Protocol for the diagnostic performance of C reactive protein, procalcitonin and interleukin-6 for serious bacterial infections among children ≤36 months old presenting with fever without source: a systematic review and meta-analysis.

INTRODUCTION: The management of fever without source in children ≤36 months old remains a diagnostic challenge as the underlying aetiologies can vary from self-limiting viral infections to serious bacterial infections (SBIs). Biomarkers such as C reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) have varying thresholds in the prediction of SBIs due to differences in SBI definitions, SBI prevalence, patient characteristics and timing of presentation. This protocol describes a systematic review and meta-analysis that aims to determine the thresholds at which CRP, PCT and IL-6 can perform optimally in distinguishing the presence of SBIs in children ≤36 months old, as well as to determine their performances in early detection of bacterial infections within 48 hours of fever onset. METHODS AND ANALYSIS: We will systematically search electronic databases including MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane CENTRAL, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Science Citation Index from 1 July 2023 to 31 July 2023. We will include studies that report the diagnostic accuracy of CRP, PCT and IL-6 in detecting SBIs in children aged ≤36 months presenting with fever without apparent source. Randomised controlled trials (RCTs) and non-randomised studies including non-RCTs and controlled before-and-after studies will be included. A meta-analysis will be performed and diagnostic performances of these biomarkers will be reported. ETHICS AND DISSEMINATION: The results of this study will provide guidance on clinical decision-making in young children presenting with fever without source. Ethics approval will not be required for this study. The authors aim to publish the findings in a peer-reviewed journal as well as present at international conferences. PROSPERO REGISTRATION NUMBER: CRD42023439093.

Metagenomic next-generation sequencing, instead of procalcitonin, could guide antibiotic usage in patients with febrile acute necrotizing pancreatitis: a multicenter, prospective cohort study.

BACKGROUNDS: The effectiveness of procalcitonin-based algorithms in guiding antibiotic usage for febrile acute necrotizing pancreatitis (ANP) remains controversial. Metagenomic next-generation sequencing (mNGS) has been applied to diagnose infectious diseases. The authors aimed to evaluate the effectiveness of blood mNGS in guiding antibiotic stewardship for febrile ANP. MATERIALS AND METHODS: The prospective multicenter clinical trial was conducted at seven hospitals in China. Blood samples were collected during fever (T ≥38.5°C) from ANP patients. The effectiveness of blood mNGS, procalcitonin, and blood culture in diagnosing pancreatic infection was evaluated and compared. Additionally, the real-world utilization of antibiotics and the potential mNGS-guided antimicrobial strategy in febrile ANP were also analyzed. RESULTS: From May 2023 to October 2023, a total of 78 patients with febrile ANP were enrolled and 30 patients (38.5%) were confirmed infected pancreatic necrosis (IPN). Compared with procalcitonin and blood culture, mNGS showed a significantly higher sensitivity rate (86.7% vs. 56.7% vs. 26.7%, P <0.001). Moreover, mNGS outperformed procalcitonin (89.5 vs. 61.4%, P <0.01) and blood culture (89.5 vs. 69.0%, P <0.01) in terms of negative predictive value. Blood mNGS exhibited the highest accuracy (85.7%) in diagnosing IPN and sterile pancreatic necrosis, significantly superior to both procalcitonin (65.7%) and blood culture (61.4%). In the multivariate analysis, positive blood mNGS (OR=60.2, P <0.001) and lower fibrinogen level (OR=2.0, P <0.05) were identified as independent predictors associated with IPN, whereas procalcitonin was not associated with IPN, but with increased mortality (Odds ratio=11.7, P =0.006). Overall, the rate of correct use of antibiotics in the cohort was only 18.6% (13/70) and would be improved to 81.4% (57/70) if adjusted according to the mNGS results. CONCLUSION: Blood mNGS represents important progress in the early diagnosis of IPN, with particular importance in guiding antibiotic usage for patients with febrile ANP.

Monitoring the efficacy of antibiotic therapy in febrile pediatric oncology patients with bacteremia using infrared spectroscopy of white blood cells-based machine learning.

