Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy.

BACKGROUND: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life. METHODS: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance. RESULTS: In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69-2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1-7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 µg/mL (range 0.005-0.12 µg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 [range 0.4-6.9] µg/mL) and without (3.1 [range 0.7-11.0] µg/mL) infections during the first year of life (P = .41). CONCLUSIONS: No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.

De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.

PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene. METHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences. RESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model. CONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.

Group A streptococcal disease in paediatric inpatients: a European perspective.

Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p < 0.001); and were younger (median 40 (IQR 21-83) vs 56 (IQR 36-85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring (p < 0.001). CONCLUSION: In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease. WHAT IS KNOWN: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited. WHAT IS NEW: • In a large, prospective cohort of children with community-acquired bacterial infection requiring hospitalisation in Europe, GAS was the most frequent pathogen, with 12% disability at discharge, and 2% mortality in patients with GAS infection. • In children with GAS sepsis, IVIG was used in only 4.6% of patients and clindamycin in 29% of patients.

Clinical validation of digital biomarkers for paediatric patients with asthma and cystic fibrosis: potential for clinical trials and clinical care.

BACKGROUND: Digital biomarkers are a promising novel method to capture clinical data in a home setting. However, clinical validation prior to implementation is of vital importance. The aim of this study was to clinically validate physical activity, heart rate, sleep and forced expiratory volume in 1 s (FEV1) as digital biomarkers measured by a smartwatch and portable spirometer in children with asthma and cystic fibrosis (CF). METHODS: This was a prospective cohort study including 60 children with asthma and 30 children with CF (aged 6-16 years). Participants wore a smartwatch, performed daily spirometry at home and completed a daily symptom questionnaire for 28 days. Physical activity, heart rate, sleep and FEV1 were considered candidate digital end-points. Data from 128 healthy children were used for comparison. Reported outcomes were compliance, difference between patients and controls, correlation with disease activity, and potential to detect clinical events. Analysis was performed with linear mixed effects models. RESULTS: Median compliance was 88%. On average, patients exhibited lower physical activity and FEV1 compared with healthy children, whereas the heart rate of children with asthma was higher compared with healthy children. Days with a higher symptom score were associated with lower physical activity for children with uncontrolled asthma and CF. Furthermore, FEV1 was lower and (nocturnal) heart rate was higher for both patient groups on days with more symptoms. Candidate biomarkers appeared able to describe a pulmonary exacerbation. CONCLUSIONS: Portable spirometer- and smartwatch-derived digital biomarkers show promise as candidate end-points for use in clinical trials or clinical care in paediatric lung disease.

Saliva as a sampling matrix for therapeutic drug monitoring of gentamicin in neonates: A prospective population pharmacokinetic and simulation study.

AIMS: Therapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non-invasive gentamicin TDM strategy using saliva was investigated. METHODS: This was a multicentre, prospective, observational cohort study including 54 neonates. Any neonate treated with intravenous gentamicin was eligible for the study. Up to eight saliva samples were collected per patient at different time-points. Gentamicin levels in saliva were determined with liquid chromatography tandem mass-spectrometry (LC-MS/MS). A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects modelling (NONMEM) to describe the relation between gentamicin concentrations in saliva and plasma. Monte Carlo simulations with a representative virtual cohort (n = 3000) were performed to evaluate the probability of target attainment with saliva versus plasma TDM. RESULTS: Plasma PK was adequately described with an earlier published model. An additional saliva compartment describing the salivary gentamicin concentrations was appended to the model with first-order input (k13 0.023 h-1 ) and first-order elimination (k30 0.169 h-1 ). Inter-individual variability of k30 was 38%. Postmenstrual age (PMA) correlated negatively with both k13 and k30 . Simulations demonstrated that TDM with four saliva samples was accurate in 81% of the simulated cases versus 94% when performed with two plasma samples and 87% when performed with one plasma sample. CONCLUSION: TDM of gentamicin using saliva is feasible and the difference in precision between saliva and plasma TDM may not be clinically relevant, especially for premature neonates.

