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To compare the incidence of respiratory symptoms and short-term consequences between children with Down syndrome and children from the general population, we conducted a prospective parent-reported observational study. Children with Down syndrome (≤ 18 years) were included between March 2012 and June 2014. Caregivers received a baseline questionnaire with follow-up 1–2 years after inclusion. Caregivers received a weekly questionnaire about respiratory symptoms, fever, antibiotic prescriptions, doctor’s visits, and consequences for school and work attendance. Children with Down syndrome were compared to a cohort of the general population (“Kind en Ziek” study) with similar weekly questionnaires. A total of 9,011 childweeks were reported for 116 participants with Down syndrome (75% response rate). The frequency of respiratory symptoms was higher in children with Down syndrome than in children from the general population (30% vs 15.2%). In addition, symptoms subsided later (around 8 vs 5 years of age). The seasonal influence was limited, both in children with Down syndrome and children from the general population. Consequences of respiratory disease were significant in children with Down syndrome compared to children from the general population, with a higher rate of doctor’s visits (21.3% vs 11.8%), antibiotic prescriptions (47.8% vs 26.3%), and absenteeism from school (55.5% vs 25.4%) and work (parents, 9.4% vs 8.1%). Conclusion: Children with Down syndrome have a higher frequency of respiratory symptoms and symptoms last until a later age, confirming the impression of professionals and caregivers. Individualized treatment plans might prevent unfavorable consequences of chronic recurrent respiratory disease in children with Down syndrome. What is Known:• Children with Down syndrome have an altered immune system and are prone to a more severe course of respiratory tract infections.• The overall conception is that patients with Down syndrome suffer from respiratory tract infections more often. What is New:• Children with Down syndrome suffer from respiratory symptoms more frequently than children from the general population.• The respiratory symptoms in children with Down syndrome subside at a later age compared to children from the general population.

OBJECTIVES Rotavirus vaccination has 87% to 100% effectiveness against severe rotavirus acute gastroenteritis (AGE) in healthy infants in high-income countries. Little is known whether infants with medical risk conditions (MRCs) are equally protected and if the vaccine is equally well tolerated. We conducted a quasi-experimental prospective multicenter before-after cohort study to assess the vaccine effectiveness (VE) and safety profile of the human rotavirus vaccine (HRV) among MRC infants that required prolonged or frequent postnatal care. METHODS The Netherlands has no national rotavirus immunization program, but HRV was implemented in routine care for MRC infants in 13 Dutch hospitals. Participants in the before and after cohort, HRV unvaccinated and vaccinated, respectively, were followed for occurrence of (rotavirus) AGE. VE of at least 1 dose was estimated by using time-to-event analysis for severe rotavirus AGE. Vaccine-related serious adverse event (AEs) after HRV were retrieved systematically from medical charts. Solicited AEs after vaccinations were prospectively collected and compared between vaccination time points with or without HRV. RESULTS In total, 1482 high-risk infants with MRC were enrolled, including 631 in the before and 851 in the after cohorts; 1302 infants were premature (88.3%), 447 were small for gestational age (30.2%), and 251 had at least 1 congenital disorder (17.0%). VE against severe rotavirus AGE was 30% (95% confidence interval [CI]: −36% to 65%). Overall, the observed number of rotavirus hospitalizations was low and not significantly different between the cohorts (2 and 2, respectively). The rate of vaccine-related serious AE was 0.24 per 100 vaccine doses. The adjusted risk ratio for any AE after HRV vaccination compared with other routine vaccinations was 1.09 (95% CI: 1.05 to 1.12) for concomitant administration and 0.91 (95% CI: 0.81 to 0.99) for single HRV administration. Gastrointestinal AEs were 10% more frequent after HRV. CONCLUSIONS In contrast to previous findings among healthy term infants, in routine use, HRV offered limited protection to vulnerable medical risk infants. HRV is generally well tolerated in this group in single administration, but when coadministered with routine vaccines, it is associated with higher risk of (mostly gastrointestinal) AE. Our study highlights the importance of studying vaccine performance in subgroups of medically vulnerable infants.