Bacteremia refers to the presence of bacteria in the bloodstream, which can lead to a serious and potentially life-threatening condition. In oncology patients, individuals undergoing cancer treatment have a higher risk of developing bacteremia due to a weakened immune system resulting from the disease itself or the treatments they receive. Prompt and accurate detection of bacterial infections and monitoring the effectiveness of antibiotic therapy are essential for enhancing patient outcomes and preventing the development and dissemination of multidrug-resistant bacteria. Traditional methods of infection monitoring, such as blood cultures and clinical observations, are time-consuming, labor-intensive, and often subject to limitations. This manuscript presents an innovative application of infrared spectroscopy of leucocytes of pediatric oncology patients with bacteremia combined with machine learning to diagnose the etiology of infection as bacterial and simultaneously monitor the efficacy of the antibiotic therapy in febrile pediatric oncology patients with bacteremia infections. Through the implementation of effective monitoring, it becomes possible to promptly identify any indications of treatment failure. This, in turn, indirectly serves to limit the progression of antibiotic resistance. The logistic regression (LR) classifier was able to differentiate the samples as bacterial or control within an hour, after receiving the blood samples with a success rate of over 95 %. Additionally, initial findings indicate that employing infrared spectroscopy of white blood cells (WBCs) along with machine learning is viable for monitoring the success of antibiotic therapy. Our follow up results demonstrate an accuracy of 87.5 % in assessing the effectiveness of the antibiotic treatment.

A Novel Combination of Host Protein Biomarkers to Distinguish Bacterial From Viral Infections in Febrile Children in Emergency Care.

BACKGROUND: Distinguishing bacterial and viral infections based on clinical symptoms in febrile children attending the emergency department (ED) is challenging. The aim of this study is to determine a novel combination of host protein biomarkers and to assess its performance in distinguishing between bacterial and viral infection in febrile children attending EDs. METHODS: A literature search was performed to identify blood protein biomarkers able to distinguish bacterial and viral infections (May 2015-May 2019). We selected 7 protein biomarkers: Procalcitonin, TNF-related apoptosis-inducing ligand (TRAIL), interleukin (IL)-4, IL-6, Interferon gamma-induced protein-10 (CXCL-10), interferon-gamma and lipocalin 2 (LCN2). These were measured in blood plasma using a bead-based immunoassay in children with a confirmed bacterial or viral infection attending EDs in the Netherlands. We used generalized linear modeling to classify bacterial and viral infections and applied a previously developed feature selection algorithm to select the optimal combination of proteins. We performed a subgroup analysis of this protein signature in patients with C-reactive protein <60 mg/L, representing a clinically challenging diagnostic group. RESULTS: In total 102 children were included (N = 67 bacterial; N = 35 viral). Individual performance of the 7 biomarkers in classifying bacterial versus viral infections ranged from 60.8%-74.5% area under the receiver operator curve (AUC). TRAIL, LCN2 and IL-6 were identified as the best 3-protein signature with an AUC of 86% (95% CI: 71.3%-100%). In 57 patients with C-reactive protein levels <60 mg/L, the 3-protein signature had an AUC of 85.1% (95% CI: 75.3%-94.9%). CONCLUSION: We demonstrate a promising novel combination of 3 host protein biomarkers; TRAIL, LCN2 and IL-6, which performs well in classifying bacterial and viral infections in febrile children in emergency care.

Clinical and microbiological profiles in post-chemotherapy neutropenic fever in hematological malignancy: exploration of clinical phenotype patterns by two-step cluster analysis.

BACKGROUND: Epidemiology of infectious diseases causing febrile illness varies geographically with human attributes. Periodic institutional surveillance of clinical and microbiological profiles in adding data to updating trends, modulating pharmatherapeutics, signifying possible excessive treatments and risk of drug resistance in post-chemotherapy neutropenic fever (NF) in hematological malignancy (HM) is limited. We aimed to review institutional clinical and microbiological data and explore clinical phenotype pattern groups among data. METHODS: Available data from 372 NF episodes were included. Demographics, types of malignancies, laboratory data, antimicrobial treatments and febrile-related outcome data such as predominant pathogens and microbiological diagnosed infections (MDIs) were collected. Descriptive statistics, two-step cluster analysis and non-parametric tests were employed. RESULTS: The occurrences of microbiological diagnosed bacterial infections (MDBIs; 20.2%) and microbiological diagnosed fungal infections (MDFIs; 19.9%) were almost equal. Gram-negative pathogens (11.8%) were comparable with gram-positive pathogens (9.9%), with gram-negative being slightly predominant. Death rate was 7.5%. Two-step cluster analysis yielded four distinct clinical phenotype pattern (cluster) groups: cluster 1 'lymphomas without MDIs', cluster 2 'acute leukemias MDBIs', cluster 3 'acute leukemias MDFIs' and cluster 4 'acute leukemias without MDIs'. Considerable NF events with antibiotic prophylaxis being not identified as MDI might have cases in low-risk with non-infectious reasons causing febrile reactions that might possibly not require prophylaxis. CONCLUSIONS: Regular institutional surveillance with active parameter assessments to signify risk levels in the post-chemotherapy stage, even prior to the onset of fever, might be an evidence-based strategy in the management of NF in HM.

