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Background The interplay among respiratory syncytial virus (RSV) loads, mucosal interferons (IFN), and disease severity in RSV-infected children is poorly understood. Methods Children 6–24 months) and multivariable analyses performed to identify predictors of disease severity. Results In 2015–2019 we enrolled 219 RSV-infected children (78 outpatients; 141 inpatients) and 34 healthy controls. Type I, II, and III IFN concentrations were higher in children aged >6 versus 0–6 months and, like CXCL10, they were higher in outpatients than inpatients and correlated with RSV loads (P < .05). Higher IL6 concentrations increased the odds of hospitalization (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.07–5.36) only in children >6 months, while higher IFN-λ2/3 concentrations had the opposite effect irrespective of age (OR, 0.38; 95% CI, .15–.86). Likewise, higher CXCL10 concentrations decreased the odds of hospitalization (OR, 0.21; 95% CI, .08–.48), oxygen administration (OR, 0.42; 95% CI, .21–.80),PICU admission (OR, 0.39; 95% CI, .20–.73), and prolonged hospitalization (OR, 0.57; 95% CI, .32–.98) irrespective of age. Conclusions Children with milder RSV infection and those aged >6 months had higher concentrations of mucosal IFNs, suggesting that maturation of mucosal IFN responses are associated with protection against severe RSV disease.

Background The role of nasopharyngeal bacteria in respiratory syncytial virus (RSV) disease has been underestimated. We measured the frequency and burden of respiratory bacteria in the upper respiratory tract of infants with RSV infection over 7 respiratory seasons, and their impact on clinical outcomes. Methods Children Results S. pneumoniae, H. influenzae, and M. catarrhalis, but not S. aureus, were detected more frequently in RSV-infected children (84%) than healthy controls (46%; P Conclusions Nasopharyngeal codetection of S. pneumoniae and H. influenzae in infants with RSV infection is associated with increased disease severity.

Data from animal models suggest a role of early-life gut microbiota in lung immune development, and in establishing susceptibility to respiratory infections and asthma in humans. This systematic review summarises the association between infant (ages 0-12 months) gut microbiota composition measured by genomic sequencing, and childhood (ages 0-18 years) respiratory diseases (ie, respiratory infections, wheezing, or asthma). Overall, there was evidence that low α-diversity and relative abundance of particular gut-commensal bacteria genera (Bifidobacterium, Faecalibacterium, Ruminococcus, and Roseburia) are associated with childhood respiratory diseases. However, results were inconsistent and studies had important limitations, including insufficient characterisation of bacterial taxa to species level, heterogeneous outcome definitions, residual confounding, and small sample sizes. Large longitudinal studies with stool sampling during the first month of life and shotgun metagenomic approaches to improve bacterial and fungal taxa resolution are needed. Standardising follow-up times and respiratory disease definitions and optimising causal statistical approaches might identify targets for primary prevention of childhood respiratory diseases.

Respiratory viral infections are associated with significant morbidity and mortality in children < 5 years of age worldwide. Among all respiratory viruses, respiratory syncytial virus (RSV) is the world’s leading cause of bronchiolitis and pneumonia in young children. There are known populations at risk for severe disease but the majority of children who require hospitalization for RSV infection are previously healthy. Viral and host factors have been associated with the pathogenesis of RSV disease, however, the mechanisms that explain the wide variability in the clinical presentation are not completely understood. Recent studies suggest that the complex interaction between the respiratory microbiome, the host’s immune response and the virus may have an impact on the pathogenesis and severity of RSV infection. In this review, we summarize the current evidence regarding the epidemiologic link, the mechanisms of viral-bacterial interactions, and the associations between the upper respiratory tract microbiome and RSV disease severity.

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a "safe and protective" immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children

The study aims to review the prevention efforts for vaccine preventable diseases. Significant progress in global vaccination coverage has been made since World Health Organization established the Expanded Programme on Immunization to ensure that all children have access to routinely recommended vaccines. Global coverage with vaccines to prevent tetanus, poliomyelitis, or measles has increased from

Background:Admission criteria and standardized management strategies for bronchiolitis are addressed in several guidelines and have shown to be beneficial; however, guidance regarding discharge criteria is limited and widely variable. We assessed the impact on clinical outcomes of a discharge protoc

