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.

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.

Open Surgery for Abdominal Aortic Aneurysm: 980 Consecutive Patient Outcomes from a High-Volume Centre in the United Kingdom.

BACKGROUND: Controversy persists regarding the optimal treatment for large abdominal aortic aneurysm (AAA), highlighted by the publication of the National Institute for Health and Care Excellence (NICE) guideline (NG156) on March 2020. The pendulum of opinion swings once more from endovascular to open surgical treatment. We report our experience over the last 15 years in treating consecutive AAA by open surgery. METHODS: A retrospective review of a prospectively collected vascular database of all patients undergoing infra-renal open abdominal aortic aneurysm repair (OR) repair from 2004 to 2019 at the largest aneurysm centre in the United Kingdom. OR for elective and emergency (ruptured and symptomatic) outcomes included early morbidity and 30-day mortality, and long-term survival. RESULTS: 1017 patients underwent OR between 2004-2019, on application of our inclusion-criteria 994 patients formed our cohort for analysis (81.2% male) with a mean age 73.6 ± 7.8 years treated by OR for AAA. In that group 672 were elective and 308 were emergency (for ruptured or symptomatic). Overall 30 day mortality was 11.3%, elective 30 day mortality was 2.5%, and emergency 30 day mortality was 29.9%. 30 day re-intervention rate was 9.5%, (elective 7.0%, emergency 15.9%). Survival at 1000 days for elective repair was 72 v 46.7% for emergency and at 2000 days was 43.4% for elective v 25% for emergency. CONCLUSION: Our data confirm that open surgery for AAA can be performed in large volume centres quite safely. Elective and Emergency surgery does affect early 30 day mortality but does not influence long-term outcome.

Systematic review and meta-analysis assessing the diagnostic test accuracy of procalcitonin in the diagnosis of invasive bacterial infections in febrile infants: a study protocol.

INTRODUCTION: Young febrile infants are at higher risk of invasive bacterial infections (IBIs) compared with older children. The clinical features of IBI are subtle in this cohort mandating that clinicians take a cautious approach to their initial assessment and management. This includes the measurement of blood biomarkers of infection such as C reactive protein (CRP) and procalcitonin (PCT). In the UK, PCT is not widely available and not recommended for routine use in hospital. This is in contrast to Europe and the USA where PCT is regularly used to assist clinical decision-making. The objective of this review and meta-analysis is to report the diagnostic test accuracy of PCT in detecting IBI in febrile infants less than 91 days old, compare its accuracy with CRP and define optimal PCT cut-off values in this cohort. METHODS AND ANALYSIS: A search strategy will include MEDLINE, EMBASE, Web of Science, The Cochrane Library and grey literature. There will be no language or date limitations. Diagnostic accuracy studies compliant with STARD criteria will be considered against eligibility criteria. Abstracts, then full texts, of potentially eligible studies will be independently screened for selection. Data extraction and quality assessment, using the QUADAS-2 tool, will be completed by two independent authors and a third author used for any inconsistencies. True positives, false positives, true negatives and false negatives will be pooled to collate specificity and sensitivity with 95% CIs. Results will be portrayed in forest plots, alongside their quality assessments. ETHICS AND DISSEMINATION: This review does not require ethical clearance. This review will be published in peer-reviewed journals and key messages will be disseminated through presentations at local and international conferences related to this field. The authors aim for this review to be completed and published in 2023.

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.

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.

Robust joint modelling of longitudinal and survival data: Incorporating a time-varying degrees-of-freedom parameter.

Monitoring of individual biomarkers has the potential of explaining the hazard of survival outcomes. In practice, these measurements are intermittently observed and are known to be subject to substantial measurement error. Joint modelling of longitudinal and survival data enables us to associate intermittently measured error-prone biomarkers with risks of survival outcomes and thus plays an important role in the analysis of medical data. Most of the joint models available in the literature have been built on the Gaussian assumption. This makes them sensitive to outliers. In this work, we study a range of robust models to address this issue. Of particular interest is the common occurrence in medical data that outliers can occur with different frequencies over time, for example, in the period when patients adjust to treatment changes. Motivated by the analysis of data gathered from patients with primary biliary cirrhosis, a new model with a time-varying robustness is introduced. Through both the motivating example and a simulation study, this research not only stresses the need to account for longitudinal outliers in the analysis of medical data and in joint modelling research but also highlights the bias and inefficiency from not properly estimating the degrees-of-freedom parameter. This work presents a number of methods in addition to the time-varying robustness, and each method can be fitted using the R package robjm.

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.

Seroprevalence of SARS-CoV-2 antibodies in children of United Kingdom healthcare workers: a prospective multicentre cohort study protocol.

BACKGROUND: A novel coronavirus SARS-CoV-2 has been responsible for a worldwide pandemic. Children typically have very mild, or no, symptoms of infection. This makes estimations of seroprevalence in children difficult. Research is therefore required to determine the seroprevalence of SARS-CoV-2 antibodies in children. The primary objective of this study is to report the seroprevalence of SARS-CoV-2 IgM and/or IgG antibodies in healthy children at baseline, 2 months and 6 months. This is the only longitudinal UK study of seroprevalence in an exclusively paediatric population. Determining the changing seroprevalence is of vital public health importance and can help inform decisions around the lifting of paediatric specific social distancing measures such as school closures and the cancellation of routine paediatric hospital services. METHODS AND ANALYSIS: 1000 healthy children of healthcare workers aged between 2 and 15 years will be recruited from five UK sites (Belfast, Cardiff, Glasgow, London and Manchester). The children will undergo phlebotomy at baseline, 2 months and 6 months to measure IgM and/or IgG positivity to SARS-CoV-2. A sample size of 675 patients is required to detect a 5% change in seroprevalence at each time point assuming an alpha of 0.05 and a beta of 0.2. Adjusted probabilities for the presence of IgG and/or IgM antibodies and of SARS-CoV-2 infection will be reported using logistic regression models where appropriate. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London - Chelsea Research Ethics Committee (REC Reference-20/HRA/1731) and the Belfast Health & Social Care Trust Research Governance (Reference 19147TW-SW). Results of this study will be made available as preprints and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT0434740; Results.

A two-stage approach to the joint analysis of longitudinal and survival data utilising the Coxian phase-type distribution.

The Coxian phase-type distribution is a special type of Markov model which can be utilised both to uncover underlying stages of a survival process and to make inferences regarding the rates of flow of individuals through these latent stages before an event of interest occurs. Such models can be utilised, for example, to identify individuals who are likely to deteriorate faster through a series of disease states and thus require more aggressive medical intervention. Within this paper, a two-stage approach to the analysis of longitudinal and survival data is presented. In Stage 1, a linear mixed effects model is first used to represent how some longitudinal response of interest changes through time. Within this linear mixed effects model, the individuals' random effects can be considered as a proxy measure for the effect of the individuals' genetic profiles on the response of interest. In Stage 2, the Coxian phase-type distribution is employed to represent the survival process. The individuals' random effects, estimated in Stage 1, are incorporated as covariates within the Coxian phase-type distribution so as to evaluate their effect on the individuals' rates of flow through the system represented by the Coxian. The approach is illustrated using data collected on individuals suffering from chronic kidney disease, where focus is given to an emerging longitudinal biomarker of interest - an individual's haemoglobin level.