Host biomarkers and combinatorial scores for the detection of serious and invasive bacterial infection in pediatric patients with fever without source.

BACKGROUND: Improved tools are required to detect bacterial infection in children with fever without source (FWS), especially when younger than 3 years old. The aim of the present study was to investigate the diagnostic accuracy of a host signature combining for the first time two viral-induced biomarkers, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon γ-induced protein-10 (IP-10), with a bacterial-induced one, C-reactive protein (CRP), to reliably predict bacterial infection in children with fever without source (FWS) and to compare its performance to routine individual biomarkers (CRP, procalcitonin (PCT), white blood cell and absolute neutrophil counts, TRAIL, and IP-10) and to the Labscore. METHODS: This was a prospective diagnostic accuracy study conducted in a single tertiary center in children aged less than 3 years old presenting with FWS. Reference standard etiology (bacterial or viral) was assigned by a panel of three independent experts. Diagnostic accuracy (AUC, sensitivity, specificity) of host individual biomarkers and combinatorial scores was evaluated in comparison to reference standard outcomes (expert panel adjudication and microbiological diagnosis). RESULTS: 241 patients were included. 68 of them (28%) were diagnosed with a bacterial infection and 5 (2%) with invasive bacterial infection (IBI). Labscore, ImmunoXpert, and CRP attained the highest AUC values for the detection of bacterial infection, respectively 0.854 (0.804-0.905), 0.827 (0.764-0.890), and 0.807 (0.744-0.869). Labscore and ImmunoXpert outperformed the other single biomarkers with higher sensitivity and/or specificity and showed comparable performance to one another although slightly reduced sensitivity in children < 90 days of age. CONCLUSION: Labscore and ImmunoXpert demonstrate high diagnostic accuracy for safely discriminating bacterial infection in children with FWS aged under and over 90 days, supporting their adoption in the assessment of febrile patients.

Atypical diabetes with spontaneous remission associated with systemic lupus erythematosus in an adolescent girl of African ancestry, a case report.

BACKGROUND: New-onset diabetes in youth encompasses type 1 diabetes, type 2 diabetes, monogenic diabetes, and rarer subtypes like Type B insulin resistance syndrome and ketosis-prone atypical diabetes in African populations. Some cases defy classification, posing management challenges. Here, we present a case of a unique, reversible diabetes subtype. CASE PRESENTATION: We describe an adolescent African girl recently diagnosed with systemic lupus erythematosus. At age 15, she presented with ketoacidosis, HbA1c of 108.7 mmol/mol (12.1%), and positive anti-insulin antibodies. Initially diagnosed with type 1 diabetes, insulin was prescribed. Due to the presence of obesity and signs of insulin resistance, we added metformin. Concurrently, she received treatment for lupus with hydroxychloroquine, mycophenolate mofetil, and prednisone. After discharge, she stopped insulin due to cultural beliefs. Five months later, her glycemia and HbA1c normalized (37 mmol/mol or 5.5%) without insulin, despite corticosteroid therapy and weight gain. Autoantibodies normalized, and lupus activity decreased. Genetic testing for monogenic diabetes was negative, and the type 1 genetic risk score was exceptionally low. CONCLUSIONS: We present a complex, reversible diabetes subtype. Features suggest an autoimmune origin, possibly influenced by overlapping HLA risk haplotypes with lupus. Lupus treatment or immunomodulation may have impacted diabetes remission. Ancestry-tailored genetic risk scores are currently designed to improve diagnostic accuracy.

[Monogenic diabetes : a pioneer in precision medicine management]. / Diabète monogénique : pionnier dans la prise en charge par la médecine de précision.

Diabetes mellitus in children is subdivided into several categories depending on the underlying pathological mechanism. Type 1 diabetes is due to the autoimmune destruction of pancreatic beta-cells, type 2 diabetes to progressive impairment in insulin secretion or insulin sensitivity, and monogenic diabetes due to genetic abnormalities, impairing insulin secretion. In monogenic diabetes, genetic defects result in pancreatic or beta-cell defects (abnormal function or destruction), resulting in neonatal or MODY (Maturity-Onset Diabetes of the Young) diabetes, depending on the age of onset. The identification of monogenic diabetes is crucial as it allows the initiation of targeted and personalized treatment.

Le diabète sucré de l'enfant est subdivisé en plusieurs catégories en fonction du mécanisme pathologique sous-jacent : de type 1 par destruction autoimmune des cellules bêta du pancréas, de type 2 par perte progressive d'une sécrétion adéquate ou de sensibilité à l'insuline et monogénique par anomalie génétique perturbant la sécrétion d'insuline. Dans ce dernier, les anomalies génétiques entraînent des défauts du développement du pancréas ou de la cellule bêta (anomalie de fonction ou destruction), menant à un diabète néonatal ou un diabète MODY (Maturity-Onset Diabetes of the Young) en fonction de l'âge d'apparition. L'identification du diabète monogénique est primordiale puisqu'elle permet l'instauration d'un traitement ciblé et personnalisé.

