External Validation of the Discriminative Validity of the ReSVinet Score and Development of Simplified ReSVinet Scores in Secondary Care.

BACKGROUND: There is no consensus on how to best quantify disease severity in infants with respiratory syncytial virus (RSV) and/or bronchiolitis; this lack of a sufficiently validated score complicates the provision of clinical care and, the evaluation of trials of therapeutics and vaccines. The ReSVinet score appears to be one of the most promising; however, it is too time consuming to be incorporated into routine clinical care. We aimed to develop and externally validate simplified versions of this score. METHODS: Data from a multinational (the Netherlands, Spain, and United Kingdom) multicenter case-control study of infants with RSV were used to develop simplified versions of the ReSVinet score by conducting a grid search to determine the best combination of equally weighted parameters to maximize for the discriminative ability (measured by area under the receiver operating characteristic curve [AUROC]) across a range of outcomes (hospitalization, intensive care unit admission, ventilation requirement). Subsequently discriminative validity of the score for a range of secondary care outcomes was externally validated by secondary analysis of datasets from Rwanda and Colombia. RESULTS: Three candidate simplified scores were identified using the development dataset; they were excellent (AUROC >0.9) at discriminating for a range of outcomes, and their performance was not significantly different from the original ReSVinet score despite having fewer parameters. In the external validation datasets, the simplified scores were moderate to excellent (AUROC, 0.7-1) across a range of outcomes. In all outcomes, except in a single dataset for predicting admission to the high-dependency unit, they performed at least as well as the original ReSVinet score. CONCLUSIONS: The candidate simplified scores developed require further external validation in larger datasets, ideally from resource-limited settings before any recommendation regarding their use.

Global Molecular Epidemiology of Respiratory Syncytial Virus from the 2017-2018 INFORM-RSV Study.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children, resulting in annual epidemics worldwide. INFORM-RSV is a multiyear clinical study designed to describe the global molecular epidemiology of RSV in children under 5 years of age by monitoring temporal and geographical evolution of current circulating RSV strains, F protein antigenic sites, and their relationships with clinical features of RSV disease. During the pilot season (2017-2018), 410 RSV G-F gene sequences were obtained from 476 RSV-positive nasal samples collected from 8 countries (United Kingdom, Spain, The Netherlands, Finland, Japan, Brazil, South Africa, and Australia). RSV B (all BA9 genotype) predominated over RSV A (all ON1 genotype) globally (69.0% versus 31.0%) and in all countries except South Africa. Geographic clustering patterns highlighted wide transmission and continued evolution with viral spread. Most RSV strains were from infants of <1 year of age (81.2%), males (56.3%), and patients hospitalized for >24 h (70.5%), with no differences in subtype distribution. Compared to 2013 reference sequences, variations at F protein antigenic sites were observed for both RSV A and B strains, with high-frequency polymorphisms at antigenic site Ø (I206M/Q209R) and site V (L172Q/S173L/K191R) in RSV B strains. The INFORM-RSV 2017-2018 pilot season establishes an important molecular baseline of RSV strain distribution and sequence variability with which to track the emergence of new strains and provide an early warning system of neutralization escape variants that may impact transmission or the effectiveness of vaccines and MAbs under development.

Metabolomic Profile of Amniotic Fluid and Wheezing in the First Year of Life-A Healthy Birth Cohort Study.

OBJECTIVES: To apply metabolomic analysis of amniotic fluid in a discovery cohort to see whether a specific biochemical-metabolic profile at birth is associated with the subsequent onset of wheezing over the first year of life. STUDY DESIGN: This prospective exploratory study was conducted in a healthy term-born Dutch cohort recruited at 2 hospitals in Utrecht (UMCU, Utrecht, and Diakonessenhuis, Utrecht), The Netherlands. A metabolomic approach based on mass spectrometry was applied to analyze 142 amniotic fluid samples collected at birth. The infants were followed up during their first year of life with recording any respiratory symptoms daily, and they were classified according to the onset of wheezing. RESULTS: Orthogonally constrained projection to latent structures discriminant analysis was used to investigate differences in the metabolic profiles of the infants with (n = 86) and without (n = 56) wheezing. A search of the available databases for amniotic fluid metabolites identified by stability selection, combined with pathway analysis, highlighted the possible metabolic perturbations involved in this condition. The model built using 16 relevant variables with plausible biological significance, showed an area under the curve of 0.82 (P < .001) and an area under the curve calculated by 7-fold full cross-validation of 0.72 (P = .003), with the steroid hormone biosynthesis and the 2-phenylalanine metabolism emerging as probably perturbed pathways. CONCLUSIONS: Infants who will or will not experience wheezing in their first year of life have distinct amniotic fluid metabolomic profiles at birth. Changes occurring in biochemical-metabolic pathways in late intrauterine life may have a pathogenic role in early-onset wheezing.

