RESUMO
BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. RESULTS: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. CONCLUSIONS: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.).
Assuntos
COVID-19/terapia , Imunoglobulina G/sangue , Insuficiência Respiratória/prevenção & controle , SARS-CoV-2/imunologia , Idoso , Idoso de 80 Anos ou mais , Transfusão de Componentes Sanguíneos , COVID-19/complicações , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Imunização Passiva , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Insuficiência Respiratória/etiologia , Índice de Gravidade de Doença , Soroterapia para COVID-19RESUMO
BACKGROUND: Information is scarce regarding the economic burden of respiratory syncytial virus (RSV) disease in low-resource settings. This study aimed to estimate the cost per episode of hospital admissions due to RSV severe disease in Argentina. METHODS: This is a prospective cohort study that collected information regarding 256 infants under 12 months of age with acute lower respiratory tract infection (ALRTI) due to RSV in two public hospitals of Buenos Aires between 2014 and 2016. Information on healthcare resource use was collected from the patient's report and its associated costs were estimated based on the financial database and account records of the hospitals. We estimated the total cost per hospitalization due to RSV using the health system perspective. The costs were estimated in US dollars as of December 2022 (1 US dollar = 170 Argentine pesos). RESULTS: The mean costs per RSV hospitalization in infants was US$587.79 (95% confidence interval [CI] $535.24 - $640.33). The mean costs associated with pediatric intensive care unit (PICU) admission more than doubled from those at regular pediatric wards ($1,556.81 [95% CI $512.21 - $2,601.40] versus $556.53 [95% CI $514.59 - $598.48]). CONCLUSIONS: This study shows the direct economic impact of acute severe RSV infection on the public health system in Argentina. The estimates obtained from this study could be used to inform cost-effectiveness analyses of new preventive RSV interventions being developed.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Lactente , Humanos , Criança , Estudos Prospectivos , Argentina/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Hospitalização , Infecções Respiratórias/epidemiologia , Efeitos Psicossociais da DoençaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).
Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Saúde Global , Mortalidade Hospitalar , Hospitalização , Humanos , Lactente , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções Respiratórias/epidemiologiaRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) disproportionally affects pregnant women and their newborn; however, little is known about variables that modulate maternal-fetal immune response to infection. METHODS: We prospectively studied socioeconomic, biologic, and clinical factors affecting humoral immunity in 87 unvaccinated pregnant women hospitalized in Buenos Aires for symptoms consistent with COVID-19. RESULTS: The number of days between symptom onset and childbirth predicted maternal and newborn virus spike protein receptor binding domain (RBD)-specific immunoglobulin G (IgG). These findings suggest newborns may benefit less when mothers deliver soon after COVID-19 infection. Similarly, a longer time between symptom onset and birth predicted higher in utero transfer of maternal IgG and its concentration in cord blood. Older gestational age at birth was associated with lower maternal to cord blood IgG ratio. Of women with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 87% developed RBD-specific IgA responses in breast milk within 96 hours of childbirth. IgA was not significantly associated with time from infection but correlated with maternal serum IgG and placental transfer. CONCLUSIONS: These results demonstrate the combined role of biologic, clinical, and socioeconomic variables associated with maternal RBD-specific antibodies and supports early vaccination strategies for COVID-19 in socioeconomically vulnerable pregnant women. CLINICAL TRIALS REGISTRATION: NCT04362956.