PURPOSE Fever is the most common reason for a child to be taken to a physician, yet the level of unwarranted antibiotic prescribing remains high. We aimed to determine the effect on antibiotic prescribing of providing an illness-focused interactive booklet on fever in children to out-of-hours primary care clinicians.\ud \ud METHODS We conducted a cluster-randomized controlled trial in 20 out-of-hours general practice centers in the Netherlands. Children aged younger than 12 years with fever were included. Family physicians at the 10 intervention sites had access to an illness-focused interactive booklet between November 2015 and June 2016. The primary outcome was antibiotic prescribing during the index consultation. Analysis was performed by fitting 2-level random intercept logistic regression models.\ud \ud RESULTS The trial took place among 3,518 family physicians and 25,355 children. The booklet was used in 28.5% of 11,945 consultations in the intervention group. Compared with usual care, access to the booklet did not significantly alter antibiotic prescribing during the index consultation (odds ratio = 0.90; 95% CI, 0.79-1.02; prescription rate, 23.5% vs 25.2%; intracluster correlation coefficient = 0.005). In contrast, use of the booklet significantly reduced antibiotic prescribing (odds ratio = 0.83; 95% CI, 0.74-0.94; prescription rate, 21.9% vs 25.2%; intracluster correlation coefficient = 0.002). Children managed by family physicians with access to the booklet were less likely to receive any drug prescription, and parents in the booklet group showed a reduced intention to consult again for similar illnesses.\ud \ud CONCLUSIONS Benefit of an illness-focused interactive booklet in improving outcomes of childhood fever in out-of-hours primary care was largely restricted to the cases in which family physicians actually used the booklet. Insight into reasons for use and nonuse may inform future interventions of this type.

Background Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. Methods In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. Results For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). Conclusion Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data. Electronic supplementary material The online version of this article (10.1186/s13073-019-0649-3) contains supplementary material, which is available to authorized users.

This study improves our understanding of the pathogenesis of tuberculous meningitis (TBM) and may direct future strategies for the prevention of immunopathology associated with TBM. Our data suggest that host biomarker signatures in the cerebrospinal fluid have promising diagnostic applications and require urgent investigation. Background. Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the host's immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. Methods. We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months–13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. Results. Unsupervised hierarchical clustering analysis revealed a disease-specific pattern of biomarkers for TBM relative to other types of meningitis. A biomarker-based diagnostic prediction model for childhood TBM based on CSF concentrations of interleukin 13 (cutoff value, 37.26 pg/mL), vascular endothelial growth factor (cutoff value, 42.92 pg/mL), and cathelicidin LL-37 (cutoff value, 3221.01 pg/mL) is presented with a sensitivity of 0.52 and a specificity of 0.95. Conclusions. These data highlight the potential of biosignatures in the host's CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae.

The intrauterine environment was long considered sterile. However, several infectious threats are already present during fetal life. This review focuses on the postnatal immunological consequences of prenatal exposure to microorganisms and related inflammatory stimuli. Both the innate and adaptive immune systems of the fetus and neonate are immature, which makes them highly susceptible to infections. There is good evidence that prenatal infections are a primary cause of preterm births. Additionally, the association between antenatal inflammation and adverse neonatal outcomes has been well established. The lung, gastrointestinal tract, and skin are exposed to amniotic fluid during pregnancy and are probable targets of infection and subsequent inflammation during pregnancy. We found a large number of studies focusing on prenatal infection and the host response. Intrauterine infection and fetal immune responses are well studied, and we describe clinical data on cellular, cytokine, and humoral responses to different microbial challenges. The link to postnatal immunological effects including immune paralysis and/or excessive immune activation, however, turned out to be much more complicated. We found studies relating prenatal infectious or inflammatory hits to well-known neonatal diseases such as respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis. Despite these data, a direct link between prenatal hits and postnatal immunological outcome could not be undisputedly established. We did however identify several unresolved topics and propose questions for further research.

