AN EVALUATION OF THE ROLE OF RESPIRATORY SYNCYTIAL VIRUS (RSV), ALONE AND WITH OTHER PATHOGENS, IN CAUSING RESPIRATORY DISEASE AMONG NATIVE AMERICAN CHILDREN

Respiratory syncytial virus (RSV) is associated with 3.2 million severe lower respiratory illness (LRI) episodes and 118,200 deaths in children <5 years of age annually, with the greatest burden in infants less than 6 months of age. There is no licensed vaccine for RSV, although several candidates are in development. It is not well understood how the prevention of RSV LRI in infancy might impact LRI with other pathogens, or long-term sequelae including subsequent wheeze and asthma. Recently, a double-blinded randomized trial of a monoclonal antibody, motavizumab, showed efficacy for the prevention of RSV-associated medically attended LRI (MALRI) in healthy Native American infants. Infants were followed through three years of age, with nasopharyngeal secretions collected at every MALRI. We tested these samples for respiratory viruses and for Streptococcus pneumoniae in order to: 1. Evaluate the role of RSV MALRI prevention in infancy on the prevalence and density of S. pneumoniae carriage in the nasopharynx 2. Evaluate the impact of RSV MALRI prevention in infancy on MALRI with other respiratory viruses, and on subsequent medically attended wheeze 3. Evaluate the risk of RSV MALRI in the second year of life RSV MALRI was associated with increased S. pneumoniae density in the nasopharynx, suggesting a role for its prevention in reducing the incidence of pneumococcal pneumonia in vaccinated children and in their communities through indirect protection. Motavizumab prevented RSV MALRI in the presence of co-infecting viruses, with increased efficacy in more severe cases. A family history of asthma, and MALRI in infancy with parainfluenza viruses, rhinovirus and coronaviruses were independently associated with subsequent medically attended wheeze at ages 1-3 years. Infants who broke through motavizumab prophylaxis to have inpatient RSV LRI had higher risk of medically attended wheezing at ages 1-3 years than children in the placebo group with inpatient RSV LRI, and may represent a subgroup at high risk for both outcomes. We found no increased risk of disease in the second RSV season following receipt of motavizumab in the first season, a finding that has not been demonstrated previously in the context of RSV prevention in healthy infants

The Diagnostic Utility of Induced Sputum Microscopy and Culture in Childhood Pneumonia.

Background. Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods. We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1–59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). Results. One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of \u3c10 squamous epithelial cells per low-power field, and 1162 (44.6%) had radiographic pneumonia. Induced sputum microscopy and culture results were not associated with radiographic pneumonia, regardless of prior antibiotic use, stratification by specific bacteria, or interpretative criteria used. Conclusions. The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice

Specimen collection for the diagnosis of pediatric pneumonia.

Diagnosing the etiologic agent of pneumonia has an essential role in ensuring the most appropriate and effective therapy for individual patients and is critical to guiding the development of treatment and prevention strategies. However, establishing the etiology of pneumonia remains challenging because of the relative inaccessibility of the infected tissue and the difficulty in obtaining samples without contamination by upper respiratory tract secretions. Here, we review the published and unpublished literature on various specimens available for the diagnosis of pediatric pneumonia. We discuss the advantages and limitations of each specimen, and discuss the rationale for the specimens to be collected for the Pneumonia Etiology Research for Child Health study

Identification and Selection of Cases and Controls in the Pneumonia Etiology Research for Child Health Project

Methods for the identification and selection of patients (cases) with severe or very severe pneumonia and controls for the Pneumonia Etiology Research for Child Health (PERCH) project were needed. Issues considered include eligibility criteria and sampling strategies, whether to enroll hospital or community controls, whether to exclude controls with upper respiratory tract infection (URTI) or nonsevere pneumonia, and matching criteria, among others. PERCH ultimately decided to enroll community controls and an additional human immunodeficiency virus (HIV)–infected control group at high HIV-prevalence sites matched on age and enrollment date of cases; controls with symptoms of URTI or nonsevere pneumonia will not be excluded. Systematic sampling of cases (when necessary) and random sampling of controls will be implemented. For each issue, we present the options that were considered, the advantages and disadvantages of each, the rationale for the methods selected for PERCH, and remaining implications and limitations

Azithromycin in labour to reduce maternal and newborn sepsis and associated deaths: the need for a harmonized approach

Maternal and newborn infections are a major contributor to mortality and morbidity globally.  Lost-cost, effective and safe interventions are needed to address these.  Based on promising findings, azithromycin has been identified as potentially effective antibiotic to reduce maternal and newborn infections in low- and middle-income countries (LMICs).  However, robust randomized clinical trials in a range of settings are needed to confirm these findings as well as to understand the implications for antimicrobial resistance.  To better understand the impact of azithromycin on maternal and newborn health, at least three clinical trials are being conducted to evaluate azithromycin in LMICs.  We describe these trials, the importance of harmonizing study measures and the potential public health impact of azithromycin in LMICs

Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma?:Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12-13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies