SARS-CoV-2 seroprevalence among children in Greece during Omicron variant period.

The Omicron variant is associated with increased transmissibility, but evidence about the impact of Omicron in seropositivity of children is limited. This study aims to evaluate SARS-CoV-2 seroprevalence in children during the different variants' subperiods. A prospective multicenter seroprevalence study was conducted in 7 University public hospitals in Greece from November 2021 to August 2022 (3 subperiods: November 2021-February 2022, March 2022-May 2022, June 2022-August 2022). Children from different age groups, admitted to the hospital or examined in outpatient clinics for reasons other than COVID-19 were enrolled. Neutralizing antibodies (Nabs), anti-Spike (anti-S) and anti-nucleocapsid (anti-N) SARS-CoV-2 IgG in serum were evaluated. A total of 2127 children (males:57,2%; median age:4,8years) were enrolled. Anti-N IgG seropositivity increased from 17,8% in the first sub-period to 40,7% in the second sub-period and then decreased in the third sub-period (36,7%). Anti-S IgG seropositivity appeared to have an increasing trend over the study period, starting from 34,8% and reaching 80,7%. Children aged 1-4 years old have significantly higher anti-N IgG titers compared to children aged 0-1 years old (p < 0,001). Infants have significantly lower anti-S IgG titers compared to all other age groups (p < 0,001). Immunocompromised children and infants have the lowest seropositivity for NAbs.Conclusions During the Omicron period, seropositivity significantly increased, as a result of higher transmissibility. Neonates and infants have lower antibody titers compared to other age groups, while young children aged 1-4 years old present higher antibody titers, suggesting that this age group may mount a higher antibody response. Continuous surveillance seroprevalence studies are needed in children, in order to identify the true extent of SARS-CoV-2 and guide the planning of adequate public health measures.

WHAT IS KNOWN: • Seroprevalence surveys among children may be extremely useful, in order to properly monitor the immunity, either natural or acquired, through the quantification of IgG antibodies and to plan further immunization policies. • There are variations in the seroprevalence of COVID-19 between the different periods, according to the vaccination rates, the type of circulating variant and the transmissibility of the virus. • The Omicron variant is associated with increased transmissibility, but evidence about the impact of Omicron in seropositivity of children is limited. WHAT IS NEW: • In this large multicenter seroepidemiological study, SARS-CoV-2 seroprevalence rate in children is higher during the Omicron period in comparison to the previous pandemic waves, due to the high transmissibility of the virus and the increased rates of reinfection. • Neonates and infants have lower antibody titers compared to other age groups, while young children aged 1­4 years old present higher antibody titers, indicating that the children of this age group mount a higher antibody response. • This study provides essential information about immunity and the level of protection in the pediatric population, as neutralizing antibodies were evaluated, in addition to the anti-N and anti-S IgG antibodies.

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.

SARS-CoV-2 Antibody Kinetics in Unvaccinated Hospitalized Children With COVID-19.

BACKGROUND: Antibody levels decline a few months post-acute COVID-19, but humoral memory persists in adults. Age and disease severity may affect antibody responses. This study aims to evaluate the presence and durability of antibody responses in children with COVID-19. METHODS: A prospective, single-center study, involving unvaccinated children 0-16 years of age who were hospitalized with COVID-19 between October 2020 and December 2021, was conducted. Serological testing for anti-Spike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG and neutralizing antibodies was performed at diagnosis and at 1-, 3-, 6- and 12-months post-infection. RESULTS: A total of 65 immunocompetent children were enrolled [mean age (±SD): 6.7 (±6.4) years; males: 56.9%]. At 3 months, 40/44 (91%) children were seropositive; seropositivity persisted in 22/26 (85%) children at 6 months and in 10/12 (83%) children at 12 months. There was no evidence that age was modifying the prediction of variance of SARS-CoV-2 IgG levels. In contrast, SARS-CoV-2 IgG levels varied with time and disease severity. The association with time was non-linear, so that with increasing time there was a significant reduction in SARS-CoV-2 IgG levels [coef, 0.044 (95% confidence interval {CI}: 0.061-0.028), P < 0.001]. For each increment of time, the higher disease severity group was associated with 0.9 lower SARS-CoV-2 IgG levels. Everyone varied from the average effect of time with an SD of 0.01, suggesting that individuals may have different trajectories across time. CONCLUSION: Disease severity, but not age, influences antibody titers among children hospitalized with COVID-19. SARS-CoV-2 infection induces durable seroconversion in these children with detectable IgG levels at 1 year after infection.