Viremia as a predictor of absence of serious bacterial infection in children with fever without source.

Most children with fever without source (FWS) require diagnostic laboratory tests to exclude a serious bacterial infection (SBI), often followed by admission and empirical antibiotics. As febrile children with a viral infection are less likely to have a SBI, identifying patients with systemic viral infection could contribute to exclude SBI. We evaluated whether the presence of virus in the blood could be used as a biomarker to rule out SBI. Children < 3 years old with FWS were prospectively enrolled and had real-time (reverse-transcription) PCR performed on the blood for adenovirus, enterovirus, parechovirus, and HHV6. 20/135 patients had SBI, and in 47/135, at least one virus was detected in the blood. Viremia had a higher sensitivity and negative predictive value (90% and 96%) to rule out SBI compared to CRP (65% and 93%) and PCT (55% and 90%). The odds ratio (OR) for the presence of SBI among non-viremic patients was 5.8 (p = 0.0225), compared to 5.5 for CRP ≥ 40 mg/l (p = 0.0009) and 3.7 for PCT ≥ 0.5 ng/mL (0.0093). This remained significant after adjusting for CRP and PCT (OR 5.6 and 5.9, respectively; p = 0.03 for both). Area under the ROC curve for CRP and PCT were 0.754 and 0.779, respectively, but increased to 0.803 and 0.832, respectively, when combined with viremia. CONCLUSION: The presence of viremia had a better performance than commonly used biomarkers to rule-out SBI and could potentially be used in conjunction with CRP and/or PCT in the evaluation of children with FWS. Larger studies should evaluate the role of point-of-care testing of viruses by (revere-transcription) PCR in the plasma in management algorithms of children with FWS. WHAT IS KNOWN: • Most children with FWS have a viral infection, but up to 15% have a SBI; most require laboratory tests, and many admission and empirical antibiotics. • Children with a viral infection are less likely to have a SBI. WHAT IS NEW: • Children with a systemic viral infection are less likely to have an SBI. • Viremia is a better predictor of absence of SBI than commonly used biomarkers and could potentially be used in conjunction with CRP and/or PCT in the evaluation of children with FWS.

Case Report: Persistent Hypogammaglobulinemia More Than 10 Years After Rituximab Given Post-HSCT.

Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells-from the immature pre-B-cell stage in the bone marrow to mature circulating B cells-while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein-Barr virus reactivation, respectively. Both patients' immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients' respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children.

Frequency, Timing, Risk Factors, and Outcomes of Desaturation in Infants With Acute Bronchiolitis and Initially Normal Oxygen Saturation.

Importance: Little is known about the natural course of oxygen desaturation in acute bronchiolitis. Information on risk factors associated with desaturation as well as the time to desaturation in infants with bronchiolitis could help physicians better treat these infants before deciding whether to hospitalize them. Objective: To prospectively determine the frequency of desaturation in infants with bronchiolitis, along with the time to desaturation and risk factors associated with desaturation, and to compare infants who were hospitalized with those discharged home and evaluate risk factors for rehospitalization. Design, Setting, and Participants: This cohort study was conducted during the 2017 to 2018 and 2018 to 2019 respiratory syncytial virus seasons in a tertiary care pediatric emergency department in Switzerland. Included individuals were 239 otherwise-healthy infants aged younger than 1 year, diagnosed with acute bronchiolitis and oxygen saturation of 90% or more on arrival. Data were analyzed from July 2019 to October 2020. Exposures: After receiving triage care, study participants admitted to the emergency department were equipped with a pulse oximeter to continuously record oxygen saturation (Spo2 levels), regardless of subsequent hospitalization or discharge home. Main Outcomes and Measures: The primary outcome was desaturation (ie, Spo2 < 90%) during the first 36 hours. Results: Of 239 infants enrolled, with a median (interquartile range [IQR]) age of 3.9 (1.5-6.5) months, 116 (48.5%) were boys and desaturation occurred in 165 infants (69.0%). Median (IQR) time to desaturation was 3.6 (1.8-9.4) hours. The rate of desaturation was similar between infants hospitalized and those discharged home (137 of 200 infants [68.5%] vs 28 of 39 infants [71.8%]; difference, -3.3%; 95% CI, -18.8% to 12.2%; P = .85). A more severe initial clinical presentation with moderate or severe retractions was the only independent risk factor associated with desaturation (odds ratio, 2.73; 95% CI, 1.49 to 5.02; P = .001). Of 39 infants discharged home, 22 infants (56.4%) experienced major desaturations. However, infants with desaturations, including those with major desaturations, had rates of rehospitalization similar to those of infants without desaturations (8 of 28 infants [28.5%] vs 3 of 11 infants [27.3%]; difference, 1.2%; 95% CI, -29.9% to 32.5; P > .99). Conclusions and Relevance: These findings suggest that rates of desaturation in infants with acute bronchiolitis were high and similar between infants who were hospitalized and those discharged home. A more severe initial clinical presentation was the only risk factor associated with desaturation. However, for infants discharged home, desaturation was not a risk factor associated with rehospitalization.