Background Differences in clinical presentation and viral loads according to age in young children with RSV, and their correlation with disease severity are poorly defined. The aim of this study was to define age-dependent the differences in demographic, clinical factors and viral loads between children < 2 years of age with mild RSV infection evaluated as outpatients versus those hospitalized with severe RSV infection. Figure 1. Sign and Symptoms according to disease severity and age in infants with RSV infection. Most relevant signs and symptoms were stratified in outpatients (orange) vs inpatients (blue) by age in (A) < 3 months, (B) between 3 and 6 months, and (C) > 6 to 24 months of age. The Y axis represents the signs and symptoms in the two disease severity groups and the X axis the frequency of that specific symptom (%). Numbers next to bars represent the exact number of patients with that specific sign/symptom. Comparisons by Fisher exact test. Symbol (*) indicate significant 2-sided p values Figure 2. Viral load differences according to age in infants with RSV infection. The Y axis represents RSV loads in log10 copies/mL and the X axis differences in viral loads in outpatients (orange) and inpatients (blue) in the three age groups. Comparisons by Mann Whitney test. Methods Previously healthy children < 2 years old with mild (outpatients) and severe (inpatients) RSV infection were enrolled and nasopharyngeal swabs were obtained for RSV typing and quantitation by real-time PCR. Patients were stratified by age (0-< 3, 3-6, and >6-24 months) and multivariable analyses were performed to identify clinical and viral factors associated with severe disease. Results From 2014-2018 we enrolled 534 children with RSV infection: 130 outpatients and 404 inpatients. Median duration of illness was 4 days for both groups, yet viral loads were higher in outpatients than inpatient in the three age groups (Fig 1). Wheezing was more frequent in outpatients of older age (>3 months) than in inpatients (p< 0.01), while fever was more common in inpatients that outpatients (p< 0.01) and increased with age (Fig 2). Adjusted analyses confirmed that increased work of breathing and fever were consistently associated with hospitalization irrespective of age, while wheezing in infants >3 months, and higher RSV loads in children >6-24 months were independently associated with reduced disease severity. Conclusion Age had a significant impact defining the interactions among viral loads, specific clinical manifestations and disease severity in children with RSV infection. These observations highlight the importance of patient stratification when evaluating interventions against RSV. Disclosures Octavio Ramilo, MD, Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Medimmune (Grant/Research Support)Merck (Advisor or Review Panel member)NIH/NIAID (Grant/Research Support)Pfizer (Consultant, Advisor or Review Panel member)Sanofi/Medimmune (Consultant, Advisor or Review Panel member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Advisor or Review Panel member)

Background Despite the high burden associated with RSV infection in young children the factors that determine disease severity are not well understood. The objective of this study was to assess the association of mucosal cytokine profiles, RSV loads (VL) and RSV disease severity. Methods Single-center, prospective study in previously healthy infants with mild (outpatients; OP), moderate (inpatient-IP; ward) or severe (IP-PICU) RSV infection. Mid-turbinate swabs were obtained to measure VL by PCR, and cytokine concentrations (conc.) using a 13-plex panel that included type I (IFN-α2), II (IFN-γ), and III (IFN-λ2/λ3) interferons (IFN), and inflammatory cytokines. Multivariable analyses were performed to identify factors predictive of disease severity. Results From 2014 to 2019 we enrolled 219 infants: 78 with mild RSV infection (OP; median [IQR] age, 6 [3.4–10.5] mo.), 101 with moderate disease (3.5 [1.3–8.3] mo.), and 40 with severe disease (2.3 [1.5–5.7] mo.). Duration of symptoms at enrollment was 4 (3–5) days and comparable between OP and IP, yet RSV VL in OP were significantly higher than in IP (8.1 [7.4–8.6] vs 7.4 [6.4–8.1] log10 copies/mL; p< 0.01) with no differences between ward and PICU infants. Median conc. of IFN-α2, IFN-γ, and IFN-λ2/λ3 were significantly higher in OP vs IP irrespective of hospitalization unit (Table 1). IP-10 conc. were also higher in OP and in ward patients vs PICU patients (p< 0.0001) and were independently associated with lower odds of supplemental O2 needs (OR, 95% CI: 0.4 [0.22–0.69]; p< 0.01) and PICU admission (0.4 [0.23–0.67]; p=0.001). In addition, higher IFN-λ2/λ3 conc. were nearly associated with lower odds of prolonged O2 use (OR: 0.35 [0.11–1.07]; p=0.07), and prolonged hospitalization (OR: 0.42 [0.16–1.03]; p=0.06). Conclusion Infants with mild RSV infection had higher RSV VL and higher conc. of IP-10 and type-I, III IFN than those hospitalized with severe disease. These findings suggest that IP-10 and mucosal IFNs are associated with protection against severe RSV disease and could be used as biomarkers for patient stratification in the clinical setting. Disclosures Octavio Ramilo, MD, Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Medimmune (Grant/Research Support)Merck (Advisor or Review Panel member)NIH/NIAID (Grant/Research Support)Pfizer (Consultant, Advisor or Review Panel member)Sanofi/Medimmune (Consultant, Advisor or Review Panel member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Advisor or Review Panel member)Roche (Advisor or Review Panel member)