Association of monocyte HLA-DR expression over time with secondary infection in critically ill children: a prospective observational study.

An impaired immune response could play a role in the acquisition of secondary infections in critically ill children. Human leukocyte antigen-DR expression on monocytes (mHLA-DR) has been proposed as marker to detect immunosuppression, but its potential to predict secondary infections in critically ill children is unclear. We aimed to assess the association between mHLA-DR expression at several timepoints and the change of mHLA-DR expression over time with the acquisition of secondary infections in critically ill children. In this prospective observational study, children < 18 years with fever and/or suspected infection (community-acquired or hospital-acquired) were included at a paediatric intensive care unit in the Netherlands. mHLA-DR expression was determined by flow cytometry on day 1, day 2-3 and day 4-7. The association between delta-mHLA-DR expression (difference between last and first measurement) and secondary infection was assessed by multivariable regression analysis, adjusted for age and Paediatric Logistic Organ Dysfunction-2 score. We included 104 patients at the PICU (median age 1.2 years [IQR 0.3-4.2]), of whom 28 patients (27%) developed a secondary infection. Compared to 93 healthy controls, mHLA-DR expression of critically ill children was significantly lower at all timepoints. mHLA-DR expression did not differ at any of the time points between patients with and without secondary infection. In addition, delta-mHLA-DR expression was not associated with secondary infection (aOR 1.00 [95% CI 0.96-1.04]).Conclusions: Our results confirm that infectious critically ill children have significantly lower mHLA-DR expression than controls. mHLA-DR expression was not associated with the acquisition of secondary infections. What is Known: • An impaired immune response, estimated by mHLA-DR expression, could play an essential role in the acquisition of secondary infections in critically ill children. • In critically ill children, large studies on the association of mHLA-DR expression with secondary infections are scarce. What is New: • Our study confirms that critically ill children have lower mHLA-DR expression than healthy controls. • mHLA-DR expression and change in mHLA-DR was not associated with the acquisition of secondary infection.

Hemostasis Proteins in Invasive Meningococcal and Nonmeningococcal Infections: A Prospective Multicenter Study.

OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.

Parental and physician's point-of-view towards antibiotic prescriptions and discharge conversations in the pediatric emergency department.

BACKGROUND: Within Europe, the Netherlands has one of the lowest antibiotic consumption rates. We aimed to gain insight into attitudes of Dutch physicians and parents towards information provided during discharge conversations in the emergency department (ED) and towards antibiotic use in children, in order to obtain information on the assumptions and beliefs that underlie a practice of low prescription rates. METHODS: Discharge conversations of 70 children presenting with an infectious disease at the ED were observed. After 7-10 days, 55 parents were called for a semi-structured interview. In addition, 29 pediatricians and pediatric residents completed a questionnaire on their prescription behaviour. RESULTS: Concerns about (recognizing) the severity of their child's infection was parents' main motivation to seek help. Both pediatricians and parents reported a general reluctance towards antibiotic use. While pediatricians took appropriateness based on indication and the risk of antimicrobial resistance development into account when considering antibiotic treatment, a thorough medical assessment was deemed more important for Dutch parents than any type of therapeutic treatment, including antibiotics. The topic most often discussed during the discharge conversations was safety netting instructions (in 86%), which were discussed more often during discharge conversations with parents of children that did not receive antibiotic treatment (91% versus 69%). CONCLUSION: Dutch pediatricians and parents are both reluctant to use antibiotics for uncomplicated infections in children, but for different reasons. The emphasis of discharge conversations was on safety netting instructions, which seems to be an alternative for (early) antibiotic use in our setting and may guide overuse prevention strategies in settings where antibiotic overuse is more common.

Theoretical Performance of Nonlinear Mixed-Effect Models Incorporating Saliva as an Alternative Sampling Matrix for Therapeutic Drug Monitoring in Pediatrics: A Simulation Study.

BACKGROUND: Historically, pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) have relied on plasma as a sampling matrix. Noninvasive sampling matrices, such as saliva, can reduce the burden on pediatric patients. The variable plasma-saliva relationship can be quantified using population PK models (nonlinear mixed-effect models). However, criteria regarding acceptable levels of variability in such models remain unclear. In this simulation study, the authors aimed to propose a saliva TDM evaluation framework and evaluate model requirements in the context of TDM, with gentamicin and lamotrigine as model compounds. METHODS: Two population pharmacokinetic models for gentamicin in neonates and lamotrigine in pediatrics were extended with a saliva compartment including a delay constant (kSALIVA), a saliva:plasma ratio, and between-subject variability (BSV) on both parameters. Subjects were simulated using a realistic covariate distribution. Bayesian maximum a posteriori TDM was applied to assess the performance of an increasing number of TDM saliva samples and varying levels of BSV and residual variability. Saliva TDM performance was compared with plasma TDM performance. The framework was applied to a known voriconazole saliva model as a case study. RESULTS: TDM performed using saliva resulted in higher target attainment than no TDM, and a residual proportional error <25% on saliva observations led to saliva TDM performance comparable with plasma TDM. BSV on kSALIVA did not affect performance, whereas increasing BSV on saliva:plasma ratios by >25% for gentamicin and >50% for lamotrigine reduced performance. The simulated target attainment for voriconazole saliva TDM was >90%. CONCLUSIONS: Saliva as an alternative matrix for noninvasive TDM is possible using nonlinear mixed-effect models combined with Bayesian optimization. This article provides a workflow to explore TDM performance for compounds measured in saliva and can be used for evaluation during model building.

The impact of lockdown on pediatric ED visits and hospital admissions during the COVID19 pandemic: a multicenter analysis and review of the literature.

The coronavirus disease 2019 pandemic has enormous impact on society and healthcare. Countries imposed lockdowns, which were followed by a reduction in care utilization. The aims of this study were to quantify the effects of lockdown on pediatric care in the Netherlands, to elucidate the cause of the observed reduction in pediatric emergency department (ED) visits and hospital admissions, and to summarize the literature regarding the effects of lockdown on pediatric care worldwide. ED visits and hospital admission data of 8 general hospitals in the Netherlands between January 2016 and June 2020 were summarized per diagnosis group (communicable infections, noncommunicable infections, (probable) infection-related, and noninfectious). The effects of lockdown were quantified with a linear mixed effects model. A literature review regarding the effect of lockdowns on pediatric clinical care was performed. In total, 126,198 ED visits and 47,648 admissions were registered in the study period. The estimated reduction in general pediatric care was 59% and 56% for ED visits and admissions, respectively. The largest reduction was observed for communicable infections (ED visits: 76%; admissions: 77%), whereas the reduction in noninfectious diagnoses was smaller (ED visits 36%; admissions: 37%). Similar reductions were reported worldwide, with decreases of 30-89% for ED visits and 19-73% for admissions.Conclusion: Pediatric ED utilization and hospitalization during lockdown were decreased in the Netherlands and other countries, which can largely be attributed to a decrease in communicable infectious diseases. Care utilization for other conditions was decreased as well, which may indicate that care avoidance during a pandemic is significant. What is Known: • The COVID-19 pandemic had enormous impact on society. • Countries imposed lockdowns to curb transmission rates, which were followed by a reduction in care utilization worldwide. What is New: • The Dutch lockdown caused a significant decrease in pediatric ED utilization and hospitalization, especially in ED visits and hospital admissions because of infections that were not caused by SARS-CoV-2. • Care utilization for noninfectious diagnoses was decreased as well, which may indicate that pediatric care avoidance during a pandemic is significant.

The influence of chest X-ray results on antibiotic prescription for childhood pneumonia in the emergency department.

