Performance of blood enterovirus and parechovirus polymerase chain reaction testing in young febrile infants: a prospective multicentre observational study.

OBJECTIVES: To analyse the performance of blood enterovirus and parechovirus PCR testing (ev-PCR) for invasive bacterial infection (IBI) (isolation of a single bacterial pathogen in a blood or cerebrospinal fluid culture) when evaluating well-appearing infants ≤90 days of age with fever without a source (FWS). METHODS: We describe the well-appearing infants ≤90 days of age with FWS and normal urine dipstick. We performed a prospective, observational multicentre study at five paediatric emergency departments between October 2020 and September 2023. RESULTS: A total of 656 infants were included, 22 (3.4%) of whom were diagnosed with an IBI (bacteraemia in all of them and associated with meningitis in four). The blood ev-PCR test was positive in 145 (22.1%) infants. One patient with positive blood ev-PCR was diagnosed with an IBI, accounting for 0.7% (95% CI 0.02 to 3.8) compared with 4.1% (95% CI 2.6 to 6.2) in those with a negative test (p=0.04). All four patients with bacterial meningitis had a negative blood ev-PCR result. Infants with a positive blood ev-PCR had a shorter hospital stay (median 3 days, IQR 2-4) compared with 4 days (IQR 2-6) for those with negative blood ev-PCR (p=0.02), as well as shorter duration of antibiotic treatment (median 2 days, IQR 0-4 vs 2.5 days, IQR 0-7, p=0.01). CONCLUSIONS: Young febrile infants with a positive blood ev-PCR are at a low risk of having an IBI. Incorporating the blood ev-PCR test into clinical decision-making may help to reduce the duration of antibiotic treatments and length of hospital stay.

A retrospective comparison of IgE-mediated cow's milk protein allergy management strategies in pediatric cohorts.

BACKGROUND: Complete avoidance of milk is the usual management for IgE-mediated cow's milk protein allergy (CMPA). A baked milk ladder is a method of dietary advancement therapy in IgE-mediated CMPA in Ireland, while in Spain, avoidance of milk awaiting natural tolerance acquisition through an oral food challenge (OFC) is employed. The aim of this study was to evaluate the use of dietary advancement therapy using a milk ladder compared with complete avoidance of milk for managing IgE-mediated CMPA. METHODS: This is a retrospective chart review of 371 pediatric patients from the population who have been treated for IgE-mediated CMPA between 2011 and 2020, with the milk ladder (Ireland) or complete avoidance followed by an OFC (Spain). The main outcome was the introduction of cow's milk. RESULTS: Milk ladder patients were 3.67 times more likely to succeed in comparison with milk avoidance (p < .001). Anaphylaxis during the treatment period occurred in 34 patients in the milk avoidance groups, while three patients in the milk ladder group experienced anaphylaxis due to accidental exposure to milk (p < .001). Failure to complete treatment was associated with a higher skin prick test in the milk avoidance group and a raised specific IgE in the milk ladder group. CONCLUSION: This is the first study that compares outcomes of dietary advancement therapy to complete avoidance for CMPA management, demonstrating that cow's milk can be successfully and safely reintroduced using dietary advancement therapy using a milk ladder.

Predictive values of indirect ultrasound signs for low risk of acute appendicitis in paediatric patients without visualisation of the appendix on ultrasound.

