Fundacion INFANT

Buenos Aires, Argentina

Fundacion INFANT

Buenos Aires, Argentina

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Scotta M.C.,Grande Rio University | Veras T.N.,Jeser Amarante Faria Childrens Hospital | Klein P.C.,Grande Rio University | Tronco V.,Grande Rio University | And 7 more authors.
Vaccine | Year: 2014

Introduction: Pneumococcal disease is a major public health problem worldwide. From March to September of 2010, 10-valent pneumococcal non-typeable Haemophilus influenzae protein conjugate vaccine (PHiD-CV) was introduced in the Brazilian childhood National Immunization Program (NIP) in all 27 Brazilian states. The aim of the present study is to report national time-trends in incidence of hospital admissions for childhood pneumonia in Brazil before and after two years of introduction of this new pneumococcal conjugate vaccine. Methods: Analysis of hospitalization data of children aged 0-4 years in Brazilian public health system with an admission diagnosis of pneumonia from 2002 to 2012 was performed comparing pre (2002-2009) and post-vaccination periods (2011-2012). Hospital number of admission due to pneumonia and all non-respiratory diseases were obtained from DATASUS, the Brazilian government open-access public health database system. Incidence of pneumonia hospitalization was compared to incidence of all non-respiratory admissions. Results: Admission rates for pneumonia decreased steadily from 2010 to 2012. In children aged less than four years, incidence of pneumonia hospitalizations decreased 12.65% when pre (2002-2009) and post-vaccination introduction periods (2011-2012) were compared and adjusted for seasonality and secular-trend (p<. 0.001). On the other hand, non-respiratory admission rates remained stable comparing both periods (p= 0.39). Conclusion: Childhood pneumonia hospitalization rates were fluctuating prior to 2010 and decreased significantly in the two years after PHiD-CV introduction. Conversely, rate of non-respiratory admissions has shown no decrease. These data are an evidence of the effectiveness and public health impact of this new pneumococcal vaccine. © 2014 Elsevier Ltd.


Monsalvo A.C.,Fundacion INFANT | Batalle J.P.,Fundacion INFANT | Lopez M.F.,Fundacion INFANT | Krause J.C.,Vanderbilt University | And 25 more authors.
Nature Medicine | Year: 2011

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition-a marker of complement activation mediated by immune complexes-was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics. © 2011 Nature America, Inc. All rights reserved.


PubMed | Fundacion INFANT and Vanderbilt University
Type: Journal Article | Journal: The Journal of infectious diseases | Year: 2016

We analyzed data from 524 Argentinean infants hospitalized with lower respiratory tract illness (LRTI) due to respiratory syncytial virus (RSV) to inform selection of clinical end points for RSV vaccine efficacy trials. Cases of LRTI due to RSV that required a mask, continuous or bilevel positive airway pressure, or mechanical ventilation were classified as critical. Oxygen saturation of 90%, tachypnea, and tachycardia were each associated with an increased odds of critical LRTI due to RSV (adjusted odds ratios [ORs], 2.30 [95% confidence interval {CI}, 1.26-4.24; P = .007], 2.22 [95% CI, 1.19-4.16; P = .012], and 2.35 [95% CI, 1.22-4.50; P = .010], respectively). The odds of critical LRTI due to RSV increased substantially (OR, 8.57; 95% CI, 2.19-73.5; P = .001) among individuals with 2 indicators. Lower chest wall indrawing was not associated with critical disease.


PubMed | Direccion Nacional de Control de Enfermedades Inmunoprevenibles DiNaCEI, CONICET, Fundacion INFANT and Vanderbilt University
Type: Journal Article | Journal: Vaccine | Year: 2016

Pertussis disease is a growing concern for developing countries. In Argentina, rates of illness and death peaked in 2011. More than 50% of fatalities due to pertussis occurred in infants younger than two months of age, too young for vaccination. In 2012, the government offered immunization with a vaccine containing Tdap to all pregnant women after 20weeks of gestation with the intent of reducing morbidity and mortality in young infants.Maternal acellular pertussis vaccine impact on reducing infant disease burden was estimated based on data from the Argentinean Health Surveillance System. We divided Argentinean states in two groups experiencing high (>50) and low (50) Tdap vaccine coverage and compared these two groups using a Bayesian structural time-series model. Low coverage regions were used as a control group, and the time series were compared before and after the implementation of the Tdap program.We observed a relative reduction of 51% (95% CI [-67%, -35%]; p=0.001) in pertussis cases in high coverage states in comparison with the low coverage areas. Analysis of infants between two and six months showed a 44% (95% CI [-66%, -24%]; p=0.001) reduction in illness. Number of deaths was highest in 2011 with 76 fatalities, for an incidence rate of 2.9 per 100,000. Comparing with 2011, rates decreased by 87% to 10 subjects, or 0.9 per 100,000 in 2013.We show an age-dependent protective effect of maternal Tdap immunization in a developing country for infants younger than six months.


PubMed | Fundacion INFANT, Lawrence Livermore National Laboratory, University of California at Berkeley and University of Regensburg
Type: | Journal: European journal of immunology | Year: 2016

Co-infections of influenza virus and bacteria are known to cause severe disease, but little information exists on co-infections with other acute viruses. Seasonal influenza and dengue viruses (DENV) regularly co-circulate in tropical regions. The pandemic spread of influenza virus H1N1 (hereafter H1N1) in 2009 led to additional severe disease cases that were co-infected with DENV. Here, we investigated the impact of co-infection on immune responses and pathogenesis in a new mouse model. Co-infection of otherwise sublethal doses of a Nicaraguan clinical H1N1 isolate and two days later with a virulent DENV2 strain increased systemic DENV titers and caused 90% lethality. Lungs of co-infected mice carried both viruses, developed severe pneumonia, and expressed a unique pattern of host mRNAs, resembling only partial responses against infection with either virus alone. A large number of monocytes were recruited to DENV-infected but not to co-infected lungs, and depletion and adoptive transfer experiments revealed a beneficial role of monocytes. Our study shows that co-infection with influenza and DENV impairs host responses, which fail to control DENV titers and instead, induce severe lung damage. Further, our findings identify key inflammatory pathways and monocyte function as targets for future therapies that may limit immunopathology in co-infected patients. This article is protected by copyright. All rights reserved.


Miller E.K.,Vanderbilt University | Hernandez J.Z.,Vanderbilt University | Wimmenauer V.,Fundacion INFANT | Shepherd B.E.,Vanderbilt University | And 20 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

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 mechanismremains 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-λ1 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-λ1, children with asthma infected withHRVwere 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-λ1 responses mediate exacerbations caused by HRV. Modulation of IFN- λ1 should be studied as a therapeutic target for exacerbations caused by HRV.


Ciencewicki J.M.,U.S. National Institutes of Health | Wang X.,U.S. National Institutes of Health | Marzec J.,U.S. National Institutes of Health | Serra M.E.,Fundacion INFANT | And 4 more authors.
FASEB Journal | Year: 2014

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 RSVinfected 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) (X2=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. © FASEB.


Acosta P.L.,Fundacion INFANT | Acosta P.L.,CONICET | Caballero M.T.,Fundacion INFANT | Polack F.P.,Fundacion INFANT | Polack F.P.,Vanderbilt University
Clinical and Vaccine Immunology | Year: 2016

In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a "peribronchiolar monocytic infiltration with some excess in eosinophils." Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4+ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates. © 2016, American Society for Microbiology. All Rights Reserved.


Kathryn Miller E.,Vanderbilt University | Bugna J.,Fundacion INFANT | Libster R.,Vanderbilt University | Shepherd B.E.,Vanderbilt University | And 12 more authors.
Pediatrics | Year: 2012

OBJECTIVES: To assess incidence, burden of illness, and risk factors for human rhinoviruses (HRVs) in a cohort of very low birth weight (VLBW) infants. METHODS: A 2-year prospective cohort study was conducted among VLBW premature infants in Buenos Aires, Argentina. Infants were enrolled in the NICU from June 1, 2003, to May 31, 2005, and managed monthly and with every acute respiratory illness (ARI) during the first year of life. Nasal wash samples were obtained during every respiratory episode and tested for HRV, respiratory syncytial virus (RSV), human parainfluenza viruses, influenza viruses, and human metapneumovirus using reverse transcriptase-polymerase chain reaction. RESULTS: Of 119 patients, 66 (55%) had HRV-associated ARIs. The incidence of HRV-associated ARI was 123 events per 100 child-years of follow-up. Of those infants experiencing an episode of bronchiolitis, 40% had HRV versus 7% with RSV. The incidence of HRV-associated bronchiolitis was 75 per 100 infant-years of follow-up. HRV was associated with 12 of 36 hospitalizations (33%), and RSV was associated with 9 of 36 hospitalizations (25%). The incidence of HRV-associated hospitalization was 12 per 100 infant-years of follow-up. The risk of HRV-associated hospitalization was higher for infants with bronchopulmonary dysplasia and those who were not breastfed. CONCLUSIONS: HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants. Copyright © 2012 by the American Academy of Pediatrics.


PubMed | CONICET, Fundacion INFANT and Vanderbilt University
Type: Historical Article | Journal: Clinical and vaccine immunology : CVI | Year: 2016

In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a peribronchiolar monocytic infiltration with some excess in eosinophils. Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4(+) T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates.

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