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In this study, we present the multiple detection of respiratory viruses in infants during primary respiratory illness, investigate the sensitivity of nasal swabs and nasopharyngeal aspirates, and assess whether patient characteristics and viral load played a role in the sensitivity. Healthy infants were included at signs of first respiratory tract infection. Paired nasopharyngeal aspirates and nasal swabs were collected. Real-time polymerase chain reaction (PCR) was carried out for 11 respiratory pathogens. Paired nasopharyngeal aspirates and nasal swabs were collected in 98 infants. Rhinovirus (n = 67) and respiratory syncytial virus (n = 39) were the most frequently detected. Co-infection occurred in 48% (n = 45) of the infants. The sensitivity of the nasal swab was lower than the nasopharyngeal aspirate, in particular, for respiratory syncytial virus (51% vs. 100%) and rhinovirus (75% vs. 97%). The sensitivity of the nasal swab was strongly determined by the cycle threshold (CT) value (p < 0.001). The sensitivity of the swab for respiratory syncytial virus, but not rhinovirus, was 100% in children with severe symptoms (score ≥11). It is concluded that, for community-based studies and surveillance purposes, the nasal swab can be used, though the sensitivity is lower than the aspirate, in particular, for the detection of mild cases of respiratory syncytial virus (RSV) infection.

Background The emergence and spread of antibiotic resistant micro-organisms is a global concern, which is largely attributable to inaccurate prescribing of antibiotics to patients presenting with non-bacterial infections. The use of ‘omics’ technologies for discovery of novel infection related biomarkers combined with novel treatment algorithms offers possibilities for rapidly distinguishing between bacterial and viral infections. This distinction can be particularly important for patients suffering from lower respiratory tract infections (LRTI) and/or sepsis as they represent a significant burden to healthcare systems. Here we present the study details of the TAILORED-Treatment study, an observational, prospective, multi-centre study aiming to generate a multi-parametric model, combining host and pathogen data, for distinguishing between bacterial and viral aetiologies in children and adults with LRTI and/or sepsis. Methods A total number of 1200 paediatric and adult patients aged 1 month and older with LRTI and/or sepsis or a non-infectious disease are recruited from Emergency Departments and hospital wards of seven Dutch and Israeli medical centres. A panel of three experienced physicians adjudicate a reference standard diagnosis for all patients (i.e., bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. Nasal swabs and blood samples are collected for multi-omics investigations including host RNA and protein biomarkers, nasal microbiota profiling, host genomic profiling and bacterial proteomics. Simplified data is entered into a custom-built database in order to develop a multi-parametric model and diagnostic tools for differentiating between bacterial and viral infections. The predictions from the model will be compared with the consensus diagnosis in order to determine its accuracy. Discussion The TAILORED-Treatment study will provide new insights into the interplay between the host and micro-organisms. New host- or pathogen-related biomarkers will be used to generate a multi-parametric model for distinguishing between bacterial and viral infections. This model will be helpful to better guide antimicrobial therapy for patients with LRTI and sepsis. This study has the potential to improve patient care, reduce unnecessary antibiotic prescribing and will contribute positively to institutional, national and international healthcare economics. Trial Registration NCT02025699 . Registration Date: January, 1, 2014.

Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae , rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.

BackgroundInflammation has been proposed as a hallmark in the pathophysiology of stroke. A functional polymorphism in the interleukin (IL)-6 gene at position-174, encoding for the pro-inflammatory cytokine IL-6, is associated with an increased risk of neonatal brain injury or development of cerebral palsy. The aim was to study whether the IL-6-174 G/C polymorphism increased the risk of perinatal arterial ischaemic stroke (PAIS) or subsequent adverse sequelae.MethodsInfants born at or above 37 weeks gestation with PAIS diagnosed by neonatal MRI (n = 63) were included. Genotyping of the IL-6-174 G/C polymorphism was performed and compared to 1008 random population controls. Perinatal variables of case infants were reviewed.ResultsThere were no differences in IL-6-174 genotype between infants with PAIS and population controls. In a multivariable analysis, independent risk factors for adverse outcome after PAIS in a middle cerebral artery territory included CG genotype (OR 5.9; 95% CI 1.02–33.9) and male sex (OR 4.2; 95% CI 1.04–17.2).ConclusionThe distribution of the IL-6-174 C >G promotor polymorphism did not differ between infants with PAIS and population controls and therefore do not seem to play a role in stroke risk. However, the IL-6-174 GC genotype was more common among infants who had an adverse outcome following PAIS in the middle cerebral artery territory, suggesting that the level of inflammation does play a role in outcome after PAIS. This may be relevant for neuroprotective strategies.