Subcutaneous Microabscesses and Myositis as Part of Immune Reconstitution Inflammatory Syndrome due to Chronic Disseminated Candidiasis in a Child With Acute Lymphoblastic Leukemia.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) occurs when there is immune recovery after a prolonged period of leucopenia as a response to an underlying latent or chronic infection due to a proinflammatory cascade. It can occur in a child on chemotherapy for acute lymphoblastic leukemia (ALL) with underlying chronic disseminated candidiasis (CDC). OBSERVATION: We present a 7-year-old girl with pre-B ALL on chemotherapy who had prolonged febrile neutropenia and CDC with microabscesses in the liver, spleen, and kidney and a prolonged intensive care unit stay. Upon neutrophil recovery, she continued to have high-grade fever (blood and urine cultures negative). She also presented severe myositis of bilateral thigh muscles and developed unusual granulomas in the subcutaneous region of the lower back and right thigh. Although IRIS was suspected, she could not be initiated on steroids due to right upper lobe collapse consolidation due to multidrug-resistant Acinetobacter baumanni, which was treated with sensitive antibiotics. Treatment with steroids resolved her fever and normalized inflammatory markers. She is currently well on maintenance chemotherapy. CONCLUSIONS: IRIS can complicate the treatment of ALL in children. Diagnosing it while having a concurrent bacterial infection is challenging. Rarely CDC can present with subcutaneous granulomas. Treatment with steroids at the right time is very crucial.

Chronic Disseminated Candidiasis in Children and the Role of Corticosteroids Therapy.

BACKGROUND: Little is known about chronic disseminated candidiasis (CDC) in children. This study was done to describe the epidemiology, risk factors and outcome of CDC in children managed at Sultan Qaboos University Hospital (SQUH), Oman, and to describe the role of corticosteroids in the management of immune reconstitution inflammatory syndrome (IRIS) complicating CDC. METHODS: We retrospectively reported demographic, clinical and laboratory data of all children managed in our center for CDC between January 2013 and December 2021. In addition, we discuss the available literature on the role of corticosteroids for management of CDC-related IRIS in children since 2005. RESULTS: Between January 2013 and December 2021, 36 immunocompromised children were diagnosed with invasive fungal infection at our center, of whom 6 had CDC (all with acute leukemia). Their median age was 5.75 years. Prolonged fever despite broad-spectrum antibiotics (6/6) followed by skin rash (4/6) were the most common clinical features of CDC. Four children grew Candida tropicalis from blood or skin. CDC-related IRIS was documented in 5 children (83%) and 2 received corticosteroids. Our literature review revealed that 28 children were managed with corticosteroids for CDC-related IRIS since 2005. The majority of these children had defervescence of fever within 48 hours. Prednisolone of 1-2 mg/kg/day for 2-6 weeks was the most common regimen used. No major side effects reported in these patients. CONCLUSION: CDC is more common in children with acute leukemia and CDC-related IRIS is not uncommon. Corticosteroid therapy looks effective and safe as adjunctive therapy for CDC-related IRIS.

Detection of Salmonella Typhi nucleic acid by RT-PCR and anti-HlyE, -CdtB, -PilL, and -Vi IgM by ELISA at sites in Ghana, Madagascar and Ethiopia.

