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1.
Artículo en Inglés | MEDLINE | ID: mdl-38278191

RESUMEN

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.

2.
Eur Respir J ; 59(6)2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-34887326

RESUMEN

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.


Asunto(s)
Asma , Fibrosis Quística , Biomarcadores , Niño , Volumen Espiratorio Forzado , Humanos , Estudios Prospectivos , Espirometría
3.
BMC Pediatr ; 22(1): 121, 2022 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-35272638

RESUMEN

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.


Asunto(s)
Antibacterianos , Médicos , Antibacterianos/uso terapéutico , Niño , Servicio de Urgencia en Hospital , Humanos , Padres , Alta del Paciente , Prescripciones
4.
Ther Drug Monit ; 43(4): 546-554, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34250966

RESUMEN

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.


Asunto(s)
Monitoreo de Drogas/métodos , Saliva , Teorema de Bayes , Niño , Humanos , Recién Nacido , Dinámicas no Lineales , Pediatría , Saliva/química
5.
Eur J Pediatr ; 180(7): 2271-2279, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33723971

RESUMEN

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.


Asunto(s)
COVID-19 , Pandemias , Niño , Control de Enfermedades Transmisibles , Servicio de Urgencia en Hospital , Hospitalización , Hospitales , Humanos , Estudios Multicéntricos como Asunto , Países Bajos/epidemiología , Estudios Retrospectivos , SARS-CoV-2
6.
Eur J Pediatr ; 180(9): 2765-2772, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33754207

RESUMEN

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.


Asunto(s)
Antibacterianos , Neumonía , Antibacterianos/uso terapéutico , Preescolar , Prescripciones de Medicamentos , Servicio de Urgencia en Hospital , Femenino , Humanos , Lactante , Masculino , Neumonía/diagnóstico por imagen , Neumonía/tratamiento farmacológico , Rayos X
7.
Respiration ; 100(10): 979-988, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34004601

RESUMEN

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.


Asunto(s)
Asma , Neumonía , Enfermedad Aguda , Cuidados Posteriores , Biomarcadores , Niño , Preescolar , Humanos , Alta del Paciente , Ruidos Respiratorios
8.
PLoS Med ; 17(1): e1003034, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-32004317

RESUMEN

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.


Asunto(s)
Antibacterianos/normas , Programas de Optimización del Uso de los Antimicrobianos/normas , Reglas de Decisión Clínica , Prescripciones de Medicamentos/normas , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/epidemiología , Antibacterianos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos/métodos , Preescolar , Análisis por Conglomerados , Femenino , Humanos , Lactante , Masculino , Países Bajos/epidemiología , Infecciones del Sistema Respiratorio/diagnóstico
9.
Eur J Clin Microbiol Infect Dis ; 38(7): 1255-1260, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30968258

RESUMEN

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.


Asunto(s)
Antibacterianos/farmacocinética , Cefotaxima/farmacocinética , Infecciones Meningocócicas/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Adolescente , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Cefotaxima/sangre , Cefotaxima/uso terapéutico , Niño , Preescolar , Enfermedad Crítica , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Infecciones Meningocócicas/sangre , Infecciones Meningocócicas/complicaciones , Neisseria meningitidis/efectos de los fármacos , Proyectos Piloto , Sepsis/microbiología , Choque Séptico/microbiología
10.
Crit Care ; 22(1): 143, 2018 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-29855385

RESUMEN

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.


Asunto(s)
Infecciones Comunitarias Adquiridas/mortalidad , Sepsis/mortalidad , Adolescente , Análisis de Varianza , Distribución de Chi-Cuadrado , Niño , Preescolar , Estudios de Cohortes , Infecciones Comunitarias Adquiridas/epidemiología , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico/organización & administración , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Masculino , Estudios Prospectivos , Sepsis/epidemiología , Estadísticas no Paramétricas
11.
Pediatr Crit Care Med ; 19(6): e286-e291, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29432403

RESUMEN

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.


Asunto(s)
Trampas Extracelulares/metabolismo , Infecciones Meningocócicas/sangre , Neutrófilos/metabolismo , Sepsis/sangre , Biomarcadores/sangre , Ácidos Nucleicos Libres de Células/metabolismo , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Masculino , Peroxidasa/metabolismo , Estudios Prospectivos
12.
Semin Thromb Hemost ; 43(1): 36-47, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27978589

RESUMEN

The host response to infection involves complex interplays between inflammation, coagulation, and fibrinolysis. Deregulation of hemostasis and fibrinolysis are major causes of critical illness and important determinants of outcome in severe sepsis. The hemostatic responses to infection vary widely between individuals, and are in part explained by polymorphisms in genes responsible for the protein C and fibrinolytic pathway. This review gives an overview of genetic polymorphisms in the protein C and fibrinolytic pathway associated with susceptibility and severity of pediatric sepsis. In addition, genetic polymorphisms associated with adult sepsis and other pediatric thromboembolic disorders are discussed, as these polymorphisms might be candidates for future molecular genetic research in pediatric sepsis.


Asunto(s)
Fibrinólisis/genética , Proteína C/genética , Sepsis/genética , Enfermedad Crítica , Humanos , Polimorfismo Genético , Sepsis/sangre
13.
J Pediatr Gastroenterol Nutr ; 65(1): e5-e15, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28644354

RESUMEN

OBJECTIVE: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in "classical" IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. METHODS: Biomaterial was collected from the IL10RA-deficient patient, pediatric patients with IBD, and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. RESULTS: The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of tumor necrosis factor α compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T-cell cytokines interferon γ and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient's decreased peripheral blood mononuclear cell-derived tumor necrosis factor production. CONCLUSIONS: With time and during immunosuppressive treatment the IL10RA-deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing interferon γ and IL-17-mediated T-cell responses.


Asunto(s)
Inmunidad Adaptativa/fisiología , Células Dendríticas/metabolismo , Inmunidad Innata/fisiología , Enfermedades Inflamatorias del Intestino/inmunología , Subunidad alfa del Receptor de Interleucina-10/deficiencia , Subgrupos de Linfocitos T/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Codón sin Sentido , Femenino , Mutación del Sistema de Lectura , Marcadores Genéticos , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/genética , Subunidad alfa del Receptor de Interleucina-10/genética , Masculino , Persona de Mediana Edad
15.
J Allergy Clin Immunol ; 136(3): 703-712.e10, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25843314

RESUMEN

BACKGROUND: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. OBJECTIVE: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. METHODS: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. RESULTS: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. CONCLUSION: CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.


Asunto(s)
Infecciones por Virus de Epstein-Barr/genética , Enfermedad de Hodgkin/genética , Linfohistiocitosis Hemofagocítica/genética , Trastornos Linfoproliferativos/genética , Mutación , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Uveítis/genética , Adolescente , Preescolar , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/patología , Exoma , Femenino , Citometría de Flujo , Heterocigoto , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Homocigoto , Humanos , Inmunofenotipificación , Lactante , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/patología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Masculino , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/deficiencia , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Uveítis/diagnóstico , Uveítis/inmunología , Uveítis/patología , Adulto Joven
16.
J Clin Immunol ; 35(8): 761-8, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26566921

RESUMEN

BACKGROUND: Jacobsen syndrome (JS) is a rare contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. Clinical features include physical and mental growth retardation, facial dysmorphism, thrombocytopenia, impaired platelet function and pancytopenia. In case reports, recurrent infections and impaired immune cell function compatible with immunodeficiency were described. However, Jacobsen syndrome has not been recognized as an established syndromic primary immunodeficiency. GOAL: To evaluate the presence of immunodeficiency in a series of 6 patients with JS. METHODS: Medical history of 6 patients with JS was evaluated for recurrent infections. IgG, IgA, IgM and specific antibodies against S. pneumoniae were measured. Response to immunization with a polysaccharide vaccine (Pneumovax) was measured and B and T lymphocyte subset analyses were performed using flowcytometry. RESULTS: Five out of 6 patients suffered from recurrent infections. These patients had low IgG levels and impaired response to S. pneumoniae polysaccharide vaccination. Moreover, we also found a significant decrease in the absolute number of memory B cells, suggesting a defective germinal center function. In a number of patients, low numbers of T lymphocytes and NK cells were found. CONCLUSIONS: Most patients with JS suffer from combined immunodeficiency in the presence of recurrent infections. Therefore, we consider JS a syndromic primary immunodeficiency. Early detection of immunodeficiency may reduce the frequency and severity of infections. All JS patients should therefore undergo immunological evaluation. Future studies in a larger cohort of patients will more precisely define the pathophysiology of the immunodeficiency in JS.


Asunto(s)
Linfocitos B/inmunología , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Centro Germinal/inmunología , Síndromes de Inmunodeficiencia/epidemiología , Infecciones/epidemiología , Síndrome de Deleción Distal 11q de Jacobsen/epidemiología , Adolescente , Adulto , Niño , Dinamarca , Femenino , Humanos , Síndromes de Inmunodeficiencia/inmunología , Infecciones/inmunología , Síndrome de Deleción Distal 11q de Jacobsen/inmunología , Masculino , Adulto Joven
17.
Eur J Pediatr ; 174(9): 1183-8, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25875249

RESUMEN

UNLABELLED: Severe combined immune deficiency (SCID) is a fatal primary immunodeficiency usually presenting in the first months of life with (opportunistic) infections, diarrhea, and failure to thrive. Hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are curative treatment options. The objective of the study was to assess the morbidity, mortality, and diagnostic and therapeutic delay in children with SCID in the Netherlands in the last 15 years. These data may help to judge whether SCID should be considered to be included in our national neonatal screening program. In the period 1998-2013, 43 SCID patients were diagnosed in the Netherlands, 11 of whom were atypical SCID (presentation beyond the first year). The median interval between the first symptom and diagnosis was 2 months (range 0-1173 months). The total mortality was 42 %. In total, 32 patients were treated with HSCT of whom 8 were deceased. Nine patients died due to severe infectious complications before curative treatment could be initiated. CONCLUSION: Because of a high mortality of patients with SCID before HSCT could be initiated, only a national newborn screening program and pre-emptive HSCT or GT will be able to improve survival of these patients. "WHAT IS KNOWN": • SCID is a fatal disease if a curative hematopoietic stem cell transplantation cannot be performed in time. • Newborn screening for SCID enables early diagnosis in the asymptomatic phase. "WHAT IS NEW": • Nine out of 43 SCID patients in the Netherlands died due to severe infectious complications before curative treatment could be initiated. • Only newborn screening and pre-emptive curative therapy will improve survival of children with SCID in the Netherlands.


Asunto(s)
Diagnóstico Precoz , Predicción , Terapia Genética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Tamizaje Neonatal/métodos , Inmunodeficiencia Combinada Grave/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Recién Nacido , Masculino , Países Bajos/epidemiología , Estudios Retrospectivos , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/terapia , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del Tratamiento
18.
J Allergy Clin Immunol ; 134(1): 135-44, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24418477

RESUMEN

BACKGROUND: Individuals with genetic defects in CD40 ligand (CD40L) or B-cell antigen receptor coreceptor molecules CD19 and CD81 suffer from an antibody deficiency. Still, these patients carry low levels of memory B cells and serum antibodies. OBJECTIVE: We sought to assess why the remaining memory B cells and antibodies in the blood of these patients do not provide functional immunity. METHODS: We included CD19-deficient patients (n = 8), CD40L-deficient patients (n = 8), and healthy controls (n = 50) to perform detailed flow cytometry on blood B cells, molecular analysis of IgA and IgG transcripts, as well as functional analysis of B-cell activation. RESULTS: CD19-deficient and CD40L-deficient patients carried reduced numbers of all memory B-cell subsets except CD27(-)IgA(+) B cells. Their immunoglobulin heavy chain class-switched transcripts contained less somatic mutations and reduced usage of IgM-distal IgG2 and IgA2 subclasses. The selection strength of mutations for antigen binding was significantly lower than in controls, whereas selection to maintain superantigen binding was normal. Furthermore, the patients showed impaired selection against inherently autoreactive properties of their immunoglobulins. Somatic hypermutation analysis revealed decreased activation-induced cytidine deaminase and uracil-DNA glycosylase 2 activity in CD40L deficiency and increased uracil-DNA glycosylase 2 but decreased mismatch repair in CD19 deficiency. B-cell activation studies revealed that this was at least in part due to transcriptional regulation of DNA repair genes. CONCLUSIONS: This study on CD19 and CD40L deficiencies illustrates that both the B-cell antigen receptor and CD40 signaling pathways are required for the selection of immunoglobulin reactivity. Still, they differentially mediate DNA repair pathways during somatic hypermutation, thereby together shaping the human in vivo antigen-experienced B-cell repertoire.


Asunto(s)
Antígenos CD19/inmunología , Ligando de CD40/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Síndromes de Inmunodeficiencia/inmunología , Mutación , Adulto , Antígenos CD19/genética , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Ligando de CD40/deficiencia , Ligando de CD40/genética , Niño , Preescolar , Citidina Desaminasa/genética , Citidina Desaminasa/inmunología , Reparación del ADN/inmunología , Femenino , Citometría de Flujo , Regulación de la Expresión Génica , Humanos , Inmunoglobulina A/genética , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/genética , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/patología , Memoria Inmunológica , Inmunofenotipificación , Lactante , Activación de Linfocitos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Transducción de Señal , Uracil-ADN Glicosidasa/genética , Uracil-ADN Glicosidasa/inmunología
19.
J Allergy Clin Immunol ; 134(6): 1346-1353.e9, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25159464

RESUMEN

BACKGROUND: Patients with Down syndrome carry immunologic defects, as evidenced by the increased risks for autoimmune diseases, hematologic malignancies, and respiratory tract infections. Moreover, the low numbers of circulating B cells suggest impaired humoral immunity. OBJECTIVE: We sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment. METHODS: We studied blood B-cell subset composition, replication history, somatic hypermutation status, and class-switch recombination in 17 children with Down syndrome. Germinal centers and plasma cells were studied in tonsils from 4 additional children with Down syndrome. RESULTS: Blood transitional B-cell numbers were normal, but naive mature and memory B-cell numbers were reduced despite slightly increased serum B cell-activating factor levels. Germinal centers and plasma cells in tonsils appeared normal, as were serum immunoglobulin levels. CD27(+)IgD(+)IgM(+) "natural effector" B cells showed reduced proliferation and somatic hypermutation levels, whereas these were normal in CD27(+)IgD(-) memory B cells. Furthermore, IgM(+) and IgA(+), but not IgG(+), memory B cells showed impaired molecular signs for antigen selection. The B-cell pattern was highly similar to that of patients with common variable immunodeficiency and a defect in B-cell activation and proliferation. CONCLUSION: Children with Down syndrome seem capable of normal germinal center and plasma cell formation. Still, blood memory B-cell numbers were reduced and showed impaired molecular maturation of IgA and IgM, which are important for mucosal immunity. The observed molecular defects in circulating IgA and IgM B-cell memory could reflect impaired local responses, which underlie the increased susceptibility to respiratory tract infections of patients with Down syndrome.


Asunto(s)
Linfocitos B/inmunología , Síndrome de Down/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Memoria Inmunológica , Adolescente , Subgrupos de Linfocitos B/inmunología , Diferenciación Celular , Niño , Preescolar , Inmunodeficiencia Variable Común/inmunología , Femenino , Centro Germinal , Humanos , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/inmunología , Recuento de Linfocitos , Masculino , Tonsila Palatina/citología , Tonsila Palatina/inmunología , Células Plasmáticas/citología
20.
J Allergy Clin Immunol ; 133(4): 1124-33, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24418478

RESUMEN

BACKGROUND: V(D)J recombination takes place during lymphocyte development to generate a large repertoire of T- and B-cell receptors. Mutations in recombination-activating gene 1 (RAG1) and RAG2 result in loss or reduction of V(D)J recombination. It is known that different mutations in RAG genes vary in residual recombinase activity and give rise to a broad spectrum of clinical phenotypes. OBJECTIVE: We sought to study the immunologic mechanisms causing the clinical spectrum of RAG deficiency. METHODS: We included 22 patients with similar RAG1 mutations (c.519delT or c.368_369delAA) resulting in N-terminal truncated RAG1 protein with residual recombination activity but presenting with different clinical phenotypes. We studied precursor B-cell development, immunoglobulin and T-cell receptor repertoire formation, receptor editing, and B- and T-cell numbers. RESULTS: Clinically, patients were divided into 3 main categories: T(-)B(-) severe combined immunodeficiency, Omenn syndrome, and combined immunodeficiency. All patients showed a block in the precursor B-cell development, low B- and T-cell numbers, normal immunoglobulin gene use, limited B- and T-cell repertoires, and slightly impaired receptor editing. CONCLUSION: This study demonstrates that similar RAG mutations can result in similar immunobiological effects but different clinical phenotypes, indicating that the level of residual recombinase activity is not the only determinant for clinical outcome. We postulate a model in which the type and moment of antigenic pressure affect the clinical phenotypes of these patients.


Asunto(s)
Estudios de Asociación Genética , Proteínas de Homeodominio/genética , Mutación , Fenotipo , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Preescolar , Regiones Determinantes de Complementariedad/genética , Expresión Génica , Genotipo , Proteínas de Homeodominio/metabolismo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Lactante , Recién Nacido , Recuento de Linfocitos , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Recombinación V(D)J
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