Objective To determine whether early initiated anti-inflammatory therapy with prolonged high dose inhaled glucocorticoids influences the occurrence and severity of recurrent wheeze after respiratory syncytial virus related lower respiratory tract infections.Design Randomised double blind placebo controlled trial.Setting Paediatric departments of 19 Dutch clinical centres.Participants 243 previously healthy infants (126 boys, 117 girls) aged less than 13 months and admitted to hospital with respiratory syncytial virus infection.Interventions 200 μg extra fine hydrofluoroalkane (HFA) beclometasone dipropionate twice daily or matched placebo administered by a pressurised metered dose inhaler and a spacer during the first three months after hospital admission.Main outcome measure The primary outcome was the number of days with wheeze in the year after the three month intervention period.Results Of the 243 eligible infants, 119 were randomised to receive beclometasone and 124 to receive placebo. No significant difference was found in the number of days with wheeze between the two groups (total days, 1761/33 568 in the beclometasone group v 2301/36 556 in the placebo group, P=0.31) and the proportion of infants with wheeze did not differ between the groups (61% in the beclometasone group v 62% in the placebo group, P=0.90). In the predefined subgroup of infants who did not need mechanical ventilation (n=221), beclometasone reduced the number of days with wheeze by 32% (relative reduction in total days, 1315/30 405 in the beclometasone group v 2120/33 149 in the placebo group, P=0.046). This reduction was most pronounced during the first six months of the follow-up year after intervention. The proportion of infants with wheeze did not differ between the groups (59% in the beclometasone group v 60% in the placebo group, P=0.89).Conclusions Early initiated high dose extra fine HFA beclometasone to infants during the first three months after hospital admission for respiratory syncytial virus infection has no major effect on recurrent wheeze. The general use of such treatment during lower respiratory tract infection with respiratory syncytial virus should not be advocated.Trial registration Current Controlled Trials ISRCTN12352714.

RSVpreF Vaccine Efficacy over Two SeasonsRespiratory syncytial virus remains a serious cause of illness in older persons. In this follow-up report of the RENOIR trial, efficacy of the RSVpreF vaccine is assessed over a second season.

•Candidate RSV vaccines are under development.•Early infant RSV illness is associated with subsequent wheeze-associated disorders.•We estimated sample sizes needed for vaccine trials to prevent these outcomes.•RSV vaccine trials will likely not be large enough to detect reductions in wheeze.•Alternative study designs to demonstrate RSV vaccine impact on wheeze are needed. Early RSV illness is associated with wheeze-associated disorders in childhood. Candidate respiratory syncytial virus (RSV) vaccines may prevent acute RSV illness in infants. We investigated the feasibility of maternal RSV vaccine trials to demonstrate reductions in recurrent childhood wheezing in general paediatric populations. We calculated vaccine trial effect sizes that depended on vaccine efficacy, allocation ratio, rate of early severe RSV illness, risk of recurrent wheezing at age 3, and increased risk of RSV infection on recurrent wheezing. Model inputs came from systematic reviews and meta-analyses. For each combination of inputs, we estimated the sample size required to detect the effect of vaccination on recurrent wheezing. There were 81 scenarios with 1:1 allocation ratio. Risk ratios between vaccination and recurrent wheezing ranged from 0.9 to 1.0 for 70% of the scenarios. Among the 57 more plausible scenarios, the lowest sample size required to detect significant reductions in recurrent wheezing was 6196 mother-infant pairs per trial arm; however, 75% and 47% of plausible scenarios required >31,060 and >100,000 mother-infant pairs per trial arm, respectively. Studies with asthma endpoints at age 5 will likely need to be larger. Clinical efficacy trials of candidate maternal RSV vaccines undertaken for licensure are unlikely to demonstrate an effect on recurrent wheezing illness due to the large sample sizes likely needed to demonstrate a significant effect. Further efforts are needed to plan for alternative study designs to estimate the impact of maternal RSV vaccine programs on recurrent childhood wheezing in general populations.

BackgroundInflammation has been proposed as a hallmark in the pathophysiology of stroke. A functional polymorphism in the interleukin (IL)-6 gene at position-174, encoding for the pro-inflammatory cytokine IL-6, is associated with an increased risk of neonatal brain injury or development of cerebral palsy. The aim was to study whether the IL-6-174 G/C polymorphism increased the risk of perinatal arterial ischaemic stroke (PAIS) or subsequent adverse sequelae.MethodsInfants born at or above 37 weeks gestation with PAIS diagnosed by neonatal MRI (n = 63) were included. Genotyping of the IL-6-174 G/C polymorphism was performed and compared to 1008 random population controls. Perinatal variables of case infants were reviewed.ResultsThere were no differences in IL-6-174 genotype between infants with PAIS and population controls. In a multivariable analysis, independent risk factors for adverse outcome after PAIS in a middle cerebral artery territory included CG genotype (OR 5.9; 95% CI 1.02-33.9) and male sex (OR 4.2; 95% CI 1.04-17.2).ConclusionThe distribution of the IL-6-174 C >G promotor polymorphism did not differ between infants with PAIS and population controls and therefore do not seem to play a role in stroke risk. However, the IL-6-174 GC genotype was more common among infants who had an adverse outcome following PAIS in the middle cerebral artery territory, suggesting that the level of inflammation does play a role in outcome after PAIS. This may be relevant for neuroprotective strategies.

In this randomized, placebo-controlled trial, otherwise healthy preterm infants received injections of palivizumab, a monoclonal antibody against respiratory syncytial virus, or placebo. Infants receiving the antibody had fewer episodes of wheezing. Illness of the lower respiratory tract that is caused by respiratory syncytial virus (RSV) is the most common cause of hospital admission in the winter season during the first year of life. 1 Severe RSV bronchiolitis has been associated with an increase in subsequent rates of early wheezing, 2 , 3 asthma, and possibly allergic sensitization later in life. 4 – 7 Early childhood wheeze after RSV infection has a high prevalence, influences quality of life, and generates substantial health care costs. 8 – 11 The pathogenesis of recurrent wheeze after RSV infection is still poorly understood. Gern and Busse distinguished two nonexclusive relationships between RSV infection . . .