A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection.

Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract infection during childhood and causes severe symptoms in some patients, which may cause hospitalization and death. Mechanisms for differential responses to RSV are unknown. Our objective was to develop an in vitro model of RSV infection to evaluate interindividual variation in response to RSV and identify susceptibility genes. Populations of human-derived HapMap lymphoblastoid cell lines (LCLs) were infected with RSV. Compared with controls, RSV-G mRNA expression varied from ~1- to 400-fold between LCLs. Basal expression of a number of gene transcripts, including myxovirus (influenza virus) resistance 1 (MX1), significantly correlated with RSV-G expression in HapMap LCLs. Individuals in a case-control population of RSV-infected children who were homozygous (n=94) or heterozygous (n=172) for the predicted deleterious A allele in a missense G/A SNP in MX1 had significantly greater risk for developing severe RSV disease relative to those with the major allele (n=108) (χ(2)=5.305, P=0.021; OR: 1.750, 95% CI: 1.110, 2.758, P=0.021). We conclude that genetically diverse human LCLs enable identification of susceptibility genes (e.g., MX1) for RSV disease severity in children, providing insight for disease risk.

A mechanistic role for type III IFN-λ1 in asthma exacerbations mediated by human rhinoviruses.

RATIONALE: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. OBJECTIVES: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. METHODS: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. MEASUREMENTS AND MAIN RESULTS: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). CONCLUSIONS: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.

Training of health referents at child care centers. Experience in Argentina. / Formación de referentes de salud en centros de cuidado infantil. Experiencia en Argentina.

An adequate child care helps to mitigate the effects of social adversity. Health prevention is a part of it. This is an innovative training program for health referents in child care centers that cater to vulnerable populations in Buenos Aires, Argentina. It consisted in training child care center staff, followed by the implementation, over 4 months, of an improvement plan developed by each participant in their center, with ongoing advisory support. In total, 26 participants from 19 centers completed the program. In total, 35 out of 49 goals proposed in the plans were achieved, including the certification in cardiopulmonary resuscitation, staff and family training, development of center policies, and improved resource management. Preventive care offered in child care centers may be improved via a simple and inexpensive intervention, including in unfavorable conditions.

El cuidado infantil de buena calidad atenúa los efectos de la adversidad social. La prevención en salud es parte de él. Se presenta un programa innovador de formación de referentes de salud en centros de cuidado infantil que atienden a poblaciones vulnerables en Buenos Aires, Argentina. Este consistió en una capacitación para personal de centros de cuidado infantil, seguido de la implementación, durante 4meses, de un plan de mejoras elaborado por cada participante para su centro, con apoyo de consultoría permanente. Veintiséis participantes de 19centros completaron el programa. Se alcanzaron 35 de 49 objetivos planteados en los planes, incluida la certificación en reanimación cardiopulmonar, la capacitación del personal y las familias, el desarrollo de políticas del centro y la mejora de la gestión de recursos. Es posible mejorar los cuidados preventivos en los centros de cuidado infantil mediante una intervención sencilla y de bajo costo, incluso en condiciones desfavorables.

Formación de referentes de salud en centros de cuidado infantil. Experiencia en Argentina / Training of health referents at child care centers. Experience in Argentina

El cuidado infantil de buena calidad atenúa los efectos de la adversidad social. La prevención en salud es parte de él. Se presenta un programa innovador de formación de referentes de salud en centros de cuidado infantil que atienden a poblaciones vulnerables en Buenos Aires, Argentina. Este consistió en una capacitación para personal de centros de cuidado infantil, seguido de la implementación, durante 4 meses, de un plan de mejoras elaborado por cada participante para su centro, con apoyo de consultoría permanente. Veintiséis participantes de 19centroscompletaron el programa. Se alcanzaron 35 de 49 objetivos planteados en los planes, incluida la certificación en reanimación cardiopulmonar, la capacitación del personal y las familias, el desarrollo de políticas del centro y la mejora de la gestión de recursos. Es posible mejorar los cuidados preventivos en los centros de cuidado infantil mediante una intervención sencilla y de bajo costo, incluso en condiciones desfavorables.

An adequate child care helps to mitigate the effects of social adversity. Health prevention is a part of it. This is an innovative training program for health referents in child care centers that cater to vulnerable populations in Buenos Aires, Argentina. It consisted in training child care center staff, followed by the implementation, over 4 months, of an improvement plan developed by each participant in their center, with ongoing advisory support. In total, 26 participants from 19 centers completed the program. In total, 35 out of 49 goals proposed in the plans were achieved, including the certification in cardiopulmonary resuscitation, staff and family training, development of center policies, and improved resource management. Preventive care offered in child care centers may be improved via a simple and inexpensive intervention, including in unfavorable conditions

Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear. METHODS: We infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates. FINDINGS: GWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV. INTERPRETATION: Translational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies).

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

Differential gender response to respiratory infections and to the protective effect of breast milk in preterm infants.

OBJECTIVE: The protective role of breastfeeding against severe acute lung disease in infants is well established, but its mechanism is unclear. Most hypotheses assume that breastfeeding confers similar passive protection to every infant; however, a few observations have suggested that the benefits of breast milk against severe lung disease may differ according to gender. The objective of this study was to determine whether the effect of breastfeeding on susceptibility to severe acute lung disease among infants at high risk is different for girls and boys. METHODS: A cohort was analyzed prospectively by use of 2 different strategies: (1) predictors of first episode of rehospitalization by univariate and multivariate analyses using robust Poisson regression and (2) mean number of rehospitalizations between groups using multiple regression negative binomial models. RESULTS: A total of 119 high-risk, very low birth weight infants were enrolled. Breast milk protected girls but not boys against severe acute lung disease. The interaction between breastfeeding and gender was clinically and statistically significant, even after adjustment for variables that can affect severity of acute lung disease. Disease was most severe in formula-fed girls (versus formula-fed boys). CONCLUSIONS: Breastfeeding decreased the risk for severe acute lung disease in girls but not in boys. These findings suggest that breast milk protection is not universally conferred by passive transfer of humoral immunity (which should be gender indifferent), show that respiratory symptoms may be amenable to nonspecific modulation, and identify nonbreastfed preterm infant girls as an at-risk group for severe acute lung disease.

The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease.

We conducted a prospective, observational study to characterize the clinical manifestations of respiratory infections caused by human metapneumovirus (hMPV) and other viruses in 194 premature infants and young children with chronic lung disease or congenital heart disease in Buenos Aires. Children had 567 episodes of respiratory illness and were monitored until they were 2 years old or until the completion of the study. hMPV elicited 12 infections (2%) year-round; 30% were of moderate or greater severity. Human parainfluenza virus type 3 caused 24 infections (4%), and 5 (25%) of 20 lung infections led to hospitalization. Respiratory syncytial virus (RSV) caused 33 episodes--17% of infections and 32% of hospitalizations during the respiratory season. None of the 10 children infected with influenza virus had severe disease. The present study of at-risk children suggests that hMPV and influenza virus are infrequent agents of severe disease and highlights the need for preventive interventions against RSV in developing countries.