Background Fever is the most common reason for a child to be taken to a general practitioner (GP), especially during out-of-hours care. It is mostly caused by self-limiting infections. However, antibiotic prescription rates remain high, especially during out-of-hours care. Anxiety and lack of knowledge among parents, and perceived pressure to prescribe antibiotics amongst GPs, are important determinants of excessive antibiotic prescriptions. An illness-focused interactive booklet has the potential to improve this by providing parents with information about fever self-management strategies. The aim of this study is to develop and determine the effectiveness of an interactive booklet on management of children presenting with fever at Dutch GP out-of-hours cooperatives. Methods/design We are conducting a cluster randomised controlled trial (RCT) with 20 GP out-of-hours cooperatives randomised to 1 of 2 arms: GP access to the illness-focused interactive booklet or care as usual. GPs working at intervention sites will have access to the booklet, which was developed in a multistage process. It consists of a traffic light system for parents on how to respond to fever-related symptoms, as well as information on natural course of infections, benefits and harms of (antibiotic) medications, self-management strategies and ‘safety net’ instructions. Children < 12 years of age with parent-reported or physician-measured fever are eligible for inclusion. The primary outcome is antibiotic prescribing during the initial consultation. Secondary outcomes are (intention to) (re)consult, antibiotic prescriptions during re-consultations, referrals, parental satisfaction and reassurance. In 6 months, 20,000 children will be recruited to find a difference in antibiotic prescribing rates of 25% in the control group and 19% in the intervention group. Statistical analysis will be performed using descriptive statistics and by fitting two-level (GP out-of-hours cooperative and patient) random intercept logistic regression models. Discussion This will be the first and largest cluster RCT evaluating the effectiveness of an illness-focused interactive booklet during GP out-of-hours consultations with febrile children receiving antibiotic prescriptions. It is hypothesised that use of the booklet will result in a reduced number of antibiotic prescriptions, improved parental satisfaction and reduced intention to re-consult. Trial registration ClinicalTrials.gov identifier: NCT02594553. Registered on 26 Oct 2015​, last updated 15 Sept 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1667-8) contains supplementary material, which is available to authorized users.

Molecular DNA-based diagnostics are increasingly being used for diagnosis of viral infections. For enteric viruses, PCR assays have also been developed. The aims of this study were to compile and evaluate a comprehensive panel of PCR assays for diagnosis of viruses causing diarrheal disease and to evaluate its use in a largely pediatric population in a 750-bed university medical center. The PCR panel was designed to include assays for detection of adenovirus, astrovirus, enterovirus, norovirus, parechovirus, rotavirus, and sapovirus. The results of the PCR panel were evaluated in relation to conventional viral diagnostics consisting of viral culture and/or rotavirus and adenovirus rapid antigen tests on samples that were taken for routine diagnostics. Comparing conventional with PCR-based testing, the number of viruses detected increased dramatically from 25 to 106 when PCR assays were used. This increase was due mainly to detection of previously undetected viruses, i.e., astrovirus, norovirus, and sapovirus. In 24% of the samples, norovirus was detected. Also, the lower detection limit of PCR-based adenovirus, enterovirus, parechovirus, and rotavirus diagnostics further increased the detection rate. By focusing on samples from patients with complaints of gastroenteritis, detection of a causative agent was increased from 49% by conventional tests to 97% by molecular diagnostics. However, many samples containing low viral loads were found in patients with complaints other than intestinal complaints. In conclusion, the proposed comprehensive PCR panel with appropriate cutoff values can be used for sensitive, rapid, and clinically relevant diagnosis of gastrointestinal viruses.

This report describes four patients with acute lymphoblastic leukaemia, suffering from posterior reversible encephalopathy syndrome during the induction period of treatment. A review of the literature on posterior reversible encephalopathy syndrome in paediatric leukaemia is given. The exact mechanism of posterior reversible encephalopathy syndrome is not clear and seems to be multifactorial. Hypertension is likely to play a major role in the development but could be also secondary. All patients in this case series presented after introduction of the new induction protocol for acute lymphoblastic leukaemia. Treatment of hypertension is likely to have a favourable role and posterior reversible encephalopathy syndrome is most often reversible. It is important to consider this diagnosis during the induction phase of leukaemia treatment in the presence of neurological symptoms. The incidence of PRES in the induction scheme should be investigated, in order to optimize the ALL treatment.

