Chapter 5 Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) infection has an estimated global incidence of 33 million cases in children younger than 5 years, with 10% requiring hospital admission and up to 199,000 dying of the disease. There is growing evidence that severe infantile RSV bronchiolitis, a condition characterised by an inflammatory reaction to the virus, is associated with later childhood wheeze in some vulnerable children; however, a direct causal relationship with asthma has not yet been established. It is also increasingly recognised as a cause of morbidity and mortality in those with underlying airway disease, immunocompromise and frail elderly persons. Novel molecular based diagnostic tools are becoming established but treatment largely remains supportive, with palivizumab being the only licensed agent currently available for passive prophylaxis of selected pre-term infants. Whilst effective treatments remain elusive, there is optimism about the testing of novel antiviral drugs and the development of vaccines that may induce long-lasting immunity without the risk of disease augmentation

Age at First Viral Infection Determines the Pattern of T Cell–mediated Disease during Reinfection in Adulthood

Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lung pathology during subsequent rechallenge. Primary RSV infection in newborn mice followed the same viral kinetics as in adults but was associated with reduced and delayed IFN-γ responses. To study rechallenge, mice were infected at 1 day or 1, 4, or 8 weeks of age and reinfected at 12 weeks. Neonatal priming produced more severe weight loss and increased inflammatory cell recruitment (including T helper 2 cells and eosinophils) during reinfection, whereas delayed priming led to enhanced interferon γ production and less severe disease during reinfection. These results show the crucial importance of age at first infection in determining the outcome of reinfection and suggest that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life. Thus, simply delaying RSV infection beyond infancy might reduce subsequent respiratory morbidity in later childhood

OX40 Ligand and Programmed Cell Death 1 Ligand 2 Expression on Inflammatory Dendritic Cells Regulates CD4 T Cell Cytokine Production in the Lung during Viral Disease

CD4-T-helper-cell (Th) differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (DCs) in regional lymph nodes and results in specific patterns of cytokine production. However, the function of costimulatory molecules on ‘inflammatory’ (CD11b+) DCs in the lung during recall responses is not fully understood, but important for development of novel interventions to limit immunopathological responses to infection. Using a mouse model in which vaccination with vaccinia virus vectors expressing the respiratory syncytial virus (RSV) fusion protein (rVVF) or attachment protein (rVVG) leads to type 1- or type 2-biased cytokine responses respectively upon RSV-challenge, we found expression of CD40 and OX40L on lung inflammatory DCs was higher in rVVF- than in rVVG-primed mice early after RSV-challenge, while the reverse was observed later in the response. Conversely, PD-L2 was higher in rVVG-primed mice throughout. Inflammatory DCs isolated at the resolution of inflammation revealed OX40L on type 1-biased DCs promoted IL-5, while on type 2-biased DCs enhanced IFNγ production by antigen-reactive Th cells. In contrast, PD-L2 promoted IFNγ production irrespective of conditions, suppressing IL-5 only if expressed on type 1-biased DCs. Thus, OX40L and PD-L2 expressed on DCs differentially regulate cytokine production during recall responses in the lung. Manipulation of these costimulatory pathways may provide a novel approach to controlling pulmonary inflammatory responses

The etiological role of common respiratory viruses in acute respiratory infections in older adults::A systematic review and meta-analysis

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9-18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4-15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3-41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7-13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0-4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report

Toward unified molecular surveillance of RSV: A proposal for genotype definition

Background: Human respiratory syncytial virus (RSV) is classified into antigenic subgroups A and B. Thirteen genotypes have been defined for RSV-A and 20 for RSV-B, without any consensus on genotype definition. Methods: We evaluated clustering of RSV sequences published in GenBank until February 2018 to define genotypes by using maximum likelihood and Bayesian phylogenetic analyses and average p-distances. Results: We compared the patterns of sequence clustering of complete genomes; the three surface glycoproteins genes (SH, G, and F, single and concatenated); the ectodomain and the 2nd hypervariable region of G gene. Although complete genome analysis achieved the best resolution, the F, G, and G-ectodomain phylogenies showed similar topologies with statistical support comparable to complete genome. Based on the widespread geographic representation and large number of available G-ectodomain sequences, this region was chosen as the minimum region suitable for RSV genotyping. A genotype was defined as a monophyletic cluster of sequences with high statistical support (≥80% bootstrap and ≥0.8 posterior probability), with an intragenotype p-distance ≤0.03 for both subgroups and an intergenotype p-distance ≥0.09 for RSV-A and ≥0.05 for RSV-B. In this work, the number of genotypes was reduced from 13 to three for RSV-A (GA1-GA3) and from 20 to seven for RSV-B (GB1-GB7). Within these, two additional levels of classification were defined: subgenotypes and lineages. Signature amino acid substitutions to complement this classification were also identified. Conclusions: We propose an objective protocol for RSV genotyping suitable for adoption as an international standard to support the global expansion of RSV molecular surveillance.Fil: Goya, Stephanie. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Laboratorio de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Galiano, Mónica. Public Health England; Reino UnidoFil: Nauwelaers, Inne. Imperial College London; Reino UnidoFil: Trento, Alfonsina. Instituto de Investigación Hospital 12 de Octubre; EspañaFil: Openshaw, Peter J.. Imperial College London; Reino UnidoFil: Mistchenko, Alicia Susana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Laboratorio de Virología; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Zambon, Maria. Public Health England; Reino UnidoFil: Viegas, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Laboratorio de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

COVID-19 Pneumothorax in the United Kingdom: a prospective observational study using the ISARIC WHO clinical characterisation protocol.

Population level data from 131 679 patients show that COVID-19 pneumothorax occurs in 0.97% of admitted patients, especially males and smokers, and is associated with increased mortality

Predicted Public Health and Economic Impact of Respiratory Syncytial Virus Vaccination with Variable Duration of Protection for Adults ≥60 Years in Belgium

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in older adults. This study used a static, cohort-based decision-tree model to estimate the public health and economic impact of vaccination against RSV in Belgians aged ≥60 years compared with no vaccination for different vaccine duration of protection profiles from a healthcare payer perspective. Three vaccine protection durations were compared (1, 3, and 5 years), and several sensitivity and scenario analyses were performed. Results showed that an RSV vaccine with a 3-year duration of protection would prevent 154,728 symptomatic RSV-ARI cases, 3688 hospitalizations, and 502 deaths over three years compared to no vaccination in older adults and would save EUR 35,982,857 in direct medical costs in Belgium. The number needed to vaccinate to prevent one RSV-ARI case was 11 for the 3-year duration profile, while it was 28 and 8 for the 1- and 5-year vaccine duration profiles, respectively. The model was generally robust in sensitivity analyses varying key input values. This study suggested that vaccination could substantially decrease the public health and economic burden of RSV in adults ≥60 years in Belgium, with benefits increasing with a longer duration of vaccine protection.</p