Enterovirus, parechovirus, adenovirus and herpes virus type 6 viraemia in fever without source.

OBJECTIVES: To evaluate the potential associations between fever without a source (FWS) in children and detection of human enterovirus (HEV), human parechovirus (HPeV), adenovirus (AdV) and human herpesvirus type 6 (HHV-6) in the plasma; and to assess whether the detection of viruses in the plasma is associated with a reduced risk of serious bacterial infection (SBI) and antibiotic use. DESIGN AND SETTING: Between November 2015 and December 2017, this prospective, single-centre, diagnostic study tested the plasma of children <3 years old with FWS. Real-time (reverse-transcription) PCR for HEV, HPeV, AdV and HHV-6 was used in addition to the standardised institutional work-up. A control cohort was also tested for the presence of viruses in their blood. RESULTS: HEV, HPeV, AdV and HHV-6 were tested for in the plasma of 135 patients of median age 2.4 months old. At least one virus was detected in 47 of 135 (34.8%): HEV in 14.1%, HHV-6 in 11.1%, HPeV in 5.9% and AdV in 5.2%. There was no difference in antibiotic use between patients with or without virus detected, despite a relative risk of 0.2 for an SBI among patients with viraemia. Controls were less frequently viraemic than children with FWS (6.0% vs 34.8%; p<0.001). CONCLUSIONS: HEV, HPeV, AdV and HHV-6 are frequently detected in the plasma of children with FWS. Antibiotic use was similar between viraemic and non-viraemic patients despite a lower risk of SBI among patients with viraemia. Point-of-care viral PCR testing of plasma might reduce antibiotic use and possibly investigations and admission rates in patients with FWS. TRIAL REGISTRATION NUMBER: NCT03224026.

Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases.

OBJECTIVE: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. STUDY DESIGN AND SETTING: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. RESULTS: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same. CONCLUSION: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility.

A mobile device application to reduce medication errors and time to drug delivery during simulated paediatric cardiopulmonary resuscitation: a multicentre, randomised, controlled, crossover trial.

BACKGROUND: Vasoactive drug preparation for continuous infusion in children is both complex and time consuming and places the paediatric population at higher risk than adults for medication errors. We developed a mobile device application (app) as a step-by-step guide for the preparation to delivery of drugs requiring continuous infusion. The app has been previously tested during simulation-based resuscitations in a previous single-centre trial. In this trial, our aim was to assess this app in various hospital settings. METHODS: We did a prospective, multicentre, randomised, controlled, crossover trial to compare this app with an internationally used drug-infusion-rates table for the preparation of continuous drug infusion during standardised, simulation-based, paediatric post-cardiac arrest scenarios using a high-fidelity manikin. The scenarios were split into two study periods to assess the two preparation methods consecutively, separated by a washout distraction manoeuvre. Nurses in six paediatric emergency centres in Switzerland were randomly assigned (1:1) to start the scenario with either the app or the infusion-rates table and then complete the scenario using the other preparation method. The primary endpoint was the proportion of participants committing a medication error, which was defined as a deviation from the correct weight dose of more than 10%, miscalculation of the infusion rate, misprogramming of the infusion pump, or the inability to calculate drug dosage without calculation and guidance help from the study team. The medication error proportions observed with both preparation methods were compared by pooling both study periods, with paired data analysed using the unconditional exact McNemar test for dependent groups with a two-sided α level of 0·05. We did sensitivity analyses to investigate the carryover effect. This trial is registered with ClinicalTrials.gov, number NCT03021122. FINDINGS: From March 1 to Dec 31, 2017, we randomly assigned 128 nurses to start the scenario using the app (n=64) or the infusion-rates table (n=64). Among the 128 drug preparations associated with each of the two methods, 96 (75%, 95% CI 67-82) delivered using the infusion-rates table were associated with medication errors compared with nine (7%, 3-13) delivered using the mobile app. Medication errors were reduced by 68% (95% CI 59-76%; p<0·0001) with the app compared with the table, as was the mean time to drug preparation (difference 148·2 s [95% CI 124·2-172·1], a 45% reduction; p<0·0001) and mean time to drug delivery (168·5 s [146·1-190·8], a 40% reduction; p<0·0001). Hospital size and nurses' experience did not modify the intervention effect. We detected no carryover effect. INTERPRETATION: Critically ill children are particularly vulnerable to medication errors. A mobile app designed to help paediatric drug preparation during resuscitation with the aim to significantly reduce the occurrence of medication errors, drug preparation time, and delivery time could have the potential to change paediatric clinical practice in the area of emergency medicine. FUNDING: Swiss National Science Foundation.