Diagnostic test accuracy of procalcitonin and C-reactive protein for predicting invasive and serious bacterial infections in young febrile infants: a systematic review and meta-analysis.

BACKGROUND: Febrile infants presenting in the first 90 days of life are at higher risk of invasive and serious bacterial infections than older children. Modern clinical practice guidelines, mostly using procalcitonin as a diagnostic biomarker, can identify infants who are at low risk and therefore suitable for tailored management. C-reactive protein, by comparison, is widely available, but whether C-reactive protein and procalcitonin have similar diagnostic accuracy is unclear. We aimed to compare the test accuracy of procalcitonin and C-reactive protein in the prediction of invasive or serious bacterial infections in febrile infants. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Web of Science, and The Cochrane Library for diagnostic test accuracy studies up to June 19, 2023, using MeSH terms "procalcitonin", and "bacterial infection" or "fever" and keywords "invasive bacterial infection*" and "serious bacterial infection*", without language or date restrictions. Studies were selected by independent authors against eligibility criteria. Eligible studies included participants aged 90 days or younger presenting to hospital with a fever (≥38°C) or history of fever within the preceding 48 h. The primary index test was procalcitonin, and the secondary index test was C-reactive protein. Test kits had to be commercially available, and test samples had to be collected upon presentation to hospital. Invasive bacterial infection was defined as the presence of a bacterial pathogen in blood or cerebrospinal fluid, as detected by culture or quantitative PCR; authors' definitions of serious bacterial infection were used. Data were extracted from selected studies, and the detection of invasive or serious bacterial infections was analysed with two models for each biomarker. Diagnostic accuracy was determined against internationally recognised cutoff values (0·5 ng/mL for procalcitonin, 20 mg/L for C-reactive protein) and pooled to calculate partial area under the curve (pAUC) values for each biomarker. Optimum cutoff values were identified for each biomarker. This study is registered with PROSPERO, CRD42022293284. FINDINGS: Of 734 studies derived from the literature search, 14 studies (n=7755) were included in the meta-analysis. For the detection of invasive bacterial infections, pAUC values were greater for procalcitonin (0·72, 95% CI 0·56-0·79) than C-reactive protein (0·28, 0·17-0·61; p=0·016). Optimal cutoffs for detecting invasive bacterial infections were 0·49 ng/mL for procalcitonin and 13·12 mg/L for C-reactive protein. For the detection of serious bacterial infections, procalcitonin and C-reactive protein had similar pAUC values (0·55, 0·44-0·69 vs 0·54, 0·40-0·61; p=0·92). For serious bacterial infections, the optimal cutoffs for procalcitonin and C-reactive protein were 0·17 ng/mL and 16·18 mg/L, respectively. Heterogeneity was low for studies investigating the test accuracy of procalcitonin in detecting invasive bacterial infection (I2=23·5%), high for studies investigating procalcitonin for serious bacterial infection (I2=75·5%), and moderate for studies investigating C-reactive protein for invasive bacterial infection (I2=49·5%) and serious bacterial infection (I2=28·3%). The absence of a single definition of serious bacterial infection across studies was the greatest source of interstudy variability and potential bias. INTERPRETATION: Within a large cohort of febrile infants, a procalcitonin cutoff of 0·5 ng/mL had a superior pAUC value to a C-reactive protein cutoff of 20 mg/L for identifying invasive bacterial infections. In settings without access to procalcitonin, C-reactive protein should therefore be used cautiously for the identification of invasive bacterial infections, and a cutoff value below 20 mg/L should be considered. C-reactive protein and procalcitonin showed similar test accuracy for the identification of serious bacterial infection with internationally recognised cutoff values. This might reflect the challenges involved in confirming serious bacterial infection and the absence of a universally accepted definition of serious bacterial infection. FUNDING: None.

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.

Role of diagnostic tests for sepsis in children: a review.

Paediatric sepsis has a significant global impact and highly heterogeneous clinical presentation. The clinical pathway encompasses recognition, escalation and de-escalation. In each aspect, diagnostics have a fundamental influence over outcomes in children. Biomarkers can aid in creating a larger low-risk group of children from those in the clinical grey area who would otherwise receive antibiotics 'just in case'. Current biomarkers include C reactive protein and procalcitonin, which are limited in their clinical use to guide appropriate and rapid treatment. Biomarker discovery has focused on single biomarkers, which, so far, have not outperformed current biomarkers, as they fail to recognise the complexity of sepsis. The identification of multiple host biomarkers that may form a panel in a clinical test has the potential to recognise the complexity of sepsis and provide improved diagnostic performance. In this review, we discuss novel biomarkers and novel ways of using existing biomarkers in the assessment and management of sepsis along with the significant challenges in biomarker discovery at present. Validation of biomarkers is made less meaningful due to methodological heterogeneity, including variations in sepsis diagnosis, biomarker cut-off values and patient populations. Therefore, the utilisation of platform studies is necessary to improve the efficiency of biomarkers in clinical practice.

Serum HCoV-spike specific antibodies do not protect against subsequent SARS-CoV-2 infection in children and adolescents.

SARS-CoV-2 infections in children are generally asymptomatic or mild and rarely progress to severe disease and hospitalization. Why this is so remains unclear. Here we explore the potential for protection due to pre-existing cross-reactive seasonal coronavirus antibodies and compare the rate of antibody decline for nucleocapsid and spike protein in serum and oral fluid against SARS-CoV-2 within the pediatric population. No differences in seasonal coronaviruses antibody concentrations were found at baseline between cases and controls, suggesting no protective effect from pre-existing immunity against seasonal coronaviruses. Antibodies against seasonal betacoronaviruses were boosted in response to SARS-CoV-2 infection. In serum, anti-nucleocapsid antibodies fell below the threshold of positivity more quickly than anti-spike protein antibodies. These findings add to our understanding of protection against infection with SARS-CoV-2 within the pediatric population, which is important when considering pediatric SARS-CoV-2 immunization policies.

Applying clinical decision aids for the assessment and management of febrile infants presenting to emergency care in the UK and Ireland: Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study protocol.

INTRODUCTION: Febrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10-20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing. METHODS AND ANALYSIS: The FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children's Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05259683.

How to interpret cardiac biomarkers in children?

Cardiac biomarkers are used as first-line diagnostic tools in suspected myocardial injury and heart failure in adult patients. Their use in paediatric patients has been limited by variability caused by age, gender and the presence of an underlying congenital cardiac condition. There are established reference ranges for both NT-proBNP and troponin in healthy children, but these cannot be applied to all paediatric patients because of limited large studies focusing on children with congenital heart disease and/or cardiomyopathy.This article will focus on the pathophysiology of myocardial injury and heart failure in children and the subsequent cardiac biomarker correlation. It will explain how to interpret the biomarker assay levels obtained for both troponin and NT-proBNP and highlights the importance of a clear clinical question prior to requesting a cardiac biomarker assay level.Clinical cases outline scenarios that may prompt consideration of biomarker analysis in children and aims to equip the reader with an understanding of how to interpret the results.

Fifteen-minute consultation: A guide to the paediatric primary survey.

It's 21:00 and you receive a stand-by call from the local ambulance service. Peter, a 9-year-old boy, was riding an electric scooter and has collided with a car. He has reduced consciousness, signs of shock and is hypoxic. How will you prepare your team? What are the possible injuries? Who will perform the primary survey? Injury is the leading cause of morbidity and mortality in the paediatric population accounting for approximately half of all attendances to paediatric emergency departments in the UK and Ireland. Major trauma can be distressing for patients, parents and physicians. Managing major trauma is challenging and it is vital to have a clear and organised approach. In this 15-minute guide we describe a structured approach to the primary survey that includes how to prepare before the child's arrival, the suggested roles of team members and the key components of the primary survey. We discuss life-threatening injuries, the life-saving bundle and the principles of resuscitation, and the role of imaging in the initial assessment of the injured child.

Diagnostic test accuracy of dipstick urinalysis for diagnosing urinary tract infection in febrile infants attending the emergency department.