BACKGROUND AND OBJECTIVES: The ability to rule appendicitis in or out using ultrasound is limited by studies where the appendix is not visualised. We determined whether the absence of indirect ultrasound signs can rule out appendicitis in children undergoing a radiology-performed ultrasound in which the appendix is not visualised METHODS: This was a single-centre retrospective observational study of patients aged 3-13 with a clinical suspicion of acute appendicitis evaluated in a Paediatric Emergency Department in Spain from 1 January 2013 to 31 December 2019. For those patients who had formal ultrasound, direct and indirect findings of ultrasound were abstracted from the ultrasound report. The surgical pathology report was established as the gold standard in patients who underwent an appendectomy. In those who did not, appendicitis was considered not to be present if there was no evidence in their charts that they had undergone an appendectomy or conservative therapy for appendicitis during the episode. The main outcome variable was the diagnosis of acute appendicitis. For patients undergoing ultrasound, the independent association of each indirect ultrasound sign with the diagnosis of appendicitis in patients without a visualised appendix was analysed using logistic regression. RESULTS: We included 1756 encounters from 1609 different episodes. Median age at the first visit of each episode was 10.1 years (IQR, 7.7-11.9) and 921 (57.2%) patients were men. There were 730 (41.6%) encounters with an Alvarado score ≤3, 695 (39.6%) with a score 4-6 and 331 (18.9%) with a score ≥7. Appendicitis was diagnosed in 293 (17.8%) episodes. Ultrasonography was performed in 1115 (61.6%) encounters, with a visualised appendix in 592 (53.1%).The ultrasound findings independently associated with appendicitis in patients without a visualised appendix were the presence of free intra-abdominal fluid in a small quantity (OR:5.0 (95% CI 1.7 to 14.6)) or in an abundant quantity (OR:30.9 (95% CI 3.8 to 252.7)) and inflammation of the peri-appendiceal fat (OR:7.2 (95% CI 1.4 to 38.0)). The absence of free fluid and inflammation of the peri-appendiceal fat ruled out acute appendicitis in patients with an Alvarado score <7 with a sensitivity of 84.6% (95% CI 57.8 to 95.7) and a negative predictive value of 99.4% (95% CI 97.8 to 99.8). CONCLUSIONS: Patients with an Alvarado score <7 and without a visualised appendix on ultrasound but who lack free fluid and inflammation of the peri-appendiceal fat are at very low risk of acute appendicitis.

Dietary Advancement Therapy Using Milk and Egg Ladders Among Children With a History of Anaphylaxis.

BACKGROUND: Anaphylaxis has been increasing in recent years, with common triggers in infants being milk and eggs. Currently, the mainstay of treatment for milk and/or egg allergy is strict avoidance. Recently, new therapies have emerged including stepwise introduction of allergens via a ladder approach. The suitability of infants for the ladders is debated. OBJECTIVE: This study aims to focus on the use of food ladders in children with anaphylaxis to egg or milk. METHODS: Retrospective review of pediatric patients diagnosed with immunoglobulin E-mediated milk and/or egg allergy between 2011 and 2021. Inclusion and exclusion criteria were applied. Anaphylaxis was defined as per the World Allergy Organization-amended criteria 2020. Data analysis utilized SPSS Version 28. RESULTS: We reviewed 1,552 patient charts, and excluded 1,094, leaving a total sample size of 458. Seventy infants had anaphylaxis at diagnosis (milk n = 36; egg n = 34). A range of 77.8% to 85.2% of infants with anaphylaxis successfully completed the ladder, 88.9% to 92.9% without anaphylaxis were successful. Children who successfully completed the ladder did so at similar rates. A range of 20.6% to 50% children presenting with anaphylaxis at diagnosis experienced allergic symptoms during treatment, compared with 17.3% to 40.7% without anaphylaxis. Reactions were mild, mostly cutaneous and not requiring medical attention. Patients experiencing allergic symptoms while on the ladder were less likely to successfully complete treatment. CONCLUSIONS: Milk and egg ladders are a safe and effective way of inducing tolerance in infants, including those with a history of anaphylaxis at diagnosis. There are no obvious predictors for who will experience allergic reactions while on the ladder; however, these children are less likely to complete the ladder, so parents should be educated in management of mild allergic reactions at home.

Performance of Febrile Infant Algorithms by Duration of Fever.

OBJECTIVES: To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. METHODS: We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants ≤90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. RESULTS: We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. CONCLUSIONS: The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules.

Analysis of guideline recommendations for treatment of asthma exacerbations in children: a Pediatric Emergency Research Networks (PERN) study.

RATIONALE: There is significant practice variation in acute paediatric asthma, particularly severe exacerbations. It is unknown whether this is due to differences in clinical guidelines. OBJECTIVES: To describe and compare the content and quality of clinical guidelines for the management of acute exacerbations of asthma in children between geographic regions. METHODS: Observational study of guidelines for the management of acute paediatric asthma from institutions across a global collaboration of six regional paediatric emergency research networks. MEASUREMENTS AND MAIN RESULTS: 158 guidelines were identified. Half provided recommendations for at least two age groups, and most guidelines provided treatment recommendations according to asthma severity.There were consistent recommendations for the use of inhaled short-acting beta-agonists and systemic corticosteroids. Inhaled anticholinergic therapy was recommended in most guidelines for severe and critical asthma, but there were inconsistent recommendations for its use in mild and moderate exacerbations. Other inhaled therapies such as helium-oxygen mixture (Heliox) and nebulised magnesium were inconsistently recommended for severe and critical illness.Parenteral bronchodilator therapy and epinephrine were mostly reserved for severe and critical asthma, with intravenous magnesium most recommended. There were regional differences in the use of other parenteral bronchodilators, particularly aminophylline.Guideline quality assessment identified high ratings for clarity of presentation, scope and purpose, but low ratings for stakeholder involvement, rigour of development, applicability and editorial independence. CONCLUSIONS: Current guidelines for the management of acute paediatric asthma exacerbations have substantial deficits in important quality domains and provide limited and inconsistent guidance for severe exacerbations.

Conundrums in the Management of Febrile Infants under Three Months of Age and Future Research.

Febrile infants under three months of age pose a diagnostic challenge to clinicians. Unlike in older children, the rates of invasive bacterial infections (IBIs), such as bacteraemia or meningitis, are high. This greater risk of IBI combined with the practical challenges of assessing young infants results in a cautious approach with many febrile infants receiving parenteral antibiotics "just in case". However, there is a range of validated tailored care guidelines that support targeted investigation and management of febrile infants, with a cohort identified as lower risk suitable for fewer invasive procedures and observation without parenteral antibiotics. This manuscript outlines five common conundrums related to the safe application of tailored-care guidelines for the assessment and management of febrile infants under three months of age. It also explores future research which aims to further refine the management of febrile infants.

Prevalence of invasive bacterial infection in febrile infants ≤90 days with a COVID-19 positive test: a systematic review and meta-analysis.

BACKGROUND: Febrile infants with an infection by influenza or enterovirus are at low risk of invasive bacterial infection (IBI). OBJECTIVE: To determine the prevalence of IBI among febrile infants ≤90 days old with a positive COVID-19 test. METHODS: MEDLINE, Embase, Cochrane Central Register databases, Web of Science, ClinicalTrials.gov and grey literature were searched for articles published from February 2020 to May 2023. INCLUSION CRITERIA: researches reporting on infants ≤90 days of age with fever and a positive test for SARS-CoV-2 (antigen test/PCR). Case reports with <3 patients, articles written in a language other than English, French or Spanish, editorials and other narrative studies were excluded. Preferred Reposting Items for Systematic Reviews and Meta-analysis guidelines were followed, and the National Institutes of Health Quality Assessment Tool was used to assess study quality. The main outcome was the prevalence of IBI (a pathogen bacterium identified in blood and/or cerebrospinal fluid (CSF)). Forest plots of prevalence estimates were constructed for each study. Heterogeneity was assessed and data were pooled by meta-analysis using a random effects model. A fixed continuity correction of 0.01 was added when a study had zero events. RESULTS: From the 1023 studies and 3 databases provided by the literature search, 33 were included in the meta-analysis, reporting 3943 febrile infants with a COVID-19 positive test and blood or CSF culture obtained. The pooled prevalence of IBI was 0.14% (95% CI, 0.02% to 0.27%). By age, the prevalence of IBI was 0.56% (95% CI, 0.0% to 1.27%) in those 0-21 days old, 0.53% (95% CI, 0.0% to 1.22%) in those 22-28 days old and 0.11% (95% CI, 0.0% to 0.24%) in those 29-60 days old. CONCLUSION: COVID-19-positive febrile infants ≤90 days old are at low risk of IBI, especially infants >28 days old, suggesting this subgroup of patients can be managed without blood tests. PROSPERO REGISTRATION NUMBER: CRD42022356507.

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPßS in Rats.

Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5'-(ß-thio)-diphosphate (ADPßS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPßS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y1), PSB0739 (P2Y12), and MRS2211 (P2Y13). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α1-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPßS were exclusively mediated by peripheral activation of P2Y1 receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPßS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y1, P2Y12, and P2Y13 receptors.

Teaching children with food allergy to recognize anaphylaxis: The caregivers' perspectives.