The aim of this study is to evaluate the influence of chest X-ray (CXR) results on antibiotic prescription in children suspected of lower respiratory tract infections (RTI) in the emergency department (ED). We performed a secondary analysis of a stepped-wedge, cluster randomized trial of children aged 1 month to 5 years with fever and cough/dyspnoea in 8 EDs in the Netherlands (2016-2018), including a 1-week follow-up. We analysed the observational data of the pre-intervention period, using multivariable logistic regression to evaluate the influence of CXR result on antibiotic prescription. We included 597 children (median age 17 months [IQR 9-30, 61% male). CXR was performed in 109/597 (18%) of children (range across hospitals 9 to 50%); 52/109 (48%) showed focal infiltrates. Children who underwent CXR were more likely to receive antibiotics, also when adjusted for clinical signs and symptoms, hospital and CXR result (OR 7.25 [95% CI 2.48-21.2]). Abnormalities on CXR were not significantly associated with antibiotic prescription.Conclusion: Performance of CXR was independently associated with more antibiotic prescription, regardless of its results. The limited influence of CXR results on antibiotic prescription highlights the inferior role of CXR on treatment decisions for suspected lower RTI in the ED. What is Known: • Chest X-ray (CXR) has a high inter-observer variability and cannot distinguish between bacterial or viral pneumonia. • Current guidelines recommend against routine use of CXR in children with uncomplicated respiratory tract infections (RTIs) in the outpatient setting. What is New: • CXR is still frequently performed in non-complex children suspected of lower RTIs in the emergency department • CXR performance was independently associated with more antibiotic prescriptions, regardless of its results, highlighting the inferior role of chest X-rays in treatment decisions.

Postdischarge Recovery after Acute Pediatric Lung Disease Can Be Quantified with Digital Biomarkers.

BACKGROUND: Pediatric patients admitted for acute lung disease are treated and monitored in the hospital, after which full recovery is achieved at home. Many studies report in-hospital recovery, but little is known regarding the time to full recovery after hospital discharge. Technological innovations have led to increased interest in home-monitoring and digital biomarkers. The aim of this study was to describe at-home recovery of 3 common pediatric respiratory diseases using a questionnaire and wearable device. METHODS: In this study, patients admitted due to pneumonia (n = 30), preschool wheezing (n = 30), and asthma exacerbation (AE; n = 11) were included. Patients were monitored with a smartwatch and a questionnaire during admission, with a 14-day recovery period and a 10-day "healthy" period. Median compliance was calculated, and a mixed-effects model was fitted for physical activity and heart rate (HR) to describe the recovery period, and the physical activity recovery trajectory was correlated to respiratory symptom scores. RESULTS: Median compliance was 47% (interquartile range [IQR] 33-81%) during the entire study period, 68% (IQR 54-91%) during the recovery period, and 28% (IQR 0-74%) during the healthy period. Patients with pneumonia reached normal physical activity 12 days postdischarge, while subjects with wheezing and AE reached this level after 5 and 6 days, respectively. Estimated mean physical activity was closely correlated with the estimated mean symptom score. HR measured by the smartwatch showed a similar recovery trajectory for subjects with wheezing and asthma, but not for subjects with pneumonia. CONCLUSIONS: The digital biomarkers, physical activity, and HR obtained via smartwatch show promise for quantifying postdischarge recovery in a noninvasive manner, which can be useful in pediatric clinical trials and clinical care.

Evaluation of a clinical decision rule to guide antibiotic prescription in children with suspected lower respiratory tract infection in The Netherlands: A stepped-wedge cluster randomised trial.

BACKGROUND: Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. METHODS AND FINDINGS: In a stepped-wedge cluster randomised trial, we included children aged 1-60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study. CONCLUSIONS: In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule. TRIAL REGISTRATION: Netherlands Trial Register NTR5326.

Correction to: Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group.

In the original version of this article unfortunately two authors were missing: Dr. Jürgen Weidemann and Dr. Daniel Berthold. The correct list of authors is presented above.

Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group.

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.

Target attainment of cefotaxime in critically ill children with meningococcal septic shock as a model for cefotaxime dosing in severe pediatric sepsis.