OBJECTIVE: To report the diagnostic test accuracy of dipstick urinalysis for the detection of urinary tract infections (UTIs) in febrile infants aged 90 days or less attending the emergency department (ED). DESIGN: Retrospective cohort study. PATIENTS: Febrile infants aged 90 days or less attending between 31 August 2018 and 1 September 2019. MAIN OUTCOME MEASURES: The sensitivity, specificity and predictive values of dipstick urinalysis in detecting UTIs defined as growth of ≥100 000 cfu/mL of a single organism and the presence of pyuria (>5 white blood cells per high-power field). SETTING: Eight paediatric EDs in the UK/Ireland. RESULTS: A total of 275 were included in the final analysis. There were 252 (92%) clean-catch urine samples and 23 (8%) were transurethral bladder catheter samples. The median age was 51 days (IQR 35-68.5, range 1-90), and there were 151/275 male participants (54.9%). In total, 38 (13.8%) participants had a confirmed UTI. The most sensitive individual dipstick test for UTI was the presence of leucocytes. Including 'trace' as positive resulted in a sensitivity of 0.87 (95% CI 0.69 to 0.94) and a specificity of 0.73 (95% CI 0.67 to 0.79). The most specific individual dipstick test for UTI was the presence of nitrites. Including trace as positive resulted in a specificity of 0.91 (95% CI 0.86 to 0.94) and a sensitivity of 0.42 (95% CI 0.26 to 0.59). CONCLUSION: Point-of-care urinalysis is moderately sensitive and highly specific for diagnosing UTI in febrile infants. The optimum cut-point to for excluding UTI was leucocytes (1+), and the optimum cut-point for confirming UTI was nitrites (trace). TRIAL REGISTRATION NUMBER: NCT04196192.

Diagnostic value of mid-regional pro-Adrenomedullin as a biomarker of invasive bacterial infection in children: a systematic review.

BACKGROUND: Invasive bacterial infections (IBI) in children present a difficult clinical challenge. They are often life-threatening, however in the early stages they can be hard to differentiate from benign viral infections. This leaves clinicians with the risk of missing a serious IBI diagnosis or inappropriately using antimicrobials in a child with a viral infection- contributing to the ongoing development of increased antimicrobial resistance. Hence, biomarkers which could aid in early detection of IBI and differentiation from viral infections are desirable. Mid-Regional pro-Adrenomedullin (MR-proADM) is a biomarker which has been associated with IBI. The aim of this systematic review was to determine its diagnostic accuracy in identifying children with IBI. METHODS: A strategy was devised to search online databases MEDLINE, Embase, Web of Science and Scopus for human clinical trials reporting the accuracy of MR-proADM in children. Against predesigned inclusion and exclusion criteria full texts were selected for inclusion and data extraction. True positives, false positives, true negatives and false negatives were extracted from each included study to fill 2 × 2 tables. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool methodological quality of each study was assessed. RESULTS: A total of 501 articles were initially identified. After the removal of duplicates and abstract screening 11 texts were fully reviewed and four texts (totaling 1404 patients) were included in the systematic analysis. Only one study was of a high quality and that study accounted for the vast majority of patients. A single study reported the diagnostic accuracy of MR-proADM for invasive bacterial infection reporting an Area under the Curve of 0.69. The paucity of available studies made meta-analysis and studies of heterogeneity impossible. CONCLUSION: There is a paucity of research regarding the diagnostic accuracy of MR-proADM in the diagnosis of invasive bacterial infections in children. Initial results would suggest that MR-proADM testing alone is poor at identifying IBI in young children. It remains unclear if MR-proADM performs differently in older children or in children with signs and symptoms of IBI. TRIAL REGISTRATION: PROSPERO CRD42018096295 .

Periorbital and orbital cellulitis in children: a survey of emergency physicians and analysis of clinical practice guidelines across the PERUKI network.

BACKGROUND: Due to limited evidence to guide management of periorbital cellulitis (POC), we surveyed current practice and assessed quality and consistency of local clinical practice guidelines (CPGs) to highlight future research priorities. METHODS: A web-based survey was sent to a designated emergency physician (who clinically assesses children) at Paediatric Emergency Research United Kingdom and Ireland (PERUKI) sites between 23 November 2018 to 22 January 2019. A nominated site lead offered one response as a department-wide perspective on admission, severity assessment, treatment, disposition and specialty consultation request. Sites shared their CPG. These were compared using a standardised data collection tool, and quality assessed using Standardised Reporting Practice Guidelines in Healthcare (RIGHT) criteria. Survey responses were also compared against CPG recommendations. RESULTS: 83% (49/59) institutions invited submitted an individual survey response. 67% of responding sites had a CPG and 63% (31/49) submitted these. CPG quality was poor (mean 6.7/35 RIGHT criteria). 21 different severity markers were identified across CPGs. Most CPGS recommend investigations for severe disease, yet 23% (7/31) advise blood culture universally. 90% of CPGs advise discharge with oral antibiotics for milder cases, yet 86% of respondents reported departmental admission of all patients with POC. Nearly all respondents included proptosis, systemically unwell and visual disturbance as indications for admission but differed regarding importance of other signs. CONCLUSIONS: We demonstrated variation in practice across the PERUKI network in assessment of severity and management of POC. CPGs vary in recommendations, and clinical practice appears to differ from CPGs. Guidelines were generally of poor quality when compared against RIGHT standards.