Respiratory syncytial virus hospitalization and mortality: Systematic review and meta-analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is a major public health burden worldwide. We aimed to review the current literature on the incidence and mortality of severe RSV in children globally. METHODS: Systematic literature review and meta-analysis of published data from 2000 onwards, reporting on burden of acute respiratory infection (ARI) due to RSV in children. Main outcomes were hospitalization for severe RSV-ARI and death. RESULTS: Five thousand two hundred and seventy-four references were identified. Fifty-five studies were included from 32 countries. The global RSV-ARI hospitalization estimates, reported per 1,000 children per year (95% Credible Interval (CrI), were 4.37 (2.98, 6.42) among children <5 years, 19.19 (15.04, 24.48) among children <1 year, 20.01 (9.65, 41.31) among children <6 months and 63.85 (37.52, 109.70) among premature children <1 year. The RSV-ARI global case-fatality estimates, reported per 1,000 children, (95% Crl) were 6.21 (2.64, 13.73) among children <5 years, 6.60 (1.85, 16.93) for children <1 year, and 1.04 (0.17, 12.06) among preterm children <1 year. CONCLUSIONS: A substantial proportion of RSV-associated morbidity occurs in the first year of life, especially in children born prematurely. These data affirm the importance of RSV disease in the causation of hospitalization and as a significant contributor to pediatric mortality and further demonstrate gestational age as a critical determinant of disease severity. An important limitation of case-fatality ratios is the absence of individual patient characteristics of non-surviving patients. Moreover, case-fatality ratios cannot be translated to population-based mortality. Pediatr Pulmonol. 2017;52:556-569. © 2016 The Authors. Pediatric Pulmonology. Published by Wiley Periodicals, Inc.

Down's syndrome is a risk factor for severe lower respiratory tract infection due to respiratory syncytial virus.

AIM: Previous studies have suggested that Down's syndrome is an independent risk factor for severe respiratory infection due to respiratory syncytial virus (RSV). We compared the clinical characteristics of children with and without Down's syndrome hospitalised due to RSV. METHODS: This retrospective cohort study compared data from hospitalisations due to RSV lower respiratory tract infections (LRTI) in children under 14 years of age with (n = 58) and without (n = 58) Down's syndrome. RESULTS: The Down's group had longer hospital stays than the controls of six versus four days (p < 0.0001), even after adjusting for age, weeks of gestation at birth, presence of asthma, bronchopulmonary dysplasia, haemodynamically significant and nonsignificant congenital heart disease. This difference increased when only children under one year of age were analysed to 11 versus five days (p < 0.0001). Children with Down's syndrome were more likely to be admitted to intensive care unit (43.1% versus 22.4%, p = 0.017), need noninvasive mechanical ventilation (36.2% versus 13.7%, p = 0.005) and be prescribed antibiotics and steroids. CONCLUSION: Children with Down's syndrome hospitalised due to RSV LRTI had longer hospital stays and worse clinical courses than controls, highlighting the need for RSV prophylaxis for children with Down's syndrome, especially under one year of age.

Distinct abnormalities in the innate immune system of children with Down syndrome.

OBJECTIVE: To analyze the frequency and phenotype of cells of the innate immune system in the peripheral blood of children with Down syndrome (DS). STUDY DESIGN: Flow cytometric analysis of expression of cell surface markers was performed in children with DS (n = 41) and healthy age-matched controls (n = 41). RESULTS: Compared with controls, children with DS had significantly lower absolute total leukocyte counts, lymphocytes, monocytes, and granulocytes, but 1.5-times higher absolute numbers of CD14(dim)CD16(+) monocytes (147 x 10(6)/L vs 93 x 10(6)/L; P = .02). This difference is fully explained by a higher percentage of CD14(dim)CD16(+) monocytes within the monocyte compartment (28.7% vs 13.4%; P <.001). The absolute numbers of myeloid dendritic cells were lower in DS (13.8 x 10(6)/L vs 22.7 x 10(6)/L; P <.001). The numbers of plasmacytoid dendritic cells and natural killer cells were normal. Absolute numbers of invariant natural killer T cells were very low overall, but significantly lower in children with DS than in controls (1.2 x 10(6)/L vs 3.7 x 10(6)/L; P = .01). CONCLUSIONS: Children with DS exhibited distinct abnormalities in cells of the innate immune system. Most strikingly, they had a high number of proinflammatory CD14(dim)CD16(+) monocytes. This elevated level of CD14(dim)CD16(+) monocytes may play an important role in the onset and maintenance of chronic inflammatory disease in DS.