BACKGROUND: Anaphylaxis is rising in prevalence among children. The current recommendations on the effective transition of anaphylaxis management to adolescents and young adults suggest preparation for the transition may be considered at 11-13 years of age in accordance with the patient's developmental stage. However, there has been limited research conducted on the perspective of caregivers regarding the transition of anaphylaxis management to their children. This study aims to determine the age caregivers feel it is appropriate to begin to teach their child to recognize anaphylaxis and use their adrenaline auto-injectors (AAI). METHODS: Caregivers of pediatric allergy patients who have been diagnosed with IgE-mediated food allergy and have an AAI prescription were contacted by phone and invited to complete a questionnaire about when they feel it is appropriate to begin to teach their child to recognize anaphylaxis and use their AAI. RESULTS: Of the 123 responses to the questionnaire received, 44.7% indicated that 9-11 years was the appropriate time for teaching their children to self-inject an AAI. History of severe anaphylaxis (94.3%), child's ability to describe reasons to inject adrenaline (87.8%), and demonstrate AAI use (82.1%) were "very important" readiness factors identified. Almost half of caregivers were "not confident" (8.94%) or "somewhat confident" (40.65%) in training their child to use AAI. Caregivers with higher household incomes more frequently identified themselves as the party responsible for training their children to use AAI (p = .04). CONCLUSION: Caregivers in this sample expressed different perspectives than the current guidelines regarding the timing to initiate the transition of anaphylaxis management to their child. Caregivers expressed suboptimal confidence in teaching their children to use AAI. Clinicians should be aware of the factors that may indicate caregivers' desire to initiate an earlier transition of anaphylaxis management to their child and ensure access to appropriate training, education and support is available.

Multicentre Delphi study of physicians resulted in quality indicators for young infants with fever without source in emergency departments.

AIM: Managing febrile infants has evolved without a generally accepted standard of care. We aimed to design quality indicators for managing infants ≤90 days old presenting to emergency departments (EDs) with fever without source. METHODS: This multicentre Delphi study was carried out by the Febrile Infant Study Group of the Spanish Paediatric Emergency Research Network, from March 2021 to November 2021, and included paediatric emergency physicians from 24 Spanish EDs. A list of care standards was produced, following an extensive literature review and the involvement of all parties. Indicators were essential if they were voted by four panelists and also received a score of ≥4 from at least 95% of the 24 investigators. RESULTS: We established 20 indicators, including one related to having a protocol, two to triage, nine to diagnostic processes, six to treatment and two to disposition. The following indicators were considered essential: having an ED management protocol, performing urinalysis on every infant, obtaining a blood culture from every infant and administering antibiotics in the ED to any febrile infant who did not appear well. CONCLUSION: The Delphi method resulted in a comprehensive list of quality indicators for managing febrile young infants in Spanish EDs.

Setting priorities for an agenda within the Spanish pediatric emergency medicine research network.

The research network of the Spanish Pediatric Emergency Society (RISeuP-SPERG Network) needs to establish its research agenda relevant to pediatric emergency medicine (PEM) to guide the development of future projects, as other networks have done before. The aim of our study was to identify priority areas in PEM for a collaborative network of pediatric emergency research in Spain. A multicenter study was developed including pediatric emergency physicians from 54 Spanish emergency departments, endorsed by the RISeuP-SPERG Network. Initially, a group of seven PEM experts was selected among the members of the RISeuP-SPERG. In the first phase, these experts elaborated a list of research topics. Then, using a Delphi method, we sent a questionnaire with that list to all RISeuP-SPERG members, to rank each item using a 7-point Likert scale. Finally, the seven PEM experts, using a modified Hanlon Process of Prioritization, weighted prevalence (A), seriousness of the condition (B), and feasibility of conducting research projects (C) on that condition to prioritize the selected items. Once the list of topics was chosen, the seven experts selected a list of research questions for each of the selected items. The Delphi questionnaire was answered by 74/122 (60.7%) members of RISeuP-SPERG. We established a list of 38 research priorities related to quality improvement (11), infectious diseases (8), psychiatric/social emergencies (5), sedoanalgesia (3), critical care (2), respiratory emergencies (2), trauma (2), neurologic emergencies (1), and miscellanea (4).   Conclusion: The RISeuP-SPERG prioritization process identified high-priority PEM topics specific to multicenter research that may help guide further collaborative research efforts within the RISeuP-SPERG network to improve PEM care in Spain. What is Known: • Some pediatric emergency medicine networks have established their priorities for research. What is New: • After a structured process, we have set the research agenda for pediatric emergency medicine in Spain. By identifying high-priority pediatric emergency medicine research topics specific to multicenter research, we may guide further collaborative research efforts within our network.

Febrile Urinary Tract Infection in Infants Less Than 3 Months of Age.

INTRODUCTION: Urinary tract infection (UTI) is the leading cause of bacterial infection in infants younger than 3 months of age with fever without a source. OBJECTIVE: The objective of the study was to analyze the characteristics of emergency department presentations of febrile infants younger than 3 months of age with a UTI and identify risk factors for invasive bacterial infection (IBI) secondary to UTI. METHODS: This was a secondary analysis of a prospective observational registry that includes infants younger than 3 months with fever without a source managed at a pediatric emergency department between 2003 and 2019. RESULTS: Of the 2850 patients included, 592 (20.8%) were diagnosed with a UTI (524, 88.5%, for Escherichia coli ). Infants with UTIs showed significant clinical differences when compared with those not diagnosed with a bacterial infection: patients with a UTI were more likely to have a history of renal/urological problems (8.3% vs. 3.5%), temperature ≥39ºC (38.3% vs. 29%) and poor feeding (13% vs. 8.7%). Yet, nearly half (285 of the 592, 48.1%) of the infants with febrile UTIs had none of these 3 risk factors. Thirty-six infants (6.1%) had a secondary IBI. We identified the following independent risk factors for secondary IBI: infants younger than 1 month of age, parent-reported irritability, procalcitonin >0.5 ng/mL, and C-reactive protein >60 mg/L. CONCLUSIONS: History and physical examination do not allow us to safely rule out a UTI among young febrile infants. Age, parent-reported irritability, and biomarkers are useful in identifying patients at increased risk of secondary IBI.

Invasive bacterial infection in children with fever and petechial rash in the emergency department: a national prospective observational study.

OBJECTIVE: To determine the incidence and clinical predictors of invasive bacterial infection (IBI) in well-appearing children who present to the emergency department (ED) with fever and petechiae. DESIGN: A prospective, observational, multicentre study was conducted in 18 hospitals between November 2017 and October 2019. PATIENTS: A total of 688 patients were recruited. MAIN OUTCOME MEASURES: The primary outcome was the presence of IBI. Clinical features and laboratory test results were described and related to the presence of IBI. RESULTS: Ten IBIs were found (1.5%), comprising eight cases of meningococcal disease and two of occult pneumococcal bacteraemia. Median age was 26.2 months (IQR 15.3-51.2). Blood samples were obtained from 575 patients (83.3%). Patients with an IBI had a shorter time from fever to ED visit (13.5 hours vs 24 hours) and between fever and rash onset (3.5 hours vs 24 hours). Values for absolute leucocyte count, total neutrophil count, C reactive protein and procalcitonin were significantly higher in patients with an IBI. Significantly fewer patients with a favourable clinical status while in the observation unit were found to have an IBI (2/408 patients, 0.5%) than when clinical status was unfavourable (3/18, 16.7%). CONCLUSIONS: The incidence of IBI among children with fever and petechial rash is lower than previously reported (1.5%). The time from fever to ED visit and to rash onset was shorter in patients with an IBI. Patients with a favourable clinical course during observation in the ED are at lower risk of IBI.

'Early Introduction' of Cow's Milk for Children with IgE-Mediated Cow's Milk Protein Allergy: A Review of Current and Emerging Approaches for CMPA Management.

IgE-mediated cow's milk protein allergy (CMPA) is one of the most prevalent food allergies in early childhood. Though the cornerstone of management involves the strict avoidance of milk products while awaiting natural tolerance, research increasingly shows that the rates of resolution are slowing down. Therefore, there is a need to explore alternative pathways to promote tolerance to cow's milk in pediatric populations. This review aims to combine and appraise the scientific literature regarding the three CMPA management methods: avoidance, the milk ladder, and oral immunotherapy (OIT) and their outcomes in terms of efficacy, safety, and immunological effects. Cow's milk (CM) avoidance virtually protects against allergic reaction until natural tolerance occurs, with hypoallergenic substitutes available in the market, but accidental ingestion represents the main issue for this strategy. Introduction to baked milk using the milk ladder was designed, with most CMPA patients successfully completing the ladder. Similar to baked milk treatment, many OIT protocols also demonstrated decreased IgE and increased IgG4 levels post protocol, as well as a reduction in wheal size diameter. Though these strategies are shown to be safe and effective in CMPA, future clinical trials should compare the safety and effectiveness of these three management strategies.