.4-17.1), positive predictive value 0.84 (95%CI 0.82-0.86)) and a rule-out threshold of 7.5% (sensitivity 95.4% (95%CI 95.0-95.8), negative likelihood ratio 0.15 (95%CI 0.14-0.16), negative predictive value 0..95 (95%CI 0.95-9.96)). Validation in a separate dataset showed an excellent AUC of 0.91 (95%CI 0.90- 0.93). The model performed well for identifying children needing PICU admission (AUC 0.95, 95%CI 0.93-0.97). A digital calculator was developed to facilitate clinical use.InterpretationPatient characteristics and NICE alarming signs available at triage can be used to identify febrile children at high risk for hospitalisation and can be used to improve ED flow.FundingEuropean Union, NIHR, NHS.
Thayyil S, Pant S, Montaldo P, et al., 2021, Hypothermia for moderate or severe neonatal encephalopathy in low and middle-income countries (HELIX): a randomised control trial in India, Sri Lanka and Bangladesh, The Lancet Global Health, Vol: 9, Pages: e1273-e1285, ISSN: 2214-109X
Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low- and middle-income countries (LMICs) remains unclear. We examined if therapeutic hypothermia alongside optimal supportive intensive care reduces death or disability after neonatal encephalopathy in South Asia. Methods: We conducted a multi-country open label randomised controlled trial involving seven tertiary neonatal intensive care units in India, Sri Lanka and Bangladesh, between August 2015 and September 2020. We allocated infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy into whole body hypothermia (33·5 0 C) for 72 hours using a servo-controlled cooling device, or usual care (control group), within six hours of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support and access to 3 Telsa magnetic resonance imaging and spectroscopy. The primary outcome was a combined end point of death or moderate or severe disability at 18 to 22 months of age, assessed by Bayley scales of infant development (Version III).Findings: Of 576 eligible infants, we assigned 202 to hypothermia and 206 to control group. Primary outcome data were available for 394 (96·5%) infants, and occurred in 98(50·3%) of the hypothermia and 94 (47·2%) of the control group (Risk Ratio (RR) 1·06;95% confidence intervals (CI) 0·87 to 1·30 (p = 0·55). Eighty-four infants (42·4%) in the hypothermia group and 63 (31·3%) (p = 0·02) infants in the control group died, of whom 72 (35·6%) and 49 (23·8%) (p = 0·009) died during neonatal hospitalisation. Interpretation: Therapeutic hypothermia did not reduce the combined outcome of death or disability at18 months after neonatal encephalopathy in LMICs, but significantly increased mortality. Therapeutic hypothermia should not
Nijman R, Oostenbrink R, Moll HA, et al., 2021, A novel framework for phenotyping children with suspected or confirmed infection for future biomarker studies, Frontiers in Pediatrics, Vol: 9, Pages: 1-18, ISSN: 2296-2360
Background: The limited diagnostic accuracy of biomarkers in children at risk of a serious bacterial infection (SBI) might be due to the imperfect reference standard of SBI. We aimed to evaluate the diagnostic performance of a new classification algorithm for biomarker discovery in children at risk of SBI.Methods: We used data from five previously published, prospective observational biomarker discovery studies, which included patients aged 0– <16 years: the Alder Hey emergency department (n = 1,120), Alder Hey pediatric intensive care unit (n = 355), Erasmus emergency department (n = 1,993), Maasstad emergency department (n = 714) and St. Mary's hospital (n = 200) cohorts. Biomarkers including procalcitonin (PCT) (4 cohorts), neutrophil gelatinase-associated lipocalin-2 (NGAL) (3 cohorts) and resistin (2 cohorts) were compared for their ability to classify patients according to current standards (dichotomous classification of SBI vs. non-SBI), vs. a proposed PERFORM classification algorithm that assign patients to one of eleven categories. These categories were based on clinical phenotype, test outcomes and C-reactive protein level and accounted for the uncertainty of final diagnosis in many febrile children. The success of the biomarkers was measured by the Area under the receiver operating Curves (AUCs) when they were used individually or in combination.Results: Using the new PERFORM classification system, patients with clinically confident bacterial diagnosis (“definite bacterial” category) had significantly higher levels of PCT, NGAL and resistin compared with those with a clinically confident viral diagnosis (“definite viral” category). Patients with diagnostic uncertainty had biomarker concentrations that varied across the spectrum. AUCs were higher for classification of “definite bacterial” vs. “definite viral” following the PERFORM algorithm than using the “SBI” vs. “non-SBI” c
McArdle AJ, Vito O, Patel H, et al., 2021, Treatment of multisystem inflammatory syndrome in children, New England Journal of Medicine, Vol: 385, Pages: 11-22, ISSN: 0028-4793
BACKGROUNDEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.METHODSWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.RESULTSData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.CONCLUSIONSWe found n
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