Uncovering Causes of Childhood Death Using the Minimally Invasive Autopsy at the Community Level in an Urban Vulnerable Setting of Argentina: A Population-Based Study.

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.

Community Mortality Due to Respiratory Syncytial Virus in Argentina: Population-based Surveillance Study.

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.

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults.

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.).

Role for Maternal Asthma in Severe Human Metapneumovirus Lung Disease Susceptibility in Children.

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.

Respiratory Failure and Death in Vulnerable Premature Children With Lower Respiratory Tract Illness.

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.

The discovery BPD (D-BPD) program: study protocol of a prospective translational multicenter collaborative study to investigate determinants of chronic lung disease in very low birth weight infants.

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.

Mortality Associated With Acute Respiratory Infections Among Children at Home.

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.

Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors.

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.

Animal leptospirosis in Latin America and the Caribbean countries: reported outbreaks and literature review (2002-2014).

Leptospirosis is a worldwide zoonotic disease whose transmission is linked through multiple factors in the animal-human-ecosystem interface. The data on leptospirosis reported to the World Organization for Animal Health (OIE) for Latin America and Caribbean (LAC) countries/sovereign territories from 2005-2011 were mapped, showing a wide distribution of outbreaks in the region. Tropical terrestrial biomes are the predominate ecosystems showing reports of outbreaks. Climatic and ecological factors were relevant to the occurrence of epidemic outbreaks. The available scientific information from 2002-2014 was summarized to obtain a general overview and identify key issues related to the One Health approach. The primary serological test used for diagnosis and for conducting surveys was the microscopic agglutination test (MAT). Reports regarding the isolation and typing of leptospires were scattered and limited to data from a few countries, but their results revealed considerable biodiversity at the species and serovar levels. A total of six out of 11 currently named pathogenic species were found in the region. There was also high diversity of animal species showing evidence of infection by leptospires, including rodents, pets, livestock and wild animals. Prevention and control measures for leptospirosis should consider issues of animal and human health in the context of ecosystems, the territorial land borders of countries and trade.