BACKGROUND: We aimed to assess the prevalence of Salmonella Typhi through DNA and IgM-antibody detection methods as a prelude to extended surveillance activities at sites in Ghana, Madagascar, and Ethiopia. METHODS: We performed species-specific real-time polymerase reaction (RT-PCR) to identify bacterial nucleic acid, and enzyme-linked immunosorbent assay (ELISA) for detecting HlyE/STY1498-, CdtB/STY1886-, pilL/STY4539- and Vi-antigens in blood and biopsy specimens of febrile and non-febrile subjects. We generated antigen-specific ELISA proxy cut-offs by change-point analyses, and utilized cumulative sum as detection method coupled with 1000 repetitive bootstrap analyses. We computed prevalence rates in addition to odds ratios to assess correlations between ELISA outcomes and participant characteristics. RESULTS: Definitive positive RT-PCR results were obtained from samples of febrile subjects originating from Adama Zuria/Ethiopia (1.9%, 2/104), Wolayita Sodo/Ethiopia (1.0%, 1/100), Diego/Madagascar (1.0%, 1/100), and Kintampo/Ghana (1.0%, 1/100), and from samples of non-febrile subjects from Wolayita Sodo/Ethiopia (1%, 2/201). While IgM antibodies against all antigens were identified across all sites, prevalence rates were highest at all Ethiopian sites, albeit in non-febrile populations. Significant correlations in febrile subjects aged < 15 years versus ≥ 15 years were detected for Vi (Odds Ratio (OR): 8.00, p = 0.034) in Adama Zuria/Ethiopia, STY1498 (OR: 3.21, p = 0.008), STY1886 (OR: 2.31, p = 0.054) and STY4539 (OR: 2.82, p = 0.022) in Diego/Madagascar, and STY1498 (OR: 2.45, p = 0.034) in Kintampo/Ghana. We found statistical significance in non-febrile male versus female subjects for STY1498 (OR: 1.96, p = 0.020) in Adama Zuria/Ethiopia, Vi (OR: 2.84, p = 0.048) in Diego/Madagascar, and STY4539 (OR: 0.46, p = 0.009) in Kintampo/Ghana. CONCLUSIONS: Findings indicate non-discriminatory stages of acute infections, though with site-specific differences. Immune responses among non-febrile, presumably healthy participants may mask recall and/or reporting bias leading to misclassification, or asymptomatic, subclinical infection signs induced by suppression of inflammatory responses. As most Ethiopian participants were ≥ 15 years of age and not at high-risk, the true S. Typhi burden was likely missed. Change-point analyses for generating ELISA proxy cut-offs appeared robust, though misclassification is possible. Our findings provided important information that may be useful to assess sites prior to implementing surveillance for febrile illness including Salmonella disease.

Febrile children with comorbidities at the emergency department - a multicentre observational study.

We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3-1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2-3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1-2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1-2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8-7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7-2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2-6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5-24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1-6.9) or PICU admission (aOR 9.7, 6.1-15.5). CONCLUSIONS: Our data show how children with comorbidities are a population at risk, as they more often are diagnosed with bacterial infections and more often require PICU admission and life-saving interventions. WHAT IS KNOWN: • While children with comorbidity constitute a large part of ED frequent flyers, they are often excluded from studies. WHAT IS NEW: • Children with comorbidities in general are more ill upon presentation than children without comorbidities. • Children with comorbidities form a heterogeneous group; specific subgroups have an increased risk for invasive bacterial infections, while others have an increased risk of invasive interventions such as PICU admission, regardless of the cause of the fever.

Serious bacterial infections in young children with fever without source after discharge from emergency department: A National Health Insurance database cohort study.