Multisystem inflammatory syndrome in children (MIS-C): A nationwide collaborative study in the Greek population.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe hyperinflammatory condition that may occur following SARS-CoV-2 infection. This retrospective, descriptive study of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) in 12 tertiary care centers from 3/11/2020 to 12/31/2021. Demographics, clinical and laboratory characteristics, treatment and outcomes are described. Among 145 patients (95 males, median age 8.2 years) included, 123 met the WHO criteria for MIS-C, while 112 (77%) had serological evidence of SARS-CoV-2 infection. Fever was present in 99%, gastrointestinal symptoms in 77%, mucocutaneous involvement in 68% and respiratory symptoms in 28%. Fifty-five patients (38%) developed myocarditis, 29 (20%) pericarditis and 19 (13%) coronary aneurysms. Among the above cases 11/55 (20%), 1/29 (3.4%) and 5/19 (26.3%), respectively, cardiac complications had not fully resolved at discharge. Underlying comorbidities were reported in 18%. Median CRP value was 155 mg/l, ferritin 535 ng/ml, PCT 1.6 ng/ml and WBC 14.2 × 109/mm3. Most patients had elevated troponin (41.3%) and/or NT-pro-BNP (49.6%). Intravenous immunoglobulin plus corticosteroids were used in 117/145 (80.6%), monotherapy with IVIG alone in 13/145 (8.9%) and with corticosteroids alone in 2/145 (1.3%). Anti-IL1 treatment was added in 15 patients (10.3%). Thirty-three patients (23%) were admitted to the PICU, 14% developed shock and 1 required ECMO. Mortality rate was 0.68%. The incidence of MIS-C was estimated at 0.69/1000 SARS-CoV-2 infections. Patients who presented with shock had higher levels of NT-pro-BNP compared to those who did not (p < 0.001). Acute kidney injury and/or myocarditis were associated with higher risk of developing shock. CONCLUSION: MIS-C is a novel, infrequent but serious disease entity. Cardiac manifestations included myocarditis and pericarditis, which resolved in most patients before discharge. Timely initiation of immunomodulatory therapy was shown to be effective. NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. Further research is required to elucidate the pathogenesis, risk factors and optimal management, and long-term outcomes of this clinical entity. WHAT IS KNOWN: • MIS-C is an infrequent but serious disease entity. • Patients with MIS-C present with multi-organ dysfunction, primarily involving the gastrointestinal and cardiovascular systems. WHAT IS NEW: • NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. • Acute kidney injury and/or myocarditis were associated with higher risk of developing shock.

Which low urgent triaged febrile children are suitable for a fast track? An observational European study.

BACKGROUND: The number of paediatric patients visiting the ED with non-urgent problems is increasing, leading to poor patient flow and ED crowding. Fast track aims to improve the efficiency of evaluation and discharge of low acuity patients. We aimed to identify which febrile children are suitable for a fast track based on presenting symptoms and management. METHODS: This study is part of the Management and Outcome of Fever in children in Europe study, which is an observational study including routine data of febrile children <18 years attending 12 European EDs. We included febrile, low urgent children (those assigned a triage acuity of either 'standard' or 'non-urgent' using the Manchester Triage System) and defined children as suitable for fast track when they have minimal resource use and are discharged home. Presenting symptoms consisted of neurological (n=237), respiratory (n=8476), gastrointestinal (n=1953) and others (n=3473, reference group). Multivariable logistic regression analyses regarding presenting symptoms and management (laboratory blood testing, imaging and admission) were performed with adjustment for covariates: patient characteristics, referral status, previous medical care, previous antibiotic use, visiting hours and ED setting. RESULTS: We included 14 139 children with a median age of 2.7 years (IQR 1.3-5.2). The majority had respiratory symptoms (60%), viral infections (50%) and consisted of self-referrals (69%). The neurological group received imaging more often (adjusted OR (aOR) 1.8, 95% CI 1.1 to 2.9) and were admitted more frequently (aOR 1.9, 95% CI 1.4 to 2.7). The respiratory group had fewer laboratory blood tests performed (aOR 0.6, 95% CI 0.5 to 0.7), were less frequently admitted (aOR 0.6, 95% CI 0.5 to 0.7), but received imaging more often (aOR 1.8, 95% CI 1.6 to 2.0). Lastly, the gastrointestinal group had more laboratory blood tests performed (aOR 1.2. 95% CI 1.1 to 1.4) and were admitted more frequently (aOR 1.4, 95% CI 1.2 to 1.6). CONCLUSION: We determined that febrile children triaged as low urgent with respiratory symptoms were most suitable for a fast track. This study provides evidence for which children could be triaged to a fast track, potentially improving overall patient flow at the ED.