Background Respiratory syncytial virus (RSV) is a leading cause of hospitalization for infants. Several vaccine strategies for RSV are being developed. Among those, live attenuated vaccine (LAV) represent an attractive alternative for young children as they mimic natural infection and induce protective immunity without causing enhanced disease. However, markers of reactogenicity and/or innate immune protection in the respiratory mucosa are not well defined. The objective of this study was to assess mucosal markers, including innate immune cytokine profiles and RSV loads (VL), and their potential association with protection from severe disease in infants with natural RSV infection. Methods Single-center, prospective study in previously healthy infants with mild (outpatients; OP) and severe (inpatients; IP) RSV infection, and aged-matched healthy controls (HC). Nasopharyngeal (NP) swabs were obtained at enrollment in all subjects to measure VL by PCR, and cytokine concentrations (conc.) using a 13-plex panel that included: Type-I, type-II, and type-III IFN, and inflammatory cytokines. Cytokine conc. and VL were compared according to hospitalization status (OP vs. IP). Results From 2014 to 2017 we enrolled 105 infants: 48 with severe RSV infection (IP; median IQR age: 2.3 [1.1–5.5] months), 36 with mild disease (OP; 6.4 [3.8–9.3] months), and 20 HC (4.9 [2.8–7.2] months). The median duration of symptoms at enrollment was 4 days for both IP and OP. IL-1β, TNF-α, and IL-10 were detected more frequently in RSV infants than in HC (39% vs. 5%, respectively), but median conc. in IP and OP were not different (P > 0.05). Detection and/or conc. of IFN-β, IP-10, IFN-γ and type III IFN (IFN-λ1, IFN-λ2/3) were significantly greater in OP vs. IP, who also had higher VL (Table 1). In addition, IP-10 (r = 0.6; P < 0.001) and IFN-λ conc. (r = 0.55, P < 0.0001) significantly correlated with RSV VL. Conclusion Infants with mild RSV infection had higher VL and a more robust type-I, -II, and -III IFN responses than those hospitalized with severe disease. These findings suggest that increase conc. of mucosal IFNs are associated with protection against severe RSV infection, and could potentially be used as surrogate markers to help the development of LAV for RSV infection in young children. Disclosures Octavio Ramilo, MD, Bill & Melinda Gates Foundation: Research Grant; Janssen: Research Grant; Merck: Advisory Board; NIH: Research Grant; Ohio Children’s Hospital Association (OCHA): Research Grant; Pfizer: Advisory Board, Consultant, Lectures; Sanofi/Medimmune: Advisory Board.

Admission criteria and standardized management strategies for bronchiolitis are addressed in several guidelines and have shown to be beneficial; however, guidance regarding discharge criteria is limited and widely variable. We assessed the impact on clinical outcomes of a discharge protocol for children2 years of age hospitalized with bronchiolitis in a tertiary care pediatric hospital.In October 2013, a protocol to standardize the discharge of children with bronchiolitis was implemented in the infectious diseases (ID) ward but not in other pediatric units caring for these children (non-ID). The protocol included objective clinical criteria and a standardized oxygen weaning pathway. Patients were identified via International Classification of Diseases-9 codes and data manually reviewed. We compared length of stay (LOS) and readmission rates within 2 weeks of discharge according to protocol implementation (ID versus non-ID), adjusted for demographic factors, comorbidities, viral etiology and stratified by pediatric intensive care unit admission.From October 2013 to May 2015, 1118 children were hospitalized in ID and 695 in non-ID units. Median age was 4.5 months, 55% were males and 28% had comorbidities. LOS was 36% longer in non-ID units (risk ratio: 1.36 [1.27-1.45]; P0.001) adjusted for age, gender, comorbidities and viral etiology. Difference in LOS remained significant after excluding children with comorbidities and stratifying by pediatric intensive care unit admission. Readmission rates were comparable between units (ID, 2.9% versus non-ID, 2.6%).A standardized discharge protocol for bronchiolitis reduced LOS without increasing readmission rates. Unifying bronchiolitis discharge criteria and oxygen weaning pathways could positively impact hospital-based patient care for this condition.