BACKGROUND: Well-appearing febrile young children discharged from the emergency department (ED) after medical assessment are still at risk for serious bacterial infections (SBI). The incidence of SBI and the effectiveness of laboratory tests in the pneumococcal conjugate vaccine era remain unknown. METHODS: We conducted a study using Taiwan's National Health Insurance claims data from 2004 to 2014. Children aged 2-24 months discharged from the ED with a diagnosis compatible with fever without source (FWS) were enrolled. RESULTS: The study identified 431,884 children from the ED with FWS. 13.53% of the children had revisits, 8.62% needed hospitalization and 1.57% developed SBI. Younger children had a higher SBI rate, but a lower revisit rate. The revisit rate was 12.22% for children aged 2-6 months, 13.61% for children aged 7-12 months and 13.77% for children aged 13-24 months (p < 0.0001). The SBI rate was 4.44% for children aged 2-6 months, 1.85% for children aged 2-6 months and 0.96% for children aged 13-24 months (p < 0.0001). Children with hemogram tests, compared to those without, had a higher revisit rate (16.30% vs. 13.15%, p < 0.0001), and a higher SBI rate in the children aged 13-24 months (1.30% vs. 0.92%, p < 0.0001); furthermore, children with urinalysis had a significantly higher revisit rate (14.42% vs. 13.24%, p < 0.0001) and higher SBI rate (2.10% vs. 1.40%, p < 0.0001). CONCLUSION: Children with FWS aged 2-24 months who were discharged from ED after blood test and urinalysis were still at risk for SBI, especially those aged 2-6 months.

Reassessing the Performance of the "Step-By-Step" Approach to Febrile Infants 90 Days of Age and Younger in the Context of the COVID-19 Pandemic: A Multicentric Retrospective Study.

BACKGROUND: Infants with COVID-19 can often present with fever without source, which is a challenging situation in infants <90 days old. The "step-by-step" algorithm has been proposed to identify children at high risk of bacterial infection. In the context of the COVID-19 pandemic, we aimed to reassess the diagnostic performance of this algorithm. METHODS: We performed a multicentric retrospective study in 3 French pediatric emergency departments between 2018 and 2020. We applied the "step-by-step" algorithm to 4 clinical entities: COVID-19, febrile urinary tract infections (FUTI), invasive bacterial infection (IBI), and enterovirus infections. The main outcome was the proportion of infants classified at high risk (ill-appearing, ≤21 days old, with leukocyturia or procalcitonin level ≥0.5 ng/mL). RESULTS: Among the 199 infants included, 40 had isolated COVID-19, 25 had IBI, 60 had FUTI, and 74 had enterovirus infection. All but 1 infant with bacterial infection were classified at high risk (96% for IBI and 100% for FUTI) as well as 95% with enterovirus and 82% with COVID-19. Infants with COVID-19 were classified at high risk because an ill-appearance (72%), an age ≤21 days (27%), or leukocyturia (19%). All these infants had procalcitonin values <0.5 ng/mL and only 1 had C-reactive protein level >20 mg/L. CONCLUSIONS: The "step-by-step" algorithm remains effective to identify infants with bacterial infection but misclassifies most infants with COVID-19 as at high risk of bacterial infection leading to unnecessary cares. An updated algorithm based adding viral testing may be needed to discriminate fever related to isolated COVID-19 in infants <90 days old.

Impact of Paired Central and Peripheral Blood Cultures in Children With Cancer.

Children with cancer require central venous access which carries risk for line-related infections. The necessity of peripheral and central blood cultures is debated for those with fevers. We evaluated and described results for first episode of paired blood cultures from children with cancer who have a central venous line using retrospective database. Blood culture results, laboratory data, and medical outcomes were included. Descriptive analyses of blood culture results and clinical data were performed. There were 190 episodes of paired positive blood cultures with 167 true positive episodes. Of the true positive episodes, 104 (62.3%) were positive in both central and peripheral cultures, 42 (25.1%) were positive in central only cultures, and 21 (12.6%) were positive in peripheral cultures only. Intensive care unit admission within 48 hours after blood cultures (n=33) differed significantly: 28.7% for both central and peripheral, 10% for central only, and 0% for peripheral only (P=0.009). Central line removal (n=34) differed by type of positivity but was not significant: 22.1% for both central and peripheral, 23.8% for central only, and 4.8% for peripheral only (P=0.15). Peripheral blood cultures provided important medical information yet had differences in short-term clinical outcomes. Further evaluation of medical decision making is warranted.

A two-transcript biomarker of host classifier genes for discrimination of bacterial from viral infection in acute febrile illness: a multicentre discovery and validation study.