Assuntos
Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/transmissão , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Adulto , Produtos Biológicos , COVID-19/sangue , Teste Sorológico para COVID-19 , Feminino , Humanos , Recém-Nascido , Placenta/metabolismo , Gravidez , Estudos Prospectivos , Glicoproteína da Espícula de Coronavírus/imunologia , Populações VulneráveisRESUMO
BACKGROUND: Severity of human metapneumovirus (hMPV) lower respiratory illness (LRTI) is considered similar to that observed for respiratory syncytial virus (RSV). However, differences in severity between these pathogens have been noted, suggesting the degree of illness may vary in different populations. Moreover, a potential association between hMPV and asthma also suggests that hMPV may preferentially affect asthmatic subjects. METHODS: In a population-based surveillance study in children aged <2 years admitted for severe LRTI in Argentina, nasopharyngeal aspirates were tested by RT-PCR for hMPV, RSV, influenza A, and human rhinovirus. RESULTS: Of 3947 children, 383 (10%) were infected with hMPV. The hospitalization rate for hMPV LRTI was 2.26 per 1000 children (95% confidence interval [CI], 2.04-2.49). Thirty-nine (10.2%) patients infected with hMPV experienced life-threatening disease (LTD; 0.23 per 1000 children; 95% CI, .16-.31/1000), and 2 died (mortality rate 0.024 per 1000; 95% CI, .003-.086). In hMPV-infected children birth to an asthmatic mother was an increased risk for LTD (odds ratio, 4.72; 95% CI, 1.39-16.01). We observed a specific interaction between maternal asthma and hMPV infection affecting risk for LTD. CONCLUSIONS: Maternal asthma increases the risk for LTD in children <2 years old hospitalized for severe hMPV LRTI.
Assuntos
Asma , Infecções por Paramyxoviridae , Infecções Respiratórias , Argentina/epidemiologia , Asma/epidemiologia , Pré-Escolar , Suscetibilidade a Doenças , Humanos , Lactente , Pulmão , Metapneumovirus , Infecções por Paramyxoviridae/complicações , Infecções por Paramyxoviridae/epidemiologia , Infecções Respiratórias/complicações , Infecções Respiratórias/epidemiologiaRESUMO
BACKGROUND: Estimating the real impact of respiratory syncytial virus (RSV) disease is key for the development of vaccines and treatments. Ascertaining the burden of community mortality due to RSV is challenging due to the lack of primary data. Therefore, conducting observational studies to determine the factors associated with community mortality due to the virus in developing countries is important. OBJECTIVE: Our aim in this study was to describe the obstacles, gaps, and challenges that investigators face in low-income, vulnerable regions in 4 developing countries on 3 continents. RESULTS: The main obstacles and challenges of ascertaining community mortality due to RSV were defining strategies to consent families for testing before burial, sampling individuals at the household level, supporting bereaved parents with different cultural and religious backgrounds, establishing tailored strategies for studies in challenging settings, and integrating RSV mortality data from nasopharyngeal samples. CONCLUSION: Detailed logistical planning based on population sociodemographic information, grief counseling, staff training, and a multidisciplinary approach with adequate laboratory infrastructure is critical to successful observational community-based RSV studies.
Assuntos
Infecções por Vírus Respiratório Sincicial , Criança , Humanos , Nasofaringe , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sinciciais Respiratórios , Fatores de RiscoRESUMO
BACKGROUND: Many deaths in infants from low-middle income countries (LMICs) occur at home or upon arrival to health facilities. Although acute lower respiratory tract illness plays an important role in community mortality, the accuracy of mortality rates due to respiratory syncytial virus (RSV) remains unknown. METHODS: An active surveillance study among children aged under 5 years old (U5) was performed in Buenos Aires, Argentina, between January and December 2019, to define the burden and role of RSV in childhood community mortality. RESULTS: A total of 63 families of children U5 participated in the study. Based on a combined approach of tissue sampling, verbal autopsies, and expert's analysis, RSV infection was found in the causal chain of 11 from 12 cases with positive molecular biology results in respiratory samples. The estimated mortality rate due to RSV among infants was 0.27 deaths/1000 live births. The mean age of RSV-related household deaths was 2.8 months of age (standard deviation [SD] 1.7), and 8/12 were male infants (66.7%). Dying at home from RSV was associated with Streptococcus pneumoniae and/or Moraxella catarrhalis lung coinfection (75%), living in slums and settlement (odds ratio [OR], 17.09; 95% confidence interval [CI], 1.3-219.2), and other underlying comorbidities (OR, 14.87; 95% CI, 1.3-164.6). CONCLUSIONS: Infant community mortality rates due to RSV are higher than those reported in industrialized countries and similar to those reported in hospital-based studies in the same catchment population.