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.
Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was optimized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at reducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was generated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharmacokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic.
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.
BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing.
OBJECTIVES: We sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing.
METHOD: We performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks.
RESULTS: Compared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty-two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01).
CONCLUSION: In this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year.
BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).
AIM: This study explored whether alcohol consumption during pregnancy increased the risk of life-threatening respiratory infections in children.
METHODS: We prospectively evaluated children under the age of two years admitted to hospitals in Buenos Aires, Argentina, with severe acute respiratory infections during the winters of 2011 and 2012. Information on maternal alcohol consumption during the third trimester of pregnancy was collected using standardised questionnaires and categorised as never, low if it was once a week and high if it was equal or more than once a week.
RESULTS: Of the 3423 children hospitalised with acute respiratory infection, 2089 (63.7%) had respiratory syncytial virus (RSV). Alcohol consumption during the last trimester was reported by 398 mothers (12.4%) and categorised as low (n = 210, 6.5%) or high (n = 188, 5.9%). A greater effect on life-threatening respiratory infection, defined as oxygen saturation of or up to 87%, was observed with higher alcohol intake due to all viruses and specifically RSV in the logistic regression analyses. Alcohol consumption was strongly associated with life-threatening disease, particularly in boys whose adjusted odds ratio rose from 3.67 to 13.52 when their mothers drank alcohol.
CONCLUSION: Alcohol consumption during pregnancy was associated with life-threatening respiratory infections in boys.
<b>BACKGROUND: </b>Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists.<b>METHODS: </b>We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores.<b>RESULTS: </b>Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.<b>CONCLUSIONS: </b>Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).
OBJECTIVES: The incidence and outcome of the acute respiratory distress syndrome in children are not well-known, especially under current ventilatory practices. The goal of this study was to determine the incidence, etiology, and outcome of acute respiratory distress syndrome in the pediatric population in the setting of lung protective ventilation.
DESIGN: A 1-yr, prospective, multicenter, observational study in 12 geographical areas of Spain (serving a population of 3.77 million ≤ 15 yrs of age) covered by 21 pediatric intensive care units.
SUBJECTS: All consecutive pediatric patients receiving invasive mechanical ventilation and meeting American-European Consensus Criteria for acute respiratory distress syndrome.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected. A total of 146 mechanically ventilated patients fulfilled the acute respiratory distress syndrome definition, representing a incidence of 3.9/100,000 population ≤ 15 yrs of age/yr. Pneumonia and sepsis were the most common causes of acute respiratory distress syndrome. At the time of meeting acute respiratory distress syndrome criteria, mean PaO2/FIO2 was 99 mm Hg ± 41 mm Hg, mean tidal volume was 7.6 mL/kg ± 1.8 mL/kg predicted body weight, mean plateau pressure was 27 cm H2O ± 6 cm H2O, and mean positive end-expiratory pressure was 8.9 cm ± 2.9 cm H2O. Overall pediatric intensive care unit and hospital mortality were 26% (95% confidence interval 19.6-33.7) and 27.4% (95% confidence interval 20.8-35.1), respectively. At 24 hrs, after the assessment of oxygenation under standard ventilatory settings, 118 (80.8%) patients continued to meet acute respiratory distress syndrome criteria (PaO2/FIO2 104 mm Hg ± 36 mm Hg; pediatric intensive care units mortality 30.5%), whereas 28 patients (19.2%) had a PaO2/FIO2 >200 mm Hg (pediatric intensive care units mortality 7.1%) (p = .014).
CONCLUSIONS: This is the largest study to estimate prospectively the pediatric population-based acute respiratory distress syndrome incidence and the first incidence study performed during the routine application of lung protective ventilation in children. Our findings support a lower acute respiratory distress syndrome incidence and mortality than those reported for adults. PaO2/FIO2 ratios at acute respiratory distress syndrome onset and at 24 hrs after onset were helpful in defining groups at greater risk of dying (clinical trials registered with http://www.clinicaltrials.gov; NCT 01142544).
BACKGROUND: Breastfeeding is a well-known protective factor against severe respiratory tract infections. Recently, a gender specific role for human milk has been described in very low birth weight infants and neonates: breast milk protected girls but not boys.
OBJECTIVE: To determine whether the protective effect of breastfeeding on the severity of acute respiratory infections in full term infants is different for girls and boys.
METHODS: A prospective cross-sectional study of infants seeking medical care for acute respiratory infection. The protective role of breastfeeding against viral pneumonia and hospitalization were assessed by univariate and multivariate analyses. Analyses were adjusted for important confounders.
RESULTS: A total of 323 patients were enrolled in this study. Breastfeeding protected girls against pneumonia and hospitalization, but did not protect boys. Nonbreastfeeding females were particularly susceptible to severe acute respiratory infections.
CONCLUSIONS: Breastfeeding had a protective effect against severe disease in infant girls experiencing their first symptomatic respiratory infection. Nonbreastfeeding females are at significant risk for severe acute lung disease and should be targeted intensively by breastfeeding campaigns.
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.