BACKGROUND: Acute febrile illness is one of the main reasons for outpatient hospital visits worldwide. However, differential diagnosis between bacterial and viral causes is challenging and misdiagnosis can result in antimicrobial overuse and hinder prompt treatment. We aimed to build and validate a diagnostic model to discriminate bacterial from viral infection in acute febrile illness by evaluating the expression of potential classifier host genes. METHODS: In this multicentre discovery and validation study, we included patients aged 14-85 years with acute febrile illness (fever for ≤14 days, axillary temperature of ≥38°C, and confirmed bacterial infection, viral infection, or non-infectious inflammatory disease), and healthy control participants (no significant medical history and no fever within the past 90 days) from four hospitals in Shandong province, China. Patients from the first hospital were divided into the screening, discovery, and internal validation groups, and patients from the three other hospitals comprised the external validation group. We measured expression of candidate genes in peripheral blood by RT-PCR, and patients for whom a successful RT-PCT result was recorded were included in the next-step analysis. For patients from the first hospital, those enrolled during the early phase of the study were assigned to the screening group, which was used to identify the optimal transcripts (IFI44L and PI3) for discrimination between bacterial and viral infections by screening four candidate genes (FAM89A, IFI44L, PI3, and ITGB2) by RT-PCR. The remaining patients were then randomly assigned (1:1) to discovery and internal validation groups by time of admission and blood drawing via the equidistant random sampling method. A logistic regression model integrating the mRNA levels of IFI44L and PI3 was built by use of the discovery group, and the diagnostic performance of the model was evaluated in the internal and external validation groups using area under the receiver operating curve (AUC), sensitivity, and specificity. FINDINGS: Between March 1, 2018, and Aug 31, 2019, we assessed 1658 individuals for inclusion in the study. After exclusion of ineligible participants, 458 participants were enrolled (178 patients with acute febrile illness caused by bacterial infection, 212 with acute febrile illness caused by viral infection, 38 with non-infectious inflammatory diseases, and 30 healthy controls). The 390 patients with bacterial or viral infections were assigned to one of four groups: screening (n=64, 33 with bacterial infections and 31 with viral infections), discovery (n=124, 55 with bacterial infections and 69 with viral infections), internal validation (n=124, 55 with bacterial infections and 69 with viral infections), and external validation (n=78, 35 with bacterial infections and 43 with viral infections). Of the four candidate host genes (FAM89A, IFI44L, PI3, and ITGB2), IFI44L and PI3 showed the most discriminative expression pattern and were used to build the logistic regression model. We established the optimal cutoff of the bacterial infection likelihood score to be 0·547598. With the diagnostic result from the gold standard tests (culture and PCR) as the reference, the two-transcript classifier model had an AUC of 0·969 (95% CI 0·937-1·000), sensitivity of 0·891 (0·782-0·949), and specificity of 0·971 (0·900-0·992) to discriminate bacterial and viral infections in the internal validation group. The model showed similar results in the external validation group (AUC 0·986, 95% CI 0·968-1·000; sensitivity 0·857, 0·706-0·937; and specificity 0·954, 0·845-0·987). INTERPRETATION: IFI44L and PI3 transcripts, measured by RT-PCR, are robust classifiers to discriminate bacterial from viral infection in acute febrile illness. This two-transcript biomarker has the potential to be transformed into a commercial panel and applied universally. FUNDING: None.

The African Network for Improved Diagnostics, Epidemiology and Management of common infectious Agents.

BACKGROUND: In sub-Saharan Africa, acute respiratory infections (ARI), acute gastrointestinal infections (GI) and acute febrile disease of unknown cause (AFDUC) have a large disease burden, especially among children, while respective aetiologies often remain unresolved. The need for robust infectious disease surveillance to detect emerging pathogens along with common human pathogens has been highlighted by the ongoing novel coronavirus disease 2019 (COVID-19) pandemic. The African Network for Improved Diagnostics, Epidemiology and Management of Common Infectious Agents (ANDEMIA) is a sentinel surveillance study on the aetiology and clinical characteristics of ARI, GI and AFDUC in sub-Saharan Africa. METHODS: ANDEMIA includes 12 urban and rural health care facilities in four African countries (Côte d'Ivoire, Burkina Faso, Democratic Republic of the Congo and Republic of South Africa). It was piloted in 2018 in Côte d'Ivoire and the initial phase will run from 2019 to 2021. Case definitions for ARI, GI and AFDUC were established, as well as syndrome-specific sampling algorithms including the collection of blood, naso- and oropharyngeal swabs and stool. Samples are tested using comprehensive diagnostic protocols, ranging from classic bacteriology and antimicrobial resistance screening to multiplex real-time polymerase chain reaction (PCR) systems and High Throughput Sequencing. In March 2020, PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and analysis of full genomic information was included in the study. Standardised questionnaires collect relevant clinical, demographic, socio-economic and behavioural data for epidemiologic analyses. Controls are enrolled over a 12-month period for a nested case-control study. Data will be assessed descriptively and aetiologies will be evaluated using a latent class analysis among cases. Among cases and controls, an integrated analytic approach using logistic regression and Bayesian estimation will be employed to improve the assessment of aetiology and associated risk factors. DISCUSSION: ANDEMIA aims to expand our understanding of ARI, GI and AFDUC aetiologies in sub-Saharan Africa using a comprehensive laboratory diagnostics strategy. It will foster early detection of emerging threats and continued monitoring of important common pathogens. The network collaboration will be strengthened and site diagnostic capacities will be reinforced to improve quality management and patient care.