Point-of-care testing in Paediatric settings in the UK and Ireland: a cross-sectional study.

BACKGROUND: Point-of-care testing (POCT) is diagnostic testing performed at or near to the site of the patient. Understanding the current capacity, and scope, of POCT in this setting is essential in order to respond to new research evidence which may lead to wide implementation. METHODS: A cross-sectional online survey study of POCT use was conducted between 6th January and 2nd February 2020 on behalf of two United Kingdom (UK) and Ireland-based paediatric research networks (Paediatric Emergency Research UK and Ireland, and General and Adolescent Paediatric Research UK and Ireland). RESULTS: In total 91/109 (83.5%) sites responded, with some respondents providing details for multiple units on their site based on network membership (139 units in total). The most commonly performed POCT were blood sugar (137/139; 98.6%), urinalysis (134/139; 96.4%) and blood gas analysis (132/139; 95%). The use of POCT for Influenza/Respiratory Syncytial Virus (RSV) (45/139; 32.4%, 41/139; 29.5%), C-Reactive Protein (CRP) (13/139; 9.4%), Procalcitonin (PCT) (2/139; 1.4%) and Group A Streptococcus (5/139; 3.6%) and was relatively low. Obstacles to the introduction of new POCT included resources and infrastructure to support test performance and quality assurance. CONCLUSION: This survey demonstrates significant consensus in POCT practice in the UK and Ireland but highlights specific inequity in newer biomarkers, some which do not have support from national guidance. A clear strategy to overcome the key obstacles of funding, evidence base, and standardising variation will be essential if there is a drive toward increasing implementation of POCT.

Validating clinical practice guidelines for the management of febrile infants presenting to the emergency department in the UK and Ireland.

OBJECTIVE: To report the performance of clinical practice guidelines (CPG) in the diagnosis of serious/invasive bacterial infections (SBI/IBI) in infants presenting with a fever to emergency care in the UK and Ireland. Two CPGs were from the National Institutes for Health and Care Excellence (NICE guidelines NG51 and NG143) and one was from the British Society for Antimicrobial Chemotherapy (BSAC). DESIGN: Retrospective multicentre cohort study. PATIENTS: Febrile infants aged 90 days or less attending between the 31 August 2018 to 1 September 2019. MAIN OUTCOME MEASURES: The sensitivity, specificity and predictive values of CPGs in identifying SBI and IBI. SETTING: Six paediatric Emergency Departments in the UK/Ireland. RESULTS: 555 participants were included in the analysis. The median age was 53 days (IQR 32 to 70), 447 (81%) underwent blood testing and 421 (76%) received parenteral antibiotics. There were five participants with bacterial meningitis (1%), seven with bacteraemia (1%) and 66 (12%) with urinary tract infections. The NICE NG51 CPG was the most sensitive: 1.00 (95% CI 0.95 to 1.00). This was significantly more sensitive than NICE NG143: 0.91 (95% CI 0.82 to 0.96, p=0.0233) and BSAC: 0.82 (95% 0.72 to 0.90, p=0.0005). NICE NG51 was the least specific 0.0 (95% CI 0.0 to 0.01), and this was significantly lower than the NICE NG143: 0.09 (95% CI 0.07 to 0.12, p<0.0001) and BSAC: 0.14 (95% CI 0.1 to 0.17, p<0.0001). CONCLUSION: None of the studied CPGs demonstrated ideal performance characteristics. CPGs should be improved to guide initial clinical decision making. TRIAL REGISTRATION NUMBER: NCT04196192.

Secondary Attack Rate and Family Clustering of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children of Healthcare Workers With Confirmed Coronavirus Disease 2019 (COVID-19).

We measured serum SARS-CoV-2 antibodies in 215 children of healthcare workers to estimate secondary attack rates. Twenty-one families had a parent with confirmed COVID-19. There was strong evidence of family clustering (P < .001): 20/21 (95.2%) children were seropositive in 9 families and none of 23 children in 12 other families.

Validating clinical practice guidelines for the management of children with non-blanching rashes in the UK (PiC): a prospective, multicentre cohort study.