Pulmonary artery aneurysm is a rare entity with a wide variety of underlying pathophysiological mechanisms. We report a 7-year-old boy who initially presented with suspected Lemierre’s syndrome (tonsillitis and jugular vein thrombosis). However, follow-up imaging studies showed progression of the thromboembolic changes into multiple dural venous structures as well as an aneurysm of the pulmonary artery, without respiratory symptoms. This rare combination of symptoms eventually led to the diagnosis of Behcet’s disease. In this report, we focus on the atypical presentation, the evolution of the clinical and radiological features and discuss the (radiological) clues, which led to the diagnosis. Int J Clin Pediatr. 2015;4(4):189-192 doi: http://dx.doi.org/10.14740/ijcp231w

We present a case of Pott's disease, where the patient presented with neurological impairment due to vertebral granulomatous necrosis, needing immediate decompression and later stabilizing and reconstructive orthopaedic surgery, in order to create awareness for TB in general, especially this forgotten form of spinal tuberculosis.

BackgroundGenetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of twoTLR9polymorphisms between clinical severity variables in MM survivors.MethodsWe used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies ofTLR9-1237 andTLR9+2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children.ResultsTheTLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture forNeisseria (N.) meningitidis(p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 – 0.9). TheTLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture forN. meningitidis(p = 0.017, OR 0.6, 95% CI 0.3 – 0.9). Cerebrospinal fluid (CSF) leukocytes per μL were higher in patients carrying theTLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower inTLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/μL were higher in patients carrying theTLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952).ConclusionsWe identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense.

In children with clinical signs of sepsis, inflammatory parameters in blood, bacterial cultures of blood, urine and cerebrospinal fluid (CSF), and viral diagnostics (herpes simplex virus) and enteroviruses (EV) in CSF and EV in faeces) are often examined, mostly followed by hospital admission and empiric antibiotic treatment. Human parechovirus (HPeV) has been identified and described as cause of sepsis-like illness, meningitis and occasionally encephalitis in children.1 Timely diagnosis of HPeV infection can influence the decision to discontinue antibiotic treatment. To establish the incidence of HPeV and EV infection, we retrospectively performed PCR analysis on CSF and faecal samples from children (birth to 18 years) with …

Background. Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, no such association with meningitis has been described. Methods. We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and 4 TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. Results. Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared with controls (p: .0098, odds ratio [OR]: .6, 95% confidence interval [CI]: .4-.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: .0237, OR 1.3, 95% CI: 1.0-1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). Conclusions. We report an association of TLR9 SNPs with susceptibility to BM, specifically MM indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an up-regulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA.

Pericarditis is a rare manifestation of tuberculosis and can be fatal. We describe a 15-year-old girl admitted for a large pericardial effusion. Subxiphoid pericardial biopsy was performed. Biopsy samples were positive for M. tuberculosis DNA by PCR, which confirmed the diagnosis of tuberculous pericarditis.

Tuberculous meningitis (TM) is a severe complication of tuberculosis that mainly occurs during childhood. No murine models are available to study this disease. The purpose of the present study was to develop a murine model to investigate the pathogenesis of TM. Mice were intracerebrally injected with Mycobacterium tuberculosis. Bacilli could be cultured from brain homogenates, and, on histopathological examination, all mice were found to have meningeal cellular infiltration. We found elevated levels of chemoattractants for mononuclear phagocytes and neutrophilic granulocytes. This is the first murine model for TM that can be used for research on the host response to TM, in particular the innate immune response.

Cutaneous zygomycosis is a rare but severe fungal infection with high risk of dissemination. Early recognition, deep surgical biopsy for diagnosis, aggressive treatment with repeated surgical debridement, and targeted pharmacotherapy are essential and can prevent dissemination and fatal outcome. We present case reports of 2 patients.

To compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted. Patients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up. The study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22–2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43–3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI. No significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI.