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Contains fulltext : 287860.pdf (Publisher’s version ) (Open Access) Dolutegravir 50 mg is registered for use in children weighing 20-40 kg. This approval is based on data from an African paediatric cohort, and no pharmacokinetic data was available from children outside of Africa. This study provides further evidence of the effective use of dolutegravir 50 mg in children weighing 20 to 40 kg by showing that concentration data gathered in clinical practice shows adequate concentration levels in Dutch children without a safety signal.

Human noroviruses are a major cause of gastroenteritis outbreaks worldwide. The majority of outbreaks and sporadic cases are caused by norovirus genotype GII.4 but 48 capsid genotypes and 60 polymerase genotypes (P-types) have been described, some of which are frequently reported while others are rarely detected. Little is known about the circulation and reservoirs of the less common genotypes. In this study, we have investigated whether children could pose a possible reservoir for undetected circulation of norovirus diversity. We, therefore, tested IgG and IgA responses of sera obtained from 287 children aged While we found no evidence to suggest that rarely detected genotypes widely circulate in children, this is the first study to investigate seroprevalence against such a wide variety of human norovirus capsid and polymerase genotypes.ImportanceNorovirus is a leading cause of epidemic acute gastroenteritis, causing severe disease in children, the elderly, and immunocompromised individuals. Although norovirus is a diverse genus of viruses, the majority of reported cases are caused by viruses of the GII.4 genotype. Many of the genotypes are rarely detected and it is unknown where they circulate between outbreaks. Here we investigated the possibility of children posing a reservoir for undetected circulation. While previous serological studies have tested antibodies against a limited set of capsid genotypes, we profiled the antibody repertoire of children against the capsid and the non-structural proteins, representing the known diversity of human noroviruses. While we detected high seroprevalence in children older than one year, we found no evidence to suggest a wide circulation of rare genotypes in children in Europe.

Placental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a specific histiocytic intervillositis. Placental fibrin depositions can decrease the maternal-fetal interface causing fetal distress. Coronavirus disease 2019-related placental inflammation can lead to SARS-CoV-2-associated pediatric inflammatory multisystem syndrome., Background In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood. Methods Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy. Results RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. Conclusions Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

IFN–gamma receptor (IFNGR) signaling via STAT1 is crucial in the defense against intracellular pathogens. Defects in this pathway enhance the susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in a primary immunodeficiency called mendelian susceptibility to mycobacterial disease (MSMD). Here we describe three patients with MSMD caused by variants in the IFNGR1 or STAT1 genes. All three patients presented with disseminated non-tuberculous mycobacterial infections caused by M. avium , M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. In Patient 1, only one heterozygous autosomal recessive variant p.(Val63Gly) in the IFNGR1 gene was identified. Patient 2 was compound heterozygous for the pathogenic null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene c.1379A>T, p.(Asn460Ile) was identified. Additional genetic analysis identified a second novel complex Alu-insertion in the IFNGR1 gene in Patient 1. Functional analysis showed that Patients 1 and 2 had reduced expression of IFNGR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 mRNA after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN–α stimulation in Patient 1 and 2, it was mildly reduced in Patient 3. We conclude that functional assays are crucial to assess the extent of IFNGR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.

Although fatigue is a common symptom in adult patients with Primary Immunodeficiencies (PID), data in pediatric patients are limited. The goal of this study is to estimate the prevalence and impact of fatigue in children with PID as reported by patients, parents and health-care providers. A retrospective single center observational study was performed. Prevalence of fatigue was measured by reviewing medical charts of 54 children in our department who are on immunoglobulin substitution therapy. Both prevalence and impact were also measured by the PedsQL-Multidimensional Fatigue Scale (MFS). This comprises age-appropriate questionnaire for self-report in patients aged 5-18 years and parent proxy-reports for patients aged 2-18 years. General, cognitive, sleep-rest fatigue was measured and a total fatigue score was calculated. Means, standard deviation and Z-scores were calculated using age-specific reference values. Intraclass correlation coefficients (ICC) were calculated for comparison of scores provided by parents vs children’s self-reported scores.Both chart review data and PedsQL-MFS showed fatigue rates of 65%. Pediatric PID patients of all ages had significantly lower scores on all subscales and total score of the PedsQL-MFS compared to healthy children. General fatigue was the most affected subscale in PID patients; indicating fatigue of these patients is mainly physical. Seventy-four % of PID patients had a Z-score lower than -1 on the General fatigue subscale indicating severe fatigue. Child-parent concordance varied between 0.24 and 0.93. Our results show high prevalence and severity of fatigue in children with PID, addressing the importance of this issue in our patient care.

We present a case of a 38+1 weeks pregnant patient (G1P0) with a proven COVID-19 infection, who was planned for induction of labour because of pre-existent hypertension, systemic lupus erythematosus, respiratory problem of coughing and mild dyspnoea without fever during the COVID-19 pandemic in March 2020. To estimate the risk of vertical transmission of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) during labour and delivery, we collected oropharyngeal, vaginal, urinary, placental and neonatal PCRs for SARS-CoV-2 during the period of admission. All PCRs, except for the oropharyngeal, were negative and vertical transmission was not observed. Labour and delivery were uncomplicated and the patient and neonate were discharged the next day. We give a short overview of the known literature about SARS-CoV-2-related infection during pregnancy, delivery and outcome of the neonate.

OBJECTIVES Persistent viral infections have been implicated in the etiology of autoimmune diseases in adulthood, but it is not known whether herpesviruses are associated with the development of celiac disease autoimmunity in childhood. We assessed whether herpesvirus infections are associated with transglutaminase type 2 antibody (TG2A) concentrations in children at 6 years of age. METHODS The present study was embedded within a population-based prospective cohort study. Serum immunoglobulin G levels against Epstein-Barr virus, cytomegalovirus (CMV), and herpes simplex virus type 1 were measured by enzyme-linked immunosorbent assay , and TG2A concentrations with fluorescence enzyme immunoassay in 4420 children at 6 years of age. Children were categorized based on TG2A concentrations into negative (

OBJECTIVES With the introduction of combined antiretroviral therapy (cART), HIV-infected children can reach adulthood with minimal clinical complications. However, long-term HIV and cART in adults are associated with immunosenescence and end-organ damage. Long-term consequences of HIV and cART in children are currently unknown. DESIGN AND METHOD We studied 69 HIV-infected children and adolescents under cART (0-23 years) for the occurrence of subclinical immunological aberrations in blood B and T cells, using detailed flow cytometric immunophenotyping and molecular analyses. RESULTS Children with undetectable plasma HIV viral loads for more than 1 year showed near-normal to normal CD4 T-cell numbers and near-normal numbers of most class-switched memory B cells. Furthermore, expansions of aberrant CD21 B cells contracted in patients with virus suppression. In contrast, CD8 effector T cells were increased, and CD4 memory T cells, Vγ9Vδ2 T cells and CD27IgA memory B cells were decreased and did not normalize under ART. Moreover, Vγ9Vδ2 T cells showed defects in their T-cell receptor repertoire selection. CONCLUSION Our results show the effectiveness of current cART to enable the build-up of phenotypically diverse B-cell and T-cell memory in HIV-infected children. However, several subclinical immune abnormalities were detected, which were partially caused by defective immune maturation. These persistent abnormalities were most severe in adolescents and therefore warrant long-term follow-up of HIV-infected children. Early identification of such immune defects might provide targets for monitoring future treatment optimization.

Doel: Het verwerven van inzicht in de sociale omstandigheden van gezinnen met hiv-geinfecteerde kinderen.