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Argentina/epidemiologia , Criança , Pré-Escolar , Hospitalização , Humanos , Lactente , Masculino , Infecções por Vírus Respiratório Sincicial/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Precise determination of the causal chain that leads to community deaths in children in low- and middle-income countries is critical to estimating all causes of mortality accurately and to planning preemptive strategies for targeted allocation of resources to reduce this scourge. METHODS: An active surveillance population-based study that combined minimally invasive tissue sampling (MITS) and verbal autopsies (VA) among children under 5 was conducted in Buenos Aires, Argentina, from September 2018 to December 2020 to define the burden of all causes of community deaths. RESULTS: Among 90 cases enrolled (86% of parental acceptance), 81 had complete MITS, 15.6% were neonates, 65.6% were post-neonatal infants, and 18.9% were children aged 1-5 years. Lung infections were the most common cause of death (CoD) in all age groups (57.8%). Among all cases of lung infections, acute bronchiolitis was the most common CoD in infants aged <12 months (23 of 36, 63.9%), and bacterial pneumonia was the most common cause in children aged >12 months (8 of 11, 72.7%). The most common comorbid condition in all age groups was undernutrition in 18 of 90 (20%). It was possible to find an immediate CoD in 78 of 81 subjects where MITS could be done. With this combined approach, we were able to determine that sudden infant death syndrome was overestimated in state reports. CONCLUSIONS: CoD determination by a combination of MITS and VA provides an accurate estimation of the chain of events that leads to death, emphasizing possible interventions to prevent mortality in children.
Assuntos
Pais , Pesquisa , Argentina/epidemiologia , Autopsia , Causas de Morte , Criança , Pré-Escolar , Humanos , Lactente , Recém-NascidoRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. METHODS: The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. RESULTS: We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8-3.3) was lower than in-hospital (2.4 months; IQR: 1.5-4.0; Pâ <â .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, Pâ <â 0.0001). CONCLUSIONS: We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Distribuição por Idade , Criança , Hospitalização , Humanos , Lactente , Morte do Lactente , Recém-Nascido , Infecções por Vírus Respiratório Sincicial/epidemiologiaRESUMO
BACKGROUND: Efforts to better understand the risk factors associated with respiratory failure (RF) and fatal lower respiratory tract infection (LRTI) in premature children in developing countries are necessary to elaborate evidenced-based preventive interventions. We aim to characterize the burden of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) LRTI in premature children and determine risk factors for RF and fatal illness in a vulnerable population. METHODS: This is a prospective, population-based, cross-sectional study. Subjects with severe LRTI were enrolled during respiratory season. Risk factors for RF and death in premature infants were investigated. RESULTS: A total of 664 premature children participated. Infant's hospitalization rate due to LRTI was 82.6/1000 (95% confidence interval [CI], 68.6-96.7/1000). Infant's RSV and hMPV rates were 40.9/1000 (95% CI, 36.3-45.6/1000) and 6.6/1000 (95% CI, 3.9-9.2/1000), respectively. The RF rate was 8.2/1000 (95% CI, 4.9-11.5/1000). The LRTI mortality was 2.2/1000 (95% CI, 0.7-3.7/1000); for RSV, the rate was 0.8/1000 (95% CI, 0-1.7/1000) with a case-fatality ratio of 1.8%. Never breastfeeding, malnutrition, younger than 6 months, congenital heart disease, and lower hematocrit were risk factors for RF. Experiencing pneumonia, pneumothorax, sepsis, or apnea were clinical determinants of poor outcomes. CONCLUSIONS: Premature children under 2 years old in vulnerable environments experience RF and death more often than term counterparts. Modifiable risk factors associated with poor outcomes should prompt evidence-based interventions.