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 multicenter study on the epidemiology of complicated parapneumonic effusion in the era of currently available pneumococcal conjugate vaccines.

BACKGROUND: Parapneumonic effusion (PPE) is a common complication of pneumonia. Streptococcus pneumoniae is the most common cause of bacterial pneumonia. A reduction in pneumonia hospitalizations has been observed since the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). Despite this apparent benefit, an increase in the incidence of PPE was recorded in some countries following PCV7 implementation. As the 13-valent pneumococcal conjugate vaccine (PCV13) was expected to provide a wider protection against PPE, the aim of the present study was to evaluate the impact of PCV13 introduction on the epidemiology of complicated parapneumonic effusion (c-PPE) among children in the Athens greater area. METHODS: All cases of community-acquired pneumonia (CAP) with PPE requiring chest tube insertion (complicated PPE, c-PPE) hospitalized in the 3 public Children's hospitals in Athens between 01/01/2004 and 31/12/2019 were included in the study. RESULTS: A total of 426 cases of c-PPE associated with pneumonia were recorded of which 198 were admitted during 2004-2010 (period A, prePCV13/PCV -7 introduction period) and 228 during 2011-2018 (period B, post - PCV13 period). A definite bacterial etiology was established in 44.4 % of all cases and of those 25.4 % were caused by S. pneumoniae. An increasing trend in c-PPE incidence was observed during period A; although, a significant decrease on c-PPE annual rates was observed during the period B (p = 0.011), a remarkable increase in serotype 3 cases was recorded. CONCLUSION: A decreasing time trend in c-PPE cases among children was shown after the introduction of PCV13 in our area. However, serotype 3 is nowadays a common cause of PPE. Hence, continuous surveillance is imperative in order to follow c-PPE epidemiology over time.

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.

SARS-CoV-2 vaccination in children and adolescents with and without type 1 diabetes mellitus.

Adults with Diabetes Mellitus (DM) have increased risk of severe clinical presentation during COVID-19 infection, while children and adolescents with type 1 diabetes (T1D) have the same mild clinical course as their healthy peers, especially those with optimal glycemic control. The present review focuses on the necessity of COVID-19 vaccination among children and adolescents with T1D, and also in their non-diabetic peers. The efficacy and safety of COVID-19 vaccines are also discussed, as well as their various side-effects, ranging from common mild to very rare and serious ones. Furthermore, the results of COVID-19 vaccination of adolescents with and without T1D are reported, as well as the efficacy and concerns about childhood vaccination. It is concluded that patients with DM of all age groups should maintain optimal diabetic control in order to avoid glycemic deterioration during COVID-19 infection. Furthermore, despite the very rare and serious complications of COVID-19 vaccines, vaccination against COVID-19 is recommended for children and adolescents with T1D to prevent glycemic deterioration and rare but serious complications of COVID-19 infection.

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.

Emergency medical services utilisation among febrile children attending emergency departments across Europe: an observational multicentre study.

Children constitute 6-10% of all patients attending the emergency department (ED) by emergency medical services (EMS). However, discordant EMS use in children occurs in 37-61% with fever as an important risk factor. We aimed to describe EMS utilisation among febrile children attending European EDs. This study is part of an observational multicentre study assessing management and outcome in febrile children up to 18 years (MOFICHE) attending twelve EDs in eight European countries. Discordant EMS use was defined as the absence of markers of urgency including intermediate/high triage urgency, advanced diagnostics, treatment, and admission in children transferred by EMS. Multivariable logistic regression analyses were performed for the association between (1) EMS use and markers of urgency, and (2) patient characteristics and discordant EMS use after adjusting all analyses for the covariates age, gender, visiting hours, presenting symptoms, and ED setting. A total of 5464 (15%, range 0.1-42%) children attended the ED by EMS. Markers of urgency were more frequently present in the EMS group compared with the non-EMS group. Discordant EMS use occurred in 1601 children (29%, range 1-59%). Age and gender were not associated with discordant EMS use, whereas neurological symptoms were associated with less discordant EMS use (aOR 0.2, 95%CI 0.1-0.2), and attendance out of office hours was associated with more discordant EMS use (aOR 1.6, 95%CI 1.4-1.9). Settings with higher percentage of self-referrals to the ED had more discordant EMS use (p < 0.05).  Conclusion: There is large practice variation in EMS use in febrile children attending European EDs. Markers of urgency were more frequently present in children in the EMS group. However, discordant EMS use occurred in 29%. Further research is needed on non-medical factors influencing discordant EMS use in febrile children across Europe, so that pre-emptive strategies can be implemented. What is Known: •Children constitute around 6-10% of all patients attending the emergency department by emergency medical services. •Discordant EMS use occurs in 37-61% of all children, with fever as most common presenting symptom for discordant EMS use in children. What is New: •There is large practice variation in EMS use among febrile children across Europe with discordance EMS use occurring in 29% (range 1-59%), which was associated with attendance during out of office hours and with settings with higher percentage of self-referrals to the ED. •Future research is needed focusing on non-medical factors (socioeconomic status, parental preferences and past experience, healthcare systems, referral pathways, out of hours services provision) that influence discordant EMS use in febrile children across Europe.

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.

European study confirms the combination of fever and petechial rash as an important warning sign for childhood sepsis and meningitis.

AIM: This study investigated febrile children with petechial rashes who presented to European emergency departments (EDs) and investigated the role that mechanical causes played in diagnoses. METHODS: Consecutive patients with fever presenting to EDs in 11 European emergency departments in 2017-2018 were enrolled. The cause and focus of infection were identified and a detailed analysis was performed on children with petechial rashes. The results are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We found that 453/34010 (1.3%) febrile children had petechial rashes. The focus of the infection included sepsis (10/453, 2.2%) and meningitis (14/453, 3.1%). Children with a petechial rash were more likely than other febrile children to have sepsis or meningitis (OR 8.5, 95% CI 5.3-13.1) and bacterial infections (OR 1.4, 95% CI 1.0-1.8) as well as need for immediate life-saving interventions (OR 6.6, 95% CI 4.4-9.5) and intensive care unit admissions (OR 6.5, 95% CI 3.0-12.5). CONCLUSION: The combination of fever and petechial rash is still an important warning sign for childhood sepsis and meningitis. Ruling out coughing and/or vomiting was insufficient to safely identify low-risk patients.

Biofilm-Forming Bacteria Implicated in Complex Otitis Media in Children in the Post-Heptavalent Pneumococcal Conjugate Vaccine (PCV7) Era.

Background: Chronic media with effusion (COME) and recurrent acute otitis media (RAOM) are closely related clinical entities that affect childhood. The aims of the study were to investigate the microbiological profile of otitis-prone children in the post-PCV7 era and, to examine the biofilm-forming ability in association with clinical history and outcome during a two-year post-operative follow-up. Methods: In this prospective study, pathogens from patients with COME and RAOM were isolated and studied in vitro for their biofilm-forming ability. The minimum inhibitory concentrations (MIC) of both the planktonic and the sessile forms were compared. The outcome of the therapeutic method used in each case and patient history were correlated with the pathogens and their ability to form biofilms. Results: Haemophilus influenzae was the leading pathogen (35% in COME and 40% in RAOM), and Streptococcus pneumoniae ranked second (12% in COME and 24% in RAOM). Polymicrobial infections were identified in 5% of COME and 19% of RAOM cases. Of the isolated otopathogens, 94% were positive for biofilm formation. Conclusions: This is the first Greek research studying biofilm formation in complex otitis media-prone children population in the post-PCV7 era. High rates of polymicrobial infections, along with treatment failure in biofilms, may explain the lack of antimicrobial efficacy in otitis-prone children.