BACKGROUND: No previous studies have validated current clinical practice guidelines for the management of non-blanching rashes in children who have received meningococcal B and C vaccinations. The aim of this study was to evaluate the performance of existing clinical practice guidelines in the diagnosis of invasive meningococcal disease in children presenting with a fever and non-blanching rash in the UK. METHODS: The Petechiae in Children (PiC) study was a prospective, multicentre cohort study involving children (aged <18 years) presenting to 37 paediatric emergency departments in the UK with a fever (≥38°C) and a new-onset non-blanching rash or features suggestive of meningococcal infection. Children with pre-existing haematological conditions (ie, haematological malignancy, idiopathic thrombocytopenic purpura, or coagulopathy) or an existing diagnosis of Henoch-Schonlein purpura were excluded. Invasive meningococcal disease was confirmed by positive culture or a quantitative PCR test for Neisseria meningitidis from either blood or cerebrospinal fluid samples. The primary outcome was the performance of six tailored clinical practice guidelines from participating centres (London, Nottingham, Newcastle-Birmingham-Liverpool, Glasgow, Chester, and Bristol) and two clinical practice guidelines from the National Institutes for Health and Care Excellence (NICE; CG102 and NG51) in identifying children with invasive meningococcal disease, assessed by the sensitivity and specificity of each clinical practice guideline. This study is registered with ClinicalTrials.gov, NCT03378258. FINDINGS: Between Nov 9, 2017, and June 30, 2019, 1513 patients were screened, of whom 1329 were eligible and were included in the analysis. The median age of patients was 24 months (IQR 12-48). 1137 (86%) of 1329 patients had a blood test and 596 (45%) received parenteral antibiotics. 19 (1%) patients had confirmed meningococcal disease. All eight clinical practice guidelines had a sensitivity of 1·00 (95% CI 0·82-1·00) for identifying meningococcal disease. The specificities of NICE guidelines CG102 (0·01 [95% CI 0·01-0·02]) and NG51 (0·00 [0·00-0·00]) for identifying meningococcal disease were significantly lower than that of tailored clinical practice guidelines (p<0·0001). The best performing clinical practice guidelines for identifying meningococcal disease were the London (specificity 0·36 [0·34-0·39]) and Nottingham (0·34 [0·32-0·37]) clinical practice guidelines. INTERPRETATION: Invasive meningococcal disease is a rare cause of non-blanching rashes in children presenting to the emergency department in the UK. Current NICE guidelines perform poorly when compared with tailored clinical practice guidelines. These findings suggest that UK national guidance could be improved by shifting towards a tailored approach. FUNDING: Public Health Agency.

Seroprevalence of SARS-CoV-2 antibodies in children: a prospective multicentre cohort study.

BACKGROUND: Studies based on molecular testing of oral/nasal swabs underestimate SARS-CoV-2 infection due to issues with test sensitivity, test timing and selection bias. The objective of this study was to report the presence of SARS-CoV-2 antibodies, consistent with previous infection. DESIGN: This multicentre observational cohort study, conducted between 16 April to 3 July 2020 at 5 UK sites, recruited children of healthcare workers, aged 2-15 years. Participants provided blood samples for SARS-CoV-2 antibody testing and data were gathered regarding unwell contacts and symptoms. RESULTS: 1007 participants were enrolled, and 992 were included in the final analysis. The median age of participants was 10·1 years. There were 68 (6.9%) participants with positive SARS-CoV-2 antibody tests indicative of previous SARS-CoV-2 infection. Of these, 34/68 (50%) reported no symptoms prior to testing. The presence of antibodies and the mean antibody titre was not influenced by age. Following multivariable analysis four independent variables were identified as significantly associated with SARS-CoV-2 seropositivity: known infected household contact OR=10.9 (95% CI 6.1 to 19.6); fatigue OR=16.8 (95% CI 5.5 to 51.9); gastrointestinal symptoms OR=6.6 (95% CI 3.0 to 13.8); and changes in sense of smell or taste OR=10.0 (95% CI 2.4 to 11.4). DISCUSSION: Children demonstrated similar antibody titres in response to SARS-CoV-2 irrespective of age. Fatigue, gastrointestinal symptoms and changes in sense of smell or taste were the symptoms most strongly associated with SARS-CoV-2 antibody positivity. TRIAL REGISTRATION NUMBER: NCT0434740.