Background Previous studies suggest that RSV increases NP bacterial colonization and may facilitate infection. However, the role of NP colonization with potentially pathogenic bacteria (PPB) in the pathogenesis of RSV bronchiolitis is not well understood. We sought to determine the frequency, type, and density of NP PPB detection in infants with RSV infection compared with healthy controls (HC), and its association with clinical outcomes. Methods Single-center, prospective study of previously healthy infants with RSV infection and age-matched HC. Inpatients (IP) were enrolled within 24 hours of hospitalization, outpatients (OP) at the ED or primary clinics and HC at well-child visits. RSV infection and the following PPB: [S. pneumoniae, M. catarrhalis, H. influenzae, and S. aureus] were detected and quantified by PCR. We compared demographic, clinical characteristics, and outcomes of care according to NP PPB detection. Results From 2010 to 2018, we enrolled 815 infants: 664 with RSV infection [IP, 560; OP, 104] and 151 HC. RSV+ OP (6.1 [3.7–10.7] months) and HC (6.9 [3.8–10.8] months) were older than IP (2.5 [1.4–5.4] months; P < 0.001). Identification of ≥1 PPB was 89% in RSV+ infants [IP, 88%; OP, 90%] versus 63% of HC (P < 0.0001). While H. influenzae or >1 PPB detection was higher in RSV infection (P < 0.001), S. aureus detection predominated in HC (P < 0.05; Figure 1). Frequency of S. pneumoniae detection was comparable between groups; however, S. pneumoniae loads were one log higher in RSV+ infants versus HC (P = 0.001) adjusted for antibiotic use. Differences in colonization rates remained different in RSV+ infants versus HC across age ranges (6–12, and >12–24 months; Figure 2). Last, RSV patients (both IP and OP) with S. pneumoniae or H. influenzae detection had fever more frequently (70%–74% vs. 25%–47%; P < 0.0001), higher clinical disease severity scores (P = 0.01), and higher blood neutrophil counts (34%–36% vs. 16%–19%; P < 0.001), versus those with M. catarrhalis, S. aureus detection or PCR negative. In addition, NP detection of H. influenzae in RSV children was associated with higher frequency of atelectasis/consolidation by chest X-ray (P < 0.005). Conclusion These data suggest that NP colonization with PPB is high in infants with RSV infection independent of age, and that specific bacteria, namely S. pneumoniae and H. influenzae, are associated with enhanced clinical disease severity. Disclosures A. Leber, Nationwide Children’s Hospital: Research Contractor, Research support. O. Ramilo, Janssen Scientific Affairs, LLC: Consultant, Consulting fee. A. Mejias, Janssen: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Abbvie: CME talks, Speaker honorarium.

Respiratory syncytial virus (RSV) remains a significant cause of morbidity and mortality in infants and young children, immunocompromised patients and the elderly. Despite the high disease burden, an effective and safe vaccine is lacking, although several candidates are currently in development. Current treatment for RSV infection remains largely supportive and RSV-specific options for prophylaxis are limited to palivizumab. In the past few years, novel therapeutic options including nanobodies, polyclonal and monoclonal antibodies have emerged and there are several products in preclinical and Phase-I, -II or -III clinical trials. The major target for antiviral drug development is the surface fusion (F) glycoprotein, which is crucial for the infectivity and pathogenesis of the virus. Solving the structures of the two conformations of the RSV F protein, the prefusion and postfusion forms, has revolutionized RSV research. It is now known that prefusion F is highly superior in inducing neutralizing antibodies. In this section we will review the stages of development and availability of different antibodies directed against RSV for the prevention and also for treatment of acute RSV infections. Some of these newer anti-RSV agents have shown enhanced potency, are being explored through alternative routes of administration, have improved pharmacokinetic profiles with an extended half-life, and may reduce design and manufacturing costs. Management strategies will require targeting not only high-risk populations (including adults or immunocompromised patients), but also previously healthy children who, in fact, represent the majority of children hospitalized with RSV infection. Following treated patients longitudinally is essential for determining the impact of these strategies on the acute disease as well as their possible long-term benefits on lung morbidity.

Background Almost all children are infected with RSV by 2 yrs of age, yet

Objectives To determine the differences in number of respiratory syncytial virus (RSV) hospitalizations and outcomes in infants 290/7-346/7 weeks' gestational age (wGA) the season before (season 1 [S1]; 2013-2014) and after (season 2 [S2]; 2014-2015) implementation of the 2014 American Academy of Pediatrics revised guidance for palivizumab prophylaxis. Study design Children