Reduced target attainment of ß-lactam antibiotics is reported in critically ill patients. However, as target attainment of cefotaxime in severely ill pediatric sepsis patients may differ from adults due to age-related variation in pharmacokinetics, we aimed to assess target attainment of cefotaxime in this pilot study using meningococcal septic shock patients as a model for severe sepsis. Secondary analysis of prospectively collected data from a randomized controlled trial. Children with meningococcal septic shock (1 month to 18 years) included in this study received cefotaxime 100-150 mg/kg/day as antibiotic treatment. Left-over plasma samples were analyzed using LC-MS/MS to determine cefotaxime concentrations. MIC values from EUCAST were used to determine target attainment of cefotaxime for Neisseria meningitidis (0.125 mg/l), but also for Streptococcus pneumoniae (0.5 mg/l), Enterobacteriaceae (1 mg/l), and Staphylococcus aureus (4 mg/l). Target attainment was adequate when all samples exceeded MIC or fourfold MIC values. One thirty-six plasma samples of 37 severe septic shock patients were analyzed for cefotaxime concentrations. Median age was 2 years with a median PRISM-score of 24 and mortality of 24.8%. The median unbound cefotaxime concentration was 4.8 mg/l (range 0-48.7). Target attainment ranged from 94.6% for the MIC of N. meningitidis to 16.2% for fourfold the MIC S. aureus. Creatinine levels were significantly correlated with cefotaxime levels. Target attainment of cefotaxime with current dosing guidelines seems to be adequate for N. meningitidis but seems to fail for more frequently encountered pathogens in severely ill children.

Correction to: Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence.

The original version of the article, "Circulating T Cells of Patients with Nijmegen Breakage Syndrome Show Signs of Senescence" incorrectly listed the affiliation of the fourth author, Iwona Solarska. The correct affiliation is "Molecular Biology Laboratory, Institute of Hematology and Transfusion Medicine.

Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).

BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.

Neutrophil Extracellular Traps in Children With Meningococcal Sepsis.

OBJECTIVES: Children with meningococcal sepsis are highly at risk for fulminant disease, multiple organ failure, and death. Recently, neutrophil extracellular traps levels have been indicated as a marker for severity in different kinds of sepsis. Our aim was to study the role of neutrophil extracellular traposis in meninogococcal sepsis in children. DESIGN: We measured myeloperoxidase-DNA, a marker for neutrophil extracellular traps, in serum of meningococcal sepsis patients upon admission to PICU, at 24 hours, and at 1 month and studied the association with clinical outcome. Subsequently, we tested whether Neisseria meningitidis, isolated from children with meningococcal sepsis, were able to induce neutrophil extracellular traposis, using confocal microscopy live imaging. SETTING: We used enzyme-linked immunosorbent assays to measure myeloperoxidase-DNA in patient serum. We also included inflammatory markers that were previously measured in this group. PATIENTS: We included exclusively children with meningococcal sepsis. INTERVENTIONS: From each patient, serum was collected for analysis. MEASUREMENTS AND MAIN RESULTS: Myeloperoxidase-DNA levels at admission (n = 35; median, 0.21 AU/mL; interquartile range, 0.12-0.27) and at 24 hours (n = 39; median, 0.14 AU/mL; interquartile range, 0.09-0.25) were significantly higher than the myeloperoxidase-DNA levels after 1 month (controls: n = 36; median, 0.07 AU/mL; interquartile range, 0.05-0.09; p < 0.001). We did not observe a correlation between myeloperoxidase-DNA levels and mortality, cell-free DNA, or other inflammatory markers. In addition, N. meningitidis are fast and strong inducers of neutrophil extracellular traposis. CONCLUSIONS: Children admitted to PICU for meningococcal sepsis have higher neutrophil extracellular traps levels at admission and after 24 hours than controls. Neutrophil extracellular traps levels were not associated with outcome, cell-free DNA, or other inflammatory markers. These neutrophil extracellular traps may be induced by N. meningitidis, since these are strong neutrophil extracellular traposis inducers.