Assuntos
Metapneumovirus/isolamento & purificação , Infecções por Paramyxoviridae/diagnóstico , Insuficiência Respiratória/etiologia , Infecções por Vírus Respiratório Sincicial/diagnóstico , Vírus Sincicial Respiratório Humano/isolamento & purificação , Infecções Respiratórias/virologia , Argentina/epidemiologia , Pré-Escolar , Estudos Transversais , Feminino , Hospitalização , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Metapneumovirus/genética , Infecções por Paramyxoviridae/epidemiologia , Infecções por Paramyxoviridae/virologia , Estudos Prospectivos , Insuficiência Respiratória/mortalidade , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/genética , Fatores de RiscoRESUMO
Background: Numerous deaths in children aged <5 years in the developing world occur at home. Acute respiratory infections (ARIs) are thought to play an important role in these deaths. Risk factors and pathogens linked to fatal episodes remain unclear. Methods: A case-control study among low-income children aged <5 years was performed in Buenos Aires, Argentina, to define risk factors and viral pathogens among those who died of ARI at home. Results: A total of 278 families of children aged <5 years (of whom 104 died and 174 were healthy controls) participated in the study. A total of 87.5% of ARI-associated deaths occurred among infants aged <12 months. The estimated mortality rate due to ARI among infants was 5.02 deaths/1000 live births. Dying at home from ARI was associated with living in a crowded home (odds ratio [OR], 3.73; 95% confidence interval [CI], 1.41-9.88), having an adolescent mother (OR, 4.89; 95% CI, 1.37-17.38), lacking running water in the home (OR, 4.39; 95% CI, 1.11-17.38), incomplete vaccinations for age (OR, 3.39; 95% CI, 1.20-9.62), admission to a neonatal intensive care unit (OR, 7.17; 95% CI, 2.21-23.27), and no emergency department visit during the ARI episode (OR, 72.32; 95% CI, 4.82-1085.6). The at-home death rate due to respiratory syncytial virus infection among infants was 0.26 deaths/100 live births and that due to influenza was 0.07 deaths/1000 live births. Conclusions: Social vulnerabilities underlie at-home mortality due to ARI. Mortality rates due to RSV and influenza virus infection are high among infants at home and are similar to those reported for hospitalized children.
Assuntos
Infecções por Vírus Respiratório Sincicial/mortalidade , Infecções Respiratórias/mortalidade , Argentina/epidemiologia , Estudos de Casos e Controles , Atenção à Saúde , Hospitalização , Humanos , Lactente , Recém-Nascido , Influenza Humana/mortalidade , Unidades de Terapia Intensiva , Análise Multivariada , Razão de Chances , Orthomyxoviridae , Pobreza , Características de Residência , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios , Infecções Respiratórias/virologia , Fatores de Risco , Fatores SocioeconômicosRESUMO
BACKGROUND: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease. METHODS: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies. DISCUSSION: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants. TRIAL REGISTRATION: Does not apply for this study.
Assuntos
Displasia Broncopulmonar/epidemiologia , Doenças do Prematuro/epidemiologia , Recém-Nascido de muito Baixo Peso , Estudos Multicêntricos como Assunto/métodos , Animais , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/genética , Doença Crônica , Progressão da Doença , Exposição Ambiental , Feminino , Seguimentos , Estudos de Associação Genética , Predisposição Genética para Doença , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/genética , Unidades de Terapia Intensiva Neonatal , Pesquisa Interdisciplinar , Colaboração Intersetorial , Pneumopatias/etiologia , Aprendizado de Máquina , Masculino , Camundongos , Pais , Estudos Prospectivos , Testes de Função Respiratória , Pesquisa Translacional BiomédicaRESUMO
To assess MUC5AC as a biomarker for respiratory syncytial virus (RSV) disease severity, we tested nasal aspirates from RSV+ children with mild, moderate, and severe disease. Levels were significantly higher in those in the severe and moderate groups compared to mild group, indicating MUC5AC may be a useful biomarker for RSV disease severity.
Assuntos
Mucina-5AC/análise , Infecções por Vírus Respiratório Sincicial/diagnóstico , Vírus Sincicial Respiratório Humano/isolamento & purificação , Índice de Gravidade de Doença , Argentina , Biomarcadores/análise , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Nariz/virologia , Curva ROC , Infecções por Vírus Respiratório Sincicial/complicações , Vírus Sincicial Respiratório Humano/genéticaRESUMO
RATIONALE: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low-income regions is unclear. OBJECTIVES: To determine the burden and risk factors for mortality due to RSV in a low-income population of 84,840 infants. METHODS: This was a prospective, population-based, cross-sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All-cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model. MEASUREMENTS AND MAIN RESULTS: A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14-21.16 for RF) (OR, 119.39; 95% CI, 50.98-273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07-21.01 for RF) (OR, 65.49; 95% CI, 28.90-139.17 for death) were the main determinants of poor outcomes. CONCLUSIONS: RSV was the most frequent cause of mortality in low-income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.
Assuntos
Infecções por Vírus Respiratório Sincicial/mortalidade , Vírus Sinciciais Respiratórios , Argentina/epidemiologia , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Modelos Logísticos , Masculino , Pneumotórax/etiologia , Pneumotórax/mortalidade , Estudos Prospectivos , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/diagnóstico , Fatores de Risco , Sepse/etiologia , Sepse/mortalidade , Fatores Sexuais , Fatores SocioeconômicosRESUMO
RATIONALE: Respiratory syncytial virus (RSV) is an important cause of hospitalization and death in infants worldwide. Most RSV deaths occur in developing countries, where burden and risk factors for life-threatening illness are unclear. OBJECTIVES: We defined the burden of life-threatening (O(2) saturation [O(2) sat] ≤ 87%) and fatal RSV infection, and characterized risk factors for life-threatening disease in hospitalized children. Special emphasis was placed on studying the impact of dietary habits during pregnancy. We hypothesized that dietary preferences, differing from those of our remote ancestors, would negatively impact children's pulmonary health. For instance, a diet rich in carbohydrates is a signature of recent millennia and typical of low-income populations, heavily burdened by life-threatening RSV disease. METHODS: Prospective study in a catchment population of 56,560 children under 2 years of age during the RSV season in Argentina. All children with respiratory signs and O(2) sat less than 93% on admission were included. MEASUREMENTS AND MAIN RESULTS: Among 1,293 children with respiratory infections, 797(61.6%) were infected with RSV: 106 of these had life-threatening disease; 1.9 per 1,000 children (95% confidence interval [CI], 1.5-2.2/1,000) under 24 months. A total of 22 hospitalized children died (9 RSV(+)), 26 died at home due to acute respiratory infection (14 attributed to RSV); all were under 12 months old. The annual attributable mortality rate for RSV was 0.7 per 1,000 infants (95% CI, 0.4-1.1/1,000). Life-threatening disease was dose-dependently associated with carbohydrate ingestion during pregnancy (adjusted odds ratio from 3.29 [95% CI, 1.15-9.44] to 7.36 [95% CI, 2.41-22.5] versus the lowest quartile). CONCLUSIONS: Life-threatening and fatal RSV infections are a heavy burden on infants in the developing world. Diets rich in carbohydrates during pregnancy are associated with these severe outcomes.
Assuntos
Carboidratos da Dieta/efeitos adversos , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções Respiratórias/virologia , Doença Aguda , Área Sob a Curva , Argentina , Países em Desenvolvimento , Inquéritos sobre Dietas , Feminino , Hospitalização , Humanos , Incidência , Lactente , Modelos Logísticos , Masculino , Pobreza , Gravidez , Estudos Prospectivos , Vírus Sinciciais Respiratórios , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/epidemiologia , Estações do AnoRESUMO
BACKGROUND: While the Northern Hemisphere experiences the effects of the 2009 pandemic influenza A (H1N1) virus, data from the recent influenza season in the Southern Hemisphere can provide important information on the burden of disease in children. METHODS: We conducted a retrospective case series involving children with acute infection of the lower respiratory tract or fever in whom 2009 H1N1 influenza was diagnosed on reverse-transcriptase polymerase-chain-reaction assay and who were admitted to one of six pediatric hospitals serving a catchment area of 1.2 million children. We compared rates of admission and death with those among age-matched children who had been infected with seasonal influenza strains in previous years. RESULTS: Between May and July 2009, a total of 251 children were hospitalized with 2009 H1N1 influenza. Rates of hospitalization were double those for seasonal influenza in 2008. Of the children who were hospitalized, 47 (19%) were admitted to an intensive care unit, 42 (17%) required mechanical ventilation, and 13 (5%) died. The overall rate of death was 1.1 per 100,000 children, as compared with 0.1 per 100,000 children for seasonal influenza in 2007. (No pediatric deaths associated with seasonal influenza were reported in 2008.) Most deaths were caused by refractory hypoxemia in infants under 1 year of age (death rate, 7.6 per 100,000). CONCLUSIONS: Pandemic 2009 H1N1 influenza was associated with pediatric death rates that were 10 times the rates for seasonal influenza in previous years.
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Surtos de Doenças , Hospitalização/estatística & dados numéricos , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Adolescente , Distribuição por Idade , Argentina/epidemiologia , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Hipóxia/etiologia , Hipóxia/mortalidade , Lactente , Recém-Nascido , Influenza Humana/classificação , Influenza Humana/complicações , Influenza Humana/mortalidade , Masculino , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/etiologia , Índice de Gravidade de Doença , Staphylococcus/isolamento & purificação , Streptococcus pneumoniae/isolamento & purificaçãoRESUMO
Respiratory syncytial virus (RSV) has a major role in respiratory infections in young infants around the world. However, substantial progress has been made in recent years in the field of RSV. A wide variety of observational studies and clinical trials published in the past decade provide a thorough idea of the health and economic burden of RSV disease in the developing world. In this review, we discuss the impact of RSV burden of disease, major gaps in disease estimations, and challenges in generating new therapeutic options and an immune response against the virus, and briefly describe next generation technologies that are being evaluated.
RESUMO
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study investigated epigenetic and transcriptomic signatures of prematurity at birth and during the neonatal period at day 14 and 28. Peripheral blood DNAs from preterm infants were applied to methylation arrays and cell-type composition was estimated by deconvolution. Covariate-adjusted robust linear regression elucidated BPD- and prolonged oxygen (≥ 14 days) exposure-associated CpGs. RNAs from cord and peripheral blood were sequenced, and differentially expressed genes (DEGs) for BPD or oxygen exposure were determined. Estimated neutrophil-lymphocyte ratios in peripheral blood at day 14 in BPD infants were significantly higher than nonBPD infants, suggesting an heightened inflammatory response in developing BPD. BPD-DEGs in cord blood indicated lymphopoiesis inhibition, altered Th1/Th2 responses, DNA damage, and organ degeneration. On day 14, BPD-associated CpGs were highly enriched in neutrophil activation, infection, and CD4 + T cell quantity, and BPD-DEGs were involved in DNA damage, cellular senescence, T cell homeostasis, and hyper-cytokinesis. On day 28, BPD-associated CpGs along with BPD-DEGs were enriched for phagocytosis, neurological disorder, and nucleotide metabolism. Oxygen supplementation markedly downregulated mitochondrial biogenesis genes and altered CpGs annotated to developmental genes. Prematurity-altered DNA methylation could cause abnormal lymphopoiesis, cellular assembly and cell cycle progression to increase BPD risk. Similar pathways between epigenome and transcriptome networks suggest coordination of the two in dysregulating leukopoiesis, adaptive immunity, and innate immunity. The results provide molecular insights into biomarkers for early detection and prevention of BPD.
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Displasia Broncopulmonar , Recém-Nascido Prematuro , Lactente , Humanos , Recém-Nascido , Displasia Broncopulmonar/etiologia , Epigenoma , Estudos Prospectivos , Perfilação da Expressão Gênica , Biomarcadores , OxigênioRESUMO
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a lung disease in premature infants caused by therapeutic oxygen supplemental and characterized by impaired pulmonary development which persists into later life. While advances in neonatal care have improved survival rates of premature infants, cases of BPD have been increasing with limited therapeutic options for prevention and treatment. This study was designed to explore the relationship between gestational age (GA), birth weight, and estimated blood cell-type composition in premature infants and to elucidate early epigenetic biomarkers associated with BPD. METHODS: Cord blood DNA from preterm neonates that went on to develop BPD (n = 14) or not (non-BPD, n = 93) was applied to Illumina 450 K methylation arrays. Blood cell-type compositions were estimated using DNA methylation profiles. Multivariable robust regression analysis elucidated CpGs associated with BPD risk. cDNA microarray analysis of cord blood RNA identified differentially expressed genes in neonates who later developed BPD. RESULTS: The development of BPD and the need for oxygen supplementation were strongly associated with GA (BPD, p < 1.0E-04; O2 supplementation, p < 1.0E-09) and birth weight (BPD, p < 1.0E-02; O2 supplementation, p < 1.0E-07). The estimated nucleated red blood cell (NRBC) percent was negatively associated with birth weight and GA, positively associated with hypomethylation of the tobacco smoke exposure biomarker cg05575921, and high-NRBC blood samples displayed a hypomethylation profile. Epigenome-wide association study (EWAS) identified 38 (Bonferroni) and 275 (false discovery rate 1%) differentially methylated CpGs associated with BPD. BPD-associated CpGs in cord blood were enriched for lung maturation and hematopoiesis pathways. Stochastic epigenetic mutation burden at birth was significantly elevated among those who developed BPD (adjusted p = 0.02). Transcriptome changes in cord blood cells reflected cell cycle, development, and pulmonary disorder events in BPD. CONCLUSIONS: While results must be interpreted with caution because of the small size of this study, NRBC content strongly impacted DNA methylation profiles in preterm cord blood and EWAS analysis revealed potential insights into biological pathways involved in BPD pathogenesis.
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Displasia Broncopulmonar , Biomarcadores , Peso ao Nascer , Displasia Broncopulmonar/genética , Metilação de DNA , Epigenoma , Humanos , Lactente , Recém-Nascido , Recém-Nascido PrematuroRESUMO
BACKGROUND: SARS-CoV-2 infected individuals ≥60 years old have the highest hospitalization rates and represent >80% fatalities. Within this population, those in long-term facilities represent >50% of the total COVID-19 related deaths per country. Among those without symptoms, the rate of pre-symptomatic illness is unclear, and potential predictors of progression for symptom development are unknown. Our objective was to delineate the natural evolution of asymptomatic SARS-CoV-2 infection in elders and identify determinants of progression. METHODS: We established a medical surveillance team monitoring 63 geriatric institutions. When an index COVID-19 case emerged, we tested all other eligible asymptomatic elders ≥75 or >60 years old with at least 1 comorbidity. SARS-CoV-2 infected elders were followed for 28 days. Disease was diagnosed when any COVID-19 manifestation occurred. SARS-CoV-2 load at enrollment, shedding on day 15, and antibody responses were also studied. RESULTS: After 28 days of follow-up, 74/113(65%) SARS-CoV-2-infected elders remained asymptomatic. 21/39(54%) pre-symptomatic patients developed hypoxemia and ten pre-symptomatic patients died(median day 13.5,IQR 12). Dementia was the only clinical risk factor associated with disease(OR 2.41(95%CI=1.08, 5.39). In a multivariable logistic regression model, dementia remained as a risk factor for COVID-19 severe disease. Furthermore, dementia status showed a statistically significant different trend when assessing the cumulative probability of developing COVID-19 symptoms(log-rank p=0.027). On day 15, SARS-CoV-2 was detectable in 30% of the asymptomatic group while in 61% of the pre-symptomatic(p=0.012). No differences were observed among groups in RT-PCR mean cycle threshold at enrollment(p=0.391) and in the rates of antibody seropositivity(IgM and IgG against SARS-CoV-2 nucleocapsid protein). CONCLUSIONS: In summary, 2/3 of our cohort of SARS-CoV-2 infected elders from vulnerable communities in Argentina remained asymptomatic after 28 days of follow-up with high mortality among those developing symptoms. Dementia and persistent SARS-CoV-2 shedding were associated with progression from asymptomatic to symptomatic infection.