Ticking on Pandora's box: a prospective case-control study into 'other' tick-borne diseases.

BACKGROUND: Tick-borne pathogens other than Borrelia burgdorferi sensu lato - the causative agent of Lyme borreliosis - are common in Ixodes ricinus ticks. How often these pathogens cause human disease is unknown. In addition, diagnostic tools to identify such diseases are lacking or reserved to research laboratories. To elucidate their prevalence and disease burden, the study 'Ticking on Pandora's Box' has been initiated, a collaborative effort between Amsterdam University Medical Center and the National Institute for Public Health and the Environment. METHODS: The study investigates how often the tick-borne pathogens Anaplasma phagocytophilum, Babesia species, Borrelia miyamotoi, Neoehrlichia mikurensis, spotted fever group Rickettsia species and/or tick-borne encephalitis virus cause an acute febrile illness after tick-bite. We aim to determine the impact and severity of these tick-borne diseases in the Netherlands by measuring their prevalence and describing their clinical picture and course of disease. The study is designed as a prospective case-control study. We aim to include 150 cases - individuals clinically suspected of a tick-borne disease - and 3 matched healthy control groups of 200 persons each. The controls consist respectively of a group of individuals with either a tick-bite without complaints, the general population and of healthy blood donors. During a one-year follow-up we will acquire blood, urine and skin biopsy samples and ticks at baseline, 4 and 12 weeks. Additionally, participants answer modified versions of validated questionnaires to assess self-reported symptoms, among which the SF-36, on a 3 monthly basis. DISCUSSION: This article describes the background and design of the study protocol of 'Ticking on Pandora's Box'. With our study we hope to provide insight into the prevalence, clinical presentation and disease burden of the tick-borne diseases anaplasmosis, babesiosis, B. miyamotoi disease, neoehrlichiosis, rickettsiosis and tick-borne encephalitis and to assist in test development as well as provide recommendations for national guidelines. TRIAL REGISTRATION: NL9258 (retrospectively registered at Netherlands Trial Register, trialregister.nl in in February 2021).

Evaluation of Empiric Vancomycin for Fevers During High-dose Cytarabine Administration.

BACKGROUND: Cytarabine is a nucleoside analog used in chemotherapy regimens for the treatment of multiple hematologic malignancies. One of the known adverse effects of cytarabine, particularly in patients receiving high-dose cytarabine (HDAC), is drug-induced fever. Multiple studies have demonstrated an increased risk of viridans group streptococcal bacteremia in patients who have received HDAC. For this reason, our institution and several other institutions across the country routinely include vancomycin as empiric coverage for patients who develop fever during HDAC, due to concern for resistance to cephalosporin monotherapy. MATERIALS AND METHODS: Patient demographic, diagnosis, treatment, and outcome information was collected by electronic chart review for each HDAC infusion from 2007 to August 2018 at the University of Iowa Stead Family Children's Hospital. If fever was documented during or within 24 hours of HDAC, additional information was collected regarding patient outcome and diagnostic testing. RESULTS: Of 208 HDAC administrations documented, patients developed fevers during the course on 82 occasions (39.4%). A median of 3 blood cultures per febrile period were obtained from time of fever onset during HDAC administration through >24 hours afebrile. One blood culture was positive for an oral flora organism determined by the microbiology lab report to be a likely contaminant. There were no other positive blood cultures in non-neutropenic or neutropenic patients. CONCLUSION: Fever due to HDAC is relatively common but appears to frequently lack association with bacteremia during the time of HDAC administration. Broad-spectrum empiric antibiotic regimens including vancomycin may be unnecessary for these patients, particularly before they become neutropenic.

Preoperative urine nitrite versus urine culture for predicting postoperative fever following flexible ureteroscopic lithotripsy: a propensity score matching analysis.

PURPOSE: Multiple studies have reported that preoperative positive urine culture is an independent risk factor for postoperative fever (POF) after ureteroscopy (URS). Urine nitrite is associated urinary tract infections (UTIs). However, none of studies has explored the role of urine nitrite in the prediction of POF after flexible URS (fURS). METHODS: Patients who underwent fURS by the same surgeon between 2009 and 2019 were screened. Sensitivity and specificity of urine culture and urine nitrite were calculated. Propensity score (PS) matching was performed to get a baseline-balanced retrospective cohort to avoid potential bias. Receiver operating characteristic-area under the curve (ROC-AUC) calculated was used to determine the predictive power of models. Decision curve analysis (DCA) was plotted to obtain the clinical benefit of the models. RESULTS: Poseoperative fever (POF) is defined as the temperature of the patient higher than 38 ℃ within 72 h after operation, with no sign of infection in other systems. 31(2.8%) of 1095 cases had POF after fURL. Urine nitrite had a better specificity than urine culture for POF diagnosis (P < 0.001). After the PS matching, a well-balanced cohort of 24 POF group and 96 no-POF group was produced. The mean AUC from the bootstrap resampling method for urine nitrite model (AUC: 0.8736; 95% CI: 0.8731-0.8743) was significantly increased than that of the urine culture model (AUC: 0.8385; 95% CI: 0.8378-0.8392). The application of two kinds of POF predicting models could bring clinical net benefit when the probability is < 35%. However, urine nitrite model showed a better clinical net benefit acquirement compared to the urine culture model. CONCLUSION: Preoperative positive urine nitrite may play a pivotal role in the prediction of POF after fURS and needs to be validated by future evidence.

[A 19-year-old woman with fever and high blood pressure]. / Eine 19-jährige Frau mit Fieber und Bluthochdruck.

A 19-year-old female patient was admitted to hospital for further diagnostics and treatment of a febrile infection. The cause was found to be a bronchopulmonary infection due to methicillin-sensitive Staphylococcus aureus (MSSA), which led to an infective endocarditis with mitral valve infestation and two splenic abscesses. Under treatment according to the antibiogram and laparoscopic excision of the splenic abscesses, the infection-related complications could be successfully resolved. Even during the physical examination there was a suspicion of Cushing's syndrome, which was confirmed by laboratory and radiological investigations and is associated with a general immune deficiency. Remarkable was that the initially difficult to adjust high blood pressure became normalized after transsphenoidal resection of the pituitary adenoma.

Outcomes and Disposition of Oncology Patients With Non-neutropenic Fever and Positive Blood Cultures.

Children with cancer and non-neutropenic fever (NNF) episodes are often treated as outpatients if they appear well. However, a small subset have bloodstream infections (BSIs) and must return for further evaluation. These patients may be directly admitted to inpatient units, whereas others are first evaluated in outpatient settings before admission. The best practice for securing care for patients discovered to have outpatient bacteremia are unclear. To determine outcomes and compare time to antibiotics between the 2 disposition, we retrospectively reviewed all NNF initially treated as outpatients and later had positive blood cultures from 2012 to 2016. Of 845 NNF cases initially treated in outpatient settings, 48 episodes (n=43 patients) had BSIs. Of those, 77.1% (n=37) were re-evaluated as outpatients and admitted; 14.6% (n=7) were direct admissions. The median time to antibiotic did not significantly differ between outpatient re-evaluations (119 min) and direct admissions (191 min), P=0.11. One patient met sepsis criteria upon return and required intensive care unit admission for vasopressor support. No patient died within 1 week of the febrile episode. Most patients with NNF and BSIs initially discharged are stable upon return. Institutions should evaluate their patient flows to ensure that patients receive timely care.